Abstract
Pulsed electromagnetic fields (PEMF) and amplitude-modulated radiofrequency electromagnetic fields (AM-RF EMF) are emerging as non-invasive adjuncts in cancer therapy. Initially approved for bone healing and pain management, PEMF has shown potential in inhibiting tumor cell proliferation, inducing apoptosis, and impairing angiogenesis in various preclinical models. This review synthesizes findings from studies involving low- and high-intensity PEMF, tumor-treating alternating electric fields, and tumor-specific AM-RF EMF across cancer cell lines, animal models, and early-phase human trials. While results are promising, therapeutic responses remain highly context-dependent and mechanistically heterogeneous. Advances in structural biology and cancer genomics offer new opportunities to rationally design field parameters targeting specific molecular pathways. We propose a framework for estimating the electromagnetic field strength needed to disrupt key protein-ligand interactions and highlight pathways for future investigation. Rigorous clinical trials and optimized protocols will be essential to fully integrate PEMF into precision oncology.

Introduction
Pulsed Electromagnetic Field (PEMF) therapy is an FDA-approved, non-invasive modality widely used in orthopedics to support bone healing in conditions such as nonunion fractures, spinal fusions, and osteotomies. Devices like Orthofix’s Physio-Stim and Biomet’s EBI Bone Healing System deliver time-varying electromagnetic fields to stimulate cellular activity and promote osteogenesis and angiogenesis. These effects are mediated through mechanisms including modulation of ion binding, upregulation of growth factors (e.g., BMP-2, TGF-β), and increased expression of osteogenic markers (Bassett et al., 1974; Aaron et al., 2004).
Beyond orthopedics, PEMF is gaining attention as a complementary therapy for chronic pain, particularly musculoskeletal conditions such as osteoarthritis, fibromyalgia, and chronic low back pain. Although not FDA-approved for general pain relief, over-the-counter devices (e.g., Oska Pulse, BEMER) are marketed under Class I or II wellness exemptions. Studies suggest PEMF may reduce pain and improve function by modulating inflammation, nociceptive signaling, and microcirculation (Foley-Nolan et al., 1990; Thomas et al., 2007).
Emerging evidence now points to a potential role for PEMF in cancer therapy. Preclinical studies demonstrate that specific PEMF exposures can inhibit tumor cell proliferation, induce apoptosis, and impair angiogenesis in models of breast, lung, and brain cancers. Animal studies support these findings (Vadala et al., 2016), and early clinical trials suggest PEMF may improve quality of life and even exert direct antitumor effects in certain contexts (Zimmermann et al., 2012).
While clinical data are still limited, recent reviews emphasize the need for rigorous trials to optimize treatment protocols and clarify mechanisms (Xu et al., 2022, Egg & Kietzmann, 2025). This review examines key findings from cellular and animal studies, as well as preliminary human trials, tracing the evolution of this field from early research on alternating fields and modulated radiofrequencies to current interest in PEMF for cancer treatment.

Low and intermediate frequency alternating electromagnetic fields
Alternating electric fields in the intermediate frequency range (100–300 kHz) at field strengths of 1–2.5 V/cm (corresponding to magnetic fields of 0.44–1.1 μT) have been shown to suppress the proliferation of various rodent and human tumor cell lines—including Patricia C, U-118, U-87, H-1299, MDA231, PC3, B16F1, F-98, C-6, RG2, and CT-26—as well as malignant tumors in animal models. This inhibitory effect is both frequency- and intensity-dependent and is selective for actively dividing cells; non-proliferating (quiescent) cells remain unaffected. The mechanism of action of these tumor treating fields (TTFields) involves disruption of mitotic spindle formation, resulting in mitotic arrest and cell death (Kirson et al., 2004). These findings have been extended to additional cell lines (e.g., MDA-MB-231 and H1299) and tumor models (e.g., intradermal B16F1 melanoma and intracranial F-98 glioma). In a pilot clinical study of 10 glioblastoma patients, TTFields therapy more than doubled both median progression-free survival and overall survival compared to historical controls (Kirson et al., 2007).
In contrast, exposure of Caco-2 human colon adenocarcinoma cells to low-frequency (50 Hz), higher-intensity (1 mT) magnetic fields promoted cell growth rather than inhibiting it. This stimulation was time-dependent and accompanied by increased protein oxidation and elevated intracellular reactive oxygen species (ROS). These changes coincided with increased intracellular calcium levels and global activation of the 20S proteasome, along with a reduction in the pro-apoptotic protein p27 (Eleuteri et al., 2009).
Other studies have reported no significant effects of 1 mT, 60 Hz electromagnetic fields on non-cancerous immortalized cell lines such as Jurkat (human T lymphocytes) and NIH3T3 (mouse embryonic fibroblasts). However, under the same conditions, both MCF-7 (human breast cancer) and MCF-10A (non-tumorigenic breast epithelial) cells exhibited significant reductions in cell number, viability, and DNA synthesis. These effects were attributed to cell cycle delay and induction of the pro-apoptotic gene PMAIP in a context-dependent manner (Lee et al., 2015).
Overall, the biological effects of low- and intermediate-frequency EMFs on cancer cells are complex and highly context-dependent. Responses vary by cell type, proliferative status, field parameters (frequency and intensity), and exposure duration, underscoring the importance of precise characterization in therapeutic and experimental applications.

Amplitude modulated radiofrequency electromagnetic fields
In 2009, Barbault et al. reported that cancer patients exhibited biofeedback responses to tumor-specific frequencies of amplitude-modulated (AM) radiofrequency electromagnetic fields (RF-EMF). These modulation frequencies, ranging from 0.1 Hz to 114 kHz, were specific to the type of tumor, while the carrier frequency was a fixed 27.12 MHz. The RF signal was generated at 100 mW into a 50-ohm load. In a limited compassionate-use clinical trial involving 28 patients with various cancer types, RF-EMF treatment was delivered intrabuccally for 60 minutes, three times daily, and continued until disease progression or death.
No significant side effects were reported. Of the 13 patients eligible for response evaluation, one breast cancer patient achieved a complete response, and another showed a partial response. Four additional patients (with thyroid, lung, pancreatic cancers, and leiomyosarcoma) exhibited stable disease. The authors concluded that the observed clinical responses were more likely due to systemic physiological effects rather than direct cytotoxic action, given the low field strength and the anatomical distance between the intrabuccal application site and the tumor sites. Estimated field strengths within 1 mm of the emitter were approximately 30 V/cm (electric) and 13 μT (magnetic).
A subsequent open-label phase I/II clinical trial involving 41 patients with hepatocellular carcinoma (HCC) confirmed the earlier findings. Using the same protocol of tumor-specific AM RF-EMF delivery, 28 patients were evaluable for response: 4 demonstrated partial responses, 16 had stable disease, and 8 showed disease progression. These preliminary outcomes were considered promising and formed the rationale for pursuing larger, randomized clinical trials (Costa et al., 2011).
Follow-up mechanistic studies investigated the effects of tumor-specific modulation frequencies on HCC (HepG2, Huh7) and breast cancer (MCF-7) cell lines. Direct in vitro exposure resulted in significant growth inhibition of malignant cells, whereas non-malignant counterparts—THLE-2 hepatocytes and MCF-10A breast epithelial cells—were unaffected. Growth suppression in HCC cells was accompanied by downregulation of the chemokine-related genes XCL2 and PLP2, as well as disruption of mitotic spindle architecture. Notably, reduced expression of XCL2 and PLP2 has been associated with improved prognosis in cancer patients (Zimmerman et al., 2012).

Low intensity PEMF
The biological effects of pulsed electromagnetic fields (PEMF) on tumor cell growth have been recognized for over two decades. Early studies demonstrated that PEMF exposure at a magnetic field intensity of 1.5 mT and pulse frequencies of 1 or 25 Hz enhanced the cytotoxicity of chemotherapeutic agents—vincristine, mitomycin, and cisplatin—against multidrug-resistant HCA-2/1cch human colon adenocarcinoma cells in vitro (Ruiz-Gómez, M.J., 2002). At the same field intensity but a higher pulse frequency (75 Hz), PEMF upregulated A3 adenosine receptor (A3AR) expression in neural tumor cell lines, including PC12 (rat adrenal pheochromocytoma) and U87MG (human glioblastoma). This upregulation was associated with inhibition of NF-κB signaling and induction of p53, ultimately leading to suppressed proliferation, increased lactate dehydrogenase (LDH) release, and elevated caspase-3 activity—markers of cytotoxicity and apoptosis, respectively (Vincenzi, F., 2012). Similarly, growth inhibition and apoptotic induction were observed in the SKOV3 human ovarian cancer cell line following PEMF exposure at 1 mT with pulse frequencies ranging from 8 to 64 Hz (Wang et al., 2012).
More recent studies have extended these findings to other tumor types. In vitro and in vivo experiments involving human breast cancer MCF-7 cells and human lung adenocarcinoma A549 cells revealed that low-intensity PEMF (0.68 and 1.19 mT) applied at higher pulse frequencies (3.846 and 40.85 kHz, respectively) significantly inhibited tumor growth (Chen et al., 2022). This effect was attributed to increased apoptotic activity, evidenced by elevated caspase-3/7 expression and greater annexin V staining, as well as an accumulation of cells in the G0 phase of the cell cycle. Gene expression analysis further indicated activation of pathways associated with DNA damage, cell cycle arrest, and growth suppression.
Notably, the systemic impact of PEMF has also been demonstrated in humans. In a recent double-blind, randomized clinical trial involving healthy female volunteers, participants were exposed to PEMF at 1 mT intensity and 50 Hz pulse frequency (Iversen et al., 2025). Sera collected from treated individuals exhibited significant anti-cancer properties up to one month post-exposure, reducing breast cancer cell proliferation, migration, and invasiveness in vitro. These effects correlated with a reduction in epithelial-mesenchymal transition (EMT) markers, suggesting a systemic modulation of anti-tumor signaling pathways.

Higher intensity PEMF exposure
For the purposes of this review, high-intensity pulsed electromagnetic fields (PEMF) are defined as those with magnetic field strengths ranging from 2 to 400 mT, remaining within the public exposure limits recommended by the International Commission on Non-Ionizing Radiation Protection (ICNIRP) (Yamaguchi-Sakeno et al., 2011). The specific pulse frequencies and exposure durations varied across the studies discussed below.
Over the past two decades, a growing body of research involving both tumor cell lines and animal models has demonstrated that PEMF—either as a stand-alone treatment or in combination with chemotherapy or gamma irradiation—can exert antiproliferative and antiangiogenic effects. These studies typically used field intensities between 2 and 20 mT, pulse frequencies from 8 to 120 Hz, and diverse exposure regimens. Tumor types studied included breast, bladder, liver, hematopoietic cancers, osteosarcoma, and fibrosarcoma.
Breast cancer cell lines, particularly MCF-7, have shown notable sensitivity to PEMF. Exposure to PEMF at 3 mT and 20 Hz for 60 minutes daily over three days significantly inhibited proliferation (Crocetti et al., 2013). A separate protocol using full-square wave PEMF at 11 mT and 8 Hz, applied for 30 minutes twice daily over five days, yielded similar antiproliferative outcomes in both MCF-7 and MDA-MB-231 breast cancer cells (Pantelis et al., 2024). These effects were mechanistically linked to DNA damage, apoptosis, and the induction of cellular senescence markers. Importantly, these effects appeared to be selective for malignant cells; normal epithelial and fibroblast cells remained unaffected under the same treatment conditions.
The potential for PEMF to enhance chemotherapy has also been explored. In MCF-7 cells, PEMF exposure significantly potentiated the cytotoxic effects of doxorubicin (Woo & Kim, 2024) and etoposide (Woo et al., 2022). Both agents inhibit cell proliferation through topoisomerase II inhibition and reactive oxygen species (ROS) generation, and these pathways appeared to be further activated in the presence of PEMF.
Findings from in vitro studies have been validated in vivo. For example, PEMF exposure inhibited the growth and vascularization of 16/C murine mammary adenocarcinoma tumors implanted in syngeneic C3H/HeJ mice. Treatment consisted of 10-minute daily exposures for 12 days using a 120 Hz pulse frequency and field intensities up to 20 mT (Williams et al., 2001). Further studies confirmed that tumor inhibition was dependent on increasing magnetic field intensity rather than increased exposure time at a fixed intensity (Cameron et al., 2014). PEMF also enhanced the effects of gamma irradiation and the chemotherapeutic agent bleomycin in mouse models bearing human MDA-MB-231 breast cancer xenografts (Cameron et al., 2005) and triple-negative breast cancer (TNBC) MX-1 xenografts in SCID mice (Berg et al., 2010).
Beyond breast cancer, PEMF has demonstrated antitumor activity in models of bladder cancer (Sanberg et al., 2025), hematologic malignancies (Radeva & Berg, 2004; Berg et al., 2010), osteosarcoma (Muramatsu et al., 2017), and fibrosarcoma (Omote et al., 1990). Of particular interest is the reported synergy between PEMF and molecularly targeted therapies: in BCR/ABL(+) leukemia-derived TCC-S cells, PEMF enhanced the efficacy of the tyrosine kinase inhibitor imatinib (Yamaguchi-Sakeno et al., 2011).

Future directions
The growing body of evidence supports the continued development of pulsed electromagnetic fields (PEMF) as a complementary modality in cancer therapeutics. At present, PEMF demonstrates its greatest efficacy when combined with conventional treatments, such as cytotoxic chemotherapy or ionizing radiation. Several novel laboratory protocols have yielded promising results and merit translation into large-scale, double-blind clinical trials to evaluate therapeutic utility and safety in a controlled setting. However, current findings also highlight important areas for further refinement and optimization.
To date, no PEMF or EMF protocol has consistently achieved irreversible tumor regression as a stand-alone intervention. Moreover, the heterogeneity in field parameters—such as frequency, waveform, intensity, and exposure duration—across studies has impeded the establishment of a unified mechanism of action. Inhibition of cancer cell growth by PEMF appears to involve multiple, and potentially interacting, cellular processes, including alterations in membrane potential, disruption of mitochondrial function, interference with mitotic spindle formation, modulation of growth signaling pathways, increased generation of reactive oxygen species (ROS), and induction of apoptosis. While the preferential sensitivity of malignant cells compared to normal cells is encouraging, the underlying basis of this selectivity remains incompletely understood and warrants further mechanistic investigation.
Reliance on empirical trial-and-error testing may be inefficient and limiting, especially given current advances in cancer genomics and the characterization of key oncogenic driver mutations (Kinnersley et al., 2024). Moving forward, it would be advantageous to rationally design PEMF protocols that specifically disrupt molecular pathways activated by such driver genes. This approach could yield targeted, mechanism-informed applications of PEMF with improved therapeutic indices. Table 1 summarizes major classes of cancer-relevant signaling pathways and representative driver genes identified through high-throughput genome sequencing.
Many of the downstream effectors of cancer-associated gene products—such as enzymes, receptors, transcription factors, DNA-binding proteins, and scaffolding proteins—have had their structures experimentally determined and deposited in the Protein Data Bank (PDB), or accurately predicted by AlphaFold. This structural information provides a powerful foundation for estimating the electromagnetic field (EMF) intensities required to perturb or disrupt their functional interactions. In particular, these insights open the door to the rational design of PEMF protocols targeting specific molecular interactions central to tumor growth and survival.
Functionally disrupting a protein's activity via EMF can be conceptualized as interfering with its interactions with a substrate, ligand, DNA target, or binding partner. This disruption can occur if the energy imparted by the EMF is sufficient to overcome the standard free energy of binding (ΔG⁰), or alternatively, the free energy required to partially unfold one or both interacting molecules (ΔGᵤ).
For binding interference, the minimum energy supplied by the EMF must match or exceed the standard free energy of binding. On a per-molecule basis, this requirement can be written as:

E(emf) = (ΔG⁰/N)                   [1]

where N is the Avogadro number (6.022 x 1023 mol-1) since ΔG⁰ values are often given per mole.
The energy provided by an electric field (E) to a dipole or charge depends on the interaction between the field and the molecule dipole moment (μ​) or charge (q). For a dipole in an electric field, the potential energy (U) is the vectorial product of the electric field (E) and the dipole moment (μ), and maximum energy occurs when the dipole is aligned with the field and

U(max) = μE                                [2]

where μ is the magnitude of the dipole moment in Debyes or C.m, and E the electric field strength in V/m.
Since the energy required by the field to disrupt binding must at least be equal to the free binding energy,

μE = ΔG⁰/N                        [3]

Solving for E,

E = ΔG⁰/(Nμ)                      [4]

In practice, ΔG⁰ could be derived from the equilibrium binding constant Keq using,

ΔG⁰ = -RTlnKeq                  [5]

where R is the universal gas constant ( ≈ 8.314 J⋅mol⁻¹⋅K⁻¹) and T the temperature in Kelvin (K).
The corresponding magnetic field strength could be derived from,

B = E/c                                  [6]
​
 a consequence of Maxwell’s equations and where c is the speed of light (≈ 3 x 108 m/s).
Table 2 shows the calculated magnetic field intensities required for disrupting the functions of selected therapeutic targets in cancer pathways. These calculated values should be regarded as preliminary approximations, given several limitations in the underlying dipole moment estimations. Notably, solvent effects and electrostatic contributions from bound ligands were not included, even though they may significantly alter the net dipole moment of the complex. Despite these limitations, the estimates can serve as a useful starting point for the design of more targeted and effective pulsed electromagnetic field (PEMF) protocols—particularly with respect to field strength, pulse frequency, and exposure duration.
As discussed earlier, a complementary approach to estimating the required magnetic field intensity involves the use of the free energy of unfolding (ΔGᵤ) of the protein or protein-ligand complex. However, accurate ΔGᵤ values typically require differential scanning calorimetry (DSC) data, which remain sparse in the literature for many of the cancer-associated targets included in this analysis.
Table 2 indicates that, in most cases, the magnetic field strengths needed to interfere with key oncogenic pathways fall within the operational range of FDA-approved PEMF devices used for specific clinical indications. Furthermore, some PEMF systems marketed for general wellness are capable of producing high peak magnetic field intensities—up to 100 mT—though often at lower frequencies. Clinical experience in areas such as bone regeneration and pain control suggests that efficacy is not solely determined by maximum field strength. Rather, an optimized combination of intensity, frequency, pulse width, and duty cycle is likely required for therapeutic benefit.
Future advances in PEMF technology—guided by personalized cancer genomic data and supported by rigorous clinical trials—may help establish electromagnetic field modulation as a viable adjunct or alternative in cancer therapy. Such progress will be essential to gaining broader acceptance within the medical community and among the general public.

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​Acknowledgement: The author thanks Bill Windsor for providing some of the literature cited in this review.

Dedication: To my brother Kiet, who in heaven will know why.

In our discussion on May 16, 2024, we explored the role of the gut microbiome in Parkinson’s disease (PD) and the potential of fecal microbiota transplants as a treatment. A recent development further underscores the gut-brain connection in PD.
 
Nishiwaki H. and colleagues at Nagoya University [1] conducted a meta-analysis of microbiome studies across multiple countries, alongside metabolomic analyses of fecal samples from PD patients. Their findings identified specific gut microbes linked to the disease and a resulting deficiency in riboflavin (vitamin B2) and biotin (vitamin B7). This discovery suggests a simple, yet potentially impactful intervention: B vitamin supplementation.
 
The authors stated:
"Supplementation of riboflavin and/or biotin is likely to be beneficial in a subset of Parkinson's disease patients, in which gut dysbiosis plays pivotal roles."
 
Their recommendation is rooted in existing research. Riboflavin has demonstrated therapeutic benefits in reducing oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity—all factors in PD pathogenesis [2]. Notably, high-dose riboflavin has been shown to improve motor function in PD patients [3].
 
Biotin, on the other hand, is known for its anti-inflammatory properties, with benefits observed in allergy relief, immune regulation, and inflammatory bowel disease [4]. In high doses, it has been proven effective in treating motor and visual impairments in multiple sclerosis [5,6]. However, clinical evidence supporting biotin’s role in alleviating PD symptoms is still lacking.
 
These findings highlight the growing understanding of the gut microbiome’s role in neurodegenerative diseases and open the door for further research into the potential of targeted nutritional interventions in PD management.
 
You could read an excellent review of Nishiwaki H. et al. paper by Sciencealert.com here:

Parkinson's Gut Bacteria Link Suggests an Unexpected, Simple Treatment
Health23 March 2025
ByTessa Koumoundouros

​References
 
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[2] Marashly, E. T. & Bohlega, S. A. Riboflavin Has Neuroprotective Potential: Focus on Parkinson’s Disease and Migraine. Front. Neurol. 8, 333 (2017).
 
[3] Coimbra, C. G. & Junqueira, V. B. High doses of riboflavin and the elimination of dietary red meat promote the recovery of some motor functions in Parkinson’s disease patients. Braz. J. Med. Biol. Res. 36, 1409–1417 (2003).
 
[4] Kuroishi, T. Regulation of immunological and inflammatory functions by biotin. Can. J. Physiol. Pharmacol. 93, 1091–1096 (2015).
 
[5] Sedel, F. et al. High doses of biotin in chronic progressive multiple sclerosis: a pilot study. Mult Scler Relat. Disord. 4, 159–169 (2015).
 
[6] Sedel, F., Bernard, D., Mock, D. M. & Tourbah, A. Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis. Neuropharmacology 110, 644–653 (2016).

​Understanding body weight is more than just looking at a number on the scale. It’s about how our bodies process energy, store fat, and regulate key metabolic functions. In this presentation, we will explore why physical appearance alone can be misleading and why not all fat is created equal. We’ll distinguish between beneficial brown fat and harmful white fat and examine how fat distribution, whether an "apple" or "pear" body shape, affects overall health.
Metabolic syndrome is a growing concern because of its potential link to body weight and obesity in particular. We’ll break down its risk factors, including how the body handles glucose and fat metabolism. With the rise of GLP-1 agonists, new therapies are revolutionizing the treatment of type 2 diabetes and weight management. We’ll also discuss the harmful effects of high blood sugar, elevated cholesterol, and triglycerides, which contribute to serious conditions like cardiovascular diseases.
Additionally, we’ll dive into the fascinating relationship between gut microbiota and diet, uncovering its surprising impact on weight and metabolism. The presentation will conclude with practical recommendations for lifestyle changes and emerging therapeutic options that can help optimize metabolic health.
Access this presentation and gain a deeper understanding of the complex factors that shape body weight and metabolic wellness by clicking on the link below.

​In recent years, scientific advancements have brought the gut microbiome—a diverse community of trillions of microorganisms living in our digestive tract—into the spotlight. Research has shown that the health of our gut microbiota plays a pivotal role in nearly every aspect of our well-being, from immune function and digestion to mental health and the prevention of chronic diseases. When this delicate balance of microorganisms is disrupted—a condition known as dysbiosis—it can contribute to issues like obesity, diabetes, autoimmune disorders, and even mental health conditions like depression.
 
Despite this growing body of evidence, public awareness about gut health remains surprisingly low. Many doctors and patients overlook the importance of monitoring digestive health until symptoms become unavoidable, at which point reactive solutions—costly tests, medications, or invasive procedures—take precedence. This reactive approach misses an important opportunity: the power of prevention through awareness and simple habits.
 
One of the easiest ways to keep tabs on your gut health is also one of the least discussed: regularly inspecting the frequency, consistency, and appearance of your stools. While it might seem unpleasant, this small act of mindfulness could provide vital clues about your overall health and help detect imbalances before they spiral into bigger problems. In this blog, we’ll explore why stool inspection should be a routine part of your self-care toolkit and how this simple practice can empower you to take charge of your gut health—without the need for expensive interventions down the line.

​The characteristics of human stool—such as consistency, frequency, and composition—serve as valuable indicators of gastrointestinal (GI) health. Monitoring these attributes can provide insights into digestive function and the state of the gut microbiome. Here's a summary of the relevant scientific literature on the subject:
 
Frequency: Regularity in bowel movements is an important aspect of gut health. Studies suggest that having at least one bowel movement per day is associated with a healthy gut microbiome. Infrequent bowel movements can lead to the buildup of toxins and an increased risk of chronic diseases, while overly frequent movements are linked to liver damage. Maintaining a "Goldilocks zone" of bowel movement frequency—neither too few nor too many—is considered optimal for health. A study published in Cell Reports Medicine [1] found that bowel movement frequency significantly influences physiology and long-term health. The best outcomes were linked with passing stools once or twice a day. Irregular bowel movements, such as constipation or diarrhea, were associated with higher risks of infections and neurodegenerative conditions.
 
Consistency: The consistency of stool is also a critical factor. The Bristol Stool Chart categorizes stool into seven types, ranging from hard lumps (Type 1) to entirely liquid (Type 7). Types 3 and 4 are considered optimal, indicating well-formed stools that are easy to pass and a healthy balance of fiber and water in the diet [2], while Types 1 and 2 suggest constipation, and Types 5 through 7 are associated with diarrhea [3].
 
Gut microbial composition affects both consistency and frequency: The gut microbiome plays a crucial role in digestion and overall health. Stool consistency is closely linked to the richness and composition of the gut microbiota. Research indicates that variations in stool form correlate with differences in microbial communities within the GI tract. For instance, a study found that stool consistency is strongly associated with gut microbiota richness and composition, enterotypes, and bacterial growth rates [4]. Research has also shown that the composition of gut bacteria is also strongly linked to bowel movement frequency. Fiber-fermenting bacteria, associated with good health, thrive in individuals who have bowel movements once or twice daily. In contrast, those with constipation or diarrhea showed higher levels of bacteria associated with protein fermentation or upper gastrointestinal tract issues [5].
 
Diet Influences stool characteristics: Diet plays a crucial role in determining stool characteristics. High-fiber foods, such as whole grains, fruits, and vegetables, contribute to stool bulk and promote regular bowel movements. For example, consuming fiber-rich snacks like dried mangoes can aid in relieving constipation by adding bulk to the stool and supporting a healthy gut microbiome [6]. Additionally, certain foods have been identified to alleviate specific digestive symptoms. Asparagus, for instance, contains prebiotics that support beneficial gut bacteria and can help reduce bloating [7].

​Toxins and Inflammation: When stools linger too long in the gut, microbes exhaust the available fiber and instead ferment proteins, producing toxins like p-cresol sulfate and indoxyl sulfate. These toxins can enter the bloodstream and burden the kidneys [1]. On the other hand, diarrhea can lead to excessive bile acid excretion, causing inflammation and liver damage [1].
 
Chronic Disease: Chronic constipation has been associated with neurodegenerative disorders and chronic kidney disease progression. However, it remains unclear whether bowel movement abnormalities are early drivers of chronic disease or merely coincidental [5].
 
Monitoring stool characteristics provides valuable insights into gut health. Maintaining optimal stool consistency and regularity through a balanced diet rich in fiber, adequate hydration, and regular physical activity can support a healthy digestive system and promote overall well-being.

​Frequency
 

• Ideally 1-2 bowel movements a day, as discussed above.
• 2-3 bowel movements a week is still considered normal, if the individual is properly hydrated, has a diet adequately rich in fibers, and has adequate level of exercise.
• Lifestyle changes and/or medical intervention would be appropriate if outside of this range

 
Consistency
 
Type 3 or 4 is considered normal, as shown in Bristol Stool Form Scale below:

[Reproduced from Wikipedia: Bristol stool scale]
 Lifestyle changes and/or medical intervention would be appropriate if outside of this range

​The color of your stool is also an important yet often overlooked indicator of your digestive and overall health. While stools are typically various shades of brown due to bile pigments, they can undergo temporary changes based on diet, medications, and supplements. However, persistent or unusual stool discoloration can sometimes signal underlying health concerns that require medical attention [1-3].
 
Common Causes of Stool Discoloration
 
1.Dietary Influences

• Green stools: Commonly caused by eating large amounts of leafy greens (e.g., spinach, kale) or green food dyes. Rapid transit through the gut can also prevent bile from fully breaking down, leading to greenish stools.
• Red stools: Beets, tomatoes, cranberries, and artificially colored foods can give stools a reddish hue. However, it is essential to differentiate between food-related changes and the presence of blood.
• Yellow or greasy stools: High-fat meals, malabsorption disorders (such as celiac disease), or excessive intake of foods like turmeric can lead to yellowish stools.

 
2.Medications, Vitamins, and Supplements

• Iron supplements and bismuth-containing medications (e.g., Pepto-Bismol) can cause black stools.
• Certain antibiotics and antacids may contribute to lighter or clay-colored stools.
• Vitamin supplements with high doses of beta-carotene (from carrots or sweet potatoes) can sometimes result in orange-hued stools.

 
When Should You Be Concerned?
 
While many changes in stool color are harmless and temporary, certain discolorations warrant medical attention:

• Bright red stools: If not explained by diet (e.g., beets), this may indicate lower GI bleeding from hemorrhoids, diverticulosis, or more serious conditions like colorectal cancer.
• Black or tarry stools (melena): This could be a sign of upper GI bleeding from ulcers, gastritis, or esophageal varices.
• Pale, clay-colored stools: A lack of bile pigments could suggest bile duct obstruction, liver disease, or gallbladder dysfunction.
• Yellow, greasy, foul-smelling stools: This may indicate fat malabsorption, often linked to pancreatic insufficiency, celiac disease, or other digestive disorders.

 
Being mindful of stool color can provide important clues about gut health. While most changes are benign and linked to diet or supplements, persistent abnormalities—especially those accompanied by other symptoms like pain, weight loss, or fatigue—should prompt further medical evaluation. A simple daily glance at your stool could be a key step in proactive health monitoring, helping you catch potential issues before they become serious.

​In current medical practice, managing pain often means reaching for a pill bottle. While medications like aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and opioids can be effective in alleviating pain, they also come with a host of potential side effects. Long-term use of NSAIDs, for instance, may lead to gastrointestinal issues, kidney damage, and increased cardiovascular risk [1]. Steroidal anti-inflammatory drugs can suppress the immune system and contribute to osteoporosis [2], while opioids carry a well-documented risk of dependency and addiction [3]. Despite these risks, society continues to lean heavily on pharmaceuticals as the primary solution for pain management.
 
Growing awareness of side effects has led many to seek non-drug alternatives. Techniques such as physical therapy, acupuncture, mindfulness meditation, and dietary changes are gaining traction for their ability to reduce pain and improve quality of life without the risks associated with medication [4]. Among these alternatives, the use of electromagnetic stimulation has emerged as a particularly intriguing option. Devices like Transcutaneous Electrical Nerve Stimulation (TENS) units and Pulsed Electromagnetic Field (PEMF) therapy are becoming more popular for their potential to manage pain in a non-invasive and drug-free manner [5,6]. The National Center for Complementary and Integrative Health (NCCIH) provides a public fact sheet on using magnetic fields for pain management [7].
 
This blog will focus specifically on Pulsed Electromagnetic Field (PEMF) therapy, exploring how it works, its applications in pain management, and the scientific evidence supporting its use. Whether you are seeking a complementary approach to traditional treatments or an alternative to medications, PEMF therapy may offer a promising solution. Let us dive in to understand more about this innovative technology and its role in pain relief.

Distinction between static and pulsed magnetic fields: Both modalities are based on the interaction between magnetic fields and biological systems, with the objective of promoting healing, alleviating pain, and enhancing cellular function. However, there are fundamental distinctions affecting their effectiveness.
 
Static magnetic therapy (SMT) involves the use of magnets that produce a constant, unchanging magnetic field. Magnets are usually embedded in bracelets, insoles, or pads and placed on or near the body. The steady magnetic field influences the alignment of charged particles in tissues and potentially affects ion exchange processes across cell membranes. In SMT, the dose is quantified by measuring the magnetic flux density, which is typically expressed in units of Gauss (G) or Tesla (T). Most therapeutic magnets have a flux density ranging from 300 to 5000 Gauss. The depth of penetration and the effectiveness of the therapy depend on the strength of the magnet and the distance from the tissue being treated. However, definitive clinical evidence supporting SMT remains limited, with studies often yielding inconclusive or modest results.
 
Pulsed electromagnetic field, by contrast, employs time-varying magnetic fields generated by electrical currents passing through coils. These magnetic fields can penetrate deeper into the body and induce electric currents within tissues, stimulating cellular activity. The dosing in PEMF therapy is multifaceted and involves parameters such as:
 
1.Types of frequencies: the field frequency (also known as carrier frequency) within the pulse, and the pulse repetition frequency itself. The latter depending on applications could vary from a few Hz to several hundreds. The field frequency on the other hand, is usually several orders of magnitude higher, in the kHz or even MHz range.

2. Wave form: The shape of the electromagnetic pulse (e.g., sinusoidal, square, or sawtooth), which may influence the biological response.

3.Intensity: The strength of the magnetic field, measured in Gauss or Tesla, which varies depending on the therapeutic application.
​
4.Duration: The length of time the field is applied, often ranging from minutes to hours per session.

PEMF influences tissues through magnetic and induced electrical fields, causing movement of ions and charged particles. Over many years of research, there is consensus that low field frequency may be more bioactive than static fields, and pulsed fields could be more effective than continuous ones. Higher pulse frequencies and magnetic flux densities lead to stronger cellular responses, especially with repeated applications over more than 10 days. When information on wave forms is available, triangle wave forms show the highest cellular response. A meta-analysis of ninety-two studies found that PEMF effects vary by cell type and origin, with osteosarcoma cells being particularly sensitive [1]. The lack of standardization in study designs and documentation, especially the documentation of wave forms and pulse duration, tends to obscure the analyses PEMF data across studies. Overcoming these caveats will improve comparisons and replications and advance the pace of research.
 
The exact mechanisms by which magnetic fields exert therapeutic effects remain a topic of research. Hypotheses include the modulation of cell membrane ion channels and receptors, especially the adenosine receptors. As a result, PEMF affects many cellular processes including apoptosis, proliferation and differentiation of osteoclasts, mesenchymal stem cells, adipose-derived stem cells and tendon stem progenitor cells. On the overall, PEMF enhances microcirculation, and stimulates cellular repair processes, not only in bone, cartilage, and tendon tissues, but in the brain as well [2].

PEMF therapy has garnered over the decades robust evidence in clinical trials resulting in six FDA approvals for the following indications:
 
1.Therapy for non-union fractures, which are fractures that fail to heal properly (1979).
2.Adjunct therapy for post operative edema and pain (1987)
3.Urinary Incontinence and Muscle Stimulation (1998).
4.Adjunct therapy to Cervical Fusion Surgery in patients at elevated risk for non-fusion (2004).
5.Therapy for depression and anxiety (2006).
6.Therapy for the treatment of brain cancer (2011).
 
Additional FDA approvals are expected in the future since clinical trials based on PEMF intervention are still on-going. A review of clinicaltrials.gov indicated that to date 150 trials are registered addressing a wide range of conditions, mostly musculoskeletal disorders, neuropathies, neurological disorders, autoimmune and metabolic diseases.

​FDA approvals notwithstanding, the National Center for Complementary and Integrative Health (NCCIH) also listed PEMF therapy as potentially effective for the following conditions:
 

• Osteoarthritis
• Low back pain
• Complex Regional Pain Syndrome
• Menstrual pain
• Multiple Sclerosis and paresthesia pain

 
These recommendations are based on reviews of clinical reports up to 2021.

​Pulsed Electromagnetic Field (PEMF) therapy has gained popularity as a therapeutic tool for pain management, but like any treatment, it is essential to understand its safety and potential side effects. It is considered safe for most people as PEMF devices and associated protocols for medical applications operate below the exposure limits set by the International Commission on Non-Ionizing Radiation [1,2]. However, some individuals may experience mild and temporary side effects [3,4], such as:
 

• Tingling, warmth, or slight redness at the application site.
• Mild headaches, fatigue, or nausea.
• Temporary changes in sleep patterns.

 
These side effects are usually short-lived and often subside as the body adjusts to the therapy. It is important to listen to your body and consult with a healthcare provider if you experience any significant side effects.
 
PEMF therapy is not recommended for certain individuals [5], including:
 

• Pregnant women: Due to limited research on the effects of PEMF on fetal development.
• Organ transplant recipients: PEMF may interfere with immunosuppressant drugs.
• Individuals with implanted medical devices: Such as pacemakers or defibrillators, as PEMF can interfere with their functioning.
• People with magnetic or ferromagnetic implants: Or those deemed unsafe for MRI.
• Individuals with bleeding disorders: Or those taking blood-thinning medications.
• People with undiagnosed health concerns: It is crucial to consult a doctor before using PEMF.

 
It is always best to consult with a healthcare provider before starting any new therapy to ensure it's appropriate for your specific health needs.

Individuals considering PEMF therapy for pain management have several options: seeing a qualified professional, seeking special treatment centers, or trying the self-help path.
 
Seeing a doctor: The following healthcare professionals are more likely to be practitioners of PEMF therapy:
 

• Orthopedic Surgeons: Specialists in bone and joint health.
• Chiropractors: Often use PEMF therapy as part of their treatment plans.
• Pain Management Specialists: Focus on treating chronic pain conditions.
• Sports Medicine Doctors: Use PEMF therapy to aid in the recovery of sports-related injuries.

 
You can find PEMF therapy doctors through resources like WebMD and the Association of PEMF Practitioners (AOPP)
 
Special Treatment Centers: There are specialized centers that offer PEMF therapy, often as part of a broader range of integrative and regenerative treatments. Some notable ones include:
 

• Pulse PEMF Centers: These centers are certified and offer professional PEMF therapy. You can find a location near you using their location map.
• The Osteopathic Center: Offers PEMF therapy along with other integrative treatments. They have locations in Miami, Knoxville, Jupiter, and Jacksonville. More details can be found on their website.
• Health Mat Review Directory: Lists over 580 locations across the USA where PEMF therapy is available. You can find a practitioner near you using their directory.

 
Self-Help Devices and Operating Procedures: If you prefer to use PEMF therapy at home, there are several devices available for direct consumer purchase. Some selected options include:
 
Oxford Medical Instruments (OMI) offers an entire range of devices for spot and whole-body treatment
DC Cure PEMF Therapeutic Device offers a specialized product for low back pain.
Sota Magnetic Pulser is small affordable and portable device for spot treatment
 
Many others are compared and reviewed at health-related websites: Healthline, HealthNews, PMEF Therapy Hub and Medical News Today. PEMF therapy can be a versatile and effective treatment option for various conditions. Whether you choose to see a doctor, visit a specialized center, or use a self-help device, it's important to consult with a healthcare professional to determine the best approach for your specific needs.

I was introduced to PEMF therapy while visiting a patient in Switzerland, terminally ill with liver cancer and who used it extensively for relief of abdominal pain. During the visit I happened to mention annoying neck pain following the long overnight cross Atlantic flight. My neck pain tends to be recurrent because of poor posture during sleep and lasts two to three days before subsiding. The patient offered PEMF treatment by his device, for which I had little information, except that it was powerful and expensive. It was made in Germany and cost the equivalent of $8000. The duration of treatment would only be half an hour with a wand applied directly to the site of pain. I took the offer and to my astonishment the pain felt much better just 12 hours after treatment.
 
Returning home and upon much reflection, I decided to try PEMF therapy but not necessarily with an expensive and powerful device. I opted instead for the Sota Magnetic Pulser, Model MP6 (shown below), purchased from Amazon in 2020 for $395 excluding tax and shipping.

​The device comes with a wand for spot application. It could be used in two modes with the following output specifications:

​I uniquely used the regular mode to obtain relief within 12-24 hours not only for neck pain, but for other ailments including:
 

• Sciatic nerve pain by applying the wand directly onto the lumbar and lower buttock area of the leg involved.
• Minor sporting injuries like back-shoulder and muscle pain following a long session of archery practice, and knee pain following a long hike uphill.

 
PEMF therapy with the Sota Magnetic Pulser was effective for my case. Irrespective of its mechanism of action, my quality of life has been better since its purchase in 2020.

Introduction
​
Recent scientific research has increasingly highlighted the profound role of the gut microbiota in supporting overall health. This diverse community of microorganisms not only aids in digestion but also plays a critical part in regulating immune responses, metabolism, and even neurological functions. Emerging evidence now links imbalances in gut microbiota, known as dysbiosis, to a wide range of diseases, including autoimmune conditions, metabolic disorders, neurological disorders, and certain cancers [1].
​
Despite the growing recognition of dysbiosis as a key factor in disease, public awareness remains limited, and concrete guidelines from government health agencies and medical societies are lacking. As this field of study continues to expand, it raises important questions about how the public might respond to these discoveries and how to address dysbiosis proactively. Preventive medicine could offer promising solutions by focusing on early diagnosis and correction of microbial imbalances. However, without clear guidelines or widespread clinical recommendations, individuals will have to navigate this complex area on their own in the near term [2]. This article explores the implications of these findings and discusses how to harness this knowledge for disease prevention in the face of regulatory uncertainty. Options range widely from simple diet adjustments, to probiotics, and for those already suffering from relevant disease states, the possibility of fecal microbiota transplantations as a therapeutic choice [3].

References
[1] Afzaal M, Saeed F, Shah YA, Hussain M, Rabail R, Socol CT, Hassoun A, Pateiro M, Lorenzo JM, Rusu AV, Aadil RM. Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol. 2022; 13;  https://doi.org/10.3389/fmicb.2022.999001
[2] Abeltino A, Hatem D, Serantoni C, Riente A, De Giulio MM, De Spirito M, De Maio F, Maulucci G. Unraveling the Gut Microbiota: Implications for Precision Nutrition and Personalized Medicine. Nutrients. 2024; 16(22):3806. https://doi.org/10.3390/nu16223806
[3] Andary CM. et al. Dissecting mechanisms of fecal microbiota transplantation efficacy in disease. Trends in Molecular Medicine, 2024; 30 (3): 209 – 222. DOI: 10.1016/j.molmed.2023.12.005

Gut dysbiosis is a concern.

The human gut microbiota [1] is a diverse ecosystem of microorganisms that play crucial roles in supporting health. Dysbiosis [2] refers to a state of imbalance in the microbiota, where shifts in the composition or function of microbial communities disrupt normal host-microbe interactions. This imbalance is present in various diseases (list provided below). Commensal bacteria, such as species from the genera Lactobacillus and Bifidobacterium, promote gut health by producing metabolites like short-chain fatty acids (SCFAs), including acetate, propionate, and butyrate (Table 1). SCFAs nourish colonocytes, strengthen the gut barrier, and exert anti-inflammatory effects [3]. Conversely, pathobionts (microorganisms that are typically harmless but can become pathogenic under certain conditions) can degrade the mucin layer that lines and protects the gut epithelium.

The gut mucin layer is a critical barrier that separates gut microbes from the epithelial cells, preventing direct contact that could trigger inflammation [4]. Pathobionts such as Akkermansia muciniphila (in overabundance), Bacteroides fragilis, Escherichia coli, Clostridium difficile, and species of Fusobacterium can degrade mucin glycoproteins, thinning this protective layer. Degradation of this barrier facilitates microbial translocation, allowing bacteria and their metabolites to penetrate the epithelial layer and enter systemic circulation. This triggers immune activation, promoting inflammation and potentially leading to diseases such as inflammatory bowel disease (IBD), colorectal cancer, and metabolic syndrome.

Dysbiosis can result from multiple factors [5], including:

• Antibiotic use: Broad-spectrum antibiotics disrupt the microbiota, often leading to the overgrowth of opportunistic pathogens.
• Dietary changes: A Western diet rich in fats and sugars but low in fiber can reduce SCFA-producing bacteria and favor the proliferation of pathobionts.
• Infections: Pathogenic infections can shift the microbial community structure.
• Stress and lifestyle: Psychological and physical stressors can alter gut motility and microbiota composition.
• Aging: Natural changes in microbial diversity occur with age, often reducing beneficial species [6].

Dysbiosis is potentially reversible through interventions such as:

• Lifestyle changes: Regular exercise, stress management, and adequate sleep contribute to microbial health.
• Dietary modifications: High-fiber diets can promote SCFA production and restore microbial balance.
• Probiotics and prebiotics [7]: Probiotics introduce beneficial bacteria, while prebiotics provide nutrients that support their growth.
• Fecal microbiota transplantation (FMT): FMT has shown success in treating recurrent C. difficile infections by restoring microbial diversity and has potential for application in other diseases [8].

In summary, dysbiosis disrupts the balance between commensal bacteria and pathobionts, compromising the integrity of the gut mucosa and helping disease. By understanding the factors that cause dysbiosis and implementing targeted interventions, the restoration of a healthy microbiota is achievable, offering potential therapeutic benefits for a wide range of diseases.

References
[1] Sommer, F, & Bäckhed, F. The gut microbiota—masters of host development and physiology. Nature Reviews Microbiology. 2013; 11(4), 227–238.  https://doi.org/10.1038/nrmicro2974
[2] Cleveland Clinic: Dysbiosis
[3] Bedu-Ferrari C, Biscarrat P, Pepke F, Vati S, Chaudemanche C, Castelli F, Chollet C, Rué O, Hennequet-Antier C, Langella P, Cherbuy C. In-depth characterization of a selection of gut commensal bacteria reveals their functional capacities to metabolize dietary carbohydrates with prebiotic potential. mSystems 2024; 9: e01401-23. https://doi.org/10.1128/msystems.01401-23.
[4] Yamaguchi, M, Yamamoto, K. Mucin glycans and their degradation by gut microbiota. Glycoconj. J. 2023; 40, 493–512. https://doi.org/10.1007/s10719-023-10124-9
[5] Healthline: What causes dysbiosis and how is it treated?
[6] Ravikrishnan, A., Wijaya, I., Png, E. et al. Gut metagenomes of Asian octogenarians reveal metabolic potential expansion and distinct microbial species associated with aging phenotypes. Nat. Commun. 2024; 15, 7751. https://doi.org/10.1038/s41467-024-52097-9
[7] Bermúdez-Humarán, L.G., Chassaing, B. & Langella, P. Exploring the interaction and impact of probiotic and commensal bacteria on vitamins, minerals, and short chain fatty acids metabolism. Microb. Cell Fact. 2024; 23, 172. https://doi.org/10.1186/s12934-024-02449-3
[8] Cleveland Clinic: Fecal Transplant

Comprehensive List of Conditions Strongly Linked to Dysbiosis [1,2]

• Rheumatoid Arthritis (RA)

• Inflammatory Bowel Disease (IBD)
• Irritable Bowel Syndrome (IBS)
• Type 1 Diabetes
• Obesity
• Colorectal Cancer
• Small Intestinal Bacterial Overgrowth (SIBO)
• Cardiovascular Diseases
• Neurological Disorders (including Alzheimer's Disease [3,4] and Parkinson's Disease [5,6])
• Chronic Fatigue Syndrome
• Metabolic Syndrome
• Asthma and Allergies
• Autism Spectrum Disorder (ASD)
• Chronic Liver Disease

____________________________________________________________
References:
[1] Cleveland Clinic: Dysbiosis
[2] WebMD: What is dysbiosis
[3] Thakkar, A, Vora, A, Kaur, G et al. Dysbiosis and Alzheimer’s disease: role of probiotics, prebiotics and synbiotics. Naunyn-Schmiedeberg's Arch. Pharmacol. 2023; 396, 2911–2923. https://doi.org/10.1007/s00210-023-02554-x
[4] Oral Dysbiosis and Alzheimer’s Disease Risk
 [5] Medical News Today: Study in humans confirms link between Parkinson's and gut bacteria imbalance.
[6] Munoz-Pinto MF, Candeias E, Melo-Marques I et al. Gut-first Parkinson’s disease is encoded by gut dysbiome. Mol. Neurodegeneration. 2024; 19, 78. https://doi.org/10.1186/s13024-024-00766-0

Table 1. Selected Short Chain Fatty Acid (SCFA) producing bacterial specie

Table 2. Selected mucin degrading bacterial specie

Diagnosis

In clinical practice, symptoms of gastrointestinal disturbances often guide the diagnosis of gut dysbiosis. Your healthcare providers could apply tests that are traditionally used to investigate potential gut microbiota imbalances. These include:

Breath tests: These tests can help diagnose conditions like small intestinal bacterial overgrowth (SIBO) [1] and carbohydrate malabsorption. Patients showing chronic digestive problems, abdominal pain, bloating, frequent passing of gas, constipation, and diarrhea, are good candidates for these tests. Hydrogen and methane production are measured after consuming a particular test sugar — usually lactose, fructose, sucrose, sorbitol, glucose, or lactulose, depending on the condition your healthcare provider is checking for [2].

Biomarker-Based Testing: For example, testing for zonulin, a protein that regulates the permeability of the tight junctions between epithelial cells in the gut lining. Elevated levels in stool or blood may be a result of increased intestinal permeability, often associated with dysbiosis. Alternatively, testing for short chain fatty acids (SCFA) levels like butyrate and propionate in stools or blood, can signal reduced beneficial microbial activity.

Stool analysis: Stool analysis could be undertaken at various levels of complexities. A focused approach consists simply of cultures to find specific pathogens or overgrowth of bacteria such as Clostridium difficile or Escherichia coli. More comprehensively, your healthcare providers could order molecular testing based on either 16S Ribosomal RNA sequencing to obtain a detailed view of microbial composition and diversity, or alternatively next generation sequencing to identify all microbial DNA in the sample, including bacteria, viruses, fungi, and archaea, offering a broader analysis compared to 16S sequencing [3,4]. At the next higher level is Comprehensive Stool Analysis (CSA), which in addition to profiling gut microbiota, will also address digestive markers (elastase, fat and protein malabsorption), inflammatory markers (calprotectin and lactoferrin), metabolic markers ( pH and beta-glucuronidase), intestinal barrier function (zonulin as discussed previously, and secretory IgA) and SCFA [5-7].

All the above aside, patients who have no obvious gastrointestinal disturbances, but preliminary symptoms of diseases linked to dysbiosis, face a difficult choice. A comparable situation exists for those without any symptoms but are known to be predisposed through family history and genetics. In the absence of conclusive cause and effect evidence, the medical profession and government health agencies stay silent about the need for evaluating the status of their gut microbiota and how to remedy any imbalances. All decisions rest with the patients and healthcare providers. On the other hand, medical literature abounds with pro and con opinions arguing either way [8]. Patients who are initiative-taking can always reach out to direct-to-consumer companies in the burgeoning gut microbiome industry [9,10]. Hopefully, they will do so with expert help from properly licensed genetic counselors [11] and healthcare providers. We will next discuss options for supporting or improving gut microbiota balance.

References
[1] Small Intestinal Bacterial Overgrowth. [Updated 2023 Apr 17]. Sorathia SJ, Chippa V, Rivas JM. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2024. https://www.ncbi.nlm.nih.gov/books/NBK546634/
[2] WebMD: What To Know About Hydrogen Breath Tests
[3] Microbiome 101: Studying, Analyzing, and Interpreting Gut Microbiome Data for Clinicians. Allaband C et al. Clinical Gastroenterology and Hepatology. 2019; 17 (2), 218 – 230. DOI: 10.1016/j.cgh.2018.09.017
[4] Clinician Guide to Microbiome Testing. Staley C, Kaiser T & Khoruts A. Dig. Dis. Sci. 2018; 63, 3167–3177. https://doi.org/10.1007/s10620-018-5299-6
[5] Genova Diagnostics: GI Effects
[6] Doctor’s Data: Comprehensive Stool Analysis
[7] Diagnostic Solutions Laboratory: GI-MAP
[8] Dr. Ruscio DC: Should You Use a Stool Test to Check Your Gut Health?
[9] Rupa Health: Revolutionizing Gut Health: The Rise of Microbiome Testing Companies and Their Impact on Personalized Medicine. Scott Bingman. October 28, 2024.
[10] Microbiome Therapeutics Innovation Group (MTIG)
[11] National Society of Genetic Counselors: Find a genetic counselor  

Lifestyle interventions

Irrespective of a diagnosis of dysbiosis you could always care for your gut microbiota by reviewing three elements of lifestyle that are known to affect gut health: exercise, sleep, and stress management.

Exercise and Gut Microbiota: Studies have shown that physical activity enhances microbial diversity, which is a marker of a healthy gut [1]. Regular exercise increases the abundance of beneficial bacteria, such as Faecalibacterium prausnitzii, Akkermansia muciniphila, Bacteroides and Roseburia, all of which are associated with anti-inflammatory effects and gut barrier integrity. Mechanistically, exercise-induced increases in butyrate-producing bacteria contribute to the production of short-chain fatty acids (SCFAs), compounds that provide energy to colonocytes and strengthen the gut barrier. Studies in both humans and animals have shown that sedentary lifestyles correlate with reduced microbial diversity, while active individuals show greater microbial richness and resilience to dysbiosis [2]. The Center for Disease Control (CDC) recommendation for adult physical activity is 150 minutes of moderate-intensity activity per week, or 75 minutes of vigorous-intensive activity, or an equivalent combination of both [3].

Sleep and Gut Health: Sleep plays a crucial role in supporting gut health [4]. Research has shown that adequate sleep helps support the integrity of the gut barrier, which prevents the entry of harmful substances and pathogens [5]. A study conducted by Shandong University found that specific gut bacteria, such as Lachnospiraceae UCG004 and Odoribacter, are associated with longer sleep duration and better sleep quality. These bacteria promote a healthy gut environment, which in turn supports better sleep [6]. Conversely, poor sleep can lead to gut dysbiosis, increasing the risk of various health issues. The minimum sleep requirement for adults (18 years or older) is 7 hours or more per day according to the Sleep Foundation [7].

Stress Management and Gut Microbiota: Chronic stress negatively affects gut health through the gut-brain axis. Stress can alter gut motility, reduce mucus secretion, and increase intestinal permeability, creating an environment conducive to dysbiosis. Elevated cortisol levels, a hallmark of stress, have been linked to shifts in microbial composition, with reductions in beneficial species like Lactobacillus and Bifidobacterium [8]. Stress management techniques, including mindfulness meditation, yoga, and deep-breathing exercises, can mitigate these effects by modulating the hypothalamic-pituitary-adrenal (HPA) axis and reducing systemic inflammation [9]. Such interventions have been shown to restore microbial diversity and improve gut health. General guidelines for finding and resolving stress are provided by the CDC [10].

In summary, regular exercise, adequate sleep, and stress management represent simple yet effective strategies to support gut health and combat dysbiosis. By fostering microbial diversity, promoting beneficial species, and reducing systemic inflammation, these lifestyle interventions empower individuals to actively contribute to their own gut health. Incorporating these habits into daily life not only improves microbial balance but also offers broader health benefits that extend beyond the gut. For a full review of lifestyle factors potentially affecting your health, please consult the Lifestyle section of this website.

References
[1] Clarke SF, Murphy EF, O'Sullivan O, et al. Exercise and associated dietary extremes impact on gut microbial diversity. Gut. 2014 ; 63 :1913-1920. https://doi.org/10.1136/gutjnl-2013-306541
[2] Khaledi, M, Darvishi, M, Sameni, F et al. Association between exercise and changes in gut microbiota profile: a review. Sport Sci. Health. 2024; 20: 273–286. https://doi.org/10.1007/s11332-023-01132-1
[3] What Counts as Physical Activity for Adults
[4] Kado, DM. Night-to-night sleep duration variability and gut microbial diversity: more evidence for a brain-gut microbiome-sleep connection. Sleep. 2024; 47(3), zsae005, https://doi.org/10.1093/sleep/zsae005
[5] Smith RP, Easson C, Lyle SM, Kapoor R, Donnelly CP, Davidson EJ, Parikh E, Lopez JV, Tartar JL. Gut microbiome diversity is associated with sleep physiology in humans. PLoS One. 2019;14(10): e0222394. doi: 10.1371/journal.pone.0222394. PMID: 31589627; PMCID: PMC6779243.
[6] Yue M, Jin C, Jiang X, Xue X, Wu N, Li Z, Zhang L. Causal Effects of Gut Microbiota on Sleep-Related Phenotypes: A Two-Sample Mendelian Randomization Study. Clocks Sleep. 2023; 5(3):566-580. doi: 10.3390/clockssleep5030037. PMID: 37754355; PMCID: PMC10527580.
[7] How much sleep do you need. Eric Suni & Abhinav Singh. Updated May 13, 2024.
[8] Almand, AT, Anderson, AP, Hitt, BD et al. The influence of perceived stress on the human microbiome. BMC Res. Notes. 2022; 15: 193. https://doi.org/10.1186/s13104-022-06066-4
[9] Chrousos, G. Stress and disorders of the stress system. Nat. Rev. Endocrinol. 2009; 5: 374–381. https://doi.org/10.1038/nrendo.2009.106
[10] CDC: Stress management

Dietary modifications

Diet plays a critical role in shaping the gut microbiota, and targeted dietary changes can help restore balance in patients diagnosed with dysbiosis. Corrective action involves identifying deficiencies or imbalances in the diet and implementing modifications to promote beneficial microbial growth while minimizing harmful influences.

Diet deficiencies identification: Professional guidance from a registered dietician [1,2] can provide a comprehensive and tailored approach to understanding dietary influences on dysbiosis. A dietitian can perform a thorough dietary assessment, often using tools like food frequency questionnaires (FFQs) or dietary recall. This helps find deficiencies in fiber, essential nutrients, or overconsumption of inflammatory foods. Patients without access to professional help can take initiatives like self-tracking. Using food diaries or apps (e.g., MyFitnessPal, Lifesum, Cronometer and MyNetDiary) can help monitor dietary patterns and identify trends, such as low fiber intake or excessive processed foods. If symptoms like bloating or irregular bowel movements are present, correlating them with dietary habits could help find triggers. Following evidence-based dietary recommendations, such as increasing whole foods and reducing processed foods, can be a good starting point.

Corrective Dietary Actions: Studies have shown that high-fiber diets increase microbial diversity and SCFA production, both critical for supporting gut health [3]. So, fiber is the cornerstone of a gut-friendly diet as it serves as a substrate for beneficial bacteria to produce short-chain fatty acids (SCFAs). Increasing dietary proportion of fruits, vegetables, legumes, whole grains, and prebiotic-rich food like garlic, onions, bananas, and asparagus are particularly beneficial. In contrast, diets high in refined sugars and low in fiber are linked to reduced microbial diversity and inflammation [4]. Excessive sugar and processed food consumption can promote the growth of pathogenic bacteria and contribute to dysbiosis. The best course of action is to replace sugary snacks with healthier options like nuts or seeds and minimize ultra-processed foods.

High intake of saturated fats can disrupt gut microbiota, while omega-3 fatty acids have been shown to increase microbial diversity and promote the growth of beneficial anti-inflammatory bacteria [5]. Saturated fats should be replaced with healthier options like fatty fish (salmon, mackerel), flaxseeds, and walnuts. Another key point to remember in a healthy diet is the effect of alcohol. Excessive alcohol intake disrupts gut microbial composition, and it is essential to reduce consumption to the recommended level or simply cut it completely from your diet [6]. Finally, the effect of hydration also requires consideration since it supports healthy digestion. Although the CDC does not have specific recommendations for daily water intake, the need of the vast majority is 3.7 L for men and 2.7 L for women, from all sources, with variations allowed for unusual circumstances like strenuous exercises, dehydration, and body habits [7,8].

Lifestyle changes and diet modifications may not be sufficient for certain conditions, intervention with probiotics is the next choice level, which we will consider below.

References
[1] Search for a dietician.
[2] Find a nutrition expert.
[3] The Impact of Dietary Fiber on Gut Microbiota in Host Health and Disease. Makki, Kassem et al.. Cell Host & Microbe.2018; 23(6), 705 – 715. https://doi.org/10.1016/j.chom.2018.05.012
[4] Singh, R.K., Chang, HW., Yan, D. et al. Influence of diet on the gut microbiome and implications for human health. J. Transl. Med. 2017; 15, 73. https://doi.org/10.1186/s12967-017-1175-y
[5] Watson H, Mitra S, Croden FC, et al. A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota. Gut. 2018; 67:1974-1983. https://doi.org/10.1136/gutjnl-2017-314968
[6] CDC: About moderate alcohol use.
[7] Michael N. Sawka, Samuel N. Cheuvront, Robert Carter, Human Water Needs, Nutrition Reviews. 2005; 63, Issue suppl_1, S30–S39, https://doi.org/10.1111/j.1753-4887.2005.tb00152.x
[8] MedicalNews Today: How much water should you drink a day?

Probiotics

Probiotics, live microorganisms that confer health benefits when consumed in adequate amounts, are a promising intervention for patients with dysbiosis. When lifestyle changes and dietary modifications prove insufficient, probiotics can help restore microbial balance [1]. However, patients face a range of choices: probiotics from fermented foods and as dietary supplements. Each option has unique benefits and considerations, often requiring medical supervision to ensure safety and efficacy.

Probiotics from Fermented Foods: Fermented foods such as yogurt, kefir, sauerkraut, kimchi, and miso naturally have probiotics [2]. These foods are rich in beneficial bacteria like Lactobacillus and Bifidobacterium, which can help restore gut balance [3]. The advantage of consuming probiotics through fermented foods is that they are part of a natural diet and can be easily incorporated into daily meals. However, the concentration of probiotics can vary, and not all fermented foods have the same strains or amounts of beneficial bacteria [2].

Probiotics as Dietary Supplements: Probiotic supplements are another choice, available in various forms such as capsules, tablets, and powders. These supplements have specific strains of bacteria like Lactobacillus rhamnosus GG, Bifidobacterium breve, or Saccharomyces boulardii, tailored to address health issues (e.g., relief of diarrhea, improved immunity). The advantage of supplements is the ability to choose products with known concentrations of probiotics and specific strains that have been studied for their health benefits [4]. However, the quality and efficacy of probiotic supplements can vary, and as dietary supplements they are not regulated by the FDA in the same way as medications [5]. It is essential to select reputable brands and consult with a healthcare provider to ensure the chosen supplement is proper for the patient's needs [6]. The need for consultation with a healthcare provider will be even more acute for patients who use the services of direct-to-consumers microbiome companies (see the microbiome profiling section of this website). In addition to the results of gut microbiota and gut health, these companies will often suggest a host of dietary supplements including pre- and probiotics as remedies. The amount of information and choices could be overwhelming to some.

Live Biotherapeutic Products (LBP): It is important to note that the FDA has recently created this new therapeutic entity defined as “ biological product that: i) contains live organisms, such as bacteria; ii) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and iii) is not a vaccine”. LBPs must undergo rigorous clinical trials and be approved before marketing. Probiotics could be defined as LBPs to treat specific diseases. To date no probiotic has been approved as LBPs.

References
[1] Cleveland Clinic: Probiotics
[2] Veryell Health: 20 Probiotic Foods With Good Bacteria. Amber J. Tresca. Published September 22, 2023
[3] WebMD: Top Foods High in Probiotics
[4] Sanders, ME, Merenstein, DJ, Reid, G et al. Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nat. Rev. Gastroenterol. Hepatol. 2019; 16, 605–616. https://doi.org/10.1038/s41575-019-0173-3
[5] Doron S, Snydman DR. Risk and Safety of Probiotics, Clinical Infectious Diseases. 2015; 60, Issue suppl_2, S129–S134, https://doi.org/10.1093/cid/civ085
[6] Clinical Guide to Probiotic Products Available in USA

Prebiotics and Synbiotics

While often mentioned together with probiotics, these terms describe distinct, yet complementary interventions aimed at supporting gut health.
Prebiotics are non-digestible food components, primarily fibers and oligosaccharides, which promote the growth and activity of beneficial gut bacteria. Unlike probiotics, which are live microorganisms, prebiotics serve as "food" for these bacteria. Common prebiotic substances include inulin, fructooligosaccharides (FOS), and galactooligosaccharides (GOS). Found in foods like garlic, onions, bananas, and whole grains, prebiotics selectively nourish beneficial bacteria such as Bifidobacteria and Lactobacilli, fostering an environment that discourages the growth of harmful microbes.

Synbiotics are products that combine prebiotics and probiotics in a synergistic way to enhance their overall effectiveness. The prebiotics in synbiotic formulations support the survival and activity of the included probiotic strains, ensuring that they reach the gut in sufficient numbers and thrive. For example, a synbiotic product might pair a strain of Bifidobacterium with its preferred prebiotic, such as FOS. This combination can amplify the health benefits, improving gut health, boosting immune function, and even supporting metabolic processes.
Prebiotics and synbiotics are often used alongside probiotics to maximize their potential benefits. For instance, adding prebiotic-rich foods or supplements to a probiotic regimen can create a more hospitable environment for the beneficial microbes, improving their efficacy. Similarly, synbiotics can streamline this process by providing both components in a specific product.
​
Together, these interventions address various health goals, from improving digestion and reducing inflammation to supporting immune health and preventing certain diseases. Their targeted use is increasingly recognized as a vital strategy for enhancing the microbiome and achieving better health outcomes.
Finally, patients who are already suffering from diseases with a strong microbiome association, the ultimate choice for correcting dysbiosis is Fecal Microbiota Transplantation which we will consider below.

Fecal Microbiota Transplantation: A Therapeutic Option for Microbiome-Linked Diseases

Fecal microbiota transplantation (FMT) is an innovative medical procedure in which processed stool from a healthy donor is introduced into a recipient's gastrointestinal tract to restore a balanced gut microbiota. This approach targets dysbiosis implicated in various diseases, as either a contributing factor or a potential cause [1]. FMT has garnered attention for its effectiveness in treating certain conditions and its potential to revolutionize microbiome-centered therapies.

FMT has achieved the greatest success in treating recurrent Clostridioides difficile infection (CDI), a condition characterized by severe diarrhea and inflammation resulting from disrupted gut microbiota, often due to antibiotic use. Studies report cure rates exceeding 85% in patients who failed traditional therapies such as antibiotics like vancomycin or metronidazole. Emerging evidence suggests FMT may also help patients with other microbiome-associated diseases [2]:

Inflammatory Bowel Disease (IBD): In conditions like ulcerative colitis (UC) and Crohn’s disease, FMT has shown potential to induce remission or improve symptoms, though results are inconsistent and depend on factors like donor selection and disease severity.
Irritable Bowel Syndrome (IBS): Some studies show symptom relief and improved quality of life following FMT in patients with IBS.

Metabolic Disorders: Research exploring FMT for obesity, insulin resistance, and metabolic syndrome shows promise but requires more evidence.

Neurological Conditions: Preliminary studies have investigated FMT’s role in autism spectrum disorders and Parkinson’s disease, hypothesizing that gut-brain axis modulation may offer therapeutic benefits.

FMT offers three advantages including the restoration of microbial diversity. It directly reintroduces a diverse microbiome, overcoming the limitations of probiotics or dietary interventions that may not sufficiently alter the gut ecosystem. It has proven more effective than antibiotics for recurrent CDI, reducing relapse rates and potentially lowering healthcare costs. Unlike antibiotics, FMT does not exert selective pressure on pathogens, reducing the risk of developing antimicrobial resistance.

On the other hand, FMT is still a subject of regulatory and safety concerns [3]. Despite its success, FMT is not universally standardized. While safe, FMT can cause mild to moderate transient adverse effects such as abdominal discomfort, fever, and bacteremia. Risks include transmission of undetected pathogens or adverse immune responses, needing stringent donor screening and oversight [4]. FMT effectiveness can depend on factors like donor microbiome composition, disease type, and recipient characteristics, which are not fully understood [5]. While FMT has shown short-term efficacy, long-term outcomes, and potential risks, such as the development of other conditions, remain unclear.

Traditional therapies, such as antibiotics for CDI or immunosuppressants for IBD, aim to manage symptoms or reduce inflammation but do not address the underlying microbial imbalance. FMT offers a unique approach by directly targeting dysbiosis. However, it is more invasive and currently lacks the robust evidence base and standardization that traditional therapies have. Additionally, its role as a frontline therapy is still limited, often being reserved for cases refractory to standard treatments.

Resources for patients and healthcare providers who wish to access FMT as a therapeutic modality include the following:

FDA-approved formulations of Fecal Microbiota Transplantation (FMT): Two formulations (Rebyota and Vowst) were approved for prescription to treat recurrence of Clostridioides difficile infection (CDI) in patients 18 years and older who have completed antibiotic treatment for recurrent CDI [6,7].

OpenBiome is a non-profit stool bank that provides investigational FMT preparations to registered physicians treating patients with recurrent Clostridioides difficile infection (CDI). They offer a "Find a doctor" tool on their website to help patients locate healthcare providers who can perform FMT.

The American Gastroenterological Association (AGA) provides guidelines and resources for FMT, including information on indications, donor screening, and procedural aspects [8].

Patients and doctors can also explore ongoing clinical trials related to FMT through databases like ClinicalTrials.gov, which provide information on eligibility criteria and study locations.

Besides helping patients and healthcare providers navigate the process of accessing FMT and they also ensure that it is used safely and effectively.

In summary, FMT is an innovative approach in treating dysbiosis-related diseases, offering a targeted and effective solution for conditions like recurrent CDI and holding promise for broader applications. While its advantages, particularly in restoring microbiome diversity, are clear, the challenges of safety, regulation, and variable outcomes must be addressed through rigorous research and standardization. As our understanding of the microbiome grows, FMT may evolve from a niche intervention to a cornerstone of personalized medicine.

References
[1] Karimi M, Shirsalimi N, Hashempour Z, Salehi OH, Sedighi E, Beigi F, Mortezazadeh M. Safety and efficacy of fecal microbiota transplantation (FMT) as a modern adjuvant therapy in various diseases and disorders: a comprehensive literature review. Frontiers in Immunology. 2024, 15.  https://doi.org/10.3389/fimmu.2024.1439176
[2] Goldenberg, D, Melmed, GY. Fecal Transplant: The Benefits and Harms of Fecal Microbiota Transplantation. 2023; In: Pimentel M, Mathur R, Barlow GM (eds) Clinical Understanding of the Human Gut Microbiome. Springer, Cham. https://doi.org/10.1007/978-3-031-46712-7_9
[3] AAMC News: The potential and pitfalls of fecal transplants
[4] Goloshchapov OV, Olekhnovich EI, Sidorenko SV et al. Long-term impact of fecal transplantation in healthy volunteers. BMC Microbiol. 2019; 19, 312. https://doi.org/10.1186/s12866-019-1689-y
[5] Lee JY, Kim Y, Kim J et al. Fecal Microbiota Transplantation: Indications, Methods, and Challenges. J Microbiol. 2024. https://doi.org/10.1007/s12275-024-00184-3
[6] AGA: FDA approves first FMT therapy and issues guidance, December 2, 2022
[7] Vowst® (Seres Therapeutics)
[8] AGA Clinical Practice Guideline on Fecal Microbiota–Based Therapies for Select Gastrointestinal Diseases. Peery AF. et al. Gastroenterology. 2024; 166 (3): 409 – 434. https://doi.org/10.1053/j.gastro.2024.01.008

​A defining feature of aging is the gradual progression toward frailty as individuals move beyond their physical prime. Frailty compromises physical, mental, and cognitive functions in the elderly, making them more susceptible to a wide array of conditions, including infectious diseases, autoimmune disorders, metabolic imbalances, neurological decline, and cancer. This deterioration leads to a marked reduction in quality of life, particularly during its later stages.
 
The underlying physiological mechanisms of frailty remain an area of ongoing research, but systemic inflammation has emerged as a key contributing factor. This persistent, low-grade inflammation, often referred to as "inflammaging," is likely driven by a combination of factors, including cellular senescence, genetic predisposition, obesity, gut microbiome imbalances, immune system dysfunction, and chronic infections.
 
Clinicians monitor systemic inflammation by assessing specific biomarkers, tailored to the individual’s family history, initial symptoms, or diagnosed conditions. Table 1 provides a comprehensive overview of common inflammatory biomarkers. Physicians typically order these tests based on clear disease symptoms or to track the progression of conditions during treatment. However, healthy seniors with a family history of certain illnesses may proactively request specific biomarkers as part of routine blood work during physical exams. For those without a known family history of disease, testing for common inflammatory biomarkers can still be beneficial.
 
Given the recommendation for annual physical examinations for individuals aged 50 and older, incorporating a complete blood count (CBC) alongside key inflammatory biomarkers could facilitate the early detection and management of age-related conditions.

Table 1. Comprehensive but not necessarily exhaustive list of inflammatory biomarkers
 
Blood cell-derived

1. White Blood Cell Count (WBC)
2. Neutrophil-to-Lymphocyte Ratio (NLR)
3. Platelet-to-Lymphocyte Ratio (PLR)
4. Eosinophil Count
5. Basophil Count
6. Erythrocyte Sedimentation Rate (ESR)

 
Blood proteins
 
Cytokines

1. Interleukin-6 (IL-6)
2. Tumor Necrosis Factor-alpha (TNF-alpha)
3. Interleukin-1 beta (IL-1β)
4. Interleukin-8 (IL-8)
5. Monocyte Chemoattractant Protein-1 (MCP-1)

 
Adhesion proteins

1. Soluble Intercellular Adhesion Molecule-1 (sICAM-1)
2. Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1)
3. Soluble E-Selectin (sE-Selectin)
4. Soluble P-Selectin (sP-Selectin)

 
Enzymes

1. Lactate Dehydrogenase (LDH)
2. Lipoprotein-associated Phospholipase A2 (Lp-PLA2)
3. Myeloperoxidase (MPO)

 
Others

1. C-Reactive Protein (CRP)
2. High-Sensitivity CRP (hs-CRP)
3. Fibrinogen
4. Ferritin
5. S100 Proteins (e.g., S100A8, S100A9)
6. Pentraxin 3 (PTX3)

 
Pteridine derivative

1. Neopterin

 

​Early detection is part of preventive medicine, it helps manage and mitigate the development of diseases that are commonly associated with advancing age. Before discussing the benefits of tracking systemic inflammation with biomarkers with your primary care doctor, it is essential to weigh the pros and cons.
 
Pros:
 
1.Early detection of chronic inflammation: Systemic inflammation is associated with various age-related diseases, such as cardiovascular disease, diabetes, and cancer.
2.Risk stratification: Inflammatory biomarkers can help identify individuals at higher risk of developing age-related diseases.
3.Targeted interventions: Monitoring inflammation allows for tailored interventions, such as lifestyle modifications or pharmacological treatments, to reduce inflammation and disease risk.
4.Monitoring disease progression: Inflammatory biomarkers can track disease progression and treatment efficacy.
 
Cons:
 
1.Limited specificity: Inflammatory biomarkers are not specific to a single disease or condition, making interpretation challenging.
2.Variability: Inflammatory biomarker levels can fluctuate due to various factors, such as infections, stress, or medications.
3.Lack of standardization: Different assays and cut-off values can lead to inconsistent results.
4.Cost and resource utilization: Regular monitoring of inflammatory biomarkers may increase healthcare costs and resource utilization.
5.Uncertainty about treatment benefits: The effectiveness of anti-inflammatory interventions in preventing age-related diseases is still unclear.

The following biomarkers are most prescribed during regular annual check-ups: C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR) and White Blood Cell Count (WBC). The popularity of these three biomarkers is due to the recommendations of medical societies and government agencies. They are well established, widely available, inexpensive, and easy to interpret.
 
C-Reactive Protein (CRP)
 
The weblink provides a more thorough discussion on C-Reactive Protein. For this discussion, suffice to know there are two types of C-Reactive Protein your doctor could prescribe: C-reactive protein (CRP) and high-sensitivity C-reactive protein (hs-CRP). They are both biomarkers of systemic inflammation, but differ in their sensitivity and clinical applications:
 
C-Reactive Protein (CRP):
 
1.Measures CRP levels above 1 mg/dL
2.Indicates acute inflammation or infection.
3.Used to diagnose and monitor conditions like bacterial infections, sepsis, and acute inflammatory diseases.
 
High-Sensitivity C-Reactive Protein (hs-CRP):
 
1.Measures CRP levels as low as 0.03 mg/dL
2.Detects chronic, low-grade inflammation.
3.Used to assess cardiovascular risk, monitor chronic inflammatory diseases, and predict disease progression.
 
Key differences:
 
1.Sensitivity: hs-CRP is more sensitive than CRP, allowing for detection of lower CR P levels.
2.Clinical application: CRP is for acute inflammation, while hs-CRP is for chronic inflammation and cardiovascular risk assessment.
3.Thresholds: CRP typically uses a threshold of 1 mg/dL, while hs-CRP uses thresholds of 0.1-0.3 mg/dL for cardiovascular risk stratification.
 
In summary, CRP is for acute inflammation, while hs-CRP is for chronic inflammation and cardiovascular risk assessment, allowing for earlier detection and intervention. The latter is more appropriate for tracking low grade systemic inflammation in older adults and geriatric.
 
Reference range [1,2]:
 
The normal reference ranges for C-reactive protein (CRP) and high-sensitivity CRP (hs-CRP) could vary depending on sources < 1mg/dL [1] or <0.5mg/dL [2]
 
For cardiac risk stratification:
Low: < 1.0 mg/dL
Average: 1.0-3.0 mg/dL
High: > 3.0 mg/dL
 
References
[1] Pagana KD, Pagana TJ, Pagana TN. Mosby’s Diagnostic and Laboratory Test Reference. 14th ed. St. Louis, MO: Elsevier; 2019. 295.
[2] ] Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
White Blood Cell Count (WBC)
 
Leukocytosis, or an elevated white blood cell (WBC) count, is a common physiological response to inflammation, infection, or tissue injury. While total WBC count can serve as a general indicator of inflammation, it has significant limitations. Factors such as stress, physical activity, or medications can also elevate WBC levels, reducing its specificity as an inflammation marker. Additionally, its sensitivity is limited, as a normal WBC count does not necessarily rule out chronic or low-grade inflammation. These limitations make WBC count a biomarker with low predictive value for inflammation. Moreover, WBC count alone cannot provide insight into the severity or specific nature of the inflammatory response.
 
WBC normal reference range*: 4000-10,000 per mcL
* Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
In modern medical practice, the assessment of inflammation rarely relies on WBC count alone. Instead, it is typically measured as part of a Complete Blood Count (CBC), which includes a differential white blood cell count. This differential provides more detailed information on lymphocytes, neutrophils, platelets, monocytes, eosinophils, and basophils. These additional data points enable clinicians to evaluate more sensitive inflammatory markers, such as the neutrophil-to-lymphocyte (N/L) ratio and the platelet-to-lymphocyte (P/L) ratio, as shown in Table 1. Other relevant biomarkers will be discussed in subsequent sections.

​ Neutrophil-to-Lymphocyte Ratio (NLR) [1]
 
The neutrophil-to-lymphocyte ratio (NLR), which reflects both innate and adaptive immune responses, is a more specific and sensitive marker of systemic inflammation. Clinicians frequently use NLR to monitor conditions such as sepsis, pneumonia (including COVID-19 pneumonia), cardiovascular disease, cancer, and major depressive disorder. Surgeons also employ NLR as a prognostic tool for assessing the risk of post-operative complications. For a detailed discussion of NLR, including guidelines for its use and references to relevant literature, please refer to the provided weblink.

Forget P. et al. [3] recently reported that the average NLR in healthy individuals is 1.65, with a lower limit of 0.78 and an upper limit of 3.53, based on 95% confidence intervals. When compared to standard hematological ranges [4], the calculated lower and upper limits for NLR are 1.67 and 2.0, respectively.
 
References
[1] Buonacera A, Stancanelli B, Colaci M and Malatino L. Neutrophil to Lymphocyte Ratio: An Emerging Marker of the Relationships between the Immune System and Diseases. Int. J. Mol. Sci. 2022; 23(7), 3636; https://doi.org/10.3390/ijms23073636
[2] Mazza MG, Lucchi S, Tringali AGM, Rosetti A, Botti ER, Clerici M. Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: A meta-analysis. Progress in Neuropsychopharmacology & Biological Psychiatry 2018; 84, 229-236. https://doi.org/10.1016/j.pnpbp.2018.03.012
[3] Forget P, Khalifa C, Defour J-P, Latinne D, Van Pel M-C & De Koch M. What is the normal value of the neutrophil-to-lymphocyte ratio? BMC Research Notes 2017; 10, 12. https://doi.org/10.1186/s13104-016-2335-5
[4] Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD. Medscape.
 
Platelet-to-Lymphocyte Ratio (PLR) [1]
 
In addition to their primary role in hemostasis (blood clot formation), platelets are actively involved in both innate and adaptive immunity. First, blood clotting forms a physical barrier against invading pathogens, indirectly supporting immune defense. Platelets also participate in a process known as immune thrombosis, where they collaborate with neutrophils and monocytes to control the spread of infection through targeted clot formation. At sites of injury or infection, platelets interact with leukocytes, contributing to inflammation by secreting cytokines, chemokines, and other inflammatory mediators.
 
In adaptive immunity, platelets express receptors for IgG on their surface. By binding to IgG-opsonized target cells, they release reactive oxygen species, host defense peptides, and proteases, facilitating direct pathogen destruction. Given their diverse immunological roles, the platelet-to-lymphocyte ratio (PLR) serves as a valuable marker for assessing inflammation.
 
Elevated PLR has been linked to a range of diseases, particularly in cardiovascular health (e.g., all phases of coronary artery disease [2,3], atherosclerosis, arrhythmias, valvular disease, myocardial infarction, heart failure, peripheral arterial disease, and acute ischemic stroke), rheumatic conditions (e.g., rheumatoid arthritis, systemic lupus erythematosus [4]), neurological disorders (e.g., bipolar disorder [5-7], attention deficit hyperactivity disorder (ADHD) [6], traumatic brain injury [8]), metabolic diseases (e.g., insulin resistance and type 2 diabetes), infectious diseases (e.g., predicting the severity of COVID-19), and various cancers (e.g., ovarian, cervical, prostate, and advanced-stage cancers).
 
Conversely, a low PLR indicates the absence of a proinflammatory or prothrombotic state. It may also be indicative of thrombocytopenia.
 
Based on clinical experience, the standard PLR for a healthy individual is typically less than 150 [1]. According to standard hematological ranges [9], the calculated lower and upper limits are 73 and 150, respectively.
 
References
[1] Biomarkers of Inflammation: Platelet/Lymphocyte Ratio (PLR). ODX Research
[2] Yüksel M, Yildiz A, Oylumlu M, Akyüz A, Aydin M, Kaya H, Acet H, Polat N, Bilik MZ, Alan S. The association between platelet/lymphocyte ratio and coronary artery disease severity. The anatolian journal of cardiology. 2015;15, 640.
[3] Akboga MK, Canpolat U, Yayla C, Ozcan F, Ozeke O, Topaloglu S, Aras D. Association of platelet to lymphocyte ratio with inflammation and severity of coronary atherosclerosis in patients with stable coronary artery disease. Angiology. 2016; 67, 89-95.
[4] El Said NY, El Adle S, Fathi HM. Clinical significance of platelet-lymphocyte ratio in systemic lupus erythematosus patients: Relation to disease activity and damage. The Egyptian Rheumatologist 2022; 44, 224-229. https://doi.org/10.1016/j.ejr.2021.12.005
[5] Kalelioglu T, Akkus M, Karamustafalioglu N, Genc A, Genc ES, Cansiz A, Emul M. Neutrophil-lymphocyte and platelet-lymphocyte ratios as inflammation markers for bipolar disorder. Psychiatry Res. 2015; 228, 925-927. http://dx.doi.org/10.1016/j.psychres.2015.05.110
[6] Mazza MG, Lucchi S, Tringali AGM, Rosetti A, Botti ER, Clerici M. Neutrophil/lymphocyte ratio and platelet/lymphocyte ratio in mood disorders: A meta-analysis. Progress in Neuropsychopharmacology & Biological Psychiatry 2018; 84, 229-236. https://doi.org/10.1016/j.pnpbp.2018.03.012
[5] Fusar-Poli L, Natale L, Amerio A, Cimpoesu P, Filioli PG, Aguglia E, Amore M, Serafini G and Aguglia A. Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte and Monocyte-to-Lymphocyte Ratio in Bipolar Disorder. Brain Sci. 2021; 11, 58. https://doi.org/10.3390/brainsci11010058
[7] Avcil S. Evaluation of the neutrophil/lymphocyte ratio, platelet/ lymphocyte ratio, and mean platelet volume as inflammatory markers in children with attention-deficit hyperactivity disorder. Psychiatry and Clinical Neurosciences 2018; 72: 522–530. doi:10.1111/pcn.12659
[8] Li W & Deng W. Platelet‑to‑lymphocyte ratio predicts short‑term mortality in patients with moderate to severe traumatic brain injury. Nature Scientific Reports 2022; 12:13976. https://doi.org/10.1038/s41598-022-18242-4
[9] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
 
Absolute Monocyte Count, Monocyte-to-Lymphocyte Ratio (MLR) and Lymphocyte-to-Monocyte Ratio (LMR)
 
Circulating monocytes play a crucial role in both the innate and adaptive immune systems. Upon migrating into tissues, monocytes differentiate into macrophages and dendritic cells, key mediators of chronic inflammation, tissue repair, and immune regulation. In addition to their differentiation, monocytes can perform phagocytosis, present antigens by incorporating antigen fragments into MHC molecules for T-cell activation, and produce cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-12. These functions enable monocytes to be actively involved in the immune response. They are also critical during the resolution phase of inflammation, helping to clear cellular debris and promote tissue healing.
 
Given their pivotal role in inflammation, the Absolute Monocyte Count (AMC), the Monocyte-to-Lymphocyte Ratio (MLR), and its inverse, the Lymphocyte-to-Monocyte Ratio (LMR), have proven to be valuable diagnostic and prognostic biomarkers for various diseases.
 
Excess monocytes in peripheral blood (monocytosis) could be attributed to many disease states. For example, chronic inflammation, sepsis, necrosis, diabetes, atherosclerosis, stress response, Cushing’s Syndrome, immune diseases, viral fever, sarcoidosis and chronic myelomonocytic leukemia. On the other hand, very low monocyte count (monocytopenia) is often associated with immune suppressive therapy with glucocorticoid.
 
Reference monocytes count in healthy individuals ranges from 200-800 per microliter. [1]
 
Over the last decade the Monocyte-to-Lymphocyte ratio (MLR) and the Lymphocyte-to-Monocyte Ratio (LMR) were found to be diagnostic or prognostic for many disease states including cancer (e.g. solid tumors [2], prostate cancer [3], hepatocellular carcinoma [4], non-small cell lung cancer [5], all cancer mortality [6]), Type 2 diabetes [7], Parkinson’s disease [8], chronic kidney disease [9], coronary artery disease [10] and many others.
 
A normal MLR in healthy individuals typically ranges from 0.1 to 0.3, although reference values may vary slightly depending on the laboratory and population studied. According to standard hematological ranges [11], the calculated lower and upper limits are 0.17 and 0.20, respectively.
 
MLR values that tend to be associated various level of inflammation can be broken down as follows:
 
- Normal MLR: 0.1-0.3
- Mild inflammation MLR: 0.3-0.5
- Moderate inflammation MLR: 0.5-0.8
- Severe inflammation MLR: >0.8
 
While keeping in mind that MLR can fluctuate due to various factors, such as: age, sex, time of day, physical activity, infections and medications.
 
For studies considering LMR, the above ranges are inverted as LMR = 1/MLR:
Normal LMR range: 10-3.33
Normal LMR calculated from hematological standards: 5.88-5.00
Mild inflammation MLR: 3.33-2.00
Moderate inflammation MLR: 2.00-1.25
Severe inflammation MLR: <1.25
 
References
[1] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
[2] Nishijima T, Muss HB, Shachar SS, Tamura K and Takamatsu Y. Prognostic value of lymphocyte-to-monocyte ratio in patients with solid tumors: A systematic review and meta-analysis.  
[3] Wang L, Li X, Liu M, Zhou X and Shao J. Association between monocyte-to-lymphocyte ratio and prostate cancer in the U.S. population: a population-based study. Front. Cell Dev. Biol. 2024; 12,1372731.  https://doi.org/10.3389/fcell.2024.1372731
[4] Minici R, Venturini M, Guzzardi G, Fontana F, Coppola A, Piacentino F, Torre F, Spinetta M, Maglio P, Guerriero P et al. A Multicenter International Retrospective Investigation Assessing the Prognostic Role of Inflammation-Based Scores (Neutrophil-to-Lymphocyte, Lymphocyte-to-Monocyte, and Platelet-to-Lymphocyte Ratios) in Patients with Intermediate-Stage Hepatocellular Carcinoma (HCC) Undergoing Chemoembolizations of the Liver. Cancers 2024; 16, 1618. https://doi.org/10.3390/cancers16091618
[5] Tanaka H, Ono T, Kajima M, Manabe Y, Fujimoto K, Yuasa Y, Shiinoki  and Matsuo M. Reports of Practical Oncology and Radiotherapy 2024; 29, 228–235. DOI: 10.5603/rpor.100168
[6] Yang L, Sun X, Chen S, Shao H. Lymphocyte-to-Monocyte Ratio: A Simple and Effective Inflammation Marker in Predicting Mortality of Non-Institutionalized Americans with Cancers. Academic Journal of Medicine & Health Sciences 2024; 5, 71-9.
[7] Dayama N, Yadav SK, Saxena P, Sharma A, Kashnia R and Sharda K. A Study of Relationships between the HbA1c Level and Inflammatory Markers, Neutrophil-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Controlled and Uncontrolled Type 2 Diabetes Mellitus. J Assoc Physicians India 2024; 72, 24–26.
[8] Li F, Weng G, Zhou H, Zhang W, Deng B, Luo Y, Tao X, Deng M, Guo H, Zhu S and Wang Q. The neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and neutrophil-to-high-density-lipoprotein ratio are correlated with the severity of Parkinson’s disease. Front. Neurol. 2024 ; 15,1322228. doi: 10.3389/fneur.2024.1322228
[9] Liu W, Weng S, Cao C, Yi Y, Wu Y, & Peng D (). Association between monocyte-lymphocyte ratio and all-cause and cardiovascular mortality in patients with chronic kidney diseases: A data analysis from national health and nutrition examination survey (NHANES) 2003-2010. Renal Failure 2024; 46(1). https://doi.org/10.1080/0886022X.2024.2352126
[10] Vakhshoori M, Nemati S, Sabouhi S, et al. Prognostic impact of monocyte-to-lymphocyte ratio in coronary heart disease: a systematic review and meta-analysis. Journal of International Medical Research. 2023; 51(10). doi:10.1177/03000605231204469
[11] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
 
The Systemic Inflammatory Index (SII) and the Systemic Inflammation Response Index (SIRI)
 
Since clinicians typically make diagnostic or prognostic assessments within a broader clinical context, rather than relying on a single biomarker, there has been a growing interest in combining multiple inflammatory markers into a single index. Over the past decade, pioneering researchers have developed and validated the Systemic Inflammatory Index (SII) and the Systemic Inflammatory Response Index (SIRI) for use across a wide range of medical conditions [1].
 
The Systemic Inflammatory Index (SII) integrates neutrophil (N), lymphocyte (L), and platelet (P) counts into a single metric, calculated as SII = (N/L) * P. Based on standard hematological ranges [2], the normal SII range for healthy individuals is estimated to be between 300 and 583. This range aligns with findings from studies comparing SII values in healthy controls versus those in individuals with immune-related diseases, as shown in the tables below, adapted from Table 1 of Mangoni AA & Zinellu A [3].
 

The Systemic Inflammation Response Index (SIRI), on the other hand, combines neutrophil (N), lymphocyte (L), and monocyte (M) counts into a single metric, calculated as SIRI = (N/L) * M. Originally developed as a prognostic tool for cancer, SIRI's diagnostic and prognostic value has since been expanded to other diseases characterized by inflammation [1].
A universally defined "normal" reference range for SIRI in healthy individuals has yet to be established, as most studies have focused on its use in clinical settings involving abnormal inflammatory responses, such as infections, malignancies, or other inflammatory conditions. However, in healthy individuals, SIRI values tend to be low due to the balanced levels of neutrophils, monocytes, and lymphocytes. For clinical purposes, studies suggest that a SIRI value below 1 is indicative of a healthy, non-inflammatory state, while higher values signal a stronger systemic inflammatory response. Based on standard hematological ranges [2], the estimated normal range for SIRI in healthy individuals is between 0.40 and 1.33.
 
References
[1] Islam MM, Satici MO, Eroglu SE. Unraveling the clinical significance and prognostic value of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, systemic inflammation response index, and delta neutrophil index: An extensive literature review. Turkish Journal of Emergency Medicine. 2024; 24, 8-19. DOI: 10.4103/tjem.tjem_198_23
[2] Medscape: Laboratory Reference Ranges in Healthy Adults. Updated: Apr 20, 2024
Author: Abimbola Farinde, PharmD, PhD.
[3] Mangoni AA, Zinellu A. The diagnostic role of the systemic inflammation index in patients with immunological diseases: a systematic review and meta-analysis. Clinical and Experimental Medicine. 2024; 24, 27. https://doi.org/10.1007/s10238-024-01294-3
 
Erythrocyte Sedimentation Rate (ESR)
 
The erythrocyte sedimentation rate (ESR) is not typically included in routine physical examinations unless your healthcare provider suspects the presence of infection or inflammation. However, if your lab results include this test, the following information will help you understand its significance.
 
ESR is a widely used blood test that measures how quickly red blood cells (erythrocytes) settle at the bottom of a test tube over a given period, typically one hour. In the presence of inflammation, red blood cells tend to clump together and settle more rapidly. Clinicians use the ESR test to evaluate and monitor the presence of inflammation in the body, which can be associated with various disease states.
 
Mechanism of ESR [1]: The principle behind the ESR test is that certain proteins produced during inflammation, especially fibrinogen and immunoglobulins, promote the aggregation of red blood cells, making them fall more rapidly in a column of blood. The faster the sedimentation rate, the higher the likelihood of an inflammatory process occurring in the body. While the ESR is a non-specific test, meaning it does not pinpoint the exact cause or location of inflammation, it provides valuable information about the presence and intensity of inflammatory processes.
 
Clinical Uses of ESR: Clinicians use the ESR test to assess a range of conditions characterized by inflammation, including:

• Infections: Bacterial infections or chronic infections like tuberculosis often result in elevated ESR levels.
• Autoimmune diseases: Conditions like rheumatoid arthritis, lupus, and vasculitis are associated with increased ESR.
• Chronic inflammatory diseases: Clinicians routinely use ESR to monitor diseases like inflammatory bowel disease (IBD), polymyalgia rheumatica, and giant cell arteritis.
• Cancer: Malignancies, particularly lymphoma and multiple myeloma, may cause a high ESR.

While ESR alone does not diagnose these conditions, healthcare providers often used it alongside other tests and clinical evaluations to support a diagnosis, assess disease activity, or monitor treatment effectiveness.
 
Normal ESR Ranges: ESR values can vary based on age and sex:

• Males:
  • Under 50 years: 0–15 mm/hour
  • Over 50 years: 0–20 mm/hour
• Females:
  • Under 50 years: 0–20 mm/hour
  • Over 50 years: 0–30 mm/hour

Clinicians consider values above these ranges elevated that may warrant further investigation.
 
 Pathologically Elevated ESR: A significantly elevated ESR, particularly values above 50 mm/hour, suggests a systemic inflammatory response and may point to underlying pathology. Extreme elevations, such as over 100 mm/hour, are often associated with serious conditions like:

• Severe infections (e.g., endocarditis, osteomyelitis)
• Autoimmune diseases in active flares
• Advanced malignancies

However, a high ESR is non-specific and could be the result of various benign conditions such as pregnancy, anemia, or even during menstruation, making clinical context crucial for interpretation.
 
Low ESR: Conditions like polycythemia (increased number of red blood cells) or certain blood disorders could result in lower-than-normal ESR. However, a low ESR is less common and typically not a concern unless accompanied by other symptoms.
 
Limitations: While ESR is useful for assessing inflammation, it has a key limitation: It is a non-specific marker. Factors unrelated to inflammation, such as anemia, kidney disease, or even high cholesterol levels can influence the sedimentation rate. As a result, clinicians often use ESR in conjunction with other markers of inflammation, like C-reactive protein (CRP), which responds more quickly to acute inflammatory changes and is often more specific.
In summary, the ESR test is a valuable tool in clinical practice for assessing inflammation. Its simplicity and low cost make it an excellent initial screening test. The lack of specificity requires interpretation of the result within the context of other clinical findings and diagnostic tests.
 
Reference
[1] Fabry TL. Mechanism of Erythrocyte Aggregation and Sedimentation. Blood 1987; 70, 1572-1576. https://doi.org/10.1182/blood.V70.5.1572.1572

​Patient X is a 73-year-old Southeast Asian male with a BMI of 24.8 and a Waist-to-Height Ratio (WHtR) of 0.51. The patient has a history of benign hypertension, hyperlipidemias (borderline high cholesterol and high triglycerides), and periodic gout attacks starting at the age of forty. Consultation with a cardiologist resulted in the initiation of drug treatment:
 
Rx2004: Fenofibrate (Antara) 130 mg QD and Valsartan 80 mg QD initiated ca. October 2004.
 
Rx2007: Vytorin 10/20 QD added ca. November 2007.
 
Rx2012: In the third quarter of 2011the patient was diagnosed with cholelithiasis and underwent cholecystectomy April 2012. A new primary care doctor withdrew both Fenofibrate and Vytorin.
 
Rx2015: 10 mg atorvastatin QD introduced ca. July 2015.
 
Rx 2017: Consultation with a Rheumatologist resulted in the prescription of 200 mg allopurinol QD.
 
The gout flares stopped after treatment with allopurinol.
 
The patient provided CBC data for studies from 1989 to present time. Below are the plots of NLR, PLR, Platelet counts, MLR, SII and SIRI over time.
 
 

​Please note the drop in platelet counts after cholecystectomy and withdrawal of fenofibrate and Vytorin (Rx2012). Administration of atorvastatin (Rx2015) and allopurinol (Rx2017) further lowered the platelet counts over time, likewise for the PLR and SII. MLR and SIRI were unremarkable except for four outliers possibly due to seasonal cold/flu infections.

Case study 2

Patient Y, is a 74-year-old Southeast Asian male with a BMI of 27.8 and a Waist-to-Height Ratio (WHtR) of 0.59. The patient has a history of syncope, hypertension, hyperlipidemia, diabetes and prostatic hypertrophy (PSA level: 14 ng/mL) and was treated with metoprolol starting in 2003, atorvastatin in 2011, metformin in 2018 and Ozempic in March 2024. His most recent (8/24/2024) differential white blood cell count (eosinophils and basophils excluded) was unremarkable with all counts falling within normal range:

​The corresponding NLR, PLR, MLR, SII and SIRI inflammatory biomarkers are shown below: 

​All five inflammatory biomarkers, NLR, PLR, MLR, SII and SIRI, from Patient Y were higher than expected from normal ranges, potentially supporting systemic inflammation from unresolved disease state.

Case Study 3

​Patient Z is a 69-year-old male. At age 67 he was diagnosed with poorly differentiated peritoneal adenocarcinoma, possibly of hepatic origin. That same year he was treated by cytoreductive surgery followed by HIPEC (hyperthermic intraperitoneal chemotherapy). Post surgery pathology work-up confirmed the diagnosis of hepatocellular carcinoma with peritoneal metastases. Unresectable hepatic tumor masses were treated four months later by two rounds of chemoembolization with doxorubicin. The patient was stable and functional for at least 6 months when relapse was evidenced by a strong resurgence in blood level of alpha-fetoprotein (AFP). He subsequently underwent five additional rounds of chemoembolization over a 6-month period, with gradual decreasing level of effectiveness as the tumors gained additional vascularization and became refractory to the procedure. Chemoembolization was then replaced by biologics treatment with a combination of Tecentriq and Avastin to boost immune response and block angiogenesis. Six infusions were performed over an 18-week period. Therapy was then discontinued since the tumor continued to grow slowly while the patient developed serious abdominal discomfort, gastrointestinal distress, and profuse peritoneal ascites. The patient was placed under palliative care and succumbed to the disease nine months later at age 69.

For a year from the beginning of biologics therapy to the end, the patient was continuously monitored for Complete Blood Count including differential white cell counts, Comprehensive Metabolic Panel, tumor biomarkers, and C-Reactive Protein. The data set allowed for a side-by-side comparison of the performance of the inflammatory C-Reactive Protein biomarker against the systemic inflammatory biomarkers derived from differential white cell counts. The results are summarized in the time plots shown below:

​All five biomarkers derived from differential white cell counts trended similarly as C-Reactive Protein albeit the sensitivity of MLR and SIRI were weaker compared to the others in detecting higher than normal levels (indicated by horizontal arrow on the corresponding Y-axes). This distinction could reflect the separate roles of neutrophils, platelets, and monocytes in response to tumor growth and biologics therapy.

Article about "Inflammaging" in the news media
Inflammaging is chronic, stealthy and can be a serious threat to your health
Wall Street Journal, Health/Wellness section, October 7, 2024

​Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease characterized by the immune system's attack on the body's own tissues, leading to widespread inflammation and tissue damage. The exact cause remains multifactorial, involving genetic, hormonal, and environmental factors. This multi-systemic disorder affects women (9:1 ratio), especially those of childbearing age, and is more prevalent in certain ethnic groups, including African Americans, Hispanics, and Asians. The typical onset age is between 15-45.
 
Epidemiologically, SLE affects 20-150 individuals per 100,000 worldwide, with significant variation based on geographic and ethnic factors. The mortality rate for SLE patients has improved with advancements in treatment; however, it remains two to three-fold higher compared to the general population, primarily due to complications such as cardiovascular disease, infections, and renal involvement.
 
The burden of SLE on patients and the medical community is substantial. Patients often experience a range of debilitating symptoms including fatigue, joint pain, skin rashes, and organ dysfunction, which can significantly impact their quality of life. The medical community faces challenges in diagnosing and managing SLE due to its heterogeneous presentation and the need for long-term, multidisciplinary care. The economic burden is also considerable, encompassing direct medical costs, such as hospitalizations and medications, and indirect costs related to loss of productivity and disability.
 
Comprehensive coverage of this subject is beyond the scope of our efforts. The leading information sources on Lupus include:
The CDC-Lupus
National Resource Center on Lupus
The Lupus Initiative
The Lupus Foundation of America
 
Medscape also provides an excellent write-up on the subject: Systemic Lupus Erythematosus (SLE)
 
Here we will focus on preventive aspects, which consist of managing risk factors. We will also examine the latest clinical trials of new therapeutics reflecting potential advances benefiting patients.

​Since the cause of the disease is multifactorial with both genetic, viral, bacterial, and environmental components, potentially predisposed individuals should pay attention to all of them.
 
Genetic components
Contribution from genetics predates the advances in genotyping, whole genome sequencing and genome wide association studies. The disease is known for its high heritability, 66%. Twin studies showed concordance rates of 24-56% versus 2-5% in monozygotic (identical) and dizygotic twins, respectively. Sibling recurrence studies showed that the risk ratio is between 8 to 29 [1]. On that basis alone, the existence of a relative suffering from Lupus should be a warning about potential predispositions to the disease. Moreover, the predisposition risk is proportional to the degree of relatedness to the patient. The predisposed individual could work with a primary care doctor to establish a surveillance program to address the risk. From a scientific point of view, genotyping to identify the major SLE risk alleles and establish a polygenic risk score could be informative in determining a proper course of action. Engaging a genetic counselor to work in concert with the primary care doctor could be highly productive.
 
 
Viral infections
The link between virus infections and SLE is well established. Most notably were infections by Epstein-Barr (EBV) virus, Cytomegalovirus (CMV), Parvovirus B19 and the retroviruses [2]. Anecdotal reports have also linked Dengue virus, Hepatitis C and Covid 19 infections to SLE [3-5]. Monitoring for these infections and implementing vaccinations as recommended by the CDC or American College of Rheumatology (ACR) should be part of any surveillance program for predisposed individuals.
 
Gut microbiota:
Multiple studies have reported on the imbalance in the gut microbiota (dysbiosis) of SLE patients compared to healthy controls [6]. Despite marked geographical differences reflecting local diets and eating habits, at least two common denominators were associated with SLE dysbiosis: an decrease in overall biodiversity accompanied by a low ratio of Firmicutes to Bacteroidetes (Low F:B ratio). These conditions favor disruption of the intestinal barrier (leaky gut) and translocation of symbionts and pathobionts (notably Lachnospiraceae, Enterococcus gallinarum, Ruminococcus gnavus and Lactobacillus reuteri) into the lamina propria resulting in local inflammation and induction of autoantibodies via antigen mimicry. Considering that the current treatment regimen for SLE remains unsatisfactory, targeting the gut microbiota is attracting significant interest. Intervention through diet, probiotics, and fecal microbiota transplantations (FMT) are all under investigation to improve clinical outcome. Preliminary small single arm clinical trials have demonstrated the potential utility of FMT [7]. At the current stage of development determining the level of dysbiosis in predisposed patients could be useful for assessing the course of the disease before the appearance of symptoms. All attempts to correct the dysbiosis by diet, probiotics or FMT, remain at the experimental stage under strict medical supervision.
 
Environmental factors
A sound understanding of the risks discussed above sets the stage for managing known environmental triggers. It would be difficult to rank-order the most significant trigger for everyone since the clinical presentation of the disease is complex and varies depending on individuals. Nevertheless, individuals predisposed to SLE need to be on high alert for the most significant triggers including:
 
Exposure to occupational and non-occupational chemicals: Multiple studies have implicated exposure to certain chemicals to the development of SLE. Industrial and agricultural workers were most affected. These chemicals include silica & silicates, pesticides (especially polychlorinated biphenyls and dibenzofurans), industrial solvents, and heavy metals (especially lead and mercury) [8, 9, 12 &13].
 
Smoking: The effect of cigarette smoking on the development and exacerbation of Lupus fueled debates for years due to conflicting study results. Nevertheless, most recent reviews and meta-analyses of the data suggest that smoking exposure not only increases SLE disease risk but also affected progression and treatment [8-10, 14].
 
UV and sun exposure: There is ample clinical evidence demonstrating a clear relationship between excessive sun exposure, especially exposure to UV-B range, and the development of different variant forms of Lupus and subsequent flares. Moreover, photosensitivity is known as a key factor in the pathogenesis of the disease [8-11].
 
Medications: the fact that certain medications could induced a variant type of Lupus known as DIL (Drug-Induced Lupus) was known since 1945 [16]. Unlike other forms of Lupus, DIL tends to resolve upon discontinuation of the drug [17]. Over the years, the list of DIL medications grew longer. A recent study of the World Health Organization pharmacovigilance data base [18] identified 118 medications where procainamide, hydralazine and three TNF-alpha inhibitors (infliximab, adalimumab, etanercept) featured prominently as being most associated with DIL.
 
Sex hormone therapy: It is a special case of medications triggering the onset of SLE. A large 10-year cohort study showed dose dependent increased risk in susceptible women who just started combined oral contraceptives [19]. In transgender women receiving sex hormones before and after sex reassignment surgery the risk also increased [20-24]. Interestingly, the contraceptives did not affect the course of the disease in women who already had active but stable Lupus, except for those with medium or elevated level antiphospholipid (aPL) antibodies [9].

References
[1] Deng Y, Tsao BP. Genetic susceptibility to systemic lupus erythematosus in the genomic era. Nat Rev Rheumatol. 2010;6(12):683-692. doi: 10.1038/nrrheum.2010.176.
[2] Blank M, Schoenfeld Y & Perl A. Cross-talk of the environment with the host genome and the immune system through endogenous retroviruses in systemic lupus erythematosus. Lupus 2009; 18: 1136-1143.
[3] Rajadhyaksha A, Mehra S. Dengue fever evolving into systemic lupus erythematosus and lupus nephritis: a case report. Lupus. 2012;21: 999-1002. doi:10.1177/0961203312437807
[4] Sayiner ZA, Haque U, Malik MU, Gurakar A. Hepatitis C virus infection and its rheumatologic implications. Gastroenterol Hepatol (N Y). 2014;10: 287-93.
[5] Zamani, B., Moeini Taba, SM. & Shayestehpour, M. Systemic lupus erythematosus manifestation following COVID-19: a case report. J Med Case Reports. 2021;15,29. https://doi.org/10.1186/s13256-020-02582-8
[6] Toumi E, Mezouar S, Plauzolles A, et al. Gut microbiota in SLE: from animal models to clinical evidence and pharmacological perspectives. Lupus Science & Medicine. 2023;10: e000776.
doi: 10.1136/lupus-2022-000776
[7] Huang C and Yi P, Zhu M et al. Safety and efficacy of fecal microbiota transplantation for treatment of systemic lupus erythematosus: An EXPLORER trial. Journal of Autoimmunity. 2022; 130: 102844. doi.org/10.1016/j.jaut.2022.102844
[8] Refai RH, Hussein MF, Abdou MH & Abou‑Raya AN. Environmental risk factors of systemic lupus erythematosus: a case–control study. Nature Scientific Reports. 2023; 13:10219. https://doi.org/10.1038/s41598-023-36901-y
[9] Cardelli C, Zucchi D, Elefante E, Signorini V, Menchini M, Stagnaro C, Mosca M & Tani C. Environment and systemic lupus erythematosus. Clinical and Experimental Rheumatology. 2024; 42: 1104-1114.
[10] Bengtsson AA, Rylander L, Hagmar L, Nivet O & Sturfelt G. Risk factors for developing systemic lupus erythromatosus: a case-controlled study in southern Sweden. Rheumatology 2002; 41: 563-571.
[11] Kuhn A, Wenzel J & Weyd H. Photosensitivity, Apoptosis, and Cytokines in the Pathogenesis of Lupus Erythematosus: a Critical Review. Clinic Rev Allerg Immunol. 2014; 47:148–162. https://doi.org/10.1007/s12016-013-8403-x
[12] Tsai P-C, Ko Y-C, Huang W, Liu H-S & Guo L. Increased liver and lupus mortalities in 24-year follow-up of the Taiwanese people highly exposed to polychlorinated biphenyls and dibenzofurans. Science of the Total Environment. 2007; 374: 216–222.
[13] Parks CG & De Roos AJ. Pesticides, chemical and industrial exposures in relation to systemic lupus erythematosus. Lupus. 2014; 23: 527–536. doi:10.1177/0961203313511680.
[14] Mak A & Tay SH. Environmental Factors, Toxicants and Systemic Lupus Erythematosus. Int. J. Mol. Sci. 2014; 15: 16043-16056. https://doi.org/10.3390/ijms150916043
[15] Arnaud L, Mertz P, Gavand P, et al. Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database. Annals of the Rheumatic Diseases. 2019;78:504-508.
[16] Hoffman BJ. Sensitivity to sulfadiazine resembling acute disseminated lupus erythematosus. Arch Dermatol Syphilol 1945; 51:190–192.
[17] Kaufman CL & Quiroz EH. Drug-Induced Lupus Erythematosus. Medscape. 2020; 1065086. https://emedicine.medscape.com/article/1065086-overview
[18] Arnaud L, Mertz P, Gavand PE et al. Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database. Ann Rheum Dis 2019; 78: 504-8. https:// doi.org/10.1136/annrheumdis-2018-214598
[19] Bernier MO, Mikaeloff Y, Hudson M et al. Combined oral contraceptive use and the risk of systemic lupus erythematosus. Arthritis Rheum. 2009; 61: 476-81. https://doi.org/10.1002/art.24398
[20] Santos-Ocampo AS. New onset systemic lupus erythematosus in a transgender man: possible role of feminizing sex hormones. J Clin Rheumatol. 2007; 13: 29-30. https://doi. org/10.1097/01.rhu.0000256169.05087.ad
[21] Zandman-Goddard G, Solomon M, Barzilai A et al.: Lupus erythematosus tu midus induced by sex reassignment surgery. J Rheumatol 2007; 34: 1938-40.
[22] Chan KL, Mok CC: Development of sys temic lupus erythematosus in a male-to-fe male transsexual: the role of sex hormones revisited. Lupus 2013; 22: 1399-402. https://doi.org/10.1177/0961203313500550
[23] Pontes LT, Camilo DT, De Bortoli MR et al.: New-onset lupus nephritis after male to-female sex reassignment surgery. Lupus 2018; 27: 2166-69. https://doi.org/10.1177/0961203318800571
[24] Hill BG, Hodge B, Misischia R: Lupus nephritis in a transgender woman on cross sex hormone therapy: a case for the role of oestrogen in systemic lupus erythematosus. Lupus 2020; 29: 1807-10. https://doi.org/10.1177/0961203320946372

​The current standard of care uses different drug classes including: antimalarials (hydroxychloroquine), nonsteroidal anti-inflammatory drugs (NSAIDs: ibuprofen, naproxen, and diclofenac), corticosteroids (prednisone, methylprednisolone) and other immunosuppressives (cyclophosphamide, methotrexate, azathioprine, mycophenolate, and immunoglobulin). Recent entities include biologics targeting the survival and development of B-lymphocytes (belimumab & rituximab), Type 1 interferon antagonist (anifrolumab) and two calcineurin inhibitors (tacrolimus & voclosporin). The current standard of care is inadequate since these drugs only mitigate the course of the disease and come with significant side effects, decreasing the quality of life of patients.
 
A review of novel therapeutics in the clinical trials database (clinicaltrials.gov) provides a glimpse of the future. The new drug in clinical trials falls into five categories including: cell therapy, biologics, small molecule, natural product, and probiotics.
 
Cell therapy is the newest promising approach since the preliminary report by Mackensen et al [1] showing the effectiveness of anti CD19 chimeric antigen receptor T cell treatment (CAR-T) in five patients. There are currently a total of 36 CAR-T trials targeting various cell surface antigens (CD3, CD19, CD20, BCMA or combinations thereof) driving T and B lymphocytes development and proliferation. Most notable among these trials is the one undertaken by Cartesian Therapeutics, which employs mRNA-based CAR-T (Descartes-08, trial NCT06038474) bypassing the need for isolating T cells from the blood of patients and ex vivo transfection. In addition, the chimeric antigen receptor technology also utilizes NK cells as two anti CD19 CAR-NK trials are recruiting patients. Cell therapy also features mesenchymal stem cell transplantations from either umbilical cord blood or bone marrow. Finally, there is a single trial employing NK cells from umbilical cord blood. The table shown below summarizes the cell therapy efforts.

​Biologics include traditional mono and bispecific monoclonal antibodies, Fab fragments, bispecific diabody, fusion proteins and cytokines. Biologics aims at a broader set of targets. Besides the B and T cell surface antigens they also target other immune modulators implicated in the pathogenesis of Lupus including the plasmacytoid dendritic cell antigens BDCA2 and ILT7, the CD40/CD40L pair, cytokine, cytokine receptors, FcRn, protein tyrosine phosphatase receptor type S and the complement system. Clinical trials with different types of biologics are summarized in the table below.

​Small molecules targeted the kinases in signal transduction pathways that are downstream of T and B cell receptors (BTK, mTOR), cytokine receptors (JAKs & TYKs) and Toll like receptors (IRAKs) implicated in the pathogenesis of Lupus. Alternative strategies include the development of protease inhibitors to block the activities of the complement system (Factor B & D) and immunoproteasomes (LMP2&7). A modulator of Sphingosine-1-phosphate receptor-1 which could rectify the balance between Treg and TH17 cells, is also in trials for effectiveness in SLE. Finally, N-acetylcysteine is in clinical trials for SLE for its dual role as antioxidant and inhibitor of the mTOR signaling pathway. The table shown below summarizes all current small molecules trials.

​Natural product: A single trial uses curcumin for Lupus Nephritis (NCT05714670) based on promising results seen in Lupus mouse models. Infiltration of neutrophils and their release of inflammatory factors decreased in renal tissues of mouse models when treated with curcumin. The effect resulted from inhibition of the PI3K/AKT/NF-κB signaling pathway, which is upregulated by interleukin-8 to induce neutrophil migration and renal inflammation.
 
 Probiotics: A single trial (NCT05433857) addresses the use of Lacteol Forte in Systemic Lupus Erythematosus. Lacteol Forte is a probiotic containing Lactobacillus acidophilus LB strain.
 
The overall failure rate in clinical trials for novel entities in the autoimmune/inflammation therapeutic area could be as high as 85% according to statistical surveys done in 2018 [2]. Accordingly, there is hope that 4 to 5 of the entities listed above could soon reach patients. A breakthrough in CAR-T cell therapy providing more than just symptomatic alleviation would be most desirable. Moreover, delivery of the chimeric antigen receptor (CAR) to T cells or NK cells via mRNA technology would be most convenient for patients.

References
[1] Mackensen, A., Müller, F., Mougiakakos, D. et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med 28, 2124–2132 (2022). https://doi.org/10.1038/s41591-022-02017-5
[2] Chi Heem Wong, Kien Wei Siah, Andrew W Lo, Estimation of clinical trial success rates and related parameters. Biostatistics 20, 273–286 (2019). https://doi.org/10.1093/biostatistics/kxx069

Introduction
 
Cerebral palsy (CP) is a group of non-progressive neurological disorders that affect movement, muscle tone, and posture. It is caused by damage or abnormalities in the developing brain, typically occurring before, during, or shortly after birth. The incidence of CP in the general population is approximately 2 to 3 cases per 1,000 live births [1]. Symptoms can vary greatly depending on the type and severity of the condition, and include impaired muscle coordination, stiff or tight muscles, exaggerated reflexes, involuntary movements, difficulty with balance and posture, and problems with speech, swallowing, and vision [2]. The etiology of CP is multifactorial and can be attributed to various causes, including genetic factors, maternal infections during pregnancy, premature birth, birth injuries, and neonatal complications such as lack of oxygen or severe jaundice [3].
 
There are four main types of CP, classified based on the area of the brain affected and the resulting movement disorder. The morbidity associated with each type of CP can vary significantly. Spastic Cerebral Palsy is the most common type, characterized by stiff and tight muscles, often affecting the legs more than the arms. It is caused by damage to the motor cortex, the area of the brain responsible for voluntary movement. Dyskinetic Cerebral Palsy involves uncontrolled, involuntary movements, such as twisting or writhing motions. It is caused by damage to the basal ganglia, which control involuntary movements. Ataxic Cerebral Palsy is due to damage to the cerebellum, which is responsible for coordinating movement and balance. Individuals with this type have poor balance and coordination. Individuals with Mixed Cerebral Palsy may exhibit symptoms of more than one type of cerebral palsy, indicating that multiple areas of the brain have been affected [4,5].
 
The standard of care for patients with CP involves a multidisciplinary approach, including physical therapy, occupational therapy, speech therapy, and medical interventions as needed. Physical therapy aims to improve muscle strength, flexibility, and mobility, while occupational therapy focuses on developing skills for daily living activities. Speech therapy can address communication and swallowing difficulties. Medications, orthotics, and surgical interventions may be recommended in some cases to manage spasticity, contractures, or other complications. Assistive devices, such as walkers, wheelchairs, or communication aids, may also be necessary for some individuals [6].
 
While CP is a lifelong condition, many individuals with milder forms have a normal life expectancy, especially with proper medical care and supportive services [7]. However, individuals with more severe forms of CP or associated conditions, such as intellectual disabilities or respiratory problems, may have a reduced life expectancy by as much as 40% compared to the general population. On average, adults with CP die 24 years earlier than adults without CP [8]. Morbidity related to neurological impairments is certainly an exacerbating factor. Two aspects of current research efforts aimed at understanding its effects leading to earlier mortality are discussed below.
 
References
[1] CDC- Data and Statistics for Cerebral Palsy
[2] NINDS: Cerebral Palsy-Symptoms
[3] CDC- Risk factors for Cerebral Palsy
[4] NINDS: Cerebral Palsy Types and corresponding brain damages
[5] Cerebral Palsy Guide: Co-existing Conditions
[6] American Academy of Pediatrics/Patient Care/Cerebral Palsy
[7] Cerebral Palsy Guide: Life Expectancy
[8] Survival and mortality in cerebral palsy: observations to the sixth decade from a data linkage study of a total population register and National Death Index. Blair E, Langdon K, McIntyre S, Lawrence D and Watson L. BMC Neurology (2019) 19: 111. https://doi.org/10.1186/s12883-019-1343-1


Causes of death among adults with and without cerebral palsy
 
In a recent study of 13,332,871 individuals who died in the US from 2013 to 2017, the causes of death were reported for individuals with CP (n=13,897) compared to those without (N=13,318,974) [1]. The leading causes of death were grouped into 11 categories including 1) heart disease, 2) pneumonitis, 3) influenza & pneumonia, 4) respiratory failure, 5) malignant neoplasms, 6) choking, 7) septicemia, 8) genitourinary diseases, 9) chronic lower respiratory diseases, 10) cerebrovascular diseases, and 11) unknown/unspecified.
 
It was evident from the results that adults with CP had a much higher likelihood than individuals without, of dying from respiratory causes including:

• Pneumonitis (adjusted odds ratio [aOR] 31.14)
• Choking (aOR 20.66)
• Respiratory failure (aOR 17.24)
• Influenza & pneumonia (aOR 8.78)

 
And also in 3 other categories:

• Unknown/unspecified causes (aOR 19.0)
• Septicemia (aOR 1.92)
• Genitourinary diseases (1.67)

 
They had a lower likelihood than individuals without, of dying from:

• Cerebrovascular diseases (aOR 0.66)
• Heart disease (aOR 0.61)
• Chronic lower respiratory diseases (aOR 0.50)
• Malignant neoplasms (aOR 0.12)

 
Interestingly, although CP individuals were less likely to die from heart disease compared to individuals without, it is the leading cause of death within the group followed closely by pneumonitis and influenza and pneumonia. Demographic differences were also noted. Among CP individuals females were more likely than males to die from respiratory failure whereas Non-Hispanic Black were more likely than Non-Hispanic White to die from heart and cerebrovascular diseases.
 
Recommendations: Overall, the implications of the study were two-fold. Despite heart disease being the leading cause of death for both groups, adults with CP faced a higher likelihood of death from preventable respiratory causes. Public health efforts should address respiratory health in this population. Non-Hispanic Black adults had specific disparities in cardiovascular health. Multifaceted approaches are needed to improve circulatory health among people with CP.
 
References
[1] Cause of death trends among adults with and without cerebral palsy in the United States, 2013−2017. Stevens J D, Turk M A and Landes S D. Annals of Physical and Rehabilitation Medicine 65 (2022) 101553. ). https://doi.org/10.1016/j.rehab.2021.101553

The study by Stevens, Turk and Landes was corroborated by a more recent meta-analysis of multiple smaller studies [2]. It also extends a 2019 study of a CP population from Western Australia [3].
 
[2] Risk Factors for Mortality in Patients With Cerebral Palsy: A Systematic Review and Meta-Analysis. Aldharman SS et al. Alhamad F S, Alharbi R M, et al. . Cureus 15(5): e39327. DOI 10.7759/cureus.39327
[3] Survival and mortality in cerebral palsy: observations to the sixth decade from a data linkage study of a total population register and National Death Index. Blair E, Langdon K, McIntyre S, Lawrence D and Watson L. BMC Neurology (2019) 19: 111. https://doi.org/10.1186/s12883-019-1343-1
 

Early onset of chronic diseases in young individuals with cerebral palsy
 
A 2022 study by Daniel G. Whitney [1] focused on a different aspect of cerebral palsy. It examined the risk of “adult-onset” chronic diseases in young children with CP utilizing a population of 5,559 aged 1-13 years from a general group of 2,324,035 children eligible for analysis. The adult-onset chronic diseases were grouped into 13 categories including 1) cerebrovascular disease, 2) cardiac conduction disorders and dysrhythmias, 3) heart failure, 4) chronic obstructive pulmonary disease, 5) type 2 diabetes, 6) chronic kidney disease stage I-IV or end stage renal disease, 7) other chronic kidney diseases, 8) hypothyroidism, 9) liver disease, 10) metastatic cancer, 11) any malignancy except malignant neoplasm of the skin, 12) depression and 13) osteoarthritis.
 
Findings: Children with CP had a higher 5-year risk of all chronic diseases compared to those without CP. The relative risk (RR) ranged from 1.19 to 64.26 (all P < 0.05) across different chronic diseases. The increased risk was observed in all age groups (baseline age groups: <1–2, 3–5, 6–8, 9–11, 12–13 years old).
 
Top tier: cerebrovascular disease (RR 64.26), heart failure (RR 15.17), chronic kidney disease stage I-IV or end stage renal disease (RR 14.97) and metastatic cancer (RR 9.81)
 
Second tier: liver disease (RR 7.97), any malignancy except malignant neoplasm of the skin (RR 6.51), other chronic kidney diseases (RR 6.49) and cardiac conduction disorders and dysrhythmias (RR 6.47)
 
Third tier: hypothyroidism (RR 5.02), osteoarthritis (RR 5.00), type 2 diabetes (RR 2.64), chronic obstructive pulmonary disease (RR 1.68) and depression (RR 1.19)
 
Among children with cerebral palsy, certain patient-level factors could slightly influence the risk of chronic diseases. For examples, comparing chronic disease risk in male versus female, most notably male had a slightly higher risk of chronic obstructive pulmonary disease (20%) but lower risk of chronic kidney disease (31%) and liver disease (35%). Co-occurrence of intellectual disabilities and/or epilepsy increases risk across all chronic diseases except depression. The use of wheelchairs also increased the risk of many chronic diseases to varying levels.
 
Clinical Implications: The study provides novel epidemiologic evidence of 5-year risk of “adult-onset” chronic diseases during important developmental stages in children with cerebral palsy. Identifying at-risk children based on patient-level factors can enhance clinical detection. These findings may inform the timing of prevention strategies and help identify those more susceptible to chronic diseases.
 
Reference
[1] 5-year risk of “adult-onset” chronic diseases during childhood and adolescent transitioning for individuals with cerebral palsy. Whitney D J. Preventive Medicine Reports 29 (2022) 101933. https://doi.org/10.1016/j.pmedr.2022.101933

Online resources
 
General Information and Education

• Cerebral Palsy Guide
• Cerebral Palsy Foundation (CPF)
• United Cerebral Palsy (UCP)
• Centers for Disease Control and Prevention (CDC) - Cerebral Palsy

 
Medical and Therapeutic Resources

• American Academy for Cerebral Palsy and Developmental Medicine (AACPDM
• National Institute of Neurological Disorders and Stroke (NINDS) - Cerebral Palsy Information Page

 
Support and Advocacy

• Cerebral Palsy Alliance Research Foundation (CPARF)
• Family Voices

 
Community and Networking

• MyChild at CerebralPalsy.org
• March of Dimes - Cerebral Palsy

 
Financial and Legal Assistance

• Social Security Administration (SSA) - Disability Benefits for Cerebral Palsy
• Patient Advocate Foundation
• Cerebral Palsy Toolkit (provided by Levin & Perconti, a private law firm)

 
These resources offer a wealth of information and support for individuals with cerebral palsy and their caregivers, helping them navigate the challenges associated with the condition and improve their quality of life.

Parkinson's disease (PD) is a neurodegenerative disorder affecting millions globally. Though not as common as Alzheimer's disease, it presents a significant challenge, with estimates suggesting 1 in 100 people over 60 will develop it [1]. While the exact cause remains elusive, PD's signature symptoms – tremors, stiffness, and balance problems – significantly impact daily life.
 
The initial diagnosis often relies on a neurological examination. Observing tremors, rigidity, slowness of movement (bradykinesia), poor balance and coordination, and speech difficulties paints a strong clinical picture [2]. In some cases, dopamine replacement therapy can provide a diagnostic clue – marked improvement following the introduction of levodopa, a dopamine precursor, strengthens the PD diagnosis. The culprit behind these motor issues lies deep within the brain. In the substantia nigra, a specific area involved in motor control, dopamine-producing neurons degenerate. Dopamine acts as a chemical messenger, facilitating smooth communication between brain regions responsible for movement. This breakdown in communication disrupts our ability to control movement freely [3].
 
While the exact cause is unknown, genetic predisposition and environmental factors play a role. Mutations in specific genes have been linked to PD, though they represent a small minority of cases. Exposure to toxins like herbicides and certain medications might also contribute. Accordingly, the common risk factors include age, genetics, environmental triggers, medications, and head injuries [4,5].
 
Currently, there is no cure for PD. Treatment focuses on managing symptoms and improving quality of life. Levodopa remains the mainstay of therapy, but its effectiveness can decline over time. Other medications, surgery in some cases, and physical therapy all contribute to symptom management. The relentless march of research offers a glimmer of hope. Scientists are actively exploring various avenues. Gene therapy holds promise for replacing or repairing faulty genes. Cell-based therapies involve the transplant of dopaminergic pluripotent stem cells. Deep brain stimulation, where electrodes deliver electrical pulses to specific brain regions, is another area of ongoing investigation [6]. Yet, another emerging area of research that has gained significant attention lately is the gut microbiome of Parkinson’s patients and the potential use of fecal microbiota transplant (FMT) for disease treatment.

​Over the last few years many studies have described dysbiosis in the microbiome of PD patients compared to healthy controls albeit with variations in results from one study to another due to variations in sampling and study designs. Recent meta-analysis [1,2] and metagenomics studies [3] have resulted in a more robust and coherent picture, which we will now attempt to summarize without overinterpretations.
 
The overall dysbiosis is confirmed and characterized by a decrease in the most abundant species of the normal flora and an increase in the rare ones. The species that are depleted are from genera (e.g. Roseburia, Fusicatenibacter, Blautia, Anaerostipes (Lachnospiraceae family), and Faecalibacterium (Ruminococcaceae family) or from the Butyricicoccaceae family, which are known to secrete short chain fatty acids (SCFAs) and butyrate critical for gut health including the enteric nervous system. Depletion of these species was also noted in the gut microbiomes of patients suffering from gastrointestinal dysfunctions, and other neuroinflammatory or neurodegenerative diseases.
 
Bacterial species that tend to increase in abundance in the gut microbiome of PD patients include those that belong to the following genera: Lactobacillus, Akkermansia, Hungatella, and Bifidobacterium. The enrichment in Lactobacillus and Bifidobacterium is not well understood as these taxa are generally known to be beneficial. Whether they contribute to PD or just prefer the pro-inflammatory gut environment remains to be determined. Likewise, there are conflicting evidence about the role of Akkermansia spp whose association with PD is not uniform and appears geographically specific [3]. They are considered beneficial and used as probiotics for treatment of metabolic diseases [4]. On the other hand, some Akkermansia species readily degrade mucin and could contribute to decrease intestinal peristalsis and constipation, a hallmark of PD. The Christensenellaceae family of bacteria also tends towards more abundance in PD. They are hydrogen producers and support the growth of the archeon methanobrevibacter, a major hydrogenotrophic methane producer in the human gut. The abundance of the latter is also known to contribute to constipation in PD.
 
Besides the effect on SCFAs depletion on gut integrity and health, at the functional level the PD microbiota is also characterized by an overall state of altered production of inflammatory species (e.g. increased lipopolysaccharides (LPS), lipoteichoic acid (LTA) and murein/bacterial lipoprotein (BLP)), altered proteolytic and amino acid degradation pathways, and dysregulation in synthesis and metabolism of neurotransmitters (dopamine, glutamate, gamma amino butyric acid and serotonin). In addition, it was reported that there is an upregulation in the pathways involved in the degradation of nicotinamide and trehalose, two neuroprotective agents. The metabolic pathways to produce the bacterial amyloidogenic protein curli were upregulated, likewise for the pathways involved in the production of trimethylamine, a toxic metabolite linked to cardiovascular diseases and stroke [3]. On the overall these changes in metabolic profiles favor an intestinal inflammatory and neurodegenerative state and indicate that dysbiosis could play a significant role in the development of PD together with genetic predisposition, environmental factors and aging.
 
The progress achieved to date has provided the impetus not only for deeper research delving into causes and effects, but also for the development of biomarkers and manipulation of the microbiome to prevent or mitigate the progression of PD. The use of probiotics was investigated resulting in modest successes [5,6]. More importantly, the application of fecal microbiota transplantation (FMT) for treatment has seen significant progress and the results of the latest clinical trials are promising.

​The concept of FMT involves transferring fecal microbiota from a healthy donor to a recipient to restore microbial balance. In 2019, the first case report by Huang et al. [1] demonstrated symptomatic improvement in a 71-year-old PD patient following FMT, sparking interest in its therapeutic potential. Subsequent observational studies and initial clinical trials further explored the safety and efficacy of FMT in PD patients. Notably, a small pilot study by Kuai et al. in 2021 [2] with 11 PD patients reported not only constipation relief but also significant improvements in motor symptoms and quality of life after a single transplant via nasoduodenal tube. These findings were corroborated by two additional studies: a small randomized, placebo-controlled study with 12 PD patients dosed with FMT orally twice weekly for 12 weeks [3], the other with 56 PD patients dosed orally once a week for 3 weeks [4]. Both studies used lyophilized encapsulated FMT for oral administration. Together the results of the three studies indicate a promising therapeutic effect of FMT on PD symptoms.
 
Despite encouraging results, these early studies faced methodological limitations, including small sample sizes, lack of standardized protocols, and heterogeneous patient populations. The variability in donor selection, fecal preparation, and administration routes also contributed to inconsistencies in outcomes. Moreover, the long-term effects and optimal dosing regimen of FMT remain uncertain, necessitating further investigation [5].
 
The field of FMT for PD is currently undergoing a paradigm shift towards more rigorous randomized controlled trials (RCTs) to establish its efficacy and safety. Notably, a single-center randomised, double-blind, placebo-controlled trial (GUT-PARFECT) with 46 early-stage PD patients was recently reported [6]. It demonstrated superior motor improvement in PD patients receiving a single FMT via nasojejunal administration compared to placebo, supporting its therapeutic potential. This finding marks another significant milestone in the clinical validation of FMT for PD.
 
Notable advancements notwithstanding, several challenges lie ahead in establishing FMT as a mainstream treatment for PD. Large-scale RCTs with long-term follow-up are needed to confirm the efficacy, safety, and durability of FMT across diverse patient populations. Standardization of protocols, including donor screening, preparation methods, and administration routes, is essential to ensure reproducibility and minimize variability. Moreover, mechanistic studies elucidating the underlying pathways linking gut dysbiosis to PD pathology will provide valuable insights for targeted interventions.
 
In conclusion, FMT holds promise as a novel therapeutic approach for alleviating motor and non-motor symptoms of Parkinson's disease. From its humble beginnings in case reports to the recent milestone RCTs, the journey of FMT in PD underscores the transformative potential of microbiome-based therapies. While challenges persist, concerted efforts towards rigorous research and clinical validation are essential to harness the full therapeutic benefits of FMT and improve the quality of life for PD patients worldwide.

Living with Parkinson's disease presents a daily challenge. However, with ongoing research and the combined efforts of medical professionals and patients, including private sector investments, the future holds promise for improved management and potentially, a cure for this debilitating disease.