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Abstract Many current gridded surface meteorological datasets are inadequate for quantifying near-surface spatiotemporal variability because they do not fully represent the impacts of land surface heterogeneity. Of note, explicit representation of the spatial structure and magnitude of local urban warming are usually lacking. Here we enhance the representation of spatial meteorological variability over urban areas in the conterminous United States (CONUS) by employing the High-Resolution Land Data Assimilation System (HRLDAS), which accounts for the fine-scale impacts of spatiotemporally varying land surfaces on weather. We also synthesize in situ meteorological data including local mesonets to create a 1 km grid spacing model-observation fusion product spanning 1981–2018 over the CONUS at daily temporal resolution. Daily maximum, minimum, and mean values for a variety of temperature estimates, humidity, and surface energy budget terms, among others, are included. This High-resolution Urban Meteorology for Impacts Dataset (HUMID) will be useful for studies examining spatial variability of near surface meteorology and the impacts of urban heat islands across many disciplines including epidemiology, ecology, and climatology.

Abstract Sentinel lymph node biopsy (SLNB) is an important technique in the staging of pediatric melanomas, sarcomas, and potentially useful for other solid tumors. Precise visual localization of the sentinel lymph node (SLN) during the operation is a key challenge of this procedure. Presently, the gold standard method employing Technetium 99 (99mTc) for localization carries a notable false-negative rate. In this context, we propose evaluating the use of Indocyanine Green near-infrared (ICG-NIR) as a supplementary tool to enhance the identification of SLN. A prospective observational study focused on pediatric and adolescent patients undergoing SLNB using ICG-NIR at a single institution from 2019 to 2022. Lymphoscintigraphy with 99mTc was performed before surgery and 99mTc was detected intraoperatively using a handheld gamma probe. ICG was administered intraoperatively and assessed using transcutaneous NIR. The study collected demographic data, intra-operative findings (Technetium 99 m, ICG fluorescence), and histopathological data. Eight patients with a median age of 16 years (range: 8–19 years) underwent fluorescence-guided sentinel lymph node harvesting with 100% sensitivity. Sentinel lymph node fluorescence was verified with a positive radiosignal in all patients. No adverse events were recorded. Fluorescence-guided assessment of the lymphatic system is both feasible and effective for sentinel lymph node identification. Nevertheless, larger-scale studies are essential to establish indocyanine green as a viable alternative rather than a complementary technique alongside the gold-standard radioisotope-guided method for sentinel lymph node assessment in children.

Abstract Adoptive T-cell immunotherapy holds great promise for the treatment of viral complications in immunocompromised patients resistant to standard anti-viral strategies. We present a retrospective analysis of 78 patients from 19 hospitals across Australia and New Zealand, treated over the last 15 years with “off-the-shelf” allogeneic T cells directed to a combination of Epstein–Barr virus (EBV), cytomegalovirus (CMV), BK polyomavirus (BKV), John Cunningham virus (JCV) and/or adenovirus (AdV) under the Australian Therapeutic Goods Administration’s Special Access Scheme. Most patients had severe post-transplant viral complications, including drug-resistant end-organ CMV disease, BKV-associated haemorrhagic cystitis and EBV-driven post-transplant lymphoproliferative disorder. Adoptive immunotherapy is well tolerated with few adverse effects. Importantly, 46/71 (65%) patients show definitive clinical improvement including reduction in viral load, clinical symptoms and complete resolution of end-organ disease. In addition, seven high-risk patients remain disease free. Based on this long-term encouraging clinical experience, we propose that a dedicated nationally funded centre for anti-viral cellular therapies should be considered to provide T cell therapies for critically ill patients for compassionate use.

Abstract Beetles exhibit an extraordinary diversity of brilliant and colourful appearances and optical effects invisible to humans. Their underlying mechanisms have received some attention, but we know little about the ecological variables driving their evolution. Here we investigated environmental correlates of reflectivity and circular polarization in a group of optically diverse beetles (Scarabaeidae–Rutelinae). We quantified the optical properties of 261 specimens representing 46 species using spectrophotometry and calibrated photographs. Then, we examined associations between these properties and environmental variables such as temperature, humidity and vegetation cover, controlling for body size and phylogenetic relatedness. Our results showed larger beetles have higher visible reflectivity in drier environments. Unexpectedly, near-infrared (NIR) reflectivity was not correlated with ecological variables. However, we found a correlation between humidity and polarization (chiral nanostructures). We identified trade-offs between optical properties: beetles without polarization-associated nanostructures had higher NIR reflectivity. By contrast, visible reflectivity was negatively correlated with the accumulation of pigments such as melanin. Our study highlights the value of a macroecological approach for testing alternative hypotheses to explain the diversity of optical effects in beetles and to understand the link between structure and function.

Abstract Blood transcriptional biomarkers of acute viral infections typically reflect type 1 interferon (IFN) signalling, but it is not known whether there are biological differences in their regulation that can be leveraged for distinct translational applications. We use high frequency sampling in the SARS-CoV-2 human challenge model to show induction of IFN-stimulated gene (ISG) expression with different temporal and cellular profiles. MX1 gene expression correlates with a rapid and transient wave of ISG expression across all cell types, which may precede PCR detection of replicative infection. Another ISG, IFI27, shows a delayed but sustained response restricted to myeloid cells, attributable to gene and cell-specific epigenetic regulation. These findings are reproducible in experimental and naturally acquired infections with influenza, respiratory syncytial virus and rhinovirus. Blood MX1 expression is superior to IFI27 expression for diagnosis of early infection, as a correlate of viral load and for discrimination of virus culture positivity. Therefore, MX1 expression offers potential to stratify patients for antiviral therapy or infection control interventions. Blood IFI27 expression is superior to MX1 expression for diagnostic accuracy across the time course of symptomatic infection and thereby, offers higher diagnostic yield for respiratory virus infections that incur a delay between transmission and testing.

Abstract Background Critically ill hospitalized patients with COVID-19 have greater antibody titers than those with mild to moderate illness, but their association with recovery or death from COVID-19 has not been characterized. Methods In a cohort study of 178 COVID-19 patients, 73 non-hospitalized and 105 hospitalized patients, mucosal swabs and plasma samples were collected at hospital enrollment and up to 3 months post-enrollment (MPE) to measure virus RNA, cytokines/chemokines, binding antibodies, ACE2 binding inhibition, and Fc effector antibody responses against SARS-CoV-2. The association of demographic variables and more than 20 serological antibody measures with intubation or death due to COVID-19 was determined using machine learning algorithms. Results Predictive models reveal that IgG binding and ACE2 binding inhibition responses at 1 MPE are positively and anti-Spike antibody-mediated complement activation at enrollment is negatively associated with an increased probability of intubation or death from COVID-19 within 3 MPE. Conclusions At enrollment, serological antibody measures are more predictive than demographic variables of subsequent intubation or death among hospitalized COVID-19 patients.

Distributional checklists of the extant, described species of five superfamilies of Hymenoptera of Canada, Alaska and Greenland are presented. In total, 296 species in 79 genera in 12 families are recorded: 55 species of Ceraphronoidea, classified in 10 genera in 2 families, 205 species of Cynipoidea in 58 genera in 5 families, 30 species of Evanioidea in 5 genera in 3 families of Evanioidea, 2 species of Stephanoidea in 2 genera in 1 family and 4 species of Trigonalyoidea in 4 genera in 1 family. Of the reported species, 281 (in 79 genera in 12 families) are listed from Canada, 31 (in 16 genera in 6 families) from Alaska, and 7 (in 5 genera in 2 families) from Greenland. The list includes 8 new generic records for Canada (1 Ceraphronoidea, 6 Cynipoidea and 1 Evanioidea) and 43 new Canadian species records (13 Ceraphronoidea, 28 Cynipoidea and 2 Evanioidea). For each species in Canada, distribution is tabulated by province or territory, except the province of Newfoundland and Labrador is divided into the island of Newfoundland and the region of Labrador. These checklists are compared with previous Nearctic and Palaearctic surveys, checklists and catalogues. Kleidotoma minima Provancher, 1883 (Figitidae) is moved from this genus to Hexacola Förster, 1869 to form H. minimum (Provancher, 1883), comb. nov. Amblynotus slossonae Crawford, 1917 (Figitidae) is moved from Melanips Walker, 1835 to Amphithectus Hartig, 1840 forming A. slossonae (Crawford, 1917), comb. nov.

Abstract The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.

Abstract High rates of cardiometabolic disease and poor physical health outcomes contribute to significant premature mortality in people living with severe mental illness (PLWSMI). Lifestyle interventions such as exercise are known to improve both physical and mental health outcomes, however the best way to deliver exercise programs for PLWSMI remains a challenge. This paper uses a pragmatic program evaluation of a co-delivered low-cost community-based exercise program implemented over a 6-month period. Of 46 referrals in the first half of 2023 to the SLHD Gym and Swim program, 13 gave consent to participate in standardised measures and qualitative interviews. Findings revealed an increase in average hours of sport/exercise, improvements in confidence to exercise independently and within group settings, as well as achievement of individualised goals. The success of the program was in part due to the co-facilitation between peer support workers and exercise physiologists, community connection and the established partnership between the public health service and the local government council. Results offer evidence to adopt and implement accessible and low-cost exercise opportunities in the community external to health services to address barriers of attendance for PLWSMI.

Abstract Background Suicide is the fourth leading cause of death among young people aged 15–29 worldwide. Young people often present to emergency departments (EDs) with self-harm and suicide-related behaviors. The period following discharge from the ED is recognized as one of elevated risk for both repeated self-harm and suicide. During this critical time, suicide prevention aftercare services are recommended. Despite their increased popularity, evidence demonstrating the effectiveness of these models is very limited. Methods Using a hybrid effectiveness-implementation type I design, this evaluation will assess the effectiveness and implementation of a suicide prevention aftercare (Hospital Outreach Post-suicidal Engagement; HOPE) service designed to reduce risk of self-harm and suicide in young people aged 12–25 who are referred to the service following an ED presentation for self-harm or suicide attempt. Two complementing theoretical frameworks will guide this evaluation, specifically the design, data collection, analysis, and interpretation of results. The RE-AIM evaluation framework will be used to assess Reach, Effectiveness (including cost-effectiveness), Adoption, Implementation and Maintenance of the HOPE aftercare service. The PRISM implementation framework will be used to assess multi-level contextual factors hypothesized to affect the RE-AIM outcomes. Several data sources will be used to assess the changes in primary and secondary outcomes from baseline to post–intervention, and at follow-up, including user and provider self-report surveys, semi-structured interviews, and routinely collected hospital data. An historical control study will also be conducted using data from the Self-Harm Monitoring System for Victoria to examine the impact of the service on rates of self-harm and suicide-related presentations to ED, and compare trends prior to and following commencement of the HOPE aftercare service. In addition, dynamic systems modelling will be used to assess the future scalability of the service. Discussion Findings from this evaluation will determine the effectiveness, including cost-effectiveness, of the HOPE aftercare service and describe the implementation context. They will inform the future development and sustainability of this and other similar services across Australia and internationally. Trial registration This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) on the 19th December 2023 (Registration number ACTRN12623001332617). We do not foresee any amendments to this protocol however, if any unforeseen modifications are required, they will be submitted to ANZCTR. Trial sponsor Orygen, 35 Poplar Road, Parkville, VIC, 3052, Australia.

Abstract Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15–50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE.

Abstract Background Most children with developmental disabilities (DD) live in low- and middle-income countries, but access to services is limited, impacting their ability to thrive. Pilot study findings of the World Health Organization’s Caregiver Skills Training (WHO CST) intervention, which equips caregivers with strategies to facilitate learning and adaptive behaviours in children with DD, are promising but evidence from an appropriately powered trial delivered by non-specialist facilitators is lacking. This study will investigate the effectiveness and the resource impacts and costs and consequences of the WHO CST intervention in four sites in rural and urban Kenya and Ethiopia. Methods This is a 2-arm multi-site hybrid type-1 effectiveness implementation cluster randomised controlled superiority trial. After baseline assessments (T0) are completed by participants in clusters comprising 7 to 10 caregiver-child dyads, the clusters will be randomised to either the WHO CST intervention arm or a waitlist enhanced care as usual control arm. Further assessments will be completed at endpoint (T1, 18 ± 2 weeks after randomisation) and follow-up (T2, 44 ± 2 weeks after randomisation). The intervention comprises three individualised home visits and nine group sessions with trained non-specialist facilitators. Participants in the control arm will receive the intervention after completing follow-up assessments. We aim to recruit 544 child-caregiver dyads, evenly distributed across the two arms and countries. The co-primary outcomes are the child-focused Child Behavior Checklist (assessing emotional and behavioural problems) and the caregiver-focused Pediatric Quality of Life Inventory (assessing caregiver quality of life), both assessed at endpoint. Secondary outcome measures comprise the two co-primary outcomes at follow-up and ten additional outcome measures at endpoint, assessing stigma-based experiences, depressive symptoms, household food insecurity, child disciplinary strategies and beliefs, CST knowledge and skill competencies, caregiver and child quality of life, social support, and children’s communication modes and functions. After quantitative follow-up assessments are completed, a mixed-methods evaluation approach will be used to investigate implementation processes and acceptability, feasibility, and potential sustainability of the intervention. Discussion The study’s findings will provide evidence of the effectiveness and resource impacts and costs and consequences of a non-specialist-delivered intervention in under-resourced contexts in one low-income and one middle-income country in East Africa. Findings will inform future research, intervention, and policy efforts to support children with DD and their families in under-resourced majority world contexts. Trial registration Pan African Clinical Trial Registry PACTR202310908063134. Registered on October 16, 2023.

(1) Background: Comprehensive and timely lung cancer (LC) staging is essential for prognosis and management. The Lung Diagnostic Assessment Program (LDAP) in Southeastern (SE) Ontario aims to provide rapid, guideline-concordant care for suspected LC patients. We evaluated factors affecting the completeness and timeliness of staging for stage I–III LC patients in SE Ontario, including the impact of LDAP management. (2) Methods: This was a population-based retrospective cohort study using the LDAP database (January 2017–December 2019), linked with the Ontario Cancer Registry, to identify newly diagnosed LC patients. A Cox model approach identified variables associated with staging completeness and timeliness. (3) Results: Among 755 patients, 459 (60.8%) were managed through LDAP. Optimal staging was achieved in 596 patients (78.9%), 23 (3.0%) had alternative staging, and 136 (18.0%) had incomplete staging. In the adjusted analyses, LDAP management was associated with a higher likelihood of complete staging (OR 2.29, p < 0.0001) and faster staging completion (β = −18.53, p < 0.0001). Increased distance to PET centres was associated with a longer time to complete staging (β = 8.95 per 100 km, p = 0.0007), as was longer time to diagnosis (β = 21.63 per 30 days, p < 0.0001). (4) Conclusions: LDAP management in SE Ontario significantly improved staging completeness and shortened staging time for stage I–III LC patients.

Abstract Background We previously reported that increases in circulating sphingolipids are associated with elevated risk of biopsy Gleason grade group (GG) upgrading in men on Active Surveillance (AS) for prostate cancer. Here, we aimed to validate these findings and establish a blood-based sphingolipid biomarker panel for identifying men on AS who are at high-risk of biopsy GG upgrading. Methods Men diagnosed with low- or intermediate-risk prostate cancer in one of two AS cohorts (CANARY PASS and MDACC) were followed for GG upgrading after diagnostic and confirmatory biopsy. The PASS cohort consisted of 544 patients whereas the MDACC Cohort consisted of 697 patients. The number of patients with GG upgrading during course of study follow-up in the PASS and MDACC cohorts were 98 (17.7%) and 133 (19.1%), respectively. Plasmas collected prior to confirmatory biopsy were used for mass spectrometry-based quantitation of 87 unique sphingolipid species. A neural network layer based on 21 sphingolipids was developed in the CANARY PASS cohort for predicting biopsy GG upgrading. Tertile-based thresholds for low-, intermediate-, and high-risk strata were subsequently developed for the sphingolipid panel as well as a model that combined the sphingolipid panel with PSA density and rate of core positivity on diagnostic biopsy. The resultant models and risk thresholds for GG upgrading were validated in the MDACC cohort. Performance was assessed using Cox proportional hazard models, C-index, AUC, and cumulative incidence curves. Results The sphingolipid panel had a HR (per unit standard deviation increase) of 1.36 (95% CI: 1.07–1.70) and 1.35 (95% CI: 1.11–1.64) for predicting GG biopsy upgrading in the PASS and MDACC cohort, respectively. The model that combined the sphingolipid panel with PSA density and rate of core positivity achieved a HR of 1.63 (95% CI: 1.33-2.00) and 1.44 (1.25–1.66), respectively. Tertile-based thresholds, established in the PASS cohort, were applied to the independent MDACC cohort. Compared to the low-risk group, MDACC patients in the high-risk strata had a GG biopsy upgrade HR of 3.65 (95% CI: 2.21–6.02), capturing 50% of the patients that had biopsy upgrading during study follow-up. Conclusions The sphingolipid panel is independently associated with GG biopsy upgrading among men in two independent AS cohorts who have previously undergone diagnostic and confirmatory biopsy. The sphingolipid panel, together with clinical factors, provides a potential means for risk stratification to better guide clinical management of men on AS.

Abstract Whole-genome sequencing studies of parent–offspring trios have provided valuable insights into the potential impact of de novo mutations (DNMs) on human health and disease. However, the molecular mechanisms that drive DNMs are unclear. Studies with multi-child families can provide important insight into the causes of inter-family variability in DNM rates but they are highly limited. We characterized 2479 de novo single nucleotide variants (SNVs) in 13 multi-child families of Mexican-American ethnicity. We observed a strong paternal age effect on validated de novo SNVs with extensive inter-family variability in the yearly rate of increase. Children of older fathers showed more C > T transitions at CpG sites than children from younger fathers. Validated SNVs were examined against one cancer (COSMIC) and two non-cancer (human germline and CRISPR-Cas 9 knockout of human DNA repair genes) mutational signature databases. These analyses suggest that inaccurate DNA mismatch repair during repair initiation and excision processes, along with DNA damage and replication errors, are major sources of human germline de novo SNVs. Our findings provide important information for understanding the potential sources of human germline de novo SNVs and the critical role of DNA mismatch repair in their genesis.

VMXm joins the suite of operational macromolecular crystallography beamlines at Diamond Light Source. It has been designed to optimize rotation data collections from protein crystals less than 10 µm and down to below 1 µm in size. The beamline has a fully focused beam of 0.3 × 2.3 µm (vertical × horizontal) with a tuneable energy range (6–28 keV) and high flux (1.6 × 1012 photons s−1 at 12.5 keV). The crystals are housed within a vacuum chamber to minimize background scatter from air. Crystals are plunge-cooled on cryo-electron microscopy grids, allowing much of the liquid surrounding the crystals to be removed. These factors improve the signal-to-noise during data collection and the lifetime of the microcrystals can be prolonged by exploiting photoelectron escape. A novel in vacuo sample environment has been designed which also houses a scanning electron microscope to aid with sample visualization. This combination of features at VMXm allows measurements at the physical limits of X-ray crystallography on biomacromolecules to be explored and exploited.

Abstract Maternal asthma is associated with increased rates of neonatal lung disease, and fetuses from asthmatic ewes have fewer surfactant‐producing cells and lower surfactant‐protein B gene (SFTPB) expression than controls. Antenatal betamethasone increases lung surfactant production in preterm babies, and we therefore tested this therapy in experimental maternal asthma. Ewes were sensitised to house dust mite allergen, and an asthmatic phenotype induced by fortnightly allergen lung challenges; controls received saline. Pregnant asthmatic ewes were randomised to receive antenatal saline (asthma) or 12 mg intramuscular betamethasone (asthma+beta) at 138 and 139 days of gestation (term = 150 days). Lambs were delivered by Caesarean section at 140 days of gestation and ventilated for 45 min before tissue collection. Lung function and structure were similar in control lambs (n = 16, 11 ewes) and lambs from asthma ewes (n = 14, 9 ewes). Dynamic lung compliance was higher in lambs from asthma+beta ewes (n = 12, 8 ewes) compared to those from controls (P = 0.003) or asthma ewes (P = 0.008). Lung expression of surfactant protein genes SFTPA (P = 0.048) and SFTPB (P

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is associated with acute brain injury (ABI), including central nervous system (CNS) ischemia (defined as ischemic stroke or hypoxic-ischemic brain injury [HIBI]) and intracranial hemorrhage (ICH). Data on prediction models for neurologic outcomes in VV-ECMO are limited. Methods: We analyzed adult (age ≥18 years) VV-ECMO patients in the Extracorporeal Life Support Organization (ELSO) Registry (2009-2021) from 676 centers. ABI was defined as CNS ischemia, ICH, brain death, and seizures. Data on 67 variables were extracted, including clinical characteristics and pre-ECMO/on-ECMO variables. Random forest, CatBoost, LightGBM, and XGBoost machine learning (ML) algorithms (10-fold leave-one-out cross-validation) were used to predict ABI. Feature importance scores were used to pinpoint the most important variables for predicting ABI. Results: Of 37,473 VV-ECMO patients (median age, 48.1 years; 63% male), 2644 (7.1%) experienced ABI, including 610 (2%) with CNS ischemia and 1591 (4%) with ICH. The areas under the receiver operating characteristic curve for predicting ABI, CNS ischemia, and ICH were 0.70, 0.68, and 0.70, respectively. The accuracy, positive predictive value, and negative predictive value for ABI were 85%, 19%, and 95%, respectively. ML identified higher center volume, pre-ECMO cardiac arrest, higher ECMO pump flow, and elevated on-ECMO serum lactate level as the most important risk factors for ABI and its subtypes. Conclusions: This is the largest study of VV-ECMO patients to use ML to predict ABI reported to date. Performance was suboptimal, likely due to lack of standardization of neuromonitoring/imaging protocols and data granularity in the ELSO Registry. Standardized neurologic monitoring and imaging are needed across ELSO centers to detect the true prevalence of ABI.

Abstract Determining the genetic contributions to Parkinson’s disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study is part of the Global Parkinson’s Genetics Program, supported by the Aligning Science Across Parkinson’s initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population.

Abstract MYCN amplification predicts poor prognosis in childhood neuroblastoma. To identify MYCN oncogenic signal dependencies we performed N-ethyl-N-nitrosourea (ENU) mutagenesis on the germline of neuroblastoma-prone TH-MYCN transgenic mice to generate founders which had lost tumorigenesis. Sequencing of the mutant mouse genomes identified the Ring Finger Protein 121 (RNF121 WT ) gene mutated to RNFM158R associated with heritable loss of tumorigenicity. While the RNF121WT protein localised predominantly to the cis-Golgi Complex, the RNF121 M158R mutation in Helix 4 of its transmembrane domain caused reduced RNF121 protein stability and absent Golgi localisation. RNF121WT expression markedly increased during TH-MYCN tumorigenesis, whereas hemizygous RNF121 WT gene deletion reduced TH-MYCN tumorigenicity. The RNF121WT-enhanced growth of MYCN-amplified neuroblastoma cells depended on RNF121WT transmembrane Helix 5. RNF121WT directly bound MYCN protein and enhanced its stability. High RNF121 mRNA expression associated with poor prognosis in human neuroblastoma tissues and another MYC-driven malignancy, laryngeal cancer. RNF121 is thus an essential oncogenic cofactor for MYCN and a target for drug development.

On 5 April 2024, 10:23 a.m. local time, a moment magnitude 4.8 earthquake struck Tewksbury Township, New Jersey, about 65 km west of New York City. Millions of people from Virginia to Maine and beyond felt the ground shaking, resulting in the largest number (>180,000) of U.S. Geological Survey (USGS) “Did You Feel It?” reports of any earthquake. A team deployed by the Geotechnical Extreme Events Reconnaissance Association and the National Institute of Standards and Technology documented structural and nonstructural damage, including substantial damage to a historic masonry building in Lebanon, New Jersey. The USGS National Earthquake Information Center reported a focal depth of about 5 km, consistent with a lack of signal in Interferometric Synthetic Aperture Radar data. The focal mechanism solution is strike slip with a substantial thrust component. Neither mechanism’s nodal plane is parallel to the primary northeast trend of geologic discontinuities and mapped faults in the region, including the Ramapo fault. However, many of the relocated aftershocks, for which locations were augmented by temporary seismic deployments, form a cluster that parallels the general northeast trend of the faults. The aftershocks lie near the Tewksbury fault, north of the Ramapo fault.

Abstract We investigate the emergence, mutation profile, and dissemination of SARS-CoV-2 lineage B.1.214.2, first identified in Belgium in January 2021. This variant, featuring a 3-amino acid insertion in the spike protein similar to the Omicron variant, was speculated to enhance transmissibility or immune evasion. Initially detected in international travelers, it substantially transmitted in Central Africa, Belgium, Switzerland, and France, peaking in April 2021. Our travel-aware phylogeographic analysis, incorporating travel history, estimated the origin to the Republic of the Congo, with primary European entry through France and Belgium, and multiple smaller introductions during the epidemic. We correlate its spread with human travel patterns and air passenger data. Further, upon reviewing national reports of SARS-CoV-2 outbreaks in Belgian nursing homes, we found this strain caused moderately severe outcomes (8.7% case fatality ratio). A distinct nasopharyngeal immune response was observed in elderly patients, characterized by 80% unique signatures, higher B- and T-cell activation, increased type I IFN signaling, and reduced NK, Th17, and complement system activation, compared to similar outbreaks. This unique immune response may explain the variant's epidemiological behavior and underscores the need for nasal vaccine strategies against emerging variants.

Social media creates the possibility for rapid, viral spread of content, but how many posts actually reach millions? And is misinformation special in how it propagates? We answer these questions by analyzing the virality of and exposure to information on Facebook during the U.S. 2020 presidential election. We examine the diffusion trees of the approximately 1 B posts that were re-shared at least once by U.S.-based adults from July 1, 2020, to February 1, 2021. We differentiate misinformation from non-misinformation posts to show that (1) misinformation diffused more slowly, relying on a small number of active users that spread misinformation via long chains of peer-to-peer diffusion that reached millions; non-misinformation spread primarily through one-to-many affordances (mainly, Pages); (2) the relative importance of peer-to-peer spread for misinformation was likely due to an enforcement gap in content moderation policies designed to target mostly Pages and Groups; and (3) periods of aggressive content moderation proximate to the election coincide with dramatic drops in the spread and reach of misinformation and (to a lesser extent) political content.

Abstract Eliciting broadly neutralizing antibodies that protect against diverse HIV-1 strains is a primary goal of AIDS vaccine research. We characterized Ab1456 and Ab1271, two heterologously-neutralizing antibodies elicited in non-human primates by priming with an engineered V3-targeting SOSIP Env immunogen and boosting with increasingly native-like SOSIP Envs derived from different strain backgrounds. Structures of Env trimers in complex with these antibodies revealed V3 targeting, but on conformational states of Env distinct from the typical closed, prefusion trimeric SOSIP structure. Env trimers bound by Ab1456 adopted conformations resembling CD4-bound open Env states in the absence of soluble CD4, whereas trimers bound by Ab1271 exhibited a trimer apex-altered conformation to accommodate antibody binding. The finding that elicited antibodies cross-neutralized by targeting altered, non-closed, prefusion Env trimer conformations provides important information about Env dynamics that is relevant for HIV-1 vaccine design aimed at raising antibodies to desired epitopes on closed pre-fusion Env trimers.

Abstract Vaccines targeting the complex pre-erythrocytic stage of Plasmodium parasites may benefit from the inclusion of multiple antigens. However, discerning protective effects can be difficult because newer candidates may not be as protective as leading antigens like the circumsporozoite protein (CSP) in the conventional pre-clinical mouse model. We developed a modified mouse model challenge strategy that maximizes the contribution of T cells induced by novel candidate antigens at the sporozoite challenge time point and used this approach to test Plasmodium P36 and P52 vaccine candidates alone and in concert with non-protective doses of CSP. Co-administration of P36 and/or P52 with CSP achieved 80-100% sterile protection in mice, compared to only 7-30% protection for each individual antigen. P36 and P52 vaccination induced murine CD4+ and CD8+ T cell responses, but not antibody responses. This study adds P36 and P52 as promising vaccine antigens that may enhance the protection achieved by CSP vaccination.

Abstract Lipid-protein interactions are crucial for virtually all biological processes in living cells. However, existing structural databases focusing on these interactions are limited to integral membrane proteins. A systematic understanding of diverse lipid-protein interactions also encompassing lipid-anchored, peripheral membrane and soluble lipid binding proteins remains to be elucidated. To address this gap and facilitate the research of universal lipid-protein assemblies, we developed BioDolphin - a curated database with over 127,000 lipid-protein interactions. BioDolphin provides comprehensive annotations, including protein functions, protein families, lipid classifications, lipid-protein binding affinities, membrane association type, and atomic structures. Accessible via a publicly available web server ( www.biodolphin.chemistry.gatech.edu ), users can efficiently search for lipid-protein interactions using a wide range of options and download datasets of interest. Additionally, BioDolphin features interactive 3D visualization of each lipid-protein complex, facilitating the exploration of structure-function relationships. BioDolphin also includes detailed information on atomic-level intermolecular interactions between lipids and proteins that enable large scale analysis of both paired complexes and larger assemblies. As an open-source resource, BioDolphin enables global analysis of lipid-protein interactions and supports data-driven approaches for developing predictive machine learning algorithms for lipid-protein binding affinity and structures.

Abstract Electrochemical technologies add a unique dimension for ore refinement, representing tunable methods that can integrate with renewable energy sources and existing downstream process flows. However, the development of electrochemical extraction technologies has been impeded by the technological maturity of hydro- and pyro-metallurgy, as well as the electrical insulating properties of many metal oxide ores. The fabrication and use of carbon/insulating material composite electrodes has been a longstanding method to enable electrochemical activation. Here, using real hectorite ore, we employ this technical approach to fabricate hectorite-carbon black composite electrodes (HCCEs) and achieve electrochemical activation of hectorite. Anodic polarization results in lithium-ion release through a multi-step chemical and electrochemical mechanism that results in 50.7 ± 4.4% removal of lithium from HCCE, alongside other alkaline ions. This technical proof-of-concept study underscores that electrochemical activation of ores can facilitate lattice deterioration and ion removal from ores.

Abstract Large-scale modes of climate variability, such as the El Niño-Southern Oscillation, North Atlantic Oscillation, and Indian Ocean Dipole, show significant regional correlations with seasonal weather conditions, and are routinely forecast by meteorological agencies attempting to anticipate seasonal precipitation patterns. Here, we use machine learning together with more traditional approaches to quantify how much precipitation variability can be explained by large-scale modes of variability, and to understand the degree to which these modes interact non-linearly. We find that the relationship between climate modes and precipitation is predominantly non-linear. In some regions and seasons climate modes can explain up to 80% of precipitation variability. However, variability explained is below 10% for more than half of the land surface, and only 1% of the land shows values above 50%. This outcome provides a clear rationale to limit expectations of predictability from modes of variability in all but a few select regions and seasons.

Abstract In this case study, a self-described biofield therapy (BT) practitioner (participant) took part in multiple (n = 60) treatment and control (non-treatment) sessions under double-blind conditions. During the treatment phases, the participant provided BT treatment at a distance of about 12 inches from the cells, alternating with rest phases where no such efforts were made. Human pancreatic cancer cell activity was assessed using three markers – cytoskeleton changes (tubulin and β-actin) and Ca2+ uptake. The study examined changes in the participant’s physiological parameters including electroencephalogram (EEG) and heart rate measures during the treatment of: (1) live cells and (2) either dead cells or medium only with no cells (control group). Changes in cellular outcomes and if there was an association between the participant’s physiological parameters and cellular outcomes were examined. The experimental setup was a 2 × 2 design, contrasting cell type (live vs. control) against session type (treatment vs. non-treatment). Parallel sham-treated control cells were examined for changes in the cell parameters over time while controlling for the presence of a person in front of the cells mimicking the distance and movements of the participant. The participant’s physiological data, including 64-channel EEG and heart rate, were continuously monitored throughout these sessions. We observed significant (p

Abstract Impaired mucociliary transport is a distinguishing sign of cystic fibrosis, but current methods of evaluation are invasive or expose young patients to ionizing radiation. Contrast-enhanced ultrasound imaging may provide a feasible alternative. We formulated a cationic microbubble ultrasound contrast agent, to optimize adhesion to the respiratory mucus layer when inhaled. Potential toxicity was evaluated in human bronchial epithelial cell (hBEC) cultures following a 24-hour exposure, compared to positive and negative control conditions. In vivo tolerability and pulmonary image enhancement feasibility were evaluated in mice, comparing oropharyngeal administration of contrast agent to saline control. When induced to flow across mucus plated on microscope slides, cationic microbubbles demonstrated greater affinity for target samples than standard microbubbles. Cationic microbubbles elicited no proinflammatory or cytotoxic response in hBECs, nor were any cross-links to the cilia observed. Unlike standard microbubbles, cationic microbubbles mixed into the mucus layer, without epithelial absorption, and were observed to move with the mucus layer by the action of mucociliary transport. When administered to mice, cationic microbubbles enhanced sonographic visualization of the trachea, and were well-tolerated with no adverse effects. This developmental work supports the safety and feasibility of a mucus-targeting contrast agent that may be useful for pulmonary ultrasound applications.

Abstract Human visual attention allows prior knowledge or expectations to influence visual processing, allocating limited computational resources to only that part of the image that are likely to behaviourally important. Here, we present an image recognition system based on biological vision that guides attention to more informative locations within a larger parent image, using a sequence of saccade-like motions. We demonstrate that at the end of the saccade sequence the system has an improved classification ability compared to the convolutional neural network (CNN) that represents the feedforward part of the model. Feedback activations highlight salient image features supporting the explainability of the classification. Our attention model deviates substantially from more common feedforward attention mechanisms, which linearly reweight part of the input. This model uses several passes of feedforward and backward activation, which interact non-linearly. We apply our feedback architecture to histopathology patch images, demonstrating a 3.5% improvement in accuracy (p

Abstract Background The digitisation of healthcare records has generated vast amounts of unstructured data, presenting opportunities for improvements in disease diagnosis when clinical coding falls short, such as in the recording of patient symptoms. This study presents an approach using natural language processing to extract clinical concepts from free-text which are used to automatically form diagnostic criteria for lung cancer from unstructured secondary-care data. Methods Patients aged 40 and above who underwent a chest x-ray (CXR) between 2016 and 2022 were included. ICD-10 and unstructured data were pulled from their electronic health records (EHRs) over the preceding 12 months to the CXR. The unstructured data were processed using named entity recognition to extract symptoms, which were mapped to SNOMED-CT codes. Subsumption of features up the SNOMED-CT hierarchy was used to mitigate against sparse features and a frequency-based criteria, combined with univariate logarithmic probabilities, was applied to select candidate features to take forward to the model development phase. A genetic algorithm was employed to identify the most discriminating features to form the diagnostic criteria. Results 75002 patients were included, with 1012 lung cancer diagnoses made within 12 months of the CXR. The best-performing model achieved an AUROC of 0.72. Results showed that an existing ‘disorder of the lung’, such as pneumonia, and a ‘cough’ increased the probability of a lung cancer diagnosis. ‘Anomalies of great vessel’, ‘disorder of the retroperitoneal compartment’ and ‘context-dependent findings’, such as pain, statistically reduced the risk of lung cancer, making other diagnoses more likely. The performance of the developed model was compared to the existing cancer risk scores, demonstrating superior performance. Conclusions The proposed methods demonstrated success in leveraging unstructured secondary-care data to derive diagnostic criteria for lung cancer, outperforming existing risk tools. These advancements show potential for enhancing patient care and results. However, it is essential to tackle specific limitations by integrating primary care data to ensure a more thorough and unbiased development of diagnostic criteria. Moreover, the study highlights the importance of contextualising SNOMED-CT concepts into meaningful terminology that resonates with clinicians, facilitating a clearer and more tangible understanding of the criteria applied.

Abstract Knowledge gaps regarding human immunity to Streptococcus pyogenes have impeded vaccine development. To address these gaps and evaluate vaccine candidates, we established a human challenge model of S. pyogenes pharyngitis. Here, we analyse antibody responses in serum and saliva against 19 antigens to identify characteristics distinguishing 19 participants who developed pharyngitis and 6 who did not. We show that pharyngitis elicits serum IgG responses to key vaccine antigens and a muted mucosal IgA response, whereas IgG responses are minimal and IgA responses more pronounced in participants without pharyngitis. Serum IgG responses to pharyngitis in adult participants resemble those in children and are inversely correlated with the magnitude of pre-existing responses. While a straightforward correlate of protection is not evident, baseline antibody signatures distinguish clinical and immunological outcomes following experimental challenge. This highlights the influence of a complex humoral imprint from previous exposure, relevant for interpreting immunogenicity in forthcoming vaccine trials.

Abstract The emergence of SARS-CoV-2 into a highly susceptible global population was primarily driven by human mobility-induced introduction events. Especially in the early stages, understanding mobility was vital to mitigating the pandemic prior to widespread vaccine availability. We conducted a systematic review of studies published from January 1, 2020, to May 9, 2021, that used population-level human mobility data to understand SARS-CoV-2 transmission. Of the 5505 papers with abstracts screened, 232 were included in the analysis. These papers focused on a range of specific questions but were dominated by analyses focusing on the USA and China. The majority included mobile phone data, followed by Google Community Mobility Reports, and few included any adjustments to account for potential biases in population sampling processes. There was no clear relationship between methods used to integrate mobility and SARS-CoV-2 data and goals of analysis. When considering papers focused only on the estimation of the effective reproductive number within the US, there was no clear relationship identified between this measure and changes in mobility patterns. Our findings underscore the need for standardized, systematic ways to identify the source of mobility data, select an appropriate approach to using it in analysis, and reporting.

Abstract Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing fine-mapped associations with 73 traits. We replicate 23 of 31 (74%) of these associations in the All of Us cohort. While this set includes several known repeat expansion disorders, novel associations we found are attributable to common polymorphic variation in TR length rather than rare expansions and include e.g. a coding polyhistidine motif in HRCT1 influencing risk of hypertension and a poly(CGC) in the 5’UTR of GNB2 influencing heart rate. Fine-mapped TRs are strongly enriched for associations with local gene expression and DNA methylation. Our study highlights the contribution of multi-allelic TRs to the “missing heritability” of the human genome.

Abstract Background Epidermal growth factor receptor (EGFR) T790M mutation often occurs during long durational erlotinib treatment of non-small cell lung cancer (NSCLC) patients, leading to drug resistance and disease progression. Identification of new selective EGFR-T790M inhibitors has proven challenging through traditional screening platforms. With great advances in computer algorithms, machine learning improved the screening rates of molecules at full chemical spaces, and these molecules will present higher biological activity and targeting efficiency. Methods An integrated machine learning approach, integrated by Bayesian inference, was employed to screen a commercial dataset of 70,413 molecules, identifying candidates that selectively and efficiently bind with EGFR harboring T790M mutation. In vitro cellular assays and molecular dynamic simulations was used for validation. EGFR knockout cell line was generated for cross-validation. In vivo xenograft moues model was constructed to investigate the antitumor efficacy of CDDO-Me. Results Our virtual screening and subsequent in vitro testing successfully identified CDDO-Me, an oleanolic acid derivative with anti-inflammatory activity, as a potent inhibitor of NSCLC cancer cells harboring the EGFR-T790M mutation. Cellular thermal shift assay and molecular dynamic simulation validated the selective binding of CDDO-Me to T790M-mutant EGFR. Further experimental results revealed that CDDO-Me induced cellular apoptosis and caused cell cycle arrest through inhibiting the PI3K-Akt-mTOR axis by directly targeting EGFR protein, cross-validated by sgEGFR silencing in H1975 cells. Additionally, CDDO-Me could dose-depended suppress the tumor growth in a H1975 xenograft mouse model. Conclusion CDDO-Me induced apoptosis and caused cell cycle arrest by inhibiting the PI3K-Akt-mTOR pathway, directly targeting the EGFR protein. In vivo studies in a H1975 xenograft mouse model demonstrated dose-dependent suppression of tumor growth. Our work highlights the application of machine learning-aided drug screening and provides a promising lead compound to conquer the drug resistance of NSCLC. Graphical Abstract

Abstract Background The therapeutic alliance is an important predictor of treatment outcomes but people who use alcohol and other drugs report mixed views of treatment providers. We analysed patients’ accounts of inpatient detoxification staff to ascertain whether, and if so how, relationships with them, and thus the therapeutic alliance, might be improved. Methods Semi-structured qualitative interviews were conducted (in 2022/2023) with 20 people (14 males; 6 females) who had just completed inpatient detoxification in sixteen different facilities. Interviews were part of a larger longitudinal qualitative evaluation of an initiative to increase inpatient detoxification capacity across England. Results Patients described how treatment was delivered by professionals with diverse roles. They rated staff highly and appreciated their personal qualities; the standard of medical care and non-medical services they provided; their willingness to provide privacy, freedom and choice; the support given at key points in the treatment journey; and the positive impact staff relationships had on their substance use and lives more generally. Criticisms of staff were infrequent, mostly related to specific individuals or events, and potentially more common when detoxification occurred within general hospitals rather than within specialist services. Conclusions Patients’ accounts of staff in this study were more positive than documented in previous literature. However, the characteristics that patients appreciated (and disliked) were consistent with earlier research. There was scope to improve in some services and patient groups not interviewed may have held more negative views of staff. Overall, the holistic and patient-centred approach that staff adopted, and patients valued, appears to contribute to a good therapeutic alliance.

Abstract Cassava mosaic disease (CMD) and cassava brown streak disease (CBSD) are the two major threats to cassava production in eastern and southern Africa. There have been several interventions over the years in the fight against the two diseases. Whether these interventions have been effective or not can best be answered by continuous and periodic assessment of the diseases. This study was designed to determine the severity, incidence, and distribution of CMD and CBSD and their vector whiteflies in Malawi. Diagnostic surveys were carried out in 16 districts to assess CMD and CBSD parameters on the leaves in 2018. The magnitude of damage on cassava roots caused by CBSD was assessed in 12 districts. The study was designed also to identify alternative hosts for CMD and CBSD. The national mean CMD severity and incidence were 1.6 and 32%, respectively. The national mean CBSD severity and incidence were 1.3 and 75%, respectively. The highest number of whiteflies were recorded in Mangochi district with about 1.8 adult whiteflies per plant in farmer’s fields. There was positive correlation between disease incidence, severity and the number of adult whiteflies for both CMD and CBSD. CMD and CBSD incidence, severity and number of adult whiteflies negatively correlated with altitude. At national level, severity and incidence were higher for CMD than CBSD. CBSD foliar and root incidence and symptom severity were prominent along the shores of lake Malawi. In the contrary, CMD was not confined to the lakeshore areas. Karonga district had the highest CBSD root severity (2.1) and incidence (56%). The national mean percentage of cassava root necrosis was 5.3%. Based on these estimates, Malawi lost about US$ 42.7 million in 2018 due to CBSD root necrosis alone which could be extrapolated to the current cassava production systems. Therefore, it is imperative to improve disease management efforts while also considering the confirmed presence of alternative hosts for CMD in Malawi.

Abstract Background Worldwide, hepatocellular carcinoma (HCC) is the second most lethal cancer, although early-stage HCC is amenable to curative treatment and can facilitate long-term survival. Early detection has proved difficult, as proteomics, transcriptomics, and genomics have been unable to discover suitable biomarkers. Methods To find new biomarkers of HCC, we utilized a spatial omics N-glycan imaging method to identify altered glycosylation in cancer tissue (n = 53) and in paired serum of individuals with HCC (n = 23). Glycoproteomics identified the glycoproteins carrying these N-glycan structures, and we utilized an antibody array-based glycan imaging method to examine all the N-glycans associated with the identified glycoproteins. N-glycans from the examined glycoproteins were used to create machine learning algorithms, which were tested in a case-control sample set of 100 patients with cirrhosis and HCC and 101 matched patients with cirrhosis alone. Results Spatial glycan imaging identifies thirteen branched, fucosylated, and high mannose glycans as altered in HCC tissue and in matched patient serum. Glycoproteomics identifies over 50 proteins containing these changes, of which sixteen glycoproteins were selected for further testing in an independent patient set. Algorithms using a combination of glycan and glycoproteins accurately differentiate early-stage and all HCC from cirrhosis with AUROC values of 0.88–0.97. Conclusions In conclusion, we present the development and application of a new biomarker platform, which can identify effective biomarkers for the early detection of HCC. This platform may also apply to other diseases, in which changes in N-linked glycosylation are known to occur.

Abstract Background Breast and prostate tumors are known to be less responsive to immune checkpoint inhibitors (ICIs). Tissue-based tumor mutation burden (tTMB) has emerged as a predictive biomarker of response to ICIs, including in these “cold tumors”. In clinical practice, when tTMB is not available, blood-based TMB score (bTMB) can be used to consider treatment with ICIs. Methods This retrospective, real-world study included a final cohort of metastatic breast and prostate cancer patients treated with an ICI following a liquid biopsy test. Multiple bTMB-High cut-offs were assessed. Clinical, genomic, and outcomes data were collected. We hypothesized that a cut-off of bTMB ≥10 mut/Mb is not a strong predictor of response to ICIs in this setting. The Guardant Health genomic database (GHGD) was then queried (N = 13,992) for associations of bTMB with genomic alterations. Results In the clinical cohort (N = 48), ICI treatment is offered after a median of 3 (1–9) lines of treatment. The median bTMB is 16.4 (10–186) mut/Mb. The median time on ICI and PFS is 2.1 (0–1.7) and 3.1 months (95%CI, 1.6–4.6) respectively; no difference by MSI/MMR status (p = 0.152). Response rate among eligible patients (n = 36) is 16.7%; only N = 1/6 in bTMB

Abstract Background p53 is a tumor suppressor gene. p53 expression in epithelial ovarian tumors (EOTs) is correlated with their biological behavior and predicts patient overall survival. However, there is a dearth of knowledge regarding p53 expression in these tumors among women from southwest Nigeria. Our study aimed to determine the patterns of p53 expression in various types of epithelial ovarian tumours. Methods We conducted a retrospective study of epithelial ovarian tumours. We retrieved formalin-fixed, paraffin-embedded (FFPE) tissue blocks of previously diagnosed epithelial tumors from the departmental archive. We performed immunohistochemical analysis using p53 antibodies. We scored the expression and staining intensity of p53 as follows: negative (0), focal/weakly positive (1 +), and diffuse/strongly positive (2 +) on the basis of the recommended Cytomation scoring system. Results The spectrum of p53 expression in the 51 histologically diagnosed cases revealed that 29 cases had no expression, consisting of 21 benign EOTs, two borderline EOTs, and six malignant EOTs. Nine cases exhibited wild-type expression, including six serous carcinomas, two mucinous carcinomas, and one signet ring cell carcinoma. p53 overexpression was observed in 13 patients overall, with 12 having serous carcinomas and one having endometrioid carcinoma. Among the 21 serous carcinoma patients, 28.6% (6 patients) presented with wild-type p53 expression, 57.1% (12 patients) presented with p53 overexpression, and 14.3% (three patients) presented negative p53 expression. There was a significant association between p53 expression and the histological grade of serous carcinoma. Conclusion Most epithelial ovarian carcinomas in our hospital are high grade, with many serous carcinomas showing either p53 overexpression or loss of expression. This may contribute to the poor patient survival rate.

Abstract This study aimed to assess the human health risks associated with groundwater consumption in Abakaliki Metropolis using Water Quality Index (WQI) and HERisk code. Groundwater samples (n = 32) obtained from boreholes were analysed for pH, Zn, Pb. Fe, Cr and NO3 to evaluate both non-carcinogenic and carcinogenic health risks. The average concentrations of these parameters, except Pb (0.02 mg/L) and Cr (0.06 mg/L), were within permissible limits. The distribution of the average concentrations of the parameters followed the order: Zn > Cr > Fe > NO3 > Pb. The WQI ranged from 0.15 to 505.67 classifying 12.50% of the water samples as excellent sources of drinking water, 9.38% as good, 9.38% as poor, 12.50% as very poor and 56.25% unfit for drinking. The HERisk code revealed significant non-carcinogenic and carcinogenic health risks exceeding safety limits (

Abstract Background Disparities in breast cancer mortality persist despite improvements in screening and therapeutic options. Understanding the impact of social determinants of health on disparate breast cancer outcomes is challenging due to heterogeneity of prior assessments. We examined the association between social vulnerability and breast cancer stage at diagnosis and mortality using a standardized measure of population risk for external stressors on health. Methods Using institutional cancer registry data, female patients aged 18 or older diagnosed with breast cancer between 2012 and 2019 were assigned a 2018 Social Vulnerability Index (SVI) rank based upon home address census tract. We used multinomial logistic regression and Cox proportional hazards model to examine the relationships between SVI and breast cancer stage at diagnosis and all-cause mortality. Covariates included age and, when assessing mortality, cancer stage, comorbidities, body mass index, insurance type, and treatment regimen. Results A total of 3,499 women with a median age of 59 (IQR 48–69) were included. 60% were White and 31% were Black. Median SVI was 0.36 (IQR 0.14–0.68) and median follow-up was 58 months (IQR 37.3–83.9). On adjusted analyses, each decile increase in SVI resulted in an 11% (OR 1.11, 95% CI 1.06–1.16, p

Abstract Background Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. While PD-1 based immunotherapies overall have led to improved treatment outcomes for this disease, a diverse response to frontline chemotherapy and immunotherapy still exist in TNBC, highlighting the need for more robust prognostic markers. Methods Tumor-intrinsic immunotranscriptomics, serum cytokine profiling, and tumor burden studies were conducted in two syngeneic mouse models to assess differential effects in both the early-stage and metastatic setting. Bioinformatic analyses of both early and metastatic TNBC patient data were performed to assess if identified NF-κB-associated factors are associated with improved patient clinical outcomes. Results NF-κB signaling driven by lymphotoxin beta expression is associated with tumor regression in TNBC mouse models. Furthermore, lymphotoxin beta expression in patient TNBC cohorts is prognostic of improved survival outcomes. Conclusions This study highlights the potential role for NF-κB-associated factors, specifically lymphotoxin beta to be used as prognostic markers in TNBC, which could ultimately provide insight for improved targeted treatment approaches in the clinic.

Abstract The deep connection between Indigenous communities and nature plays a pivotal role in biodiversity conservation. Ethiopia, one of Africa's priority countries for bird conservation, harbours 821 bird species and 83 ethnic groups of Indigenous people. However, cultural and spiritual ties between Indigenous peoples and bird species remain largely unexplored. This is particularly true for remote Indigenous communities such as the Nuer. Relying on preexisting bird survey data, we conducted focussed group discussions and semi‐structured interviews with Indigenous Nuer in western Ethiopia to explore human–bird interactions and documented associated traditional ecological knowledge and considered their conservation implications. We found that Nuers have strong ties with birds. In Nuer community, birds are collectively known by three interchangeable terms: ‘gaatkuoth’ to mean sacred children of god, ‘kuoth’ meaning bearers of spirit and ‘diit’ symbols of human twins (since birds nurture multiple offspring, they associate the incidence of twins in human with birds). We identified 71 culturally important bird species that were used in seven different use categories. Among these species, 10 were used as bushmeat, five for traditional medicine, eight as fish indicators, seven as omens (believed to indicate upcoming misfortunes), three as amulets (believed to protect against danger when bird's body parts are used as necklaces and bracelets), three as season indicators and 45 for their scenic beauty. An informant consensus factor for species in all use categories was >90%, except for the scenic value, indicating a high homogeneity of knowledge about species uses. Bird species with multiple uses have significant cultural values among locals, emphasizing the need to understand these values in conservation efforts. Nuer traditional systems regulate the direct use of birds including for bushmeat. Hunting is permitted only by impoverished households during severe food shortages and is prohibited for those with a history of twins in their ancestry. The Nuer people exhibit a profound cultural connection to birds, viewing them as sacred and spiritually valuable beings. This deep‐seated reverence and traditional knowledge highlight the importance of integrating Indigenous perspectives into bird conservation strategies to enhance their effectiveness and respect cultural values. Read the free Plain Language Summary for this article on the Journal blog.

ABSTRACT: One suggested approach to improve the reproductive performance of dairy herds is through the targeted management of subgroups of biologically similar animals, such as those with similar probabilities of becoming pregnant, termed pregnancy risk. We aimed to use readily available farm data to develop predictive models of pregnancy risk in dairy cows. Data from a convenience sample of 108 dairy herds in the UK were collated, and each herd was randomly allocated, at a ratio of 80:20, to either training or testing datasets. Following data cleaning, there were a total of 78 herds in the training dataset and 20 herds in the testing dataset. Data were further split by parity into nulliparous, primiparous, and multiparous subsets. An XGBoost model was trained to predict the insemination outcome in each parity subset, with predictors from farm records of breeding, calving, and milk recording. Training data comprised 74,511 inseminations in 45,909 nulliparous animals, 86,420 inseminations in 39,439 primiparous animals, and 158,294 inseminations in 32,520 multiparous animals. The final models were evaluated by predicting with the testing data, comprising 31,740 inseminations in 19,647 nulliparous animals, 38,588 inseminations in 16,215 primiparous animals, and 65,049 inseminations in 12,439 multiparous animals. Model discrimination was assessed by calculating the area under receiver operating characteristic curves (AUC); model calibration was assessed by plotting calibration curves and compared across test herds by calculating the expected calibration error (ECE) in each test herd. The models were unable to discriminate between insemination outcomes with high accuracy, with an AUC of 0.63, 0.59, and 0.62 in the nulliparous, primiparous, and multiparous subsets, respectively. The models were generally well calibrated, meaning the model-predicted pregnancy risks were similar to the observed pregnancy risks. The mean (SD) ECE in the test herds was 0.038 (0.023), 0.028 (0.012), and 0.020 (0.008) in the nulliparous, primiparous, and multiparous subsets respectively. The predictive models reported here could theoretically be used to identify subgroups of animals with similar pregnancy risk to facilitate targeted reproductive management; or provide information about cows' relative pregnancy risk compared with the herd average, which may support on-farm decision making. Further research is needed to evaluate the generalizability of these predictive models and understand the source of variation in ECE between herds; however, this study demonstrates that it is possible to accurately predict pregnancy risk in dairy cows using readily available farm data.

Australia is a sink for low pathogenicity avian influenza viruses, with isolated circulation occurring on the continent. We report the incursion of a Eurasian low pathogenicity avian influenza H5 virus into Australia. This report benefits surveillance and diagnostic work because of the risk and current absence of highly pathogenic avian influenza A(H5N1).

We investigated a blastomycosis cluster among humans and canines in a neighborhood in Wisconsin, United States. We conducted interviews and collected serum specimens for Blastomyces antibody testing by enzyme immunoassay. Although no definitive exposure was identified, evidence supports potential exposures from the riverbank, riverside trails or yards, or construction dust.