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PubMed2026

Open repairs with biceps rerouting does not impact retears in large to massive rotator cuff tears compared to conventional open repair: a randomized clinical trial.

BACKGROUND: The treatment of large to massive rotator cuff tears leads to a high failure rate and several techniques have been proposed to improve these results. Rerouting the long head of the biceps tendon (LHBT) appears to be a biological reinforcement to increase tendon healing. Therefore, this study aimed to compare the clinical and radiological outcomes of open repair for large and massive rotator cuff tears reinforced with the LHBT to conventional open repair. METHODS: A prospective randomized study was conducted with patients diagnosed with large to massive rotator posterosuperior rotator cuff tear and intact LHBT, randomized into 2 groups: biceps rerouting and conventional open repair. The functional outcomes were assessed by the American Shoulder and Elbow Surgeon score, University of California at Los Angeles score, and SF-12 questionnaire preoperatively and at 6, 12, and 24 months postoperatively. Pain level was also assessed by the visual analog scale including the first day and 2 weeks postoperatively. Structural outcomes were rotator cuff and LHBT healing with magnetic resonance imaging and acromiohumeral distance (AHD) through radiography. RESULTS: We evaluated 58 patients, 29 in each group. At the end of the follow-up there were no statistically significant differences between groups in American Shoulder and Elbow Surgeon (76.1 vs. 80.4, P = .761), University of California at Los Angeles (27.1 vs. 29.1, P = .634), or visual analog scale scores (1.3 vs. 1.1, P = .781). Additionally, rotator cuff healing rates (48.3% vs. 44.8%, P = .402) and LHBT healing rates (79.3% vs. 82.7%, P = .738) were similar. AHD increased in both groups, with no significant difference in delta AHD (P = .513). Both groups showed significant clinical improvement over time in all evaluated outcomes (P < 0,01). No postoperative complications were reported. CONCLUSIONS: We could not identify an advantage of open repair with LHBT rerouting as reinforcement over conventional open repair. Nonetheless, all clinical scores improved at the end of the 24 months of follow-up in both groups.

Humans↗

PubMed2026

Do wound protectors reduce contamination in total shoulder arthroplasty? A randomized controlled trial.

HYPOTHESIS: Cutibacterium acnes is the most frequent cause of shoulder prosthetic joint infection with skin edges as a source of wound contamination. The primary purpose of this study was to determine if the use of a wound protector device decreases the deep wound bacterial colonization in primary shoulder arthroplasty. The secondary purpose was to assess the effect of device usage on deltopectoral muscle and cephalic vein injury. METHODS: This was a prospective, randomized controlled trial. A total of 100 patients undergoing primary total shoulder arthroplasty were enrolled and randomized into 2 groups: a wound protector group and a control group. Five patients withdrew from the study, leaving 48 patients in the wound protector group and 47 controls. Three deep wound culture swabs were taken after final arthroplasty implantation. The surgeon also graded deltoid, pectoralis major, and cephalic vein injury on a 0-3 scale based on modification to the Tscherne classification of soft tissue injury. The primary outcome of this study was positive culture results for C acnes. Secondary outcomes included total bacterial culture positivity as well as soft tissue injury grades. A subanalysis removing likely contaminant positive cultures (growth >7 days and 1 colony only) was also performed. Comparisons between groups were made using Fisher exact test for categorical outcomes and t tests and Mann-Whitney U tests for continuous variables. RESULTS: The use of a wound protector did not result in any significant differences compared with controls in the rate of positive cultures for C acnes (15% vs. 21%, P = .593) or all bacteria (15% vs. 26%, P = .304). Removing likely contaminant positive cultures did not demonstrate any significant difference in culture positivity (9% vs. 17%, P = .355, for C acnes; 9% vs. 19%, P = .231, for all bacterial species). The wound protector group had better soft tissue injury scores for the deltoid muscle (P < .001) and pectoralis muscle (P < .001). No difference in cephalic vein injury was noted between the 2 groups (P > .05). No difference in surgical time was noted. CONCLUSION: The use of a surgical wound protector device in total shoulder arthroplasty did not significantly decrease bacterial colonization of the deep wound. However, soft tissue damage to the deltoid and pectoralis muscle was less severe in the wound protector group. These findings suggest that this device reduces iatrogenic soft tissue injury.

Humans↗

PubMed2026

Hypoxaemia and mortality in children with lower respiratory infection in low-income and middle-income countries: systematic review and meta-analysis.

BACKGROUND: Hypoxaemic lower respiratory infections (LRIs) are a leading cause of childhood mortality, with the highest burden in low-income and middle-income countries (LMICs). Hypoxaemia-low peripheral capillary oxyhaemoglobin saturation (SpO2)-is a marker of severity, and WHO recommends hospitalisation and oxygen administration for patients with SpO2 <90%. We aimed to update estimates from a 2015 systematic review and meta-analysis examining the association between hypoxaemia and mortality among children with LRIs in LMICs by incorporating studies published over the subsequent decade and evaluating mortality risk across multiple SpO2 thresholds. METHODS: We conducted a systematic review with meta-analysis by searching PubMed, Embase, LILACS, Global Index Medicus, Web of Science, and Scopus for peer-reviewed studies published between Jan 1, 2015, and June 18, 2025, with combined terms related to pneumonia, children, mortality, and LMICs. We also included selected earlier studies through citation checking. Eligible studies reported associations between hypoxaemia and mortality in children younger than 5 years with LRIs in LMICs. We excluded case reports and case series with fewer than five deaths, studies focused exclusively on the neonatal period, and those limited to children with specific comorbidities or to postoperative patients, for consistency with the original review. Two reviewers independently screened studies, extracted data, and assessed quality. Eligible studies were combined with those from the original review and analysed using random-effects models to estimate odds ratios (ORs) by hypoxaemia threshold subgroup. The protocol was registered on PROSPERO (CRD42023433946). FINDINGS: We identified 7734 records; 26 new studies met inclusion criteria and were combined with 18 from the original review. The 44 studies were published between 1993 and 2024 and were primarily from Africa (25 [57%] of 44) or Asia (19 [43%]); some studies spanned multiple locations. Data from 33 studies including 155 633 participants were included in the primary meta-analysis. Hypoxaemia of any threshold was associated with higher odds of LRI mortality (OR 4·36 [95% CI 3·52-5·39]) compared with no hypoxaemia. For SpO2 <90% versus 90-100%, OR for death was 4·75 (95% CI 3·42-6·58). For SpO2 90-94% versus 95-100%, mortality risk was more than twice as high (OR 2·27 [95% CI 1·22-4·25]). Heterogeneity was substantial (I2 64-85% across analyses), and eight (24%) of 33 studies in the primary meta-analysis had a high overall risk of bias; however, a sensitivity analysis restricted to studies with low or moderate risk of bias yielded similar results. INTERPRETATION: SpO2 <90% strongly predicts mortality in children with LRIs in LMICs. Children with SpO2 90-94% also have elevated risk, suggesting that paediatric LRI and pneumonia treatment algorithms should consider management at this hypoxaemia threshold. FUNDING: None.

Journal Article↗

PubMed2026

Oil and gas well development and coccidioidomycosis risk in Kern County, CA, USA: a case-crossover study.

BACKGROUND: Coccidioidomycosis is an emerging fungal disease caused by inhaling Coccidioides spp spores. As spores reside in soil, activities that disturb soil and generate dust can aerosolise and transport the pathogen. The oil and gas industry has been extensively developed in some regions that are endemic for Coccidioides spp and has been associated with dust emissions. Although several adverse health outcomes have previously been associated with oil and gas development, its impact on coccidioidomycosis risk has not been investigated. We aimed to estimate the association between exposure to oil and gas well development (ie, wells in preproduction) and risk of coccidioidomycosis among residents living near new wells. METHODS: In this case-crossover study, we obtained information on reported coccidioidomycosis cases and oil and gas well development between 2007 and 2022 in Kern County, CA, USA. We then compared exposure to preproduction wells within 5 km of each individual's place of residence during both hazard (ie, the 49-139 days before case onset) and control periods using conditional logistic regression. FINDINGS: During the study period, 658 108 (72·4%) of 909 282 of Kern County residents lived within 5 km of at least one preproduction well, and 116 020 (12·8%) lived within 5 km of 23 or more preproduction wells within a single 90-day period. We estimated that the odds of coccidiomycosis incidence were 12·5% (95% CI 5·8-19·6) higher in the 90 days following exposure to at least one preproduction well within 5 km of an individual's place of residence and that the odds of infection increased by 0·7% (0·4-0·9) for each additional preproduction well developed within this distance. INTERPRETATION: These findings support a previously-unrecognised association between the development of oil and gas wells and transmission of coccidioidomycosis, potentially driven by dust generation. Given the prevalence of oil and gas development in the study region, its impact on coccidioidomycosis incidence might be large. FUNDING: National Institutes of Health, National Science Foundation.

Journal Article↗

PubMed2026

MRI-Negative Posterior Reversible Encephalopathy Syndrome: Comparison of Hypertensive Encephalopathy With and Without Vasogenic Edema.

OBJECTIVE: To explore whether posterior reversible encephalopathy syndrome (PRES) can present with negative magnetic resonance imaging (MRI) by comparing clinical features between cases of PRES with vasogenic edema and cases of hypertensive encephalopathy without MRI changes. PATIENTS AND METHODS: Patients diagnosed with hypertensive encephalopathy from August 1, 2008, to December 31, 2017, were identified retrospectively and matched by age (±5 years) and sex in a 1:2 ratio to patients retrospectively identified as having PRES from January 1, 2002, to November 30, 2017. A review of MRI images and clinical information was performed. RESULTS: We identified 16 cases of hypertensive encephalopathy and 32 age- and sex-matched controls with PRES showing vasogenic edema on MRI. There were no statistically significant differences in the odds of presentation with headache (odds ratio [OR], 1.372; 95% CI, 0.458 to 4.106), encephalopathy (OR, 2.303; 95% CI, 0.433 to 12.236), visual disturbance (OR, 0.826; 95% CI, 0.185 to 3.697), or focal neurologic deficit (OR, 4.000; 95% CI, 0.767 to 20.872). Seizures were more common in patients with vasogenic edema (OR, 0.082; 95% CI, 0.010 to 0.664). There were no significant differences in odds of acute kidney injury (OR, 2.90; 95% CI, 0.679 to 12.449) or odds of having a history of malignancy (OR, 0.295; 95% CI, 0.076 to 1.152), transplantation (OR, 3.347; 95% CI, 0.594 to 18.880), or autoimmune disease (OR, 0.400; 95% CI, 0.104 to 1.532). Systolic blood pressure at presentation was higher in patients with hypertensive encephalopathy and negative MRI as compared with patients with PRES and vasogenic edema (OR, 1.03; 95% CI, 1.01 to 1.05). CONCLUSION: Most presenting symptoms and risk factors were not significantly different between cases of hypertensive encephalopathy with and without vasogenic edema, arguing that the diagnosis of PRES in the setting of acute severe hypertension may not depend on MRI confirmation.

Humans↗

PubMed2026

Ketamine assisted psychotherapy to reduce chronic neuropathic pain: A mixed-methods randomized pilot trial.

BACKGROUND: Intravenous ketamine can provide short-term analgesia in chronic neuropathic pain but benefits often wane after treatment. We conducted a randomized pilot trial to assess the feasibility of combining ketamine infusions with psychotherapy to inform future efficacy trials. METHODS: In this single-center, randomized, outcome-assessor-blinded pilot trial at a Canadian tertiary pain clinic, adults with moderate-to-severe chronic neuropathic pain were randomly assigned in 1:1:1 ratio to the ketamine, psychotherapy, or combined ketamine plus psychotherapy arm. Ketamine was delivered as three intravenous infusions over 16 weeks; psychotherapy consisted of 16 weekly cognitive behavioral therapy and mindfulness-based meditation sessions. The primary outcome was feasibility, assessed using prespecified progression criteria. Exploratory outcomes included changes in pain interference (PROMIS 6a T-score), pain intensity, mood, and qualitative interview findings at week 20 (ClinicalTrials.gov: NCT05639322). FINDINGS: Between October 23, 2023, and March 31, 2025, 30 participants were randomized, and 26 (87%) completed 20-week follow-up. Most feasibility criteria, including consent, retention, data completeness, and absence of study-related serious adverse events, were met; adherence targets were partially met. Exploratory pain outcomes showed numerical improvement across groups, with clinically meaningful reductions observed for pain interference and pain intensity. Sixty-four adverse events were recorded, mostly mild and in ketamine-containing groups; no serious study-related adverse events occurred. CONCLUSIONS: Combined ketamine and psychotherapy was feasible and acceptably safe in this pilot trial, supporting evaluation in a larger efficacy-powered study. FUNDING: The study was funded by the St. Michael's Hospital Innovation Fund, The Canadian Pain Society Early Investigator Award and the Physician Services Incorporation Early Career Researcher Award.

Humans↗

PubMed2026

Uncovering hidden complexity in the Apis mellifera mitotranscriptome: a polyadenylation-centered perspective.

Mitochondrial transcription is gaining increasing attention as researchers seek to better understand the full coding potential of mitochondrial DNA (mtDNA). Emerging evidence suggests that mtDNA may encode additional elements beyond classical oxidative phosphorylation genes, pointing to a more complex transcriptional architecture than previously recognized. In this study, we explored the mitochondrial transcriptome of Apis mellifera (Insecta: Hymenoptera), with a particular focus on polyadenylation-associated features. Our analysis revealed that both sense and antisense transcripts undergo polyadenylation, although transcript abundance and poly(A) tail lengths varied markedly across mitochondrial genes. Several transcripts exhibited alternative isoforms, either extended or truncated, frequently including intergenic regions. These regions may represent functional non-coding elements or structural variants rather than conventional untranslated regions (UTRs). Interestingly, some transcripts also contained non-templated nucleotide additions particularly cytosine residues immediately upstream of the poly(A) tails. Monocistronic units that included portions of downstream intergenic regions were among the most abundantly represented, suggesting a possible regulatory role for these sequences. To experimentally validate our in silico findings, we performed RT-qPCR to assess relative gene expression and applied 3' RACE-PCR to define transcript boundaries. These approaches confirmed the presence of multiple transcript isoforms and supported the involvement of polyadenylation in shaping mitochondrial RNA diversity. Together, our findings reveal a previously underappreciated level of complexity in the A. mellifera mitochondrial transcriptome and highlight the potential regulatory significance of polyadenylation dynamics and intergenic region transcription.

Animals↗

PubMed2026

Differential contributions of mt-Tr and Cs variants to developmental cochlear defects and mitochondrial dysfunction in A/J mice.

A/J mice exhibit early-onset hearing loss linked to Cdh23, mitochondrial tRNA-Arg (mt-Tr), and citrate synthase (Cs) variants. Although developmental cochlear defects have been identified in juvenile A/J mice, the hierarchical contributions of mt-Tr versus Cs remain unclear. Using reciprocal intercross-derived strains to decouple mitochondrial haplotypes from nuclear factors, we demonstrate that the mitochondrial background is the primary determinant of auditory dysfunction. Mice with A/J mtDNA (AXB strains) displayed significantly higher ABR thresholds, accelerated hair cell attrition, and severe stereocilia dysmorphology compared to those with B6 mtDNA (BXA strains), occurring largely independently of the Cs genotype. While the Cs mutation exacerbated hearing loss, its impact was secondary to that of the dominant mitochondrial background. Systemic behavioral assessments and mitochondrial assays confirmed that A/J mitochondria exert a more profound metabolic impact than the Cs mutation. Our findings establish that the mitochondrial genomic background, with the mt-Tr locus as a prominent candidate variant, serves as the principal driver of developmental cochlear defects and early-onset hearing loss in A/J mice, while the nuclear Cs mutation acts as a synergistic modifier. This study underscores the critical role of mitonuclear crosstalk in inner ear maturation and provides new insights into the etiology of hereditary hearing loss.

Animals↗

PubMed2026

Histopathologic, Genomic, and Clinical Characteristics of Primary Cutaneous Melanocytic Tumors With Concomitant NRAS Q61 and IDH1 R132C Mutations.

Cutaneous melanocytic tumors with concomitant NRAS Q61 and IDH1 R132C mutations have been described as intermediate-grade melanocytomas with characteristic biphasic morphology, but the malignant end of this genotype-defined spectrum remains poorly characterized. We assessed histopathologic, immunohistochemical, molecular, and clinical features of 16 primary cutaneous melanocytic tumors harboring both mutations. Following integrated review, 7 tumors were classified as melanocytoma and 9 as melanoma. Melanocytomas showed reproducible biphasic architecture with congenital nevus-like features, a biphasic HMB-45 pattern, low Ki-67, PRAME negativity, retained p16, and minimal copy number variations (CNVs). Melanomas retained partial morphologic overlap in a subset but were distinguished by higher-grade cytology, immunohistochemical features supportive of malignancy, and progression-associated genomic alterations, including TERT promoter mutation (9/9), 9p21/CDKN2A loss (4/7), and higher CNV burden. NRAS and IDH1 variant allele frequencies were strongly concordant (r = 0.83, P < 0.001), supporting their presence in the same dominant clone. Clinically, two patients presented with stage IIIB disease, but no distant metastasis or melanoma-related death occurred during a median melanoma follow-up of 3.9 years (IQR, 2.5-5.1). In exploratory analyses, moderate-to-severe atypia (RR, 6.2; 95% CI, 1.0-38.8; P = .009), Ki-67 ≥10% (RR, 4.4; 95% CI, 1.1-18.4; P = .003), lymphocytic infiltrate (RR, 2.4; 95% CI, 1.1-5.3; P = .03), absence of the typical biphasic pattern (RR, 2.4; 95% CI, 1.1-5.3; P = .03), and complete p16 loss (RR, 2.4; 95% CI, 1.1-5.3; P = .03) were associated with molecular or clinical progression to melanoma, defined as the presence of at least one of the following: TERT promoter mutation, pathogenic CDKN2A mutation, 9p21/CDKN2A loss, ≥3 genome-wide segmental CNVs, or any metastasis. These findings support the existence of NRAS/IDH1 co-mutated melanoma as the malignant counterpart of NRAS/IDH1-mutated melanocytoma within a single genotype-defined spectrum.

IDH1 mutations↗

PubMed2026

Quantitative susceptibility mapping in neurodegenerative diseases: An umbrella review of iron-related biomarkers and mechanisms.

Pathological iron accumulation is a common pathophysiological hallmark across multiple neurodegenerative diseases (NDDs), motivating the need for accurate, non-invasive quantification methods. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique that enables in vivo measurement of tissue magnetic susceptibility (χ), providing a sensitive proxy for iron content. This umbrella review systematically evaluates the diagnostic accuracy, clinical correlations, and distinct iron distribution patterns of QSM in major NDDs, such as Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and atypical Parkinsonism. We included 15 (13/15 were rated Low or Critically Low on AMSTAR 2) systematic reviews and meta-analyses (through July 15, 2026); however, the findings should be interpreted cautiously because of heterogeneity and the low methodological quality. A Corrected Covered Area (CCA) analysis demonstrated only slight overlap of primary studies across the included reviews (CCA = 5.42%). Collectively, the evidence indicates that QSM provides comparable or higher diagnostic sensitivity and reliability than conventional R2* and SWI techniques, particularly for deep gray matter structures. The findings support significant iron overload in the substantia nigra, particularly in the pars compacta, as a robust biomarker for PD that correlates with motor severity and disease duration. Furthermore, regional iron profiling in the basal ganglia is critical for differential diagnosis; specifically, elevated χ in the putamen and globus pallidus effectively distinguishes multiple system atrophy and progressive supranuclear palsy from idiopathic PD. Distinctively, AD and ALS exhibit specific χ alterations in the thalamus, motor cortex, and hippocampus, reflecting divergent iron-related pathophysiological mechanisms, which correlate with cognitive impairment and upper motor neuron signs. Overall, QSM shows diagnostic promise and offers mechanistic insights into iron-related neurodegenerative processes.

Humans↗

PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗

PubMed2026

Mapping the immune-genetic architecture of Epstein-Barr virus-related phenotypes and multiple sclerosis through a single-cell genetic framework for target prioritization and pharmacologic hypothesis generation.

BACKGROUND: Multiple sclerosis (MS) is a severe neuroinflammatory disease causing substantial long-term disability. Strong epidemiologic evidence links Epstein-Barr virus (EBV) exposure with MS risk, but genetic evidence for immune target prioritization in EBV-related phenotypes remains limited. METHODS: We integrated single-cell cis-eQTL data from 14 immune cell types with GWASs of an EBV-related clinical phenotype and MS using a single-cell Mendelian randomization framework with colocalization analyses. Candidate eGenes were evaluated in independent cohorts. For multi-SNP instruments, we performed heterogeneity, pleiotropy, MR-Egger, weighted median, mode-based, and MR-PRESSO sensitivity analyses. We also conducted phenome-wide association analyses and queried DrugBank to annotate candidate compounds targeting prioritized genes. RESULTS: We prioritized 43 immune-cell-specific candidate eGenes with convergent genetic support, including 6 for the EBV-related phenotype and 37 for MS. SERPINB1 in NK cells was associated with increased risk of the EBV-related phenotype, whereas HLA-G was associated with decreased risk. For MS, APOM and MSH5 showed protective associations, while AHI1 showed cell-type-dependent, bidirectional associations across immune lineages. Colocalization and independent cohort evaluation supported these findings. Among FDR-significant multi-SNP associations, MR-Egger intercept tests did not indicate directional pleiotropy, although a small subset showed heterogeneity or MR-PRESSO signals. Phenome-wide analyses identified no significant adverse phenotypic associations among evaluable genes at the prespecified threshold. DrugBank annotation nominated sodium nitroprusside, fasudil, artenimol, and choline as hypothesis-generating compounds for experimental follow-up. CONCLUSIONS: This study provides a single-cell genetic framework for prioritizing immune-cell-specific candidate targets for EBV-related phenotypes and MS, and nominates genetically supported targets and pharmacologic hypotheses for experimental investigation.

Humans↗

PubMed2026

Perspectives of participating neurologists and study nurses - Mixed-methods process evaluation of a web-based program for relapse management in multiple sclerosis (POWER@M2).

BACKGROUND: Relapsing-remitting multiple sclerosis is a chronic inflammatory disease of the central nervous system and the leading cause of disability in young adults. In Germany, 90% of relapses are treated with high-dose intravenous glucocorticoids, despite limited evidence for long-term benefit and international preference for oral administration. Time constraints often hinder informed decision-making. The multicentre Randomized Controlled Trial (RCT) POWER@MS2 (N = 160, 2020-2023), conducted at 18 German MS-centres, aimed to promote self-determined relapse management through a complex intervention (dialogue-based decision aid, nurse-led webinar, online-chat). OBJECTIVE: While RCTs demonstrate effectiveness, process evaluations are essential to understand implementation, mechanisms of impact and contextual factors. This study explored healthcare professionals' experiences and attitudes toward implementing relapse self-management and self-medication in clinical practice. METHODS: A mixed-methods process evaluation followed the UK Medical Research Council- framework. Quantitative data were collected via validated questionnaires at up to three time points and analysed descriptively. Interview guides were developed based on these results. Qualitative data from neurologist and study nurse interviews were thematically analysed. Results were triangulated using a joint display. RESULTS: Data were collected from 55 neurologists and 17 study nurses (quantitative) and from 7 neurologists and 4 nurses (qualitative) (2020-2024). Most neurologists opposed routine steroid use, reserving it for severe relapses. Some voiced concerns about self-management, but informed patients were generally viewed as capable of safe self-medication. Study nurses gave mixed feedback on the intervention, citing overload and improved guidance. CONCLUSION: Clinicians showed openness toward implementing the intervention. Enhancing accessibility and addressing specific concerns may support broader adoption.

Humans↗

PubMed2026

Bi-compartmental CSF-serum analysis of NfL and GFAP differentiates central and peripheral pathology in neuroinfectious diseases: A monocentric real-world cohort study.

Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), established biomarkers of neuroaxonal injury and astroglial pathology, are frequently only assessed in blood, which limits conclusions regarding their origin. Bi-compartmental analyses of CSF and serum may help differentiate central or peripheral origin of biomarker elevation. Moreover, studies on NfL and GFAP in distinct neuroinfectious disease (NID) phenotypes, particularly those based on real-world cohorts, are limited. This retrospective monocentric study analyzed CSF and serum from patients with (meningo-)encephalitis/myelitis (TI+; n = 48), meningitis (TI-; n = 80), (cranial) nerve palsies/polyradiculitis (PND; n = 61), and 113 non-neuroinflammatory/non-neurodegenerative controls. A bi-compartmental model using scatter plots and simple linear regression was applied to assess the origin of blood biomarker levels and discriminate between central and peripheral pathology. CSF and serum NfL and GFAP z-scores were significantly higher in TI+ compared with TI- (CSF-GFAP p < 0.001/sGFAP p = 0.0083; CSF-NfL p = 0.003/sNfL p = 0.0004). TI+ and PND differed only in GFAP levels, which were higher in TI+ (CSF-GFAP p = 0.0049/sGFAP p = 0.003). The overall group effect (p ≤ 0.003) and principal findings remained significant after adjustment for age, sex, QAlb, and time since (symptom) onset to LP. Bi-compartmental analysis revealed simultaneous elevation of CSF and serum NfL in TI+, indicating predominantly central origin, whereas PND demonstrated a shift toward higher sNfL levels suggesting peripheral origin. Higher clinical severity (modified Rankin Scale 3-5) was associated with elevated serum and CSF GFAP and NfL (sGFAP p = 0.012/sNfL p = 0.002; CSF-GFAP p < 0.0001/CSF-NfL p = 0.0001), which also predicted unfavorable outcome at discharge (sGFAP p = 0.006/sNfL p = 0.004; CSF-GFAP p = 0.003/CSF-NfL p = 0.012). NfL and GFAP were associated with brain/myelon involvement in NID, predominantly reflecting central pathology. Despite strong CSF-serum correlations, bi-compartmental approaches provide additional insight into biomarker origin and disease compartment.

Humans↗

PubMed2026

Circular RNAs in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons, with most cases lacking a clear genetic basis. Emerging evidence highlights the involvement of non-coding RNAs, particularly circular RNAs (circRNAs), in disease onset and progression. Here, we investigated circRNAs implicated in ALS and related motor neuron diseases (MNDs). Here, we provide a general overview of circular RNA metabolism and cellular functions. We then present our systematic literature review that identified ALS-associated circRNAs, followed by in silico analyses of 15 circular RNA candidates that were selected based on the most compelling data regarding ALS. Our results revealed that several circular RNAs regulate ALS-related genes, such as unfolded protein response, oxidative stress, cell cycle regulation, and apoptosis. Protein-RNA interaction analysis further showed that ALS-related circRNAs can sponge 20 RNA-binding proteins. Additionally, molecular docking analysis demonstrated that ALS-associated FUS variants significantly alter its binding affinity to circular RNAs. RNA-seq data from ALS patients confirmed significant alterations in the expression of host genes of ALS-related circRNAs and hub proteins in ALS-affected CNS tissues. Collectively, our findings identify circRNAs as potential key contributors to ALS pathogenesis.

Amyotrophic Lateral Sclerosis↗

PubMed2026

Comparative effectiveness of game-based learning modalities in nursing and medical education: a systematic review and Bayesian network meta-analysis.

BACKGROUND: Game-based learning (GBL) is increasingly used in healthcare education, but educators must choose among diverse modalities (e.g., quiz platforms, apps, serious games and metaverse environments). Comparative evidence on which modalities perform best across learning domains (knowledge, attitudes, and practice) remains limited. AIM: To compare the effects of distinct GBL modalities on knowledge, attitudes, and practice outcomes in nursing and medical education and to explore whether comparative effects differ by learner group (pre-licensure students and in-service professionals). DESIGN: PRISMA-NMA-aligned systematic review and Bayesian network meta-analysis. METHODS: We searched eight databases and trial registries through September 2, 2024, for randomized controlled trials comparing GBL with traditional teaching (TT). Outcomes were transformed to a 0-100 scale and analysed as change from baseline in Bayesian consistency models; random-effects models were selected using deviance information criterion (DIC). Risk of bias was assessed using RoB 2. We report mean differences (MDs) with 95% credible intervals (CrIs) versus TT, ranking probabilities, and subgroup NMAs by learner group. RESULTS: Thirty-one RCTs (n = 3439) were included; 15 contributed complete data to the network. Risk of bias was low in 15 trials and raised some concerns in 16. The network was modest for knowledge (11 trials) and sparse for attitudes (3) and practice (4). Compared with TT, metaverse-based learning showed improved attitudes (MD 15; 95% CrI 12 to 18), based on a single trial. For knowledge and practice, Kahoot-based quizzes (MD 9.1; 95% CrI -8.9 to 27) and app-based learning (MD 4.6; 95% CrI -4.4 to 14) had the highest estimated mean improvements, but credible intervals were wide and included the null for most comparisons. Subgroup rankings differed by learner group, but several comparisons were imprecise and uncertainty was substantial, particularly in sparse networks. CONCLUSIONS: GBL modalities may improve learning outcomes compared with TT, but relative effects appear domain-specific and the certainty of rankings is limited by sparse evidence and imprecision. Future trials should prioritise head-to-head comparisons, robust outcome measurement, and longer-term retention and transfer outcomes in both student and in-service populations.

Humans↗

PubMed2026

Prophylactic folinic acid prevents pemetrexed myelosuppression: A randomized trial toward safer treatment with chemotherapy in non-small cell lung cancer.

Background Pemetrexed is a cornerstone in advanced non-small cell lung cancer treatment. Although generally well tolerated, severe myelosuppression occurs in 26% of patients. Preventing chemotherapy-associated toxicity has become increasingly important with the introduction of osimertinib combined with pemetrexed-based chemotherapy. Due to substantial toxicity, this regimen is often not administered to frail patients. Folinic acid prophylaxis can mitigate pemetrexed-induced toxicity, however its preventive use has not been routinely studied. We aimed to investigate the efficacy of folinic acid prophylaxis to reduce myelosuppression. Methods Fifty patients treated with pemetrexed were randomized (1:1) to receive pemetrexed with or without oral folinic acid prophylaxis on days 2-4 after each chemotherapy cycle. The primary endpoint was absolute neutrophil count (ANC) after the first chemotherapy cycle. Secondary endpoints included ANC after the second cycle, grade neutropenia, treatment efficacy, renal function and incidence of dose modifications. Results Twenty-four patients received folinic acid and twenty-six served as controls. Higher ANC were observed in the folinic acid group after the first cycle (median 3.79; IQR 2.22-4.93 vs. 1.85; IQR 1.43-3.78; p.

Humans↗

PubMed2026

A systematic review of human avoidance learning: Cognition, computation, and methods.

Avoidance behaviour is fundamental for survival but can become maladaptive in clinical conditions. A large body of literature has accumulated on the dynamics of human avoidance learning. However, current theories and overviews do not provide an exhaustive account of this evidence. In this systematic review, we identify N = 116 studies on human avoidance learning. We analyse these studies with the goal of distilling robust empirical phenomena as a basis for theory-building, and examine their diagnostic value in differentiating between competing theories. We find that the evidence is difficult to reconcile with foundational two-factor and classical safety-signal accounts, and most strongly supports expectancy- and inference-based views, in which avoidance responses are selected with respect to represented consequences. At the same time, no current framework provides a complete account of the evidence: several findings point to an additional role for operant valuation, Pavlovian influences, and contextual or latent-state control over the expression of avoidance. Methodologically, we observe that the problem setting in the most common experimental paradigms is radically simpler than real-world avoidance and therefore unlikely to expose the limits of inferential or reflective mechanisms. Consequently, we argue that paradigms with greater computational demands and more realistic action affordances are required to identify the mechanisms underlying avoidance learning. Collectively, these insights provide a foundation for theoretical refinement, computational modelling, and methodological innovation, with implications for advancing interventions targeting maladaptive avoidance.

Humans↗