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Abstract Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS of the 12 estimated phenotypes identified 28 genome-wide significant variants at 13 loci, one of which (in DAOA) has not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover unique biological mechanisms influencing quantitative traits.

Abstract Perinatal traits are influenced by fetal and maternal genomes. We investigate the performance of three strategies to detect loci in maternal and fetal genome-wide association studies (GWASs) of the same quantitative trait: (i) the traditional strategy of analysing maternal and fetal GWASs separately; (ii) a two-degree-of-freedom test which combines information from maternal and fetal GWASs; and (iii) a one-degree-of-freedom test where signals from maternal and fetal GWASs are meta-analysed together conditional on estimated sample overlap. We demonstrate that the optimal strategy depends on the extent of sample overlap, correlation between phenotypes, whether loci exhibit fetal and/or maternal effects, and whether these effects are directionally concordant. We apply our methods to summary statistics from a recent GWAS meta-analysis of birth weight. Both the two-degree-of-freedom and meta-analytic approaches increase the number of genetic loci for birth weight relative to separately analysing the scans. Our best strategy identifies an additional 62 loci compared to the most recently published meta-analysis of birth weight. We conclude that whilst the two-degree-of-freedom test may be useful for the analysis of certain perinatal phenotypes, for most phenotypes, a simple meta-analytic strategy is likely to perform best, particularly in situations where maternal and fetal GWASs only partially overlap.

Abstract The organization of DNA into nucleosomes is a ubiquitous and ancestral feature that was once thought to be exclusive to the eukaryotic domain of life. Intriguingly, several representatives of the Nucleocytoplasmic Large DNA Viruses (NCLDV) encode histone-like proteins that in Melbournevirus were shown to form nucleosome-like particles. Medusavirus medusae (MM), a distantly related giant virus, encodes all four core histone proteins and, unique amongst most giant viruses, a putative acidic protein with two domains resembling eukaryotic linker histone H1. Here, we report the structure of nucleosomes assembled with MM histones and highlight similarities and differences with eukaryotic and Melbournevirus nucleosomes. Our structure provides insight into how variations in histone tail and loop lengths are accommodated within the context of the nucleosome. We show that MM-histones assemble into tri-nucleosome arrays, and that the putative linker histone H1 does not function in chromatin compaction. These findings expand our limited understanding of chromatin organization by virus-encoded histones.

Abstract Globally, aquatic ecosystems are one of the largest but most uncertain sources of methane, a potent greenhouse gas. It is unclear how climate change will affect methane emissions, but recent work suggests that glacial systems, which are melting faster with climate change, may be an important source of methane to the atmosphere. Currently, studies quantifying glacial emissions are limited in number, and the role of methanotrophy, or microbial methane oxidizers, in reducing atmospheric emissions from source and receiving waters is not well known. Here we discuss three potential sites for methane oxidation that could mitigate emissions from glaciers into the atmosphere: under ice oxidation, oxidation within proglacial lakes, and oxidation within melt rivers. The research presented here increases the number of glacial sites with methane concentration data and is one of only a few studies to quantify the net microbial activity of methane production and oxidation in two types of land-terminating glacial runoff (lake and river). We find that oxidation in a glacial river may reduce atmospheric methane emissions from glacial melt by as much as 53%. Incorporating methane oxidation in estimates of glacial methane emissions may significantly reduce the estimated magnitude of this source in budgeting exercises.

Abstract Wildfires can produce large plumes of smoke that are transported across vast distances, altering nutrient cycling of undisturbed watersheds exposed downwind. To date, wildfire smoke influence on stream biogeochemical signatures remains an important knowledge gap. Here we evaluate the impacts of wildfire smoke on phosphorus (P) biogeochemical cycling in a temperate watershed in the Finger Lakes Region of Central New York located downwind from record setting Canadian forest fires during the summer of 2023. Daily sampling of stream and rainwaters was conducted over the 2 month smoke period, generating a robust geochemical dataset. Stream dissolved P showed high sensitivity to smoke events, attaining concentrations 2–3 × greater than the pre-smoke period. Subsequent rain events after smoke deposition were identified as a potentially important factor in magnitude and timing of dissolved P responses. These findings demonstrate the capacity for wildfire smoke to trigger rapid, observable changes to stream P chemistry.

Abstract Young children receiving outpatient cancer care are vulnerable to undermanaged pain. App‐based solutions that provide pain treatment advice to parents in real‐time and in all environments may improve access to quality pain care. We used a parent co‐design approach involving iterative rounds of user testing and software modification to develop a usable Pain Caregiver Resource (PainCaRe) real‐time pediatric cancer pain management app. Parents of children (2–11 years) with cancer completed three standardized modules using a PainCaRe prototype. App usability and acceptability were evaluated using the validated System Usability Scale and a thematic analysis of app testing sessions and interviews. Iterative testing sessions were conducted until data saturation. Interview themes were synthesized into action items that guided revisions to PainCaRe and additional testing rounds were conducted as necessary. Twenty‐two parents participated in three testing cycles. Overall, parents described PainCaRe as an acceptable and potentially clinically useful pain management tool. Mean system usability scores were in the acceptable scale range during each testing cycle. Usability issues identified and resolved included those related to software malfunction, complicated app navigation logic, lack of clarity on pain assessment questions, and the need for pain management advice specifically tailored to child developmental stage. Using co‐design methods, the PainCaRe cancer pain management app was successfully refined for its acceptability and utility to parents. Next steps will include a PainCaRe pilot study before evaluating the impact of the app on younger children's pain outcomes in a randomized controlled trial.

Background and Purpose The management of acute ischemic stroke (AIS) due to distal medium vessel occlusion (DMVO) remains uncertain, particularly in comparing the effectiveness of intravenous thrombolysis (IVT) plus mechanical thrombectomy (MT) versus IVT alone. This study aimed to evaluate the safety and efficacy in DMVO patients treated with either MT-IVT or IVT alone. Methods This multinational study analyzed data from 37 centers across North America, Asia, and Europe. Patients with AIS due to DMVO were included, with data collected from September 2017 to July 2023. The primary outcome was functional independence, with secondary outcomes including mortality and safety measures such as types of intracerebral hemorrhage. Results The study involved 1,057 patients before matching, and 640 patients post-matching. Functional outcomes at 90 days showed no significant difference between groups in achieving good functional recovery (modified Rankin Scale 0–1 and 0–2), with adjusted odds ratios (OR) of 1.21 (95% confidence interval [CI] 0.81 to 1.79; P=0.35) and 1.00 (95% CI 0.66 to 1.51; P>0.99), respectively. Mortality rates at 90 days were similar between the two groups (OR 0.75, 95% CI 0.44 to 1.29; P=0.30). The incidence of symptomatic intracerebral hemorrhage was comparable, but any type of intracranial hemorrhage was significantly higher in the MT-IVT group (OR 0.43, 95% CI 0.29 to 0.63; P

Abstract Intracellular infections by Gram-negative bacteria are a significant global health threat. The nuclear receptor Nur77 (also called TR3, NGFI-B, or NR4A1) was recently shown to sense cytosolic bacterial lipopolysaccharide (LPS). However, the potential role for Nur77 in controlling intracellular bacterial infection has not been examined. Here we show that Nur77 protects against intracellular infection in the bladder by uropathogenic Escherichia coli (UPEC), the leading cause of urinary tract infections (UTI). Nur77 deficiency in mice promotes the formation of UPEC intracellular bacterial communities (IBCs) in the cells lining the bladder lumen, leading to persistent infection in bladder tissue. Conversely, treatment with a small-molecule Nur77 agonist, cytosporone B, inhibits invasion and enhances the expulsion of UPEC from human urothelial cells in vitro, and significantly reduces UPEC IBC formation and bladder infection in mice. Our findings reveal a new role for Nur77 in control of bacterial infection and suggest that pharmacologic agonism of Nur77 function may represent a promising antibiotic-sparing therapeutic approach for UTI.

Abstract Sarcoidosis and tuberculosis (TB) are two granulomatous diseases that often share overlapping clinical features, including uveitis. We measured 368 inflammation-related proteins in serum in both diseases, with and without uveitis from two distinct geographically separated cohorts: sarcoidosis from the Netherlands and TB from Indonesia. A total of 192 and 102 differentially expressed proteins were found in sarcoidosis and active pulmonary TB compared to their geographical healthy controls, respectively. While substantial overlap exists in the immune-related pathways involved in both diseases, activation of B cell activating factor (BAFF) signaling and proliferation-inducing ligand (APRIL) mediated signaling pathways was specifically associated with sarcoidosis. We identified a B-lymphocyte activation signature consisting of BAFF, TNFRSF13B/TACI, TRAF2, IKBKG, MAPK9, NFATC1, and DAPP1 that was associated with sarcoidosis, regardless of the presence of uveitis. In summary, a difference in B-lymphocyte activation is a key discriminative immunological feature between sarcoidosis/ocular sarcoidosis (OS) and TB/ocular TB (OTB).

Abstract Background The aim of this study was to describe salivary flow rate, subjective oral dryness and dental caries 5 years post haematopoietic cell transplantation (HCT). Methods HCT survivors of a previous longitudinal observational cohort study in the Netherlands (the H-OME study) were invited to participate in this additional follow-up after 5 years (the HOME2 study). During the additional follow-up appointment, stimulated (SWS) and unstimulated whole saliva (UWS) was collected, participants rated subjective oral dryness on a 0 – 10 scale, and caries lesions were assessed. Furthermore, dental records, including treatments and radiographs, were requested for the 5 years preceding and the 5 years following transplantation. Paired t-tests were performed to determine changes in UWS and SWS flow rates and subjective oral dryness from pre-HCT, and to compare the number of caries-related dental treatments (restorations, endodontic treatments or extractions) before and after HCT. Hyposalivation of UWS ( 3 treatments) over the 5 years post-HCT. Results Five years post-HCT, 39 HCT survivors were included. The mean UWS flow rate was 0.36 mL/min (SD 0.26) and the mean SWS flow rate 1.02 (SD 0.57); survivors were diagnosed with a median of 0 dentine lesions (range 0 – 12) and 73% reported a subjective oral dryness score ≥ 1. Survivors underwent a median of 3 (range 0 – 20) dental treatments during the 5 years following transplantation. The mean difference in UWS 5 years post-HCT compared to pre-HCT was 0.03 (95% CI: -0.07 – 10.12), the mean difference for SWS was -0.18 (95% CI: -0.45 – 0.08) and for subjective oral dryness 1.2 (95% CI: 0.2 – 2.1). In the 5 years post-HCT, non-significantly more treatments were performed compared to the 5 years pre-HCT (mean difference: 0.5, 95%CI: -1.2 – 2.2). Seventy eight percent of patients with hyposalivation of SWS at 12 months had a high dental treatment need, compared with 38% with no hyposalivation. Conclusions Five years post-HCT, mean UWS and SWS flow rates were not significantly different from pre-HCT levels but subjective oral dryness scores were elevated.

Abstract The contribution of endocardial cells (EdCs) to the hematopoietic lineages has been strongly debated. Here, we provide evidence that in zebrafish, the endocardium gives rise to and maintains a stable population of hematopoietic cells. Using single-cell sequencing, we identify an endocardial subpopulation expressing enriched levels of hematopoietic-promoting genes. High-resolution microscopy and photoconversion tracing experiments uncover hematopoietic cells, mainly hematopoietic stem and progenitor cells (HSPCs)/megakaryocyte-erythroid precursors (MEPs), derived from EdCs as well as the dorsal aorta stably attached to the endocardium. Emergence of HSPCs/MEPs in hearts cultured ex vivo without external hematopoietic sources, as well as longitudinal imaging of the beating heart using light sheet microscopy, support endocardial contribution to hematopoiesis. Maintenance of these hematopoietic cells depends on the adhesion factors Integrin α4 and Vcam1 but is at least partly independent of cardiac trabeculation or shear stress. Finally, blocking primitive erythropoiesis increases cardiac-residing hematopoietic cells, suggesting that the endocardium is a hematopoietic reservoir. Altogether, these studies uncover the endocardium as a resident tissue for HSPCs/MEPs and a de novo source of hematopoietic cells.

Abstract Background Diet and exercise are important components of treatment for complex chronic conditions, however access to allied health support is limited. When available, support is often siloed and fragmented. Digital health incorporating patient choice may help to align health care services with preferences and goals. This study evaluated the implementation of a ubiquitously accessible patient-centred digital health diet and exercise service. Methods U-DECIDE was a single-centre, 26-week randomised controlled trial set in kidney and liver disease clinics in a tertiary hospital in Brisbane, Australia. Participants were adults with a complex chronic condition referred for dietetic consultation with at least one feature of the metabolic syndrome. All participants received a dietary consultation, an activity monitor and usual care. Intervention participants were offered one text message per week and access to additional digital health options (increased text message frequency, nutrition app, exercise app, group-based diet and/or exercise video consultations). The primary outcome of feasibility was determined by safety (study-related serious adverse events: SRSAEs), recruitment (≥ 50% eligible patients), retention (≥ 70%), exposure uptake (≥ 75% of intervention group had greater access to health professional contact than comparator) and video consultation adherence (≥ 80% attendance). Secondary outcomes included process evaluation metrics and clinical outcomes. Results Of 67 participants (intervention n = 33, comparator n = 34), 37 (55%) were men, median (IQR) age was 51 (41–58) years. The most chosen digital health options were the nutrition app (n = 29, 88%) and exercise video consultations (n = 26, 79%). Only one participant chose no additional digital health options. The intervention group had no SRSAEs. The study exceeded targets for recruitment (52%), retention (81%) and exposure uptake (94%). Video consultation adherence was 42%. Engagement across digital health options was inconsistent. Conclusions Digital health options incorporating patient choice were feasible and can be offered to people with complex chronic disease as a service model option. Trial registration Australia and New Zealand Trials Register: Trial Registration Number: ACTRN12620001282976. Registered 27th November 2020.

Abstract Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. For the alveolar subtype (ARMS), the presence of the PAX3::FOXO1 fusion gene and/or metastases are strong predictors of poor outcome. Metastatic PAX3::FOXO1 + ARMS often responds to chemotherapies initially, only to subsequently relapse and become resistant with most patients failing to survive beyond 8 years post-diagnosis. No curative intent phase II or phase III clinical trial has been available for patients in the past 10 years (ARST0921). Thus, metastatic ARMS represents a significantly unmet clinical need. Chemotherapy resistance in ARMS has previously been attributed to PAX3::FOXO1-mediated cell cycle checkpoint adaptation, which is mediated by an HDAC3-SMARCA4-miR-27a-PAX3::FOXO1 circuit that can be disrupted by HDAC3 inhibition. In this study, we investigated the therapeutic efficacy of combining the epigenetic regulator entinostat, a Class I Histone Deacetylase (HDAC1-3) inhibitor, with RMS-specific chemotherapies in patient derived xenograft (PDX) models of RMS. We identified single agent, additive or synergistic relationships between relapse-specific chemotherapies and clinically relevant drug exposures of entinostat in three PAX3::FOXO1 + ARMS mouse models. This preclinical data provides further rationale for clinical investigation of entinostat, already known to be well tolerated in a pediatric phase I clinical trial (ADVL1513).

Abstract Background Asthma is a leading cause of children’s hospitalizations, emergency department visits, and missed school days. Our school-based asthma intervention has reduced asthma exacerbations for children experiencing health disparities in the Denver Metropolitan Area, due partly to addressing care coordination for asthma and social determinants of health (SDOH), such as access to healthcare and medications. Limited dissemination of school-based asthma programs has occurred in other metropolitan and rural areas of Colorado. We formed and engaged community advisory boards in socioeconomically diverse regions of Colorado to develop two implementation strategy packages for delivering our school-based asthma intervention — now termed “Better Asthma Control for Kids (BACK)" — with tailoring to regional priorities, needs and resources. Methods In this proposed type 2 hybrid implementation-effectiveness trial, where the primary goal is equitable reach to families to reduce asthma disparities, we will compare two different packages of implementation strategies to deliver BACK across four Colorado regions. The two implementation packages to be compared are: 1) standard set of implementation strategies including Tailor and Adapt to context, Facilitation and Training termed, BACK-Standard (BACK-S); 2) BACK-S plus an enhanced implementation strategy, that incorporates network weaving with community partners and consumer engagement with school families, termed BACK-Enhanced (BACK-E). Our evaluation will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, including its Pragmatic Robust Implementation Sustainability Model (PRISM) determinants of implementation outcomes. Our central hypothesis is that our BACK-E implementation strategy will have significantly greater reach to eligible children/families than BACK-S (primary outcome) and that both BACK-E and BACK-S groups will have significantly reduced asthma exacerbation rates (“attacks”) and improved asthma control as compared to usual care. Discussion We expect both the BACK-S and BACK-E strategy packages will accelerate dissemination of our BACK program across the state – the comparative impact of BACK-S vs. BACK-E on reach and other RE-AIM outcomes may inform strategy selection for scaling BACK and other effective school-based programs to address chronic illness disparities. Trial registration Clinicaltrials.gov identifier: NCT06003569, registered on August 22, 2023, https://classic.clinicaltrials.gov/ct2/show/NCT06003569 .

Abstract Lassa fever virus (LASV), a member of the Arenavirus family, is the etiological agent of Lassa fever, a severe hemorrhagic disease that causes considerable morbidity and mortality in the endemic areas of West Africa. LASV is a rodent-borne CDC Tier One biological threat agent and is on the World Health Organization’s (WHO) Priority Pathogen list. Currently, no FDA-licensed vaccines or specific therapeutics are available. Here, we describe the efficacy of a deactivated rabies virus (RABV)-based vaccine encoding the glycoprotein precursor (GPC) of LASV (LASSARAB). Nonhuman primates (NHPs) were administered a two-dose regimen of LASSARAB or an irrelevant RABV-based vaccine to serve as a negative control. NHPs immunized with LASSARAB developed strong humoral responses to LASV-GPC. Upon challenge, NHPs vaccinated with LASSARAB survived to the study endpoint, whereas NHPs in the control group did not. This study demonstrates that LASSARAB is a worthy candidate for continued development.

Abstract Objectives The clinical activity score (CAS) and European severity scale (ESS) are established clinical tools to assess thyroid eye disease (TED) but are limited in terms of subjectivity and their reliability in non-Caucasian individuals, and can underestimate significant disease in the posterior orbit. Preliminary data from pilot studies have shown that diffusion-weighted imaging (DWI) using extraocular muscle (EOM) apparent diffusion coefficient (ADC) measurements may provide complementary information in TED. This study expands on previous research to assess for correlations between clinical scores and EOM-ADCs in stratifying disease activity and severity in a large patient cohort from an ethnically diverse population. Methods A retrospective review of TED clinics between 2011 and 2021 identified 96 patients with a documented CAS and ESS and an orbital MRI that included DWI. From regions of interest manually placed on EOM bellies, the highest ADC was computed for each patient and analysed for correlations and associations with CAS and ESS using Spearman Rank correlation and Mann–Whitney U tests, and any potential discriminatory cut-offs using Receiver Operator Curve analyses. A p-value

Abstract The COVID-19 pandemic has led to the deaths of millions of people and severe global economic impacts. Small molecule therapeutics have played an important role in the fight against SARS-CoV-2, the virus responsible for COVID-19, but their efficacy has been limited in scope and availability, with many people unable to access their benefits, and better options are needed. EDP-235 is specifically designed to inhibit the SARS-CoV-2 3CLpro, with potent nanomolar activity against all SARS-CoV-2 variants to date, as well as clinically relevant human and zoonotic coronaviruses. EDP-235 maintains potency against variants bearing mutations associated with nirmatrelvir resistance. Additionally, EDP-235 demonstrates a ≥ 500-fold selectivity index against multiple host proteases. In a male Syrian hamster model of COVID-19, EDP-235 suppresses SARS-CoV-2 replication and viral-induced hamster lung pathology. In a female ferret model, EDP-235 inhibits production of SARS-CoV-2 infectious virus and RNA at multiple anatomical sites. Furthermore, SARS-CoV-2 contact transmission does not occur when naïve ferrets are co-housed with infected, EDP-235-treated ferrets. Collectively, these results demonstrate that EDP-235 is a broad-spectrum coronavirus inhibitor with efficacy in animal models of primary infection and transmission.

Patients undergoing transurethral resection of the prostate (TURP) surgery can develop TURP syndrome and post-TURP bleeding. Post-TURP bleeding can be surgical, from arteries or venous sinuses, or non-surgical, due to coagulopathy preventing clot formation. Non-surgical post-TURP bleeding may be due to high concentrations of urokinase and tissue plasminogen activator (tPA) in the urine that cause fibrinolytic changes and increase bleeding risk. Urine urokinase and tPA may have both local and systemic fibrinolytic effects that may prevent blood clot formation locally at the site of surgery, and cause fibrinolytic changes systemically through leaking into the blood stream. Another post-TURP complication that may happen is TURP syndrome, due to absorption of hypotonic glycine fluid through the prostatic venous plexus. TURP syndrome may present with hyponatremia, bradycardia, and hypotension, which may be preceded by hypertension. In this case report, we had a patient with benign prostatic hyperplasia (BPH) who developed both TURP syndrome and non-surgical post-TURP bleeding. These complications were transient for one day after surgery. The local effect of urine urokinase and tPA explains the non-surgical bleeding after TURP by preventing clot formation and inducing bleeding. Coagulation studies showed fibrinolytic changes that may be explained by urokinase and tPA leakage into the blood stream. In conclusion, non-surgical bleeding after TURP can be explained by the presence of fibrinolytic agents in the urine, including urokinase and tPA. There is a deficiency in existing studies explaining the pathophysiology of the fibrinolytic changes and risk of bleeding after TURP. Herein, we discuss the possible pathophysiology of developing fibrinolytic changes after TURP. More research effort should be directed to explore this area to investigate the appropriate medications to treat and prevent post-TURP bleeding. We suggest monitoring patients’ coagulation profiles and electrolytes after TURP because of the risk of developing severe acute hyponatremia, TURP syndrome, fibrinolytic changes, and non-surgical bleeding. In our review of the literature, we discuss current clinical trials testing the use of an antifibrinolytic agent, Tranexamic acid, locally in the irrigation fluid or systemically to prevent post-TURP bleeding by antagonizing the fibrinolytic activity of urine urokinase and tPA.

ABSTRACT Acarbose is a type 2 diabetes medicine that prevents dietary starch breakdown into glucose by inhibiting host amylase and glucosidase enzymes. Numerous gut species in the Bacteroides genus enzymatically break down starch and change in relative abundance within the gut microbiome in acarbose-treated individuals. To mechanistically explain this observation, we used two model starch-degrading Bacteroides, Bacteroides ovatus (Bo), and Bacteroides thetaiotaomicron (Bt). Bt growth on starch polysaccharides is severely impaired by acarbose, whereas Bo growth is much less affected by the drug. The Bacteroides use a starch utilization system (Sus) to grow on starch. We hypothesized that Bo and Bt Sus enzymes are differentially inhibited by acarbose. Instead, we discovered that although acarbose primarily targets the Sus periplasmic GH97 enzymes in both organisms, the drug affects starch processing at multiple other points. Acarbose competes for transport through the TonB-dependent SusC proteins and binds to the Sus transcriptional regulators. Furthermore, Bo expresses a non-Sus GH97 (BoGH97D) when grown in starch with acarbose. The Bt homolog, BtGH97H, is not expressed in the same conditions, nor can overexpression of BoGH97D complement the Bt growth inhibition in the presence of acarbose. This work informs us about unexpected complexities of Sus function and regulation in Bacteroides, including variation between related species. Furthermore, this indicates that the gut microbiome may be a source of variable response to acarbose treatment for diabetes.IMPORTANCEAcarbose is a type 2 diabetes medication that works primarily by stopping starch breakdown into glucose in the small intestine. This is accomplished by the inhibition of host enzymes, leading to better blood sugar control via reduced ability to derive glucose from dietary starches. The drug and undigested starch travel to the large intestine where acarbose interferes with the ability of some bacteria to grow on starch. However, little is known about how gut bacteria interact with acarbose, including microbes that can use starch as a carbon source. Here, we show that two gut species, Bacteroides ovatus (Bo) and Bacteroides thetaiotaomicron (Bt), respond differently to acarbose: Bt growth is inhibited by acarbose, while Bo growth is less affected. We reveal a complex set of mechanisms involving differences in starch import and sensing behind the different Bo and Bt responses. This indicates the gut microbiome may be a source of variable response to acarbose treatment for diabetes via complex mechanisms in common gut microbes.

Per- and poly-fluoroalkyl substances (PFAS) are chemicals of concern—they are ubiquitous, persistent, with known and suspected health impacts. Well studied, primary sources of exposure to PFAS are drinking water and food. The presence of PFAS in human tissue of general populations suggests other important exposure sources/pathways. House dust measurements suggest widespread presence of PFAS in residences. Limited studies report paired analyses of PFAS occurrence in indoor media and PFAS concentrations in serum. While paired samples of house dust and blood serum are currently rare, the National Children’s Study (NCS) contains paired samples, as well as sociodemographic information, from pregnant people that participated in the study. These archived NCS data and specimens for 104 participants collected between 2009 and 2014 were leveraged and analyzed for 16 commonly measured PFAS. We evaluated PFAS levels in the home, and the relationships between PFAS in dust and serum, and sociodemographic or housing variables. In addition, mechanistic exposure models, and then steady-state serum level models with simple parameters were used to estimate dust contributions of PFAS to serum. The geometric means for the most commonly found PFAS (full names in table 1) in serum were: 4.1 ng/mL for PFOS, 1.1 ng/mL for PFOA, 0.87 ng/mL for PFHxS, 0.16 ng/mL for PFDA. The geometric means of PFAS in dust were: 17 µg/kg for PFOS, 16 µg/kg for PFOA, 9.6 µg/kg for PFDS, 4.5 µg/kg for PFHpA, 4.4 µg/kg for PFNA, 3.9 µg/kg for PFHxS, 3.5 µg/kg for PFDA, 2.3 µg/kg for PFDoA, 2.1 µg/kg for PFUdA. PFOA was significantly correlated in serum and dust as was the sum of all PFAS detected in > 50 % of serum and dust. PFAS in serum was significantly associated with: Higher income, recent renovations, years lived in the home, and educational attainment. PFAS in dust was significantly associated with: Higher participant age, type of home, amount of carpet, educational attainment, higher income, recent renovation, and membership in the military. For some PFAS, 25 % of the overall exposure, on average, is from dust, but for others, 3–4 % is attributed to dust.We were able to identify important associations in PFAS exposure in the homes of pregnant people based on paired serum and dust samples. This built a clearer picture of which PFAS and at what quantities they exist in these homes, how they relate to each other, and how they are tied to sociodemographic and housing factors. Our results demonstrate that exposure to PFAS via house dust may contribute up to 25% of total exposure for adults, highlighting the importance of understanding what drives residential exposures.

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.

ABSTRACTDengvaxia is the first dengue vaccine recommended in the United States (U.S.). It is recommended for children aged 9–16 y with laboratory-confirmed previous dengue infection and living in areas where dengue is endemic. We conducted focus groups with parents and in-depth interviews with key informants (i.e. practicing pediatricians, physicians from immunization clinics, university researchers, and school officials) in Puerto Rico (P.R.) to examine acceptability, barriers, and motivators to vaccinate with Dengvaxia. We also carried out informal meetings and semi-structured interviews to evaluate key messages and educational materials with pediatricians and parents. Barriers to vaccination included lack of information, distrust toward new vaccines, vaccine side effects and risks, and high cost of/lack of insurance coverage for laboratory tests and vaccines. Motivators included clear information about the vaccine, a desire to prevent future dengue infections, the experience of a previous dengue infection or awareness of dengue fatality, vaccine and laboratory tests covered by health insurance, availability of rapid test results and vaccine appointments. School officials and parents agreed parents would pay a deductible of $5–20 for Dengvaxia. For vaccine information dissemination, parents preferred an educational campaign through traditional media and social media, and one-on-one counseling of parents by healthcare providers. Education about this vaccine to healthcare providers will help them answer parents’ questions. Dengvaxia acceptability in P.R. will increase by addressing motivators and barriers to vaccination and by disseminating vaccine information in plain language through spokespersons from health institutions in P.R.

Background: This targeted and comprehensive policy scan examined how different levels of governments in Australia and Canada responded to the financial crisis brought on by the COVID-19 pandemic. We mapped the types of early policy responses addressing financial strain and promoting financial wellbeing. We also examined their equity considerations. Methods: Through a systematic search, snowballing, and manual search, we identified Canadian and Australian policies at all government levels related to financial strain or financial wellbeing enacted or amended in 2019–2020. Using a deductive-inductive approach, policies were categorized by jurisdiction level, focal areas, and target population groups. Results: In total, 213 and 97 policies in Canada and Australia, respectively, were included. Comparisons between Canadian and Australian policies indicated a more diversified and equity-targeted policy landscape in Canada. In both countries, most policies focused on individual and family finances, followed by housing and employment areas. Conclusions: The policy scan identified gaps and missed opportunities in the early policies related to financial strain and financial wellbeing. While fast, temporary actions addressed individuals’ immediate needs, we recommend governments develop a longer-term action plan to tackle the root causes of financial strain and poor financial wellbeing for better health and non-health crisis preparedness. Statement on Ethics and Informed Consent: This research reported in this paper did not require ethical clearance or patient informed consent as the data sources were published policy documents. This study did not involve data collection with humans (or animals), nor any secondary datasets involving data provided by humans (or from animal studies).

Background: The NOVA study (NCT01847274) compared niraparib with placebo as a maintenance treatment for patients with recurrent ovarian cancer (OC) but was not powered to detect an overall survival (OS) improvement. Objective: To compare OS in a real-world population of patients with BRCA wild-type ( BRCA wt) recurrent OC who received second-line maintenance (2LM) niraparib monotherapy versus active surveillance (AS). Design: A retrospective study using a US-based nationwide deidentified electronic health record-derived database. Methods: Patients diagnosed with epithelial OC (January 1, 2011–May 31, 2021) who completed second-line (2L) therapy (January 1, 2017–March 2, 2022) and were BRCA wt were included. A NOVA study-like subpopulation included patients with an Eastern Cooperative Oncology Group performance status score of 0–1 and platinum-sensitive disease. Patients were assigned to 2LM niraparib or AS cohorts. Follow-up was measured from the index date (2L non-maintenance therapy end) until the first of study end (May 31, 2022), last clinical activity, or death. Median OS (mOS) and hazard ratios were estimated with an emulated trial methodology. Results: The overall population comprised 199 patients in the 2LM niraparib monotherapy cohort and 707 patients in the AS cohort; the NOVA study-like subpopulation included 123 patients in the 2LM niraparib monotherapy cohort and 143 in the AS cohort. Demographic and clinical characteristics were similar in both populations. Overall, adjusted mOS was 24.1 months for the 2LM niraparib monotherapy cohort versus 18.4 months for the AS cohort (hazard ratio, 0.8; 95% confidence interval [CI]: 0.7–0.9). In the NOVA study-like subpopulation, adjusted mOS was 28.1 months for the 2LM niraparib monotherapy cohort versus 21.5 months for the AS cohort (hazard ratio, 0.6; 95% CI: 0.5–0.9). Conclusion: These results provide important real-world OS data for patients with recurrent BRCA wt OC who received niraparib monotherapy compared with patients receiving AS.

Background Acute ischemic stroke arising from medium vessel occlusions (MeVO) poses substantial challenges in treatment and management. This study aims to elucidate the outcomes and factors contributing to achieving excellent recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] 2c–3) versus successful recanalization (mTICI 2b) in patients with MeVO stroke undergoing mechanical thrombectomy (MT). Methods We conducted a multinational study analyzing data from the MAD‐MT (Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy) registry, encompassing 37 centers across North America, Asia, and Europe, collected between September 2017 and July 2023. The study included acute ischemic stroke patients with MeVO treated with MT, with or without intravenous thrombolysis, who achieved mTICI 2b–3 post‐MT. Results Among 1463 patients with successful recanalization (mTICI 2b–3), 523 achieved mTICI 2b recanalization, and 940 achieved mTICI 2c–3. Distal occlusions exhibited higher odds of excellent recanalization compared with proximal MeVO vessel occlusions (odds ratio, 1.58; 95% CI, 1.17–2.15; P = 0.003). Cardioembolic stroke pathogenesis was associated with a higher likelihood of excellent recanalization (1.67; 95% CI, 1.07–2.59; P = 0.018). Patients achieving mTICI 2c–3 recanalization demonstrated lower initial National Institutes of Health Stroke Scale scores, significant improvements in postprocedural National Institutes of Health Stroke Scale shift, and a higher percentage of favorable 90‐day outcomes compared with those with mTICI 2b. However, no significant difference in 90‐day mortality rates was observed. Conclusion This study underscores that among patients with MeVO stroke with successful recanalization (mTICI 2b–3) there is higher likelihood of achieving excellent recanalization (mTICI 2c–3) in distal occlusions and cardioembolic pathogenesis. mTICI 2c–3 scores post‐MT correlate with improved clinical outcomes compared with mTICI 2b, affirming the superiority of excellent recanalization over successful recanalization in patients with MeVO stroke. Further prospective studies and randomized controlled trials are warranted for validation.

Most people in the United States have been exposed to per- and polyfluoroalkyl substances (PFAS) which have been linked to a wide array of adverse health conditions in adults and children. The consumption of contaminated drinking water is an important human exposure pathway to PFAS. Residential sources also contribute to PFAS exposure through dermal contact and ingestion of house dust, which acts as an aggregate of chemicals from sources like furnishing materials and consumer products. The U.S. Department of Housing and Urban Development (HUD) conducted the first nationwide survey of residential hazards called the American Healthy Homes Survey (AHHS) in 2005, followed by a second survey (AHHS II) in 2017. The U.S. Environmental Protection Agency (EPA) collaborated with HUD on both efforts and subsequently analyzed PFAS in household tap water and house dust collected from the same homes during the AHHS II study. This study leverages these paired samples to investigate potentially important exposure sources and pathways in the residential environment. Here we report results for paired household tap water and house dust samples from 241 homes for 13 and 16 PFAS chemicals, respectively. All 13 targeted chemicals were detected in the household tap water samples with detections ranging from 100 % for PFBS to 1 % for PFNS, and all 16 targeted chemicals were detected in the house dust samples with detections ranging from 97 % for PFOA to 9 % for PFNS. Four chemicals (PFOA, PFOS, PFHxS, and PFHpA) were measured above the limit of detection in at least 50 % of the samples in both media. All households had at least one of the targeted PFAS detected in both their tap water and house dust. Results provided evidence that geographical factors, such as proximity to ambient contamination sources, were main drivers of PFAS contamination in tap water, while PFAS contamination in house dust was driven mainly by within-home sources. Exposure estimates calculated from the measured PFAS concentrations highlight the importance of addressing potential sources of exposure to PFAS within homes in addition to ambient sources affecting communities’ drinking water, particularly to reduce children’s exposure to these chemicals.

Summary: T cell surface CTLA4 sequesters the costimulatory ligands CD80 and CD86 on antigen-presenting cells (APCs) to prevent autoimmunity. Therapeutic immunosuppression by recombinant CTLA4-immunoglobulin (Ig) fusion proteins, including abatacept, is also attributed to CD80/CD86 blockade. Recent studies show that CTLA4-Ig binding to APC surface cis-CD80:PD-L1 complexes can release the inhibitory ligand PD-L1, but whether this contributes to T cell inhibition remains unclear. Here, we show that PD-L1 liberation by CTLA4-Ig is strictly limited, both in extent and context, relative to PD-L1-competing anti-CD80 antibodies. At APC surface CD80:PD-L1 ratios exceeding 2:1, CTLA4-Ig therapies fail to release PD-L1 regardless of their CD80 affinity. Additionally, introducing flexibility into CTLA4-Ig by modifying its rigid homodimer interface produces biologics that retain bivalent CD80 binding without dissociating cis-bound PD-L1. These findings demonstrate that CTLA4-Ig therapies liberate PD-L1 through a CD80 reorientation mechanism that imposes a strict context dependence to their PD-1 checkpoint agonism and resultant T cell inhibition.

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.

A new discipline, implementation science, has emerged in recent years. This has resulted in confusion between what ‘implementation science’ is and how it differs from real-world scale-up of health interventions. While there is considerable overlap, in this perspective, we seek to highlight some of the differences between these two concepts in relation to their origin, drivers, research methods and implications for population impact and practice. We recognise that implementation science generates new information on optimal methods and strategies to facilitate the uptake of evidence-based practices. This new knowledge can be used as part of any scaling-up endeavour. However, real-world scale-up is influenced to a much greater extent by political and strategic needs and key actors and generally requires the support of governments or large agencies that can fund population-level scale-up. Furthermore, scale-up often occurs in the absence of any evidence of effectiveness. Therefore, while implementation science and scale-up both ultimately aim to facilitate the uptake of interventions to improve population health, their immediate intentions differ, and these distinctions are worth highlighting for policymakers and researchers.

Abstract Analysis of virus-like particles (VLPs) is an essential task in optimizing their implementation as vaccine antigens for virus-initiated diseases. Interrogating VLP collections for elasticity by probing with a rigid atomic force microscopy (AFM) tip is a potential method for determining VLP morphological changes. During VLP morphological change, it is not expected that all VLPs would be in the same state. This leads to the open question of whether VLPs may change in a continuous or stepwise fashion. For continuous change, the statistical distribution of observed VLP properties would be expected as a single distribution, while stepwise change would lead to a multimodal distribution of properties. This study presents the application of a Gaussian mixture model (GMM), fit by the Expectation-Maximization (EM) algorithm, to identify different states of VLP morphological change observed by AFM imaging.

Abstract Background Childhood, adolescent, and young adult (CAYA) cancer survivors, at risk for late effects, including cancer-related fatigue, cardiovascular issues, and psychosocial challenges, may benefit from interventions stimulating behaviour adjustments. Three nurse-led eHealth interventions (REVIVER) delivered via video calls and elaborating on person-centred care, cognitive behaviour therapy and/or motivational interviewing were developed. These interventions target: 1) fatigue management, 2) healthier lifestyle behaviours, and 3) self-efficacy and self-management. This study aimed to assess the feasibility and potential effectiveness of the REVIVER interventions for CAYA cancer survivors and healthcare professionals. Methods In a single-group mixed methods design, CAYA cancer survivors aged 16–54, more than five years post-treatment, were enrolled. Feasibility, assessed via Bowen's outcomes for feasibility studies, included acceptability, practicality, integration and implementation, demand and adherence. Qualitative data from semi-structured interviews and a focus group interview with survivors and healthcare professionals supplemented the evaluation. Paired sample t-tests assessed changes in self-reported quality of life, fatigue, lifestyle, self-management, and self-efficacy at baseline (T0), post-intervention (T1), and 6-month follow-up (T2). Results The interventions and video consults were generally acceptable, practical, and successfully integrated and implemented. Success factors included the nurse consultant (i.e., communication, approach, and attitude) and the personalised approach. Barriers included sustainability concerns, technical issues, and short intervention duration. Regarding demand, 71.4%, 65.4%, and 100% of eligible CAYA cancer survivors engaged in the fatigue (N = 15), lifestyle (N = 17) and empowerment (N = 3) intervention, respectively, with 5, 5 and 2 participants interviewed, correspondingly. Low interest (demand) in the empowerment intervention (N = 3) and dropout rates of one-third for both fatigue and empowerment interventions were noted (adherence). Improvements in quality of life, fatigue (fatigue intervention), lifestyle (lifestyle intervention), self-efficacy, and self-management were evident among survivors who completed the fatigue and lifestyle interventions, with medium and large effect sizes observed immediately after the intervention and six months post-intervention. Conclusions Our study demonstrates the feasibility of nurse-led video coaching (REVIVER interventions) despite lower demand for the empowerment intervention and lower adherence to the fatigue and empowerment interventions. The medium and high effect sizes found for those who completed the interventions hold potential clinical significance for future studies investigating the effectiveness of the REVIVER interventions.

Abstract Background Niemann-Pick disease, type C1 (NPC1) is a rare lysosomal disorder with progressive neurological manifestations, historically recognized as a pediatric disease. However, awareness of the adult-onset (AO) subtype is increasing, often with non-specific symptoms leading to delayed and misdiagnosis. Dysphagia, commonly recognized as a clinical morbidity in NPC1, raises concerns for swallowing safety and aspiration risk. This study aims to characterize swallowing function in AO NPC1, addressing the gap in understanding and clinical management. Methods Fourteen AO NPC1 individuals in a prospective natural history study (NCT00344331) underwent comprehensive assessments, including history and physical examinations utilizing the NPC1 severity rating scale, videofluoroscopic swallowing studies with summary interpretive analysis, and cerebrospinal fluid (CSF) collection for biomarker evaluation at baseline visit. Descriptive statistics and multivariate statistical modeling were employed to analyze NPC1 disease covariates, along with the American Speech-Language-Hearing Association National Outcome Measure (ASHA-NOMS) and the NIH Penetration Aspiration Scale (NIH-PAS). Results Our cohort, comprised of 14 predominately female (n = 11, 78.6%) individuals, had an average age of 43.1 ± 16.7 years at the initial visit. Overall, our AO patients were able to swallow independently with no/minimal cueing, with 6 (43%) avoiding specific food items or requiring more time. Upon risk analysis of aspiration, the cohort demonstrated no obvious aspiration risk or laryngeal aspiration in 8 (57%), minimal risk with intermittent laryngeal penetration and retrograde excursion in 5(36%), and moderate risk (7%) in only one. Dietary modifications were recommended in 7 (50%), particularly for liquid viscosities (n = 6, 43%) rather than solids (n = 3, 21%). No significant correlations were identified between swallowing outcomes and NPC1-related parameters or CSF biomarkers. Conclusion Despite the heterogeneity in NPC1 presentation, the AO cohort displayed functional swallowing abilities with low aspiration risk with some participants still requiring some level of dietary modifications. This study emphasizes the importance of regular swallowing evaluations and management in AO NPC1 to address potential morbidities associated with dysphagia such as aspiration. These findings provide clinical recommendations for the assessment and management of the AO cohort, contributing to improved care for these individuals.

Abstract Mutations in CHCHD10, a mitochondrial protein with undefined functions, are associated with autosomal dominant mitochondrial diseases. Chchd10 knock-in mice harboring a heterozygous S55L mutation (equivalent to human pathogenic S59L) develop a fatal mitochondrial cardiomyopathy caused by CHCHD10 aggregation and proteotoxic mitochondrial integrated stress response (mtISR). In mutant hearts, mtISR is accompanied by a metabolic rewiring characterized by increased reliance on glycolysis rather than fatty acid oxidation. To counteract this metabolic rewiring, heterozygous S55L mice were subjected to chronic high-fat diet (HFD) to decrease insulin sensitivity and glucose uptake and enhance fatty acid utilization in the heart. HFD ameliorated the ventricular dysfunction of mutant hearts and significantly extended the survival of mutant female mice affected by severe pregnancy-induced cardiomyopathy. Gene expression profiles confirmed that HFD increased fatty acid utilization and ameliorated cardiomyopathy markers. Importantly, HFD also decreased accumulation of aggregated CHCHD10 in the S55L heart, suggesting activation of quality control mechanisms. Overall, our findings indicate that metabolic therapy can be effective in mitochondrial cardiomyopathies associated with proteotoxic stress.

Abstract Trace elements are important for human health but may exert toxic or adverse effects. Mechanisms of uptake, distribution, metabolism, and excretion are partly under genetic control but have not yet been extensively mapped. Here we report a comprehensive multi-element genome-wide association study of 57 essential and non-essential trace elements. We perform genome-wide association meta-analyses of 14 trace elements in up to 6564 Scandinavian whole blood samples, and genome-wide association studies of 43 trace elements in up to 2819 samples measured only in the Trøndelag Health Study (HUNT). We identify 11 novel genetic loci associated with blood concentrations of arsenic, cadmium, manganese, selenium, and zinc in genome-wide association meta-analyses. In HUNT, several genome-wide significant loci are also indicated for other trace elements. Using two-sample Mendelian randomization, we find several indications of weak to moderate effects on health outcomes, the most precise being a weak harmful effect of increased zinc on prostate cancer. However, independent validation is needed. Our current understanding of trace element-associated genetic variants may help establish consequences of trace elements on human health.

Abstract Direct air capture has gained traction as a method for carbon dioxide removal. How and whether direct air capture can be deployed requires securing social license to operate, and increasingly demands environmental justice and just transition principles. Here we use a nationally representative survey to evaluate public perceptions of direct air capture, paired with focus groups to assess community perceptions across four communities in the United States: Houston, Texas; Monaca, Pennsylvania; Bakersfield, California; and Rock Springs, Wyoming. We find conditional support for direct air capture deployment among focus group participants, and majority support for direct air capture deployment among national survey respondents. The most important determinants of project support were procedural justice elements—in particular community involvement in planning and implementation—and anticipated community benefits in the forms of local infrastructure and workforce development, supporting the need to center environmental justice and just transition principles into project planning and implementation. Where concerns over environmental and health implications are strong, direct air capture may not gain local social license to operate, especially in communities with previous negative experiences with industry.

Per- and poly-fluoroalkyl substances (PFAS) are highly persistent chemicals commonly found in surface protectants, and class B aqueous film forming foams (AFFF), and many other consumer and industrial products. As a result of their widespread application and use, PFAS are now found in environmental media across the globe. Research has revealed that exposure to environmentally relevant concentrations of PFAS can reduce reproductive success and have immunological effects in laboratory animals, including birds. Further, PFAS can be passed down from parents to offspring, posing a threat to sensitive life stages. PFAS may enter the brain by disrupting tight junctions or binding to transporters, but our overall understanding of the interactions and accumulation of PFAS in the avian brain is limited due to the lack of data. We obtained archived samples of male-female pairs of Northern bobwhite quail (NBWQ) from chronic toxicity studies where adults were exposed to either individual PFAS or binary mixtures through drinking water for at least 60 days. PFAS were detected in the brains of exposed adult quail, while brains from control birds had only occasional detections of PFAS; mostly perfluorooctane sulfonic acid (PFOS), likely because our source of birds was pen-raised animals and many PFAS are ubiquitous. Despite similar average daily intake (ADI) for both males and females, we observed higher concentrations of most PFAS in the brains of male birds compared to female birds, with the exception of perfluoroheptanoic acid (PFHpA). For the binary mixture exposures, PFOS appeared to reduce brain concentrations of perfluorohexane sulfonic acid (PFHxS) in both males and females to levels that could not be explained by ADI differences alone. Collectively, study results demonstrated that brain accumulation of short-chain PFAS in birds was not significantly affected by sex, however, long-chain PFAS exposure resulted in avian brain accumulation with generally higher PFAS concentrations in males compared to females. The findings of this study offer insights into the accumulation of PFAS in the avian brain and suggest that there may be sex differences in potential risks associated with exposure to these pervasive chemicals.

Lemur tail kinase 3 (LMTK3) belongs to a family of tyrosine kinases that are known to correlate with tumor grade and patient survival in some cancers. Here, we validated LMTK3 as a specific target and a prognostic biomarker in ovarian cancer (OC). In samples from 204 stage I–II OC patients, immunohistochemical studies revealed a higher cytoplasmic-to-nuclear staining intensity of LMTK3, which correlated with worse overall survival (p

Introduction and Objectives: La Clínica Latina is a free clinic that strives to meet the healthcare needs of the Spanish-speaking population of Franklin County, Ohio, including metropolitan Columbus. As a student-run free clinic, care is provided each week by volunteer medical students and resident physicians under the administrative leadership of the medical student board and clinical supervision of licensed physicians. Patients served by the clinic have a multitude of chronic health conditions, which are managed by clinic volunteers through the delivery of over 1500 appointments per year. In order to better serve the rapidly growing patient population, this study describes the delivery and results of an assessment aimed at understanding the needs that are being met sufficiently at the clinic and what pitfalls still exist in the clinic’s provision of care. Methods: By delivering a survey inquiring about the experiences of patients at La Clínica Latina, clinic workflow can be optimized for the provision of patient-centered care. Results: Insights collected from a convenience sample of 30 patients demonstrate mobile phone use as the primary mode of communication with clinic volunteers, previously under-appreciated musculoskeletal health concerns, longer than desired wait times after check-in, and variable experiences of health literacy by patient gender. Conclusion: By addressing each of these insights in updates to clinic workflow, La Clínica Latina may prove to become an even more useful resource to the region’s growing Hispanic population.

Recent research has shown that there is a link between the trend of cardiovascular disease (CVD), chronic symptoms of SARS-CoV-2 (COVID-19), and medical nutrition therapy. Making positive changes to an individual’s lifestyle can help to reduce the symptoms that follow exposure to CVD and COVID-19. Sustainable nutrition and lifestyle changes can positively impact an individual’s health. Studies have considered the risk factors associated with the disease, medical history, the link between nutrition and peripheral vascular disease (PVD), symptom management, and the interrelationship between nutrition, COVID-19, and PVD. One study has demonstrated that Western Dietary intake can boost the innate immune system while suppressing humoral response, causing chronic inflammation and poor host defense against viruses. However, further investigation is needed to confirm. Patients with PVD and COVID-19 have experienced a reduction in side effects when prescribed a regimen of medical nutrition therapy, heart-healthy diets, and adequate physical activity before and after symptoms of both diseases appear. This approach has proven to be a protective factor during the combination of both illnesses. Our findings indicate that balanced diet and lifestyle are essential in supporting an optimal immune system that can reduce the risk of virus load in individuals at risk of infection and symptoms from COVID-19 and PVD.

Abstract Introduction The Emergency Department (ED) has seen increased patient attendance and difficulty meeting demands. New healthcare professions such as Physician Associates (PAs) are being utilised to complement the existing medical workforce. Despite the growth of their professions in the United Kingdom, little evidence is available about the perceptions of their roles. Objective This study aims to provide evidence of doctors', PAs' and patients' perceptions of the PA role in the UK ED. Methods A mixed methods approach consisted of the following: 1. An online exploratory survey of ED doctors at one English ED over 1 month (February–March 2022). 2. Post consultation semi‐structured patient questionnaires over 2 weeks (April 2022). 3. Semi‐structured virtual interviews with ED consultants across the four regions of the United Kingdom (3 months in 2022). 4. Semi‐structured virtual interviews with ED PAs across the four regions of the United Kingdom (3 months in 2022). The analysis methods that were used included frequency counts and percentages from closed questions, and hybrid thematic analysis of free text and interview transcripts. Results Four ED consultants and four ED PAs across the United Kingdom were interviewed. Twenty‐eight ED doctors participated in the online survey. Fifty‐seven patients completed the post consultation questionnaire. Four main themes (PAs being fit for purpose; patient recognition of PAs, PAs providing continuity of care, and future PAs and regulation) were deduced as per the General Medical Council, Good Medical Practice domains (knowledge, skills and development; patients, partnership and communication; colleagues, culture and safety; and trust and professionalism). Other subthemes were induced via hybrid thematic analysis. In this study, doctors and patients had mixed comments about the role of PAs. Most of them were positive as doctor participants perceived PAs to be knowledgeable, highly skilled, with mostly good communication skills, team players, providing continuity of care and overall being fit for purpose. However, some doctor participants commented negatively about PAs for providing little quality healthcare and being inexperienced. There was a desire for career progression among the PA participants and a need to work to their full potential. Although the clinicians of this study displayed a clear understanding of the PA role in the ED, a high frequency of surveyed patients mistook PAs for doctors. It was suggested that future PAs could complete a postqualification programme in emergency medicine, combine roles, be paid on an alternative scale and be formally regulated. Conclusion In this study, mixed views were expressed by ED consultants, ED junior doctors and patients regarding the role of the PA in the ED. Stakeholders can use the information presented to develop a better understanding of the perceptions of the PA role within the UK ED. Patient or Public Contribution The Patient and Public Involvement and Engagement (PPIE) group, led by Healthwatch, made significant contributions to the study's design by providing valuable feedback on the information sheets and consent forms utilised. The patients' responses helped guide the study's direction and shape its future work. As part of the dissemination activities, the study findings was shared with both the PPIE team and Healthwatch media production team.

Abstract It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVβ3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low‐density sEV subpopulation. This low‐density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVβ3 and an αVβ3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell‐derived sEVs containing the αVβ3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.

Abstract Background Psychosocial impacts of lung cancer screening (LCS) can cause both harm to individuals and serve as barriers to screening participation and adherence. Early data suggest that the psychosocial impacts of LCS are moderated by certain factors (e.g. sociodemographic characteristics and beliefs), but evidence synthesis is lacking. This systematic review aimed to understand individual‐level risk factors for psychosocial burden during LCS as a precursor to developing strategies to identify and support participants, and improve LCS engagement. Methods Four databases were searched for full‐text articles published in English reporting any association between participant factors and psychosocial outcomes experienced during LCS. Study quality was assessed by two independent investigators; findings were synthesised narratively. The review was pre‐registered with PROSPERO and adhered to PRISMA guidelines. Results Thirty‐five articles were included; most (33/35) studies were assessed at high or moderate risk of bias. Study designs were pre‐post (n = 13), cross‐sectional (n = 13), qualitative (n = 8) and mixed‐methods (n = 1) and conducted primarily in the United States (n = 17). Psychological burden in LCS varied, and was often associated with younger age, female gender, current smoking status or increased smoking history, lower education, lower socio‐economic group, not being married or co‐habiting and experience with cancer. However, results were mixed, and non‐significant associations were also reported across all factors. Beliefs (e.g. fatalism, stigma and expectation of LDCT results) and comorbid psychological burden were also linked to psychosocial outcomes, but evidence was sparse. Associations between risk perception, other participant factors and other psychosocial outcomes was inconclusive, likely reflecting individual biases in risk conceptualisation. Conclusion(s) Several participant factors are consistently reported to be associated with psychosocial impacts of LCS, though study heterogeneity and high risk of bias necessitate more robust evaluation. Further research on how perceptions, beliefs and expectations can be used to improve psychosocial outcomes during LCS is needed.

The potential and threat of digital tools to achieve health equity has been highlighted for over a decade, but the success of achieving equitable access to health technologies remains challenging. Our paper addresses renewed concerns regarding equity in digital health access that were deepened during the COVID-19 pandemic. Our viewpoint is that (1) digital health tools have the potential to improve health equity if equitable access is achieved, and (2) improving access and equity in digital health can be strengthened by considering behavioral science–based strategies embedded in all phases of tool development. Using behavioral, equity, and access frameworks allowed for a unique and comprehensive exploration of current drivers of digital health inequities. This paper aims to present a compilation of strategies that can potentially have an actionable impact on digital health equity. Multilevel factors drive unequal access, so strategies require action from tool developers, individual delivery agents, organizations, and systems to effect change. Strategies were shaped with a behavioral medicine focus as the field has a unique role in improving digital health access; arguably, all digital tools require the user (individual, provider, and health system) to change behavior by engaging with the technology to generate impact. This paper presents a model that emphasizes using multilevel strategies across design, delivery, dissemination, and sustainment stages to advance digital health access and foster health equity.

Background: The skin microbiome is disrupted in atopic dermatitis (AD). Existing research focuses on moderate to severe, unmedicated disease. Objective: We sought to investigate metagenomic- and culture-based bacterial strain–level differences in mild, medicated AD and the effects these have on human keratinocytes (HKs). Methods: Skin swabs from anterior forearms were collected from 20 pediatric participants (11 participants with AD sampled at lesional and nonlesional sites and 9 age- and sex-matched controls). Participants had primarily mild to moderate AD and maintained medication use. Samples were processed for microbial metagenomic sequencing and bacterial isolation. Isolates identified as Staphylococcus aureus were tested for enterotoxin production. HK cultures were treated with cell-free conditioned media from representative Staphylococcus species to measure barrier effects. Results: Metagenomic sequencing identified significant differences in microbiome composition between AD and control groups. Differences were seen at the species and strain levels for Staphylococci, with S aureus found only in participants with AD and differences in Staphylococcus epidermidis strains between control and AD swabs. These strains showed differences in toxin gene presence, which was confirmed in vitro for S aureus enterotoxins. The strain from the participant with the most severe AD produced enterotoxin B levels more than 100-fold higher than the other strains (P < .001). Strains also displayed differential effects on HK metabolism and barrier function. Conclusions: Strain-level differences in toxin genes from Staphylococcus strains may explain varying effects on HK, with S aureus and non–aureus strains negatively affecting viability and barrier function. These differences are likely important in AD pathogenesis.

Introduction Peripheral intravenous catheters (PIVCs) are the most commonly used vascular access device in hospitalised patients. Yet PIVCs may be complicated by local or systemic infections leading to increased healthcare costs. Chlorhexidine gluconate (CHG)-impregnated dressings may help reduce PIVC-related infectious complications but have not yet been evaluated. We hypothesise an impregnated CHG transparent dressing, in comparison to standard polyurethane dressing, will be safe, effective and cost-effective in protecting against PIVC-related infectious complications and phlebitis.Methods and analysis The ProP trial is a multicentre, superiority, randomised clinical and cost-effectiveness trial with internal pilot, conducted across three centres in Australia and France. Patients (adults and children aged ≥6 years) requiring one PIVC for ≥48 hours are eligible. We will exclude patients with emergent PIVCs, known CHG allergy, skin injury at site of insertion or previous trial enrolment. Patients will be randomised to 3M Tegaderm Antimicrobial IV Advanced Securement dressing or standard care group. For the internal pilot, 300 patients will be enrolled to test protocol feasibility (eligibility, recruitment, retention, protocol fidelity, missing data and satisfaction of participants and staff), primary endpoint for internal pilot, assessed by independent data safety monitoring committee. Clinical outcomes will not be reviewed. Following feasibility assessment, the remaining 2624 (1312 per trial arm) patients will be enrolled following the same methods. The primary endpoint is a composite of catheter-related infectious complications and phlebitis. Recruitment began on 3 May 2023.Ethics and dissemination The protocol was approved by Ouest I ethic committee in France and by The Queensland Children’s Hospital Human Research Ethics Committee in Australia. The findings will be disseminated through presentation at scientific conferences and publication in peer-reviewed journals.Trial registration number NCT05741866.

Background: Cancer cell evasion of the immune response is critical to cancer development and metastases. Clinicians' ability to kickstart the immune system to target these rogue cells is an ever-growing area of research and medicine. This study delved into the relationship between lipid metabolism, High Mobility Group Box 1 protein (HMGB1)–a pro-inflammatory damage-associated molecular pattern protein–and immune regulation within non-small cell lung adenocarcinoma (NSCLC).Method: To address this question, we used a combination of proteomics, molecular biology, and bioinformatic techniques to investigate the relationship between fatty acids and immune signals within NSCLC.Results: We found that the expression of stearoyl CoA desaturase 1 (SCD1) was decreased in NSCLC tumors compared to normal tissues. This emphasized the critical role of lipid metabolism in tumor progression. Interestingly, monounsaturated fatty acid (MUFA) availability affected the expression of programmed death ligand-1 (PD-L1), a pivotal immune checkpoint target in lung cancer cells and immune cells, as well as HMGB1, suggesting a novel approach to modulating the immune response. This study uncovered a complex interplay between SCD1, PD-L1, and HMGB1, influencing the immunological sensitivity of tumors.Conclusion: Our work underscores the critical importance of understanding the intricate relationships between lipid metabolism and immune modulation to develop more effective NSCLC treatments and personalized therapies. As we continue to explore these connections, we hope to contribute significantly to the ever-evolving field of cancer research, improving patient outcomes and advancing precision medicine in NSCLC.

Objective Acute myeloid leukaemia (AML) prognosis is enhanced with intensive remission induction chemotherapy (ICT) in eligible patients. However, ICT eligibility perceptions may differ among healthcare professionals. This nationwide, population-based study aimed to explore regional variation in ICT application and its relation with overall survival (OS).Methods and analysis We compared nine Dutch regional networks using data from the Netherlands Cancer Registry. Regional variance was assessed for the entire population and age subgroups (ie, ≤60 years and >60 years) using multivariable mixed effects logistic and Cox proportional hazard regression analyses, expressed via median OR (MOR) and median HR (MHR).Results Including all adult AML patients from 2014 to 2018 (N=4060 patients; 58% males; median age, 70 years), 1761 (43%) received ICT. ICT application varied from 36% to 57% (MOR 1.36 (95% CI 1.11 to 1.58)) across regions, with minor variations for patients aged ≤60 years (MOR 1.16 (95% CI 1.00 to 1.40)) and more extensive differences for those aged >60 years (MOR 1.43 (95% CI 1.16 to 1.63)). Median OS spanned 4.9–8.4 months across regions (MHR 1.11 (95% CI 1.00 to 1.15)), with pronounced differences in older patients (MHR 1.12 (95% CI 1.08 to 1.20)) but negligible differences in the younger group (MHR 1.02 (95% CI 1.00 to 1.14)). Survival differences for the total population and the older patients decreased to respectively, MHR 1.09 (95% CI 1.00 to 1.13) and 1.10 (95% CI 1.04 to 1.18), after additional adjustment for the probability of receiving ICT within a region, indicating approximately 10% unexplained differences.Conclusion Regional disparities in ICT application and survival exist, especially in older AML patients. However, ICT application differences partially explain survival disparities, indicating the need for more standardised ICT eligibility criteria and a better understanding of underlying causes of outcome disparities.

BackgroundMachine learning (ML) models can yield faster and more accurate medical diagnoses; however, developing ML models is limited by a lack of high-quality labeled training data. Crowdsourced labeling is a potential solution but can be constrained by concerns about label quality. ObjectiveThis study aims to examine whether a gamified crowdsourcing platform with continuous performance assessment, user feedback, and performance-based incentives could produce expert-quality labels on medical imaging data. MethodsIn this diagnostic comparison study, 2384 lung ultrasound clips were retrospectively collected from 203 emergency department patients. A total of 6 lung ultrasound experts classified 393 of these clips as having no B-lines, one or more discrete B-lines, or confluent B-lines to create 2 sets of reference standard data sets (195 training clips and 198 test clips). Sets were respectively used to (1) train users on a gamified crowdsourcing platform and (2) compare the concordance of the resulting crowd labels to the concordance of individual experts to reference standards. Crowd opinions were sourced from DiagnosUs (Centaur Labs) iOS app users over 8 days, filtered based on past performance, aggregated using majority rule, and analyzed for label concordance compared with a hold-out test set of expert-labeled clips. The primary outcome was comparing the labeling concordance of collated crowd opinions to trained experts in classifying B-lines on lung ultrasound clips. ResultsOur clinical data set included patients with a mean age of 60.0 (SD 19.0) years; 105 (51.7%) patients were female and 114 (56.1%) patients were White. Over the 195 training clips, the expert-consensus label distribution was 114 (58%) no B-lines, 56 (29%) discrete B-lines, and 25 (13%) confluent B-lines. Over the 198 test clips, expert-consensus label distribution was 138 (70%) no B-lines, 36 (18%) discrete B-lines, and 24 (12%) confluent B-lines. In total, 99,238 opinions were collected from 426 unique users. On a test set of 198 clips, the mean labeling concordance of individual experts relative to the reference standard was 85.0% (SE 2.0), compared with 87.9% crowdsourced label concordance (P=.15). When individual experts’ opinions were compared with reference standard labels created by majority vote excluding their own opinion, crowd concordance was higher than the mean concordance of individual experts to reference standards (87.4% vs 80.8%, SE 1.6 for expert concordance; P