British Journal of Pharmacology

Psilocybin shows therapeutic promise for several psychiatric disorders, but the acute perceptual and cognitive alterations produced by conventional doses (10-25 mg) require in-clinic supervision, which limits scalability. Whether the therapeutically relevant pharmacology of psilocybin can be separated from its hallucinogenic activity remains unresolved. To address this gap, we conducted a Phase 1, randomized, double-blind, placebo-controlled, single ascending dose study to characterize the safety, pharmacokinetics and pharmacodynamics of low doses of psilocybin. Fifty-six healthy adults received a single oral dose of psilocybin (0.5, 1.0, 1.5, 2.5, 3.5 or 4.0 mg) or matching placebo across seven sequential cohorts, with each dose escalation reviewed by a Drug Safety Review Committee. All participants completed the study with no serious adverse events or discontinuations. Treatment-emergent adverse events were comparable to placebo and most prominently arose as somnolence. Plasma psilocin appeared rapidly with a median time to maximum concentration < 1 h with dose-proportional exposure and a short terminal half-life. Subjective drug effects were dose-related and became distinguishable from placebo at doses at or below 2.5 mg. Peak subjective ratings increased with dose, while any signs of hallucinations or altered-states scores remained low and not different than placebo. Psychophysiological engagement was confirmed by a clear dose-dependent pupillary dilation while cognitive performance (attention, vigilance, working memory, impulse control) showed no dose-dependent decrement and state anxiety did not increase at any dose. These findings indicate that the perceptible pharmacology of psilocybin can be dissociated from significant perceptual alterations and cognitive impairment at low doses. They further support controlled investigations in outpatient Phase 2 studies evaluating the safety and feasibility of repeated, self-administered low-dose psilocybin. ClinicalTrials.gov #NCT07710027

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.

IntroductionBipolar disorder (BD) is characterized by recurring episodes of mania and depression. Despite extensive research, the pathophysiology underlying these mood swings remains elusive. Emerging evidence indicates a potential role for neuroinflammation and microglial activation in the pathophysiology of BD. MethodsWe employed a reverse-translational approach to generate directly induced microglia-like (iMG) cells from peripheral blood monocytes of a single patient with BD, repeatedly sampled across depressive, manic, and subsequent depressive phases. RNA sequencing was performed on iMG cells at each time point to identify differentially expressed genes related to mood state transitions. ResultsA thorough analysis of longitudinal gene expression data has led to the identification of three functional gene categories: "state-dependent genes", "depression-to-mania transition genes (named: firing genes)", and "mania-to-depression transition genes (named: extinguishing genes)". A total of 168 firing, 59 extinguishing, and 77 state-dependent genes were identified. Notably, functional annotation revealed that, compared to the extinction gene set, the firing gene set was enriched in immune and inflammatory response pathways, particularly early-response cytokines such as IL1B and TNF. ConclusionsBased on these findings, we propose that inflammatory immunomodulation by microglia contributes to mood switching in BD, especially in the process of depression-to-mania transition. The classification of genes by their relationship to state transitions offers a novel framework for understanding the molecular mechanisms underlying this complex disorder and may identify potential therapeutic targets to stabilize mood. Further validation with larger cohorts is warranted.

Stress-related psychiatric disorders and inflammatory bowel diseases share high co-morbidity and contribute to the symptom severity of one another. In mice, ten days of Chronic Social Defeat Stress (CSDS) is sufficient to reduce gut microbiome diversity and the relative abundance of Firmicutes, which are hallmarks of inflammatory bowel diseases. However, mechanisms by which stress causes gut microbiome dysbiosis are largely unknown. Here, we demonstrate that pharmacologically inhibiting {beta}-adrenergic receptors (ARs), which are activated by (nor)adrenaline during stress, mitigates gut dysbiosis otherwise caused by CSDS. Compared to vehicle-treated mice following CSDS, propranolol-treated mice displayed a modest increase in sociability, increased alpha diversity, and increased abundance of anaerobic commensal Clostridia. Abundance of short-chain fatty acid-producing anaerobic Firmicutes abundance correlated with sociability following CSDS across all treatments. Pharmacologically blocking -ARs during stress increased subsequent sociability, but had little effect on gut microbiome composition. Together, our findings support the hypothesis that {beta}-AR activation contributes to stress-induced changes of the gut microbiome. One Sentence SummaryPharmacologically inhibiting beta-adrenergic receptors during chronic stress mitigates reductions in anaerobic, short-chain fatty acid-producing bacteria in the gut.

BackgroundMicroglia drive neuroinflammation in Alzheimers disease (AD), yet no approved therapy targets this compartment. Human genome-wide association studies consistently implicate innate immune loci in AD risk, establishing microglial transcriptional programs as therapeutically relevant but pharmacologically underexploited targets. ObjectiveWe sought to identify transcription factors (TFs) governing microglial state transitions computationally and to nominate structurally tractable drug repurposing candidates. MethodsWe applied trajectory inference (PAGA), pseudobulk DESeq2, pySCENIC gene regulatory network (GRN) inference, CellChat, and virtual screening of 1,962 approved compounds to 236,002 microglial nuclei from 84 donors (SEA-AD atlas). ResultsIKZF1 was the sole target TF retained under cisTarget v10 motif constraints, with peak regulon activity in LateAD-DAM (pseudotime {rho} = +0.309) and replication in an independent bulk cohort (GSE95587; adjusted P value =.004). CellChat identified SLIT2[-&gt;]ROBO2 from multiple neuron subtypes (predominantly inhibitory interneurons) as the top predicted pathway to microglia. Tafamidis ([-&gt;]IRF8) and diflunisal ([-&gt;]PPARG) were top virtual screening hits; all evaluated compounds failed the pre-specified selectivity threshold. ConclusionsIKZF1 is prioritised as a candidate late-disease microglial TF, supported by six convergent evidence dimensions including independent bulk replication. Tafamidis and diflunisal are low-confidence repurposing hypotheses requiring experimental validation.

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

Prenatal alcohol exposure (PAE) is a major cause of neurodevelopmental disorders, yet most children are diagnosed late or misdiagnosed. Neuroplacentology suggest that placental factors released into maternal and/or umbilical cord blood contribute to fetal brain development. Consistently, a preclinical inter-organ transcriptomic database revealed that PAE disrupts the expression ratio of angiogenic and inflammatory factors suggesting an angio-inflammatory response. This study aimed i) to assay, by multiplex immunoassay, angiogenic and inflammatory factors in maternal and umbilical cord blood from alcohol-consuming women and ii) to perform a maternofetal analysis according to neonatal sex. Afterwards, dysregulated factors from mothers who gave birth to females or males were submitted to STRING and ShinyGO analyses. Results showed that PAE differently altered the distribution profiles of dysregulated angiogenic and inflammatory factors in maternal and umbilical cord blood. Moreover, sex-specific differences were observed, with 36% of dysregulated proteins specific to males, 48% to females, and 16% common to both. STRING analysis revealed robust functional protein-protein interactions linking together inflammatory and angiogenic clusters while the ShinyGO analysis identified enriched pathways related to vascular shear stress. These findings provide the first maternofetal analysis of combined angiogenic and inflammatory factors from alcohol-consuming mothers.

Background: Opioid use disorder (OUD) is heritable, yet most genome-wide association studies (GWAS) have focused on European populations, leaving the genetic architecture of OUD in non-European populations underexplored. Methods: We conducted GWAS of OUD across three ancestries using electronic health records and genomic data from 52,357 All of Us Research Program participants (8,912 cases; 43,445 matched opioid-exposed controls; 48.5% female). Participants were stratified into European (EUR), African (AFR), and Admixed American (AMR) ancestry groups for logistic regression GWAS, with independent replication in the Million Veteran Program. We then applied the deep-learning model AlphaGenome to predict the tissue-specific transcriptomic and splicing consequences of top risk variants across 13 reward-pathway brain regions. Results: We identified and replicated a novel DDX6 risk locus, alongside established OPRM1 and FURIN signals. AlphaGenome predicted the DDX6 regulatory allele downregulates the stress-resistance gene FOXR1 in the nucleus accumbens, while the protective OPRM1 variant (rs1799971) upregulates OPRM1 expression across reward networks. Other signals of interest included IL6R and SHISA9 (EUR); GHR (AFR); and ASTN2 (AMR). Conclusions: This study identifies DDX6 as a novel OUD risk locus, replicates associations with OPRM1 and FURIN, and highlights biologically plausible ancestry-specific signals in AFR and AMR populations. We also replicated top variants in an independent population. Finally, integrating GWAS with deep-learning annotations provides specific, localized biological hypotheses to guide future experimental validation and targeted therapeutics.

Cognitive flexibility is an executive function that allows individuals to adjust behaviour in response to changing environmental demands. We assessed volitional switching under uncertainty, without rule-based learning, in the Change Your Mind task. Nineteen patients with obsessive-compulsive disorder (OCD), 19 patients with attention-deficit hyperactivity disorder (ADHD) and matched control participants (20 per group) completed the task whilst undergoing a functional MRI scan. The task was a two-alternative forced choice paradigm where each stimulus was presented twice successively, with spurious feedback following the first presentation. This allowed participants the opportunity to repeat or change their response. Participants with ADHD changed their response more frequently than controls following a previously correct response, associated with reduced accuracy on the second trial. This was accompanied with smaller differences between change and repeat trials in the superior frontal gyrus, paracingulate gyrus and frontal pole compared to controls. Participants with OCD did not differ from healthy controls in their performance but exhibited greater activity on both change and repeat trials in the pre- and postcentral gyri than controls. These results point to distinct neurobehavioural differences in patients with ADHD and OCD underlying what is often termed more broadly inflexible behaviour.

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.

Preeclampsia (PE), new onset hypertension after 20 weeks of gestation, affects 10% of all pregnancies in the U.S. and it is associated with progesterone deficiency, chronic inflammation, elevated angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) and endothelial dysfunction. Progesterone, through its receptors, stimulates an anti- inflammatory protein called Progesterone Induced Blocking Factor (PIBF) which decreases during various pregnancy disorders. Therefore, this study was designed to test the hypothesis that a progestogen, in the form of 17-hydroxyprogesterone caproate, stimulates PIBF, lowers vasoactive mechanisms which reduces maternal blood pressure in women with early-onset preeclampsia (EOPE). PE women received 17-OHPC (250 mg, I.M.) and blood draws were collected before and after 17-OHPC supplementation. Placentas were collected at the delivery. 17-OHPC prolonged time of delivery beyond 72h on average and maternal blood pressure was significantly decreased in PE+17- OHPC. Progesterone and PIBF levels were reduced in PE group vs. NP group. Importantly, 17-OHPC increased PIBF and decreased vasoactive mechanisms and markers of inflammation. In conclusion, 17-OHPC or progesterone supplementation improves maternal outcomes in response to EOPE without causing further harm to the fetus.

Recently, an observational study demonstrated that a lower fractional excretion of uric acid (FEUA) is significantly associated with a higher risk of kidney failure. This study aimed to assess the efficacy of switching from febuxostat to dotinurad, which increases FEUA, in patients with chronic kidney disease (CKD) and hyperuricemia (HUA).This was a non-randomized, open-label, single-center, prospective, single-arm study involving 60 patients with CKD and HUA who received febuxostat. Participants first underwent a 3-month observation period, followed by a 3-month intervention period, during which treatment was switched from febuxostat to dotinurad. The primary outcomes were changes from baseline to 3-months after switching in the estimated glomerular filtration rate (eGFR) calculated from serum creatinine (eGFRcreat) and serum cystatin C (eGFRcys), as well as the serum uric acid levels. The secondary outcome was defined as the correlation between{Delta}FEUA and the changes in both eGFRcreat({Delta}eGFRcreat) and eGFRcys({Delta}eGFRcys), respectively. During the observation period, mean eGFRcreat decreased significantly. The baseline eGFRcreat (mL/min/1.73 m{superscript 2}) was 36.0 {+/-} 15.2, and the serum urate level (mg/dL) was 5.5 {+/-} 1.2. During the intervention period, eGFRcreat increased in contrast to the significant decline observed in eGFRcys. After 3 months of switching to dotinurad, the mean serum UA levels increased significantly from 5.5 {+/-} 1.2 to 6.1 {+/-} 1.4 mg/dL, despite a significant elevation in FEUA. Both {Delta}eGFRcreat and {Delta}eGFRcys after switching to dotinurad were positively correlated with {Delta}FEUA. Switching from febuxostat to dotinurad resulted in discrepant changes in eGFRcreat and eGFRcys, suggesting that renal function should be assessed carefully after switch. Additionally, the risk of elevated serum UA levels should be considered when switching from febuxostat to dotinurad in patients with CKD.

Extensive experiments document that SPARCL1, a secreted protein that is produced primarily by astrocytes in brain and endothelia throughout the body and that is also known as Hevin, enhances synapse formation. However, the mode of action of SPARCL1 at synapses remains unclear owing to divergent results in the literature. Here, we use cultured neurons from newborn male and female mouse embryos to show that the C-terminal follistatin-like and Ca2+-binding domains of SPARCL1, which account for only 35% of the total SPARCL1 sequence, are sufficient to potently enhance synapse numbers. SPARCL1 acts at nanomolar concentrations at which SPARCL1 does not robustly bind to neurexins, neuroligins or neurexin/neuroligin complexes but avidly interacts with all teneurins. Strikingly, the follistatin-like domain of SPARCL1 on its own strongly binds to teneurins but is unable to stimulate synapse formation. Only when combined with the SPARCL1 Ca2+- binding domain does the follistatin-like domain induce synapses, suggesting that SPARCL1 enhances synapse numbers by binding to teneurins via its C-terminal follistatin-like domain and by activating synapse formation via its Ca2+-binding domain. SIGNIFICANCE STATEMENTSPARCL1 (also known as Hevin) is a synaptogenic factor that is produced primarily by astrocytes in brain, and that enhances synapse formation. How SPARCL1 acts at synapses, however, remains unclear because divergent results describe its binding partners at synapses and the sequences involved in its synaptogenic activity remain unclear. In the present study, we show that SPARCL1 avidly binds to the presynaptic teneurins adhesion molecules, that this binding is mediated by its small follistatin-like domain, and that its synaptogenic activity requires both its follistatin-like and its Ca2+-binding EC domains. Thus, our results suggest that SPARCL1 is recruited to developing synapses by binding of its follistatin-like domain to teneurins and then induces synapse assembly via its Ca2+-binding domain.

The endoplasmic reticulum (ER) and its muscle-specialized form, the sarcoplasmic reticulum (SR), are crucial organelles in muscle cells, involved notably in protein synthesis, calcium regulation and muscle contraction. A well-known process involved in ER remodeling and homeostasis is ER-phagy, also called reticulophagy, a selective form of autophagic process in which ER-phagy receptors mediate the delivery of ER portions to lysosomes for degradation. SH3KBP1 is an adaptor protein involved in membrane trafficking. Recently, it was shown to control ER morphology and SR formation in striated skeletal muscle. In this study, we demonstrate that SH3KBP1 can bind to LC3B and CKAP4 proteins, bridging ER to autophagosome membranes, and is degraded by autophagy, in developing muscle fibers. Moreover, SH3KBP1 down-regulation impacts basal autophagy efficiency and ER-phagy stimulation; it also impairs the turnover of numerous ER-resident proteins. Our work highlights a new role for SH3KBP1 as a soluble ER-phagy receptor in striated skeletal muscle.

Internal-tandem-duplication of the receptor tyrosine kinase FLT3 (FLT3-ITD) generates ligand-independent signaling and is highly recurrent in acute myeloid leukemias (AMLs). One way signaling pathways can quickly influence cell fates is by phosphorylating key fate-determining proteins to trigger their proteolysis. We investigated the master transcription factor (MTF) driver of granulo-monocytic lineage-fates, CEBPA, for regulation by this mechanism because we found high CEBPA mRNA but little CEBPA protein in FLT3-ITD versus FLT3-wildtype AML cells, and inhibiting FLT3-ITD signaling with tyrosine kinase inhibitors (TKI) rapidly rescued CEBPA protein. Mass spectrometry analyses of CEBPA and its interactome demonstrated prominent interactions with major ubiquitin-proteosome pathway (UPP) components UHRF1 and USP7. TKI treatments decreased CEBPA and USP7 phosphorylations at serine 21 and serine 18 respectively alongside shifts in CEBPA interactions from degradative ubiquitin-ligase UHRF1 toward protective deubiquitinase USP7. The rescued CEBPA activated granulocytic-differentiation. Supporting that the serine-phosphorylations were phospho-degrons, UPP-inhibitors (bortezomib, MG132) increased phosphorylated and total CEBPA and USP7. The MTF regulator of apoptosis p53 is a known USP7 client, therefore, we also evaluated p53 status: TKIs and UPP-inhibitors stabilized USP7 and p53, triggering apoptosis in addition to granulocytic-differentiation specifically in FLT3-ITD but not FLT3-wildtype AML cells. UPP-inhibitors produced these consequences in TKI-resistant FLT3-ITD AML cells also. These data predicted genetic loss-of-function to CEBPA or TP53 is redundant in the FLT3-ITD context, borne out by mutual exclusivity of the mutations in clinical series. In summary, FLT3-ITD signals for CEBPA and p53 proteolysis to block lineage-maturation and apoptosis, positioning UPP-inhibitors as therapeutic candidates acting downstream of TKIs. KEY POINTSO_LIThe oncoprotein kinase FLT3-ITD signals for CEBPA and p53 proteolysis and hence suppresses lineage-differentiation and apoptosis C_LIO_LIProteosome-inhibitors are candidate remedies to restore CEBPA and p53, acting downstream of presently used FLT3-ITD kinase inhibitors C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/738455v1_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@6ae211org.highwire.dtl.DTLVardef@12003bforg.highwire.dtl.DTLVardef@d62eb9org.highwire.dtl.DTLVardef@1958693_HPS_FORMAT_FIGEXP M_FIG C_FIG

Introduction Hospitalised community-acquired pneumonia (CAP) is heterogeneous in aetiology, severity, and outcome. Phenotyping and endotyping approaches offer potential to stratify patients biologically and guide targeted therapy, but require well-characterised cohorts with linked biosamples. We describe the PARIS (Pneumonia: Acute Respiratory Infection +/- Sepsis) study: a prospective observational cohort of hospitalised patients with pneumonia, designed to characterise functional outcomes and to provide a biobank for translational immunological research. Methods Adults admitted with CAP to a single NHS district general hospital were enrolled within 24 hours of admission between December 2020 and March 2022. Clinical, functional, and physiological data were collected at enrolment, hospital discharge, and 6-8 week follow-up. Serial blood samples were collected for flow cytometry, transcriptomics, pathogen DNA detection, and plasma biobanking. Results Forty-seven patients were enrolled (15 without and 32 with sepsis [SOFA >=2] at enrolment); 87% met sepsis criteria by 24 hours post enrolment. Most patients (30/47, 64%) were managed as COVID-19, microbiologically confirmed in 27. Mean age was 57 years (SD 16), 70% were male, and baseline comorbidity burden was low. Severity was moderate (median NEWS2 4 at enrolment, rising to 6 by 24 hours post enrolment; p<0.001). Mortality was 4/47 (8.5%), with 44/47 (94%) alive at hospital discharge. Median length of stay was 8 days (IQR 5.5-11). Translational samples were collected from the majority: fresh flow cytometry (44/47, 94%), transcriptomics from the sepsis subgroup (31/32, 97%), pathogen DNA sampling (35 samples received across study timepoints; see Table 5), and stored plasma (29/47, 62%). The primary outcome of functional decline (Barthel score decrease >=1.85) occurred in only 1/29 patients with paired assessments (3.4%). Persistent CRP elevation (>3 mg/L) at 6-8 week follow-up was present in 16/31 (52%) survivors with available data. Conclusions The PARIS cohort provides a well-characterised clinical platform and linked biobank to support translational studies of pneumonia and sepsis. The low rate of functional decline reflects the younger, lower-comorbidity, COVID-predominant population recruited. Primary protocol endpoints were not achieved owing to pandemic-related disruption. Data and samples underpin a programme of linked translational studies.

Background: Actigraphy-derived rest-activity rhythm (RAR) features are widely used to characterize clinical states in bipolar disorder (BD). Both mean levels and temporal variability of these features have been associated with mood episodes; however, variability measures are often statistically coupled with the mean, particularly in skewed distributions. This raises a question as to whether variability reflects a separate characteristic of the data or whether the observed association arises from statistical properties of the data. Objective: In this study, we aim to determine whether temporal variability of actigraphy-derived RAR features provides standalone information on mood episodes in BD beyond mean activity levels after accounting for mean-variance dependence. Methods: We analyzed actigraphy data from a subset of 72 participants with BD drawn from a larger longitudinal study, extracting 22 daily RAR features aggregated weekly as sample mean (MEAN) and within-week temporal variability computed as sample standard deviation (VAR). Variance-stabilizing transformations (Box-Cox or Yeo-Johnson) were applied to the entire study cohort to reduce mean-variance dependence. Associations with mood episodes and remission (mania: n=34; depression: n=58 annotated participants) were evaluated using generalized linear mixed-effects models with a logistic link function, including univariate (MEAN or VAR) and multivariate (MEAN+VAR) specifications, assessed by likelihood-based metrics and the area under the receiver operating characteristic curve (AUC). Results: Transformations reduced mean-absolute correlations from 0.43 to below 0.06. Temporal variability remained significantly associated with clinical state for 11/22 RAR features in mania and 16/22 features in depression, with all significant associations remaining after false discovery rate correction (p<0.05). Joint models showed modest incremental gains (AUC 3%-4% overall; up to 12% in mania, 7% in depression), with absolute performance remaining limited (AUC 0.50-0.66). In both mania and depression, nearly all significant variability-based regressors contributed incremental information beyond mean-based models. Only sleep duration and activity changes around wake time (+-1 hour), did not improve discrimination between mania and remission. Conclusions: Temporal variability in RAR features can be considered a standalone state marker of mood episodes not captured by mean activity. We found it to be more consistently associated with depression than mania. Its incremental discriminative contribution is modest, suggesting greater utility within multivariate or multimodal frameworks.

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

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.

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