Pharmacology Research & Perspectives

Background: Diabetes mellitus is an increasing public health challenge in Sierra Leone, where access to diagnosis, treatment, and long-term care remains limited. Traditional medicine continues to play a significant role in disease management; however, ethnobotanical knowledge related to diabetes remains insufficiently documented. Methods: A cross-sectional ethnobotanical survey was conducted among 40 informants, including traditional healers, herbalists, and knowledgeable community members in Waterloo, Pendembu, and Bo. Data were collected using structured questionnaires administered via Kobo Toolbox and paper-based tools. Information on medicinal plants, plant parts used, preparation methods, routes of administration, and knowledge transmission pathways was obtained. Quantitative ethnobotanical indices, including Frequency of Citation (FC), Relative Frequency of Citation (RFC), and Informant Consensus Factor (ICF), were calculated. Results: A total of 21 medicinal plant species were documented. The most frequently cited species were Moringa oleifera (FC = 9; RFC = 0.225), Vernonia amygdalina (FC = 7; RFC = 0.175), and both Cassia siberiana and Telfairia occidentalis (FC = 6; RFC = 0.150). Leaves were the most commonly utilized plant part (40.9%), and decoction was the predominant preparation method (76.2%), with oral administration accounting for 95.2% of use. The Informant Consensus Factor (ICF = 0.69) indicated a relatively high level of agreement among informants. Knowledge was primarily transmitted through apprenticeship and inherited family practices. Conclusion: Traditional medicinal plants remain an important component of diabetes management in Sierra Leone. The high level of consensus among informants and the repeated citation of specific plant species suggest structured and culturally validated therapeutic practices. The findings provide a foundation for future phytochemical and pharmacological investigations and highlight the need for documentation, preservation, and sustainable utilization of ethnobotanical knowledge.

Introduction: Conventional substance-level disproportionality analysis may miss safety patterns specific to a dose form, route, or intended site. More granular analyses are hindered by incomplete, inconsistent reporting of product information. The Pharmaceutical Product Identifier (PhPID), representing products by substance, strength, and dose form, may support more granular analyses. Objective: To explore the use of PhPID-like dose form information for site-specific disproportionality analysis in dexamethasone. Methods: We evaluated VigiBase reports (January 1, 2001 - December 31, 2024) for completeness of dose form and route data. We standardized dexamethasone entries to PhPID Level 3 standards, representing substance and administrable dose form. Through disproportionality analysis (Information Component, IC) we compared substance-level and site-specific results. Results: Among 56.4 million suspected/interacting drugs, dose form was reported in 47.7%, route in 69.4%. Among 109,248 dexamethasone entries, 703 dose form and 80 route variations were mapped to 53 and 44 standard codes respectively; about half could be mapped unambiguously. Site-specific analyses revealed biologically plausible patterns not apparent in substance-level analyses. Ocular use showed higher ICs for glaucoma and cataract, while systemic use showed higher IC for psychiatric and endocrine events (e.g., depression, agitation, Cushing's syndrome). IC time-trends suggested that some signals (e.g., cataract with Ocular use) could emerge earlier in site-specific analyses. Conclusion: More granular product information, aligned with PhPID, may improve signal detection and characterization of site-specific safety issues. These findings support granular identifiers in pharmacovigilance while highlighting the need for better capture and standardization of dose form and route of administration data.

Background. Compounded tirzepatide is prescribed at scale as a cheaper substitute for branded Mounjaro and Zepbound, yet the cost case is almost always built by setting one compounded price against one branded list price. That framing ignores the question that actually decides the answer: cheaper than which branded price the patient can reach. Branded tirzepatide is now sold at sharply different tiers, namely insurance copay (often $25-$150/month), LillyDirect Self Pay ($299-$449/month), and retail cash price ($1,000-$1,200/month). Whether compounded saves money turns entirely on which of these a given patient faces. A second open question is whether the two formulations even produce comparable effectiveness, since observed differences may reflect selection on insurance, baseline characteristics, and adherence rather than the drug. Methods. We conducted a retrospective cohort study of tirzepatide users in the Mochi Health telehealth program, classified by formulation from their refills as branded-only (Mounjaro/Zepbound; 6,238), compounded-only (71,683), or switchers (4,996); switchers were excluded from the formulation contrast. Among single-formulation patients with a documented six-month weight observation, the analytic cohort was 7,271 (869 branded, 6,402 compounded). The primary outcome was six-month percent body weight loss; the secondary outcome was >=10% response. We used 1:1 nearest-neighbor propensity-score matching (0.25 SD caliper) on baseline covariates only - age, sex, baseline BMI, baseline weight, comorbid diabetes, hypertension, dyslipidemia, prior bariatric surgery, and self-reported insurance coverage - deliberately excluding post-treatment variables such as adherence and time in program, which are mediators of the formulation effect. We pre-specified an equivalence margin of +/-2 percentage points on mean loss and tested equivalence with two one-sided tests (TOST). A directed acyclic graph (DAG) makes the identifying assumptions explicit; metformin use could not be reliably ascertained and is treated as an unmeasured confounder. The cost comparison reports the savings or premium of compounded versus branded under five branded price scenarios: retail list, LillyDirect Self Pay (two dose tiers), and insurance copay (typical and low end). It is a cost comparison (cost-minimization under demonstrated similar effectiveness), not a formal cost-effectiveness analysis: we computed no ICER, QALY, or discounting. Results. Branded and compounded patients had similar outcomes even before adjustment (mean loss 11.7% vs 11.5%; >=10% response 60.9% vs 58.8%). The largest baseline difference between the groups was insurance coverage (branded patients far more likely insured; standardized mean difference 0.67), which matching balanced to 0.01. After 1:1 matching (718 pairs, all |SMD| < 0.04), mean loss was 11.4% vs 11.4% (difference +0.08 pp, 95% CI -0.70 to +0.80) and >=10% response 59.3% vs 57.2% (difference +2.1 pp, 95% CI -3.1 to +7.1). The two formulations were statistically equivalent within the pre-specified +/-2 pp margin (TOST p < 0.001). Cost depends on the branded scenario: compounded saves $6,000 over six months versus retail list price, $1,494 versus LillyDirect maintenance-dose (5-15 mg) Self Pay, and $594 over a low-dose (2.5 mg) LillyDirect prescription, while it costs $300 more than branded under a typical insurance copay ($150/month) and is more expensive still at lower copays (savings turn negative below $200/month). Conclusions. Branded and compounded tirzepatide were statistically equivalent in six-month effectiveness within a pre-specified +/-2 pp margin, so the choice between them is essentially a cost decision - and that cost advantage is real but conditional on the branded price the patient can access. It is large against retail list price and shrinks to zero or reverses against LillyDirect Self Pay or a low insurance copay. Whether compounded is the lower-cost choice for an individual patient is, therefore, a question about which price tier that patient faces.

Background Liver transplantation is a complex surgical procedure featuring prolonged operative time and extensive surgical trauma, which results in a high anesthetic risk. Especially during anesthesia induction and the anhepatic-to-reperfusion phases, where marked hemodynamic fluctuations may readily lead to malignant cardiovascular events. Liver transplantation is associated with numerous postoperative complications, including pulmonary complications, postoperative delirium, acute kidney injury, and delayed emergence, all of which may adversely affect patient prognosis. Studies on remimazolam besylate (hereafter referred to as remimazolam) have suggested that it has minimal impact on patient hemodynamics. In theory, this renders remimazolam an ideal sedative agent for liver transplantation. This study aims to verify the hypothesis that the use of remimazolam during liver transplantation can reduce the incidence of postreperfusion syndrome (PRS). In addition, we further explored the effects of remimazolam on postoperative complications in liver transplant recipients, particularly focusing on perioperative liver and kidney function, pulmonary complications, and postoperative delirium. Methods This study is a prospective randomized controlled trial. 120 participants aged 18-60 years who are scheduled to undergo liver transplantation under general anesthesia will be enrolled. In the intervention group, remimazolam besylate will be used for anesthesia induction and maintenance at doses of 0.2-0.4 mg/kg and 1-3 mg/kg/h until the end of surgery. In the control group, propofol will be used for anesthesia induction and maintenance at doses of 1-2 mg/kg and 4-12 mg/kg/h until the end of surgery. In both groups, anesthetic drug doses or sevoflurane administration for intravenous-inhalational combined anesthesia will be adjusted based on vital signs and BIS values. All other anesthetic medications will be conducted according to the anesthetist's preference and remain consistent. Discussion This trial will investigate whether remimazolam besylate can be used during liver transplantation to reduce the incidence of postreperfusion syndrome. It will also examine whether the drug provides potential benefits regarding perioperative complications such as postoperative delirium and acute kidney injury. Trial Registration: Chinese Clinical Trial Registry,ChiCTR2500095774, registered on January 13, 2025 Keywords: liver transplantation, remimazolam, postreperfusion syndrome, complications

Background. GLP-1 receptor agonist trials are tightly controlled: standardized titration, intensive dietary counseling, frequent in-person follow-up, and rigorous exclusion criteria. The real world is none of those things. In a U.S. telehealth GLP-1 program, diet engagement, exercise, medication choice, dose timing, and out-of-pocket cost vary substantially from patient to patient. Whether trial-level efficacy translates into the outcomes a patient and clinician will actually see is an open question, and the answer matters, because telehealth is now where most GLP-1 prescribing happens. Methods. We conducted a retrospective cohort study of 13,507 adults who used a single GLP-1 agent (tirzepatide or semaglutide) through the Mochi Health telehealth obesity program and had a documented six-month weight observation. The primary outcome was achievement of >=10% total body weight loss at six months. To address selection bias in the tirzepatide-semaglutide comparison, we used 1:1 nearest-neighbor propensity-score matching on age, sex, baseline BMI, baseline weight, and comorbid diabetes, hypertension, dyslipidemia, and prior bariatric surgery (recorded at intake), with a 0.25 SD caliper on the propensity logit. We drew a directed acyclic graph (DAG) with a clinical co-author to make the identifying assumptions explicit and to mark where unobserved variables (insurance, socioeconomic status, concomitant medications such as metformin) limit causal interpretation. We report multivariable predictors via logistic regression, compute an E-value for the matched contrast, and benchmark our point estimates against landmark RCT outcomes. Results. Overall, 59.1% of patients achieved >=10% loss at six months, with mean loss of 11.5% (median 11.3%). Threshold attainment was 86.6% at >=5%, 59.1% at >=10%, 27.5% at >=15%, and 9.1% at >=20%. The unadjusted tirzepatide-semaglutide response gap was +16.0 percentage points (68.8% vs 52.8%); after 1:1 propensity-score matching (3,480 pairs, all post-match |SMD| < 0.05) the gap was +18.1 percentage points (69.6% vs 51.6%, 95% CI +15.9 to +20.3). Matching on the measured covariates did not attenuate the advantage, indicating that selection on those characteristics does not explain it; the matched risk ratio was 1.35 (E-value 2.04). The gap was unchanged when a self-reported insurance indicator was added to the matching (+18.4 pp) and remained large (+14.2 pp) within patients who reached a therapeutic dose. Multivariable predictors of response were tirzepatide (OR 2.10, 1.95-2.26), female sex (OR 1.37, 1.20-1.56), and prior bariatric surgery (OR 1.36, 1.18-1.57); response was lower with comorbid diabetes (OR 0.84, 0.77-0.92) and, modestly, with higher baseline BMI per unit (OR 0.98, 0.97-0.99). Response varied by baseline BMI, from 58.0% in overweight patients (BMI <30) and a peak of 63.5% in Obese I to 52.4% in Obese III. Conclusions. Real-world response to GLP-1 therapy in a telehealth setting is meaningfully attenuated from RCT benchmarks but remains clinically substantial: roughly three in five patients reach the 10% threshold. The tirzepatide advantage over semaglutide is large and, notably, does not shrink under propensity-score matching on measured confounders, so it is not an artifact of the observed selection variables; an unmeasured confounder would need a risk-ratio association of about 2.0 with both drug choice and response to explain it away (E-value 2.04). The findings are observational, conditional on the DAG's identifying assumptions, and unmeasured confounders (insurance, socioeconomic status, concomitant medications) remain possible.

Rheumatoid arthritis is a chronic inflammatory joint disease in which progressive destruction of cartilage and bone drives long-term disability. Current disease-modifying therapies target the immune and cytokine networks that sustain synovial inflammation, but none is directed at the chondrocyte, the resident cell responsible for maintaining cartilage matrix. Chondrocyte survival and matrix homeostasis depend on {beta}1-integrin-mediated adhesion to the extracellular matrix, and dysregulated integrin signalling has been implicated in cartilage injury. Here we test the hypothesis that allosteric modulation of {beta}1 integrin, rather than simple adhesion blockade, is chondroprotective. Using the monoclonal antibody JB1a, which binds an epitope in the hybrid domain of {beta}1 integrin and stabilises the receptor in a low-affinity conformation, we show that intra-articular administration produces both functional and structural amelioration of Freunds complete adjuvant (FCA)-induced arthritis in mice. JB1a abolished the FCA-induced increase in joint diameter and hyperalgesia and markedly reduced synovial inflammation, pannus formation and cartilage erosion, with no effect on the contralateral joint and no observed adverse effects. These changes were accompanied by a reduction in chondrocyte apoptosis in vivo. In primary human articular chondrocytes, JB1a abolished interleukin-1{beta} (IL-1{beta})-induced caspase 3/7 activation, reduced IL-8 secretion, and restored the sinusoidal oscillation of intracellular ATP that was otherwise abrogated by IL-1{beta}. In contrast, the adhesion-blocking, integrin-clustering antibody 6S6 activated caspase 3/7 and amplified IL-1{beta}-induced IL-8 secretion, indicating that the therapeutic effect is a property of the specific mode of receptor engagement rather than of adhesion blockade per se. These findings identify {beta}1-integrin conformational state as a determinant of chondrocyte energy homeostasis and survival, and nominate allosteric {beta}1-integrin modulation as a mechanistically distinct, chondrocyte-directed therapeutic strategy in inflammatory arthritis.

Polysubstance use is rising and linked to heightened overdose rates and increased treatment challenges, further exacerbated by increasing detection of adulterants (e.g., xylazine) in the street drug supply. Harm reduction groups provide sterile syringes in exchange for used ones, creating a unique opportunity to characterize prevalent polysubstance combinations and inform translational and preclinical research We analyzed residues from used syringes (N=3,168) obtained from several harm reduction organizations in Jefferson County, KY (Jan-Dec 2025) for the presence of substances using gas chromatography mass spectrometry (GC-MS). We classified compounds as adulterants (e.g., diphenhydramine [DPH]/Benadryl), byproducts/precursors of synthesis (e.g., 4-ANPP), and recreational drugs (e.g., meth). We excluded byproducts/precursors and determined the most frequent substance and pairs/trios containing one or more recreational substance. Results. Of 3,168 syringes, 2,522 (79.61%) tested positive for substances. Out of those positive, the top recreational substances were meth (n=1,387; 54.99%), fentanyl (n=1,220; 48.37%), and heroin (n=653; 25.89%). Top adulterants were DPH (n=1021; 40.48%), dimethyl sulfone (n=749; 29.69%), and lidocaine (n=736; 29.18%). The most common pairs were DPH+fentanyl (n=670; 26.57%), lidocaine+fentanyl (n=659; 26.13%), dimethyl sulfone+meth (n=621; 24.62%), and fentanyl+heroin (n=484; 19.19%). The most common trios were DPH+lidocaine+fentanyl (n=369; 14.63%), DPH+fentanyl+heroin (n=327; 12.97%), lidocaine+fentanyl+heroin (n=297; 11.77%), diphenhydramine+xylazine+fentanyl (n=273; 10.82%), and meth+lidocaine+fentanyl (n=262; 10.39%). Our findings highlight evolving patterns of multiple-opioid and opioid-stimulant polysubstance use, generating insights that can be rapidly applied to strengthen clinical, preclinical, and translational polysubstance research. These insights allow for investigations into biobehavioral mechanisms and consequences of emerging use patterns, accelerating development of novel therapeutics.

Background: We sought to determine the changing prevalence, incidence, and temporal trends in real-world, recorded diagnoses of metabolic dysfunction-associated steatotic liver disease (MASLD) and assess availability of fibrosis risk stratification following awareness campaigns and guideline updates over the last decade. Methods: This population-based cohort study identified MASLD diagnoses made between 2003 to 2022 in the UK primary-care Clinical Practice Research Datalink (CPRD) to estimate prevalence and incidence. A nested case-control analysis, utilising 1:4 age-, sex-, and general practice-matched controls, assessed clinical characteristics, availability of Fibrosis-4 (Fib-4) components, and its temporal trend pre- and post-2015. Findings: 11.7 million individuals were active in CPRD in 2022. 365,797 comprised the study cohort of people with a MASLD diagnosis (matched to 1,460,288 controls). From 2012-2022, recorded MASLD prevalence rose from 0.52% [N=51,028] to 2.42% [N=283,762] (p<0.001); recorded incidence doubled from 1.60 to 3.31 per 1000 person-years (p<0.001). People with MASLD diagnosis had a higher prevalence of type 2 diabetes (21.0% [N=76,640] vs 7.7% [N=112,812]) and hypertension (35.3% [N=129,156] vs 18.7% [N=273,502]). People of South Asian ethnicity were overrepresented in MASLD cohort but had the lowest availability of Fib-4 components (14.6% [N=4,467]; adjusted odds ratio 0.67, 95% CI: 0.65-0.70, vs White). Overall, Fib-4 availability increased pre- to post-2015 (4.3% [N=4,945] to 22.8% [N=56,634]). Among those with a calculable score, fewer South Asian individuals had indeterminate/high risk (18.6% [N=833] vs 35.3% [N=15,115] in White individuals, p<0.001). Interpretation: Recorded MASLD prevalence has increased 5-fold in a decade, yet a diagnostic gap persists. Fibrosis risk stratification has improved, but remains low and is potentially inequitable for people of South Asian ethnicity. Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Barts Charity. Keywords: Epidemiology, Real-world data, Real-world evidence, MASLD, Primary Care

Bipolar androgen therapy (BAT) exploits the paradoxical vulnerability of castration-resistant prostate cancer (CRPC) cells to rapid cycling between castrate and supraphysiologic androgen concentrations, but clinical BAT uses testosterone, which can also activate wild-type androgen receptor (AR) in androgen-responsive tissues, causing systemic side effects. 5{beta}-dihydrotestosterone (5{beta}-DHT) is a naturally occurring testosterone metabolite generally considered androgenically inactive because it binds wild-type AR weakly, yet its activity against clinically relevant AR mutants has not been systematically evaluated. Here, we tested whether 5{beta}-DHT and related 5{beta}-reduced testosterone metabolites activate AR signaling and growth programs in prostate cancer models that carry AR mutations. In C4-2 cells, 5{beta}-DHT and 3{beta}-etiocholanediol (3{beta}-ecdiol) increased canonical AR target genes, including KLK3 and TMPRSS2, with weaker activity than testosterone, whereas other 5{beta} metabolites showed limited activity. In androgen-responsive LNCaP and C4-2 models, 5{beta}-DHT and 3{beta}-ecdiol promoted cell growth under androgen-depleted conditions, and this effect was suppressed by enzalutamide, supporting AR dependence. RNA-seq confirmed that 5{beta}-DHT and 3{beta}-ecdiol induced androgen-response gene sets substantially overlapping with testosterone, albeit at lower transcriptional magnitude. Further, we found that 5{beta}-DHT, but not 3{beta}-ecdiol, suppresses cell proliferation of LNCaP, C4-2, and PC-3 cells stably expressing the clinically relevant AR gain-of-function mutants W742C and H875Y through activating AR-induced senescence-like features after high-dose exposure, consistent with the therapeutic logic of BAT. These findings identify 5{beta}-DHT as an overlooked mutant-AR agonist capable of BAT-like tumor suppression and propose it as a testosterone surrogate in BAT with potentially reduced systemic androgenic side effects. HighlightsO_LI5{beta}-DHT and 3{beta}-ecdiol promote AR-dependent prostate cancer cell growth C_LIO_LIBoth are weaker AR agonists than testosterone by RNA-seq and qPCR C_LIO_LISupraphysiologic 5{beta}-DHT suppresses growth via AR-mediated senescence C_LIO_LIGrowth suppression extends to AR mutants W742C and H875Y C_LIO_LI5{beta}-DHT may be a lower-androgenicity testosterone surrogate for BAT C_LI

Background. When a GLP-1 patient stops responding, should the clinician push the dose or change the drug? Observational answers conflate two distinct sources of confounding. Most early-week "escalations" in real-world data are FDA-mandated titration steps rather than deliberate clinical decisions, and patients who deviate do so for reasons we cannot observe. Semaglutide and tirzepatide are also not equivalent milligram-for-milligram, so naive class-switch comparisons mix mechanism and dose. We resolve both by restricting to post-titration patients and reclassifying treatments under the Whitley 2023 dose-equivalence framework. Methods. From 68,969 telehealth GLP-1 patients we built a post-titration cohort. Each patient's index time is the day they completed at least four weeks at therapeutic dose (Whitley tier 3 or higher: semaglutide 1.0 mg or tirzepatide 5 mg). Confirmed slow response is less than 5% total weight loss at the index, consistent with FDA weight-management drug-development guidance and AACE/ACE criteria. We compared four post-index strategies against continuing the current regimen: within-class dose escalation, equipotent class switch (a Whitley tier change of 1 or fewer), and class switch with potency increase. Direction-specific analyses split switches into semaglutide-to-tirzepatide and tirzepatide-to-semaglutide arms. Outcomes were percent weight loss at 12 and 24 weeks post-index. We estimated effects six ways: propensity-score matching; IPTW with linear and gradient-boosted propensities; the g-formula with linear and gradient-boosted outcome models; and AIPW, the doubly-robust estimator we use as the tiebreaker. Two-layer inverse probability of censoring weighting addressed strategy adherence and outcome ascertainment. We computed E-values, ran a negative-control specification, and stratified by tolerability. Results. The post-titration cohort comprised 24,876 confirmed slow responders. Within-class dose escalation produced a small consistent benefit at 24 weeks: AIPW +0.64 pp (95% CI +0.16 to +1.12), with five non-AIPW estimators ranging +0.47 to +0.76 pp. The continue arm itself lost an additional 8.07 pp over the same window (96% continued to lose), so escalation is a marginal addition to a substantial natural slope, not a rescue. Equipotent class switching from semaglutide to tirzepatide was inconclusive: linear and matching estimators ranged +1.26 to +1.80 pp, but AIPW was -0.33 pp (95% CI -1.27 to +0.60) with only 90 treated patients and limited propensity-score overlap. Class switch with simultaneous potency increase (sema to tirz) gave AIPW +0.65 pp at 12 weeks (95% CI +0.37 to +0.92, n = 80). A negative-control specification yielded ATE -0.13 pp, indicating the pipeline did not generate spurious signal. A held-out-fold prognostic-threshold sensitivity gave a null effect (+0.04 pp), correcting an earlier circular +1.06 pp estimate. Conclusions. Among confirmed post-titration slow responders, within-class dose escalation adds approximately 0.6 percentage points at 24 weeks on top of an 8 percentage point natural slope, consistently across six estimators including doubly-robust inference. This headline effect is small and not robust to modest unmeasured confounding (E-value 1.27) or to MNAR-style outcome attrition (tipping point delta approximately 1.2 pp), so it should be read as hypothesis-generating rather than practice-changing. Class-switching evidence is inconclusive; linear-estimator results suggesting benefit did not survive doubly-robust estimation in small treated samples with limited propensity overlap. The dose-ladder framework, with phase-specific evidence grading, is hypothesis-generating and insufficient on its own to change practice.

Background: Urinary tract infection (UTI) is the most common secondary condition among people with spinal cord injury/disease (SCI/D). Intravesical Lacticaseibacillus rhamnosus GG (LGG) is an antibiotic-sparing approach to managing urinary symptoms. Objective: Determine the optimal number of doses of intravesical LGG for urinary symptom reduction. Design: Prospective, randomized, two-arm dosing trial. Setting: National recruitment with a local subsample providing urine samples in Washington, DC, USA. Participants: Adults with SCI/D and neurogenic lower urinary tract dysfunction (NLUTD) who use intermittent catheterization (IC); 177 enrolled and randomized (intention-to-treat), with 76 compliant instillers (39 low-dose, 37 high-dose) in the per-protocol analytic sample. Interventions: Two (2 doses/24 hours) or four (4 doses/36 hours) intravesical LGG regimens, self-initiated in response to cloudier or malodorous urine per the Self-Management Protocol using Probiotics (SMP-Pro). Main Outcome Measures: Primary: proportion achieving [&ge;]20% reduction on the Urinary Symptom Questionnaire for Neurogenic Bladder-Intermittent Catheter version (USQNB-IC). Secondary: urinary biomarkers (leukocyte esterase, nitrite, white blood cells, urinary neutrophil gelatinase-associated lipocalin [uNGAL]) and standard urine culture (SUC) in a local subsample. Results: By Day 2, 57.9% (63.8% low-dose; 51.2% high-dose) achieved [&ge;]20% total symptom reduction; high-dose success rose to 70.0% by Day 4. Thirty percent of high-dose participants did not respond at either time point and could not be distinguished from responders by demographics or urine biomarkers. Urinary biomarkers and SUC were unchanged pre- to post-instillation. No serious adverse events were adjudicated as attributable to intravesical LGG by an independent Data Safety Monitoring Board (DSMB). Conclusions: A two-dose course of intravesical LGG yields clinically meaningful symptom improvement in the majority of people with SCI/D and NLUTD who use IC; four doses benefits a meaningful subgroup of two-day non-responders, while a small cohort remains nonresponsive. These results provide preliminary dosing guidance and support progression to a definitive trial.

Objective: There is a bidirectional relationship between emotional distress and pain. However, this relationship is understudied in people with HIV in low-resource settings. This study sought to describe the temporal relationship between emotional distress and pain in people with HIV. Design: Longitudinal observational study. Methods: Participants with virally suppressed HIV, reporting either no pain or persistent pain at baseline, provided weekly remote ratings of distress, worst pain, and average pain using 0-10 visual analogue scales. Within-individual fluctuations in distress and pain were visualised over time. Group-level correlations were determined using Spearman's correlation tests. Cumulative link mixed models assessed whether distress and pain each predicted the other in the following week. Results: 72 participants provided responses over 49 weeks. The participants had a median (IQR) age of 43 (37-51) years, 63% (n=45) were unemployed and most were females (n=51;71%). Distress and pain fluctuated concurrently within individuals: distress was positively correlated with worst pain ({rho}=0.66, 95% CI= 0.60-0.72, p<0.001) and average pain ({rho}=0.70, 95% CI=0.64-0.75, p<0.001) intensity within the same week. Worst pain (OR=1.42, 95% CI=1.17-1.71, p<0.001) and average pain (OR=1.43, 95% CI=1.20-1.71, p<0.001) intensity both predicted distress in the next week. Distress predicted worst pain intensity (OR=1.25, 95% CI=1.07-1.46, p=0.023) but not average pain intensity (OR=1.19, 95% CI=1.01-1.40, p=0.152) in the next week. Conclusions: The temporal relationship between distress and worst pain intensity was bidirectional, whereas distress did not temporally predict average pain intensity. Both pain and emotional distress should receive attention from HIV research and clinical care in low-resource settings.

Introduction Parkinson's disease (PD) is a multifactorial disorder, affecting multiple neurotransmitter systems, including the cholinergic system. Cholinergic denervation is heterogeneous across patients and difficult to predict based on clinical presentation. In this study, we assessed the sensitivity of structural MRI (sMRI) and functional MRI (fMRI) to cholinergic degeneration related to PD and to cognitive functioning in PD. We compared our results to results from previously reported [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) PET imaging, which is considered the gold standard for cholinergic imaging. Methods 34 PD patients and 10 healthy controls underwent structural T1-weighted MRI. A subset of 14 patients and 9 controls also underwent resting-state fMRI. We extracted the bilateral volumes of the nucleus basalis of Meynert (NBM) from the sMRI images. Functional connectivity (FC) from the NBM to the cortex (NBM-FC) was determined using fMRI data. Principal component analysis (PCA) was applied to reduce the dimensionality of the NBM-FC images. We assessed performances for NBM-FC in distinguishing patients from controls using stepwise logistic regression. Similarly, NBM volume was used using logistic regression. Furthermore, the relation between these measures and cognitive function in several domains was investigated with (stepwise) linear regression. Leave-one-out cross validation (LOOCV) and bootstrapping was performed to assess robustness of the results. Results NBM-FC was well able to discriminate patients from controls with an AUC of 0.84 (95% CI: 0.62-1). NBM volume showed lower performance, but was still better than chance: AUC: 0.75 (95% CI: 0.57-0.93). Significant correlations were found between 1) cognition in the attentional domain and NBM-FC (r=0.63; p=.015) and 2) global cognition and NBM volume (r=0.55, p=.001). These results were inferior to those previously reported using [18F]FEOBV tracer uptake (see Chapter 6). Bootstrapping revealed that NBM volume of only the left hemisphere was stably related to PD diagnosis and global cognition in PD patients. We found that a lower NBM-FC in specific brain areas, including the fusiform gyrus, supramarginal gyrus and dorsolateral prefrontal cortex, was related to PD diagnosis. Bootstrapping revealed no stable NBM-FC pattern related to attention. Conclusion Although MRI results were slightly inferior to [18F]FEOBV PET data, MRI may provide a cheaper and more widely available alternative for cholinergic imaging. We recommend testing the utility of MRI as predictor and monitor of cholinergic treatment effect in a longitudinal study.

White matter lesion (WML) identification, assessment, and characterization using magnetic resonance imaging (MRI) are fundamental for diagnosis and monitoring of multiple sclerosis (MS). Portable ultra-low field (pULF) MRI at 64 millitesla (mT) has been shown to visualize WML with at least one dimension greater than 4 mm. An automated WML segmentation tool catered to pULF-MRI can provide standardized and accurate quantitative measurements of WML volume. In this study, we sought to investigate and compare the accuracy of machine-learning (ML) and deep-learning (DL) pULF MRI segmentation tools. Same-day paired pULF (64mT) and high-field (HF, 3T) MRI scans from 84 adults with MS or suspected-MS (mean age {+/-} SD: 48 {+/-} 13, 62 females) included T2-FLAIR and T1w images. Reference WML segmentations were manually annotated on pULF T2-FLAIR for all scans, with WML confirmed with registered HF T2-FLAIR. HF reference WML segmentations were created. Four automated segmentation methods were applied to pULF scans: Method for Inter-Modal Segmentation Analysis (MIMoSA), an ML algorithm trained on HF WML masks; WMH-SynthSeg, a convolutional neural network model with flexible segmentation capabilities across field strengths and resolution; nnU-Net, a DL algorithm trained on pULF reference WML masks; and Pseudo-Label Assisted nnU-Net (PLAn), a DL algorithm pre-trained on HF reference WML masks and refined with 64mT reference WML masks. Two models were trained with nnU-Net, one using T2-FLAIR images only (nnU-Net-FL) and one using T1w and T2-FLAIR images (nnU-Net-FL/T1). The same was done with PLAn, creating PLAn-FL and PLAn-FL/T1. The six automated WML segmentation outputs were compared to the manual segmentations to determine Dice Similarity Coefficient (DSC) scores. Associations of WML volume estimates with clinical measures were investigated. DSC scores with pULF reference WML masks from PLAn-FL (DSC mean {+/-} SD: 0.50 {+/-} 0.24) outperformed MIMoSA (0.24 {+/-} 0.20, p < 0.0001), WMH-SynthSeg (0.30 {+/-} 0.18, p < 0.0001), nnU-Net-FL (0.41 {+/-} 0.24, p < 0.0001), and nnU-Net-FL/T1 (0.41 {+/-} 0.26, p = 0.0004). Worse Expanded Disability Status Scale (EDSS) and Scripps Neurologic Rating Scale (SNRS) scores were correlated with higher WML volumes in the pULF and HF reference masks. They were also correlated with WML volumes derived from WHM-SynthSeg, nnU-Net-FL, nnU-Net-FL/T1, PLAn-FL, and PLAn-FL/T1, but not MIMoSA. After adjusting for age, WHM-SynthSeg, nnU-Net FL, nnU-Net-FL/T1, PLAn-FL, and PLAn-FL/T1 had significant associations with EDSS and SNRS scores. nnU-Net and PLAn performed best in segmenting WML on pULF-MRI at 64 mT, providing accurate quantitative estimates of WML burden. Moreover, WML volumes estimated by these algorithms were associated with clinical measures of disability, underscoring their utility for reflecting clinical and radiological disease severity. Given pULF-MRI's mobility and lower cost, these findings highlight its relevance in clinical trials, particularly in involving more participants who face logistical constraints and barriers.

Abstract Objective: To synthesize the available evidence on the association between SARS-CoV-2-related microvascular thrombosis and acute kidney injury (AKI), with emphasis on renal outcomes, mortality, and renal replacement therapy requirements. Methods: This systematic review followed the PRISMA 2020 statement and was prospectively registered in PROSPERO (CRD420251132701). PubMed/MEDLINE, Scopus, and Embase were searched for systematic reviews, including meta-analyses, and umbrella reviews investigating the association between SARS-CoV-2-related microvascular thrombosis and acute kidney injury. Two reviewers independently performed study selection, data extraction, and methodological quality assessment using AMSTAR-2 and ROBIS. Evidence was synthesized through a structured narrative synthesis supported by quantitative data extracted from the included reviews. Results: Six evidence syntheses evaluating kidney involvement, thrombotic events, and microvascular mechanisms in COVID-19 were included. AKI incidence was 9.2% (95%CI 4.6-13.9) among hospitalized patients and 32.6% (95%CI 8.5-56.6) among critically ill patients. In children with multisystem inflammatory syndrome associated with SARS-CoV-2, AKI incidence was 20% (95%CI 14-28). Microvascular or thrombotic events were associated with adverse renal outcomes (OR 2.14; 95%CI 1.32-3.48). AKI was associated with increased mortality (OR 4.68; 95%CI 1.06-20.70) and greater likelihood of renal replacement therapy requirement (OR 2.87; 95%CI 1.45-5.68). The certainty of evidence ranged from moderate to high for the principal outcomes. Conclusion: Current evidence supports an important association between microvascular thrombotic injury and COVID-19-associated AKI. These findings reinforce the relevance of endothelial dysfunction and thromboinflammatory pathways in kidney involvement during COVID-19 and highlight the need for early renal monitoring, risk stratification, and kidney-protective strategies in high-risk patients. Keywords: COVID-19; Acute Kidney Injury; Microvascular Thrombosis; SARS-CoV-2; Renal Replacement Therapy; Systematic Review

Background: Post-stroke dysphagia (PSD) contributes to aspiration, pneumonia, malnutrition, prolonged hospitalization and mortality. We evaluated the discrimination, validity and readiness of machine learning and data-driven prediction models for PSD-related outcomes. Methods: Following a prospectively registered protocol (PROSPERO CRD420261419259), we searched PubMed/MEDLINE, Embase, Web of Science Core Collection, CINAHL and CENTRAL from inception through June 7, 2026. Eligible studies developed or validated multivariable prediction models for PSD-related outcomes in adults with stroke. We used PROBAST and PROBAST+AI to assess risk of bias and applicability and TRIPOD+AI to evaluate reporting. Area under the curve (AUC) estimates were pooled on the logit scale with random-effects models. Results: Twenty-four studies were included and ten contributed to meta-analysis. Four studies predicting early or incident PSD yielded a pooled AUC of 0.94 (95% CI 0.60-0.99; I2 = 95.6%). Pooled AUCs were 0.84 (95% CI 0.71-0.92) for aspiration or penetration-aspiration and 0.89 (95% CI 0.24-1.00) for severe dysphagia. The exploratory analysis of all ten risk-prediction models produced an AUC of 0.90 (95% CI 0.80-0.95), but heterogeneity was substantial (I2 = 90.3%) and the prediction interval was 0.51-0.99. Every study had high risk of bias because of analysis-domain concerns; calibration and external validation were uncommon. Conclusions: Reported discrimination was often high, but the evidence does not establish reliable performance in care. Independent validation, calibration, complete model reporting and clinical-impact studies are needed before these models guide post-stroke swallowing care. Keywords: Post-stroke dysphagia; Stroke; Deglutition disorders; Machine learning; Clinical prediction model; Area under the curve; Meta-analysis

Abstract Background: Remote clinical reviews have become an integral component of contemporary nursing practice across community and acute care settings. Nurses increasingly make autonomous clinical decisions using telephone, video, and online/digital systems, often with limited sensory information and under conditions of uncertainty. However, empirical understanding of how nurses make clinical decisions via remote reviews remains limited. Aim: To explore and understand how registered nurses (RNs) make clinical decisions about patient care via remote reviews. Methods: A convergent mixed-methods design was employed. Quantitative data (analytic quantitative sample N=53) were collected using validated questionnaires that measured decision-making processes, physician-nurse collaboration, decision-making stress, and perceived decision-making ability. Qualitative data (N=23) were generated through semi-structured interviews. Data collection took place between October 2024 and April 2025. Quantitative data were analysed using descriptive statistics, correlation, and multiple regression. Qualitative data were analysed using framework analysis. Integration was achieved through pillar-building and theory-driven synthesis and illustrated by joint display tables. Results: Most nurses demonstrated a flexible decision-making style, integrating analytical and intuitive reasoning. Both analytical and intuitive processes were positively associated with perceived decision-making ability. Physician-nurse collaboration emerged as a strong predictor of decision-making confidence, while decision-related stress was not a significant predictor. Qualitative findings identified three themes: characteristics of remote review; making adaptive decisions shaped by both internal and external constraints and enablers; and external influencing factors. The integrated findings informed a theory-informed ICE framework to illustrate how nurses make clinical decisions via remote reviews. Conclusion: Remote clinical decision-making is a dynamic cognitive-environmental process rather than a purely individual cognitive act. The ICE framework conceptualises this interaction, extending existing decision-making theories to digitally mediated care. Impact: Understanding remote decision-making supports training design, clinical governance, and the development of Artificial Intelligence-enhanced decision-support tools grounded in ecological bounded rationality. Patient or Public Contribution: Patient and public representatives contributed to stakeholder discussions that informed the development of the interview topic guide and the theoretical model. Patients or members of the public were not involved in recruitment, data collection, analysis, interpretation of findings, or preparation of the manuscript. Keywords: clinical decision-making, remote reviews, telehealth, nursing, mixed methods, ecological bounded rationality

Background with objective: Detecting EGFR mutations is critical for treating lung adenocarcinoma with highly effective targeted therapies. However, standard genetic testing is expensive, complex, and often unavailable in resource-limited settings like Bangladesh. Because elevated serum CEA has been linked to these genetic alterations, it could serve as an accessible screening tool. This study aims to evaluate the association between serum CEA levels and EGFR mutation status to determine if routine CEA testing can reliably predict these mutations and guide treatment. Methodology: In this cross-sectional analytical study, we recruited 58 patients with histologically confirmed treatment naive lung adenocarcinoma. The presence of EGFR mutations in the ctDNA was determined via ARMS (Amplification Refractory Mutation System) PCR. Patient data was statistically analyzed to assess the diagnostic correlation between serum CEA levels and the presence of EGFR mutations. Result: The overall EGFR mutation rate was 43.1% with exon 19 deletion (48%) and exon 21 mutations (44%) were the predominant types. Median serum CEA levels were significantly higher in patients with EGFR mutations compared to wild-type cases (14.6 ng/ml vs 2.8 ng/ml, p<0.001). A multivariate analysis revealed a 14% increased likelihood of an EGFR mutation for 1 ng/ml rise in serum CEA. Furthermore, serum CEA showed strong diagnostic accuracy for ctDNA samples at a 6.39 ng/ml cut-off (AUC 0.82, sensitivity 68.0%, specificity 84.8%). Conclusion: Serum CEA is a valuable, cost-effective, and non-invasive biomarker demonstrating significantly higher levels and strong diagnostic accuracy in EGFR-mutated lung adenocarcinoma compared to wild-type cases.

Objective: Photobiomodulation therapy has emerged as a promising modality to facilitate scar healing and pain management in dermatology and plastic surgery. However, its role in postoperative care following spine surgeries remains understudied. This double-blinded, placebo-controlled study aimed to investigate the effects of photobiomodulation in patients with chronic lower back pain undergoing lumbar decompression, with postoperative wound healing as the primary outcome and pain reduction and functional recovery as secondary outcomes. Methods: Patients were randomized to receive either active photobiomodulation braces (N=13) or placebo braces (N=12). Follow-up assessments were performed at 2, 4, 6, 8, and 12 weeks postoperatively. Outcomes included wound healing (Stony Brook Scar Evaluation Scale), back and leg pain (Visual Analog Scale), quality of life (EuroQol 5D), and functional status (Oswestry Disability Index). Results: Compared to the placebo group, the photobiomodulation treatment group had a 4.12-fold cumulative improvement in final scar scores, with significant between-group differences at postoperative weeks 6, 8, and 12 (p = 0.0062, 0.010, 0.042). Among patients with severe preoperative disability, treatment resulted in a 1.89-fold faster improvement in back pain (p=0.025) and a 1.80-fold faster improvement in ODI scores (p=0.025); and superior treatment effect on wound healing were again observed at weeks 6, 8, and 12. Among patients with poor initial scars, treatment led to a significantly better scar outcome than placebo at week 6 and a 1.94-fold faster EQ5D improvement (p=0.052), with significant gains observed as early as two weeks after surgery. There were no adverse events associated with photobiomodulation treatment. Conclusions: Photobiomodulation significantly promoted postoperative wound healing following lumbar decompression surgery, with therapeutic benefits preserved even in patients with poor baseline scar scores and functional impairment. This indicates that the efficacy of photobiomodulation is not limited by the initial scar condition or disability, supporting its broad clinical applicability. Additionally, patients with severe preoperative disability experienced greater benefits from photobiomodulation than placebo, including faster reduction in back pain and more rapid improvement in functional capacity, highlighting its role in postoperative pain management and rehabilitation. These therapeutic effects are likely mediated by photobiomodulation-induced reduction of inflammation and enhancement of tissue repair. Together, this study suggests that photobiomodulation can be a promising adjunct therapy to facilitate postoperative recovery in patients undergoing spine surgery.

Chronic kidney disease and heart failure disproportionately burden populations of African ancestry, yet Mendelian randomisation (MR) studies of the causal relationship between kidney function and heart failure subtypes have been conducted exclusively in European ancestry populations. We performed a forward two-sample MR analysis to evaluate the causal effect of genetically predicted estimated glomerular filtration rate (eGFR) on heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) in individuals of African ancestry. Genetic instruments were selected from an African ancestry eGFR genome-wide association study (N = 67,943) at genome-wide significance, with linkage disequilibrium clumping using an African ancestry reference panel. Heart failure subtype summary statistics were obtained from the Million Veteran Program (HFpEF: 5,379 cases / 113,041 controls; HFrEF: 9,104 cases / 109,632 controls). Six independent SNPs (F-statistics 30.5 &#8211 107.3; R&#178 = 0.62%) were retained as instruments. The primary inverse-variance weighted analysis provided no evidence of a causal effect of eGFR on HFpEF (OR 0.92, 95% CI 0.80 &#8211 1.06, p = 0.248) or HFrEF (OR 0.98, 95% CI 0.78 &#8211 1.23, p = 0.878). Sensitivity analyses were directionally consistent. There was no evidence of heterogeneity or directional pleiotropy. Minimum detectable effects at 80% power were OR 1.28 for HFpEF and OR 1.22 for HFrEF. These null findings should be interpreted as inconclusive given current power constraints; larger ancestry-matched studies are needed.