The analysis pooled data from nine randomized controlled trials encompassing 1,814 older adults, a population in which cognitive decline and late-life depression frequently overlap and reinforce one another. Seven of the included trials contributed data on global cognitive function, typically measured with screening instruments such as the Mini-Mental State Examination or the Montreal Cognitive Assessment, while five trials provided data on depressive symptoms, most often captured with the Geriatric Depression Scale. The interventions all had to contain two ingredients: multicomponent exercise, meaning training programs that blend several physical capacities such as aerobic conditioning, resistance work, balance, and coordination, and a structured nutritional component, ranging from dietary counseling to supplementation.

When the results were combined under a random-effects model using Hedges’ g as the effect size measure, the combined intervention showed a small but statistically significant benefit for cognition, with g equal to 0.31 and a 95 percent confidence interval of 0.08 to 0.54. For depressive symptoms, the effect was larger: g equaled negative 0.51, with a confidence interval of negative 0.93 to negative 0.09, indicating a moderate reduction in symptom scores. In plain terms, older adults who exercised in multiple modes while also receiving nutritional support scored somewhat better on thinking tests and reported fewer depressive symptoms than their controls, on average.

Those headline numbers, however, come with statistical asterisks that the authors do not hide. Both analyses displayed moderate-to-high heterogeneity, with I-squared values of 68.54 percent for cognitive function and 63.54 percent for depressive symptoms. Heterogeneity of that magnitude means the individual trials varied substantially in their observed effects, which can reflect differences in populations, intervention design, duration, outcome measures, or study quality. When studies disagree this much, the pooled estimate becomes a rough average of a noisy landscape rather than a precise measurement of a single underlying truth.

To probe where that variability came from, the researchers ran subgroup analyses stratified by nutrition type, baseline cognitive status, and exercise modality. None of these factors produced statistically significant between-subgroup differences, with P values above 0.05. The one exception was intervention duration for global cognitive function, where the subgroup difference was significant at P less than 0.001. That finding hints that longer programs may matter for cognitive outcomes, a biologically plausible idea given that structural and functional changes in the aging brain—synaptic remodeling, vascular adaptation, shifts in inflammatory signaling—typically unfold over months rather than weeks. Yet the authors caution that the subgroup analyses were underpowered, meaning the small number of studies in each stratum makes it difficult to detect real differences even if they exist.

The most sobering caveat concerns publication bias, the well-documented tendency for journals to publish positive findings more readily than null ones. The team applied trim-and-fill analysis, a statistical technique that estimates how missing negative studies might shift a pooled effect. After this adjustment, the estimates for both cognitive function and depressive symptoms were attenuated, and their 95 percent confidence intervals crossed zero. In other words, once the analysis accounts for the possibility that unpublished negative trials exist, the apparent benefits lose statistical significance. The authors explicitly state that the conclusions should be regarded as exploratory and interpreted with caution.

Why would combining exercise with nutrition outperform either approach alone? The mechanistic rationale is grounded in the biology of brain aging. Physical activity, particularly multicomponent training that challenges the cardiovascular system, muscles, and balance circuits simultaneously, is known to elevate circulating levels of brain-derived neurotrophic factor, a protein that supports neuronal survival, synaptic plasticity, and hippocampal function. Exercise also improves insulin sensitivity, vascular health, and sleep quality, all of which feed into cognitive performance and mood. Nutritional intervention targets a complementary set of pathways: adequate protein intake preserves muscle mass that supports physical activity, while nutrients emphasized in patterns such as the Mediterranean-DASH Intervention for Neurodegenerative Delay diet supply antioxidants, omega-3 fatty acids, and B vitamins that participate in neuronal membrane integrity and homocysteine metabolism. The hypothesis is that these two levers act synergistically, with exercise providing the stimulus and nutrition supplying the substrates for repair and growth.

The clinical stakes are considerable. The world’s population is aging rapidly, and no disease-modifying drug for age-related cognitive decline has yet delivered the kind of benefit patients and families hope for. Late-life depression, meanwhile, is both common and underdiagnosed, and it accelerates cognitive deterioration in a vicious cycle. Lifestyle interventions are attractive because they are low-cost, broadly scalable, and largely free of the adverse effects that complicate pharmacotherapy. If a combined exercise-and-nutrition program genuinely delivers even a small cognitive benefit alongside a moderate mood benefit, the public health implications would be substantial, particularly in community and long-term care settings where such programs could be embedded into routine practice.

Still, the study’s limitations temper any temptation to declare victory over cognitive aging. Nine trials and 1,814 participants is a modest evidence base for a question of this complexity, and the trials themselves likely differed in how they defined multicomponent exercise, what nutritional support they delivered, how long they lasted, and how rigorously they blinded outcome assessors. The authors call for future high-quality randomized controlled trials with larger sample sizes, longer follow-up periods, and standardized intervention protocols to validate or refute the findings. Standardization matters because without it, meta-analysts are forced to pool apples and oranges, and the heterogeneity observed here is the predictable result.

For older adults and their families, the practical takeaway is less about a guaranteed cognitive boost and more about the convergence of evidence across many lines of research. Exercise remains one of the most consistently supported interventions for healthy brain aging, and good nutrition is its natural partner. This meta-analysis adds a cautiously optimistic data point suggesting that doing both together may be better than doing either alone, especially over longer timeframes. Until larger and more rigorous trials arrive, the wisest reading of the new work is that a varied exercise routine paired with sound nutrition is a reasonable, low-risk bet for body and mind alike—one whose full payoff science has not yet finished counting.

Subject of Research: Effects of combined multicomponent exercise and nutritional intervention on cognition and depression in older adults

Article Title: Effects of multicomponent exercise combined with nutritional intervention on global cognitive function and depressive symptoms in older adults: a systematic review and meta-analysis

Article References: Zhang, W., Li, X., Zheng, J., & Zhang, D. (2026). Effects of multicomponent exercise combined with nutritional intervention on global cognitive function and depressive symptoms in older adults: a systematic review and meta-analysis. BMC Geriatrics. https://doi.org/10.1186/s12877-026-08493-5

Image Credits: AI Generated

DOI: 10.1186/s12877-026-08493-5

Keywords: multicomponent exercise, nutritional intervention, cognitive function, depressive symptoms, older adults, meta-analysis, randomized controlled trials, brain-derived neurotrophic factor, cognitive aging, geriatrics, publication bias, MIND diet

Cancer anorexia–cachexia syndrome is a complex metabolic disorder defined by progressive weight loss and the selective depletion of skeletal muscle, with or without loss of fat tissue. It is far more than simple malnutrition: the syndrome is not fully reversible with conventional nutritional support, and it is closely linked to shortened survival, increased treatment-related toxicity, poor adherence to anticancer therapy, and a marked deterioration in quality of life. For patients with hepatocellular carcinoma, the predominant form of liver cancer and the third leading cause of cancer death worldwide, the problem is especially acute. Approximately one-third of HCC patients already show pre-cachexia at diagnosis, and nearly one in four meets full criteria for cachexia.

The burden is concentrated in the patient population this new trial targets. According to the Barcelona Clinic Liver Cancer staging system, the prevalence of cachexia reaches 23.5 percent among those with stage B disease and 34.7 percent among those with stage C, the advanced stages where curative options have typically been exhausted. Anorexia affects an estimated 50 to 60 percent of HCC patients undergoing transarterial chemoembolization, and roughly 35 percent of those receiving systemic targeted therapy develop cachexia, which has been recognized as an independent adverse prognostic factor for both overall and progression-free survival.

The standard-of-care context is important. For patients with BCLC stage B or C hepatocellular carcinoma, locoregional interventions such as transarterial chemoembolization, in which chemotherapy is delivered directly to the tumor through the hepatic artery followed by embolization of its blood supply, or hepatic arterial infusion chemotherapy, can be combined with systemic agents including tyrosine kinase inhibitors, antiangiogenic drugs, and immune checkpoint inhibitors. These combinations may enhance tumor control and prolong survival. Yet patients who lose weight during treatment generally fare worse, creating an urgent need to protect appetite and body composition while antitumor therapy proceeds.

The drug under investigation is megestrol acetate, a progestational agent widely regarded as a key pharmacological option for cancer-related wasting because of its well-documented effects on appetite stimulation and weight gain. Progestogens are thought to suppress inflammatory cytokines through humoral and neuroregulatory mechanisms, thereby enhancing appetite and promoting weight gain, and animal studies have shown that megestrol acetate stimulates food intake through effects on hypothalamic neuropeptide pathways. Dose–response data from a randomized trial of cancer cachexia patients testing 160, 480, 800, and 1,280 milligrams per day found the greatest improvements in appetite and weight at 800 milligrams daily.

But conventional megestrol acetate has a fundamental pharmaceutical flaw. It is classified as a Biopharmaceutics Classification System class II drug, meaning its dissolution in the gut and subsequent oral bioavailability are strongly influenced by whether the drug is taken with food. Systemic exposure is substantially lower under fasting conditions than fed conditions, producing unpredictable drug levels in patients who, by the nature of their disease, often eat erratically or not at all. The nanocrystalline formulation, delivered as an oral suspension, is designed to reduce this food-dependent variability in absorption. In pharmacokinetic studies, 625 milligrams of nanocrystalline megestrol acetate achieved exposure comparable to 800 milligrams of the conventional formulation under fed conditions, and greater exposure under fasting conditions, although investigators caution these findings do not by themselves establish clinical dose equivalence.

Early clinical signals have been encouraging. A prospective real-world study in China compared nanocrystalline megestrol acetate at 625 milligrams per day with the conventional 800-milligram formulation, both given continuously for 12 weeks, in patients with cancer anorexia–cachexia syndrome. At week 12, the nanocrystalline group achieved a mean weight gain of 4.49 kilograms versus 2.10 kilograms in the conventional group, a mean difference of 2.39 kilograms that was highly statistically significant. Patients on the nanocrystalline drug also showed significantly greater improvements in anorexia, nausea and vomiting, and overall health status. What remains unknown, and what the new trial is designed to determine, is whether these benefits translate into meaningful clinical gains when layered on top of combined systemic and interventional anticancer therapy in HCC patients.

The trial design is a prospective, multicenter, randomized, open-label, parallel-group Phase II study that will enroll 68 adults aged 18 to 75 years with BCLC stage B or C hepatocellular carcinoma who meet protocol-defined criteria for pre-cachexia or cachexia. Participants will be stratified by tumor stage and by the percentage of weight loss during the previous six months, then randomized 1:1 to receive either nanocrystalline megestrol acetate at 625 milligrams per day for 12 weeks alongside antitumor therapy, or antitumor therapy alone. Because no placebo suspension is used, participants and treating investigators will not be blinded, but the imaging and body-composition assessors and the statisticians will remain blinded to treatment allocation. Enrollment is planned from March 2026 to March 2028, followed by 12 months of follow-up after the last participant is enrolled.

The diagnostic thresholds are grounded in international consensus definitions. Pre-cachexia requires anorexia, non-volitional weight loss of up to 5 percent, and systemic inflammation marked by C-reactive protein above 5 milligrams per liter. Cachexia is defined by anorexia or systemic inflammation combined with either non-volitional weight loss exceeding 5 percent within six months, or a body mass index below 18.5 kilograms per square meter with weight loss exceeding 2 percent. The co-primary endpoints at week 12 are the proportion of responders on the Anorexia/Cachexia Subscale-12 questionnaire, defined as a gain of at least 4 points from baseline, and the proportion of body mass index responders, defined as any increase from baseline. Secondary endpoints include objective tumor response by modified RECIST criteria, one-year progression-free survival, changes in the L3 skeletal muscle index measured on CT or MRI, and adverse event rates, with exploratory endpoints tracking inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha, nutritional markers including albumin and hemoglobin, and quality of life via the EORTC QLQ-C30 questionnaire.

The investigators are candid about the study’s limitations. The antitumor regimens are not fully standardized, potentially introducing heterogeneity into efficacy outcomes; the open-label design may bias patient-reported appetite and quality-of-life measures; the sample size limits subgroup analyses; and body mass index can be distorted by ascites and fluid retention in HCC patients, which is why the protocol specifies estimated dry-weight corrections for ascites and edema and pairs BMI with objective muscle measurements at the third lumbar vertebra. The sample size of 68, allowing for 15 percent attrition, was powered at 80 percent with a one-sided alpha of 0.025 to detect appetite response rates of 50 percent versus 15 percent and BMI response rates of 40 percent versus 10 percent. With ethics approval from West China Hospital and registration on ClinicalTrials.gov, the study represents a serious attempt to bring a nanotechnology-enabled formulation to bear on a syndrome that has long resisted treatment, and its results could reshape how clinicians support patients through the most vulnerable phase of advanced liver cancer therapy.

Subject of Research: Nanocrystalline megestrol acetate for cancer cachexia in advanced hepatocellular carcinoma

Article Title: NMA plus antitumor therapy versus antitumor therapy alone in patients with BCLC stage B or C hepatocellular carcinoma and pre-cachexia or cachexia: protocol for a prospective, multicenter, randomized, open-label phase II trial

Article References: Dai, R., Lu, F., Leng, W., He, Q., Guo, W., Hai, T., & Liu, C. (2026). NMA plus antitumor therapy versus antitumor therapy alone in patients with BCLC stage B or C hepatocellular carcinoma and pre-cachexia or cachexia: protocol for a prospective, multicenter, randomized, open-label phase II trial. Frontiers in Gastroenterology, 5, Article 1926294. https://doi.org/10.3389/fgstr.2026.1926294

Image Credits: AI Generated

DOI: 10.3389/fgstr.2026.1926294

Keywords: cancer cachexia, hepatocellular carcinoma, nanocrystalline megestrol acetate, BCLC stage B and C, randomized controlled trial, transarterial chemoembolization, hepatic arterial infusion chemotherapy, anorexia-cachexia syndrome, skeletal muscle index, clinical trial protocol, nutritional intervention, liver cancer

The biological centerpiece of this framework is metabolic reprogramming, one of the updated Hallmarks of Cancer. Head and neck squamous cell carcinoma cells rely heavily on aerobic glycolysis, the so-called Warburg effect, burning through enormous quantities of glucose and converting it to lactate even in the presence of oxygen. This inefficient ATP generation might seem like a design flaw, but it allows rapid proliferation and creates a continuous drain on the body’s nutrient supply. The lactate released by tumors does not simply disappear; it enters the Cori cycle, forcing the liver to spend energy converting it back into glucose through gluconeogenesis. The result is a futile substrate loop that raises resting energy expenditure and contributes to the hypermetabolic state long observed in cancer patients.

The review emphasizes that the tumor behaves, in the authors’ framing, as a metabolic sink. Glucose, lipids, and amino acids are redirected from skeletal muscle, liver, and adipose tissue toward the growing malignancy. Cytokine-driven activation of proteolytic pathways in muscle triggers the breakdown of contractile proteins and the release of glutamine and other amino acids that can be funneled into tumor metabolism. Meanwhile, tumor-derived factors such as parathyroid hormone-related protein promote lipolysis and the browning of white adipose tissue, converting energy stored in fat into heat rather than usable fuel. These processes, the authors stress, do not directly nourish the tumor; instead, they force the host to mobilize substrates in a losing attempt to maintain homeostasis, producing thermogenic inefficiency and accelerating energy wasting.

Chronic systemic inflammation amplifies this catabolic storm. Elevated circulating levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta are commonly found in head and neck cancer patients and correlate with weight loss, sarcopenia, and poorer clinical outcomes. Interleukin-6 has been strongly linked to loss of body mass and adipose tissue depletion, while tumor necrosis factor-alpha enhances ubiquitin-proteasome-mediated protein degradation and impairs glucose transport in peripheral tissues. Within skeletal muscle, activation of the myostatin/SMAD signaling pathway suppresses protein synthesis and accelerates atrophy. Together, these mechanisms create a self-perpetuating loop in which inflammation sustains catabolism, tissue wasting further fuels inflammatory signaling, and the patient’s metabolic reserve erodes progressively, often before any anticancer therapy has begun.

This model explains a clinical observation that has long puzzled oncologists: many patients lose weight and muscle mass early in the disease course, even when their oral intake appears adequate, and caloric supplementation alone frequently fails to prevent muscle loss or cachexia. The internationally accepted GLIM criteria for diagnosing malnutrition already recognize inflammation as a key etiologic driver, requiring at least one phenotypic criterion such as weight loss or reduced muscle mass alongside an etiologic criterion such as reduced intake or disease-related inflammation. The new review goes further, arguing that in head and neck cancer the inflammatory and metabolic components dominate, and that nutritional impairment should be viewed as a dynamic, tumor-driven process rather than a simple caloric deficit.

Translating this biology into measurable clinical tools is where the review makes its most distinctive contribution. Sarcopenia, the progressive loss of skeletal muscle, is one of the most clinically relevant manifestations of cancer-related metabolic derangement. Because patients with head and neck cancer rarely undergo routine abdominal imaging, cross-sectional muscle assessment at the level of the third cervical vertebra has emerged as a validated surrogate for whole-body muscle mass. The resulting C3 skeletal muscle index can identify muscle depletion that body mass index misses entirely, and it carries prognostic weight: sarcopenia has been consistently associated with poorer overall survival, increased treatment-related toxicity, and reduced quality of life, making it a robust biomarker rather than a mere byproduct of treatment intolerance.

On the metabolic side, functional imaging offers a window into the tumor’s glycolytic appetite. Total lesion glycolysis, derived from 18F-FDG PET scans, integrates tumor volume with metabolic activity to reflect the overall glucose consumption of the malignancy. High values have been associated with aggressive tumor biology, greater inflammatory burden, and adverse oncologic outcomes. Crucially, recent prospective data in locally advanced head and neck squamous cell carcinoma showed that higher tumor metabolic activity measured by total lesion glycolysis was significantly associated with reduced skeletal muscle mass at the third cervical vertebra, elevated inflammatory markers, and impaired nutritional status at the start of treatment. This provides clinical validation of the biological model: tumor-driven hypermetabolism and inflammation translate into measurable deterioration of body composition and nutritional reserve.

The authors are careful to acknowledge the limitations of the current evidence base. The studies linking PET-derived metabolic parameters with nutritional impairment remain limited in number and observational in design, and external validation in larger prospective cohorts is still needed. Methodological heterogeneity in PET acquisition protocols, lesion segmentation strategies, and cutoff values complicates comparisons across studies, and standardized imaging protocols and universally accepted thresholds for C3-based muscle assessment have not yet been fully established. Metabolic imaging biomarkers should therefore be considered complementary tools alongside conventional nutritional and body composition assessment rather than stand-alone diagnostic markers. In practice, the review advocates a multimodal approach combining clinical nutritional evaluation, C3-derived muscle assessment when available, inexpensive and widely accessible inflammatory markers such as C-reactive protein and the neutrophil-to-lymphocyte ratio, and metabolic imaging parameters in patients already undergoing PET imaging.

The therapeutic implications are perhaps the most consequential part of the framework. If malnutrition is an immune-metabolic syndrome, then early nutritional intervention should aim not merely to increase calories but to modulate systemic inflammation and preserve functional body composition. Current European Society for Clinical Nutrition and Metabolism guidelines support early nutritional intervention as a cornerstone of multidisciplinary care in head and neck oncology, and intervention appears most effective during the pre-cachectic or early cachectic phases, when metabolic alterations remain potentially reversible. Immunonutrition enriched with arginine, omega-3 fatty acids, and nucleotides has shown promising effects, including improvement of the CD4/CD8 T-cell balance and accelerated postoperative recovery, but the evidence remains heterogeneous, and the authors caution that adequately powered randomized trials are needed before routine use beyond current guideline indications can be recommended.

Patients with locally advanced disease, high tumor metabolic burden, marked systemic inflammation, and early muscle depletion are especially vulnerable, as are those with advanced age, HPV-negative tumors, extensive smoking histories, dysphagia, or treatment with concurrent chemoradiotherapy. For these individuals, the review argues, nutritional management should prioritize preservation of lean body mass over weight maintenance alone, with adequate protein and energy provision embedded in integrated supportive care that includes pain control and oncologic treatment planning. Nutritional support alone is unlikely to fully reverse the underlying immune-metabolic alterations, but early recognition of high-risk features could shift the paradigm from reactive nutritional rescue to proactive metabolic management. By uniting tumor metabolism, systemic inflammation, and imaging-based body composition into a single conceptual framework, the Naples team offers oncologists a way to identify vulnerable patients before cachexia takes hold, and a biological rationale for treating the tumor’s metabolic sabotage, not just the patient’s empty plate, as the true target of nutritional care in head and neck cancer.

Subject of Research: Tumor-driven immune-metabolic mechanisms of cancer-related malnutrition in head and neck squamous cell carcinoma

Article Title: Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC)

Article References: Zurlo, V., Piccirillo, A., Marciano, M. L., Pontone, M., Rampetta, F. R., Perri, E., & Perri, F. (2026). Beyond reduced intake: tumor metabolism and immune dysregulation drive cancer-related malnutrition in head and neck squamous cell carcinoma (HNSCC). Supportive Care in Cancer, 34(10), Article 1056. https://doi.org/10.1007/s00520-026-11115-w

Image Credits: AI Generated

DOI: 10.1007/s00520-026-11115-w

Keywords: head and neck cancer, cancer-related malnutrition, sarcopenia, tumor metabolism, Warburg effect, systemic inflammation, immunonutrition, total lesion glycolysis, C3 skeletal muscle index, cachexia, PET imaging, nutritional intervention

Obesity has long been recognized as a state of chronic low-grade inflammation, a smoldering immune activation that contributes to insulin resistance, fatty liver disease, and cardiovascular risk. At the same time, obesity is marked by circadian disruption: the molecular clocks that orchestrate daily cycles of metabolism, hormone secretion, and immune activity fall out of sync. What has remained unclear is whether these two phenomena are merely parallel consequences of excess weight or whether they are mechanistically intertwined, and, crucially, whether a dietary intervention can pull both back into alignment at the same time.

The new study, led by Claudia Pivonello and senior author Annamaria Colao, set out to address exactly that question. Thirty-eight adults with obesity completed a twelve-week hypocaloric Mediterranean diet program. Before and after the intervention, the researchers collected detailed anthropometric and metabolic measurements, including body weight, body mass index, waist circumference, fat mass percentage, fat-free mass, muscle mass, and HDL cholesterol. They also assessed each participant’s chronotype using the Morningness–Eveningness Questionnaire, a validated instrument that captures whether a person’s natural tendencies lean toward morning or evening activity.

The most technically ambitious part of the study involved the participants’ peripheral blood mononuclear cells, or PBMCs, a mixed population of immune cells that includes lymphocytes and monocytes. Blood samples were drawn at two fixed time points, eight in the morning and four in the afternoon, allowing the researchers to track how gene expression shifted across the day. Using quantitative reverse-transcription PCR, they measured the expression of five core clock genes: BMAL1, PER1, PER2, CRY1, and CRY2. These genes form the interlocking feedback loops that constitute the molecular circadian oscillator, with BMAL1 acting as the positive driving element and the PER and CRY proteins as the negative limbs that restrain its activity on a roughly twenty-four-hour cycle. Alongside the clock genes, the team quantified expression of two innate immune receptors, TLR4 and TLR8, members of the Toll-like receptor family that detect microbial components and trigger inflammatory signaling.

The metabolic results were consistent with what clinicians have come to expect from a well-executed Mediterranean diet intervention. Participants showed significant reductions in body weight, body mass index, waist circumference, and fat mass percentage, together with increases in fat-free mass, muscle mass, and HDL cholesterol. Their MEQ scores also rose significantly, indicating a shift toward greater morningness, although the distribution of chronotype categories did not change in a statistically significant way. In other words, participants drifted somewhat toward morning preference without crossing into a new chronotype classification.

The molecular findings were more striking. At baseline, before any dietary change, expression of TLR4 and TLR8 in PBMCs was significantly higher in the afternoon than in the morning, a diurnal pattern in innate immune receptor expression that the researchers documented for the first time in this cohort. After twelve weeks of the Mediterranean diet, the picture had changed in a coordinated fashion. BMAL1 expression increased significantly in the morning samples, while PER1, TLR4, and TLR8 expression decreased significantly in the afternoon samples. Moreover, all five clock genes examined, BMAL1, PER1, PER2, CRY1, and CRY2, displayed a more pronounced morning-to-afternoon expression pattern following the intervention, which the authors interpret as evidence of improved diurnal organization of the peripheral clock.

Perhaps the most intriguing observation was the correlation structure linking the two systems. The researchers found significant positive correlations between BMAL1 expression and both TLR4 and TLR8 expression at both sampling time points. This statistical relationship supports the hypothesis of a bidirectional interaction between the molecular clock and innate immune pathways, a connection that has been suggested by animal and cellular studies but rarely examined in the context of a human dietary intervention. If BMAL1 activity helps govern the daily rhythm of Toll-like receptor expression, then dietary signals that strengthen the clock could, in principle, dampen the inappropriate immune activation that characterizes obesity.

The authors frame their results as evidence of partial restoration of diurnal–immune homeostasis. Increased morning BMAL1 together with reduced afternoon TLR4 and TLR8 suggests that the intervention did not simply suppress inflammation indiscriminately but instead rebalanced the temporal architecture of immune readiness. They propose that dietary modulation of what they call the BMAL1–TLR axis may represent a mechanism linking metabolic improvement to diurnal regulation, and they identify peripheral clock gene expression as a potential translational biomarker of response to lifestyle interventions. If validated, such a biomarker could allow clinicians to monitor, at the level of gene expression in a simple blood draw, whether a patient’s body clock and immune system are responding to dietary therapy.

Important caveats temper these conclusions. The study lacked a comparator arm, meaning there was no control group of patients with obesity who did not receive the intervention or who received an alternative diet. Without such a group, the findings must be interpreted as associations rather than proof of causation, and the authors are explicit on this point, calling for confirmation in randomized controlled studies. The sample size of thirty-eight participants, while adequate for an exploratory interventional design, is modest, and the two-time-point sampling strategy captures only a coarse snapshot of the full twenty-four-hour rhythm. The study was registered at ClinicalTrials.gov as NCT06236932 and was approved by the Ethical Committee of Federico II University of Naples, and it was funded by the Italian Ministry of University and Research through a Projects of Relevant National Interest grant.

Even with those limitations, the study adds a compelling piece to a rapidly growing body of work on the circadian–immune axis. It suggests that the Mediterranean diet, already celebrated for its cardiovascular and metabolic benefits, may exert part of its influence by entraining the peripheral clocks embedded in immune cells and by smoothing out the aberrant daily oscillations of innate immune receptors. For patients with obesity, the practical message is familiar but now carries deeper mechanistic weight: what you eat, and presumably when you eat it, may help decide not only how much you weigh but how well your body’s internal timekeeping and immune surveillance work together. For researchers, the message is that the blood-borne clock may be a readable, and potentially modifiable, target of nutritional therapy.

Subject of Research: Effects of a hypocaloric Mediterranean diet on circadian clock gene and innate immune receptor expression in patients with obesity

Article Title: A 12-week hypocaloric Mediterranean diet is associated with metabolic improvement and modulation of diurnal clock gene and innate immune receptor expression in peripheral blood mononuclear cells of patients with obesity

Article References: Pivonello, C., Magnacca, N., Graziadio, C., Negri, M., Vetrani, C., Amatrudo, F., Vozza, E., Vecchio, G. D., Tini, S., Celano, S., Prodam, F., Auriemma, R. S., Pivonello, R., & Colao, A. (2026). A 12-week hypocaloric Mediterranean diet is associated with metabolic improvement and modulation of diurnal clock gene and innate immune receptor expression in peripheral blood mononuclear cells of patients with obesity. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09013-0

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09013-0

Keywords: Mediterranean diet, obesity, circadian rhythm, clock genes, BMAL1, Toll-like receptors, TLR4, TLR8, peripheral blood mononuclear cells, inflammation, chronotype, nutritional intervention

At the heart of the new approach is a multimodal fusion model that integrates three distinct but complementary data streams: clinical variables such as gender, age, body mass index, haemoglobin, and albumin; high-dimensional radiomics features extracted from computed tomography images; and deep learning features derived from a ResNet50 convolutional neural network. The research, published in the Journal of Cachexia, Sarcopenia and Muscle, drew on data from 1067 patients who underwent gastric cancer surgery at two hospitals affiliated with Wenzhou Medical University between 2014 and 2022. Of these, 978 patients formed the training and validation sets, while 89 patients from a second hospital served as an external test set to evaluate the model’s ability to generalize to unseen data.

Defining sarcopenia accurately was central to the study’s design. Rather than relying solely on the skeletal muscle index (SMI) measured at the third lumbar vertebral (L3) level—the widely accepted reference standard for assessing muscle mass—the researchers adhered to the European Working Group on Sarcopenia in Older People (EWGSOP2) criteria. Sarcopenia was defined by the presence of both low muscle strength and low muscle quantity or quality, while severe sarcopenia required the additional presence of low physical performance. Muscle strength was assessed using grip strength, with cutoff values defined as less than 28 kilograms for men and less than 18 kilograms for women. Physical performance was evaluated using the 6-meter gait speed test, with a speed below 1.0 meters per second indicating low performance. This comprehensive definition better captures the combined structural and functional nature of the condition compared with studies that rely on CT-derived muscle area alone.

The technical pipeline behind the model is as sophisticated as it is elegant. Automated skeletal muscle segmentation was performed using TotalSegmentator, a deep learning tool that eliminates the need for manual delineation by radiologists. Axial slices at the L3 level, along with one adjacent slice above and below, were extracted from preoperative abdominal CT scans. From these images, the researchers used the PyRadiomics library to extract 1288 quantitative features spanning shape, first-order intensity, and texture classes. After Z-score normalization and removal of highly correlated features, LASSO regression with 10-fold cross-validation whittled the set down to 26 sarcopenia-related features. An extreme gradient boosting (XGBoost) model trained on these features achieved an area under the curve (AUC) of 0.93 in the training set and 0.85 in the validation set, demonstrating the diagnostic power of radiomic texture information alone.

Alongside the radiomics approach, the team developed 2D and 2.5D deep learning models based on the ResNet50 architecture pretrained on the ImageNet dataset. The 2D model processed a single L3-level muscle slice, while the 2.5D model combined three consecutive slices as a three-channel input, capturing critical anatomical spatial continuity across adjacent sections. Transfer learning was performed on the training set, with network parameters iteratively updated using backpropagation and the Adam optimizer. Data augmentation strategies, including random horizontal and vertical flipping, helped improve generalizability. After training, 2048 deep learning features were extracted from the penultimate global average pooling layer of the network for each patient. The 2.5D model outperformed its 2D counterpart, achieving an AUC of 0.83 in the external test set compared with 0.81, prompting the team to select 2.5D features for the final multimodal fusion.

The integration of these heterogeneous data sources was accomplished through a transformer-based architecture that treats clinical variables, radiomics features, and deep learning features as three independent input modalities. Each modality was separately fed into modality-specific encoding networks composed of fully connected hidden layers to learn high-dimensional discriminative representations. Dropout regularization was applied during encoding to reduce overfitting. The encoded features from all three modalities were then projected into a 64-dimensional latent space and fused using a transformer encoder with two encoder layers and eight attention heads—a mechanism borrowed from natural language processing that allows the model to weigh the relative importance of different pieces of information dynamically. The model’s output consisted of two independent classification heads, one estimating the probability of sarcopenia and the other estimating the probability of severe sarcopenia.

The results are striking. In the external test set, the integrated model achieved an AUC of 0.89 for sarcopenia and 0.84 for severe sarcopenia, with accuracy rates of 0.80 and 0.73 respectively. In the training set, performance was even more impressive, with AUCs of 0.95 for sarcopenia and 0.93 for severe sarcopenia. Decision curve analysis confirmed that the model provided positive net benefit across clinically relevant threshold probabilities, suggesting genuine utility in real-world screening scenarios. Among the cohort, the prevalence of sarcopenia was 20.0 percent and severe sarcopenia was 12.3 percent, proportions that remained consistent across all three patient sets. Kaplan-Meier survival analysis revealed that patients with sarcopenia had significantly poorer overall survival than those without, reinforcing the clinical urgency of early identification.

Interpretability was not neglected in the rush toward higher performance. The researchers employed SHapley Additive exPlanations (SHAP) analysis to quantify the contribution of individual features in both the radiomics and XGBoost models. Notably, the leading SHAP features in the XGBoost model spanned all three modalities, and several were significantly correlated with grip strength and SMI, supporting the clinical and biological relevance of the features the model had learned to prioritize. This kind of transparency matters in a medical context, where clinicians need to trust that a model’s predictions are grounded in meaningful physiological signals rather than spurious correlations.

The implications extend beyond gastric cancer. Tumor-associated chronic inflammation disrupts protein metabolism and impairs a patient’s ability to tolerate surgical stress, making muscle wasting a reflection of underlying global physiological vulnerability rather than a simple reduction in body weight. As these pathophysiological alterations directly influence postoperative recovery and long-term prognosis, comprehensive risk stratification has become central to personalized prehabilitation. The automated workflow established by this study facilitates the integration of high-dimensional radiological data with clinical information and may provide a feasible approach for early screening, helping to identify high-risk patients who could benefit from earlier targeted nutritional and functional interventions before surgery even begins.

Despite the promising results, the researchers acknowledge several limitations. Further validation in large-scale prospective cohorts is needed to confirm the model’s real-world predictive performance, and incorporating volumetric data from a broader range of abdominal levels may provide a more comprehensive assessment of systemic muscle wasting. The study also relied primarily on CT-based assessments, so generalizability to clinical settings that use different body composition technologies—such as bioelectrical impedance analysis or dual-energy X-ray absorptiometry—remains to be established. Nevertheless, by simplifying and optimizing the evaluation workflow, the model reduces reliance on labour-intensive manual assessments and provides a foundation for earlier implementation of individualized nutritional and functional interventions in routine clinical practice, offering a glimpse of how artificial intelligence can quietly transform the care of some of medicine’s most vulnerable patients.

Subject of Research: A multimodal artificial intelligence model combining radiomics, deep learning, and clinical variables for automated detection of sarcopenia in gastric cancer patients.

Article Title: Integrated Assessment of Sarcopenia in Patients with Gastric Cancer Using Deep Learning and Radiomics

Article References: Zhi, H., Zheng, J., Chen, H., Yang, X., Jiang, Z., Shi, A., Wu, D., Lv, L., He, J., Chen, X., Pan, B., Shen, X., & Zhang, W. (2026). Integrated Assessment of Sarcopenia in Patients with Gastric Cancer Using Deep Learning and Radiomics. Journal of Cachexia, Sarcopenia and Muscle, 17(5), Article e70377. https://doi.org/10.1002/jcsm.70377

Image Credits: AI Generated

DOI: 10.1002/jcsm.70377

Keywords: sarcopenia, gastric cancer, deep learning, radiomics, computed tomography, multimodal fusion, transformer, muscle wasting, XGBoost, ResNet50, clinical prediction, nutritional intervention

Autism spectrum disorder is a heterogeneous neurodevelopmental condition characterized by persistent difficulties in social communication and interaction, along with restricted, repetitive patterns of behavior or interests. Epidemiological surveillance across the globe has documented a steady rise in prevalence, intensifying the search for interventions that go beyond the current standards of care. Behavioral therapies remain the cornerstone of treatment, and medications can address certain comorbidities such as irritability or attention problems, but their efficacy for core symptoms is limited. That gap has prompted researchers to look toward metabolic approaches, including the ketogenic diet, a high-fat, low-carbohydrate regimen long used to treat refractory epilepsy.

The rationale for testing a ketogenic diet in autism rests on several converging lines of biological evidence. Ketone bodies, produced by the liver when carbohydrate intake is sharply restricted, serve as an alternative fuel for the brain and can alter neurotransmitter balance, mitochondrial function, and oxidative stress, all of which have been implicated in autism-related neurobiology. Animal models and small clinical studies have previously hinted at behavioral benefits, but large, well-controlled trials in young children have been scarce. The new study was designed to address that evidence gap with a prospective, randomized design and validated clinical outcome measures.

Between January 2024 and January 2025, the research team enrolled 62 young children diagnosed with autism spectrum disorder who were admitted to Hefei Maternal and Child Health Hospital. Participants were randomly assigned in equal numbers, 31 per group, to a treatment group or a control group. Both groups underwent an identical rehabilitation program consisting of hospital-based training on weekdays and home-based rehabilitation on weekends across a two-month period. The only difference between the arms was dietary: the treatment group additionally received a modified ketogenic diet built around ketogenic nutritional powder and a structured dietary plan.

The dietary protocol was deliberately engineered for real-world feasibility in families with young children. On training days, lunch was provided at the hospital, ensuring direct supervision of a substantial portion of daily intake, while breakfast, dinner, weekend dietary implementation, and home monitoring were managed by caregivers following the structured plan. The control group, by contrast, maintained a regular diet throughout the same rehabilitation program. This hybrid delivery model, combining clinical oversight with caregiver administration, reflects a pragmatic attempt to test whether a modified ketogenic approach can be implemented outside highly controlled metabolic wards, a persistent obstacle in pediatric dietary research.

Symptom change was assessed with two widely used clinical instruments: the Autism Behavior Checklist, known as the ABC, and the Childhood Autism Rating Scale, or CARS. Both scales quantify the severity and breadth of autism-related behaviors, with higher scores indicating more pronounced symptoms. After two months of intervention, both groups showed statistically significant reductions in ABC and CARS scores compared with their own baselines, indicating that the rehabilitation program itself conferred measurable benefit to all participants.

The decisive comparison, however, lay between the groups. When the researchers examined individual change scores, children receiving the modified ketogenic diet demonstrated significantly larger reductions on both measures. The between-group difference in ABC change scores reached statistical significance with a Mann-Whitney U statistic of 324.000 and a p-value of 0.027, while the CARS comparison yielded an even stronger signal, with U equal to 273.500 and a p-value of 0.003. In practical terms, adding the dietary intervention appeared to amplify the improvements attributable to rehabilitation training over the short term.

The authors conclude that in this cohort of young children with autism, the modified ketogenic diet combined with rehabilitation training was associated with greater short-term reductions in ABC and CARS scores than rehabilitation alone, and that the intervention demonstrated acceptable short-term feasibility. The use of ketogenic nutritional powder rather than a strictly classical ketogenic diet likely contributed to tolerability, since modified formulations can ease the burden of achieving and maintaining ketosis in children who are often selective eaters. Caregiver-mediated home implementation, supported by hospital-provided meals on training days, offers a template for how metabolic interventions might be scaled in clinical rehabilitation settings.

Nevertheless, the trial has boundaries that temper interpretation. The intervention lasted only two months, leaving open whether gains persist, plateau, or erode over longer follow-up. The sample, while adequate for detecting between-group differences, comprised children from a single hospital, raising questions about generalizability across demographic and clinical profiles. Blinding is notoriously difficult in dietary trials, as caregivers inevitably know what their children are eating, and outcome assessments may be influenced by expectations despite the use of standardized rating scales. The study was registered with the China Clinical Trial Registry under identifier ChiCTR2300075057 on 24 August 2023, and was funded by the Hefei Health Commission Research Fund, with no competing interests declared by the authors.

Even with those caveats, the results represent one of the more encouraging randomized evaluations of ketogenic dietary therapy in pediatric autism to date. They align with a broader shift in neuroscience toward viewing metabolic health as a modifiable lever in neurodevelopmental disorders, echoing the diet’s established success in epilepsy and emerging studies in conditions ranging from schizophrenia to Alzheimer’s disease. Larger, longer, and preferably multicenter trials will be needed to confirm the effect, identify which children benefit most, and define the optimal formulation and duration of treatment. For now, families and clinicians have reason for cautious optimism that a carefully supervised modified ketogenic diet may offer a meaningful complement to rehabilitation in early autism intervention.

Beyond the headline results, the trial offers a window into the practical physiology of ketogenic therapy in early childhood. When carbohydrate intake falls sufficiently low, hepatic metabolism shifts toward producing beta-hydroxybutyrate and acetoacetate, molecules that cross the blood-brain barrier and supply neurons with an energy substrate that yields more ATP per unit of oxygen than glucose. This metabolic flexibility matters in neurodevelopmental conditions, because a growing body of work links mitochondrial electron transport chain dysfunction and impaired cellular energy supply to subsets of autism spectrum disorder. By providing an efficient alternative fuel, ketogenic approaches may partially bypass compromised glucose utilization, which neuroimaging studies have occasionally documented in affected brain regions.

The clinical instruments used in the trial deserve closer attention for readers unfamiliar with pediatric assessment tools. The Autism Behavior Checklist originated in the 1980s as one component of the Autism Screening Instrument for Educational Planning and contains 57 items spanning sensory, relational, body and object use, language, and social domains, typically completed by caregivers or teachers. The Childhood Autism Rating Scale, developed by Eric Schopler and colleagues, contrasts a child’s behavior against age-typical norms across fifteen domains, with scores above a conventional threshold supporting an autism diagnosis. Because both instruments rely on observed behavior rather than biomarkers, their scores can fluctuate with context, rater training, and the child’s daily state, which is why randomized designs that balance such noise across arms carry particular weight.

Safety considerations loom large whenever a ketogenic regimen is proposed for young children, whose growth demands stable nutrition. Classical ketogenic diets, long deployed in epilepsy centers, carry recognized risks including constipation, dyslipidemia, kidney stones, and slow weight gain, and they typically require vitamin and mineral supplementation alongside careful monitoring of lipids, urine ketones, and growth trajectories. Modified variants relax the strict fat-to-carbohydrate ratios of the classical approach, trading some ketone elevation for improved palatability and adherence. In this study, the use of a powdered nutritional formulation with a structured plan suggests an attempt to standardize intake precisely because free-form ketogenic cooking in children, who frequently exhibit food selectivity, is difficult to control and document.

The shared improvement observed in both arms also merits interpretation. Intensive rehabilitation, with its predictable routines, structured social exposure, and engaged caregivers, is itself an active intervention, and the design wisely treated it as the comparator standard rather than an untreated baseline. Against that backdrop, the dietary supplement’s incremental effect on rating scale scores, while statistically robust by nonparametric testing, was measured over a window short enough that regression to the mean and heightened caregiver attention in the treatment group cannot be fully excluded. Objective correlates, such as sleep quality, gastrointestinal symptoms, attention measures, or biochemical markers of ketosis, would strengthen causal confidence in future work.

Looking forward, the field would benefit from trials that enroll diverse populations, stratify participants by metabolic or mitochondrial phenotype, and track outcomes well beyond the initial months of intervention. Dose-response relationships, the durability of ketosis achieved at home, and the identification of responder subgroups all represent open questions. If replicated at scale, a metabolically informed adjunct to behavioral rehabilitation could reshape early intervention pathways, but until then the present findings are best viewed as a promising signal that justifies expansion of controlled investigation rather than a basis for unsupervised dietary change outside clinical guidance.

Subject of Research: A randomized controlled trial evaluating a modified ketogenic diet as an adjunct therapy for children with autism spectrum disorder.

Article Title: Evaluating the therapeutic efficacy of a modified ketogenic diet in children with autism spectrum disorder: a randomized controlled trial

Article References: Liu, L., Zhao, Q., Zhou, J., Liu, Z., Wu, D., & He, K. (2026). Evaluating the therapeutic efficacy of a modified ketogenic diet in children with autism spectrum disorder: a randomized controlled trial. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07708-3

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07708-3

Keywords: autism spectrum disorder, ketogenic diet, randomized controlled trial, BMC Pediatrics, pediatric rehabilitation, ketosis, Autism Behavior Checklist, Childhood Autism Rating Scale, metabolic therapy, neurodevelopmental disorders, nutritional intervention, child health