Medicine and Pharmacology

Abstract: Major depressive disorder pathophysiology involves complex gut-brain axis interactions, yet the systemic non-neurochemical impacts of selective serotonin reuptake inhibitors re-main poorly defined. This study evaluated the multidimensional effects of chronic fluoxe-tine administration in Sprague-Dawley rats. Male rats received fluoxetine (10 mg/kg/day) or water for 60 days, followed by behavioral phenotyping, fecal microbiological quantifi-cation, serum biochemistry, complete blood count analysis, and immunohistochemical assessment of the immediate-early gene product c-Fos (cellular proto-oncogene protein) in the striatum. Fluoxetine treatment significantly reduced immobility time in the forced swim test, whereas object recognition memory deteriorated without alterations in anxie-ty-like behavior. Pharmacological intervention markedly depleted fecal bacterial popula-tions and significantly decreased serum vitamin D concentrations. Hematologically, treated animals exhibited significant reductions in total leukocytes, red blood cells, and platelets, alongside elevated hematocrit and mean corpuscular volume. Concurrently, c-Fos-positive neuronal activation increased significantly within the striatal nucleus ac-cumbens. In conclusion, chronic fluoxetine exposure induces profound systemic disrup-tion, altering gut microbial homeostasis, depleting vitamin D, and modulating peripheral blood profiles while enhancing central striatal neuronal plasticity. These findings under-score the necessity of monitoring gut-brain axis integrity during prolonged antidepressant therapy.

Abstract: A substantial minority of patients do not recover fully after mild traumatic brain injury. Persistent post-concussion syndrome includes both cognitive and non-cognitive manifestations, yet DSM-5 and ICD-11 withdrew the syndrome as a distinct diagnosis and reorganized its persistent sequelae exclusively within neurocognitive categories. While this reorganization addresses the cognitive component of the syndrome, it fails to account for its non-cognitive consequences, including vestibular, oculomotor, headache-related, autonomic, sleep, and pain-related manifestations. In some patients, these may be the most disabling consequences of the injury. This narrative review examines the resulting diagnostic gap and other continuing disagreements. Published criteria differ in symptom count, duration, and other requirements, yielding an unacceptably wide range of prevalence estimates, from 11.4% to 38.7%. We review the current status of this syndrome and propose an approach that separates diagnosis from attribution. Finally, we discuss the interactions between cognitive and non-cognitive consequences through shared neural substrates, so abnormalities in one domain may influence function in another. Because cognitive and non-cognitive manifestations may dissociate, a patient may have normal or minimal findings in one domain and functionally significant abnormalities in the other; therefore, evaluation confined to one domain alone (as reflected in the new classifications) cannot exclude the syndrome.

Abstract: Background: Patients with dementia frequently present with multiple chronic conditions (MCCs). Growing evidence indicates these conditions do not co-occur by chance but may interact in ways that accelerate cognitive decline. In this study, we presented a machine-learning framework to identify these non-random, personalized MCC patterns associated with dementia, based on patients’ pre-existing conditions. Furthermore, we demonstrated a patient example illustrating how this approach enables the early detection of emerging MCC trajectories. Methods: To address this challenge, we introduced a lazy decision tree (lazyDT-MCCPath) framework using National Alzheimer’s Coordinating Center data. For each patient, lazyDT-MCCPath dynamically fine-tunes its training distribution based on pre-existing conditions from the preceding 3-5 years, while remaining MCCs were used to predict dementia risk. The decision tree provides a transparent pathway showing which emerging MCCs were associated with higher dementia risk. Results: Unlike traditional eager decision trees (eagerDT), which lacked sufficient training data for 17%-33% of patient profiles, lazyDT-MCCPath successfully modeled all profiles and achieved a 0.17 improvement in AUROC (0.66 vs. 0.83). Conclusions: lazyDT-MCCPath effectively translates pre-existing MCC profiles into personalized dementia risk probabilities for emerging conditions, which may help clinicians prioritize MCCs to monitor more closely.

Abstract: Objective: Flow-diverting devices treat intracranial aneurysms by modifying blood exchange between the parent artery and aneurysm. We quantified local flow changes after implantation using patient-specific Computational Fluid Dynamics(CFD). Methods: Three patients were evaluated: two treated with a flow-diverting device alone and one with adjunctive coiling. Patient-specific vascular models were reconstructed from clinical images. Devices and coils were virtually deployed, and steady-state CFD with explicit device geometry compared untreated and treated conditions. Findings were descriptively compared with immediate and 12-month angiography. Results: Device implantation redistributed lesion-region flow and reduced mean velocity by 11.9%, 29.4%, and 6.7% in Cases 1-3. In the giant aneurysm, adjunctive coiling produced additional reductions of 65.1% in sac-averaged velocity and 17.7% in neck-plane velocity. Immediate angiography showed contrast stasis in all cases. At 12 months, all lesions were completely occluded and parent arteries remained patent, consistent with the direction of flow suppression observed by CFD. Conclusion: Across these representative patient-specific configurations, the device produced local flow redirection while preserving parent-artery patency. Adjunctive coiling provided additional intra-saccular flow suppression in the giant aneurysm case.

Abstract: Background/Objectives: Diffuse glioma surgery requires balancing cytoreduction, distributed brain function, and individual priorities. We propose a patient-oriented, resource-adaptive framework and a testable hypothesis concerning postoperative functional recovery. Methods: A targeted narrative synthesis informed seven steps across network characterization, patient priorities, and therapeutic decision-making. A graph formulation separates expected resected tumor volume, direct functional cost, structural perturbation, and residual connectivity. A synthetic example illustrates its internal logic. Results: The framework links lesion topography and baseline function to patient-defined activities, consequences of loss, benefit–risk assessment, operative boundaries, and shared decisions. Connected candidate resections are compared under anatomical protections, declared cost limits, and independently audited connectivity thresholds. We hypothesize that model-estimated perturbation and residual connectivity add prognostic information about functional recovery beyond conventional clinical, anatomical, and molecular variables. Topological compensation is a possible mechanism; IDH status is an exploratory effect modifier. Population atlases provide probabilistic information, whereas individualized methods reduce uncertainty. Resource limitations may require restricted objectives or referral. Conclusions: The proposal makes the oncofunctional balance explicit and auditable. Mathematical consistency and the synthetic illustration establish no clinical efficacy or safety. Prospective validation is required before prescriptive use.

Abstract: Autism spectrum disorder (ASD) is usually diagnosed by looking at behavioral and developmental traits. This approach helps identify the autistic profile, describe strengths and challenges, set clinical baselines, and monitor changes. Still, focusing only on behavior does not explain the biological reasons for how autistic features appear, change, or improve. Studies in genetics, neuroscience, immunology, microbiology, mitochondrial biology, and metabolomics show that autism involves many complex and interacting processes. These include immune and inflammatory regulation, gut health and the microbiome, mitochondrial and metabolic function, oxidative balance, neural signaling, and more. There is no single cause or set of abnormalities that applies to all autistic people. Similar behaviors can come from different biological factors, which may change as a person grows. Autism should be seen as a dynamic biological process, a behavioral syndrome, or a set of fixed biological factors that interact with changing physiological states, health, environment, and treatment. Diagnosis should combine behavioral and developmental information with ongoing, broad biological assessment, while avoiding the early use of unproven biomarkers in clinical care. This approach can help separate stable risk factors from those that can be changed, identify key patterns, and clarify how different biological systems relate to clinical symptoms. Future treatments should look beyond behavior and focus on proven, mechanism-based strategies tailored to each person’s biology as it changes over time. Considering biological mechanisms alongside observed traits may improve long-term assessment, biomarker validation, treatment, and precision medicine in autism.

Abstract: The incidence of trigeminal neuralgia (TN) rises steeply with age, yet reluctance to offer posterior fossa surgery to patients aged 85 years and older persists, and no series of fully endoscopic microvascular decompression (e-MVD) confined to this group has been reported. To address this, we assessed the technical feasibility, perioperative course, and early pain outcomes of keyhole fully e-MVD in six patients aged ≥85 years with medically refractory TN treated at a single institution between May 2024 and October 2025. Procedures utilized a 3.5–4 cm retrosigmoid incision, a 1.5 cm keyhole craniotomy, a 4 mm 0° endoscope, retraction-free cerebellar relaxation, and continuous brainstem auditory evoked potential monitoring, with pain graded via the Barrow Neurological Institute (BNI) score. The median patient age was 87 years, the median operative time was 66 minutes, and estimated blood loss was minimal (0–5 mL) with zero transfusions. Preoperative BNI scores were V in five patients and IV in one; at a median follow-up of 12 months, scores improved to I in five patients and II in one (100% BNI I–II, p = 0.031) with zero recurrences. Fully endoscopic microvascular decompression is technically achievable at ≥85 years with short operative times and excellent pain relief, demonstrating that chronological age alone is an insufficient reason to withhold definitive decompression from physiologically suitable patients.

Abstract: Background/Objectives: Electrocardiographic (ECG) abnormalities are common in acute ischemic stroke and may reflect cardiac involvement associated with cerebrovascular injury. This study aimed to assess the prevalence and patterns of ECG abnormalities and compare their occurrence between patients of working age (18–65 years) and older patients (66–75 years), with particular attention to cardiac rhythm, repolarization abnormalities, and cardiac troponin T (TnT) levels. Methods: This one-year prospective study included 230 patients with first acute ischemic stroke admitted to the Clinic for Neurology, University Clinical Center Tuzla, Bosnia and Herzegovina. Standard 12-lead ECG and TnT levels were assessed on the first day of admission. ECG findings and TnT levels were compared between the two age groups, and their association with clinical outcome was evaluated using modified Rankin scale (mRS). Results: The study included 103 working-age patients and 127 older patients. The most frequent ECG abnormalities were T-wave inversion (47.8%), ST-segment depression (37.8%), bundle branch blocks (35.7%), and atrial fibrillation (19.1%). Sinus rhythm was significantly more frequent among working-age patients than older patients (90.3% vs. 74.0%; χ²=9.91; p=0.002), whereas atrial fibrillation was more prevalent in older patients (26.8% vs. 9.7%; χ²=10.70; p=0.001). T-wave inversion was also more frequent among older patients (54.3% vs. 39.8%; χ²=4.82; p=0.028). ST-segment depression showed the greatest difference between groups (49.6% vs. 23.3%; χ²=16.73; p<0.001; Cramer's V=0.270). TnT levels differed significantly between groups (U=9097.00; p<0.001), with higher mean ranks in older patients. Elevated TnT levels were associated with unfavorable clinical outcomes in the older group. Conclusions: Age-related differences were observed in ECG abnormalities and TnT levels in acute ischaemic stroke. Atrial fibrillation, T-wave inversion, ST-segment depression, and higher TnT levels were more prominent among older patients. Elevated TnT may have prognostic relevance in older patients with acute ischaemic stroke.

Abstract: Background: Vestibular migraine (VM) and benign paroxysmal positional vertigo (BPPV) frequently present with overlapping positional symptoms, making their differential diagnosis challenging. This study aimed to characterize positional vestibular manifestations in patients with suspected VM. Methods: In this observational study, 85 adult patients presenting with positional vertigo or dizziness in whom typical BPPV could not be demonstrated were evaluated. All patients underwent detailed clinical and neurotological assessment, videonystagmography, standardized positional testing. Results: Definite VM was diagnosed in 51/85 patients (60.0%) and probable VM in 23/85 (27.1%), accounting together for 87.1% of the selected cohort. Positional nystagmus was documented in 52 patients (61.2%), of whom 38/52 (73.1%) showed at least one atypical characteristic. Pupillary Nystagmus (PNy) was detected in 61/85 patients (71.8. Among 14 patients with an initially BPPV-like positional pattern, five responded to canalith repositioning maneuvers, whereas nine had persistent or recurrent symptoms requiring diagnostic reassessment. At 3 months, 60/74 patients (81.1%) with definite or probable VM reported marked overall clinical improvement, while complete resolution of positional vertigo or dizziness occurred in 49/74 (66.2%). Positional nystagmus resolved in 36/47 patients (76.6%) who had presented with this finding at baseline. Conclusions: VM should be considered in patients with recurrent positional vestibular symptoms when positional findings are atypical, variable, or inconsistent with a single semicircular canal disorder, particularly when repositioning maneuvers are ineffective. PNy may provide an additional supportive finding, although its di-agnostic value requires validation in controlled studies. Treatment response may support the overall clinical interpretation but should not be regarded as an independent diagnostic criterion.

Abstract: Neurodegenerative diseases (NDs) have traditionally been regarded as brain-centered disorders driven primarily by the accumulation of pathological proteins. However, increasing evidence indicates that systemic metabolic dysfunction, chronic inflammation, intestinal dysbiosis, hepatic abnormalities, and barrier impairment may substantially influence disease susceptibility and progression. This review integrates current evidence on the gut–liver–brain axis (GLBA) and proposes Systemic Metabolic–Immune Reprogramming (SMIR) as a systems-level framework for understanding how peripheral disturbances may be translated into central nervous system vulnerability. Within this model, the gut generates microbial and metabolic signals, the liver functions as a metabolic–immune integrator that senses, transforms, buffers, or amplifies these signals, and the brain represents a downstream vulnerable organ in which persistent systemic disturbances reshape neuroimmune states and neuronal homeostasis. Particular emphasis is placed on the sequential and bidirectional interactions among intestinal barrier dysfunction, hepatic metabolic–immune activation, systemic inflammatory remodeling, blood–brain barrier vulnerability, and central neuroimmune dysregulation. Key molecular mediators include short-chain fatty acids, bile acids, tryptophan–kynurenine metabolites, trimethylamine N-oxide, ceramides, hepatokines, complement components, extracellular vesicles, and inflammatory cytokines, together with signaling pathways involving TLRs, FXR/TGR5, NLRP3, mitochondrial stress, and cGAS–STING. We further discuss how microglial and astrocytic metabolic reprogramming, mitochondrial dysfunction, ferroptosis, and impaired proteostasis may connect systemic metabolic stress with neuronal injury. Disease-specific manifestations of this framework are examined in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and multiple system atrophy, highlighting both shared systemic mechanisms and distinct patterns of organ susceptibility. Emerging approaches, including longitudinal multi-omics, spatial transcriptomics, metabolomics, extracellular-vesicle profiling, organoid models, and artificial intelligence-assisted integration, may enable reconstruction of inter-organ communication networks and identification of disease-specific SMIR signatures. Therapeutically, this framework supports a shift from isolated downstream targets toward coordinated modulation of microbiome composition, hepatic metabolism, immune activity, barrier integrity, nutrition, and CNS pathology. Although causal relationships remain to be established, the GLBA–SMIR perspective provides a testable conceptual foundation for earlier diagnosis, patient stratification, precision nutrition, and multi-system intervention in neurodegenerative diseases.

Abstract: The core mechanism of epilepsy is generally summarized as abnormal synchronized neuronal firing. Although antiseizure medications, surgery, vagus nerve stimulation, and the ketogenic diet continue to improve, some patients continue to have drug-resistant epilepsy and often also have forward head posture, neck pain, insomnia, anxiety, autonomic dysfunction, and brain fog. These comorbidities are difficult to attribute entirely to epilepsy itself or to medication side effects, suggesting an underrecognized downstream amplification mechanism. Within the framework of investing fascia–carotid sheath–six-system coupling, this paper proposes a testable hypothesis: in some patients with epilepsy, fibrosis of the investing fascia and mechanical coupling of the carotid sheath may act as downstream amplifying factors and contribute to a reduced seizure threshold through impaired venous return, decreased glymphatic and meningeal lymphatic clearance, autonomic imbalance, sleep disruption, and neuroinflammation. Investing fascia release, through mechanical unloading, may reduce abnormal mechanical input, improve clearance and autonomic function, and thereby reverse this amplification process and raise the seizure threshold. Currently, there is no direct clinical evidence for this hypothesis, and it cannot replace standard treatment. Another subgroup hypothesis is that in patients with epilepsy who have objective evidence of altered blood supply, investing fascia release may improve blood supply and raise the seizure threshold; in those without such evidence, the effect may be less apparent. This paper is a theoretical derivation based solely on published literature and proposes testable predictions and a validation framework.

Abstract: Background: Although the corpus callosum is the principal commissure connecting the cerebral hemispheres, it remains unclear whether its macrostructure and microstructure are associated with greater structural symmetry between the hemispheres. Objective: To examine associations of callosal macrostructure and microstructure with left–right symmetry of cortical thickness in healthy developing children. Methods: In 8,131 children aged 9 to 10 from the Adolescent Brain Cognitive Development Study (ABCD), we related 16 callosal measures to per-child hemispheric similarity indices computed across 75 paired cortical regions. Degree-of-symmetry indices are based on the mean absolute left-minus-right difference, reversed so that higher values denote greater symmetry; pattern indices express the correlation between the two hemispheric profiles. Results: All 16 callosal measures were positively associated with cortical thickness symmetry and 15 reached significance, the strongest at r = −.096. The probability that 16 measures would share a direction by chance is 3.1 × 10⁻⁵. Across 128 tests of callosal structure against hemispheric similarity, 51 reached significance against 6.4 expected. The yield was concentrated in magnitude indices rather than pattern indices. Conclusions: A larger and more myelinated corpus callosum accompanies hemispheres whose cortical thickness is more symmetrical. The association concerns the degree of symmetry rather than its regional pattern.

Abstract: Allostatic accounts explain migraine chronification as the cumulative cost of repeated attacks, and an active-inference account explains the single attack as a reset forced by unresolved interoceptive prediction errors. This article proposes that one variable joins them: the predictability of the attacks themselves. As attack frequency approaches 15 days a month, the uncertainty left by cues as weak as those patients report nears its maximum, and the hypothesis adds that threshold-driven attacks dilute the reliability of the cues. The proposed response is a rise in the weight given to bodily signals, felt as uncertainty and clinically as anticipatory anxiety, expressed in the salience network and paid for in fragmented sleep and strained clearance and energy supply, which lower the attack threshold. Graded against the evidence, salience-network change and rising allostatic load have direct but small support, the interoceptive findings are small and conflicting, the anxiety link is indirect and confounded by medication overuse, the sleep link indirect and unstratified, the clearance findings rest on an indirect imaging proxy, and slow-wave sleep loss is contradicted. Six predictions are stated with the results that would refute them and with what rival accounts expect; one tests the ordering of the loop directly.

Abstract: Geographic atrophy (GA) is a vision-threatening late manifestation of age-related macular degeneration (AMD) and is increasingly recognized as the atrophic endpoint toward which advanced dry and neovascular AMD may converge. This review examines the clinical and translational progression from early AMD to GA, focusing on the key pathogenic factors, affected tissues, and stage-specific therapeutic approaches. We performed a mechanism-oriented synthesis of clinical, translational, and preclinical evidence identified through search of Medline, Web of Science Core Collection, and Scopus conducted from February to September 2026. Aging, genetic susceptibility, oxidative stress, mitochondrial dysfunction, impaired heterophagy and autophagy, retinoid by-product accumulation, complement dysregulation, and Bruch’s membrane remodeling progressively disrupt outer-retinal homeostasis. Drusen and subretinal pigment epithelium deposits represent structural markers of this imbalance and contribute to a self-amplifying microenvironment of impaired transport, local inflammation, and tissue remodeling. As reparative capacity fails, regulated cell-death programs including ferroptosis, necroptosis, apoptosis, pyroptosis, and inflammation-associated injury, promote lesion formation and expansion of atrophic areas. Current therapies remain stage-specific: anti-vascular endothelial growth factor agents control exudation in neovascular AMD, whereas complement inhibitors slow GA enlargement without restoring lost RPE-photoreceptor architecture. GA should therefore be regarded as the final expression of cumulative metabolic, immune, vascular, and extracellular matrix failure, supporting earlier multifaceted therapeutic strategies.

Abstract: Depression, anxiety and psychosis occur in people with epilepsy far more often than in the general population, and each can precede the first unprovoked seizure, which points to shared neurobiology rather than psychosocial reaction. This narrative review examined original human research published between 2016 and 2026, identified by keyword searching and selected purposively, spanning eighteen studies across neuroimaging, neurotransmitter and neuroendocrine systems, neuroinflammation, genetic architecture and psychiatric phenotype. Imaging separated the psychiatric phenotypes: depression was associated with reduced connectivity across salience, attention and default mode networks, whereas psychosis was associated with parietal grey matter loss and disrupted long association tracts, although temporal lobe epilepsy, hippocampal sclerosis and family history of schizophrenia predicted psychosis. Brain-derived neurotrophic factor separated epilepsy from health but not comorbid depression, and anti-seizure medication accounted for much of its variance, whereas serotonergic and hippocampal glutamatergic measures tracked depression specifically. The hypothalamic-pituitary-adrenal axis showed elevated basal cortisol with abolished stress reactivity, whereas inflammatory findings were inconsistent. Genome-wide analyses identified shared loci including SCN1A, and Mendelian randomisation supported major depressive disorder as an antecedent of epilepsy; psychiatric polygenic burden and suicidality at diagnosis each predicted treatment resistance. Depression and psychosis appear to have separable substrates and should not be pooled.

Abstract: Resveratrol-inspired methoxy-substituted pyrrolidine- and morpholine-based carba-mates bearing oxazole or benzimidazole moieties were synthesized and evaluated for their cholinesterase-inhibitory and anti-inflammatory activities. A series of twelve compounds (1–12) was prepared and structurally characterized using spectroscopic methods. Their inhibitory activities against acetylcholinesterase (AChE) and butyryl-cholinesterase (BChE) were determined using a modified Ellman assay, while an-ti-inflammatory activity was assessed by measuring TNF-α production in lipopolysac-charide-stimulated human peripheral blood mononuclear cells. The investigated com-pounds selectively inhibited BChE, while showing weak or negligible inhibition of AChE. Pyrrolidine-based oxazole carbamate 1 exhibited the highest BChE inhibitory potency (IC₅₀ = 0.09 μM), approximately 25-fold greater than standard rivastigmine. Compound 1 was also the only tested derivative to concentration-dependently inhibit TNF-α production (IC₅₀ = 4.3 μM) without affecting cell viability. Molecular docking of compounds 1 and 9, the best pyrrolidine- and morpholine-based carbamates, indicated that both fit within the BChE active-site gorge through extensive aromatic, hydrophobic, and polar interactions. Overall, the results identify compound 1 as a promising multi-functional lead for further investigation of the relationship between cholinesterase in-hibition and anti-inflammatory activity.

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: 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: 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.

Abstract: Alzheimer’s disease (AD) pathology is primarily driven by the self-assembly of amyloid-β (Aβ) peptides, a process significantly stabilized through π-π stacking interactions between the aromatic residues Phe19 and Phe20. To competitively disrupt this crucial interaction, we designed novel peptide inhibitors derived from the Aβ recognition motif KLVFFA (Aβ16−21), in which phenylalanine residues were replaced with L-3,4-dihydroxyphenylalanine (DOPA), a residue featuring an enhanced π-stacking and hydrogen-bonding catechol moiety. The DOPA-substituted peptides effectively inhibited Aβ1−42 (Aβ42) aggregation, as demonstrated by Thioflavin T fluorescence assays, circular dichroism spectroscopy, and transmission electron microscopy. These complementary analyses collectively exhibited substantial suppression of β-sheet formation and fibril elongation. Notably, the anti-aggregation potency was dependent on the substitution position, with the Phe19-substituted analogue (KDF) exhibiting stronger inhibitory activity than the Phe20-substituted analogue (KFD). The dual-substituted analogue (KDD) displayed the greatest overall anti-aggregation activity. Molecular simulations further supported the superior activity of KDF over KFD, revealing a more favorable binding free energy for KDF compared to the parent peptide. Furthermore, the DOPA-peptides potently mitigated Aβ42-induced neurotoxicity in SH−SY5Y cells, with the dual-substituted analogue (KDD) providing the highest level of cytoprotection. Collectively, these findings validate that targeted modulation of aromatic interactions through DOPA substitution represents a powerful molecular strategy for controlling Aβ42 self-assembly, presenting these peptides as promising therapeutic leads for AD.