Medicine and Pharmacology

Abstract: Platinum-based chemotherapy remains a key treatment for epithelial ovarian cancer, but platinum resistance is a major cause of treatment failure and mortality. Traditionally, platinum resistance has been defined by the interval between the last platinum treatment and disease progression, with progression within six months generally classified as platinum-resistant. This six-month platinum-free interval has long provided a useful framework for treatment selection. However, growing preclinical and clinical evidence suggests that this interval should not be treated as a strict biological boundary. Platinum susceptibility can change as tumors evolve, with some tumors retaining residual sensitivity while others develop stable or potentially modifiable resistance mechanisms. These mechanisms include restoration of homologous recombination, altered DNA-damage tolerance, epigenetic regulation, changes in platinum transport and detoxification, adaptive survival signaling, and alterations in cell-death pathways. Some resistance mechanisms are relatively stable, whereas others may remain biologically plastic and potentially amenable to therapeutic modification. This distinction has important implications for platinum rechallenge. Responses to platinum reintroduction in selected patients previously classified as platinum-resistant indicate that the six-month interval does not fully capture the biology of platinum responsiveness. However, renewed clinical activity after rechallenge should not automatically be interpreted as biological resensitization. True resensitization requires evidence that a defined resistance mechanism has been modified and that this alteration increases platinum susceptibility. Preclinical studies have identified multiple strategies to modify platinum-resistance pathways, but clinical translation remains limited. This perspective therefore proposes that platinum resistance should be understood as a clinically defined phenotype encompassing biologically heterogeneous states, some of which may be stable and others potentially reversible. Recognizing this distinction has implications for biomarker development, treatment selection, trial design, and interpretation of platinum rechallenge. Prospective studies incorporating longitudinal tumor profiling and functional assessments of platinum susceptibility may ultimately identify patients in whom platinum activity can be therapeutically restored.

Abstract: Background: Short sleep and depression frequently co-occur in older adults, but whether they share a gut microbiota signature or carry largely phenotype-specific features remains unresolved. We therefore characterized fecal microbiota features shared by or specific to short sleep and depression using American Gut Project 16S rRNA data. Methods: Using American Gut Project (AGP) V4 16S rRNA data (PRJEB11419), we assigned older adults to four mutually exclusive groups: healthy controls (HC; 7-8 h sleep, no depression), short-sleep only (SSD), depression only (DP), and short-sleep plus depression (SSD + DP; exploratory). Complete age, sex, and BMI data with at least 1,000 reads yielded 1,056 participants (HC 617; SSD 255; DP 148; SSD + DP 36). We examined diversity, taxonomy, covariate-adjusted genus-level associations, and cross-validated discrimination. Scale-upgraded sensitivity analyses included 1,307 participants, 146 genera, and 20 multiply imputed data sets. Results: Richness (q = 0.001; adjusted q = 0.007), Shannon diversity (q = 0.031; adjusted q = 0.111), and Faith's diversity (q = 0.001; adjusted q = 0.007) differed across groups; adjusted richness and Faith's diversity also differed among depression-only participants (both q = 0.003). PERMANOVA showed no global separation (minimum P = 0.065). Significant genera numbered 3 in SSD, 3 in DP, and 0 in SSD + DP: SSD was associated with UCG-002 (log2FC = -1.01), UCG-003 (-0.76), and Erysipelatoclostridium (+0.69), and DP with UCG-003 (-1.21), [Ruminococcus] gnavus group (+1.06), and Lachnospiraceae UCG-010 (-0.71). Core clinical AUCs were 0.554 (95% CI 0.514-0.596) and 0.623 (0.579-0.668), rising to 0.599 (0.559-0.640) and 0.654 (0.611-0.695) with extended clinical variables; adding microbiota features lowered these to 0.566 (0.524-0.608) and 0.637 (0.593-0.680), providing no gain. Sensitivity AUCs were 0.575-0.610 and 0.643-0.675. Scale-upgraded OLS/limma confirmed 17 genera and 8 interaction genera, with AUCs of 0.585 and 0.645; additional models reached 0.622 and 0.687. A phenotype-matched constipation contrast (78 cases, 695 controls) yielded AUCs of 0.771 and 0.798. Conclusion: Short sleep and depression showed modest, largely non-overlapping microbiota signals, whereas constipation showed a clearer but still non-diagnostic signal. These findings are hypothesis-generating and do not support clinical or causal interpretation.

Abstract: Surgical interventions in cirrhotic patients are a relevant problem due to the high rates of perioperative morbidity and mortality. The purpose of this review is to provide up–to-date information on the current principles of extrahepatic abdominal surgery in cirrhotic patients. They are based on stratification of patients by risk groups and a multidisciplinary individual approach to the choice of treatment strategy. The implementation of these provisions includes the use of scores for predicting perioperative risk, diagnosis and possible correction of clinically significant portal hypertension, prophylaxis of infectious complications and postoperative venous thromboembolism, monitoring of coagulopathy and cardiovascular disorders, nutritional support and etiological therapy. When choosing the optimal method of surgical treatment in urgent cases, one should strive to use minimally invasive technologies. If elective operations are considered, a thorough examination of patients is necessary to determine the risk factors for adverse outcome, resolve issues of preoperative preparation, and choice of the scope and timing of the surgical intervention. It can be assumed that the thoughtful implementation of these principles in clinical practice and, in prospect, the use of robotics and artificial intelligence will improve the safety of extrahepatic abdominal surgery in cirrhotic patients.

Abstract: In the frame of our ongoing research on multitarget alkaloid-derived anticancer agents, relying on a modular synthetic strategy terminated by well-established sequential Sonogashira and CuAAC protocols, we synthesized a systematic selection of chalcone-vindoline hybrids incorporating 1,4-disubstituted 1,2,3-triazole as a linker. The use of the same synthetic approach led to the construction of a zidovudine-derived vindoline hybrid, which served as a negative control highlighting the essential contribution of the chalcone moiety to the antiproliferative activity. Two analogous aryl-substituted chalcone hybrids 14a,b were also prepared to assess the contribution of the vindoline fragment to the desired effect. The targeted hybrids and the references were evaluated for their antiproliferative activity against a panel of human adherent gynecological cancer cell lines (HeLa, SiHa, MCF-7, MDA-MB-231 and A2780) as well as on non-malignant fibroblasts (NIH/3T3). Vindoline hybrids 10a and 10i comprising 3,4,5- and 1,4,6-trimethoxyphenyl-substituted chalcone fragments, respectively, displayed substantial activity, featuring IC₅₀ values lower than 0.4 µM on all the investigated cancer cell lines. On the other hand, hybrids 10c–e containing monomethoxy-substituted chalcones, also featuring submicromolar IC₅₀ values on malignant cells, showed moderately lower activities against non-malignant fibroblasts (NIH/3T3), indicating a certain degree of cancer selectivity. The related ferrocene-derived hybrid (10i) and vindoline-free chalcones 14a,b were identified as antiproliferative agents with significantly decreased efficiency, while the ferrocene hybrid comprising an alternative enone sequence in the chalcone residue (11) as well as the zidovudine-derived vindoline hybrid 12 were inactive. Modeling results indicate that the vindoline hybrids bind to the inter-dimer vinca crevice of tubulin oligomers and confirm that the two segments exert a mutually stabilizing effect on the binding of the other, providing a framework for future structure optimization.

Abstract: Introduction: Genetic variants in the Tenascin-XB (TNXB) gene have been associated with autosomal recessive Ehlers-Danlos Syndrome (classical-like) without vascular features. Here, we report the contribution of two TNXB variants, in cis or trans, to the development of arterial aneurysms and bicuspid aortic valves with or without connective tissue disease features present. Methods: The identification of compound heterozygosity in TNXB (c.8791+1G>A, c.12469+2T>C) in a 52-year-old female with fibromuscular dysplasia, bilateral vertebral artery dissections, and thoracic aortic aneurysm by whole exome sequencing (WES) prompted screening for TNXB variants in an institutional WES registry comprising 350 individuals with aneurysms and/or dissections. Multigene panel testing (MGPT) results from 1844 individuals tested at Ambry Genetics for a personal or family history of aneurysms, dissections, or other connective tissue disease features were used for replication analysis. Random exomes of 26,922 unaffected individuals were used as controls. Statistical analysis using Fisher’s exact test was carried out to compare the frequency of two or more TNXB variants in cases vs. controls. AlphaFold3 structural modeling was used to assess the effects of variants in cis on the 3-D structure and molecular interaction with the TGF-beta-3 proprotein. Results: There were significantly higher numbers of individuals who carried two or more rare, nonsynonymous TNXB variants, in cis or trans, in both WES (n=5/350; 1.4%) and MGPT (n=19/1844, 1.0%) datasets (p<0.01) compared to ethnically matched controls (n=89/26922; 0.14%). Additionally, there was a significantly higher prevalence of bicuspid aortic valve (BAV) in the MGPT cohort compared to the general population (11% vs. <2 % reported). The analysis by AlphaFold3 structural modeling revealed increased distortion of the 3-D structure caused by the presence of two variant(s) in cis vs. one variant in TNXB. Conclusion: This data strongly suggests an association between vascular aneurysm and/or dissection or bicuspid aortic valves and individuals with two TNXB variants.

Abstract: Background/Objectives: Parkinson’s disease (PD) is a rapidly growing cause of neurological disability, yet diagnosis is often delayed in settings with limited access to movement-disorder specialists, including Kazakhstan and other Central Asian countries. This study aimed to develop a brief, self-administered, two-stage machine-learning-derived questionnaire based on binary symptom responses to identify individuals with possible clinically manifest PD who may benefit from specialist neurological assessment, and to evaluate its performance. Methods: From outpatient records of 402 patients with confirmed PD, a preliminary 100-item yes/no questionnaire was compiled. In a development cohort of 389 participants aged 60 to 90 years (146 with PD, 243 controls) recruited in Almaty, Kazakhstan, we used ElasticNet logistic regression, random forest, and gradient boosting to select features, reducing the instrument to 35 items (15 in Stage 1, 20 in Stage 2). We assessed performance on a held-out test set (n=78) and in an interim prospective external-validation cohort (n=290) recruited independently, with neurologists blinded to questionnaire results. Results: On the held-out test set, sensitivity was 86.2%, specificity 89.8%, accuracy 88.5%, and Stage 1 AUC 0.9557. In the interim external validation, sensitivity was 95.1%, specificity 94.4%, accuracy 94.5%, NPV 99.2%, and Stage 1 AUC 0.9962; only 12.1% of participants required Stage 2. Conclusion: The two-stage questionnaire showed strong case-finding ability in identifying individuals who warrant neurological evaluation. Findings are interim; completion of external validation, larger geographically diverse cohorts, and comparison against existing instruments are needed before wider implementation.

Abstract: Background/Objectives: Postoperative management after cataract surgery involves topical anti-inflammatory and antimicrobial treatments, whose clinical performance may be affected by adherence, administration technique, and intraocular exposure. This study evaluated a biodegradable poly(lactic-co-glycolic acid) intracameral implant containing moxifloxacin hydrochloride and dexamethasone, designed for intraoperative placement. Methods: Clinical tolerability, anti-inflammatory activity in a uveitis model, and antibacterial performance following a low-inoculum intravitreal challenge with Pseudomonas aeruginosa were evaluated in New Zealand White rabbits. Aqueous humor pharmacokinetic profiles were also assessed in phakic and aphakic eyes. Clinical follow-up included slit-lamp biomicroscopy and intraocular pressure measurements. Concentration–time data were analyzed by means of nonlinear mixed-effects models and model-based simulations. Results: No visible implant material remained four weeks after insertion. A transient pseudo-membrane was observed shortly after implantation in some implanted eyes, but it resolved spontaneously and was not accompanied by clinical inflammatory signs. No sustained increase in intraocular pressure was observed during follow-up. Untreated bacterially challenged eyes rapidly developed severe endophthalmitis, whereas implant-treated eyes showed no clinical evidence of endophthalmitis. In the exploratory uveitis experiment, implant-treated eyes showed lower clinical inflammatory scores and faster recovery than matched eyes without the implant. Model-based simulations suggested persistent dexamethasone exposure through day 30, whereas moxifloxacin reached an early peak and was predominantly below the limit of quantification from day 7 onward. Conclusions: These findings provide preliminary preclinical proof-of-concept evidence supporting the clinical tolerability and pharmacological activity of the implant under the experimental conditions evaluated. The results are hypothesis-generating, should not be extrapolated to clinical safety or efficacy, and do not demonstrate microbiological eradication. Further studies with larger cohorts, pseudophakic models, microbiological and histopathological endpoints, and optimized pharmacokinetic sampling are required.

Abstract: Family-based treatment (FBT) is an evidence-based treatment for adolescents with restrictive eating disorders (EDs). However, FBT is delivered within social and healthcare environments where weight stigma and diet culture remain pervasive. This creates a paradox: young people are asked to challenge fears of weight gain, restore weight, and normalize eating, while encountering messages that reinforce thinness, weight loss, and restrictive behaviours. These tensions are particularly salient in FBT, where weight restoration, parent-led renourishment, and discussions of growth and body change are central. In this narrative review, we examine how weight stigma may enter or interfere with FBT principles through the people and processes involved in treatment. Drawing on existing literature and an author-developed clinical training workshop, we propose practical considerations for delivering weight-inclusive FBT while preserving its core therapeutic functions. These include ongoing clinician self-reflection, weight-inclusive treatment environments, and team alignment on weight goals, alongside FBT-specific approaches to recognizing illness and activating urgency, establishing treatment targets and supporting weight restoration, supporting parent-led renourishment, navigating weighing and body changes, returning autonomy, and relapse prevention. Weight-inclusive practice need not compete with FBT fidelity; recognizing and addressing weight stigma may instead strengthen clinicians’ ability to achieve FBT’s fundamental aims across the weight spectrum.

Abstract: Background: Cannabidiol (CBD) is increasingly used as self-treatment for psychiatric symptoms despite limited evidence of efficacy. This systematic review examined clinical trials investigating effects of CBD on anxiety, mood, and trauma-related disorders and symptoms. Methods: Following PRISMA 2020 guidelines, MEDLINE, PsycINFO, and Embase were searched from inception to August 2026 for randomized controlled trials (RCTs) of CBD in adults with anxiety, mood, or trauma-related disorders or subthreshold anxiety, mood, or trauma-related symptoms. Risk of bias (RoB) was assessed using Cochrane RoB 2. Results: Of 733 publications identified, 12 reports from 10 RCTs met inclusion criteria: six examined anxiety, two mood / depressive, and four PTSD/trauma-related disorders or symptoms. In anxiety studies, CBD monotherapy reduced anxiety symptoms and negative self-evaluation in some populations, although effects varied across outcomes and dosing paradigms. Adjunctive CBD with exposure therapy for social anxiety disorder and panic disorder with agoraphobia provided no benefit over placebo. Trials in bipolar depression and depressive symptoms showed no CBD-specific effects. In trauma studies, CBD generally did not improve trauma-related, depressive, or anxiety symptoms. However, two reports from a single trial found that a single dose of CBD attenuated cognitive impairment induced by trauma-recall. One of these reports reported reduced anxiety among participants with nonsexual trauma. Two reports were low risk of bias, seven had some concerns, and three were high risk. Limitations: CBD adherence was objectively verified in three trials. The small, heterogeneous evidence base limited comparisons across diagnoses and outcomes. Conclusions: Evidence for CBD as treatment of anxiety, depressive, and trauma-related symptoms remains preliminary. Some anxiety trials found reductions in anxiety symptoms with CBD monotherapy, but findings were inconsistent across populations, outcomes, and dosing paradigms. Evidence was insufficient to determine CBD-specific effects on depressive or trauma-related symptoms. Future RCTs should standardize and objectively verify dosing and incorporate cognitive, physiological, and neurobiological outcomes.

Abstract: Background: Doxycycline post-exposure prophylaxis (doxy-PEP) prevents bacterial sexually transmitted infections and has scaled into guidance internationally. Doxycycline also selects tetracycline resistance beyond its target, and Staphylococcus aureus - a commensal and pathogen for which doxycycline is one of a limited number of oral options - is a clinically relevant bystander. Objectives: To determine whether the guidance and surveillance deployed around doxy-PEP could follow the bystander-resistance signal the pivotal trial's final analysis resolved, rather than to estimate a population effect. Methods: We conducted a reproducible public-data audit of clinical trials, governmental guidance and deployed US surveillance. Trials and surveillance were evaluated against externally specified relative-risk benchmarks; guidance was assessed for whether S. aureus monitoring was specified. Results: The final randomised DoxyPEP analysis reported a 3.89-fold higher hazard of incident doxycycline-resistant S. aureus under doxy-PEP (95% CI 1.42-10.68; 68 of 393 versus 5 of 163 incident events), with no effect on colonisation clearance. Yet 0 of 6 outbreak-matched governmental guidelines (0 of 10 coded) required S. aureus monitoring, and 0 of 12 established US surveillance systems linked doxy-PEP exposure to an S. aureus tetracycline phenotype at a common population denominator. Under realistic exposure-density and isolate-volume assumptions, population surveillance would require a within-exposed RR of approximately 6-28 to produce a detectable rate change. Conclusions: The final trial resolved a doxycycline-resistant S. aureus signal that current guidance and US surveillance are not configured to monitor. Following the signal requires sentinel surveillance linking doxy-PEP exposure to the S. aureus tetracycline phenotype at a common denominator. No population-level causal claim is made.

Abstract: Debate about weight loss on GLP-1-based medicines has centered on how much lean mass is lost. Lean mass alone is an insufficient gauge. In older adults strength declines about three times faster than lean mass, power declines earlier still, and strength rather than mass predicts mortality; in pooled cohorts DXA lean mass does not predict falls, mobility limitation, hip fracture or death. On these medicines functional results diverge: walking distance improves in several trials, and grip strength rose in one cohort and fell in another. Assessing strength before treatment has already been recommended. This Perspective, opened by a clinical case, adds a construct and a rule. Functional discordance is a within-person decline in strength or physical performance beyond measurement error in the absence of a corresponding adverse lean-mass signal. I propose a pragmatic schedule: grip strength, five-times chair-stand time and usual gait speed, with a timed stair climb where feasible, before treatment, at 3, 6 and 12 months, and around dose reduction or discontinuation; change called real only beyond the measurement error of the test; results judged against the patient's baseline and a fixed threshold; assistance recorded. A confirmed functional decline beyond error should prompt clinical review, whatever lean mass shows. The rationale is strongest in older and vulnerable patients. The proposal is falsifiable: if lean-mass change reliably identifies the patients whose function declines, surveillance adds little; if discordance is common, lean mass is an inadequate surrogate for preserved capacity.

Abstract: Purpose of Review Trials of non-pharmacological treatment in chronic migraine report inconsistent effects on headache frequency. This review groups recent trials and syntheses by mechanism and asks whether mechanism explains the inconsistency and what it implies for treatment order. Recent Findings A primary-care education and self-management programme (CHESS) improved pain self-efficacy, while headache impact, headache days and medication overuse were unchanged at 12 months. Mindfulness added to withdrawal and prophylaxis (MIND-CM) increased the proportion with at least 50% fewer headache days (78% versus 48%). In chronic migraine with medication overuse, eptinezumab added to brief education reduced monthly migraine days in weeks 1–4 by 3.2 more than placebo (RESOLUTION). Syntheses rate the frequency effects of cognitive-behavioural, relaxation and mindfulness treatments as low-certainty; acceptance-based treatment improved disability without a significant frequency effect, and mindfulness reduced attack frequency slightly. During withdrawal, a nurse-led behavioural programme reduced acute-medication days at week 24 without changing migraine days. Summary Grouped by mechanism, treatments that lower ascending nociceptive drive, including calcitonin gene-related peptide (CGRP) pathway blockade and, on weaker evidence, behavioural treatment of insomnia, reduce headache frequency. Treatments aimed at the appraisal of pain improve self-efficacy and, in several trials, disability; no trial identified isolated their effect on frequency after a documented fall in drive, most tested packages mix both mechanisms, and some trials do not fit. The proposed rule is to start drive-lowering treatment first, behavioural forms included, and to offer interpretation-directed treatment alongside it when waiting is inappropriate. Five falsifiable predictions follow.

Abstract: Nicotinamide adenine dinucleotide (NAD⁺/NADH) metabolism occupies a central position in both tumour pathogenesis and cellular aging. Current therapeutic strategies pursue apparently contradictory objectives: oncology seeks to deplete NAD⁺ in cancer cells, while anti-aging practice administers NAD⁺ intravenously to restore levels that decline with age. This work proposes the pulsed imposition of a reductive load as an integrated anti-cancer and anti-aging strategy. The core proposition concerns a kinetic condition rather than any specific molecular vehicle: reducing equivalents arising faster than the cell can dispose of them. Where the respiratory chain retains proton-pumping capacity, that load produces a more specific thermodynamic state — over-reduction of the mitochondrial coenzyme Q pool sustained at elevated membrane potential — and because under normoxic operation the pool receives electrons from several dehydrogenases while discharging them through a single oxygen-dependent outlet, that state is reachable in two directions: addition of the electron donor, or subtraction of the terminal acceptor. Where proton-pumping capacity is compromised the same load instead limits free NAD⁺ as electron acceptor, in two compartmentally distinct arms that the two routes do not reach equivalently. NADH is discussed as the illustrative first-line donor because it is the native substrate of the respiratory chain and has an existing clinical precedent for intravenous administration, but it is explicitly not the ideal vehicle, being limited by molecular instability, restricted membrane permeability and stoichiometric consumption. A second class of donor, entering at or below the quinone pool rather than through the pyridine nucleotide pools, is identified; the sulfide couple is the endogenous case, and is notable in performing both directions of intervention with one species. Selectivity is proposed to arise from differential redox buffering capacity between healthy and transformed cells, through two complementary mechanisms: reverse electron transport at Complex I in cells retaining proton-pumping capacity, and limitation of free NAD⁺ in cells that cannot re-oxidise NADH, arresting mitochondrial substrate-level phosphorylation in the matrix and glycolysis in the cytosol. The origin of selectivity differs between routes — metabolic under donor addition, perfusional and spatial under acceptor subtraction — so that the two have largely disjoint zones of resistance and are complementary in domain as well as multiplicative in magnitude. Healthy cells are proposed to escape both by possessing simultaneously the respiratory reserve to dispose of the imposed load and the gradient-discharging flux required to discharge the accumulated proton gradient. A protocol of brief, intense pulses followed by recovery phases (redox press-pulse) is proposed, in combination with glucose restriction and optimisation of intracellular magnesium. The framework generates dissociable experimental signatures, an explicitly predicted zone of resistance, and a candidate predictive biomarker. Principal limitations, including cytosolic lactate dehydrogenase and mitochondrial proton leak as escape routes and the vulnerability of cardiac and neural tissue to the same reverse-electron-transport mechanism, are stated explicitly.

Abstract: Background/Objectives: Mandibular fractures frequently require restoration of occlusion, stabilization of bone fragments, and maintenance of intermaxillary relationships during healing. Conventional Erich arch bars remain a widely used method of maxillomandibular fixation (MMF), but are associated with prolonged operative time, mucosal trauma, plaque accumulation, needle-stick risk, and reduced comfort. Bone-supported intermaxillary fixation (IMF) screws have been introduced as an alternative, yet screw-related complications continue to limit their universal adoption. This narrative review synthesizes the clinical, morphological, biomechanical, technical, and practical rationale for a proposed method of mandibular fracture stabilization using self-tapping titanium orthodontic screws, with heads placed intraorally in the alveolar process of the maxilla and mandible, connected by elastic intermaxillary traction. Methods: A narrative literature review was undertaken across five thematic domains: mandibular fracture management, Erich arch bars, intermaxillary fixation screws, orthodontic miniscrews, and the biomechanics of elastic maxillomandibular fixation. The proposed technique was appraised against these existing fixation concepts and their documented clinical limitations. Results: Screw-based intermaxillary fixation can shorten operative time and avoid extensive circumdental wiring relative to conventional arch bars, with a potential but meta-analytically mixed hygiene benefit. Elastic traction between screws near a fracture line is not new: it was first described as "Elastic Internal Traction" in 2004, and a more recent precedent combines IMF screws with orthodontic elastic chains; the present proposal extends this lineage using orthodontic titanium screws with a provisional, not yet anatomically validated interradicular placement scheme (approximately 8 mm from the gingival margin, at least one tooth from the fracture edge), connected by elastic rings. Biomechanically, elastic intermaxillary traction is proposed to distribute force between the maxilla and mandible, but this has not been tested for this specific combination. Conclusions: Orthodontic screw-assisted intermaxillary fixation represents a promising, minimally invasive intraoral strategy for selected mandibular fractures, with potential advantages including reduced intraoral bulk, improved hygiene access, and controlled fragment stabilization. Prospective clinical trials, CBCT-based anatomical safety studies, and dedicated biomechanical analyses are required before broad clinical use.

Abstract: Cadherin-4 (CDH4/R-cadherin) is a type I cadherin involved in diverse processes of neural development and cancer. Although several anti-CDH4 monoclonal antibodies (mAbs) have been established for Western blotting, mAbs suitable for flow cytometric analysis of CDH4 have not been described. To generate anti-CDH4 mAbs for flow cytometry, we used a flow cytometry-based high-throughput screening strategy. Among the generated mAbs, Ca₄Mab-3 (IgG₁, κ) selectively recognized CDH4-overexpressed Chinese hamster ovary-K1 (CHO/CDH4) cells by flow cytometry and showed no detectable cross-reactivity with 21 other CDHs, including both type I and type II CDHs. Ca4Mab-3 also detected endogenous CDH4 in human breast cancer (MDA-MB-231) and osteosarcoma (U2OS) cell lines. The apparent dissociation constants (KD) of Ca₄Mab-3 for CHO/CDH4 and U2OS cells were 1.4 × 10⁻⁹ M and 1.1 × 10⁻⁹ M, respectively. In addition, Ca4Mab-3 successfully detected endogenous CDH4 in Western blotting. These results indicate that Ca₄Mab-3 is a highly specific anti-CDH4 mAb that can be used in flow cytometry and Western blotting. Ca₄Mab-3 may serve as a useful tool for investigating CDH4 function and may have potential applications in the development of therapeutic strategies for CDH4-positive tumors.

Abstract: Objective: To determine whether childhood attention-deficit/hyperactivity disorder (ADHD) predicts the subsequent emergence of psychiatric disorders independent of disorders already present in childhood, and to translate the evidence into clinical recommendations. Method: Narrative review of meta-analyses, systematic reviews, prospective longitudinal cohorts, population-based register studies, and clinical practice guidelines identified through searches of PubMed/MEDLINE, Embase, PsycINFO, and Web of Science, prioritizing studies with substantial citation impact. Results: Childhood ADHD robustly and independently predicts later substance use disorders, with 2- to 3-fold elevations that survive adjustment for childhood comorbidity. Prospective and genetically informed studies support an association with incident depression and suicidal behavior, though adjusted community models attenuate these effects. Associations with anxiety and antisocial personality disorder are substantially explained by childhood comorbidity in community samples, while clinic cohorts show an elevated risk window for new onsets confined largely to adolescence. Register and meta-analytic data link ADHD to increased risk of psychotic and eating disorders, and genome-wide studies document extensive shared genetic liability across ADHD, depression, schizophrenia, and autism spectrum disorder. Conclusion: Childhood ADHD is associated with the subsequent emergence of psychiatric disorders, but independence from childhood comorbidity varies by outcome domain. Substance use disorders show the strongest evidence of independent emergence; internalizing outcomes are partially confounded by baseline comorbidity. Systematic monitoring for depression, suicidality, and substance use across adolescence, and structured transition to adult services, are warranted for children with ADHD.

Abstract: Background: Mumps virus remains an important cause of outbreaks in vaccinated populations despite widespread use of measles–mumps–rubella/varicella (MMR/V) vaccines. Early in 2026, an increase in mumps cases was identified within the Johns Hopkins Health System (JHHS), coinciding with statewide reported cases in the state of Maryland. Methods: Molecular testing was implemented for case confirmation, and positive specimens underwent whole-genome sequencing. Epidemiologic and clinical data were abstracted from medical records. Phylogenetic analysis was performed using complete and partial genomes. Results: Eight patients with laboratory-confirmed mumps infection were identified. The median age was 31 years. Parotitis was the predominant presentation, followed by epididymo-orchitis. Whole-genome sequencing demonstrated that all viruses belonged to mumps virus genotype C and formed a tightly clustered monophyletic lineage with 99.95% nucleotide similarity, consistent with local transmission. Sequences were genetically distinct from genotype G strains reportedly associated with outbreaks in the United States. Comparison with the Jeryl Lynn vaccine strains (genotype A) showed ~7.5% nucleotide divergence. Amino acid analysis of the hemagglutinin-neuraminidase protein identified multiple substitutions in antigenic regions. Conclusions: A genotype C mumps virus cluster was identified during the 2026 Maryland outbreak. Findings are consistent with the introduction and local transmission of an uncommonly reported genotype, supporting the need for widespread molecular diagnostics, and highlighting the value of whole-genome sequencing for outbreak characterization.

Abstract: Objective: To assess whether the systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), AST-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) score, derived from first-trimester tests, discriminate intrahepatic cholestasis of pregnancy (ICP) and predict adverse perinatal outcomes within ICP. Materials and Methods: This retrospective case–control study included 115 women with ICP and 64 healthy controls. Indices were derived from 11–14-week values. The composite adverse outcome comprised preterm birth, meconium-stained amniotic fluid, fetal distress, neonatal intensive care admission or a 1-minute Apgar score <7. ROC analysis with DeLong comparisons and logistic regression adjusted for age and body mass index were used. Results: APRI (p < 0.001), NLR (p = 0.002) and SII (p = 0.011) were higher in ICP; FIB-4 was similar. Among derived markers, APRI had the highest area under the curve (AUC 0.786; 95% CI 0.718–0.851); however, ALT alone performed better (AUC 0.895; DeLong p = 0.003), and APRI and SII added nothing to ALT (AUC 0.904; p = 0.465). In the adjusted model, APRI (OR 3.36 per 0.1 unit; 2.16–5.25) and SII (OR 1.45 per 100 units; 1.08–1.96) remained independent. Within the ICP group, no index predicted adverse outcomes; only serum bile acids did (AUC 0.754; OR 2.39 per 10 µmol/L; 1.54–3.69), which persisted, though attenuated, after excluding the protocol-driven preterm component (AUC 0.681). Conclusion: First-trimester APRI and SII carry an early hepatocellular–inflammatory signal in women who later develop ICP, but add no diagnostic value beyond transaminases and do not predict perinatal risk; surveillance and delivery timing should continue to rely on bile acids.

Abstract: Drug discovery has traditionally been driven by strategies aimed at identifying a single molecular target for a given disease, an approach inspired by Paul Ehrlich's "magic bullet" concept. While enormously productive, this reductionist paradigm has progressively given way to more comprehensive views, first through polypharmacology and multi-target drug design, then through network medicine. This article traces this conceptual evolution through a simple graph-based formalism, arguing that the natural endpoint of this trajectory is a fully systems-level paradigm, here termed System-Based Drug Discovery, in which the organism itself is modeled as a complex, multiscale, and multilayer network. Grounded in complexity science, this framework does not replace but integrates the traditional top-down and bottom-up discovery strategies within a unifying representation. The growing availability of biological data and computing power, together with recent advances in molecular generative models, is already turning this conceptual shift into practice, extending network-based reasoning from target identification and drug repositioning to the actual design of new molecular entities.

Abstract: International guidance increasingly permits calcitonin gene-related peptide (CGRP)-targeted therapies to be considered at the initial preventive-treatment decision, but clinical eligibility does not ensure registration, reimbursement, practical access, or first prescribing. We reviewed contemporary preventive evidence and used the six Gulf Cooperation Council (GCC) health systems as a regional test case for this evidence-to-access gap. This structured evidence review used a focused PubMed/MEDLINE working set of 2,443 records through September 1, 2026, complementary bibliographic and trial-registry searches, professional guidance, and targeted GCC regulatory, procurement, and real-world sources. Prioritized assessment included 248 full texts and a 135-document working evidence corpus. A targeted update on September 29, 2026 checked for additional major guidance and head-to-head evidence without altering the original numerical workflow. Network meta-analyses support efficacy across several established and CGRP-targeted preventives but do not establish a simple class hierarchy. In their respective trials, HER-MES and TEMPLE reported lower adverse-event discontinuation and higher at least 50% responder rates with erenumab and atogepant than with topiramate; their populations and single-comparator designs limit generalization to universal first-treatment superiority. AAN/AHS 2026 emphasizes individualized choice; NICE and 2026 BASH guidance illustrate how national access pathways can remain sequential. Public GCC evidence is uneven, with the clearest clinical and regulatory documentation in the United Arab Emirates, Saudi Arabia, and Kuwait and important transparency gaps elsewhere. We therefore propose a five-layer implementation audit separating scientific eligibility, regulatory availability, clinical preference, reimbursement/formulary eligibility, and actual prescribing. The resulting patient-stratified framework preserves conventional-first, CGRP-targeted-first, and phenotype/comorbidity-driven pathways. The principal implication is not universal CGRP-first prescribing, but explicit separation of evidence-based choice from health-system access rules, with outcome-based reassessment and country-specific economic evaluation.