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Abstract Background: Neonatal herpes simplex virus (HSV) infection is life-threatening, with a mortality of up to 70–80% when disseminated, often due to vague symptoms and delayed treatment. Neonatal screening using dried blood spot (DBS) samples is among the most impactful preventative health measures ever implemented, but screening for HSV has not been investigated. Methods: We investigated high throughput multiplexed proteomics on DBS samples collected on days 2–3 of life from a nationwide cohort of neonates with HSV infection (n = 53) and matched controls. We measured 2941 proteins using the Olink Explore 3072 panels and proximity extension assays, followed by differential protein expression by Analysis of Variance with post-hoc correction and functional annotation. Results: Here, we show distinct protein profiles in neonates with disseminated HSV disease, with differences in 20 proteins compared to controls. These proteins are associated with innate and adaptive immune responses and cytokine activation. Conclusions: Our findings indicate the potential of neonatal screening for disseminated HSV disease to ensure early treatment and reduce the high mortality.

Abstract Consumer purchase data (CPD) is a promising instrument to assess the impact of purchases on health, but is limited by the need for manual scanning, a lack of access to data from multiple retailers, and limited information on product data and health outcomes. Here we describe the My Purchases cohort, a web-app enabled, prospective collection of CPD, covering several large retail chains in Denmark, that enables linkage to health outcomes. The cohort included 459 participants as of July 03, 2023. Up to eight years of CPD have been collected, with 2,225,010 products purchased, comprising 223,440 unique products. We matched 88.5% of all products by product name or item number to one generic food database and three product databases. Combined, the databases enable analysis of key exposures such as nutrients, ingredients, or additives. We found that increasing the number of retailers that provide CPD for each consumer improved the stability of individual CPD profiles and when we compared kilojoule information from generic and specific product matches, we found a median modified relative difference of 0.23. Combined with extensive product databases and health outcomes, CPD could provide the basis for extensive investigations of how what we buy affects our health.

Abstract Background Next-generation sequencing (NGS) based population screening holds great promise for disease prevention and earlier diagnosis, but the costs associated with screening millions of humans remain prohibitive. New methods for population genetic testing that lower the costs of NGS without compromising diagnostic power are needed. Methods We developed double batched sequencing where DNA samples are batch-sequenced twice — directly pinpointing individuals with rare variants. We sequenced batches of at-birth blood spot DNA using a commercial 113-gene panel in an explorative (n = 100) and a validation (n = 100) cohort of children who went on to develop pediatric cancers. All results were benchmarked against individual whole genome sequencing data. Results We demonstrated fully replicable detection of cancer-causing germline variants, with positive and negative predictive values of 100% (95% CI, 0.91–1.00 and 95% CI, 0.98–1.00, respectively). Pathogenic and clinically actionable variants were detected in RB1, TP53, BRCA2, APC, and 19 other genes. Analyses of larger batches indicated that our approach is highly scalable, yielding more than 95% cost reduction or less than 3 cents per gene screened for rare disease-causing mutations. We also show that double batched sequencing could cost-effectively prevent childhood cancer deaths through broad genomic testing. Conclusions Our ultracheap genetic diagnostic method, which uses existing sequencing hardware and standard newborn blood spots, should readily open up opportunities for population-wide risk stratification using genetic screening across many fields of clinical genetics and genomics.

Предложен подход к техническому диагностированию сложных технических систем по результатам обработки телеметрической информации внешней системой контроля и диагностирования с использованием гибридных сетевых структур. Рассмотрен принцип построения диагностических комплексов сложных технических систем, обеспечивающий автоматизацию процесса технического диагностирования и основанный на использовании при обработке телеметрической информации моделей в виде гибридных сетевых структур, включающих многослойные нейронные сети и дискретные байесовские сети со стохастическим обучением. Разработаны модель изменения параметров технического состояния сложных технических систем на основе многослойных нейронных сетей, позволяющая сформировать вероятностную оценку отнесения текущей ситуации функционирования сложной технической системы к множеству рассмотренных ситуаций функционирования по отдельным телеметрируемым параметрам, и многоуровневая иерархическая модель технического диагностирования сложных технических систем на основе дискретной байесовской сети со стохастическим обучением, позволяющая агрегировать полученную от нейросетевых моделей информацию и распознавать текущую ситуацию функционирования сложной технической системы. В условиях нештатных ситуаций функционирования сложной технической системы по результатам обработки телеметрической информации локализуются неисправные функциональные узлы и формируется объяснение причины возникновения нештатной ситуации. Детализированы этапы реализации технического диагностирования сложных технических систем с использованием предложенных гибридных сетевых структур при обработке телеметрической информации. Представлен пример использования разработанного подхода к решению задач технического диагностирования бортовой системы космического аппарата. Показаны преимущества предлагаемого подхода к техническому диагностированию сложных технических систем в сравнении с традиционным подходом, основанном на анализе принадлежности значений телеметрируемых параметров заданным допускам.

Abstract Spermine oxidase (SMOX) catalyzes the oxidation of spermine to spermidine. Observational studies have reported SMOX as a source of reactive oxygen species associated with cancer, implying that inhibition of SMOX could be a target for chemoprevention. Here we test causality of SMOX levels with cancer risk using a Mendelian randomization analysis. We performed a GWAS of spermidine/spermine ratio to identify genetic variants associated with regulation of SMOX activity. Replication analysis was performed in two datasets of SMOX gene expression. We then did a Mendelian randomization analysis by testing the association between the SMOX genetic instrument and neuroblastoma, gastric, lung, breast, prostate, and colorectal cancers using GWAS summary statistics. GWAS of spermidine/spermine ratio identified SMOX locus (P = 1.34 × 10–49) explaining 32% of the variance. The lead SNP rs1741315 was also associated with SMOX gene expression in newborns (P = 8.48 × 10–28) and adults (P = 2.748 × 10–8) explaining 37% and 6% of the variance, respectively. Genetically determined SMOX activity was not associated with neuroblastoma, gastric, lung, breast, prostate nor colorectal cancer (P > 0.05). A PheWAS of rs1741315 did not reveal any relevant associations. Common genetic variation in the SMOX gene was strongly associated with SMOX activity in newborns, and less strongly in adults. Genetic down-regulation of SMOX was not significantly associated with lower odds of neuroblastoma, gastric, lung, breast, prostate and colorectal cancer. These results may inform studies of SMOX inhibition as a target for chemoprevention.

INTRODUCTION:Infusion of glyceryl trinitrate (GTN), a donor of nitric oxide, induces immediate headache in humans that in migraineurs is followed by a delayed migraine attack. In order to achieve increased knowledge of mechanisms activated during GTN-infusion this present study aims to investigate transcriptional responses to GTN-infusion in the rat trigeminal ganglia. METHODS:Rats were infused with GTN or vehicle and trigeminal ganglia were isolated either 30 or 90 minutes post infusion. RNA sequencing was used to investigate transcriptomic changes in response to the treatment. Furthermore, we developed a novel method for Gene Set Analysis Of Variance (GSANOVA) to identify gene sets associated with transcriptional changes across time. RESULTS:15 genes displayed significant changes in transcription levels in response to GTN-infusion. Ten of these genes showed either sustained up- or down-regulation in the 90-minute period after infusion. The GSANOVA analysis demonstrate enrichment of pathways pointing towards an increase in immune response, signal transduction, and neuroplasticity in response to GTN-infusion. Future functional in-depth studies of these mechanisms are expected to increase our understanding of migraine pathogenesis.