Medicine and Pharmacology

Abstract: Background. The etiology of amyotrophic lateral sclerosis (ALS) remains unknown in approximately 90% of cases [1]. A unified mechanism linking environmental mycotoxin exposure, gut-brain axis dysfunction, and motor neuron disease has not been systematically investigated. Hypothesis. Chronic colonization of the gastric mucosa by a mycotoxin-producing mold, concealed beneath a mucosal biofilm and therefore potentially undetectable by standard endoscopy, is proposed to drive sustained motor-neuron hyperexcitability through three concurrent mechanisms: (1) TLR activation on vagal afferent fibers projecting excitatory signals to brainstem motor nuclei via neural spill-over; (2) cross-reactive immune attack on motor-neuron surface proteins via molecular mimicry; and (3) Dectin-1-mediated neuroinflammation during biofilm disruption. Case. Five-year index case: five positive urinary Trichothecene assays including one after a 32-hour fast (internal source confirmed); six immunological assessments, including five CD25 measurements, showing markedly reduced measured T-cell activation markers and cytokine responses (CD25 1.0–3.1%, reference 13–24%; IFN-γ 79.5 pg/ml, reference ≥118; IL-17 5.4 pg/ml, reference ≥9.6); EMG-confirmed neurogenic remodeling followed by documented stabilization; over 30 reproducible pharmacological observations consistent with the proposed mechanism; and formal diagnostic exclusion across four institutions over three years. Implications. Convergent findings from the published literature, together with more than 30 internally consistent pharmacological observations, support formal investigation of the proposed model. Proposed initial investigations include urinary mycotoxin testing, lymphocyte transformation testing, mycotoxin antibody testing, visual contrast sensitivity screening, and biofilm-directed endoscopy with confocal laser endomicroscopy, targeted biopsy, and PCR analysis.

Abstract: Background/Objectives: Long-term evidence on microbiome-targeted nutraceuticals in inflammatory bowel disease (IBD) is limited; we evaluated two regimens over 12 months. Methods: In this single-center, double-blind, nonrandomized, two-arm pilot trial, patients with ulcerative colitis (UC) or Crohn’s disease (CD) on stable standard-of-care therapy received fructooligosaccharides, galactooligosaccharides, yeast β-glucan, and minerals, alone (Suppl) or with silymarin (Suppl Plus), and were assessed at baseline, 6, and 12 months. The primary outcome was remission or mild activity at 12 months (UC, Mayo endoscopic subscore; CD, Simple Endoscopic Score for Crohn’s Disease). Secondary outcomes included fecal calprotectin, C-reactive protein (CRP), 16S rRNA gene profiles, and fecal nuclear magnetic resonance metabolomics. Registration: Brazilian Registry of Clinical Trials, RBR-7hvd26h. Results: Of 87 participants enrolled, 75 completed follow-up (UC, n=50; CD, n=25); four died. In UC, remission or mild activity increased from 44.0% to 82.0% (p<0.001), and median calprotectin declined from 406 to 286 µg/g (p=0.046); CRP was unchanged. In CD, it remained 88.0% (p=1.000), without calprotectin change (p=0.968). Remission did not differ between arms (UC, p=1.000; CD, p=0.593). Among completers, gastrointestinal adverse effects were self-limited; flatulence increased from 2.7% to 16.0% (p=0.009). Genus-level α-diversity increased, and Dorea and Blautia were enriched in UC at 6 months; community structure did not differ between arms. In UC, fecal xanthine (+139%), 4-pyridoxate (+130%), and nicotinate (+105%) increased. Conclusions: In this nonrandomized, single-center pilot without placebo, 12-month supplementation was associated with increased remission and reduced fecal calprotectin in UC; silymarin conferred no significant advantage. Randomized, placebo-controlled, multicenter trials are warranted.

Abstract: One of the biggest problems for researchers working in the field of idiopathic Parkinson's disease and patients is the lack of success in clinical trials attempting to develop new drugs that can slow or halt the progression of the disease. Enormous human and financial resources have been spent on preclinical research that has not led to the discovery of new drugs; however, a serious discussion about the causes of these failures is lacking. In our opinion, the problem lies in the fact that the preclinical studies on which the failed clinical trials were used an exogenous neurotoxin that induce a rapid and expansive degenerative process, which contrasts with the extremely slow degenerative process of idiopathic Parkinson's disease, which takes years. We have proposed that the neurodegenerative process of the nigrostriatal system, which culminates in the loss of dopaminergic neurons containing neuromelanin, is governed by a single-neuron neurodegeneration model. This degenerative process is triggered by the formation of aminochrome within neurons that synthesize neuromelanin, inducing a neurotoxic process without expansive effects on other neurons. This implies that the neurotoxic effects of aminochrome are restricted to a single neuron and that the loss of a single neuron accumulates over time until motor symptoms appear.

Abstract: Rosmarinic acid is a chemically attractive immunopharmacology scaffold, but its high polarity, ionization, metabolic lability, and incomplete target definition limit translation. This original communication defines AIIP RA DMAE 001, the internal code assigned to rosmarinic acid 2-(N,N-dimethylamino)ethyl ester, an artificial-intelligence-guided phytochemical-derived analogue generated within an AI-based immunopharmacology program. The design replaces the parent carboxylic acid with an ionizable 2-(dimethylamino)ethyl ester while retaining the natural rosmarinic-acid stereocenter and E-caffeoyl geometry. The free-base structure has the formula C22H25NO8, an average molecular weight of 431.44 g mol−1, and the isomeric SMILES CN(C)CCOC(=O)[C@@H](Cc1ccc(O)c(O)c1)OC(=O)/C=C/c1ccc(O)c(O)c1. Public exact-identity searches performed on 10 October 2026 found no individualized record for this structure, although closely related alkyl rosmarinates, methyl-rosmarinate derivatives, and a permanently charged rosmarinylcholine analogue are known and broad patent Markush language may encompass aminoalkyl esters. The compound is therefore described as putatively structurally novel, not as pharmacologically or therapeutically novel. A prior design record reported hypothesis-generating AutoDock Vina scores of −7.8, −8.1, and −8.3 kcal mol−1 against generic IgG, IgA, and IgM structures, respectively; these values do not establish binding and require prospective reproduction. The tertiary amine is expected to permit salt formation and substantial protonation near physiological pH, whereas the catechols and ester linkages create oxidation, assay-interference, hydrolysis, and distribution liabilities. We propose an evidence-gated program spanning synthesis and spectroscopic confirmation, pKa and stability measurement, orthogonal target-engagement studies, innate and adaptive immune phenotyping, and exposure-linked disease models. The most credible initial translational hypotheses concern type I interferon signaling and macrophage inflammatory state; direct immunoglobulin modulation should remain a higher-bar secondary hypothesis. AIIP RA DMAE 001 is thus a testable molecular proposal and a framework for transparent progression from AI design to immunological evidence.

Abstract: A recent paper by Nikolaidis and colleagues provides the first bottom-up calculation of the energetic cost of building 1 kg of wet human skeletal muscle, estimating a central value of 14,570 kJ/kg (3,481 kcal/kg). The paper's most striking finding is that common applied surpluses of 300–500 kcal/day are nearly tenfold higher than the calculated tissue-specific requirement. This commentary accepts the paper's calculation as a valuable reference point and asks two questions that the paper leaves open: (1) What determines the protein deposition efficiency, and (2) Where does the surplus go? The mass-balance framework suggests that protein deposition efficiency is not a free parameter but a consequence of myonuclear capacity, which scales with surface area. And the surplus does not disappear – it goes to fat mass, because muscle accretion is geometrically constrained while fat accretion is not. The commentary proposes a two-panel figure to illustrate both points. The framework is not a critique of the paper; it is a refinement that connects the calculation to the geometry of tissue accretion.

Abstract: Neonatal infections remain a major clinical challenge, particularly in preterm infants. This single-center retrospective observational study compared clinical, maternal, perinatal, laboratory, microbiological, antimicrobial resistance, and therapeutic characteristics between 10 preterm and 42 term neonates treated for suspected neonatal infection between January 2024 and April 2026. Microbiological support for infection was identified in 48/52 neonates (92.3%). Most inflammatory indices did not differ significantly between groups. Among neonates with available procalcitonin measurements (n = 14), concentrations were higher in preterm than in term neonates (p = 0.008); however, this finding should be considered exploratory because of the limited sample size. ESBL-producing Enterobacterales were more frequently identified in preterm than in term neonates (57.1% vs. 14.8%, p = 0.037), although based on small numbers. Meropenem use was more frequent in preterm neonates (30.0% vs. 2.4%, p = 0.019), and antimicrobial treatment duration was longer (median 7.5 vs. 5.0 days, p = 0.041). These findings suggest differences in antimicrobial resistance and treatment patterns between preterm and term neonates and support continued local microbiological surveillance and antimicrobial stewardship.

Abstract: Background and Objectives: The use of cryopreserved hematopoietic cells in allogeneic hematopoietic cell transplantation (HCT) has become widespread all over the world and in our country, especially after the SARS-CoV-2 pandemic. This situation has increased the importance of the effect of cryopreservation on engraftment, the incidence of transplantation-related complications, and the survival of patients. This study aimed to compare the transplant results between the patient group receiving peripheral blood-derived cryopreserved cells and the patient group receiving fresh products in patients over the age of 18 who had hematological diseases and underwent allogeneic HCT. Materials and Methods: A total of 222 patients over the age of 18 with hematological diseases who underwent allogeneic HCT were included in the study. Neutrophil engraftment time, platelet engraftment time, disease-free survival, overall survival, graft versus host disease incidence, cytomegalovirus reactivation/infection and transplant-related mortality rates were retrospectively compared between the cryopreserved and fresh product groups. Results: No significant difference was found between the cryopreserved and fresh product groups in terms of median age, gender, body weight, hematological disease subtype, disease status before HCT, Sorror comorbidity index, blood group compatibility, and preparation regimen intensity. On the other hand, the haploidentical HCT count was higher in the fresh cell group. The number of CD34+ stem cells received by patients receiving cryopreserved products was lower than the number of CD34+ stem cells received by patients receiving fresh products. No significant difference was found between the cryopreserved and fresh product groups in terms of platelet and neutrophil engraftment time, engraftment failure rate, cytomegalovirus reactivation/infection rate in the first 100 days after HCT, development of graft versus host disease, transplant-related death, disease-free survival and overall survival. Conclusions: Cryopreservation and cell storage is very important in order to prevent complications such as delays in the patient's transplantation process due to donor-related problems, prolonged hospital stay, and related complications. When done properly, cryopreservation can produce HCT outcomes similar to those obtained with fresh products.

Abstract: (+)-Nootkatone (NTK) is a bioactive sesquiterpene with significant therapeutic potential, but its application is hindered by low aqueous solubility and physical instability. Inclusion complexation with βcyclodextrin (βCD) offers an effective strategy to overcome these biopharmaceutical limitations. The present study investigated the antinociceptive effects of isolated nootkatone and its β-cyclodextrin inclusion complex (NTK/βCD) in murine models of acute nociception. The NYK/βCD complex was obtained by solvent co-evaporation method, and the drug content was quantified at 43.37% by GC-FID. Animals received NTK and NTK/βCD orally at 10 mg/kg. Central nervous system (CNS) effects were assessed using the rotarod and open-field tests, while antinociceptive activity was evaluated through the acetic acid-induced abdominal writhing test (1% acetic acid) and the formalin test (2.5% formalin). Additional assessment of antinociceptive effects was conducted using the hot plate and tail-flick tests. To elucidate the involvement of specific pain-signaling pathways, the opioid, nitric oxide, vanilloid, glutamatergic, cyclic guanosine monophosphate (cGMP), α1- and α2-adrenergic, dopaminergic, and serotonergic pathways were examined. Administration of NTK and NTK/βCD (10 mg/kg) did not produce significant effects on the CNS. In the acetic acid-induced abdominal writhing test, NTK and NTK/βCD reduced the number of writhes by 90.21% and 84.78%, respectively. In the formalin test, reductions of 51.81% and 47.58% were observed during the first phase, while reductions of 81.82% and 74.29% were observed during the second phase. In the hot plate test, NTK and NTK/βCD increased response latency by 116.72% and 121.66%, respectively. In the tail-flick test, response latency increased by 79.87% and 100.55%, respectively. Crucially, as NTK/βCD exhibited a drug content of 43.37%, the 10 mg/kg dose supplied an effective active payload of only 4.34 mg/kg and showed antinociceptive efficacy statistically equivalent to 10 mg/kg of uncomplexed NTK. The findings indicate that NTK and NTK/βCD may exert antinociceptive effects through the opioid, nitric oxide, vanilloid, glutamatergic, cGMP, and α2-adrenergic signaling pathways. Collectively these results demonstrate that that NTK and NTK/βCD possess significant antinociceptive potential and that β-cyclodextrin inclusion significantly enhances the dose efficiency of nootkatone, enabling equivalent pain management at less than half the active ingredient dose, rendering them promising candidates for the development of alternative therapeutic strategies for pain management.

Abstract: Bio-encoded nanostructures use nucleic-acid or protein sequence information to specify aspects of nanoscale assembly, ligand display, cargo organization, or stimulus-responsive function. Their pharmacological promise depends not only on whether a structure can be designed, but on whether the intended architecture survives manufacture and biological exposure, reaches the relevant compartment, produces target engagement, and does so with acceptable safety. This narrative review examines DNA and RNA nanostructures, self-assembling protein nanoparticles, virus-like particles, and selected biomimetic systems through a pharmacology-first lens. Rather than treating programmability as evidence of therapeutic superiority, it links design features to testable development questions: What product attributes must be measured? Which experiment can identify a failure in assembly, stability, biodistribution, intracellular delivery, or pharmacodynamic activity? What evidence is needed before a candidate advances? The review proposes a six-layer framework spanning molecular information, assembly, biological recognition, disposition, response, and translation, then converts it into a practical failure-analysis workflow with measurable readouts and decision points. The framework is a proposed development aid, not a validated predictive model or an established regulatory classification. Its value will depend on prospective testing against platform-specific datasets and demonstration that it improves experimental prioritization. By separating demonstrated findings from hypotheses and linking each design claim to an assay and a development decision, the review aims to help researchers more precisely diagnose translational bottlenecks and reduce the risk of advancing nanostructures based on in vitro programmability alone.

Abstract: Polygonatum odoratum is widely consumed as a functional food and is traditionally used for respiratory complaints, yet the material basis of its anti-pneumonia activity and the effect of extraction solvent on that activity remain unclear. Here, untargeted LC-QTOF-MS profiling of the aqueous extract was combined with TCMSP database mining to screen potential active components, and their core targets and binding modes were predicted by network pharmacology and molecular docking. Of 38 potential active components screened by oral bioavailability and drug-likeness, 28 were mapped to 123 pneumonia-related targets. IL6, AKT1, IL1B, TNF, TGFB1, TP53, MMP9, PIK3CG, HIF1A and CASP3 occupied hub positions in the PPI network and were enriched in the IL-17, TNF and PI3K-Akt pathways. Molecular docking of 7 representative components against 9 core targets gave 24 systems with binding energies all below −4.8 kcal/mol, and different components frequently occupied the same binding pocket, indicating a multi-component, multi-target mode of action. Critically, all nine docking targets were functionally interrogated in LPS/IFN-γ-stimulated MLE-12 cells: the 50% methanol extract significantly improved 9 of 10 indicators, outperforming the aqueous extract on all 10, with significant differences in p-AKT and p-CREB (P < 0.05). Medium-lipophilic homoisoflavonoids are therefore the principal material basis of the anti-pneumonia activity, and hydroalcoholic extraction better retains them. These findings support the use of P. odoratum as a functional food ingredient for respiratory health.

Abstract: Patient satisfaction has become a dominant metric of health care quality, embedded in public reporting, accreditation, and pay-for-performance programs. Its prominence rests on an implicit assumption that satisfied patients have been treated well and have improved. This narrative review synthesizes conceptual and empirical literature to examine whether, how often, and why patients can be highly satisfied despite minimal clinical gain or dissatisfied despite substantial gain. The 2 constructs are related but explain little of each other. In a cohort of 2116 surgical patients, no outcome measure accounted for more than 8% of the variance in satisfaction, which tracked absolute postoperative state rather than change. Complications and readmissions show weak, inconsistent associations with satisfaction, whereas communication and shared decision-making are strongly and independently associated with it. Six mechanisms explain the divergence: expectancy disconfirmation (unmet expectations raised the odds of dissatisfaction after knee arthroplasty more than 10-fold), relational determinants, health-status confounding, placebo and nocebo effects, response shift (detected in 86.7% of longitudinal studies), and measurement artifacts such as ceiling effects and response bias. In low- and middle-income settings, more than half of respondents rated poor-quality care as good or better. Satisfaction should be neither discarded nor used as a surrogate for effectiveness; complementary measurement of care experience, clinical outcome, and expectation fulfillment is the defensible path.

Abstract: Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease in which calcium phosphate microliths fill the alveoli. Although the cause of it remained unknown for some time, more recently loss-of-function variants in SLC34A2, which encodes the sodium-phosphate cotransporter NPT2b, explain nearly all genetically tested cases; failure to clear phosphate from the alveolar lining fluid leads to microlith formation, and an epithelial Npt2b-knockout mouse reproduces the human phenotype. Diagnosis now rests mainly on characteristic high-resolution CT and, increasingly, on genotyping rather than lung biopsy. The protracted course has been described in some series of cases, with death from respiratory failure. No drug has proven efficacy; lung transplantation is the only established therapy, and no allograft recurrence has been documented. Preclinical data support phosphate restriction, EDTA lavage and gene-directed approaches. However, controlled trials with more genotype-phenotype correlation and prospective natural-history data are still needed.

Abstract: Background. Antibiotic use in bronchiolitis is generally discouraged by international guidelines, given that concurrent bacterial superinfection is uncommon. Reported prevalence varies widely across countries and settings, with no prior comparable data for Latin American neonatal units.Objective. To describe, for antimicrobial stewardship surveillance, the prevalence of documented antibiotic use during bronchiolitis episodes in a Latin American neonatal cohort (2010–2025) not explained by an identifiable alternative reason, and to place it in context against the international literature.Methods. Descriptive, retrospective, multicenter study. Bronchiolitis episodes were identified through free-text searching of the diagnosis field. An antibiotic exposure window was defined from one day before to 20 days after diagnosis. Every case with documented antibiotic use underwent manual case-by-case review, cross-referencing treatment duration (≤3 documented days = unconfirmed suspicion) against other recorded diagnoses to identify reasonable alternative reasons for use, distinct from bronchiolitis itself. Sites were randomly pooled into 6 anonymized groups.Results. 685 bronchiolitis episodes were identified; 19 (2.8%) were excluded for infection documented at diagnosis, leaving 666 analytic episodes. Documented antibiotic use was observed in 48 episodes (7.2%; 95% CI 5.5–9.4%). After manual review, 28 of 48 (58%) had an identifiable alternative cause, leaving 20 episodes (3.0%; 95% CI 2.0–4.6%) without one. Group 5 showed the highest relative prevalence (33.3%; 7/21). No significant baseline differences were found between exposed and unexposed infants. One death occurred among all 685 episodes, in a case excluded for concurrent infection (685 g, 26 weeks, group B Streptococcus sepsis); no deaths occurred within the analytic cohort (0/666).Conclusions. Documented antibiotic use in bronchiolitis without an identified alternative cause in this Latin American cohort (3.0%) is considerably lower than reported in most international literature (typical ranges 13%–55%). Nearly 60% of crude antibiotic use is explained by causes other than uncomplicated bronchiolitis, underscoring the importance of individual case review over administrative records alone.

Abstract: Background: Mycotic Aortic aneurysms (MAA) are saccular aneurysms of the infected aortic wall. Mycobacterium, compared with other bacteria, is less likely to cause MAA; most cases follow, but it is a rare, late, systemic, and serious complication of intravesical Bacillus Calmette-Guérin (BCG) instillation for bladder cancer. Case Presentation: A 65-year-old male with a history of hypertension, hyperlipidemia, diabetes mellitus, diabetic foot ulcer with methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia, status post partial toe amputation, and papillary urothelial carcinoma treated with transurethral resection and intravesical BCG instillation, recently underwent a computed tomography (CT) abdomen 2 weeks ago for abdominal pain, which revealed colonic stool without other pathological findings, who currently presented with worsening abdominal pain, and the CT scan identified a new 2.5-centimeter pseudoaneurysm of the infrarenal aorta, associated with a periaortic and aortocaval mass, likely a hematoma, infectious mycotic aneurysm, or neoplastic process. The patient received intravenous piperacillin-tazobactam for presumed MSSA, a potential cause of a mycotic aneurysm, which was later discontinued after negative blood cultures. Vascular surgery consultation led to endovascular aortic stenting. Infectious disease recommended a Karius test; despite no warning signs, it returned positive for the Mycobacterium tuberculosis complex, and a diagnosis of a BCG-induced aneurysm was made. The patient was treated with isoniazid, rifampin, ethambutol, and pyridoxine, then continued isoniazid and rifampin for 9 months. Conclusion: We presented a rare case of a BCG-induced mycotic aortic aneurysm that developed within 2 weeks. Therefore, we need a low threshold for MAA in patients with a history of intravesical BCG instillations who present with worsening abdominal pain, even if prior imaging 2 weeks ago showed no warning signs and instillations were given 2 years ago. Testing and diagnosing a BCG-induced aneurysm are necessary despite endovascular intervention, because it can further infect the stent and form an abscess if untreated.

Abstract: The tumor microenvironment (TME) has now become a fundamental concept in oncology research, as it changes the traditional viewpoint of tumors as an autonomously functioning assembly of cancer cells. In this review, we evaluate recent advances in the understanding of the bidirectional crosstalk between the malignant cells and the neighboring, but non-malignant, stromal/immune cells. The roles of stromal cell subsets – mesenchymal stem cells, endothelial cells, and cancer-associated fibroblasts – as well as immunosuppressive immune cell populations, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, are considered. Furthermore, the mechanisms underlying the interactions of tumor-derived molecules, metabolic modifications, and exosome signaling with extracellular matrix (ECM) and tumor immune modulation that enable tumor evasion, angiogenesis, and pre-metastasis niche formation are discussed. As a result, we discuss the current state of several therapeutic possibilities, including vascular normalization, ECM disruption, metabolic targeting, and sophisticated nanotechnology-based drug delivery platforms. This review provides evidence that, in order to counteract TME-driven tumor progression, it is vital to develop combinatorial treatments targeting multiple aspects of microenvironmental networks, which form a necessary basis.

Abstract: Intranasal esketamine has been available for treatment-resistant depression (TRD) since 2019, but the trials that led to its approval answer only some of the questions prescribers face. About 97% of trial participants had failed only one or two antidepressant classes, and patients with bipolar disorder, psychosis, obsessive–compulsive disorder, four personality disorders, moderate-to-severe substance use disorder, or recent suicidal intent were excluded, although such patients are common in practice. This review is meant as a practical guide for prescribers. We discuss the mechanism of action and its clinical implications, ideal and real-world candidates, patients with suicidal ideation, psychiatric comorbidity (including borderline personality disorder), dosing, concomitant medications, prevention and management of adverse effects, comorbid substance use disorder, treatment duration in responders and non-responders, and contraindications. Six tables summarise the drug’s characteristics, receptor pharmacology, patient selection, concomitant medications, adverse-event management and contraindications, including differences between the US and European labels. For each recommendation, we indicate whether it comes from the label, from expert consensus, or from untested practice. The evidence does not show that 84 mg is more effective than 56 mg; comorbidity has seldom predicted non-response in real-world cohorts; the standing benzodiazepine dose should be reviewed before induction; and response is often judged too early.

Abstract: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition arising from interactions among genetic susceptibility, environmental exposures, altered cellular responses and progressive lung injury. This complexity limits the ability of conventional clinical measures or any single molecular layer to explain differences in disease development, progression and treatment response. This review examines how artificial intelligence (AI)-mediated integration of selected omics including genomics, epigenomics, transcriptomics, single-cell and spatial omics, proteomics, metabolomics, lipidomics and microbiomics could provide a more connected understanding of COPD biology. These complementary layers capture inherited susceptibility, exposure-related regulation, cell-specific dysfunction, active molecular pathways, metabolic alterations and host-microbial interactions. Although previous publications have examined COPD multi-omics, computational integration or AI applications, this review proposes a conceptual, hypothesis-generating framework linking selected omics across disease development and biological mechanisms to potential biomarkers and therapeutic opportunities. Such integration may generate testable hypotheses, identify patient subgroups with biologically meaningful characteristics and help in biomarker development, therapeutic-target identification, drug repurposing, treatment-response prediction and clinical-trial design. However, direct evidence demonstrating the clinical value of AI-integrated COPD omics is warranted. Translation could be further constrained by small and selected cohorts, technical heterogeneity, confounding factors like smoking, treatments, limited population diversity and insufficient independent and prospective validation. By focusing on selected omics layers that are among the most relevant to COPD biology and clinical heterogeneity, this framework identifies timely opportunities for integrative research that could lay the groundwork for developing and testing biomarkers and therapeutic strategies. Progress will require longitudinal multicenter studies, standardized measurements, interpretable and biologically informed AI methods, experimental confirmation and prospective evidence that resulting approaches improve clinical decisions or patient outcomes.

Abstract: A recent analytical paper by Arencibia-Albite demonstrates that the energy balance model (EBM) is internally inconsistent. The proof does not rely on any empirical dataset. The argument is that EBM’s own equations require energy balance and body weight stability to be simultaneous equilibrium states. That equilibrium requires stable fat mass and fat-free mass. Stable fat-free mass requires nitrogen balance. Nitrogen balance is impossible given obligatory nitrogen losses. The model cannot simultaneously satisfy its own equilibrium conditions. This commentary explains the proof for a general nutrition science audience, situates it within the broader critique of the energy balance framework, and discusses its implications for research and practice. The proof is analytical, not empirical. It shows that the model’s equations do not close. This does not mean that energy is irrelevant. It means that energy balance alone cannot describe body weight regulation. Mass balance offers a more complete description. The clinical implication is direct: when patients fail to lose weight despite adherence to caloric restriction, the failure may lie in the framework, not in the patient.

Abstract: Standard psychiatric rating scales such as the PANSS, HAM-D and MADRS remain the dominant outcome measures in clinical trials and routine care, yet they were built to quantify symptom severity rather than to register the full range of change that matters to patients. This narrative review synthesized psychometric, validation, epidemiological and trial evidence, together with consensus reports, to identify clinically and personally meaningful improvements that symptom-focused scales fail to detect. Evidence converged on ten under-measured outcome domains: real-world functioning, which correlates only weakly with symptoms and often lags behind them; cognition and social cognition; negative symptoms and motivational anhedonia; the subjective experience of medication; quality of life and positive mental health; personal recovery (connectedness, hope, identity, meaning and empowerment); internalized stigma; physical health and premature mortality, with all-cause mortality two to three-and-a-half times that of the general population; sleep and circadian function; and shared decision-making as a process outcome of care. Two cross-cutting limitations compound these gaps: systematic discordance among clinician, self-report and informant ratings, and the inability of retrospective, clinic-based instruments to capture the momentary, context-dependent dynamics now accessible through ecological momentary assessment and passive sensing. We propose a pragmatic, tiered outcome set that pairs every symptom scale with measures of functioning and of quality of life or recovery, adds physical health, sleep and medication burden, and reserves digital methods for settings that can support them. Improvement in psychiatry is multidimensional; measuring it as such is a scientific necessity, not a refinement.

Abstract: Survivors of sexual violence carry a disproportionate burden of age-related morbidity, including cardiovascular disease, type 2 diabetes and inflammatory conditions, raising the possibility that sexual trauma accelerates the biology of aging rather than acting solely through psychological distress or health behaviors. This narrative review synthesizes translational, epidemiological and biomarker evidence across five mechanistic domains. Epigenetically, posttraumatic stress disorder (PTSD) is associated with accelerated DNA-methylation age, most consistently on the mortality-calibrated GrimAge clock, whereas meta-analytic evidence for cumulative childhood adversity on first- and second-generation clocks is weak. At the cellular level, severe childhood sexual abuse is associated with shorter leukocyte telomeres in several, though not all, studies, and PTSD with telomere attrition, T-cell senescence and oxidative DNA damage. Endocrinologically, childhood sexual abuse produces enduring hypothalamic-pituitary-adrenal axis sensitization and earlier pubertal maturation in girls. Inflammatory evidence is the most robust: childhood maltreatment prospectively predicts adult C-reactive protein, and PTSD is consistently associated with elevated pro-inflammatory cytokines. Metabolically, PTSD is associated with a high prevalence of metabolic syndrome, and childhood sexual abuse with obesity and type 2 diabetes in women. Glucocorticoid-FKBP5-NF-κB signaling and allostatic load emerge as bridges between domains, and we propose an integrated six-step model. Causal inference remains limited by retrospective trauma assessment, confounding by co-occurring adversity and scarce trauma-type-specific analyses. Priorities include prospective, sexual-trauma-specific multi-omic studies and trials testing whether trauma-focused, anti-inflammatory or metabolic interventions can slow the pace of biological aging in survivors.