SARS-CoV-2 ferritin nanoparticle vaccines produce hyperimmune equine sera with broad sarbecovirus activity.

The rapid emergence of SARS-CoV-2 variants of concern (VoC) and the threat of future zoonotic sarbecovirus spillover emphasizes the need for broadly protective next-generation vaccines and therapeutics. We utilized SARS-CoV-2 spike ferritin nanoparticle (SpFN), and SARS-CoV-2 receptor binding domain ferritin nanoparticle (RFN) immunogens, in an equine model to elicit hyperimmune sera and evaluated its sarbecovirus neutralization and protection capacity. Immunized animals rapidly elicited sera with the potent neutralization of SARS-CoV-2 VoC, and SARS-CoV-1 pseudoviruses, and potent binding against receptor binding domains from sarbecovirus clades 1b, 1a, 2, 3, and 4. Purified equine polyclonal IgG provided protection against Omicron XBB.1.5 virus in the K18-hACE2 transgenic mouse model. These results suggest that SARS-CoV-2-based nanoparticle vaccines can rapidly produce a broad and protective sarbecovirus response in the equine model and that equine serum has therapeutic potential against emerging SARS-CoV-2 VoC and diverse sarbecoviruses, presenting a possible alternative or supplement to monoclonal antibody immunotherapies.

ReNU syndrome - a newly discovered prevalent neurodevelopmental disorder.

Two recent papers have identified genetic variants in the noncoding gene RNU4-2 to cause a frequent neurodevelopmental disorder. This work will have a substantial impact on the rare disease community, leading to thousands of diagnoses worldwide. These studies also highlight the untapped diagnostic potential of noncoding regions.

Genome-wide study of gene-by-sex interactions identifies risks for cleft palate.

Structural birth defects affect 3-4% of all live births and, depending on the type, tend to manifest in a sex-biased manner. Orofacial clefts (OFCs) are the most common craniofacial structural birth defects and are often divided into cleft lip with or without cleft palate (CL/P) and cleft palate only (CP). Previous studies have found sex-specific risks for CL/P, but these risks have yet to be evaluated in CP. CL/P is more common in males and CP is more frequently observed in females, so we hypothesized there would also be sex-specific differences for CP. Using a trio-based cohort, we performed sex-stratified genome-wide association studies (GWAS) based on proband sex followed by a genome-wide gene-by-sex (G × S) interaction testing. There were 13 loci significant for G × S interactions, with the top finding in LTBP1 (RR = 3.37 [2.04-5.56], p = 1.93 × 10-6). LTBP1 plays a role in regulating TGF-ß bioavailability, and knockdown in both mice and zebrafish lead to craniofacial anomalies. Further, there is evidence for differential expression of LTBP1 between males and females in both mice and humans. Therefore, we tested the association between the imputed genetically regulated gene expression of genes with significant G × S interactions and the CP phenotype. We found significant association for LTBP1 in cell cultured fibroblasts in female probands (p = 0.0013) but not in males. Taken altogether, we show there are sex-specific risks for CP that are otherwise undetectable in a combined sex cohort, and LTBP1 is a candidate risk gene, particularly in females.

RSV Neutralizing Antibodies Following Nirsevimab and Palivizumab Dosing.

BACKGROUND: Data describing respiratory syncytial virus (RSV) neutralizing antibody (nAb) levels for nirsevimab, a recently approved, extended half-life, anti-RSV fusion protein (F protein) monoclonal antibody, relative to the previous standard of care, palivizumab, have not been reported. METHODS: The MEDLEY trial was a randomized, palivizumab-controlled, phase 2/3 study of nirsevimab during 2 RSV seasons (season 1 and 2) in infants born preterm (≤35 weeks' gestational age; dosed season 1 only) or with congenital heart disease or chronic lung disease of prematurity (dosed seasons 1 and 2). Participants were randomly assigned to receive a single dose of nirsevimab followed by 4 monthly placebo doses, or 5 once-monthly doses of palivizumab. Anti-RSV fusion protein serology (ie, levels of prefusion [pre-F]/postfusion [post-F] conformation antibodies), nirsevimab and palivizumab serum concentrations, and RSV nAbs were measured in participant samples collected at baseline (pre-dose) and days 31, 151, and 361. RESULTS: Serologic data were similar in seasons 1 and 2. Nirsevimab predominately conferred pre-F antibodies, whereas palivizumab conferred pre-F and post-F antibodies. Nirsevimab and palivizumab serum concentrations were highly correlated with nAb levels in both seasons. In season 1, the nAb levels in nirsevimab recipients were highest in day 31 samples and gradually declined but remained 17-fold above baseline at day 361. nAb levels in palivizumab recipients increased incrementally with monthly doses to day 151. nAb levels followed similar patterns in season 2. nAb levels were ∼10-fold higher with nirsevimab compared with palivizumab across both seasons. CONCLUSIONS: Nirsevimab prophylaxis confers ∼10-fold higher and more sustained RSV nAb levels relative to palivizumab.

Phenome-wide profiling identifies genotype-phenotype associations in Phelan-McDermid syndrome using family-sourced data from an international registry.

BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by 22q13 deletions that include the SHANK3 gene or pathogenic sequence variants in SHANK3. It is characterized by global developmental delay, intellectual disability, speech impairment, autism spectrum disorder, and hypotonia; other variable features include epilepsy, brain and renal malformations, and mild dysmorphic features. Here, we conducted genotype-phenotype correlation analyses using the PMS International Registry, a family-driven registry that compiles clinical data in the form of family-reported outcomes and family-sourced genetic test results. METHODS: Data from the registry were harmonized and integrated into the i2b2/tranSMART clinical and genomics data warehouse. We gathered information from 401 individuals with 22q13 deletions including SHANK3 (n = 350, ranging in size from 10 kb to 9.1 Mb) or pathogenic or likely pathogenic SHANK3 sequence variants (n = 51), and used regression models with deletion size as a potential predictor of clinical outcomes for 328 phenotypes. RESULTS: Our results showed that increased deletion size was significantly associated with delay in gross and fine motor acquisitions, a spectrum of conditions related to poor muscle tone, renal malformations, mild dysmorphic features (e.g., large fleshy hands, sacral dimple, dysplastic toenails, supernumerary teeth), lymphedema, congenital heart defects, and more frequent neuroimaging abnormalities and infections. These findings indicate that genes upstream of SHANK3 also contribute to some of the manifestations of PMS in individuals with larger deletions. We also showed that self-help skills, verbal ability and a range of psychiatric diagnoses (e.g., autism, ADHD, anxiety disorder) were more common among individuals with smaller deletions and SHANK3 variants. LIMITATIONS: Some participants were tested with targeted 22q microarrays rather than genome-wide arrays, and karyotypes were unavailable in many cases, thus precluding the analysis of the effect of other copy number variants or chromosomal rearrangements on the phenotype. CONCLUSIONS: This is the largest reported case series of individuals with PMS. Overall, we demonstrate the feasibility of using data from a family-sourced registry to conduct genotype-phenotype analyses in rare genetic disorders. We replicate and strengthen previous findings, and reveal novel associations between larger 22q13 deletions and congenital heart defects, neuroimaging abnormalities and recurrent infections.

Toward an understanding of collective intellectual humility.

The study of intellectual humility (IH), which is gaining increasing interest among cognitive scientists, has been dominated by a focus on individuals. We propose that IH operates at the collective level as the tendency of a collective's members to attend to each other's intellectual limitations and the limitations of their collective cognitive efforts. Given people's propensity to better recognize others' limitations than their own, IH may be more readily achievable in collectives than individuals. We describe the socio-cognitive dynamics that can interfere with collective IH and offer the solution of building intellectually humbling environments that create a culture of IH that can outlast the given membership of a collective. We conclude with promising research directions.

Assessing the Impact of Psychological Readiness on Performance and Symmetry in Functional Testing After ACL Reconstruction in Pediatric and Adolescent Patients.

Background: Readiness for return to sports involves both physical and psychological aspects of recovery; however, the relationship between psychological and physical variables after anterior cruciate ligament (ACL) reconstruction (ACLR) is poorly understood. Hypothesis: ACLR patients with a higher psychological readiness would demonstrate better functional testing results at 6 months. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Participants were evaluated at 6 months after ACLR with various patient-reported outcome metrics: Hospital for Special Surgery Pediatric Functional Activity Brief Scale, pediatric or adult International Knee Documentation Committee Questionnaire (IKDC), Patient-Reported Outcomes Measurement Information System (PROMIS) - Psychological Stress Experience and ACL - Return to Sport After Injury (ACL-RSI) scale. Functional testing included quadriceps, hamstrings, and gluteal strength testing; Y-balance test; single-leg single hop, crossover hop, and triple hop tests; and timed 6-m hop test. Pearson correlation coefficient and multivariable regression were used to determine associations between the limb symmetry index (LSI) on functional testing and patient-reported outcomes. Those with LSI deficits <20% (better performance) were compared with those with deficits >20% (worse performance). Results: A total of 229 participants (89 male, 140 female) with a median age of 17 years (range, 10.3-30.6 years) were enrolled. IKDC had a moderate negative correlation with PROMIS - Psychological Stress Experience (r = -0.39; 95% CI = -0.49, -0.27; P < .001) and a moderate positive correlation with ACL-RSI (r = 0.55; 95% CI = 0.46, 0.64; P < .001). A total of 151 patients completed functional testing. ACL-RSI demonstrated a positive correlation with single-hop LSI (r = 0.21; 95% CI = 0.05, 0.35; P = .01) and timed 6-m hop (r = 0.28; 95% CI, 0.42; P = .001). When adjusting for sex, age, and graft type, patients who had <20% deficit on the single-hop test scored 16.6 points higher on ACL-RSI (P = .001), and those with <20% deficit on crossover hop testing scored a mean 13.9 points higher on ACL-RSI (P = .04). Conclusion: Higher psychological readiness for return to sport was associated with better performance and greater symmetry on hop testing 6 months after ACLR, suggesting a potential link between physical and psychological recovery.

Cross-site Validation of AI Segmentation and Harmonization in Breast MRI.

This work aims to perform a cross-site validation of automated segmentation for breast cancers in MRI and to compare the performance to radiologists. A three-dimensional (3D) U-Net was trained to segment cancers in dynamic contrast-enhanced axial MRIs using a large dataset from Site 1 (n = 15,266; 449 malignant and 14,817 benign). Performance was validated on site-specific test data from this and two additional sites, and common publicly available testing data. Four radiologists from each of the three clinical sites provided two-dimensional (2D) segmentations as ground truth. Segmentation performance did not differ between the network and radiologists on the test data from Sites 1 and 2 or the common public data (median Dice score Site 1, network 0.86 vs. radiologist 0.85, n = 114; Site 2, 0.91 vs. 0.91, n = 50; common: 0.93 vs. 0.90). For Site 3, an affine input layer was fine-tuned using segmentation labels, resulting in comparable performance between the network and radiologist (0.88 vs. 0.89, n = 42). Radiologist performance differed on the common test data, and the network numerically outperformed 11 of the 12 radiologists (median Dice: 0.85-0.94, n = 20). In conclusion, a deep network with a novel supervised harmonization technique matches radiologists' performance in MRI tumor segmentation across clinical sites. We make code and weights publicly available to promote reproducible AI in radiology.

Wearable nitric oxide-releasing antibacterial insert for preventing device-associated infections.

Medical device-associated infections are a pervasive global healthcare concern, often leading to severe complications. Bacterial biofilms that form on indwelling medical devices, such as catheters, are significant contributors to infections like bloodstream and urinary tract infections. This study addresses the challenge of biofilms on medical devices by introducing a portable antimicrobial catheter insert (PACI) designed to be efficient, biocompatible, and anti-infective. The PACI utilizes nitric oxide (NO), known for its potent antimicrobial properties, to deter bacterial adhesion and biofilm formation. To achieve this, a photoinitiated NO donor, S-nitroso-N-acetylpenicillamine (SNAP), is covalently linked to a polydimethylsiloxane (PDMS) polymer. This design allows for higher NO loading for long-term impact and prevents premature donor leaching, a common challenge with SNAP-blended polymers. The SNAP-PDMS material was applied to a side-glowing fiber optic and connected to a wearable light module emitting 450 nm light, creating a functional antimicrobial insert. Activation of the fiber optic, accomplished with a one-click mechanism, enables real-time NO release, maintaining controlled NO levels for a minimum of 24  hours. The therapeutic levels of NO released via photocatalysis from the PACI demonstrated remarkable efficacy, with >90 % reduction in bacterial viability against S. aureus, S. epidermidis, and P. mirabilis without any cytotoxic impact on mammalian cells. This study underscores the potential of the NO-releasing insert in clinical settings, providing a portable and adaptable solution for preventing catheter-associated infections.

Cost-effectiveness of bioimpedance-guided fluid management in patients undergoing haemodialysis: the BISTRO RCT.

Background: The BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial investigated the effect of bioimpedance spectroscopy added to a standardised fluid management protocol on the risk of anuria and preservation of residual kidney function (primary trial outcomes) in incident haemodialysis patients. Despite the economic burden of kidney disease, the cost-effectiveness of using bioimpedance measurements to guide fluid management in haemodialysis is not known. Objectives: To assess the cost-effectiveness of bioimpedance-guided fluid management against current fluid management without bioimpedance. Design: Within-trial economic evaluation (cost-utility analysis) carried out alongside the open-label, multicentre BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial. Setting: Thirty-four United Kingdom outpatient haemodialysis centres, both main and satellite units, and their associated inpatient hospitals. Participants: Four hundred and thirty-nine adult haemodialysis patients with > 500 ml urine/day or residual glomerular filtration rate > 3 ml/minute/1.73 m2. Intervention: The study intervention was the incorporation of bioimpedance technology-derived information about body composition into the clinical assessment of fluid status in patients with residual kidney function undergoing haemodialysis. Bioimpedance measurements were used in conjunction with usual clinical judgement to set a target weight that would avoid excessive fluid depletion at the end of a dialysis session. Main outcome measures: The primary outcome measure of the BioImpedance Spectroscopy to maintain Renal Output economic evaluation was incremental cost per additional quality-adjusted life-year gained over 24 months following randomisation. In the main (base-case) analysis, this was calculated from the perspective of the National Health Service and Personal Social Services. Sensitivity analyses explored the impact of different scenarios, sources of resource use data and value sets. Results: The bioimpedance-guided fluid management group was associated with £382 lower average cost per patient (95% CI -£3319 to £2556) and 0.043 more quality-adjusted life-years (95% CI -0.019 to 0.105) compared with the current fluid management group, with neither values being statistically significant. The probability of bioimpedance-guided fluid management being cost-effective was 76% and 83% at commonly cited willingness-to-pay threshold of £20,000 and £30,000 per quality-adjusted life-year gained, respectively. The results remained robust to a series of sensitivity analyses. Limitations: The missing data level was high for some resource use categories collected through case report forms, due to COVID-19 disruptions and a significant dropout rate in the informing BioImpedance Spectroscopy to maintain Renal Output trial. Conclusions: Compared with current fluid management, bioimpedance-guided fluid management produced a marginal reduction in costs and a small improvement in quality-adjusted life-years. Results from both the base-case and sensitivity analyses suggested that use of bioimpedance is likely to be cost-effective. Future work: Future work exploring the association between primary outcomes and longer-term survival would be useful. Should an important link be established, and relevant evidence becomes available, it would be informative to determine whether and how this might affect longer-term costs and benefits associated with bioimpedance-guided fluid management. Funding details: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 14/216/01 (NIHR136142).

'Bioimpedance' is a measure of how difficult it is for an electric current to pass through a biological object. Bioimpedance is used in devices that assess fluid status (over- or under-hydration) because it is very sensitive to the amount of water in tissue. Bioimpedance can be used in addition to clinical judgement when deciding how much water should be removed from someone with kidney failure during a dialysis treatment session. This is the first study to examine whether using this treatment represents a cost-effective use of National Health Service resources. We carried out an economic evaluation within a large randomised controlled trial in patients with kidney disease undergoing haemodialysis. We calculated the additional costs and quality-adjusted life-years (a measure that combines quality and quantity of life) using established methods. Over 2 years, our study showed that taking into account bioimpedance measurements about target weight resulted in slightly lower costs and marginally more quality-adjusted life-years, although there is uncertainty around these findings.