Role of toll-like receptor 4/mutant myeloid differentiation primary response 88/nuclear factor kappa-B mediated inflammation in diabetes mellitus with Northwest dryness syndrome.

OBJECTIVE: To investigate the role of toll-like receptor 4 (TLR4)/mutant myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa-B (NF-κB) signaling pathway-mediated inflammation in diabetes mellitus with Northwest dryness syndrome. METHODS: Rats were randomly divided into the normal control, type 2 diabetes (T2DM) model, Northwest dryness syndrome + T2DM (Northwest dryness), and simple internal dampness + T2DM (internal dampness) groups. Enzyme-linked immunosorbent assay was used to detect biochemical indexes and inflammatory factors. The histopathological observation was performed. Quantitative real-time polymerase chain reaction and Western blot analysis were used to detect the mRNA and protein expression levels, respectively. RESULTS: Compared with the T2DM group, the glycosylated hemoglobin A1c, insulin, glucose tolerance, the homeostasis model assessment of insulin resistance, tumor necrosis factor-α, interleukin 1ß, interleukin 16, malondialdehyde, blood lipid, alanine aminotransferase, and aspartate aminotransferase were significantly elevated in the internal dampness group. Their levels were significantly elevated in the Northwest dryness group than in the T2DM and internal dampness groups. The superoxide dismutase, glutathione peroxidase, liver glycogen, and organ-to-weight ratio were significantly declined in the internal dampness group and the Northwest dryness group than in the T2DM group. However, these levels were elevated in the Northwest dryness group than in the internal dampness group. Moreover, the mRNA expression levels of interferon regulatory factor 5 and NF-κB p65, and the protein expression levels of TLR4, MyD88, and NF-κB were significantly higher in the internal dampness and the Northwest dryness groups than the T2DM group. Additionally, the mRNA and protein levels were significantly higher in the Northwest dryness group than in the internal dampness group. CONCLUSION: Northwest dryness syndrome-mediated TLR4/MyD88/NF-κB pathway and chronic inflammation might be associated with the occurrence and development of T2DM.

Risk factors and early outcomes associated with prolonged pleural effusion/chylothorax after paediatric cardiac surgery.

OBJECTIVES: Prolonged pleural effusion/chylothorax (PPE/C) is a less investigated complication following paediatric cardiac surgery, and its true incidence, risk factors and impact on postoperative outcomes are not well described. We aim to address these gaps in knowledge using data from a prospective, multicentre study. METHODS: Data on 9 post-operative morbidities (unplanned reinterventions, extracorporeal life support, necrotising enterocolitis, PPE/C, renal replacement therapy, major adverse events, acute neurological events, feeding issues and postsurgical infection) were prospectively collected at 5 UK centres between 2015 and 2017, following paediatric cardiac surgery. Incidence of PPE/C, associations with procedure types, and risk factors were described. Mortality (30-day and 6-month) and hospital length of stay (HLoS) were compared between those with isolated PPE/C, single non-PPE/C morbidity, no morbidity, multimorbidity PPE/C and non-PPE/C multimorbidity. RESULTS: A total of 3090 procedures (2861 patients) were included (median age, 228 days). There were 202 PPE/C (incidence of 6.5%), occurring at a median of 6 days postoperatively (IQR: 3-10). PPE/C was associated with excess early mortality only when complicating scenarios where at least two other post-operative morbidities occurred. On average PPE/C is associated with 8 more HLoS days, but the relative impact is greatest when comparing isolated PPE/C with no morbidity (p < 0.001), whereas in multimorbidity scenarios, PPE/C does not significantly contribute to an increase of HLoS. CONCLUSIONS: Addition of PPE/C increases mortality but not HLoS in multimorbidity and HLoS only in single morbidity scenarios. This reinforces the important role of prevention, early detection and management of PPE/C in complex situations.

Dynamics of gas exchange and heart rate signal entropy in standard cardiopulmonary exercise testing during critical periods of growth and development.

Standard cardiopulmonary exercise testing (CPET) produces a rich dataset but its current analysis is often limited to a few derived variables such as maximal or peak oxygen uptake (V̇O2). We tested whether breath-by-breath CPET data could be used to determine sample entropy (SampEn) in 81 healthy children and adolescents (age 7-18 years old, equal sex distribution). To overcome challenges of the relatively small time-series CPET data size and its nonstationarity, we developed a Python algorithm for short-duration physiological signals. Comparing pre- and post-ventilatory threshold (VT1) CPET phases, we found: (1) SampEn decreased by 9.46% for V̇O2 and 5.01% for V̇CO2 (p < 0.05), in the younger, early-pubertal participants; and (2) HR SampEn fell substantially by 70.8% in the younger and 77.5% in the older participants (p < 0.001). Across all ages, females exhibited greater HR SampEn than males during both pre- and post VT1 CPET phases by 14.10% and 23.79%, respectively, p < 0.01. In females, late-pubertal had 17.6% lower HR SampEn compared to early-pubertal participants (p < 0.05). Breath-by-breath gas exchange and HR data from CPET are amenable to SampEn analysis that leads to novel insight into physiological responses to work intensity, and sex and maturational effects.

Assays of Variant Effect and Automated Patch Clamping Improve KCNH2-LQTS Variant Classification and Cardiac Event Risk Stratification.

BACKGROUND: Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2. Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes. METHODS: We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 current density for 533 variants by automated patch clamping. We calibrated the strength of evidence of MAVE data according to ClinGen guidelines. We deeply phenotyped 1458 patients with KCNH2 missense variants, including QTc, cardiac event history, and mortality. We correlated variant functional data and Bayesian long QT syndrome penetrance estimates with cohort phenotypes and assessed hazard ratios for cardiac events. RESULTS: Variant MAVE trafficking scores and automated patch clamping peak tail currents were highly correlated (Spearman rank-order ρ=0.69; n=433). The MAVE data were found to provide up to pathogenic very strong evidence for severe loss-of-function variants. In the cohort, both functional assays and Bayesian long QT syndrome penetrance estimates were significantly predictive of cardiac events when independently modeled with patient sex and adjusted QT interval (QTc); however, MAVE data became nonsignificant when peak tail current and penetrance estimates were also available. The area under the receiver operator characteristic curve for 20-year event outcomes based on patient-specific sex and QTc (area under the curve, 0.80 [0.76-0.83]) was improved with prospectively available penetrance scores conditioned on MAVE (area under the curve, 0.86 [0.83-0.89]) or attainable automated patch clamping peak tail current data (area under the curve, 0.84 [0.81-0.88]). CONCLUSIONS: High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.

ParSE-seq: a calibrated multiplexed assay to facilitate the clinical classification of putative splice-altering variants.

Interpreting the clinical significance of putative splice-altering variants outside canonical splice sites remains difficult without time-intensive experimental studies. To address this, we introduce Parallel Splice Effect Sequencing (ParSE-seq), a multiplexed assay to quantify variant effects on RNA splicing. We first apply this technique to study hundreds of variants in the arrhythmia-associated gene SCN5A. Variants are studied in 'minigene' plasmids with molecular barcodes to allow pooled variant effect quantification. We perform experiments in two cell types, including disease-relevant induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). The assay strongly separates known control variants from ClinVar, enabling quantitative calibration of the ParSE-seq assay. Using these evidence strengths and experimental data, we reclassify 29 of 34 variants with conflicting interpretations and 11 of 42 variants of uncertain significance. In addition to intronic variants, we show that many synonymous and missense variants disrupted RNA splicing. Two splice-altering variants in the assay also disrupt splicing and sodium current when introduced into iPSC-CMs by CRISPR-Cas9 editing. ParSE-seq provides high-throughput experimental data for RNA-splicing to support precision medicine efforts and can be readily adopted to study other loss-of-function genotype-phenotype relationships.

Ablation for Atrial Fibrillation in Patients With Rare Pathogenic Variants in Cardiomyopathy and Arrhythmia Genes.

BACKGROUND: Patients with rare, pathogenic cardiomyopathy (CM) and arrhythmia variants can present with atrial fibrillation (AF). The efficacy of AF ablation in these patients is unknown. OBJECTIVE: This study tested the hypotheses that: 1) patients with a pathogenic variant in any CM or arrhythmia gene have increased recurrence following AF ablation; and 2) patients with a pathogenic variant associated with a specific gene group (arrhythmogenic left ventricular CM [ALVC], arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, or a channelopathy) have increased recurrence. METHODS: We performed a prospective, observational, cohort study of patients who underwent AF catheter ablation and whole exome sequencing. The primary outcome measure was ≥30 seconds of any atrial tachyarrhythmia that occurred after a 90-day blanking period. RESULTS: Among 1,366 participants, 109 (8.0%) had a pathogenic or likely pathogenic (P/LP) variant in a CM or arrhythmia gene. In multivariable analysis, the presence of a P/LP variant in any gene was not significantly associated with recurrence (HR 1.15; 95% CI 0.84-1.60; P = 0.53). P/LP variants in the ALVC gene group, predominantly LMNA, were associated with increased recurrence (n = 10; HR 3.75; 95% CI 1.84-7.63; P < 0.001), compared with those in the arrhythmogenic right ventricular CM, dilated CM, hypertrophic CM, and channelopathy gene groups. Participants with P/LP TTN variants (n = 46) had no difference in recurrence compared with genotype-negative-controls (HR 0.93; 95% CI 0.54-1.59; P = 0.78). CONCLUSIONS: Our results support the use of AF ablation for most patients with rare pathogenic CM or arrhythmia variants, including TTN. However, patients with ALVC variants, such as LMNA, may be at a significantly higher risk for arrhythmia recurrence.

Surgical outcomes and risk factors for overall mortality in brain arteriovenous malformations patients: a retrospective analysis.

Background: Brain arteriovenous malformations (AVMs) are challenging vascular lesions. Extensive follow-up studies are necessary to refine the therapeutic algorithm, and to improve long-term survival in these patients. The aim of the study was to assess surgical outcomes, and to evaluate overall long-term mortality in patients treated for brain AVMs. Methods: This retrospective single-center study included 191 patients with brain AVMs, admitted between 2012 and 2022. Clinical and angiographical particularities have been analyzed, to identify factors that might influence early outcome and overall long-term mortality. Results: Out of 79 patients undergoing surgery, 51 had ruptured AVMs with total resection achieved in 68 cases (86.1%). Deep venous drainage was associated with incomplete resection. Female sex, admission modified Rankin Scale (mRS) > 2, and eloquent location were independent predictors of poor outcomes. Multiple venous drainage was associated with a higher risk of worsened early outcome. Eloquent brain region involvement, conservative treatment, increasing age, admission mRS > 2, and comorbidities significantly decrease survival in brain AVM patients. Patients treated with interventional treatments had significantly better survival than the conservatively managed ones, when adjusting for age and admission mRS. Conclusion: The study identified female sex, poor neurologic status on admission and eloquence as independent prognostic factors for a negative outcome after surgery. Patients who received interventional treatment had significantly better survival than patients managed conservatively. We recommend employing tailored, proactive management strategies as they significantly enhance long-term survival in brain AVM patients.

Evaluating the Effect of Financial Penalty on Hospital-Acquired Infections.

Purpose: This study explores the effects of CMS reimbursement financial penalties from the Hospital-Acquired Condition Reduction Program (HACRP) on hospital-acquired infections (HAI) in hospitals across the United States. Methods: Hospital-level data for 2896 hospitals in the United States were evaluated using multiple linear regression models with random effects analysis through a difference-in-differences study design to examine HAIs under the HACRP between hospitals that were financially penalized or not from calendar years 2013 to 2020. Results: This study showed significant differences from the pre-program Total HAC scores to the most recent reviewed year, validating the efficacy of the HACRP, and showing a reduction of overall HAIs over the years evaluated in the study. The multiple linear regression model with random effects analysis produced a significant (p < 0.001) interaction term between hospitals expected to be penalized in 2013 and each year evaluated in the study (-0.412 estimate) confirming decreases in HAI scores, and overall decreases in HAIs across the years of the study. Notably, 98% of hospitals in the worst-performing, expected to be financially penalized quartile from 2013, were found to have decreased their HAIs in their facilities, while only 38.8% of hospital in the performing, non-penalized quartiles showed decreases in HAIs across their facilities, by 2020. Conclusion: Our research indicates that implementing financial disincentives through reimbursement reductions could potentially decrease the incidence of HAIs. Our study further suggests that incorporating financial penalties and incentives for HAIs annually across all hospitals may lead to significant reductions in HAIs throughout the US healthcare system.

Detection of distant relatedness in biobanks to identify undiagnosed cases of Mendelian disease as applied to Long QT syndrome.

Rare genetic diseases are typically studied in referral populations, resulting in underdiagnosis and biased assessment of penetrance and phenotype. To address this, we develop a generalizable method of genotype inference based on distant relatedness and deploy this to identify undiagnosed Type 5 Long QT Syndrome (LQT5) rare variant carriers in a non-referral population. We identify 9 LQT5 families referred to a single specialty clinic, each carrying p.Asp76Asn, the most common LQT5 variant. We uncover recent common ancestry and a single shared haplotype among probands. Application to a non-referral population of 69,819 BioVU biobank subjects identifies 22 additional subjects sharing this haplotype, which we confirm to carry p.Asp76Asn. Referral and non-referral carriers have prolonged QT interval corrected for heart rate (QTc) compared to controls, and, among carriers, the QTc polygenic score is independently associated with QTc prolongation. Thus, our innovative analysis of shared chromosomal segments identifies undiagnosed cases of genetic disease and refines the understanding of LQT5 penetrance and phenotype.

PheMIME: an interactive web app and knowledge base for phenome-wide, multi-institutional multimorbidity analysis.

OBJECTIVES: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies. MATERIALS AND METHODS: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies. RESULTS: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME_supplementary_materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME. DISCUSSION: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records. CONCLUSION: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization.

Postoperative Stroke Following Anterior Cervical Spine Surgery: A Case Report.

Vascular complications succeeding anterior cervical spine surgery are rare, but their consequences represent a major burden for the patient. Cerebral infarction following anterior cervical discectomy and fusion (ACDF) is uncommon. However, screening for risk factors before surgery should become mandatory. We present the case of a patient with no significant medical history who underwent ACDF for a C5/C6 herniated disc with myelopathy. Although the surgery was uneventful, after the surgery, partial right palpebral ptosis and miosis were noted, suggestive of Horner syndrome. On the fifth postoperative day, the patient experienced left hemiplegia and drowsiness. An emergency CT scan and cerebral MRI revealed ischemia in the right middle cerebral artery territory. The patient was transferred to a neurology center for mechanical thrombectomy, which revealed a complete occlusion of the right internal carotid artery. The procedure had to be halted due to blood extravasation at the internal carotid artery bifurcation to prevent further complications. An angio-CT examination of the cervical arteries exposed a soft atheromatous plaque on the right internal carotid artery, immediately after the bifurcation. Despite the patient having no significant medical history, blood tests indicated dyslipidemia. At the two-month follow-up, the patient remained hemiplegic, with mild dysphasia. Performing carotid and vertebral Doppler ultrasound before cervical spine surgery might be useful, whenever possible, to assess high-risk factors for ischemic events and avoid such debilitating complications.

Genetic testing in early-onset atrial fibrillation.

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%-11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research-mechanistic, translational, and clinical-is urgently needed.

A new protocol for a single-stage combined cardiopulmonary and echocardiography exercise test: a pilot study.

Aims: The value of cardiopulmonary exercise testing (CPET) and exercise stress echocardiography (ESE) in managing cardiac disease is well known, but no standard CPET-ESE protocol is currently recommended. This pilot study aims to compare feasibility and cardiac function responses between a new high-intensity single-stage combined test (CPET-hiESE) and a standard maximal ESE (smESE). Methods and results: After screening and maximal CPET, all volunteers (n = 21) underwent three ESE modalities: (i) based on the gas exchange threshold (hiESE-GET, 40% of peak-GET, 6 min), (ii) based on heart rate (HR) (hiESE-HR, 80% of peak HR, 6 min), and (iii) smESE (85% of predicted peak HR for age, 3 min). Speckle tracking echocardiography (STE) and tissue Doppler imaging (TDI) were measured at each step. There was superior image quality and data completeness for the right ventricle strain for both hiESE modalities compared with smESE (71.4 and 76.2 vs. 42.9%, P = 0.07). Left ventricular STE data completeness was similar for all three conditions. Despite systematically higher HR, work rate and levels of exertion in the smESE compared with hiESE, STE and TDI parameters were not systematically different. Concordance correlation coefficients ranged from 0.56 to 0.88, lowest for strain rate parameters and mean difference from -0.34 to 1.53, highest for TDI measurements. Conclusion: The novel CPET-hiESE protocol allowed for better data completeness, at lower levels of exertion compared with smESE, without systematically different cardiac reserve measurements in healthy participants. This single-stage protocol can be individualized to clinical populations, which would provide practical advantages to standard testing.

Extrinsic outflow graft obstruction of the HeartMate 3 LVAD: A state-of-the-art review.

While notable improvements in survival, the incidence of hemocompatibility-related adverse events, hospitalizations, and cost have been demonstrated with the only commercially available durable left ventricular assist device, a category of pump malfunctions characterized by outflow graft obstruction has been noted with broader use and clinical follow-up of recipients of this technology. Of particular concern is the accumulation of acellular biodebris between the outflow graft and bend relief covering the outflow graft at its origin with the pump (which we term extrinsic outflow graft obstruction at the bend relief). This process tends to be insidious, occurs late in the postoperative course, can be challenging to diagnose, and can result in significant morbidity and mortality. Herein, we provide a review of this complication and outline diagnostic, treatment, and preventive strategies.

Multisite Validation of a Functional Assay to Adjudicate SCN5A Brugada Syndrome-Associated Variants.

BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.

Natural History and Predictors for Hemorrhage in Supratentorial Brain Arteriovenous Malformations.

Background/Objectives: Approximately half of the patients harboring supratentorial brain arterio-venous malformations (stAVMs) present with hemorrhage, and another considerable proportion suffer from epileptic seizures. An important milestone in the management of this vascular pathology is acknowledging their natural history, especially across long periods of time. The aim of this study was to assess the predictive factors for hemorrhage and for epileptic seizures as presenting symptoms in stAVMs. Methods: We retrospectively analyzed patients with stAVMs admitted to our institution between 2012 and 2022 and evaluated predictive factors for hemorrhage and the risk factors associated with epileptic seizures. Results: The cohort included 169 patients, 78 of them (46.2%) presenting with intracerebral hemorrhage (ICH). Seventy-seven (45.5%) patients suffered from epileptic seizures. The annual hemorrhagic rate was 1.28%/year. Unruptured lesions (p = 0.001, OR 3.1, 95% CI 1.6-6.2), superficial venous drainage (p = 0.007, OR 2.7, 95% CI 1.3-5.7) and large nidus size (p = 0.025, OR 4, 95% CI 1.2-13.5) were independently associated with seizures. Among unruptured lesions, superficial venous drainage (OR 2.6, p = 0.036, 95% CI 1.06-6.3) and frontal/temporal/parietal location (OR 2.7, p = 0.040, 95 CI% 1.04-6.9) significantly increased the risk of seizures as a presenting symptom in multivariate analysis. Patients younger than 18 (p = 0.003, OR 4.5, 95% CI 1.6-12.2), those with AVMs < 3 cm (p = 0.03, OR 2, 95% CI 1.07-3.9) or those with deep located AVMs (p = 0.035, OR 2.3, 95% CI 1.06-5.1) presented statistically more often with ICH in multivariate regression. Small size (HR 1.8, 95% CI 1.09-3, p = 0.022) and exclusively deep venous drainage (HR 2.2, 95% CI 1.2-4, p = 0.009) were independent predictors for ICH, in time-dependent birth-to-diagnosis analysis. After shifting the birth-to-diagnosis curve by 10 years, unique arterial feeder demonstrated a positive correlation with ICH presentation as well. Conclusions: Small AVMs, those with exclusively deep venous drainage, unique arterial feeder or deep location may pose higher hemorrhagic risks for the patient, and therapeutic strategies should be tailored accordingly. When managing unruptured brain AVMs, it is important to consider the risk of developing seizures, in addition to the lifelong risk of hemorrhage, in determining the optimal treatment approach for each patient.

Benchmarking computational variant effect predictors by their ability to infer human traits.

BACKGROUND: Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns of circularity and bias have limited previous methods for evaluating and comparing predictors. Population-level cohorts of genotyped and phenotyped participants that have not been used in predictor training can facilitate an unbiased benchmarking of available methods. Using a curated set of human gene-trait associations with a reported rare-variant burden association, we evaluate the correlations of 24 computational variant effect predictors with associated human traits in the UK Biobank and All of Us cohorts. RESULTS: AlphaMissense outperformed all other predictors in inferring human traits based on rare missense variants in UK Biobank and All of Us participants. The overall rankings of computational variant effect predictors in these two cohorts showed a significant positive correlation. CONCLUSION: We describe a method to assess computational variant effect predictors that sidesteps the limitations of previous evaluations. This approach is generalizable to future predictors and could continue to inform predictor choice for personal and clinical genetics.

Investigating the stability of aromatic carboxylic acids in hydrated magnesium sulfate under UV irradiation to assist detection of organics on Mars.

The Scanning Habitable Environments with Raman and Luminescence for Organics and Chemicals (SHERLOC) instrument onboard the Mars 2020 Perseverance rover detected so far some of the most intense fluorescence signals in association with sulfates analyzing abraded patches of rocks at Jezero crater, Mars. To assess the plausibility of an organic origin of these signals, it is key to understand if organics can survive exposure to ambient Martian UV after exposure by the Perseverance abrasion tool and prior to analysis by SHERLOC. In this work, we investigated the stability of organo-sulfate assemblages under Martian-like UV irradiation and we observed that the spectroscopic features of phthalic and mellitic acid embedded into hydrated magnesium sulfate do not change for UV exposures corresponding to at least 48 Martian sols and, thus, should still be detectable in fluorescence when the SHERLOC analysis takes place, thanks to the photoprotective properties of magnesium sulfate. In addition, different photoproduct bands diagnostic of the parent carboxylic acid molecules could be observed. The photoprotective behavior of hydrated magnesium sulfate corroborates the hypothesis that sulfates might have played a key role in the preservation of organics on Mars, and that the fluorescence signals detected by SHERLOC in association with sulfates could potentially arise from organic compounds.

Direct 3D-printed ring-resonator photonic circuit on a dual core fiber tip for remote sensing applications.

On-chip optical sensors using ring- and disk-resonators have many potential sensing applications, yet robust and efficient fiber-to-chip coupling and the differing form factor between the two pose deployment challenges. To resolve this, we 3D-printed a ring-resonator onto the tip of a dual-core fiber and demonstrate its use as a remote temperature sensor. The fiber-tip optical circuit is fabricated using direct laser writing (DLW) with two-photon absorption photopolymer material IP-Dip, forming micrometer-scale waveguide cores having a refractive index of 1.53 with a surrounding air cladding. We connect the two-fiber cores by a printed bus-waveguide, utilizing total internal reflection mirrors, allowing light launched into one core to be guided back to the other core. Furthermore, a DLW printed racetrack resonator evanescently coupled to the bus waveguide (Q ∼ 3000) imposes spectral dips on resonance wavelengths. Light sent down into one core is interrogated upon return from the second core, all from the distal end of the sensor. When the sensing end's temperature is varied, we find a sensitivity of 78 pm/K, due to the polymer's thermo-optic index variation. The ring-resonator could be functionalized for other sensing applications.