Functional Connectivity Relationships to Longitudinal Motor Outcomes Differ in Very Preterm Children With and Without Brain Injury.

Background and Objectives: Children born very preterm (VPT) have high rates of motor disability, but mechanisms for early identification remain limited, especially for children who fall behind in early childhood. This study examines the relationship between functional connectivity (FC) measured at term-equivalent age and motor outcomes at 2 and 5 years. Methods: In this longitudinal observational cohort study, VPT children (gestational age 30 weeks and younger) with and without high-grade brain injury underwent FC MRI at term-equivalent age. Motor development was assessed using the Bayley Scales of Infant Development, Third Edition, at corrected age 2 years and Movement Assessment Battery for Children, Second Edition, at age 5 years. Logistic and negative binomial/Poisson regression models examined relationships between FC measures and 5-year task scores, with and without 2-year scores as covariates. Infants were categorized as "injured" or "uninjured" based on structural MRI findings at term-equivalent age. Results: In the injured group (n = 34), each 1 SD decrease in neonatal left-right motor cortex FC was related to approximately 4× increased odds of being unable to complete a fine motor task at age 5 (log odds = -1.34, p < 0.05). In the uninjured group (n = 41), stronger basal ganglia-motor cortex FC was related to poorer fine motor scores (Est = -0.40, p < 0.05) and stronger cerebellum-motor cortex FC was related to poorer balance and fine motor scores (Est = -0.05 to -0.23, p < 0.05), with balance persisting with adjustment for 2-year scores. Discussion: In VPT children with brain injury, interhemispheric motor cortex FC was related to motor deficits at 5-year assessment, similar to previous findings at 2 years. In uninjured children, FC-measured disruption of the motor system during the neonatal period was associated with motor planning/coordination difficulties that were not apparent on 2-year assessment but emerged at 5 years, suggesting that the neural basis of these deficits was established very early in life. Subsequently, 2-year follow-up may not be sufficient to detect milder motor deficits in VPT children, and they should be monitored for motor difficulties throughout the preschool years. For all VPT children, FC at term-equivalent age has the potential to improve our ability to predict disability before it presents behaviorally.

Relationships between social determinants of health and healthy body composition among Aboriginal and Torres Strait Islander youth in the Next Generation: Youth Well-being study.

ISSUE ADDRESSED: Little is currently known about the relationships between body composition and the social determinants of health among Aboriginal and Torres Strait Islander youth in Australia, which could help inform policy responses to address health inequities. METHODS: This study aimed to explore the relationship between various social factors and healthy body mass index (BMI) and waist/height ratio (WHtR) among Aboriginal and Torres Strait Islander youth aged 16-24 years. Baseline survey data from 531 participants of the 'Next Generation: Youth Well-being study' were used. Robust Poisson regression quantified associations between healthy body composition and self-reported individual social factors (education, employment and income, government income support, food insecurity, home environment, relationship status, racism), family factors (caregiver education and employment) and area-level factors (remoteness, socioeconomic status). RESULTS: Healthy body composition was less common among those living in a crowded home (healthy WHtR aPR 0.67 [0.47-0.96]) and those receiving government income support (healthy BMI aPR 0.74 [0.57-0.95]). It was more common among those with tertiary educated caregivers (healthy BMI aPR 1.84 [1.30-2.61]; healthy WHtR aPR 1.41 [1.05-1.91]) and those in a serious relationship (healthy BMI aPR 1.33 [1.02-1.75]). CONCLUSIONS: Social factors at the individual and family level are associated with healthy body composition among Aboriginal and Torres Strait Islander youth. SO WHAT?: The findings of this study highlight the potential for health benefits for youth from policies and programs that address social inequities experienced by Aboriginal and Torres Strait Islander people in Australia.

Isolated humeral distalization in reverse total shoulder arthroplasty: a biorobotic shoulder simulator study.

BACKGROUND: Humeral distalization is inherent to reverse total shoulder arthroplasty (rTSA) and is often produced with concomitant humeral lateralization via the level of the humeral head cut, implant positioning, implant neck shaft angle, and polymer insert thickness. Biomechanical data on the isolated effects of humeral distalization remain limited but could be important to consider when optimizing postoperative rTSA shoulder function. This study investigated the effects of isolated humeral distalization on shoulder biomechanics using a biorobotic shoulder simulator. METHODS: Eight fresh-frozen cadaveric shoulders were tested using custom polymer inserts that translated the bearing surface 0, +5, +10, and +15 mm along the humeral stem axis, producing isolated distalization without lateralization. Specimens underwent passive elevation in the scapular plane with a static scapula to assess glenohumeral range of motion. Scapular plane abduction motion trajectories were then performed, driven by previously collected scapulothoracic and glenohumeral kinematics from rTSA patients. The effect of isolated distalization on passive elevation was tested using mixed-effects linear regression and the effect on muscle force, joint reaction force, and muscle excursion during active scapular-plane abduction was tested using statistical parametric mapping random effects analysis. RESULTS: Maximum passive scapular plane elevation increased with humeral distalization (4° per 5 mm distalization). During active elevation, deltoid and rotator cuff muscle forces, and joint reaction forces, increased up to 37% per 5 mm of distalization. Simulated deltoid muscle excursion was altered with increasing distalization but amounted to no more than 0.8 mm change from baseline per 5 mm of distalization. Rotator cuff muscles were consistently lengthened throughout abduction, up to 1.6 mm per 5 mm of distalization. These trends were observed across various patient motions. CONCLUSIONS: Isolated humeral distalization caused dramatic increases in the muscle forces required to perform scapular-plane abduction. Joint reaction forces increased correspondingly. These results suggest that implant and surgical strategies to generate deltoid muscle tension without humeral distalization may promote better active range of motion and more durable long-term outcomes over approaches that rely on distalization.

Unemployment and Personal Income Loss After Traumatic Brain Injury.

Importance: Employment and personal income loss after traumatic brain injury is a major source of postinjury stress and a barrier to societal reintegration. The magnitude of labor market ramifications following traumatic brain injury remains largely unknown. Objectives: To quantify the 3-year postinjury labor market consequences following traumatic brain injury in Canada. To also estimate the incurred national labor market cost over the study period. Design, Setting, and Participants: This retrospective quasi-experimental, pan-Canadian observational cohort study used linked administrative health and federal taxation data obtained between 2007 and 2017. Mixed-effects difference-in-difference regressions were constructed to estimate the annualized magnitude of the personal income and employment loss during each of the 3 years following injury, respectively, relative to preinjury baseline. Participants included tax-filing adult (19 to 61 years old) traumatic brain injury survivors. Exposure: Traumatic brain injury. Main Outcome Measures: Coprimary outcomes were personal income loss and the proportion of newly unemployed individuals per annum. Secondary objectives were to quantify income and employment loss within mild, moderate, and severe traumatic brain injury subgroups. Results: A total of 18 050 patients with traumatic brain injury between 2007 and 2017 were identified (mean age, 38.0 [SD, 12.4] years; 13 360 male [74.0%]), each of whom was followed up with for 3 consecutive fiscal years. Mean income was CAD $42 600 (US $31 083) in the fiscal year prior to injury and 82% were employed at time of injury. The adjusted mean loss of personal income was CAD $7635 (US $5650) in the first year after injury (Y+1) and CAD $5000 (US $3700) in the third year after injury (Y+3) relative to uninjured controls. In each of the 3 postinjury years, 7.8% individuals were newly unemployed compared with the preinjury baseline. The adjusted average personal income loss for mild, moderate, and severe traumatic brain injury subgroups were CAD $3354 (US $2482), CAD $6750 (US $4995), and CAD $17 375 (US $12 859), respectively, at Y+3; the proportion of unemployed individuals increased by 5.8%, 9.2%, and 20% across the same groups at Y+3 after injury relative to preinjury baseline. The estimated total reduction in personal income aggregated over the 3 postinjury years for the affected participants was CAD $588 million (US $435 million). Conclusions and Relevance: This work represents national cohort data quantifying the labor market implications of traumatic brain injury. These results may be used to inform economic evaluations and social service resource allocation.

Optimal Pediatric Outpatient Antibiotic Prescribing.

Importance: In the US, 50% of all pediatric outpatient antibiotics prescribed are unnecessary or inappropriate. Less is known about the appropriateness of pediatric outpatient antibiotic prescribing. Objective: To identify the overall percentage of outpatient antibiotic prescriptions that are optimal according to guideline recommendations for first-line antibiotic choice and duration. Design, Setting, and Participants: This cross-sectional study obtained data on any clinical encounter for a patient younger than 20 years with at least 1 outpatient oral antibiotic, intramuscular ceftriaxone, or penicillin prescription filled in the state of Tennessee from January 1 to December 31, 2022, from IQVIA's Longitudinal Prescription Claims and Medical Claims databases. Each clinical encounter was assigned a single diagnosis corresponding to the lowest applicable tier in a 3-tier antibiotic tier system. Antibiotics prescribed for tier 1 (nearly always required) or tier 2 (sometimes required) diagnoses were compared with published national guidelines. Antibiotics prescribed for tier 3 (rarely ever required) diagnoses were considered to be suboptimal for both choice and duration. Main Outcomes and Measures: Primary outcome was the percentage of optimal antibiotic prescriptions consistent with guideline recommendations for first-line antibiotic choice and duration. Secondary outcomes were the associations of optimal prescribing by diagnosis, suboptimal antibiotic choice, and patient- and clinician-level factors (ie, age and Social Vulnerability Index) with optimal antibiotic choice, which were measured by odds ratios (ORs) and 95% CIs calculated using a multivariable logistic regression model. Results: A total of 506 633 antibiotics were prescribed in 488 818 clinical encounters (for 247 843 females [50.7%]; mean [SD] age, 8.36 [5.5] years). Of these antibiotics, 21 055 (4.2%) were for tier 1 diagnoses, 288 044 (56.9%) for tier 2 diagnoses, and 197 660 (39.0%) for tier 3 diagnoses. Additionally, 194 906 antibiotics (38.5%) were optimal for antibiotic choice, 259 786 (51.3%) for duration, and 159 050 (31.4%) for both choice and duration. Acute otitis media (AOM) and pharyngitis were the most common indications, with 85 635 of 127 312 (67.3%) clinical encounters for AOM and 42 969 of 76 865 (55.9%) clinical encounters for pharyngitis being optimal for antibiotic choice. Only 257 of 4472 (5.7%) antibiotics prescribed for community-acquired pneumonia had a 5-day duration. Optimal antibiotic choice was more likely in patients who were younger (OR, 0.98; 95% CI, 0.98-0.98) and were less socially vulnerable (OR, 0.84; 95% CI, 0.82-0.86). Conclusions and Relevance: This cross-sectional study found that less than one-third of antibiotics prescribed to pediatric outpatients in Tennessee were optimal for choice and duration. Four stewardship interventions may be targeted: (1) reduce the number of prescriptions for tier 3 diagnoses, (2) increase optimal prescribing for AOM and pharyngitis, (3) provide clinician education on shorter antibiotic treatment courses for community-acquired pneumonia, and (4) promote optimal antibiotic prescribing in resource-limited settings.

Longevity of size-dependent particle removal performance of do-it-yourself box fan air filters.

Filtration performance of do-it-yourself (DIY) box fan filters deployed across a university campus was assessed over an academic year. Four DIY air filters were constructed from box fans and air filters with a minimum efficiency reporting value (MERV) of 13 and deployed in four spaces (two laboratories that include sources of particles and two offices). They were operated 9 hours daily with a programmable timer and were continuously monitored with power meters. Particle concentrations in the spaces were continuously monitored with low-cost nephelometers. The particle size dependent clean air delivery rate (CADR) and single pass filtration efficiency for each box was measured in a laboratory before deployment and every 10 weeks, for a total of five measurements over 40 weeks. We find that these DIY box fan filters maintain robust performance over time, with each air filter maintaining at least 60% of its initial CADR at the end of the 40 week study even with daily operation in environments with modest particle concentrations. CADR values for particles of 1.0-3.0 µm optical diameter averaged 34% higher than CADR values for 0.35-1.0 µm particles, aligning with MERV 13 filter size-dependent filtration expectations. Reductions in CADR over time were attributed to a reduction in filtration efficiency, likely due to a loss of filter electrostatic charge over time. There was no strong indication that increased resistance due to particle accumulation on filters appreciably decreased flow rates over time for any of the fans. The long-term robustness of DIY box fan air filters demonstrates their validity as a cost-effective, high performance, alternative to portable high efficiency particulate air (HEPA) filters.

Neonatal Neurocritical Care Training-The Time Has Come.

This Viewpoint describes the advent of neonatal neurocritical care training, the data supporting the need and its efficacy, and the ways this training can optimize outcomes for vulnerable patients and their families.

Conceptual Framework for Community-Based Prevention of Brown Dog Tick-Associated Rocky Mountain Spotted Fever.

Rocky Mountain spotted fever (RMSF) is a severe tickborne disease that can reach epidemic proportions in communities with certain social and ecologic risk factors. In some areas, the case-fatality rate of brown dog tick-associated RMSF is up to 50%. Because of the spread of brown dog tick-associated RMSF in the southwestern United States and northern Mexico, the disease has the potential to emerge and become endemic in other communities that have large populations of free-roaming dogs, brown dog ticks, limited resources, and low provider awareness of the disease. By using a One Health approach, interdisciplinary teams can identify communities at risk and prevent severe or fatal RMSF in humans before cases occur. We have developed a conceptual framework for RMSF prevention to enable communities to identify their RMSF risk level and implement prevention and control strategies.

Understanding the Significance of Layer Bonding in Melt Electrowriting.

Melt electrowriting (MEW) is a high-resolution additive manufacturing technology capable of depositing micrometric fibers onto a moving collector to form 3D scaffolds of controlled mechanical properties. While the critical role of layer bonding to achieve mechanical integrity in fused deposition modeling has been widely reported, it remains largely unknown in MEW, in part due to a lack of methods to assess it. Here, a systematic framework is developed to unravel the significance of layer bonding in MEW scaffolds and its ultimate effect on their mechanical properties. Results show that printing parameters, scaffold design, and print path have a strong impact on layer bonding strength of poly(ɛ-caprolactone) MEW scaffolds. This study demonstrates that a small increase of 5 µm in fiber diameter can enhance the layer bonding strength by as much as 70%, greatly impacting the overall scaffold properties. A method is also established to control MEW scaffold layer bonding using a heated collector. Importantly, this study reveals that scaffold architecture alone is not responsible for the overall mechanical properties. Finally, a method to obtain tailored layer bond strengths within a given scaffold is established. This has significant implications as provides new possibilities to control mechanical properties of MEW scaffolds through layer bonding.

Cinchona Organocatalyzed Enantioselective Amination for Quaternized Serines as Tertiary Amides.

Herein, we describe a Cinchona-aminocatalyzed enantioselective α-hydrazination of an α-formyl amide for the production of protected quaternized serines as tertiary amides with ee's of generally >98% and ≤99% yields. The proposed TS model supported by density functional theory calculations involves a quinuclidinium ion Brønsted acid-assisted delivery of DtBAD, which occurs from the Re face of an H-bonded enaminone when using a 9S-cinchonamine catalyst, resulting in a hydrazide with the R-configuration as determined by X-ray analysis.

Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.

Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.

Adverse Childhood Experiences and Socio-Emotional Outcomes of Children Born Very Preterm.

OBJECTIVE: To examine whether adverse childhood experiences (ACEs) confer risk for socio-emotional problems in children born very preterm (VPT) STUDY DESIGN: As part of a longitudinal study, 96 infants born VPT at 23-30 weeks of gestation were recruited from a level III neonatal intensive care unit and underwent follow-up at ages 2 and 5 years. Eighty-three full-term (FT, 37-41 weeks gestation) children were recruited from an adjoining obstetric service and the local community. ACEs were assessed with the Child Life Events Scale at age 2 and Preschool Age Psychiatric Assessment at age 5. At age 5, internalizing, externalizing, and Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms were assessed with the Child Behavior Checklist and Conner's Rating Scale-Revised, respectively. Covariates including socioeconomic disadvantage, maternal distress, and parent ADHD symptoms were assessed at the 2- and/or 5-year follow-up. Mediation and moderation analysis, accounting for family clustering, examined associations between birth group, ACEs, and socio-emotional outcomes. RESULTS: After covariate adjustment, children born VPT experienced more ACEs (p<0.001), particularly medical ACEs (p<0.01), and had worse ADHD and internalizing outcomes (p<.05) than FT children. ACEs mediated the association between birth group and ADHD outcomes (95% CIs: 0.11 - 4.08). There was no evidence of mediation for internalizing outcomes. Higher parent ADHD symptoms (p<.001) and maternal distress (p<.05) were associated with poorer internalizing outcomes. CONCLUSIONS: Screening for childhood ACEs should be embedded in the follow-up care of children born VPT and their families. Strategies to screen for and address parent psychosocial functioning may be important to support children's socio-emotional development.

Impaired axon initial segment structure and function in a model of ARHGEF9 developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEE) are rare but devastating and largely intractable childhood epilepsies. Genetic variants in ARHGEF9, encoding a scaffolding protein important for the organization of the postsynaptic density of inhibitory synapses, are associated with DEE accompanied by complex neurological phenotypes. In a mouse model carrying a patient-derived ARHGEF9 variant associated with severe disease, we observed aggregation of postsynaptic proteins and loss of functional inhibitory synapses at the axon initial segment (AIS), altered axo-axonic synaptic inhibition, disrupted action potential generation, and complex seizure phenotypes consistent with clinical observations. These results illustrate diverse roles of ARHGEF9 that converge on regulation of the structure and function of the AIS, thus revealing a pathological mechanism for ARHGEF9-associated DEE. This unique example of a neuropathological condition associated with multiple AIS dysfunctions may inform strategies for treating neurodevelopmental diseases.

Tuning Chemical DNA Ligation within DNA Crystals and Protein-DNA Cocrystals.

Biomolecular crystals can serve as materials for a plethora of applications including precise guest entrapment. However, as grown, biomolecular crystals are fragile in solutions other than their growth conditions. For crystals to achieve their full potential as hosts for other molecules, crystals can be made stronger with bioconjugation. Building on our previous work using carbodiimide 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) for chemical ligation, here, we investigate DNA junction architecture through sticky base overhang lengths and the role of scaffold proteins in cross-linking within two classes of biomolecular crystals: cocrystals of DNA-binding proteins and pure DNA crystals. Both crystal classes contain DNA junctions where DNA strands stack up end-to-end. Ligation yields were studied as a function of sticky base overhang length and terminal phosphorylation status. The best ligation performance for both crystal classes was achieved with longer sticky overhangs and terminal 3'phosphates. Notably, EDC chemical ligation was achieved in crystals with pore sizes too small for intracrystal transport of ligase enzyme. Postassembly cross-linking produced dramatic stability improvements for both DNA crystals and cocrystals in water and blood serum. The results presented may help crystals containing DNA achieve broader application utility, including as structural biology scaffolds.

Physical Activity Behaviour and Motivation During and Following Pulmonary and Cardiac Rehabilitation: A Repeated Measures Study.

BACKGROUND: Exercise rehabilitation programmes are important for long-term health and wellbeing among people with cardiac and pulmonary diseases. Despite this, many people struggle to maintain their physical activity once rehabilitation ends. This repeated measures study tracked changes in physical activity behaviour and motivation during and after completing a community-based exercise rehabilitation programme. METHODS: Cardiac and pulmonary exercise rehabilitation patients (N = 31) completed six once-monthly measures of physical activity (MET·min), self-determined motivation, intention, and habit strength for rehabilitation exercise (within rehabilitation sessions) and lifestyle physical activity (outside of rehabilitation sessions). Linear regression and random effects models with estimated marginal means were used to test for associations between physical activity motivation and behaviour and change during and post-rehabilitation. RESULTS: Overall physical activity decreased after rehabilitation (823 MET·min) despite patients becoming more self-determined for lifestyle physical activity during rehabilitation. More self-determined motivation, stronger intentions, and stronger habits were associated with more lifestyle physical activity behaviour. However, none of these motivation variables were significantly associated with rehabilitation exercise behaviour. CONCLUSIONS: Among community-based cardiac and pulmonary rehabilitation patients, physical activity levels decreased following exercise rehabilitation programmes. The findings revealed clear distinctions in the motivation of rehabilitation exercise compared to lifestyle physical activity. Exercise rehabilitation programmes might improve the longevity of outcomes by integrating approaches to enhance lifestyle physical activity beyond the clinic.

Life History Strategies Drive Meso-Scale Distribution Patterns in Coastal Benthic Macroinvertebrates.

The environment shapes the spatial distribution of species, but species also comprise suites of traits which may indicate their adaptability to a specific environment. This forms the basis of trait biogeography studies. We thus examined how a species distribution is not only influenced by its environment and traits, but by interactions among its traits. Trait information was collected for 150 intertidal macroinvertebrates along a 3000 km environmental and biogeographic gradient on the South African coast. This information was analysed, as functional entities (FEs) were species performing similar functions that have the same trait values and were further condensed into two trait domains (Reproduction and Lifestyle). We then defined Life History Strategies (LHS) as specific combinations of Lifestyle and Reproduction FEs. Seven combinations of Lifestyle and Reproduction formed LHS that dominated total biomass. Some of these LHS were ubiquitous, while others showed geographic patterns across our west-east environmental gradient. For Lifestyle, filter-feeders exhibited high abundances on the East (subtropical, oligotrophic) and West (cool-temperate, eutrophic) extremes of the biogeographic gradient, but differed between the two in size at reproductive maturity and larval development type. This similarity in functionality of feeding mechanism and mobility with different reproductive strategies suggests a trait trade-off (investment in one trait reduces resources for others) between the Reproduction and Lifestyle domains. Within the Reproduction domain, gonochoristic, annual planktotrophic reproduction was common across bioregions, reflecting spin-offs (investment in one trait facilitates another trait) among these traits. Gonochoristic investment in less frequent episodic reproduction is another trade-off, with investment in large size and delayed maturation being a trade-off for many reproductive cycles. Overall, although our data supports the habitat templet model (i.e., the importance of environmental drivers), it further indicates that species distribution patterns observed along the South African coast reflect strong trait interactions and biomass patterns related to their LHS.

Baby Open Brains: An Open-Source Repository of Infant Brain Segmentations.

Reproducibility of neuroimaging research on infant brain development remains limited due to highly variable protocols and processing approaches. Progress towards reproducible pipelines is limited by a lack of benchmarks such as gold standard brain segmentations. Addressing this core limitation, we constructed the Baby Open Brains (BOBs) Repository, an open source resource comprising manually curated and expert-reviewed infant brain segmentations. Markers and expert reviewers manually segmented anatomical MRI data from 71 infant imaging visits across 51 participants, using both T1w and T2w images per visit. Anatomical images showed dramatic differences in myelination and intensities across the 1 to 9 month age range, emphasizing the need for densely sampled gold standard manual segmentations in these ages. The BOBs repository is publicly available through the Masonic Institute for the Developing Brain (MIDB) Open Data Initiative, which links S3 storage, Datalad for version control, and BrainBox for visualization. This repository represents an open-source paradigm, where new additions and changes can be added, enabling a community-driven resource that will improve over time and extend into new ages and protocols. These manual segmentations and the ongoing repository provide a benchmark for evaluating and improving pipelines dependent upon segmentations in the youngest populations. As such, this repository provides a vitally needed foundation for early-life large-scale studies such as HBCD.

Loss of Function in Protein Z (PROZ) is Associated with Increased Risk of Ischemic Stroke in the UK Biobank.

BACKGROUND: The vitamin K-dependent coagulation factor protein Z (PZ), encoded by the PROZ gene, is canonically considered to have anticoagulant effects through negative regulation of factor Xa. Paradoxically, higher circulating PZ concentrations have repeatedly been associated with an elevated risk of acute ischemic stroke. OBJECTIVE: We performed a large-scale genetic association study to examine the relationship between germline genetic variants in PROZ and the risk of ischemic stroke. METHODS: Using whole exome sequencing and clinical data for 416,711 participants in the UK Biobank (UKB), we identified individuals with rare (MAF ≤ 0.1%) putatively function-altering variants in PROZ. Using Firth's logistic regression and controlling for known stroke risk factors, we evaluated the association between variant carrier status and non-cardioembolic ischemic stroke (NCEIS). Additionally, we evaluated differences in the plasma levels of 1,472 proteins between PROZ variant carriers and non-carriers in a subset of 48,893 UKB participants. RESULTS: After accounting for missing data, qualifying variants in PROZ were identified in 414 UKB participants (99.0% heterozygous). Variant carriers had a significantly increased risk of NCEIS (OR=2.34, 95% CI: 1.15-4.13, P=0.02) but not of venous thromboembolism, myocardial infarction, or peripheral artery disease. Plasma proteomics analysis revealed that PROZ variant carriers had significantly elevated levels of two proteins related to the response to cerebral ischemia, peroxiredoxins 1 and 6 (PRDX1, fold-change=1.83, P=1.3 x 10-5 and PRDX6, fold-change=1.78, P=9.6 x 10-10). CONCLUSIONS: Lifelong exposure to decreased PZ levels confers a significantly increased risk of NCEIS, consistent with the role of PZ as an anticoagulant factor.

Endovascular Ablation of the Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: The REBALANCE-HF Randomized Clinical Trial.

Importance: Greater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF). Objective: To explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM). Design, Setting, and Participants: This was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024. Intervention: SAVM vs sham control procedure. Main Outcomes and Measures: The primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP. Results: A total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, -0.03 mm Hg; 95% CI, -2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, -6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, -9.2% to 18.8%; P = .48). Conclusions and Relevance: Results show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT04592445.