Bone

Fracture nonunion remains a major cause of morbidity, yet patient-specific factors associated with impaired healing remain incompletely characterized. Anemia has been associated with adverse orthopaedic outcomes, but its relationship with fracture nonunion is poorly understood. We examined whether pre-fracture anemia, anemia burden, and clinically relevant anemia subtypes were associated with nonunion following tibial or femoral fractures. Using commercial and Medicare fee-for-service claims from 2016 through 2023, we identified adults aged 19 years or older with a tibial or femoral fracture, continuous enrollment during the preceding year and for at least six months after fracture, and no baseline cancer. Pre-fracture anemia was evaluated as any anemia, the number of distinct anemia diagnoses, and nutritional, hemolytic, aplastic, and other anemia subgroups. Nonunion occurring six to eighteen months after fracture was assessed using incidence rates and multivariable-adjusted hazard models. Among 326,673 adults, 149,704 had pre-fracture anemia and 176,969 did not. The crude incidence of nonunion was 42% higher among individuals with anemia than among those without anemia (incidence rate ratio, 1.42; 95% confidence interval, 1.32 to 1.53) and increased with greater anemia burden. After adjustment for demographic and clinical characteristics, including prior fractures at other anatomical sites, pre-fracture anemia remained associated with nonunion following tibial and femoral fractures, with hazard ratios of 1.83 (95% confidence interval, 1.54 to 2.18) and 1.38 (95% confidence interval, 1.26 to 1.50), respectively. Associations were also observed for nutritional and other anemias, whereas estimates for hemolytic and aplastic anemias were limited by few nonunion events. Within the femur, the association was strongest for distal fractures. These findings demonstrate that pre-fracture anemia is independently associated with nonunion. The increase in risk with greater anemia burden and findings across evaluable subgroups suggest that pre-fracture anemia may help identify patients at increased risk of impaired fracture healing.

Abstract Introduction: Proximal humerus fractures account for approximately 5-6% of all adult fractures and are primarily managed nonoperatively. Healing is conventionally monitored with radiographs, with radiopaque callus formation indicating healing. Visible radiographic callus appears weeks after biological union begins. Ultrasound provides a dynamic, radiation-free, and cost-effective method that can detect early callus formation before x-ray visibility. Although ultrasound has demonstrated utility for fracture healing in the clavicle and humeral shaft, its role in proximal humerus fractures remains unclear. Methods: This single-centre prospective study will be conducted in two phases. The pilot phase will measure inter-rater reliability for ultrasound detection of early callus formation at 2 and 4 weeks post-injury. Ten patients with proximal humerus fractures treated nonoperatively will undergo standardized anterior and lateral scans. Each patient will generate four saved images (short- and long-axis views), producing forty anonymized images independently reviewed by two raters. The prospective cohort phase will recruit approximately thirty additional patients. Results: Reliability will be quantified using Cohens kappa. A power calculation will be performed after pilot analysis. Results from the prospective cohort phase will help determine the association and predictive value of early ultrasound-detected bridging callus for radiographic and clinical union at three and six months. Patient reported outcome measures will be assessed using the Quick Disabilities of Arm, Shoulder and Hand (QuickDASH) questionnaire. Discussion: This study will develop and validate a standardized ultrasound protocol for assessing early fracture healing in proximal humerus fractures. By establishing both inter-rater reliability and predictive value, the findings may support ultrasound as a reproducible, radiation-free adjunct to conventional imaging and enable earlier identification of union status.

Purpose: Pathogenic variants in NFIX cause Marshall-Smith syndrome and Malan syndrome (MALNS). We identified a severe subtype of MALNS characterized by adolescent-onset musculoskeletal deterioration and investigated functional consequences of underlying variants. Methods: Clinical data were collected from seven individuals with pathogenic NFIX variants. Wild-type and mutated recombinant NFIX DNA-binding domains (DBDs) were evaluated using biochemical, structural, and DNA-binding assays. Results: Six individuals carrying R116W, R116P, K125E, or G147E NFIX substitutions developed progressive muscle wasting, markedly reduced body mass index, and rapidly progressive scoliosis after the typical childhood features of MALNS; two died from disease-related complications. A seventh individual with R116G did not develop this severe phenotype. Functional studies on recombinant NFIX DBDs showed complete or near-complete loss of DNA-binding activity for R116W, R116P, K125E, and G147E despite preserved protein folding, consistent with disrupted DNA recognition and a potential dominant-negative mechanism. In contrast, R116G exhibited a 7.7{degrees}C decrease in thermal stability, which may support haploinsufficiency mediated by protein degradation. Conclusion: Specific NFIX missense variants define a severe subtype of MALNS associated with progressive musculoskeletal deterioration. In vitro functional studies support variant-specific disruption of DNA binding, providing a mechanistic basis of genotype-phenotype correlations and informing prognosis, clinical surveillance, and therapy development.

ABSTRACT Background: Metallic implants such as orthopedic screws, prostheses, and dental hardware produce beam-hardening, photon-starvation, and streak artifacts that degrade computed tomography (CT) image quality, and the metal artifact reduction (MAR) methods developed to mitigate them require objective, reproducible benchmarking. Purpose: Objective evaluation of MAR algorithms in CT is hindered by the absence of phantoms that simultaneously provide anatomically realistic backgrounds, embedded implants of known geometry, and controllable, ground-truth--referenced artifact intensity. We present a dual-filament, voxel-level three-dimensional (3D) printing method that fulfills these requirements and demonstrate its capabilities on a clinically representative cervical spine case with embedded orthopedic spinal screws. Methods: The proposed method extends the PixelPrint framework, a fused-deposition-modeling (FDM) workflow that converts clinical Digital Imaging and Communications in Medicine (DICOM) data directly into 3D-printer Geometric code (G-code) without intermediate segmentation or surface meshing, to interleaved, voxel-level deposition of two filaments: a calcium-doped polylactic acid (PLA) for soft tissue and bone, and a higher-attenuation metal-doped PLA for metallic implants. For demonstration, anonymized DICOM data of a healthy cervical spine were used to design and fabricate three matched phantoms, each with six embedded spinal screws at C4--C6: a 0% metal-infill ground-truth phantom, a 50% medium-metal-infill phantom, and an 85% high-metal-infill phantom. All phantoms were scanned on a clinical spectral CT system at 120 kVp and 1000 mAs, reconstructed at 0.67 mm slice thickness with virtual monoenergetic imaging (VMI) across 50--190 keV. Method performance was characterized by region of interest (ROI)-based Hounsfield Unit (HU) agreement with the source patient data and by the noise-independent Gumbel-distribution p-index metric. Results: The dual-filament method reproduced patient anatomy, soft-tissue contrast, and screw geometry with high fidelity. ROI HU values agreed with patient data within {+/-}25 HU for soft tissue and trabecular bone; cortical regions were underestimated owing to the current ceiling of the calcium-doped PLA used in this study. The tunable-artifact behavior was quantified as follows: the Gumbel location parameter scaled monotonically from 46.7 HU (no-metal background) to 57.1 HU (50% infill) to 90.5 HU (85% infill) for the VMI 70 keV with standard filter. High-keV VMI reconstructions substantially reduced streak and beam-hardening artifacts while preserving anatomic detail. Conclusions: The proposed dual-filament, voxel-level PixelPrint method enables the fabrication of patient-specific, multi-material CT phantoms with embedded metallic implants and controllable, ground-truth--referenced artifact intensity. Although demonstrated here in a single cervical-spine case, the workflow is anatomy- and implant-agnostic by construction and could in principle be adapted to other musculoskeletal sites (e.g., knee, hip, dental) and implant materials, providing a reproducible methodological foundation for benchmarking MAR algorithms, characterizing spectral CT performance, and validating emerging photon-counting detector systems. Keywords: 3D printing methodology; fused deposition modeling; voxel-level multi-material printing; spectral computed tomography; metal artifact reduction; phantom design; orthopedic implants; dual filament; PixelPrint.

Introduction Adolescent idiopathic scoliosis (AIS) requires frequent x-rays for management, exposing young patients to cumulative radiation risks. While radiation-sparing imaging modalities exist, access across the National Health Service (NHS) remains uneven and information given to patients is variable. This qualitative study investigated the systemic, geographic, and interpersonal dynamics of AIS imaging in England. Design This qualitative study employed in-depth semi-structured interviews with healthcare professionals (HCPs) from NHS paediatric spinal centres, patients aged 13 to 25 years old with AIS and parents/carers of young people with AIS. Setting England. Participants A total of 22 HCPs from 13/24 NHS paediatric spinal centres in England, 19 10-25 years with AIS and 11 parents/carers. Results Conventional x-ray remains the main imaging modality. Significant geographic inequality exists. The most commonly available radiation-sparing imaging modality available is the EOS system, which uses slot-scanning technology, is available at 7 centres in England, primarily in London imaging networks. Acquisition of EOS systems is currently driven by local charitable funding rather than a centralised strategy, with high capital and installation costs cited as primary barriers. Inconsistent knowledge of imaging within primary care and a lack of specialist expertise in local secondary care services led to diagnostic redundancy, gatekeeping, and low value inconsistent imaging. These systemic delays frequently closed the window for conservative treatments like bracing. A professional balancing act exists between the duty to inform and the desire to minimise patient anxiety. HCPs often use selective communication regarding radiation risks. Conversely, families demonstrate high relational trust with HCPs and low baseline knowledge of cumulative exposure, often viewing frequent imaging as a reassuring marker of clinical progress. In centres with EOS systems, clinicians felt empowered to lead proactive, transparent risk discussions. In standard X-ray settings, dialogue remains reactive and infrequent, leading to a reliance on implied rather than truly informed consent. Conclusions AIS imaging in England is variable. Geographic location dictates access to low-dose radiation technology and the quality of informed consent. Systemic inefficiencies and fragmented referral pathways contribute to diagnostic redundancy and delayed specialist care. National standardisation of clinical pathways, information provision and a centralised strategy for low-dose technology procurement are essential to eliminate structural inequalities and ensure equitable, transparent care for all patients.

Consumer-grade bioelectrical impedance analyzers have become widely used for body composition assessment, yet their accuracy varies considerably across devices. The Hume Pod is a popular consumer-grade analyzer marketed as being highly accurate, but independent validation is lacking. The purpose of this study was to evaluate the reliability and validity of the Hume Pod relative to both a four-compartment (4C) model and dual-energy X-ray absorptiometry (DXA). Sixty-seven adults (42 females, 25 males; age 37.2 +/- 13.5 years, body mass index: 24.6 +/- 4.9 kg/m2, body fat percentage [BF%]: 26.4 +/- 10.2%) completed duplicate Hume Pod assessments alongside DXA and 4C evaluations. Reliability was evaluated using the technical error of measurement (TEM) and intraclass correlation coefficients (ICC). Validity was assessed using equivalence testing, Lin's concordance correlation coefficient (CCC), standard error of the estimate (SEE), Bland-Altman analysis, and additional tests. The Hume Pod demonstrated strong reliability, with ICCs >/= 0.993 and TEMs of 0.8% for BF% and 0.6 kg for fat mass (FM) and fat-free mass (FFM). Relative to the 4C model, BF%, FM, and FFM estimates were statistically equivalent (all p<0.05), with strong agreement (CCC=0.95-0.98), low SEE values (3.1%, 2.3 kg, and 2.2 kg, respectively), moderate limits of agreement (+/-6.1%, +/-4.5 kg, and +/-4.5 kg), and no proportional bias. Compared with DXA, generally strong agreement was also observed. These findings indicate that the Hume Pod demonstrates strong reliability and validity compared with laboratory reference methods for body composition estimation, supporting its potential use as a consumer body composition assessment.

Distal radius fractures (DRFs) can delay return to activities of daily living and social participation because of postoperative pain, temporary joint immobilization, and limited wrist and forearm range of motion. The Ghost System developed at Saitama Prefectural University, Japan, combines visual action observation with tendon vibration stimulation and has shown potential as an adjunct to conventional rehabilitation. This Study Protocol describes a modified Ghost system intended to improve clinical implementation by replacing the head-mounted virtual reality display with iPad-based action observation and by using a wristband-type vibrator. This single-center, single-arm, open-label feasibility trial will enroll 10 adults after palmar locking plate fixation for DRF. The intervention will be delivered twice weekly during outpatient rehabilitation follow-up sessions from the early postoperative period (postoperative days 2-10 after enrollment) through the approved early postoperative rehabilitation period (generally up to postoperative week 8), in parallel with standard rehabilitation practices. Primary feasibility and preliminary clinical outcomes include device fit and acceptability, pain assessed using a 100-mm Visual Analog Scale, and wrist/forearm range of motion. Secondary implementation and safety outcomes include Disabilities of the Arm, Shoulder and Hand (DASH), Patient-Rated Wrist Evaluation (PRWE), Hand20 Questionnaire (HANDS-20), EuroQol 5 Dimensions 5 Levels (EQ-5D-5L), body ownership and hand-illusion questionnaires, setup time, setup errors, adherence, adverse events, and device incidents. We hypothesize that the modified Ghost system will be feasible and acceptable for early postoperative outpatient rehabilitation and will be delivered without serious device-related adverse events. Clinical outcomes will be summarized descriptively to inform a future controlled study rather than to establish efficacy.

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.

Objectives. Radiomics pipelines extract hundreds of quantitative features that are widely known to be redundant, but the structure of this redundancy is usually treated as a per-dataset nuisance to be pruned away. We tested the alternative hypothesis that a substantial number of feature-feature correlations are universal: they persist across patients and across anatomically distinct structures because they reflect shared mathematical and image-statistical properties of how the image is summarised, rather than properties of the tissue being imaged. Materials and Methods. We re-analysed the publicly available Radiomics Atlas Dataset of normal Abdominal and Pelvic CT (RADAPT), restricting the analysis to the 526 non-contrast-enhanced examinations of the 531-subject atlas and to the 107 original (non-filtered) PyRadiomics features. The 53 segmented structures were grouped into four broad anatomical categories -- bones, muscles, vessels, and parenchymal organs. RADAPT is distributed as one Excel file per structure, with patients as rows and features as columns. Within each structure file we z-score-normalised every feature across patients, computed the absolute Spearman correlation matrix, and retained edges with |{rho}| [&ge;] {tau} for {tau} in {0.70, 0.80, 0.90}. We then intersected the edge sets across all structure files to obtain a "universal" correlation graph, in which an edge survives only if it exceeds the threshold in every structure (each estimated across the full patient sample). Stable feature communities were defined as the maximal cliques of this graph. Robustness to patient sampling was tested by repeating the entire pipeline on five independent random splits of each file into two patient halves (10 sub-cohorts per threshold), and the implementation was independently reproduced in R. Results. Despite the strictness of the global-intersection criterion, 34, 24, and 14 stable feature communities survived at {tau} = 0.70, 0.80, and 0.90 respectively, with the largest cliques containing six members at {tau} = 0.70 and {tau} = 0.80 and five members at {tau} = 0.90. The community structure was clearly interpretable: separate cliques captured (i) variance-like intensity dispersion, (ii) long-run / low-frequency (coarse) texture, (iii) high gray-level texture, (iv) low gray-level texture, (v) volume and surface shape, and (vi) local-homogeneity and energy/entropy duals. On random-half resampling the exact-match recovery rate of these communities was 81.5 %, 86.7 %, and 80.7 % across the three thresholds; departures from exact recovery were almost always a single boundary feature added or dropped, consistent with finite-sample fluctuation of near-threshold edges rather than structural instability. The R re-implementation reproduced the Python results exactly. Conclusion. A substantial portion of radiomics feature collinearity is universal across patients and tissues. We distinguish two layers within it: trivial near-algebraic duals that are universal by construction, and non-trivial cross-matrix-family communities that are the genuine empirical finding. Together they provide an interpretable, definition-grounded basis for aggressive dimensionality reduction, for retrospectively reconciling apparently different feature selections in the literature, and for moving radiomics pipelines toward organ-agnostic, more reproducible models. Clinical relevance statement. Selecting a single representative feature from each universal community shrinks the original-feature space by roughly an order of magnitude without sacrificing biologically distinct information. For example, the five variance-family members (first-order Variance, GLCM SumSquares, GLCM ClusterTendency, GLDM and GLRLM GrayLevelVariance) can be replaced by a single representative, removing redundant degrees of freedom that would otherwise inflate model variance; and labelling each retained feature by its community lets two studies that selected different variance-family names be recognised as having found the same signal, simplifying model development and improving cross-cohort generalisability in clinical CT workflows.

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.

Background and Aims The optimal treatment for first episodes and first recurrences of Clostridioides difficile infections (CDI) is unknown and there is emerging evidence for pulse and taper (P-T) regimens. Therefore, we sought to estimate the relative efficacy of treatment options. Methods MEDLINE and CENTRAL were searched from database inception to May 21, 2025 and unpublished conference abstracts were searched from recent infectious disease conferences. RCTs on the treatment of first episodes or first recurrences of CDI comparing fixed-dose or P-T regimens of fidaxomicin or vancomycin were included. The primary and secondary outcomes were 40- and 56-day CDI recurrence, respectively. A random-effects network meta-analysis on the risk ratio (RR) scale was conducted using a standard regimen (10-14 days) of vancomycin as the comparator. Treatments were ranked using the surface under the cumulative ranking curve (SUCRA). Results 8 RCTs were included comprising a total of 2181 patients. For 40-day recurrence, fidaxomicin P-T had the highest probability of ranking best (RR=0.10, 95%Confidence Interval [95%CI]=0.10-0.49, SUCRA=1.00), followed by vancomycin P-T (RR=0.49, 95%CI=0.32-0.76, SUCRA=0.61), fixed-dose fidaxomicin (RR=0.61, 95%CI=0.49-0.76, SUCRA=0.39), and, finally, fixed-dose of vancomycin (SUCRA=0.00). The treatments ranked in the same order for 56-day recurrence, though only 3 RCTs reported on this timepoint. Conclusion Vancomycin P-T, fidaxomicin P-T, and fixed-dose fidaxomicin were all superior to a fixed-dose vancomycin. Head-to-head comparative effectiveness RCTs are needed to quantify their relative effect sizes of and impact on long-term prevention of recurrent CDI.

Background The 2022-2023 global mpox outbreak highlighted the critical need for robust genomic surveillance capabilities to track mpox virus (MPXV) evolution and transmission dynamics. Methods Building upon our established SARS-CoV-2 sequencing infrastructure, we implemented a Molecular Loop probe-based long-read sequencing approach using Pacific Biosciences Sequel II technology for comprehensive MPXV genomic surveillance across the United States (US). From August 2024 to June 2025, we generated 326 high-quality whole genome sequences from residual mpox-positive clinical specimens collected by Labcorp across all 10 US Department of Health and Human Services regions. Results Our analysis identified two samples containing clade Ib MPXV in January and June 2025 and captured shifting trends in clade IIb diversity, with 13 distinct lineages observed. We also identified multiple instances of large (~1.6-17.6kb) deletions proximal to the inverted terminal repeats in clade IIb genomes. APOBEC3 mutation analysis indicated substantial evidence of human-to-human transmission among both clades. Further, we observed significantly higher APOBEC3-associated SNPs per kilobase (P<0.001) in clade IIb genomic variable regions relative to their central conserved region. Our assay exhibited strong reproducibility across biological replicates from individual patients and accuracy was confirmed via parallel sequencing of select specimens by US Centers for Disease Control and Prevention (CDC) using metagenomic sequencing. We also demonstrated via custom simulation that our assay discriminates all known MPXV clades and lineages, including those we have not observed in the US. Conclusions Our integrated nationwide surveillance system facilitates real-time genomic tracking of outbreak evolution, with demonstrated capacity across SARS-CoV-2 and MPXV, positioning this platform for rapid deployment during future pathogen emergence.

Background: Monoclonal antibodies have emerged as a prophylactic strategy to prevent symptomatic SARS-CoV-2 infection in immunocompromised individuals. However, the evolutionary and clinical implications of breakthrough infections under this regime remain unclear. Methods: A male in their 80s with a haematological/oncological diagnosis received a 2000 mg intravenous infusion of sotrovimab in March 2023 and was diagnosed with COVID-19 by RT-qPCR from a nasopharyngeal swab in August 2023. Weekly samples (n=24) were collected through February 2024 (171 days). All samples underwent whole-genome sequencing, with select mutations subjected to functional assessment. Findings: Sequencing identified the GE.1 lineage at all timepoints. An intra-host recombination event in ORF1ab (positions 8942-12458) was detected prior to 23 weeks post-detection, followed by a 14-fold increase in viral load (7.42e+06 to 1.00e+08 RNA copies/mL) and a marked shift in the viral population. E340D, a sotrovimab resistance mutation, was detected at low abundance (46%) within the first week post-infection, fluctuated over time, and was nearly fixed by week 15 (107 days) post-detection. We assessed five spike mutations - V36M, S98F, and V213G in the N-terminal domain, Y505P in the receptor-binding domain, and P681Q near the S1/S2 cleavage site - and additionally evaluated the impact of E340D. V36M conferred the highest infectivity across all cell lines, with the most significant effect in low-TMPRSS2 cells. While all mutations showed enhanced infectivity with the addition of E340D, the effect was most pronounced in mutations with lower baseline infectivity. The addition of E340D significantly decreased relative neutralizing titres for V36M, S98F, and V213G, enabling escape from neutralizing antibodies in XBB-responsive individuals, illustrating an enhanced phenotypic advantage. Patient neutralizing activity was absent pre-sotrovimab, and sotrovimab-induced neutralization was further compromised by selection of E340D. Interpretation: Sotrovimab pre-exposure prophylaxis in an immunocompromised patient did not prevent SARS-CoV-2 infection, and selected for resistant mutation E340D, with unexpected fitness consequences across non-receptor binding domain spike regions.

Estimating dengue force of infection (FOI) is essential for understanding transmission dynamics and targeting intervention programmes, yet surveillance data in endemic settings required for estimations are often incomplete, with varying formats. We developed a Bayesian hierarchical catalytic model that jointly fits age-stratified case data, aggregate case data, and seroprevalence surveys within a single framework, incorporating external covariates to improve parameter identifiability. Synthetic validation showed that covariates alone recovered accurate FOI point estimates even when most districts contributed only aggregate data, but did so with poorly calibrated uncertainty; anchoring the model with a single seroprevalence survey was necessary to bring credible interval coverage close to nominal. Applied to 128 districts across Java and Bali, Indonesia (2016-2024), the model revealed substantial spatial heterogeneity in FOI and reporting rates. Many districts in Java exceeded the WHO-suggested seroprevalence threshold for vaccine introduction, yet were classified as low-priority when using reported incidence as prioritisation criterion, particularly in areas with weak surveillance. Model-based seroprevalence estimation, integrating multiple data sources, offers a more consistent basis for identifying high-priority districts for vaccine introduction, and is less susceptible to surveillance bias than reported incidence.

Stochastic epidemic models are a cornerstone of infectious disease epidemiology and are often used to study intervention scenarios. However, large run-to-run variability can make intervention effects difficult to estimate precisely. We revisit the epidemic Sellke construction, which assigns each individual an infection threshold for the cumulative infection hazard such that, conditional on the thresholds, the epidemic trajectory becomes deterministic. This enables coupling of simulations with and without an intervention, yielding low-variance effect estimates even when outcomes such as final size or peak incidence vary widely between runs. We develop an exact, event-driven implementation that maintains infection and recovery events in priority queues. Cumulative infection-hazard updates require O(log N) time per event, yielding overall complexity O(Elog N) for E events in a population of size N. The implementation achieves computational performance comparable to the classical Gillespie algorithm while naturally accommodating non-Markovian infectious periods and complex infectiousness profiles. We illustrate the approach using distance-dependent spread of avian influenza between poultry farms in the Netherlands and a multilayer population with households, schools, and workplaces. In both examples, coupling enables efficient within-run comparisons of intervention scenarios across stochastic realisations.

Purpose: Nonresponse to routinely collected patient-reported outcome measures (PROMs) threatens the representativeness of aggregated data. We characterized patient-, provider-, and clinic-level factors associated with PROMIS Global-10 nonresponse in routine radiation oncology care. Methods: In this retrospective cohort study, all adults seen at five Mass General Brigham radiation oncology clinics over one year were included. The primary outcome was patient-level nonresponse, defined as never completing the portal-administered Global-10 versus completing it at least once. Using iterative mixed-effects logistic regression, we modeled patient-, provider-, and clinic-level factors. Results: Among 12,214 patients, 71 providers, and five clinics, patient- and appointment-level response rates were 35.4% and 10.9%, with patient-level response ranging nearly fivefold across clinics (12.8% to 66.2%). In Model 1, male sex, lower education, not working, and recent surgery had higher odds of nonresponse, and longer time since diagnosis lower odds. After provider- and clinic-level factors were added, patient sex, education, and employment became nonsignificant, whereas recent surgery (adjusted odds ratio [aOR] 1.97) and longer time since diagnosis (aOR 0.46 for >12 months) persisted. A provider's historical collection rate was protective but attenuated at the clinic level. There, a later program launch (aOR 0.29) and higher historical collection rate (aOR 0.79) correlated with lower nonresponse, whereas academic versus community setting did not. Conclusions: Nonresponse to routinely collected PROMs is a multilevel phenomenon driven substantially by clinic-level implementation factors, not patient characteristics alone. Because response rate is only a proxy for representativeness, PROMs programs and PRO-based performance measures should prioritize representative collection over volume.

Background: Children born prematurely (before 37 weeks) or admitted to the neonatal unit (NNU) are at increased risk of adverse long-term physical health outcomes. It is also recognised that there is an association with later academic performance and special educational needs, however it is not clear whether these broad risk factors could be used as stand-alone heuristics to identify children who may benefit from additional support in educational settings. We aimed to examine the associations between neonatal unit (NNU) admission and educational attainment in mid-childhood. Methods and Findings: Pregnancy data from a prospective birth cohort (Pregnancy Outcome Prediction Study, Cambridge, United Kingdom, 2008-2012) were linked to national educational outcomes (Department for Education, United Kingdom). Multivariable regression models adjusted for maternal, child, and socioeconomic factors were used to evaluate associations between (i) all NNU admissions, (ii) at term NNU admissions >48 hours, (iii) preterm birth without ongoing physical health needs, and educational outcomes at ages 5-11 years. Children who required any NNU care were more likely not to meet expected educational standards across multiple ages and domains in early and mid-childhood: age 5 early year foundation (aOR 1.64, 95% CI 1.19-2.27, p=0.003), phonics at age 6 (aOR 2.43, 95% CI 1.72-3.57, p<0.001), and at age 7 (here assessments were divided into multiple domains): reading (aOR 1.67, 95% CI 1.18-2.38, p=0.004), writing (aOR 1.72, 95% CI 1.25-2.38, p<0.001), mathematics (aOR 1.56, 95% CI 1.09-2.22, p=0.020), and science (aOR 1.85, 95% CI 1.22-2.78, p=0.003). Similar patterns were observed among both at term-born infants who stayed >48hrs in NNU (phonics assessment at age 6 aOR 2.26, 95% CI 1.51-3.36, p<0.001) and in children born preterm without long-term physical health sequelae (phonics assessment at age 6 aOR 3.07, 95% CI 1.96-4.81, p<0.001). These associations were robust to adjustment for demographic, perinatal, and socio-economic factors. By age 11, differences in academic attainment were attenuated and no longer clearly distinguishable across all exposure groups. However, there was an increased likelihood of special educational needs (SEN) at age 11 associated with any NNU admission (aOR 1.78, 95% CI 1.15-2.73, p=0.009), at term NNU admission for >48hrs (aOR 1.88, 95% CI 1.19-3.00, p=0.007), and children born preterm without long-term physical health sequelae (aOR 1.50, 95% CI 1.00-2.25, p=0.049). Predictive performance of any NNU admission for SEN at age 11 was moderate (AUC 0.70, 95% CI: 1.14-2.65, p=0.010), with balanced sensitivity and specificity and high negative predictive value. Conclusions: NNU admission, for both term and preterm infants, is associated with poorer educational outcomes and an increased likelihood of special educational needs in mid-childhood.

Background Post-infection conditions (PICs), such as Long Covid, are associated with heterogeneous, fluctuating symptoms that profoundly affect daily functioning. Despite moderate-certainty evidence from the NIHR-funded LISTEN trial (COV-LT2-0009) that personalised self management support improves outcomes and may reduce societal and economic impacts of Long Covid, many people living with PICs still receive condition-specific services, generic advice, or stand-alone digital tools that do not address their complex needs. Aim To map care approaches in general practice and synthesise UK evidence for PIC management. Design and setting Scoping review and online survey. Method A two-phase study was conducted: (1) a scoping review of UK evidence on PIC management in general practice; and (2) a supplementary online survey of practitioners working in UK general practice to provide contextual insights. Results The scoping review identified 32 studies focused on Long Covid. One study included a comparator group (ME/CFS). Study populations were predominantly white ethnicity and female. Evidence for non-Covid PICs in UK general practice was largely absent. The supplementary survey (n=46) provided preliminary practice-level insights. Healthcare practitioners reported varied PIC presentations, diagnostic uncertainty, limited referral pathways, inequitable access, and low confidence in managing PICs. Conclusion Evidence informing PIC management in UK general practice remains predominantly Long Covid-focused and may not reflect the range of PICs encountered in practice. While survey findings are preliminary and require confirmation in larger samples, they highlight uncertainty around PIC management. Further research is needed to evaluate whether existing Long Covid pathways should be expanded or complemented by broader PIC models. Keywords general practice; Long Covid; self-management; post-viral syndromes

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.

Lithium has been the gold standard for the treatment and prevention of relapse in bipolar disorder for over 60 years. Guidance from the National Institute for Health and Clinical Excellence states explicitly to 'offer lithium as a first-line, long-term pharmacological treatment for bipolar disorder'. Yet, in the last two decades its use has been in decline with clinicians favouring anticonvulsants or antipsychotics when treating this condition. In this study, we have used three openly available datasets containing prescribing data from primary and secondary care to explore trends in the use of lithium in England, showing both regional and temporal variance between 2015-2024. We have shown that lithium use declined in primary care by 20.9% in the last ten years (2015-2024) and 10.9% overall in the last five years (2019 to 2025). We have also shown how there is some regional variation in the source of lithium for patients, although the vast majority is prescribed in primary care. Further research into clinical behaviour is needed to understand what is driving the decrease in lithium usage, and what barriers and enablers may influence its use across the country.