When is prostate cancer really cancer?

Prostate cancer (PC) is a major cause of cancer-related deaths worldwide, with far more diagnoses than deaths annually. Recent discussions have challenged whether Grade Group 1 (GG1) PC should be labeled "cancer" due to its indolent nature. To address this question, an international symposium convened stakeholders from various fields. We summarize key discussion points: autopsy studies reveal GG1 is so common in aging males as to be perhaps a normal aspect of aging. Pure GG1 has no capacity to metastasize. Modern diagnostic pathways focus on detecting higher-grade disease, explicitly omitting biopsy if GG 2 or higher is not suspected, so GG1 has effectively become an "incidentaloma." Recent spatial transcriptomics of prostate sections identifies a continuum of genomic changes-including alterations characteristic of malignancy in histologically normal regions, so the designation of cancer based entirely on conventional pathology findings increasingly seems arbitrary at least to an extent. Pathologists discussed heterogeneity and diagnostic challenges, suggesting "acinar neoplasm" as one possible alternative label. GG1 should not be considered "normal," and absolutely requires ongoing active surveillance; whether patients would adhere to surveillance absent a cancer diagnosis is unknown. Patient perspectives highlighted the adverse effects of overtreatment and the burden of a cancer diagnosis. The anticipated impact on screening and treatment varies across health-care systems, but many believe public health would on balance greatly improve if GG1-along with lesions in other organs with no capacity to cause symptoms or threaten life-were labeled something other than "cancer." Ultimately, our goal is to reduce PC mortality while minimizing harms associated with both overdiagnosis and overtreatment.

Inflammation and aging-related disease: A transdisciplinary inflammaging framework.

Inflammaging, a state of chronic, progressive low-grade inflammation during aging, is associated with several adverse clinical outcomes, including frailty, disability, and death. Chronic inflammation is a hallmark of aging and is linked to the pathogenesis of many aging-related diseases. Anti-inflammatory therapies are also increasingly being studied as potential anti-aging treatments, and clinical trials have shown benefits in selected aging-related diseases. Despite promising advances, significant gaps remain in defining, measuring, treating, and integrating inflammaging into clinical geroscience research. The Clin-STAR Inflammation Research Interest Group was formed by a group of transdisciplinary clinician-scientists with the goal of advancing inflammaging-related clinical research and improving patient-centered care for older adults. Here, we integrate insights from nine medical subspecialties to illustrate the widespread impact of inflammaging on diseases linked to aging, highlighting the extensive opportunities for targeted interventions. We then propose a transdisciplinary approach to enhance understanding and treatment of inflammaging that aims to improve comprehensive care for our aging patients.

Offset Considerations in Total Hip Arthroplasty.

To perform total hip arthroplasty (THA) successfully, a surgeon must be able to place the implants in a position that will restore and duplicate the patient's baseline anatomy and soft-tissue tension. One of the critical factors is the restoration of femoral offset. It is the goal of this review to precisely define measurement of offset in THA, describe its role in hip joint biomechanics, outline alterations that can be performed intraoperatively, and explain how it can create potential pathologic states. If there is a lack of offset restoration, it can result in a host of complications, including bony impingement with pain, edge loading or prosthetic joint instability, and alterations in the muscle length-tension relationship leading to reduced motor performance. Excessive femoral offset can increase hip abductor muscle and iliotibial band tension resulting in greater trochanteric pain regardless of the surgical approach. The purpose of this review was to analyze intraoperative surgical factors, choice of prosthetic implant type and position that are required to maximize stability, and dynamic motor performance after THA.

Association of circulating fatty acids with cardiovascular disease risk: Analysis of individual-level data in three large prospective cohorts and updated meta-analysis.

BACKGROUND: Associations of saturated and unsaturated fatty acids (FAs) with cardiovascular disease (CVD) remain controversial. We therefore aimed to investigate the prospective associations of objectively measured FAs with CVD, including incident coronary heart disease (CHD) and stroke, as well as CVD mortality. METHODS: Circulating FA concentrations expressed as the percentage of total FAs were assayed in 172,891 participants without prior vascular disease at baseline from the European Prospective Investigation into Cancer and Nutrition-CVD (EPIC-CVD) (7,343 CHD; 6,499 stroke), UK Biobank (1,825; 1,474), and INTERVAL (285; 209) cohort studies. Hazard ratio (HR) per 1-standard deviation (SD) higher FA concentrations was estimated using Cox regression models and pooled by random-effects meta-analysis. Systematic reviews with meta-analysis published by 6 May 2023 on associations between FAs and CVDs were systematically searched and updated meta-analyses using random-effects model were conducted. Evidence from randomized controlled trials (RCTs) was also summarized. RESULTS: Higher concentrations of total saturated FAs (SFAs) were associated with higher cardiovascular risks in the combined analysis, with differential findings noted for SFA subtypes in further analysis restricted to EPIC-CVD: positive associations for even-chain SFA [HR for CHD 1.24 (95% CI: 1.18-1.32); stroke 1.23 (1.10-1.38)] and negative associations for odd-chain [0.82 (0.76-0.87); 0.73 (0.67-0.78)] and longer-chain [0.95 (0.80-1.12); 0.84 (0.72-0.99)] SFA. In the combined analysis, total n-3 polyunsaturated FA (PUFA) [0.91 (0.85-0.97)], including docosahexaenoic acid (DHA) [0.91 (0.84-0.98)], was negatively associated with incident CHD risk. Similarly, total n-6 PUFA [0.94 (0.91-0.98)], including linoleic acid (LA) [0.89 (0.83-0.95)], was negatively associated with incident stroke risk. By contrast, more detailed analyses in EPIC-CVD revealed that several downstream n-6 PUFAs of LA were positively associated with CHD risk. Updated meta-analyses of 37 FAs including 49 non-overlapping studies, involving between 7,787 to 22,802 CHD and 6,499 to 14,221 stroke cases, showed broadly similar results as our combined empirical analysis and further suggested significant inverse associations of individual long-chain n-3 PUFAs and LA on both CHD and stroke. The findings of long-chain n-3 PUFAs were consistent with those from published RCTs on CHD despite insufficient evidence in monotherapy, while RCT evidence remained unclear for the rest of the explored FAs. CONCLUSIONS: Our study provides an overview of the most recent evidence on the associations between objectively measured FAs and CVD outcomes. Collectively, the data reveals notable differences in associations by SFA subtypes and calls for further studies, especially RCTs, to explore these links.

We conducted the largest analysis to date to examine the association of circulating saturated and unsaturated fatty acids, either individually or in combination, with incident cardiovascular disease outcomes. Our study reinforces that cardiovascular disease associations vary importantly across saturated fatty acid subtypes, with positive associations for even-chain saturated fatty acids but negative associations for odd-chain and longer-chain saturated fatty acids, challenging the current broad dietary recommendations focused solely on lowering overall saturated fat intake.Marine-derived n-3 polyunsaturated fatty acids and linoleic acid were negatively associated with both coronary heart disease and stroke, except for eicosapentaenoic acid which was null for stroke. It supports the potential cardiovascular benefits of individual marine-derived n-3 polyunsaturated fatty acids and linoleic acid and provides evidence to help inform currently inconsistent and insufficient trial evidence.

Untargeted Metabolomics for Inborn Errors of Metabolism: Development and Evaluation of a Sustainable Reference Material for Correcting Inter-Batch Variability.

BACKGROUND: Untargeted metabolomics has shown promise in expanding screening and diagnostic capabilities for inborn errors of metabolism (IEMs). However, inter-batch variability remains a major barrier to its implementation in the clinical laboratory, despite attempts to address this through normalization techniques. We have developed a sustainable, matrix-matched reference material (RM) using the iterative batch averaging method (IBAT) to correct inter-batch variability in liquid chromatography-high-resolution mass spectrometry-based untargeted metabolomics for IEM screening. METHODS: The RM was created using pooled batches of remnant plasma specimens. The batch size, number of batch iterations per RM, and stability compared to a conventional pool of specimens were determined. The effectiveness of the RM for correcting inter-batch variability in routine screening was evaluated using plasma collected from a cohort of phenylketonuria (PKU) patients. RESULTS: The RM exhibited lower metabolite variability between iterations over time compared to metabolites from individual batches or individual specimens used for its creation. In addition, the mean variation across amino acid (n = 19) concentrations over 12 weeks was lower for the RM (CVtotal = 8.8%; range 4.7%-25.3%) compared to the specimen pool (CVtotal = 24.6%; range 9.0%-108.3%). When utilized in IEM screening, RM normalization minimized unwanted inter-batch variation and enabled the correct classification of 30 PKU patients analyzed 1 month apart from 146 non-PKU controls. CONCLUSIONS: Our RM minimizes inter-batch variability in untargeted metabolomics and demonstrated its potential for routine IEM screening in a cohort of PKU patients. It provides a practical and sustainable solution for data normalization in untargeted metabolomics for clinical laboratories.

The common, VTE-protective, G haplotype of F5 increases factor V-short, TFPI function, and risk of bleeding.

The G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Even though seven percent of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA-seq data from 4,651 blood donors in the INTERVAL study we detected a rare excision event at the FV-short splice sites in 5% of F5-G/Gs as compared with 2.16% of homozygotes for the F5 reference sequence (F5-ref) (p=0.003). Highly elevated (~10-fold) FV-short, an FV isoform lacking most of the B-domain, has been linked with increased tissue factor inhibitor alpha (TFPIα) levels in rare hemorrhagic diathesis including East Texas Bleeding Disorder. To ascertain whether the enhanced FV-short splicing seen in F5-G/G INTERVAL participants translated to increased plasma FV-short levels we analyzed plasma samples from 7 F5-G/G and 13 F5-ref individuals in a recall-by-genotype study. A ~2.2-fold higher amount of FV-short was found in a plasma pool from F5-G/G participants as compared with F5-refs (p=0.029), but no difference in total FV levels. Whilst no significant difference in TFPI levels were found, F5-G/Gs showed a ~1.4-fold TFPI-dependent increase in lag time to thrombin generation compared to F5-refs (p=0.0085). Finally, in an analysis of 117,699 UK Biobank participants we discovered that, while being protective against VTE, the G haplotype also confers an increase in bleeding episodes (p=0.011). Our study provides evidence that the effect of the common G haplotype is mediated by the FV-short/TFPI pathway.

Considerations on the basis of medical reasoning for the use in AI applications.

This study discusses the integration of artificial intelligence (AI) and machine learning (ML) in medical reasoning and decision-making, with a focus on the challenges and opportunities associated with the massive consumption of data required for training AI systems, and contrasts this with the limited data typically available to medical practitioners. We advocate for a balanced approach that includes small data and emphasize the importance of maintaining the art of clinical reasoning amid technological advancements. Finally, we highlight the potential of multidisciplinary research in addressing the complexities of medical reasoning and suggest the necessity of careful abstraction and conceptual modeling in AI applications.

Long-Term Outcomes After Septal Reduction Therapies in Obstructive Hypertrophic Cardiomyopathy: Insights From the SHARE Registry.

BACKGROUND: Septal reduction therapy (SRT) provides substantial symptomatic improvement in patients with obstructive hypertrophic cardiomyopathy (HCM). However, long-term disease course after SRT and predictors of adverse outcomes have not been systematically examined. METHODS: Data from 13 high clinical volume HCM centers from the international SHARE (Sarcomeric Human Cardiomyopathy Registry) were analyzed. Patients were followed from the time of SRT until last follow-up or occurrence of heart failure (HF) composite outcome (cardiac transplantation, implantation of a left ventricular assist device, left ventricular ejection fraction <35%, development of New York Heart Association class III or IV symptoms), ventricular arrhythmias composite outcome (sudden cardiac death, resuscitated cardiac arrest, or appropriate implantable cardioverter defibrillator therapy), or HCM-related death. Cox proportional hazards models were used to identify predictors of outcome. RESULTS: Of the 10 225 patients in SHARE, 1832 (18%; 968 [53%] male) underwent SRT, including 455 (25%) with alcohol septal ablation and 1377 (75%) with septal myectomy. The periprocedural 30-day mortality rate was 0.4% (8 of 1832) and 1499 of 1565 (92%) had a maximal left ventricular outflow tract gradient <50 mm Hg at 1 year. After 6.8 years (range, 3.4-9.8 years; 12 565 person-years) from SRT, 77 (4%) experienced HCM-related death (0.6% per year), 236 (13%) a composite HF outcome (1.9% per year), and 87 (5%) a composite ventricular arrhythmia outcome (0.7% per year). Among adults, older age at SRT was associated with a higher incidence of HCM death (hazard ratio, 1.22 [95 CI, 1.1-1.3]; P<0.01) and the HF composite (hazard ratio, 1.14 [95 CI, 1.1-1.2] per 5-year increase; P<0.01) in a multivariable model. Female patients also had a higher risk of the HF composite after SRT (hazard ratio, 1.4 [95 CI, 1.1-1.8]; P<0.01). De novo atrial fibrillation occurred after SRT in 387 patients (21%). Among pediatric patients followed for a median of 13 years after SRT, 26 of 343 (16%) developed the HF composite outcome, despite 96% being free of recurrent left ventricular outflow tract obstruction. CONCLUSIONS: Successful short- and long-term relief of outflow tract obstruction was observed in experienced multidisciplinary HCM centers. A subset of patients progressed to develop HF, but event-free survival at 10 years was 83% and ventricular arrhythmias were rare. Older age, female sex, and SRT during childhood were associated with a greater risk of developing HF.

Visceral adiposity in postmenopausal women is associated with a pro-inflammatory gut microbiome and immunogenic metabolic endotoxemia.

BACKGROUND: Obesity, and in particular abdominal obesity, is associated with an increased risk of developing a variety of chronic diseases. Obesity, aging, and menopause are each associated with differential shifts in the gut microbiome. Obesity causes chronic low-grade inflammation due to increased lipopolysaccharide (LPS) levels which is termed "metabolic endotoxemia." We examined the association of visceral adiposity tissue (VAT) area, circulating endotoxemia markers, and the gut bacterial microbiome in a cohort of aged postmenopausal women. METHODS: Fifty postmenopausal women (mean age 78.8 ± 5.3 years) who had existing adipose measurements via dual x-ray absorptiometry (DXA) were selected from the extremes of VAT: n = 25 with low VAT area (45.6 ± 12.5 cm2) and n = 25 with high VAT area (177.5 ± 31.3 cm2). Dietary intake used to estimate the Healthy Eating Index (HEI) score was assessed with a food frequency questionnaire. Plasma LPS, LPS-binding protein (LBP), anti-LPS antibodies, anti-flagellin antibodies, and anti-lipoteichoic acid (LTA) antibodies were measured by ELISA. Metagenomic sequencing was performed on fecal DNA. Female C57BL/6 mice consuming a high-fat or low-fat diet were treated with 0.4 mg/kg diet-derived fecal isolated LPS modeling metabolic endotoxemia, and metabolic outcomes were measured after 6 weeks. RESULTS: Women in the high VAT group showed increased Proteobacteria abundance and a lower Firmicutes/Bacteroidetes ratio. Plasma LBP concentration was positively associated with VAT area. Plasma anti-LPS, anti-LTA, and anti-flagellin IgA antibodies were significantly correlated with adiposity measurements. Women with high VAT showed significantly elevated LPS-expressing bacteria compared to low VAT women. Gut bacterial species that showed significant associations with both adiposity and inflammation (anti-LPS IgA and LBP) were Proteobacteria (Escherichia coli, Shigella spp., and Klebsiella spp.) and Veillonella atypica. Healthy eating index (HEI) scores negatively correlated with % body fat and anti-LPS IgA antibodies levels. Preclinical murine model showed that high-fat diet-fed mice administered a low-fat diet fecal-derived LPS displayed reduced body weight, decreased % body fat, and improved glucose tolerance test parameters when compared with saline-injected or high-fat diet fecal-derived LPS-treated groups consuming a high-fat diet. CONCLUSIONS: Increased VAT in postmenopausal women is associated with elevated gut Proteobacteria abundance and immunogenic metabolic endotoxemia markers. Low-fat diet-derived fecal-isolated LPS improved metabolic parameters in high-fat diet-fed mice giving mechanistic insights into potential pro-health signaling mediated by under-acylated LPS isoforms. Video Abstract.

Serum per- and polyfluoroalkyl substance (PFAS) levels and health-related biomarkers in a pilot study of skiers in New England.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS), synthetic chemicals with adverse health effects, are used extensively in consumer products. Ski waxes, applied to the base of skis, contain up to 100% PFAS by mass, but exposure and health effects are poorly characterized. OBJECTIVES: Our objectives were to quantify serum PFAS concentrations among skiers and explore associations with reported ski wax use and biomarkers of cardiometabolic, thyroid, and immune health. METHODS: We recruited 30 active adult skiers to provide non-fasting blood samples and complete questionnaires. We quantified 18 PFAS using mass spectrometry, and measured serum lipids, thyroid hormones, and immunoglobulins. We explored associations of individual and aggregate measures of serum PFAS with wax use indicators and health biomarkers using multivariable regression models, adjusted for age and gender identity. RESULTS: Nine PFAS (PFBS, PFHpS, PFHxS, Sm-PFOS, n-PFOS, PFDA, PFNA, PFUnDA, n-PFOA) were detected in 100% of participants, and MeFOSAA in 93%. Compared to NHANES, median serum concentrations (ng/ml) were similar, but higher in coaches (e.g., PFOAall: 1.1, PFOAcoaches: 2.7, PFOANHANES: 1.2; PFNAall: 0.5, PFNAcoaches: 1.7, PFNANHANES: 0.4). Factors reflecting wax exposure were positively associated with PFAS: e.g., >10 years as a snow sport athlete, compared to <10 years, was associated with 3.2 (95% CI: 0.7, 5.6) ng/ml higher aggregate PFAS, as defined by National Academies of Science, Engineering, and Medicine (NASEM). An IQR (6.3 ng/ml) increase in NASEM PFAS was associated with 32.1 (95% CI: 7.0, 57.2), 35.5 (13.5, 57.5), and 12.8 (0.6, 25.1) mg/dl higher total cholesterol, LDL-C, and sdLDL-C, respectively. DISCUSSION: Our study provides early evidence that recreational skiers, particularly coaches, are exposed to PFAS through ski wax. Several PFAS were associated with higher serum lipids among these physically active adults. Interventions to remove PFAS from fluorinated wax could decrease direct exposure to skiers and reduce PFAS release into the environment.

Sparse-Coding Variational Autoencoders.

The sparse coding model posits that the visual system has evolved to efficiently code natural stimuli using a sparse set of features from an overcomplete dictionary. The original sparse coding model suffered from two key limitations, however: (1) computing the neural response to an image patch required minimizing a nonlinear objective function via recurrent dynamics and (2) fitting relied on approximate inference methods that ignored uncertainty. Although subsequent work has developed several methods to overcome these obstacles, we propose a novel solution inspired by the variational autoencoder (VAE) framework. We introduce the sparse coding variational autoencoder (SVAE), which augments the sparse coding model with a probabilistic recognition model parameterized by a deep neural network. This recognition model provides a neurally plausible feedforward implementation for the mapping from image patches to neural activities and enables a principled method for fitting the sparse coding model to data via maximization of the evidence lower bound (ELBO). The SVAE differs from standard VAEs in three key respects: the latent representation is overcomplete (there are more latent dimensions than image pixels), the prior is sparse or heavy-tailed instead of gaussian, and the decoder network is a linear projection instead of a deep network. We fit the SVAE to natural image data under different assumed prior distributions and show that it obtains higher test performance than previous fitting methods. Finally, we examine the response properties of the recognition network and show that it captures important nonlinear properties of neurons in the early visual pathway.

A multispecific antibody against SARS-CoV-2 prevents immune escape in vitro and confers prophylactic protection in vivo.

Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.

Surgically treated brain metastases of gastric origin: a case series and systematic review.

BACKGROUND: The incidence of brain metastases from gastric origin is less than 1% in those with primary gastric cancer. Given this exceedingly rare presentation, there is limited literature describing the outcomes of their neurosurgical treatment. We wish to identify the role of surgical intervention for brain lesions in metastatic gastric cancer via institutional case series and systematic review. METHODS: This study was divided into two sections: (1) a retrospective, single-center patient series assessing outcomes of neurosurgical treatment modalities in patients with malignancy arising from the stomach with brain metastases and (2) a systematic review abiding by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines between the years of 1980 and 2021 assessing outcomes of patients with primary stomach cancer with metastasis to the brain treated with surgery. RESULTS: Four patients with gastric brain metastases were treated at our institution, and 16 patients were identified in literature from a total of 9 studies and case reports. The mean age at the time of stomach cancer diagnosis was 57.3 years, with a mean time to brain metastases of 14.8 months. The primary gastric cancer was most commonly adenocarcinoma (70%). Patients most presented with single lesions (58%) and were treated with multimodal neurosurgical intervention (65%). Mean overall survival following neurosurgery was 12.45 months. CONCLUSION: Brain metastases from gastric origin are extremely rare. Surgical resection of metastatic brain lesions should be considered as a treatment modality in surgical candidates. Future attention should be given to the effect of adjuvant therapies and surgical techniques on survival and quality of life.

Viscous terahertz photoconductivity of hydrodynamic electrons in graphene.

Light incident upon materials can induce changes in their electrical conductivity, a phenomenon referred to as photoresistance. In semiconductors, the photoresistance is negative, as light-induced promotion of electrons across the bandgap enhances the number of charge carriers participating in transport. In superconductors and normal metals, the photoresistance is positive because of the destruction of the superconducting state and enhanced momentum-relaxing scattering, respectively. Here we report a qualitative deviation from the standard behaviour in doped metallic graphene. We show that Dirac electrons exposed to continuous-wave terahertz (THz) radiation can be thermally decoupled from the lattice, which activates hydrodynamic electron transport. In this regime, the resistance of graphene constrictions experiences a decrease caused by the THz-driven superballistic flow of correlated electrons. We analyse the dependencies of the negative photoresistance on the carrier density, and the radiation power, and show that our superballistic devices operate as sensitive phonon-cooled bolometers and can thus offer, in principle, a picosecond-scale response time. Beyond their fundamental implications, our findings underscore the practicality of electron hydrodynamics in designing ultra-fast THz sensors and electron thermometers.

Update and validation of the Beliefs about Losing Control Inventory-II (BALCI-II): a psychometric investigation.

The Beliefs about Losing Control Inventory (BALCI) was developed to assess negative beliefs about losing control in obsessive-compulsive disorder (OCD). Since its creation, research and theoretical work support negative beliefs about losing control as a potential transdiagnostic construct. The present study revised and expanded the original BALCI to be more inclusive of control-related concerns beyond those that would be expected in OCD (e.g. concerns about losing control over how one comes across to others in social anxiety disorder; SAD). Undergraduate students (N = 440) completed a questionnaire battery including the BALCI-II item pool. An exploratory factor analysis of the 32-item BALCI-II supported a four-factor solution. Three of the identified factors capture the feared consequences of losing control: 1) overwhelming emotions, 2) dangerous behaviour, and 3) madness. The fourth factor captures inflated beliefs about probability/severity of those losses. The BALCI-II was found to have good convergent and divergent validity, good to excellent internal, and retest reliability and was shown to have predictive utility in both OCD and SAD, above and beyond existing disorder-specific maladaptive belief domains. Results suggest the BALCI-II is an improvement over the previous version and supports the relevance of these beliefs beyond OCD.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS) and immune effector cell-associated hematotoxicity (ICAHT), predisposing for life-threatening infections. METHODS: This retrospective observational study examined a total of 129 patients with RRMM who had received idecabtagene vicleucel (ide-cel) at two major myeloma centers in Germany and one center in the USA to assess the Endothelial Activation and Stress Index (EASIX) as a risk marker for an unfavorable clinical course and outcome after CAR T-cell therapy. EASIX is calculated by lactate dehydrogenase (U/L) × creatinine (mg/dL) / platelets (109 cells/L) and was determined before lymphodepletion (baseline) and at the day of CAR T-cell infusion (day 0). The analysis was extended to EASIX derivatives and the CAR-HEMATOTOX score. RESULTS: An elevated baseline EASIX (>median) was identified as a risk marker for severe late ICAHT, manifesting with an impaired hematopoietic reconstitution and pronounced cytopenias during the late post-CAR-T period. Patients with high EASIX levels (>upper quartile) were particularly at risk, as evidenced by an increased rate of an aplastic phenotype of neutrophil recovery, severe late-onset infections and ICANS. Finally, we found associations between baseline EASIX and an inferior progression-free and overall survival. Moreover, the EASIX at day 0 also demonstrated potential to serve as a risk marker for post-CAR-T complications and adverse outcomes. CONCLUSIONS: In conclusion, EASIX aids in risk stratification at clinically relevant time points prior to CAR T-cell therapy with ide-cel. Increased EASIX levels might help clinicians to identify vulnerable patients to adapt peri-CAR-T management at an early stage.

A corpus of GA4GH phenopackets: case-level phenotyping for genomic diagnostics and discovery.

The Global Alliance for Genomics and Health (GA4GH) Phenopacket Schema was released in 2022 and approved by ISO as a standard for sharing clinical and genomic information about an individual, including phenotypic descriptions, numerical measurements, genetic information, diagnoses, and treatments. A phenopacket can be used as an input file for software that supports phenotype-driven genomic diagnostics and for algorithms that facilitate patient classification and stratification for identifying new diseases and treatments. There has been a great need for a collection of phenopackets to test software pipelines and algorithms. Here, we present Phenopacket Store. Version 0.1.19 of Phenopacket Store includes 6668 phenopackets representing 475 Mendelian and chromosomal diseases associated with 423 genes and 3834 unique pathogenic alleles curated from 959 different publications. This represents the first large-scale collection of case-level, standardized phenotypic information derived from case reports in the literature with detailed descriptions of the clinical data and will be useful for many purposes, including the development and testing of software for prioritizing genes and diseases in diagnostic genomics, machine learning analysis of clinical phenotype data, patient stratification, and genotype-phenotype correlations. This corpus also provides best-practice examples for curating literature-derived data using the GA4GH Phenopacket Schema.

Randomized Immunogenicity Trial Comparing 2019-2020 Recombinant and Egg-Based Influenza Vaccines among Frequently Vaccinated Healthcare Personnel in Israel.

BACKGROUND: Trivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016-2019. We conducted a randomized immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants. METHODS: From October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titers against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titer (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 versus ≤2). RESULTS: Among 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titers than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0). CONCLUSIONS: RIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4.

Rare variant contribution to the heritability of coronary artery disease.

Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Time domain characterization of nonstationary low-Mach number aeroacoustic sources using principal component analysis.

This paper presents the use of principal component analysis (PCA) for time domain microphone array denoising to characterize an impulsive aeroacoustic source, which is illustrated with the aeroacoustic emission caused by a vortex ring/edge interaction. Prior studies have used signal processing approaches that required assumptions about the source directivity or user intervention at low signal-to-noise ratio (SNR) conditions. In this context, PCA, a matrix decomposition tool which identifies the most common features across an ensemble of observations, provides a data-driven (hands-off) approach to signal processing. For microphone array time series, particular attention is paid to the temporal alignment of the signals to facilitate PCA. A time domain approach is necessary when sources are impulsive and nonstationary. Two such signal arrangements are discussed in this work. Results from this method are in good agreement with theory, validated by prior results using an ensemble averaging approach requiring user support. Furthermore, the results of this method are improved when compared to the ensemble averaging approach without user intervention. A SNR limit is identified where PCA becomes less effective for the vortex/edge interaction problem. This SNR limit is intended to aid in the design of similar future experiments.