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In the past four decades, reports of an unusual vascular disease affecting young and otherwise healthy endurance athletes have begun to emerge. This rare entity has been coined as external iliac artery endofibrosis (EIAE). It has been primarily described in high-level competitive cyclists, suggesting a biomechanical etiology given the repetitive flexion and extension of the hip joint associated with cycling.1,2 Patients present with symptoms of claudication at peak levels of exertion, levels not usually achievable by the untrained individual. Lesions are predominantly isolated to the external iliac artery (EIA), and histologic examination reveals endothelial thickening and fibrosis without evidence of atherosclerosis.1–5 Cases of EIAE have been overwhelmingly described in male athletes, with a paucity of reports in females.2,3 We herein describe two cases of elite female athletes afflicted by EIAE and review the current literature pertaining to this entity in females. Both patients consented to publication of their case details and images.

Objective: Epicardial adipose tissue (EAT) is implicated in the pathogenesis and progression of coronary artery disease (CAD). Limited data exists on the interplay between EAT and atherosclerosis in young individuals. Our study aims to explore the relationship between EAT and CAD in a young cohort. Methods: All young (18–45 years) patients without prior CAD, referred for coronary computed tomography angiography (CCTA) from 2016 to 2022 were included. EAT volume and coronary artery calcium (CAC) were calculated from dedicated non-contrast scans. Coronary plaque presence, extent, and volume were quantified from CCTA. Multivariable logistic regression models for the presence of CAD, defined as any coronary atherosclerosis, were performed. Results: Overall, 712 patients (39±4.8 years, 54 % female) with 45 % Hispanic, and 21 % non-Hispanic Black were included. Patients with CAD had higher EAT volume than those without (80.80 mL ± 36.00 vs 55.16 mL ± 27.92; P < 0.001). In those with CAC=0, higher EAT was associated with the presence of CAD compared to lower EAT volume (P < 0.001). An EAT volume >76 mL was associated with higher CAC (P < 0.001), segment involvement score (P < 0.001), and quantitative total, non-calcified, and low-attenuation plaque volumes (P < 0.002). At multivariable analysis, EAT volume (per 10 mL, OR: 1.21; 95 %CI: 1.12–1.30; P < 0.0001) was independently associated with the presence of CAD. Conclusion: In a diverse cohort of young adults without history of CAD and undergoing a clinically indicated CCTA, EAT volume was independently associated with the presence of CAD. Our findings highlight EAT potential as a novel marker for CAD risk-assessment and a potential therapeutic target in young patients.

We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype.

Background: Metastasis to the spinal column is a common complication of malignancy, potentially causing pain and neurologic injury. An automated system to identify and refer patients with spinal metastases can help overcome barriers to timely treatment. We describe the training, optimization and validation of a natural language processing algorithm to identify the presence of vertebral metastasis and metastatic epidural cord compression (MECC) from radiology reports of spinal MRIs. Methods: Reports from patients with spine MRI studies performed between January 1, 2008 and April 14, 2019 were reviewed by a team of radiologists to assess for the presence of cancer and generate a labeled dataset for model training. Using regular expression, impression sections were extracted from the reports and converted to all lower-case letters with all nonalphabetic characters removed. The reports were then tokenized and vectorized using the doc2vec algorithm. These were then used to train a neural network to predict the likelihood of spinal tumor or MECC. For each report, the model provided a number from 0 to 1 corresponding to its impression. We then obtained 111 MRI reports from outside the test set, 92 manually labeled negative and 19 with MECC to test the model's performance. Results: About 37,579 radiology reports were reviewed. About 36,676 were labeled negative, and 903 with MECC. We chose a cutoff of 0.02 as a positive result to optimize for a low false negative rate. At this threshold we found a 100% sensitivity rate with a low false positive rate of 2.2%. Conclusions: The NLP model described predicts the presence of spinal tumor and MECC in spine MRI reports with high accuracy. We plan to implement the algorithm into our EMR to allow for faster referral of these patients to appropriate specialists, allowing for reduced morbidity and increased survival.

Severe asthma has been shown to occur in the combined presence of high pollen and thunderstorm conditions, also known as ‘thunderstorm asthma.’ First studied as severe epidemic events, recent longitudinal work studied less dramatic but more frequent occurrences. We explore thunderstorm asthma-related emergency department visits in the Minneapolis-St. Paul metropolitan area and evaluated risk differences by sex and age. We define a thunderstorm asthma exposure event as the daily occurrence of 2 or more lightning strikes during high pollen periods, and use daily counts of asthma-related emergency department visits to estimate relative and absolute risk of severe asthma during thunderstorm asthma events for the full population and for sex and age subgroups. The overall population had a 1.06 (95 % CI: 1.02, 1.09) times higher risk of asthma-related ED visits during thunderstorm asthma events compared to days without thunderstorm asthma events. Children under 18 show no higher risk (RR 1.02; 95 % CI: 0.97 1.08), but adults 18–44 years (RR 1.08; 95 % CI: 1.02, 1.13) and 45 and up (RR 1.08; 95 % CI 1.02, 1.15) show higher relative risk. Absolute risk measures show similar patterns to the age and sex results, but age-sex subgroups show more variation in absolute vs relative risk. Our results support an association between ED visits and thunderstorm asthma and provide evidence of varying risks by sex across the life course. These differences in risk have implications for clinical treatment of this allergic type of asthma and for future research into this poorly recognized environmental exposure.Plain Language Summary: Recent research has highlighted the existence of Thunderstorm asthma events, a phenomenon in which pollen grains rupture in the conditions that occur with a thunderstorm, releasing sub-pollen particles that are capable of triggering severe asthma in susceptible populations. Where severe asthma is a disease that usually impacts children, we find in this study that asthma ED visits associated with thunderstorm asthma events more frequently impact adults, particularly males 18–44 and females 45 and up.

Camera trapping networks have the potential to monitor wildlife diversity at large scales. However, their efficacy in detecting different species varies, leading to considerable disparities in population density estimates. Furthermore, species of different trophic levels and body sizes naturally occur at different densities, challenging the evenness assumptions inherent in conventional diversity indices. Here we present a novel index: Fractional Richness, which is specifically designed for application in extensive camera trap networks. The index addresses situations where evenness is uninformative, for example in communities characterized by multiple trophic levels, diverse body sizes, variable population densities, or other complications. To determine the effectiveness of our Fractional Richness index, we modeled spatial patterns of Shannon diversity, species richness, and Fractional Richness for two wildlife communities in Wisconsin USA to quantitatively measure which index best reflected ecologically relevant landscape patterns. One community was much more uneven than the other, with detection rates ranging across three orders of magnitude. The more even community could be modeled accurately with both Shannon diversity and Fractional Richness, but the highly uneven community could only be modeled accurately with Fractional Richness. Maximum population density varies by species, and most wildlife survey methods are not equally capable of detecting all species. In communities with both high and low-density species, or when detectability varies, evenness may not be the most informative measure. In these situations, Fractional Richness may be a more suitable index.

Zebrafish (Danio rerio) are a good model for cancer research including studies on chemotherapy treatments. We treated wild-type and miR-34a deletion mutant zebrafish embryos at 24 h post-fertilization with 1 µM of the topoisomerase I inhibitor, camptothecin (CPT), for 4 h to catalogue gene expression changes induced by this DNA damage treatment and to understand if these changes are influenced by loss of miR-34a. The 4 sample groups of 3 independent biological samples consisting of 30 embryos each were analyzed by RNA-sequencing using the recently updated zebrafish transcriptome annotation based on GRCz11, which enabled a more complete and sensitive read mapping and gene assignment than standard annotations. Using this gene expression estimates dataset as the primary resource, we performed a differentially expressed gene (DEG) analysis based on treatment as loss of miR-34a had minimal effects on CPT-induced expression changes. The DEGs were analyzed for Gene Ontology and KEGG pathway terms. Enriched terms and pathways among up-regulated genes were mostly related to stress, cell death, cell cycle regulation, transcriptional regulation, cell signalling, developmental processes and synthesis of retinol and steroid hormones. By contrast, down-regulated genes were most strongly associated with genes involved in key developmental processes, adhesion molecules, as well as some transport and metabolic pathways, together suggesting a “developmental shutdown”. We also identified interferon-regulated genes and p53 target genes activated or inhibited by DNA damage due to topoisomerase I inhibition, suggesting that they are important components of the response to this type of DNA damage in zebrafish embryos.

Granulosa cell tumors (GCT) represent a rare subtype of ovarian cancers. A majority of these tumors express androgen receptor (AR), making them hormonally sensitive. AR positivity not only suggests a potential role of anti-androgen therapy in treating these tumors but also poses a cause for concern: female to male (FTM) transgender patients undergoing exogenous testosterone therapy may be at risk for recurrence, progression, or even incidence of this type of cancer. Although treatment of GCT in transgender individuals has not been well-described, the impact of exogenous hormone use on cancer physiology and treatment should be considered, while also addressing gender dysphoria throughout treatment and in surveillance. Here, we describe a FTM transgender patient with recurrent AR-positive adult granulosa cell tumor after starting testosterone supplementation, along with a literature review to explore the current knowledge of ovarian changes observed following FTM gender transition and subsequent risk of ovarian cancer.

Reintroduced animals face disease risks, potentially impacting both the reintroduced and the local wildlife/domestic populations. This study focuses on the Asiatic wild asses (Equus hemionus) reintroduced to the Negev desert in southern Israel. Despite potential threats of disease spill-over to and from domesticated donkeys and horses in the area, there are no records of the gastrointestinal nematodes (GIN) of the wild ass population. We used DNA metabarcoding on fecal samples of wild asses collected across seasons and habitats, near water sources that they frequently use. Ten GIN species were detected in the feces, nine belonging to the family Strongylidae, which commonly infects and causes disease in equids worldwide, such as horses, zebras, and donkeys. Some of these Strongylidae species are also found in domesticated equids in Israel, thus raising concerns regarding potential parasite transmission between wild and domestic animals. The high prevalence of certain GIN species suggests frequent transmission, likely due to the congregation of the wild asses around water sources. While we observed statistically significant variations in some GIN species across seasons and habitats, we did not find clear overall differences between GIN communities. DNA metabarcoding proves to be a valuable tool for identifying GIN species in wild animals, with potential applications in monitoring their health and preventing disease transmission to and from domestic animals.

Background: Bisphenol A (BPA; or 4,4′-isopropylidenediphenol) is an endocrine disrupting chemical. It was widely used in a variety of plastic-based manufactured products for several years. The European Food Safety Authority (EFSA) recently reduced the Tolerable Daily Intake (TDI) for BPA by 20,000 times due to concerns about immune-toxicity. Objective: We used human biomonitoring (HBM) data to investigate the general level of BPA exposure from 2007 to 2014 of European women aged 18–73 years (n = 4,226) and its determinants. Methods: Fifteen studies from 12 countries (Austria, Belgium, Denmark, France, Germany, Greece, Israel, Luxembourg, Slovenia, Spain, Sweden, and the United Kingdom) were included in the BPA Study protocol developed within the European Joint Programme HBM4EU. Seventy variables related to the BPA exposure were collected through a rigorous post-harmonization process. Linear mixed regression models were used to investigate the determinants of total urine BPA in the combined population. Results: Total BPA was quantified in 85–100 % of women in 14 out of 15 contributing studies. Only the Austrian PBAT study (Western Europe), which had a limit of quantification 2.5 to 25-fold higher than the other studies (LOQ=2.5 µg/L), found total BPA in less than 5 % of the urine samples analyzed. The geometric mean (GM) of total urine BPA ranged from 0.77 to 2.47 µg/L among the contributing studies. The lowest GM of total BPA was observed in France (Western Europe) from the ELFE subset (GM=0.77 µg/L (0.98 µg/g creatinine), n = 1741), and the highest levels were found in Belgium (Western Europe) and Greece (Southern Europe), from DEMOCOPHES (GM=2.47 µg/L (2.26 µg/g creatinine), n = 129) and HELIX-RHEA (GM=2.47 µg/L (2.44 µg/g creatinine), n = 194) subsets, respectively. One hundred percent of women in 14 out of 15 data collections in this study exceeded the health-based human biomonitoring guidance value for the general population (HBM-GVGenPop) of 0.0115 µg total BPA/L urine derived from the updated EFSA’s BPA TDI. Variables related to the measurement of total urine BPA and those related to the main socio-demographic characteristics (age, height, weight, education, smoking status) were collected in almost all studies, while several variables related to BPA exposure factors were not gathered in most of the original studies (consumption of beverages contained in plastic bottles, consumption of canned food or beverages, consumption of food in contact with plastic packaging, use of plastic film or plastic containers for food, having a plastic floor covering in the house, use of thermal paper…). No clear determinants of total urine BPA concentrations among European women were found. A broader range of data planned for collection in the original questionnaires of the contributing studies would have resulted in a more thorough investigation of the determinants of BPA exposure in European women. Conclusion: This study highlights the urgent need for action to further reduce exposure to BPA to protect the population, as is already the case in the European Union. The study also underscores the importance of pre-harmonizing HBM design and data for producing comparable data and interpretable results at a European-wide level, and to increase HBM uptake by regulatory agencies.

The production of wild fish has remained relatively stable in the last two decades, whereas aquaculture organism production has increased to the point where it has exceeded wild catches. In this context, accurate and up-to-date information about the current usage of marine areas for aquaculture is crucial for the planning of marine activities. However, this data is often limited to national authorities, and discrepancies between planned and real practices can arise in available data. In this study, a novel methodology to automatically map and verify the current activity of aquaculture crops across European regions based on freely available satellite data is proposed. The European Space Agency’s (ESA) Sentinel-1 mission provides Synthetic Aperture Radar (SAR) images, which serve as the basis for the analysis. Multiple SAR images of the same locations are processed using ESA Sentinel Application Platform (SNAP) software and merged to remove temporal noise-like artifacts caused by factors such as ships and waves. Next, the iDPolRAD algorithm is employed to detect potential aquaculture sites, which initially include noise from coastal zones and unwanted human and natural structures that pass through the filter. The aquaculture sites are classified using a ResNet18 model with 93% of the sites correctly classified. This implies that it is feasible to monitor marine areas using satellite radar data to track aquaculture areas. However, generalization power across regions is poor likely due to the diversity of types of structures used and species cultivated. Further studies are needed to investigate factors influencing the detectability of different aquaculture sites such as cage geometry or SAR image resolution in order to enhance the accuracy and comprehensiveness of the mapping process. This study highlights the potential of SAR data, coupled with image processing and classification techniques, as a viable means to map large marine areas dedicated to aquaculture.

Summary: Background: Longitudinal changes in vaccination-induced immune response remain inadequately characterized in adolescents. We present long-term safety, immunogenicity, and COVID-19 incidence following a 2-dose mRNA-1273 100-μg primary series, and immunogenicity following a single dose of mRNA-1273 50 μg in vaccine-naïve adolescents. Methods: TeenCOVE (NCT04649151) Part 1 randomized adolescents (12–17 years) to 2-dose mRNA-1273 100 μg (n = 2490) or placebo (n = 1243) 28 days apart. Subsequently, placebo recipients (n = 91) could receive open-label mRNA-1273. Primary objectives included prespecified adverse events through 12 months; secondary objectives were COVID-19 incidence and neutralizing and spike-binding antibodies (nAbs/bAbs) against SARS-CoV-2 (ancestral/variants) through 12 months (study period: December 2020–January 2022). In Part 2, vaccine-naïve adolescents (n = 52) received up to 2 doses of mRNA-1273 50 μg; interim analysis included Day 28 (D28) nAbs post-injection 1 in SARS-CoV-2-baseline-positive participants (serologic/virologic evidence of prior infection). Findings: In SARS-CoV-2-baseline-negative adolescents (N = 369), mRNA-1273 induced robust nAb responses versus baseline (geometric mean concentration [GMC] = 11; 95% CI, 11–12) at D28 (1868 [1759–1985]), 6 months (625 [583–670]) and 12 months (550 [490–618]) post-injection 2. Similar bAb responses were observed to alpha/beta/delta/gamma variants; nAb/bAb responses were similar in SARS-CoV-2-baseline-positive adolescents. The 2-dose mRNA-1273 100-μg primary series was generally well-tolerated; one case of nonserious, moderate, probable acute myocarditis resolved by 8 days from symptom onset. A single dose of mRNA-1273 50 μg in SARS-CoV-2-baseline-positive adolescents induced higher D28 nAb GMCs against ancestral SARS-CoV-2 than 2-dose mRNA-1273 100 μg in young adults (geometric mean ratio = 4.322 [3.274-5.707]). Interpretation: The overall risk–benefit profile of mRNA-1273 remains favorable in adolescents, with durable 12-month immune responses against SARS-CoV-2 (ancestral/variants). A single mRNA-1273 50-μg injection in vaccine-naïve adolescents elicited robust immune responses against SARS-CoV-2. Funding: This project has been funded in whole or in part with federal funds by the Department of Health and Human Services, United States; Administration for Strategic Preparedness and Response, United States; Biomedical Advanced Research and Development Authority, United States, under Contract No. 75A50120C00034. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.

Testicular seminoma is rarely associated with occlusive venous thrombosis. Several investigators describe percutaneous guidewire recanalization for iliofemoral vein thrombosis; however, this technique is ill-documented for occlusion of the inferior vena cava, and even less information is available on managing pervasive iliocaval obstruction. Furthermore, there is limited data on percutaneous mechanical thrombectomy for malignancy-induced venous thrombosis. We present a case of symptomatic chronic occlusion of the inferior vena cava and iliac veins following remission for metastatic seminoma, with percutaneous intervention necessitating a unique combination of sharp wire recanalization, mechanical thrombectomy, and stenting to restore iliocaval patency.

The strong association between lipoprotein (a) [Lp(a)] and atherosclerotic cardiovascular disease has led to considerations of Lp(a) being a potential target for mitigating residual cardiovascular risk. While approximately 20 % of the population has an Lp(a) level greater than 50 mg/dL, there are no currently available pharmacological lipid-lowering therapies that have demonstrated substantial reduction in Lp(a). Novel therapies to lower Lp(a) include antisense oligonucleotides and small-interfering ribonucleic acid molecules and have shown promising results in phase 2 trials. Phase 3 trials are currently underway and will test the causal relationship between Lp(a) and ASCVD and whether lowering Lp(a) reduces cardiovascular outcomes. In this review, we summarize emerging insights related to Lp(a)’s role as a risk-enhancing factor for ASCVD, association with calcific aortic stenosis, effects of existing therapies on Lp(a) levels, and variations amongst patient populations. The evolving therapeutic landscape of emerging therapeutics is further discussed.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are pressing public health problems occurring alongside the rising prevalence of obesity and diabetes. This feasibility study explored the use of a novel prescription digital therapeutic (PDT) in this patient population. Methods: A prospective, open-label study was conducted at two hepatology clinics. Eligible patients had a baseline FibroScan controlled attenuation parameter >274 dB/m. Participants were given access to a PDT containing a novel form of cognitive behavioral therapy designed to treat cardiometabolic disease. Laboratory assessments, FibroScan, and magnetic resonance imaging proton density fat fraction (MRI-PDFF) imaging were conducted preintervention and postintervention. Results: Twenty-two participants were enrolled. Mean baseline fat fraction on MRI-PDFF was 18.7%. After the 90-day intervention, the mean relative reduction in MRI-PDFF was −16.2% (P = .011) in those with baseline PDFF ≥10%. Mean alanine transaminase decreased by −17.1 IU/L (P = .002). Participants achieved an average total body weight loss of −2.9% (P = .008) and controlled attenuation parameter score was reduced by −18.8 dB/m (P = .021). No serious or device-related adverse events were reported. An average improvement in health-related quality of life of +2.2 Healthy Days per month (P = .500) and high treatment satisfaction (mean Net Promoter Score of +75) were reported. Conclusion: After 90 days of digitally delivered cognitive behavioral therapy, improvements were observed in multiple endpoints without any adverse device effects. The safety, efficacy, and usability data observed strengthen the hypothesis that PDTs provide a scalable tool to address unmet behavioral treatment needs in metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (ClinicalTrials.gov number, NCT05357248).

Background: Heart failure with preserved ejection fraction (HFpEF) is the most common cardiac complication in patients with coronary microvascular dysfunction (CMD), yet its underlying pathways remain unclear. Aortic pulse-wave velocity (aPWV) is an indicator of large artery stiffness and a predictor for cardiovascular disease. However, aPWV in CMD and HFpEF is not well characterized and may provide understanding of disease progression. Methods: Among participants without obstructive coronary artery disease, we evaluated 51 women with suspected CMD and 20 women and men with evidence of HFpEF. All participants underwent aPWV measurement (SphygmoCor, Atcor Medical) with higher aPWV indicating greater vascular stiffness. Cardiac magnetic resonance imaging (CMRI) assessed left ventricular (LV) ejection fraction, CMD via myocardial perfusion reserve index (MPRI), and ventricular remodeling via LV mass-volume ratio. . Statistical analysis was performed using Wilcoxon rank sum tests, Pearson correlations and linear regression analysis. Results: Compared to the suspected CMD group, the HFpEF participants were older (65 ± 12 vs 56 ± 11 yrs., p = 0.002) had higher BMI (31.0 ± 4.3 vs 27.8 ± 6.7 kg/m2, p = 0.013), higher aPWV (10.5 ± 2.0 vs 8.0 ± 1.6 m/s, p = 0.05) and lower MPRI (1.5 ± 0.3 vs1.8 ± 0.3, p = 0.02), but not remodeling. In a model adjusted for cardiovascular risk factors, the HFpEF group had a lower LVEF (estimate −4.78, p = 0.0437) than the suspected CMD group. Conclusions: HFpEF participants exhibit greater arterial stiffness and lower myocardial perfusion reserve, with lower LVEF albeit not remodeling, compared to suspected CMD participants. These findings suggest arterial stiffness may contribute to progression from CMD to HFpEF. Prospective work is needed and ongoing.

Summary: Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD. Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants. Findings: We found both tau metrics significantly elevated across increasing disease stages (p

Brain networks are continuously modified throughout development, yet this plasticity can also make functional networks vulnerable to early life stress. Little is currently known about the effect of early life stress on the functional organization of the brain. The current study investigated the association between environmental stressors and network topology using data from the Adolescent Brain Cognitive DevelopmentSM (ABCD®) Study. Hierarchical modeling identified a general factor of environmental stress, representing the common variance across multiple stressors, as well as four subfactors including familial dynamics, interpersonal support, neighborhood SES deprivation, and urbanicity. Functional network topology metrics were obtained using graph theory at rest and during tasks of reward processing, inhibition, and affective working memory. The general factor of environmental stress was associated with less specialization of networks, represented by lower modularity at rest. Local metrics indicated that general environmental stress was also associated with less efficiency in the subcortical-cerebellar and visual networks while showing greater efficiency in the default mode network at rest. Subfactors of environmental stress were associated with differences in specialization and efficiency in select networks. The current study illustrates that a wide range of stressors in a child’s environment are associated with differences in brain network topology.

ABSTRACT: Black soldier fly (BSF) larvae have gained significant attention as ingredients for poultry feed to improve value chain circularity and sustainability. Black soldier fly larvae contain bioactive compounds which can potentially improve broiler health and thereby performance. However, the functionality of bioactive compounds likely depends on how larvae are processed prior to feeding and to which extent larvae products are included in the diet. This may explain the variable results reported in literature on broiler performance and carcass characteristics when feeding them different types of BSF larvae products at different inclusion levels. Therefore, the present research aimed to investigate the effects of different BSF larvae products and inclusion levels in diets on performance and carcass characteristics of slow-growing broilers. The experiment started with 1,728 one-day-old slow-growing male broilers (Hubbard JA757). Nine dietary treatments were used, each replicated eight times. One group of broilers was given a control diet. The following BSF larvae products were investigated: live larvae, a combination of BSF larvae meal and oil mimicking the nutritional composition of the live larvae, and BSF larvae meal and oil separately. All insect products were tested at two inclusion levels. All diet programs were nutritionally comparable (isoenergetic and based on balanced levels of digestible essential amino acids). During the 7-wk trial, several performance parameters and carcass characteristics were measured. The results show that comparable or better broiler performance was achieved with the inclusion of BSF larvae products in the diets compared to the control. Based on the feed conversion ratio (FCR), the unprocessed larvae product and the highest inclusion level led to the most favorable results. Carcass characteristics remained unchanged when BSF larvae products were used in the diets compared to the control group, indicating favorable production output. The BSF larvae products investigated seem suitable feed ingredients for broilers at the current levels tested, generating performance benefits.

Summary: Pubertal timing, including age at menarche (AAM), is a heritable trait linked to lifetime health outcomes. Here, we investigate genetic mechanisms underlying AAM by combining genome-wide association study (GWAS) data with investigations of two rare genetic conditions clinically associated with altered AAM: Williams syndrome (WS), a 7q11.23 hemideletion characterized by early puberty; and duplication of the same genes (7q11.23 Duplication syndrome [Dup7]) characterized by delayed puberty. First, we confirm that AAM-derived polygenic scores in typically developing children (TD) explain a modest amount of variance in AAM (R2 = 0.09; p = 0.04). Next, we demonstrate that 7q11.23 copy number impacts AAM (WS

Background: Distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) have been identified via gene expression profiling. Objective: We investigated the feasibility of a simple immunohistochemistry (IHC)-based Lund subtyping method and the association of MIBC subtypes with oncological outcomes for patients after bladder-preserving radiation-based therapy. Design, setting, and participants: Transurethral resected tumor tissues from 104 patients treated with radiation-based therapy were sampled on tissue microarray blocks. Outcome measurements and statistical analysis: The expression of KRT5, GATA3, and p16 proteins was scored via digital image analysis. Hierarchical clustering was used to classify tumors as the basal subtype or one of two luminal subtypes: genomically unstable (GU) or urothelial-like (URO). Subtypes were evaluated for association with complete response (CR), recurrence-free survival (RFS), and overall survival (OS). Results and limitations: The median OS was 43 mo (95% confidence interval 19–77) and median follow-up was 55 mo (interquartile range 39–75). Age and clinical stage had a significant impact on OS (p

Background: Grade of non–muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1–3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design, setting, and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non–muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the “old” World Health Organization (WHO) 1973 and the “new” WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.

Background: The incidence of mechanical circulatory support (MCS) for early graft dysfunction (EGD) following heart transplantation varies from 2.3% to 28.2%. Low pulmonary pulsatility index (PAPI) is associated with higher mortality in advanced heart failure and cardiogenic shock. We hypothesized that a lower pulmonary pulsatility index following heart transplantation is associated with MCS use for EGD Methods: Two-center study of consecutive heart transplantation from May 2018 to December 2022. Hemodynamic parameters and inotropic/vasoconstrictor data were investigated on admission to the intensive care unit (T0) and at 6 hours later (T6). Results: Of the 173 patients included in this study, 24 had MCS for EGD. PAPI in the group that required MCS was lower at T0 (1.21 (0.84) vs 1.67 (1.23), p = 0.001) and T6 (0.77 (0.52) vs 1.44 (0.82), p =

Understanding spatial and temporal heterogeneity in ecosystems is essential to forecasting the effects of environmental changes. Freshwater microbes, including cyanobacteria, play a crucial role in food-web structures and biochemical processes, yet can exhibit substantial heterogeneity through space and time. They also act as powerful indicators of natural and human-induced stress due to their high metabolic and rapid response to environmental change. The formation of cyanobacteria blooms can be particularly important due to the potential production of toxins that are harmful to humans and wildlife. While high water temperatures and high nutrients are largely recognized as triggers of cyanobacterial bloom formation, there is growing evidence of the role of its associated microbiome in bloom formation. The inability to accurately forecast cyanobacteria blooms is challenged by uncertainty in the degree to which microbial diversity, and bloom forming taxa in particular, exhibit spatial heterogeneity and how spatial heterogeneity varies seasonally or between lakes spanning the trophic gradient. Here, we used long-read sequencing of the 16S rRNA gene to quantify variations in microbial spatiotemporal dynamics over the course of an ice-free season between two lakes that varied substantially in trophic status. Our results showed that the microbial community composition of eutrophic Chautauqua Lake was seasonally and spatially structured; however, during bloom events we observed lower diversity and a homogeneous community dominated by Microcystis and enriched with Gammaproteobacteria. In oligotrophic Lake George, seasonality rather than the basin of origin played a major role in structuring the microbial community; however, there was a significant difference between basins when controlling for the temporal effect and was linked to a South-to-North anthropogenic gradient. This study provides a solid foundation for exploiting long-read sequencing of prokaryotes and couples sequencing with traditional water quality monitoring to assess microbial dynamics (e.g., cyanobacteria bloom microbiome) and the effect of local and global stressors.

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.

Photosensitivity to structurally diverse drugs is a common but under-reported adverse cutaneous reaction and can be classified as phototoxic or photoallergic. Phototoxic reactions occur when the skin is exposed to sunlight after administering topical or systemic medications that exhibit photosensitizing activity. These reactions depend on the dose of medication, degree of exposure to ultraviolet light, type of ultraviolet light, and sufficient skin distribution volume. Accurate prediction of the incidence and phototoxic response severity is challenging due to a paucity of literature, suggesting that phototoxicity may be more frequent than reported. This paper reports an extensive literature review on phototoxic drugs; the review employed pre-determined search criteria that included meta-analyses, systematic reviews, literature reviews, and case reports freely available in full text. Additional reports were identified from reference sections that contributed to the understanding of phototoxicity. The following drugs and/or drug classes are discussed: amiodarone, voriconazole, chlorpromazine, doxycycline, fluoroquinolones, hydrochlorothiazide, nonsteroidal anti-inflammatory drugs, and vemurafenib. In reviewing phototoxic skin reactions, this review highlights drug molecular structures, their reactive pathways, and, as there is a growing association between photosensitizing drugs and the increasing incidence of skin cancer, the consequential long-term implications of photocarcinogenesis.

Summary: Background: Myocardial perfusion imaging (MPI) is one of the most common cardiac scans and is used for diagnosis of coronary artery disease and assessment of cardiovascular risk. However, the large majority of MPI patients have normal results. We evaluated whether unsupervised machine learning could identify unique phenotypes among patients with normal scans and whether those phenotypes were associated with risk of death or myocardial infarction. Methods: Patients from a large international multicenter MPI registry (10 sites) with normal perfusion by expert visual interpretation were included in this cohort analysis. The training population included 9849 patients, and external testing population 12,528 patients. Unsupervised cluster analysis was performed, with separate training and external testing cohorts, to identify clusters, with four distinct phenotypes. We evaluated the clinical and imaging features of clusters and their associations with death or myocardial infarction. Findings: Patients in Clusters 1 and 2 almost exclusively underwent exercise stress, while patients in Clusters 3 and 4 mostly required pharmacologic stress. In external testing, the risk for Cluster 4 patients (20.2% of population, unadjusted hazard ratio [HR] 6.17, 95% confidence interval [CI] 4.64–8.20) was higher than the risk associated with pharmacologic stress (HR 3.03, 95% CI 2.53–3.63), or previous myocardial infarction (HR 1.82, 95% CI 1.40–2.36). Interpretation: Unsupervised learning identified four distinct phenotypes of patients with normal perfusion scans, with a significant proportion of patients at very high risk of myocardial infarction or death. Our results suggest a potential role for patient phenotyping to improve risk stratification of patients with normal imaging results. Funding: This work was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health [R35HL161195 to PS]. The REFINE SPECT database was supported by the National Heart, Lung, and Blood Institute at the National Institutes of Health [R01HL089765 to PS]. MCW was supported by the British Heart Foundation [FS/ICRF/20/26002].

Background: We present the case of a patient who presents with a high velocity thoracoabdominal gunshot wound requiring ultramassive transfusion who exhausted the county blood bank requiring adjunctive therapies to balanced blood product transfusion while additional blood products could be obtained. Summary: Thoracoabdominal gunshot wounds carry a high mortality of 14–37 % because of the risk to produce cardiopulmonary, solid organ as well as major vascular injuries (Mandal and Oparah (1989) [1]). Ultramassive transfusion (>20 units of blood product transfusion) also carries high morbidity and mortality and management has generally centered on balanced transfusion (Matthay et al. (2021) [2]). Conclusion: Balanced blood product transfusion reduces mortality for patients requiring ultramassive transfusion but when this is not possible utilization of adjuncts to blood products may temporize resuscitation until additional blood products can be obtained.

An aberrant right subclavian artery, the most common anatomic variant of the aortic arch, occurs in 0.5% of the population. Symptoms generally result from compression of the esophagus and/or trachea as the aberrant vessel passes posteriorly in the mediastinum. Treatment includes revascularization of the right subclavian artery from the right common carotid artery using a cervical approach combined with occlusion of the origin of the aberrant vessel from the thoracic aorta. We describe a hybrid treatment approach for a symptomatic aberrant right subclavian artery using cervical revascularization and branched thoracic stent graft coverage of the origin of the aberrant vessel.

Superior vena cava (SVC) syndrome is a spectrum of potentially life-threatening clinical manifestations resulting from either partial or complete obstruction of central venous blood flow. Approximately 70% of cases are caused by malignancy. The primary treatment end point for SVC syndrome is the achievement of long-term patency of the SVC. Malignant SVC syndrome is managed by either radiation therapy, open surgical intervention, or endovascular therapy with angioplasty and stenting. The current report describes an uncommon case of nonmalignant SVC syndrome resulting from complications of hemodialysis catheters that was managed with open revascularization between the right internal jugular and brachiocephalic veins and the right atrium.

Background: Hospital-at-Home (HAH) is a valid alternative for in-hospital stay for a wide variety of clinical indications. Occult myocardial injury, associated with acute illness, mainly occurs in patients with a background of non-obstructive coronary disease. The aim of this study was to describe the prevalence of this phenomenon in our HAH population. Methods: A retrospective description and analysis of data collected for patients admitted to the Sheba beyond's HAH services during 14 months. Results: During a period of 14 months (7/10/21–6/12/22), blood troponin measurements were available for 213 patients (median age 78 years, 52% males) hospitalized mainly for infectious causes. The median HS (highly sensitive) troponin level was 7.7 ng/L (IQR = 13.2 ng/L) (the normal upper limit is 12 ng/L) with 31% of all patients demonstrating an abnormally increased troponin level (68/213). Of all patients, 64% had a background diagnosis of a cardiovascular disease (138/213), of whom, 49% had abnormal HS troponin levels (68/138). No patient suffered from acute cardiac function deterioration and no patient died during their hospital-at-home stay. Conclusion: The prevalence of occult myocardial injury amongst elderly patients admitted to hospital-at-home stay for diagnoses other than myocardial infarction is relatively high but it is not associated with worse short-term clinical outcomes.

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Therapeutic Area: ASCVD/CVD in Women Background: Lipoprotein (a) [Lp(a)] is a risk factor for atherosclerotic cardiovascular disease (ASCVD). However, sex based differences in the association of Lp(a) with myocardial infarction (MI) have not been well established, particularly for those without prior ASCVD. Our aim was to evaluate the association of Lp(a) with MI among females and males without prior ASCVD. Methods: Patients without known ASCVD, defined as no history of MI, coronary revascularization, or ischemic stroke, were identified in the Mass General Brigham Lp(a) registry – a retrospective cohort of patients who had Lp(a) measured as part of routine care from 2000-2019. Lp(a) percentile groups were categorized as 1st-50th (reference), 51st-70th, 71st-90th, and 91st-100th. The primary outcome was a composite of fatal or non-fatal MI. Analyses were adjusted for age, race, hypertension, hyperlipidemia, diabetes mellitus, chronic kidney disease, and smoking. Results: A total of 6,238 patients were included, of whom 45% were female. Median age was 55 in females and 54 in males. Females had higher median total cholesterol, LDL-C, and HDL-C, while males had higher rates of diabetes mellitus, atrial fibrillation, and smoking. Females had a lower rate of statin use at baseline than males. Median Lp(a) was 33.2 nmol/L in females and 28.9 nmol/L in males. Higher Lp(a) percentile group was associated with an increased incidence of fatal or non-fatal MI, with females in the 91st-100th percentile group (>217 nmol/L) having an adjusted hazard ratio (HR) of 2.57 (95% CI 1.35-4.88) and males having an adjusted HR of 3.35 (95% CI 1.94-5.78). Kaplan Meier curves for the cumulative incidence of fatal or non-fatal MI showed a significant overall difference between Lp(a) percentile groups for both sexes (p

Introduction: Low-attenuation non-calcified plaque (LAP) burden and vascular inflammation by pericoronary adipose tissue (PCAT) measured from coronary CT angiography (CCTA) have shown to be predictors of cardiovascular outcomes. We aimed to investigate the relationships of cardiometabolic risk factors including lipoprotein(a) and epicardial adipose tissue (EAT) with CCTA high-risk imaging biomarkers, LAP and vascular inflammation. Methods: The patient population consisted of consecutive patients who underwent CCTA for stable chest pain and had a complete cardiometabolic panel including lipoprotein(a). Plaque, PCAT and EAT were measured from CT using semiautomated software. Elevated LAP burden and PCAT attenuation were defined as ≥4% and ≥70.5 HU, respectively. The primary clinical end-point was a composite of myocardial infarction, revascularization or cardiovascular death. Results: A total of 364 consecutive patients were included (median age 56 years, 64% female); the majority of patients were of Hispanic (60%), and the rest were of non-Hispanic Black (21%), non-Hispanic White (6%) and non-Hispanic Asian (4%) race/ethnicity. The prevalence of elevated LAP burden and PCAT attenuation was 31 and 18%, respectively, while only 8% had obstructive stenosis. There were significant differences in plaque characteristics among different racial/ethnic groups (p

Background: Recent research has raised concerns about the potential health effects of perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure, particularly during critical periods of development such as pregnancy. In this study, we sought to investigate the presence and potential impacts of PFAS in the placenta. Methods: We measured 13 PFAS compounds in placental tissue samples among 50 women who gave birth at a tertiary medical center in southern Israel. The sample comprised of 10 women with pregnancy-related complications (preterm birth, preeclampsia, gestational diabetes or small-for-gestational age) and 40 women without complications individually matched to cases by age. Results: For five (5) out of 13 PFAS compounds (Perfluorooctane Sulfonate (PFOS), perfluorooctanoic acid (PFOA), Perfluorohexanesulphonic acid (PFHxS), Perfluorononanoic acid (PFNA), Perfluorodecanoic acid (PFDA)) median concentrations were lower or comparable to placental measurements in different international populations. Geometric mean was estimated at 0.09 ng/g (90%CI:0.07;0.10) for PFOA, 0.05 ng/g for PFNA (90%CI:0.04;0.07), 0.03 ng/g for PFDA (90%CI:0.01;0.03), 0.06 ng/g for PFHxS (90%CI:0.05;0.07), 0.23 ng/g for PFOS linear measurement (90%CI:0.20;0.26) and 0.25 ng/g (90%CI:0.22;0.30) for PFOS summed concentrations that included non-linear isomers. Composite outcome of pregnancy-related complications was associated with elevated PFOA placental concentrations at an odds ratio (OR)= 1.82 (90%CI:1.06;3.13) for an increase of one quintile of PFOA value and adjusted to maternal gravidity in a conditional logistic regression. Conclusion: This pilot study indicates a widespread exposure to multiple PFAS compounds in placental tissue of pregnant women in Israel. These findings warrant further validation through comprehensive national human biomonitoring initiatives.

Alcohol Use Disorders (AUD) are widespread and have serious consequences, but are among the most undertreated mental disorders. Internet interventions have been found effective in treating AUD, but we know little about long-term outcomes, two years or more after treatment. This study explored 12- and 24-month outcomes in alcohol consumption following initial 6-month improvements after a therapist-guided high-intensity internet intervention and an unguided low-intensity internet intervention among individuals with alcohol use disorder. Between-group comparisons were analyzed, as well as within-group comparisons with (1) pre-treatment measurements (2) post-treatment measurements. Participants consisted of a general population sample of internet help-seekers in Sweden. A total of 143 adults (47% men) with a score of 14 (women)/16 (men) or more on the Alcohol Use Disorders Identification Test, alcohol consumption of 11 (women)/14 (men) or more standard drinks the preceding week and ≥ 2 DSM-5 alcohol use disorder (AUD) criteria based on a diagnostic interview were included. The high- and low-intensity internet interventions (n = 72 and n = 71 respectively) consisted of modules based on relapse prevention and cognitive-behavioral therapy. The primary outcome was self-reported alcohol consumption in the preceding week measured as (1) number of standard drinks and (2) number of heavy drinking days. Attrition from self-reported questionnaires was 36% at the 12-month follow-up and 53% at the 24-month follow-up. No significant between-group differences occurred in outcomes at either long-term follow-up. Regarding within-group differences, compared to pre-treatment, alcohol consumption was lower in both high- and low-intensity interventions at both long-term follow-ups [within-group standard drinks effect sizes varied between g = 0.38–1.04 and heavy drinking days effect sizes varied between g = 0.65–0.94]. Compared to post-treatment, within-group alcohol consumption in the high intensity intervention increased at both follow-ups; for the low-intensity intervention, within-group consumption decreased at 12-month follow-up, but did not differ compared to post-treatment at 24 months. Both high- and low-intensity internet interventions for AUD were thus associated with overall reductions in alcohol consumption at long term follow-ups, with no significant differences between the two. However, conclusions are hampered by differential and non-differential attrition.

Objective: Endovascular aneurysm repair (EVAR) is a widely used option for patients with suitable vascular anatomy who have a large infrarenal abdominal aortic aneurysm (AAA). Neck diameter is the primary anatomical determinant of EVAR eligibility and device durability. Doxycycline has been proposed to stabilise the proximal neck after EVAR. This study explored doxycycline mediated aortic neck stabilisation in patients with small AAA, monitored by computed tomography over two years. Methods: This was a multicentre prospective randomised clinical trial. Subjects from the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT, NCT01756833) were included in this secondary a priori analysis. Female baseline AAA maximum transverse diameter was between 3.5 and 4.5 cm, and male was between 3.5 and 5.0 cm. Subjects were included if they completed pre-enrolment and two year follow up computed tomography (CT) imaging. Proximal aortic neck diameter was measured at the lowest renal artery, and 5, 10, and 15 mm caudal to this point; mean neck diameter was calculated from these values. Unpaired, two tailed parametric t test analysis with post hoc Bonferroni correction was used to detect differences between neck diameters in subjects treated with placebo vs. doxycycline at baseline and two years. Results: One hundred and ninety-seven subjects (171 male, 26 female) were included in the analysis. All patients, regardless of treatment arm, demonstrated larger neck diameter caudally, a slight increase in diameter at all anatomical levels over time, and greater growth caudally. There was no statistically significant difference in infrarenal neck diameter between treatment arms at any anatomical level at any time point, nor mean change in neck diameter over two years. Conclusion: Doxycycline does not demonstrate infrarenal aortic neck growth stabilisation in small AAA followed for two years by thin cut CT imaging using a standardised acquisition protocol and cannot be recommended for mitigation of growth of the aortic neck in patients with untreated small abdominal aortic aneurysms.

Summary: Background: The COVID-19 pandemic disrupted healthcare and may have impacted ethnic inequalities in healthcare. We aimed to describe the impact of pandemic-related disruption on ethnic differences in clinical monitoring and hospital admissions for non-COVID conditions in England. Methods: In this population-based, observational cohort study we used primary care electronic health record data with linkage to hospital episode statistics data and mortality data within OpenSAFELY, a data analytics platform created, with approval of NHS England, to address urgent COVID-19 research questions. We included adults aged 18 years and over registered with a TPP practice between March 1, 2018, and April 30, 2022. We excluded those with missing age, sex, geographic region, or Index of Multiple Deprivation. We grouped ethnicity (exposure), into five categories: White, Asian, Black, Other, and Mixed. We used interrupted time-series regression to estimate ethnic differences in clinical monitoring frequency (blood pressure and Hba1c measurements, chronic obstructive pulmonary disease and asthma annual reviews) before and after March 23, 2020. We used multivariable Cox regression to quantify ethnic differences in hospitalisations related to diabetes, cardiovascular disease, respiratory disease, and mental health before and after March 23, 2020. Findings: Of 33,510,937 registered with a GP as of 1st January 2020, 19,064,019 were adults, alive and registered for at least 3 months, 3,010,751 met the exclusion criteria and 1,122,912 were missing ethnicity. This resulted in 14,930,356 adults with known ethnicity (92% of sample): 86.6% were White, 7.3% Asian, 2.6% Black, 1.4% Mixed ethnicity, and 2.2% Other ethnicities. Clinical monitoring did not return to pre-pandemic levels for any ethnic group. Ethnic differences were apparent pre-pandemic, except for diabetes monitoring, and remained unchanged, except for blood pressure monitoring in those with mental health conditions where differences narrowed during the pandemic. For those of Black ethnicity, there were seven additional admissions for diabetic ketoacidosis per month during the pandemic, and relative ethnic differences narrowed during the pandemic compared to the White ethnic group (Pre-pandemic hazard ratio (HR): 0.50, 95% confidence interval (CI) 0.41, 0.60, Pandemic HR: 0.75, 95% CI: 0.65, 0.87). There was increased admissions for heart failure during the pandemic for all ethnic groups, though highest in those of White ethnicity (heart failure risk difference: 5.4). Relatively, ethnic differences narrowed for heart failure admission in those of Asian (Pre-pandemic HR 1.56, 95% CI 1.49, 1.64, Pandemic HR 1.24, 95% CI 1.19, 1.29) and Black ethnicity (Pre-pandemic HR 1.41, 95% CI: 1.30, 1.53, Pandemic HR: 1.16, 95% CI 1.09, 1.25) compared with White ethnicity. For other outcomes the pandemic had minimal impact on ethnic differences. Interpretation: Our study suggests that ethnic differences in clinical monitoring and hospitalisations remained largely unchanged during the pandemic for most conditions. Key exceptions were hospitalisations for diabetic ketoacidosis and heart failure, which warrant further investigation to understand the causes. Funding: LSHTM COVID-19 Response Grant (DONAT15912).

Background: C-reactive protein (CRP) is a marker of inflammation and infection. The main proinflammatory cytokine that leads to CRP gene expression is IL-6. The study aimed to compare CRP level between patients who were treated with Tocilizumab (TCZ), an il-6 receptor blocker, and other advanced anti-inflammatory treatments (AAIT), as well as with other admitted and non-admitted populations. Methods: A cross-sectional study of all patients (≥18 years) hospitalized at tertiary medical center between December 2009 and February 2020 and treated before hospitalization with (AAIT). Only the first hospitalization of each patient was included. Women admitted to obstetrics department were excluded. Demographic data, first blood tests results, and comorbidities were collected. Results: The study included 563 patients treated with AAIT (2.5% received TCZ). Patients treated with TCZ were older (median 75 vs. 50 years, p

Exposure to environmental pesticides during pregnancy is associated with adverse health outcomes such as low birth weight and impaired neuro-development. In this study, we assessed maternal leukocyte telomere lengths (TL) in Palestinian pregnant women and compared the data with urinary organophosphate concentrations, demographic, lifestyle and dietary factors, birth weight, body length, gestational age, and head circumference. Women with high urine levels of creatinine adjusted diethylphosphate(DE)derived pesticide metabolites DEP, DETP or DEDTP had shorter telomeres (p = 0.05). Women living in proximity to agricultural fields had shorter telomeres compared to women not living in proximity to agricultural fields (p = 0.011). Regular consumption of organic food was associated with shorter telomeres (p = 0.01), whereas the consumption of other vegetables such as artichokes was rather associated with longer telomeres. By contrast, urine levels of dimethylphosphate(DM)-derived pesticide metabolites DMTP and DMDTP were associated with lower birth weight (p = 0.05) but not with shrter telomeres. In conclusion organophosphate pesticides and living in proximity to agriculture are associated with shorter TL, likely due to higher consumption of contaminated fruits and vegetables and/or the transport of pesticides to non-treatment sites. DE and DM substituted pesticides seem to have different effects on telomeres and development.

Summary: Background: Heart transplantation is an effective treatment offering the best recovery in both quality and quantity of life in those affected by refractory, severe heart failure. However, transplantation is limited by donor organ availability. The reintroduction of heart donation after the circulatory determination of death (DCD) in 2014 offered an uplift in transplant activity by 30%. Thoraco-abdominal normothermic regional perfusion (taNRP) enables in-situ reperfusion of the DCD heart. The objective of this paper is to assess the clinical outcomes of DCD donor hearts recovered and transplanted from donors undergoing taNRP. Method: This was a multicentre retrospective observational study. Outcomes included functional warm ischaemic time, use of mechanical support immediately following transplantation, perioperative and long-term actuarial survival and incidence of acute rejection requiring treatment. 157 taNRP DCD heart transplants, performed between February 2, 2015, and July 29, 2022, have been included from 15 major transplant centres worldwide including the UK, Spain, the USA and Belgium. 673 donations after the neurological determination of death (DBD) heart transplantations from the same centres were used as a comparison group for survival. Findings: taNRP resulted in a 23% increase in heart transplantation activity. Survival was similar in the taNRP group when compared to DBD. 30-day survival was 96.8% ([92.5%–98.6%] 95% CI, n = 156), 1-year survival was 93.2% ([87.7%–96.3%] 95% CI, n = 72) and 5-year survival was 84.3% ([69.6%–92.2%] 95% CI, n = 13). Interpretation: Our study suggests that taNRP provides a significant boost to heart transplantation activity. The survival rates of taNRP are comparable to those obtained for DBD transplantation in this study. The similar survival may in part be related to a short warm ischaemic time or through a possible selection bias of younger donors, this being an uncontrolled observational study. Therefore, our study suggests that taNRP offers an effective method of organ preservation and procurement. This early success of the technique warrants further investigation and use. Funding: None of the authors have a financial relationship with a commercial entity that has an interest in the subject.

Background: Benzophenone-3 (BP-3) and its major metabolite benzophenone-1 (BP-1) are widely used as UV filters in sunscreens and cosmetics to prevent sunburn and skin damage, or as stabilizers to prevent photodegradation in many commercial products. As a result, their presence is ubiquitous in the environment, wildlife and humans. Based on endocrine disruption concerns, international regulatory agencies are performing a closer evaluation. Objective and methods: This work aimed to comprehensively review the available human relevant evidence for safety issues in MEDLINE/PubMed in order to create a structured database of studies, as well as to conduct an integrative analysis as part of the Human Biomonitoring for Europe (HBM4EU) Initiative. Results: A total of 1,635 titles and abstracts were screened and 254 references were evaluated and tabulated in detail, and classified in different categories: i) exposure sources and predictors; ii) human biomonitoring (HBM) exposure levels to perform a meta-analysis; iii) toxicokinetic data in both experimental animals and humans; iv) in vitro and in vivo rodent toxicity studies; and v) human data on effect biomarkers and health outcomes. Our integrative analysis showed that internal peak BP-3 concentrations achieved after a single whole-body application of a commercially available sunscreen (4% w/w) may overlap with concentrations eliciting endocrine disrupting effects in vitro, and with internal concentrations causing in vivo adverse female reproductive effects in rodents that were supported by still limited human data. The adverse effects in rodents included prolonged estrous cycle, altered uterine estrogen receptor gene expression, endometrium hyperplasia and altered proliferation and histology of the mammary gland, while human data indicated menstrual cycle hormonal alterations and increased risk of uterine fibroids and endometriosis. Among the modes of action reported (estrogenic, anti-androgenic, thyroid, etc.), BP-3 and especially BP-1 showed estrogenic activity at human-relevant concentrations, in agreement with the observed alterations in female reproductive endpoints. The meta-analysis of HBM studies identified a higher concern for North Americans, showing urinary BP-3 concentrations on average 10 and 20 times higher than European and Asian populations, respectively. Discussion and conclusions: Our work supports that these benzophenones present endocrine disrupting properties, endorsing recent European regulatory efforts to limit human exposure. The reproducible and comprehensive database generated may constitute a point of departure in future risk assessments to support regulatory initiatives. Meanwhile, individuals should not refrain from sunscreen use. Commercially available formulations using inorganic UV filters that are practically not absorbed into systemic circulation may be recommended to susceptible populations.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0–2; n = 66), CCI intermediate (3–4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs

Objective: Coronary artery calcium score (CAC) is a validated tool to predict and reclassify cardiovascular risk. Additional metrics such as regional distribution and extent of CAC over Agatston CAC score may allow further risk stratification. In this study, we evaluate the prognostic significance of proximal CAC involvement in asymptomatic population from the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) registry, focusing on patients with mild CAC (score 1-99). Methods: This study included a total of 2,047 adult asymptomatic subject who underwent baseline CAC scan and 14-year follow-up for MACE, defined as myocardial infarction, late revascularization, or cardiac death. Proximal involvement was defined as presence of CAC in the LM, proximal LAD, LCX or RCA. CAC was categorized as 0, 1-99, and ≥100. Results: 1,090 (53.2%) subjects had no CAC, 576 (28.1%) had CAC 1-99, and 381 (18.7%) had CAC ≥100. Proximal involvement was seen in 67.2% of subjects with CAC 1-99 and 97.3% of subjects with CAC ≥100. In the CAC 1-99 category, the presence of proximal CAC was associated with increased MACE risk after adjustment for CAC score, CAC extent and conventional risk factors compared to those without proximal CAC (HR: 2.84 95% CI: 1.29-6.25, p=0.009). Conclusion: In asymptomatic subjects with CAC scores of 1-99, the presence and extent of proximal CAC plaques provides strong independent prognostic information in predicting MACE