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Abstract Background Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest. Methods To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas. Results We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components. Conclusion Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.

Objective: This study evaluated the safety and efficacy of elamipretide in dry age-related macular degeneration (AMD) with noncentral geographic atrophy (GA). Design: ReCLAIM-2 was a prospective, phase II, randomized, placebo-controlled, double-masked, multicenter trial (NCT03891875). Subjects: Patients aged ≥55 years with ≥1 eye with dry AMD with GA were enrolled. Methods: Administration of daily subcutaneous elamipretide 40 mg was investigated in subjects for 48 weeks followed by a 4-week follow-up period. Main Outcome Measures: The primary efficacy end points were the mean change from baseline (BL) in low-luminance best-corrected visual acuity (LL BCVA) and the change in square root (Sqrt) converted GA area from BL as measured by OCT. Additional predefined end points included ellipsoid zone (EZ) integrity preservation assessment and categorical changes in LL BCVA. The primary safety end point was the incidence and severity of adverse events. Results: Of the 176 patients randomized, there were 117 and 59 patients in the elamipretide and placebo groups, respectively. Although elamipretide did not meet statistical significance for the primary end points (mean change in LL BCVA and mean change in Sqrt converted GA area), elamipretide produced a 43% reduction in the mean progression from BL in the macular percentage of total EZ attenuation/loss (i.e., complete loss of EZ band; nominal P = 0.0034) and 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (i.e., EZ-retinal pigment endothelium thickness of ≤20 microns; nominal P = 0.0040) versus placebo at week 48. Elamipretide treatment was also associated with significantly more patients experiencing a ≥10 letter gain in LL BCVA versus placebo (14.6% vs. 2.1%; nominal P = 0.0404). Adverse events were reported in 86% of those receiving elamipretide and 71% of the placebo group with the most common events being injection site reactions (e.g., pruritus, injection site pain, bruising, and erythema). Conclusions: While the primary end points were not met in this phase II study, elamipretide treatment was associated with a slowing of progressive EZ degradation/loss, a surrogate for photoreceptor damage. These findings have important clinical relevance since EZ attenuation/photoreceptor loss precedes and predicts the progressive pathological changes associated with vision loss and AMD. The EZ attenuation/loss end point will serve as the regulatory approved primary end point in the elamipretide phase III clinical development program. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Category: Arthroscopy; Midfoot/Forefoot Introduction/Purpose: Hallux rigidus is a degenerative disorder of the first metatarsophalangeal (MTP) joint. Patients with this condition experience symptoms including pain, stiffness, and reduced range of motion of the 1st MTP joint. Cheilectomy is a surgical treatment option that removes dorsal periarticular osteophytes to alleviate pain and improve range of motion. Minimally invasive cheilectomy is becoming a more prominent surgical approach due to its clinical benefits including smaller incisions, reduced complications, and faster return to function. This systematic review aims to analyze and present the current literature on patient-reported outcomes (PROs) following MIS cheilectomy for mild to moderate hallux rigidus. Methods: A systematic review of the literature was conducted using articles pulled from PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus databases in December 2023 using the search term “cheilectomy.” ​​This systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in Prospero (Blinded ID:XX). Articles were included in the systematic review if they reported on preoperative or postoperative patient-reported outcomes in patients undergoing minimally invasive cheilectomy (MIS) in English. Minimally invasive was defined as an arthroscopic or percutaneous approach. The primary outcome measure was scored patient-reported outcomes. The secondary outcome measures included complications, secondary surgeries, surgical techniques, qualitative patient experiences, and grades of hallux rigidus. Results: Eight studies met the inclusion criteria, and a total of 284 patients were evaluated. 130/284 underwent an MIS percutaneous approach with burr, 70/284 underwent arthroscopy with shaver, and 84/284 had a combination of both techniques. Most patients (79%) had Coughlin-Shurnas grade one or two hallux rigidus (range: 1-3). The mean American Orthopaedic Foot & Ankle Society scores improved from 57.7 (range: 43-71) to 90.1 (range: 87-97). The mean range of motion (dorsiflexion) improved from 28.5 (range: 8-42) to 49.5 (range: 30-73) degrees. Complication rates were low at 18/284 (6%). The most common complication was numbness, affecting 6/284 (2%) patients. Four out of eight articles reported zero complications. 113/125 (90.4%) patients would recommend the procedure. Conclusion: Treatment of hallux rigidus with MIS cheilectomy appears to result in favorable and safe outcomes when performed for patients with early degenerative disease who have failed conservative treatment. Patients reported high satisfaction rates, significant symptomatic improvements, and experienced low complication rates.

Background HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.Methods The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.Results A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.Conclusions HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.Trial registration number NCT04727164.

In this review, we present a case report of an immunocompetent 58-year-old male who presented with disseminated histoplasmosis (DH) outside of the known endemic regions. Due to his atypical clinical presentation that did not fit the classical clinical picture of DH, the diagnosis was delayed. In addition, we researched DH in the immunocompetent hosts as these cases are not common and leave the patient population vulnerable to delayed diagnosis. The literature supports considering histoplasmosis in the differential diagnosis among patients who present with possible exposures outside of endemic regions and are immunocompetent.

Autophagy is a crucial mechanism for recycling intracellular materials, and under normal metabolic conditions, it is maintained at low levels in cells. However, when nutrients are deficient or under hypoxic conditions, the level of autophagy significantly increases. Particularly in cancer cells, which grow more rapidly than normal cells and tend to grow in a three-dimensional manner, cells inside the cell mass often face limited oxygen supply, leading to inherently higher levels of autophagy. Therefore, the initial development of anticancer drugs targeting autophagy was based on a strategy to suppress these high levels of autophagy. However, anticancer drugs that inhibit autophagy have not shown promising results in clinical trials, as it has been revealed that autophagy does not always play a role that favors cancer cell survival. Hence, this review aims to suggest anticancer strategies based on the changes in the role of autophagy according to survival conditions and tumorigenesis stage.

Abstract Background More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. Methods We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP’s main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10–9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10–8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10–8). GRN (rs5848, P = 4.21 × 10–8) and PURG (rs117523305, P = 1.73 × 10–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10–8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10–9) and PTPRD (rs145989094, P = 8.34 × 10–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10–8) and PTPRD (rs145989094, P = 3.85 × 10–8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Category: Ankle Arthritis; Ankle Introduction/Purpose: There is a paucity of aggregate literature reporting on long-term patient-reported outcomes (PROs) and implant failure after total ankle arthroplasty (TAA). The purpose of this study is to report an aggregate of literature on minimum 10-year patient-reported outcomes after total ankle arthroplasty. Methods: A systematic review on minimum 10-year PROs of TAA was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pubmed, Scopus, and Cochrane Trials were queried on December 28th, 2022, with the following keywords: (ankle) AND (replacement or arthroplasty) AND (long-term or 10-year). Primary research articles were included if they reported minimum 10-year PROs for patients undergoing primary TAA and written in English. Forest plots with heterogeneity were created for PROs reported preoperatively and postoperatively in three or more studies. Long-term was defined as minimum 10-year follow-up. Survivorship was defined by implant failure which was determined uniquely by each study. Results: Six studies met the inclusion criteria with all 6 studies being level IV. A total of 277 ankles with average age range of 54-60.9 years were included in the study with follow up ranging from 10 to 24 years. The primary indication for total ankle replacement was osteoarthritis. Two of the six studies reported significant improvement in PROs following surgery. The remaining 4 studies also demonstrated improvement in PRO however no p values were reported. A forest plot was generated for the AOFAS score and I2 of 67% was calculated. Survivorship at a minimum of 10 year follow up ranged from 66-94.4%. Average time to implant failure ranged from 54.7-166 months. Conclusion: Patients undergoing primary TAA demonstrated improved outcomes at minimum 10-year follow-up. However, they demonstrated variable rates of survivorship ranging from 66-94.4% with average time to implant failure ranging from 54.7 – 166 months.

ABSTRACTPatients with Special Health Care Needs (SHCN) encounter many barriers in achieving optimal health. This includes primary care, mental health, and oral health. Social workers are adept at addressing these barriers and are trained to provide additional assistance such as emotional counseling, clinical case management, community resource navigation, patient education, and anticipatory guidance. While their assistance is well documented in medical care and hospital settings, collaboration between dentistry and social work is less common. The initiation and integration of a social worker program in dentistry that focused on patients with SHCNs was examined. It was found that social work integration allowed for improved identification of unmet psychosocial needs and decreased barriers to care. As a result, initial appointment attendance rates increased post-integration. Social work in a dental setting has demonstrated the ability to improve bio-psychosocial wellbeing in patients and families, helping address unmet social and psychological needs and reducing barriers to oral health care.

Abstract Histopathologic assessment is indispensable for diagnosing colorectal cancer (CRC). However, manual evaluation of the diseased tissues under the microscope cannot reliably inform patient prognosis or genomic variations crucial for treatment selections. To address these challenges, we develop the Multi-omics Multi-cohort Assessment (MOMA) platform, an explainable machine learning approach, to systematically identify and interpret the relationship between patients’ histologic patterns, multi-omics, and clinical profiles in three large patient cohorts (n = 1888). MOMA successfully predicts the overall survival, disease-free survival (log-rank test P-value

Objectives: To determine whether first-year college students cluster in networks based on subjective perceptions of loneliness. Participants: 492 first-year Notre Dame students completed surveys across two semesters and provided communication data used to reconstruct their social networks. Methods: Subjective perceptions of loneliness are measured using the Social and Emotional Loneliness Scale for Adults (SELSA). Correlations between an individual's loneliness and the average loneliness of their alters are compared to associations in random networks created using a rewiring algorithm to determine statistical significance. Results: During their first semester, students are more likely than chance to form ties with other students with similar levels of family and romantic loneliness. In their second semester, students cluster on romantic loneliness but not on family or social loneliness. Conclusions: Students are more likely than chance to form ties with people with similar self-perceived levels of loneliness, but only for certain types of loneliness and during certain periods.

Here, Diot et al. use the nematode Caenorhabditis elegans as a model to identify off-target toxicity mechanisms for tamoxifen, and find that these include fatty acid metabolism and cell death, which can be modulated by different bacterial species.

Abstract Introduction A major challenge to enabling precision health at a global scale is the bias between those who enroll in state sponsored genomic research and those suffering from chronic disease. More than 30 million people have been genotyped by direct-to-consumer (DTC) companies such as 23andMe, Ancestry DNA, and MyHeritage, providing a potential mechanism for democratizing access to medical interventions and thus catalyzing improvements in patient outcomes as the cost of data acquisition drops. However, much of these data are sequestered in the initial provider network, without the ability for the scientific community to either access or validate. Here, we present a novel geno-pheno platform that integrates heterogeneous data sources and applies learnings to common chronic disease conditions including Type 2 diabetes (T2D) and hypertension. Methods We collected genotyped data from a novel DTC platform where participants upload their genotype data files and were invited to answer general health questionnaires regarding cardiometabolic traits over a period of 6 months. Quality control, imputation, and genome-wide association studies were performed on this dataset, and polygenic risk scores were built in a case–control setting using the BASIL algorithm. Results We collected data on N = 4,550 (389 cases / 4,161 controls) who reported being affected or previously affected for T2D and N = 4,528 (1,027 cases / 3,501 controls) for hypertension. We identified 164 out of 272 variants showing identical effect direction to previously reported genome-significant findings in Europeans. Performance metric of the PRS models was AUC = 0.68, which is comparable to previously published PRS models obtained with larger datasets including clinical biomarkers. Discussion DTC platforms have the potential of inverting research models of genome sequencing and phenotypic data acquisition. Quality control (QC) mechanisms proved to successfully enable traditional GWAS and PRS analyses. The direct participation of individuals has shown the potential to generate rich datasets enabling the creation of PRS cardiometabolic models. More importantly, federated learning of PRS from reuse of DTC data provides a mechanism for scaling precision health care delivery beyond the small number of countries who can afford to finance these efforts directly. Conclusions The genetics of T2D and hypertension have been studied extensively in controlled datasets, and various polygenic risk scores (PRS) have been developed. We developed predictive tools for both phenotypes trained with heterogeneous genotypic and phenotypic data generated outside of the clinical environment and show that our methods can recapitulate prior findings with fidelity. From these observations, we conclude that it is possible to leverage DTC genetic repositories to identify individuals at risk of debilitating diseases based on their unique genetic landscape so that informed, timely clinical interventions can be incorporated.

Abstract Background Lysophosphatidic acid receptor 3 (LPAR3) is coupled to Gα i/o and Gα 11/q signaling. Previously, we reported that LPAR3 is highly methylated in carcinogen-induced transformed cells. Here, we demonstrate that LPAR3 exhibits malignant transforming activities, despite being downregulated in transformed cells. Methods The LPAR3 knockout (KO) in NIH 3 T3 and Bhas 42 cells was established using the CRISPR/Cas9 system. Both RT-PCR and DNA sequencing were performed to confirm the KO of LPAR3. The cellular effects of LPAR3 KO were further examined by WST-1 assay, immunoblotting analysis, transwell migration assay, colony formation assay, wound scratch assday, in vitro cell transformation assay, and autophagy assay. Results In v-H-ras-transformed cells (Ras-NIH 3 T3) with LPAR3 downregulation, ectopic expression of LPAR3 significantly enhanced the migration. In particular, LPAR3 knockout (KO) in Bhas 42 (v-Ha-ras transfected Balb/c 3 T3) and NIH 3 T3 cells caused a decrease in cell survival, transformed foci, and colony formation. LPAR3 KO led to the robust accumulation of LC3-II and autophagosomes and inhibition of autophagic flux by disrupting autophagosome fusion with lysosome. Conversely, autolysosome maturation proceeded normally in Ras-NIH 3 T3 cells upon LPAR3 downregulation. Basal phosphorylation of MEK and ERK markedly increased in Ras-NIH 3 T3 cells, whereas being significantly lower in LPAR3 KO cells, suggesting that increased MEK signaling is involved in autophagosome–lysosome fusion in Ras-NIH 3 T3 cells. Conclusions Paradoxical downregulation of LPAR3 exerts cooperative tumor-promoting activity with MEK activation through autophagy induction in Ras-transformed cells. Our findings have implications for the development of cancer chemotherapeutic approaches.

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on human DNMT1. Functional studies in human and mouse cells further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that preferentially occurs at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

Background:. An elevated brain natriuretic peptide (BNP) level has been shown to be associated with mortality and cardiac events in cardiac surgery, but its utility in the prediction of morbidity and mortality in hip fracture surgery is unknown. The primary aim of this study was to determine if there is a difference in BNP level at the time of injury between patients who do and do not develop complications after hip fracture surgery. The secondary aim was to determine if there is a predictive relationship between complications associated with the initial BNP level and mortality. Methods:. A retrospective chart review of 455 hip fractures in patients ≥60 years old that were operatively treated between February 2014 and July 2018 was performed. Patients were included if they had a BNP level within 48 hours after injury (BNPi). Specific perioperative (≤7 days), 30-day, 1-year, and 2-year postoperative complications were recorded. Wilcoxon rank-sum tests were used to determine if higher BNPi values were associated with greater morbidity. The complications associated with higher BNPi values were further analyzed to assess if they were predictive of mortality, using univariate and multivariable analyses. Results:. Higher BNPi was significantly associated with greater morbidity at all postoperative time points and with higher mortality at 1 and 2 years postoperatively. Furthermore, several complications including cardiac failure or exacerbation and altered mental status were associated with mortality at all time points in univariate analysis and at many time points in multivariable analysis. Conclusions:. Patients with higher BNPi levels were more likely to develop complications up to 1 year postoperatively, and several of these complications were associated with increased mortality. Future studies to determine if delaying surgery until BNP levels are normalized or lowered may help guide management, and may be useful in determining the need for further medical optimization. Future studies aimed at defining a threshold BNP value at the time of injury may also help in better managing patients preoperatively. Level of Evidence:. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Abstract Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc—but not with a vasodilator—strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.

Research-based Theatre (RbT) offers a powerful stimulus for dialogue about the challenges of graduate supervisory relationships. This paper traces the implementation process for Rock the Boat, an open-access educational resource that includes four professionally acted scenes, a facilitator’s guide, and supplementary reading materials. The resource has been used extensively in online, in-person, and hybrid workshops to identify difficulties in graduate supervision, heighten awareness of power dynamics, and increase reflective practice among participants. Reflecting on lessons learned about the importance of pedagogy and practical logistics, we suggest that implementation aspects of RbT methodology are as vital as the creative and developmental.

Aim: To assess the impact of the COVID-19 pandemic on admissions of patients with acute coronary syndromes (ACS) and primary percutaneous coronary intervention (PPCI) in countries participating in the Stent-Save a Life (SSL) global initiative. Methods and Results: We conducted a multicenter observational survey to collect data on patient admissions for ACS, ST-elevation myocardial infarction (STEMI) and PPCI in participating SSL member countries through a period during the COVID-19 outbreak (March and April 2020) compared with the equivalent period in 2019. Of the 32 member countries of the SSL global initiative, 17 agreed to participate in the survey (three in Africa, five in Asia, six in Europe and three in Latin America). Overall reductions of 27.5% and 20.0% were observed in admissions for ACS and STEMI, respectively. The decrease in PPCI was 26.7%. This trend was observed in all except two countries. In these two, the pandemic peaked later than in the other countries. Conclusions: This survey shows that the COVID-19 outbreak was associated with a significant reduction in hospital admissions for ACS and STEMI as well as a reduction in PPCI, which can be explained by both patient- and system-related factors. Resumo: Objetivos: Avaliar o impacto da pandemia COVID-19 nas admissões de doentes com síndromes coronárias agudas (SCA) e angioplastia coronária primária (PPCI) em países que participam da iniciativa global Stent-Save a Life (SSL). Métodos e resultados: Realizámos estudo observacional multicêntrico para coletar dados sobre admissões de doentes por ACS, STEMI e PPCI nos países participantes no SSL durante um período do surto COVID-19 (março e abril de 2020) em comparação com o período homólogo de 2019. Dos 32 países membros da iniciativa global SSL, 17 aceitaram participar no estudo (3 de África, 5 da Ásia, 6 da Europa e 3 da América Latina (LATAM)). Observámos uma redução global de 27,5% e 20,0% nos internamentos com SCA e STEMI, respetivamente. A diminuição do PPCI foi de 26,7%. Essa tendência foi observada em todos os países, exceto dois. Nestes dois países, a pandemia atingiu o pico mais tarde do que nos restantes. Conclusões: Este estudo mostra que o surto de COVID-19 foi associado a uma redução significativa de admissões hospitalares por SCA e STEMI, bem como uma redução de PPCI, o que pode ser explicado por fatores relacionados com o doente e com o sistema.

Abstract Interfacial solar steam generation holds great promise in water desalination thanks to its high energy efficiency by heating only the top layer of water for evaporation. While three‐dimensional (3D) evaporators have been proven to increase the evaporation rate by harnessing the energy from the surroundings, further development is still required in terms of convenient fabrication with potential scalability. Herein, we propose to overcome this challenge by using a high internal phase emulsion (HIPE) to template the synthesis of 3D hierarchically porous evaporators. The HIPE‐templated synthesis combined with a molding process can efficiently fabricate the desired 3D shape without wasting any materials and generate a hierarchically porous internal structure for continuous water supply. Engineering the overall shape and internal pores produces a 3D evaporator that can suppress conduction heat loss and efficiently collect thermal energy from its surroundings, boosting the evaporation rate to 2.82 kg/(m2 h) under 1‐sun illumination, which is significantly higher than conventional 2D evaporators. HIPE‐templating synthesis is an easy but effective way to produce various porous polymers, promising for a wide range of applications where easy production, excellent shape control, and potential scalability are critical.

Shaytards was widely considered the original YouTube family vlog, and the family built their massive following with representations of wholesome, heteronormative, religious Americans who could have fun with everyday life. As classic microcelebrities (Senft 2013), the family of six created a valuable brand for millions of fans, which led to fame and wealth. But when the father and driving force of the vlog was caught sending sexually explicit texts to a “cam model”, more than the family brand collapsed. Shay’s persona, as the steady father force for an imagined family (Friedman & Schultermandl 2016) of millions was sent into disarray. This article follows the comments across multiple channels that show how the imagined family negotiated this collapse, demonstrating how an audience can establish a deep personal connection with a microcelebrity’s persona.

Abstract Background Triage is a critical component of prehospital emergency care. Effective triage of patients allows them to receive appropriate care and to judiciously use personnel and hospital resources. In many low-resource settings prehospital triage serves an additional role of determining the level of destination facility. In South Africa, the Western Cape Government innovatively implemented the South African Triage Scale (SATS) in the public Emergency Medical Services (EMS) service in 2012. The prehospital provider perspectives and experiences of using SATS in the field have not been previously studied. Methods In this qualitative study, focus group discussions with cohorts of basic, intermediate and advanced life support prehospital providers were conducted and transcribed. A content analysis using an inductive approach was used to code transcripts and identify themes. Results 15 EMS providers participated in three focus group discussions. Data saturation was reached and four major themes emerged from the qualitative analysis: Implementation and use of SATS; Effectiveness of SATS; Limitations of the discriminator; and Special EMS considerations. Participants overall felt that SATS was easy to use and allowed improved communication with hospital providers during patient handover. Participants, however, described many clinical cases when their clinical gestalt triaged the patient to a different clinical acuity than generated by SATS. Additionally, they stated many clinical discriminators were too subjective to effectively apply or covered too broad a range of clinical severity (e.g., ingestions). Participants provided examples of how the prehospital environment presents additional challenges to using SATS such as changing patient clinical conditions, transport times and social needs of patients. Conclusions Overall, participants felt that SATS was an effective tool in prehospital emergency care. However, they described many clinical scenarios where SATS was in conflict with their own assessment, the clinical care needs of the patient or the available prehospital and hospital resources. Many of the identified challenges to using SATS in the prehospital environment could be improved with small changes to SATS and provider re-training.

Abstract The passive elastic modulus of muscle fiber appears to be size-dependent. The objectives of this study were to determine whether this size effect was evident in the mechanical testing of muscle fiber bundles and to examine whether the muscle fiber bundle cross-section is circular. Muscle fibers and fiber bundles were extracted from lumbar spine multifidus and longissimus of three cohorts: group one (G1) and two (G2) included 13 (330 ± 14 g) and 6 (452 ± 28 g) rats, while Group 3 (G3) comprised 9 degenerative spine patients. A minimum of six muscle fibers and six muscle fiber bundles from each muscle underwent cumulative stretches, each of 10% strain followed by 4 minutes relaxation. For all specimens, top and side diameters were measured. Elastic modulus was calculated as tangent at 30% strain from the stress–strain curve. Linear correlations between the sample cross sectional area (CSA) and elastic moduli in each group were performed. The correlations showed that increasing specimen CSA resulted in lower elastic modulus for both rats and humans, muscle fibers and fiber bundles. The median ratio of major to minor axis exceeded 1.0 for all groups, ranging between 1.15–1.29 for fibers and 1.27–1.44 for bundles. The lower elastic moduli with increasing size can be explained by relatively less collagenous extracellular matrix in the large fiber bundles. Future studies of passive property measurement should aim for consistent bundle sizes and measuring diameters of two orthogonal axes of the muscle specimens.

Abstract Blockade of the binding between neonatal Fc receptor and IgG‐Fc reduces circulating IgG, and thus emerges as a potential therapy for IgG‐mediated autoimmune conditions. This was a double blind, randomized, single ascending dose study to evaluate the safety, pharmacokinetics, and pharmacodynamics of HBM9161 (a fully humanized Fc receptor monoclonal antibody) in healthy Chinese volunteers. Subjects were randomized to receive a single s.c. dose of HBM9161 or placebo in a 3:1 ratio in 3 dosing cohorts (340 mg, 510 mg, or 680 mg, respectively), and then followed up for 85 days. Study end points included incidence of adverse event (AE), serum drug concentration, IgG and its subclasses, and anti‐drug antibodies (ADAs). Twenty‐four subjects were randomized. Dose‐dependent reduction of total IgG occurred rapidly from baseline to reach nadir at day 11, then recovered steadily from day 11 to day 85. The mean maximum percentage reductions from baseline total IgG were 21.0 ± 9.3%, 39.8 ± 5.13%, and 41.2 ± 10.4% for subjects receiving HBM9161 340 mg, 510 mg, and 680 mg, respectively. The exposure of HBM9161 (areas under the curve [AUCs] and peak plasma concentration [Cmax]) increased in a more than dose‐proportional manner at the dose examined. All reported AEs were mild in severity. The most reported AEs in the HBM9161 groups were influenza‐like illness and rash. Two subjects developed ADA during the study period. A single s.c. dose of HBM9161 results in sustained and dose‐dependent IgG reduction, and was well‐tolerated at a dose up to 680 mg in Chinese subjects. The data warrant further investigation of its effects in IgG‐mediated autoimmune disorders.

Abstract The use of key performance indicators (KPIs) to assist on-farm decision making has long been seen as a promising strategy to improve operational efficiency of agriculture. The potential benefit of KPIs, however, is heavily dependent on the economic relevance of the metrics used, and an overabundance of ambiguously defined KPIs in the livestock industry has disincentivised many farmers to collect information beyond a minimum requirement. Using high-resolution sheep production data from the North Wyke Farm Platform, a system-scale grazing trial in southwest United Kingdom, this paper proposes a novel framework to quantify the information values of industry recommended KPIs, with the ultimate aim of compiling a list of variables to measure and not to measure. The results demonstrated a substantial financial benefit associated with a careful selection of metrics, with top-ranked variables exhibiting up to 3.5 times the information value of those randomly chosen. When individual metrics were used in isolation, ewe weight at lambing had the greatest ability to predict the subsequent lamb value at slaughter, surpassing all mid-season measures representing the lamb’s own performance. When information from multiple metrics was combined to inform on-farm decisions, the peak benefit was observed under four metrics, with inclusion of variables beyond this point shown to be detrimental to farm profitability regardless of the combination selected. The framework developed herein is readily extendable to other livestock species, and with minimal modifications to arable and mixed agriculture as well.

There is an unmet clinical need to develop therapies to alleviate metastatic bone pain, frequently observed in patients with advanced cancers. Here, using mouse models of bone cancer pain, the authors show that STING agonists not only suppress bone cancer tumor burden, but also attenuate bone pain and reduce cancer-induced bone destruction.