The evolution of early hominin food production and sharing.

How did humans evolve from individualistic to collective foraging with sex differences in production and widespread sharing of plant and animal foods? While current evolutionary scenarios focus on meat, cooking, or grandparental subsidies, considerations of the economics of foraging for extracted plant foods (e.g., roots, tubers), inferred to be important for early hominins (∼6 to 2.5 mya), suggest that early hominins shared such foods with offspring and others. Here, we present a conceptual and mathematical model of early hominin food production and sharing, prior to the emergence of frequent hunting, cooking, and increased lifespan. We hypothesize that extracted plant foods were vulnerable to theft, and that male mate guarding protected females from food theft. We identify conditions favoring extractive foraging and food sharing across mating systems (i.e., monogamy, polygyny, promiscuity), and we assess which system maximizes female fitness with changes in the profitability of extractive foraging. Females extract foods and share them with males only when: i) extracting rather than collecting plant foods pays off energetically; and ii) males guard females. Males extract foods when they are sufficiently high in value, but share with females only under promiscuous mating and/or no mate guarding. These results suggest that if early hominins had mating systems with pair-bonds (monogamous or polygynous), then food sharing by adult females with unrelated adult males occurred before hunting, cooking, and extensive grandparenting. Such cooperation may have enabled early hominins to expand into more open, seasonal habitats, and provided a foundation for the subsequent evolution of human life histories.

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors.

The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina's capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of -8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 µM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson-Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (-46.97 to -118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

Access to novel drugs and therapeutics for children and youth: Eliciting citizens' values to inform public funding decisions.

INTRODUCTION: The unique evidentiary, economic and ethical challenges associated with health technology assessment (HTA) of precision therapies limit access to novel drugs and therapeutics for children and youth, for whom such challenges are amplified. We elicited citizens' perspectives about values-based criteria relevant to the assessment of paediatric precision therapies to inform the development of a child-tailored HTA framework. METHODS: We held four citizen panels virtually in May-June 2021, informed by a plain-language citizen brief summarizing global and local evidence about the challenges, policy and programmatic options and implementation strategies related to enhancing access to precision therapies for Canadian children and youth. Panellists were recruited through a nationally representative database, medical/patient networks and social media. We inductively coded and thematically analysed panel transcripts to generate themes and identify priority values. RESULTS: The perspectives of panellists (n = 45) coalesced into four overlapping themes, with attendant subthemes, relevant to a child-tailored HTA framework: (1) Childhood Distinctions: vulnerability, 'fair innings', future potential, family impacts; (2) Voice: agency of children and youth; lived versus no lived experience; (3) One versus Many: disease severity, rarity, equity, unmet need and (4) Health System Governance: funding, implementation inequities, effectiveness and safety. Participants broadly agreed that childhood distinctions, particularly family impacts, justify child-tailored HTA. Dissent arose over whose voice should inform HTA and how such perspectives are best incorporated. CONCLUSIONS: Citizens can offer unique insights into criteria relevant to the development or revision of HTA frameworks to capture holistic, societally responsive dimensions of value attached to unique contexts or populations, including children. Balancing the hopes and expectations of patients and caregivers for access to expensive but potential life-altering therapies against the opportunity costs borne by encompassing health systems is a fundamental challenge that will require rigorous methods to elicit, weigh and reconcile varied views. PATIENT OR PUBLIC CONTRIBUTION: A patient advocate served on the steering committee of this study and co-authored this article. Key informants for the Citizen Brief included patient advocates and caregivers; a separate patient advocate reviewed the Brief before dissemination. Qualitative and quantitative data were collected from the general public and caregivers of children, with written consent.

Molecular Structure-Based Screening of the Constituents of Calotropis procera Identifies Potential Inhibitors of Diabetes Mellitus Target Alpha Glucosidase.

Diabetes mellitus is a disorder characterized by higher levels of blood glucose due to impaired insulin mechanisms. Alpha glucosidase is a critical drug target implicated in the mechanisms of diabetes mellitus and its inhibition controls hyperglycemia. Since the existing standard synthetic drugs have therapeutic limitations, it is imperative to identify new potent inhibitors of natural product origin which may slow carbohydrate digestion and absorption via alpha glucosidase. Since plant extracts from Calotropis procera have been extensively used in the treatment of diabetes mellitus, the present study used molecular docking and dynamics simulation techniques to screen its constituents against the receptor alpha glucosidase. Taraxasterol, syriogenin, isorhamnetin-3-O-robinobioside and calotoxin were identified as potential novel lead compounds with plausible binding energies of -40.2, -35.1, -34.3 and -34.3 kJ/mol against alpha glucosidase, respectively. The residues Trp481, Asp518, Leu677, Leu678 and Leu680 were identified as critical for binding and the compounds were predicted as alpha glucosidase inhibitors. Structurally similar compounds with Tanimoto coefficients greater than 0.7 were reported experimentally to be inhibitors of alpha glucosidase or antidiabetic. The structures of the molecules may serve as templates for the design of novel inhibitors and warrant in vitro assaying to corroborate their antidiabetic potential.

Studies on the binding of nitrogenous bases to protoporphyrin IX iron(II) in aqueous solution at high pH values.

Studies are reported on the formation of low-spin six-coordinate [Fe(PPIX)L2] complexes from iron(II) protoporphyrin where L is one of a series of nitrogenous ligands (aliphatic, aromatic or heterocyclic). The bonding constants have been determined by titration of the metal complex with these ligands and are compared in relation to previous studies. The adduct formation was monitored utilising optical spectroscopy. In addition, MÓ§ssbauer spectroscopic experiments were conducted to monitor the electronic environment around the central iron atom in these complexes. The two complementary spectroscopic methods indicated that all nitrogen ligands formed low-spin octahedral complexes. The magnitude of the overall binding constants (ß2 values) are discussed and related to (a) the pKa values of the free ligands and (b) the Mössbauer parameter ΔEQ, which represents the quadrupole splitting of the haem iron. The ß2 and ΔEQ values are also discussed in terms of the structure of the ligand. Cooperative binding was observed for nearly all the ligands with Hill coefficients close to 2 for iron(II) protoporphyrin; one of these ligands displayed a much greater affinity than any we previously studied, and this was a direct consequence of the structure of the ligand. Overall conclusions on these and previous studies are drawn in terms of aliphatic ligands versus aromatic ring structures and the absence or presence of sterically hindered nitrogen atoms. The implications of the work for the greater understanding of haem proteins in general and in particular how the nitrogenous ligand binding results are relevant to and aid the understanding of the binding of inhibitor molecules to the cytochrome P450 mono-oxygenases (for therapeutic purposes) are also discussed. Changes in the electronic absorption spectra of five-coordinate [Fe(II)(PPIX)(2-MeIm)] that occurred as the temperature was lowered from room temperature to 78° K.

Consuming a Protein and Fiber-Based Supplement Preload Promotes Weight Loss and Alters Metabolic Markers in Overweight Adults in a 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Higher protein and fiber diets promote weight management and metabolic health. OBJECTIVES: This study aimed to determine if greater weight loss and positive changes in metabolic outcomes could be achieved with twice-daily consumption of a high-protein and fiber-based multi-ingredient nutritional shake (HPF) compared with an isocaloric low-protein, lower fiber-based placebo (LPF). METHODS: Study procedures were conducted by an independent research organization under clinicaltrials.gov registration NCT03057873. Healthy overweight and obese adults [n = 206; BMI (kg/m2): 27-35; 70% female] were randomly assigned to HPF or LPF. All participants were prescribed an energy-restricted diet (500 kcal/d less than energy needs) and consumed a HPF (17 g protein, 6 g fiber) or LPF (1 g protein, 3 g fiber) shake 30 min before breakfast and lunch for 12 wk. Primary outcomes included body weight and total body fat percentage. Blood samples were collected at days (D) 0, 28, 56, and 84 for secondary analyses related to metabolic markers of health. RESULTS: Although weight loss occurred in both groups, HPF had greater weight loss at D84 compared with LPF (-3.3 kg vs. -1.8 kg, P < 0.05). Percentage body fat decreased in both groups (HPF: -1.33%, LPF: -1.09%; P < 0.001) with no differences between groups. Serum total cholesterol, LDL cholesterol, and oxidized LDL decreased between -5.1% to -8.3%, whereas adiponectin increased over time in both groups; these changes occurred to a greater extent in HPF compared with LPF (all P < 0.05). CONCLUSIONS: A multi-ingredient HPF nutritional supplement shake consumed as a preload before breakfast and lunch positively influenced weight management and metabolic outcomes in overweight adults compared with an LPF placebo. These findings suggest that specific nutrient factors (i.e., potentially including protein, fiber, and bioactive content) other than calorie reduction alone influence the success of a weight-loss regimen. This trial was registered at www.clinicaltrials.gov as NCT03057873.

Framing physical literacy for aging adults: an integrative review.

PURPOSE: Physical literacy is an important component for improving functional health for adults. However, little is known how physical literacy can be framed to support the rehabilitation needs of aging adults. METHODS: An integrative review was conducted to understand what components are used to frame physical literacy for adults. Electronic databases were searched from 2000-2021 for eligibility criteria including: 1) adults ≥45 years of age, 2) addressed physical literacy OR physical literacy components AND referred to outcomes assessing either mobility, physical function, rehabilitation, health promotion, health prevention, public health, or physical activity. RESULTS: A total of 22 articles met the inclusion criteria. The varied methodological quality, including grey literature (50%) to systematic reviews (14%), indicates that physical literacy for adults is a novel topic. When defining physical literacy for adults, 13 new constructs emerged with purposeful activities, knowledge of age-related changes and social interaction as the top three. Physical literacy interventions demonstrated improvements in self-efficacy, physical function, and exercise behaviour. CONCLUSION: Findings from the current literature indicate that engagement in purposeful, social, and diverse activities, obtaining knowledge of age-related changes and being able to self-adapt to mobility fluctuations is the foundation to becoming a physically literate adult.Implications for RehabilitationPhysical literacy is emerging as a promising health strategy for adults and older adults.Reconceptualization of the physical literacy construct to include rehabilitation approaches is needed to address the mobility challenges associated with aging.The foundation to becoming a physically literate adult involves monitoring one's ability for movement and having the knowledge to identify and remediate changes in function while engaging in purposeful movements.Physical literacy programs for adults and older adults have potential to positively impact important health outcomes equitably for all individuals.

Intraperitoneal local anaesthetic instillation versus no intraperitoneal local anaesthetic instillation for laparoscopic cholecystectomy.

BACKGROUND: Pain is one of the important reasons for delayed discharge after laparoscopic cholecystectomy. Use of intraperitoneal local anaesthetic for laparoscopic cholecystectomy may be a way of reducing pain. A previous version of this Cochrane Review found very low-certainty evidence on the benefits and harms of the intervention. OBJECTIVES: To assess the benefits and harms of intraperitoneal instillation of local anaesthetic agents in people undergoing laparoscopic cholecystectomy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and three other databases to 19 January 2021 together with reference checking of studies retrieved. We also searched five online clinical trials registries to identify unpublished or ongoing trials to 10 September 2021. We contacted study authors to identify additional studies. SELECTION CRITERIA: We only considered randomised clinical trials (irrespective of language, blinding, publication status, or relevance of outcome measure) comparing local anaesthetic intraperitoneal instillation versus placebo, no intervention, or inactive control during laparoscopic cholecystectomy, for the review. We excluded non-randomised studies, and studies where the method of allocating participants to a treatment was not strictly random (e.g. date of birth, hospital record number, or alternation). DATA COLLECTION AND ANALYSIS: Two review authors collected the data independently. Primary outcomes included all-cause mortality, serious adverse events, and quality of life. Secondary outcomes included length of stay, pain, return to activity and work, and non-serious adverse events. The analysis included both fixed-effect and random-effects models using RevManWeb. We performed subgroup, sensitivity, and meta-regression analyses. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). We assessed risk of bias using predefined domains, graded the certainty of the evidence using GRADE, and presented outcome results in a summary of findings table. MAIN RESULTS: Eighty-five completed trials were included, of which 76 trials contributed data to one or more of the outcomes. This included a total of 4957 participants randomised to intraperitoneal local anaesthetic instillation (2803 participants) and control (2154 participants). Most trials only included participants undergoing elective laparoscopic cholecystectomy and those who were at low anaesthetic risk (ASA I and II). The most commonly used local anaesthetic agent was bupivacaine. Methods of instilling the local anaesthetic varied considerably between trials; this included location and timing of application. The control groups received 0.9% normal saline (69 trials), no intervention (six trials), or sterile water (two trials). One trial did not specify the control agent used. None of the trials provided information on follow-up beyond point of discharge from hospital. Only two trials were at low risk of bias. Seven trials received external funding, of these three were assessed to be at risk of conflicts of interest, a further 17 trials declared no funding. We are very uncertain about the effect intraperitoneal local anaesthetic versus control on mortality; zero mortalities in either group (8 trials; 446 participants; very low-certainty evidence); serious adverse events (RR 1.07; 95% CI 0.49 to 2.34); 13 trials; 988 participants; discharge on same day of surgery (RR 1.43; 95% CI 0.64 to 3.20; 3 trials; 242 participants; very low-certainty evidence). We found that intraperitoneal local anaesthetic probably results in a small reduction in length of hospital stay (MD -0.10 days; 95% CI -0.18 to -0.01; 12 trials; 936 participants; moderate-certainty evidence). No trials reported data on health-related quality of life, return to normal activity or return to work. Pain scores, as measured by visual analogue scale (VAS), were lower in the intraperitoneal local anaesthetic instillation group compared to the control group at both four to eight hours (MD -0.99 cm VAS; 95% CI -1.19 to -0.79; 57 trials; 4046 participants; low-certainty of evidence) and nine to 24 hours (MD -0.68 cm VAS; 95% CI -0.88 to -0.49; 52 trials; 3588 participants; low-certainty of evidence). In addition, we found two trials that were still ongoing, and one trial that was completed but with no published results. All three trials are registered on the WHO trial register. AUTHORS' CONCLUSIONS: We are very uncertain about the effect estimate of intraperitoneal local anaesthetic for laparoscopic cholecystectomy on all-cause mortality, serious adverse events, and proportion of patients discharged on the same day of surgery because the certainty of evidence was very low. Due to inadequate reporting, we cannot exclude an increase in adverse events. We found that intraperitoneal local anaesthetic probably results in a small reduction in length of stay in hospital after surgery. We found that intraperitoneal local anaesthetic may reduce pain at up to 24 hours for low-risk patients undergoing laparoscopic cholecystectomy. Future randomised clinical trials should be at low risk of systematic and random errors, should fully report mortality and side effects, and should focus on clinical outcomes such as quality of life.

Profiles of intended responses to requests for assisted dying: A cross-sectional study.

BACKGROUND: Responding to legal medically assisted dying requests may become the most frequent form of nurses' participation in that service. Recent research has explored nurses' discrete responses to requests about or for assisted dying; however, nurses likely hold intentions for multiple responses to these requests. These intentions form patterns shaped by individual factors such as attitude and beliefs. No research has investigated patterns of multiple responses to requests for assisted dying, how these patterns form profiles of nurses and factors that might explain these response profiles. OBJECTIVES: Identify patterns of multiple responses that nurses intend for requests for assisted dying. Explore how these patterns form profiles of nurses' who share similar patterns of intended responses. Finally, investigate how attitude, norms and beliefs distinguish response profiles. DESIGN: Cross-sectional survey SETTINGS: Online survey of Australian nurses PARTICIPANTS: 365 experienced registered nurses (years in nursing mean = 23, SD = 14.21) working primarily with adults across various practice settings. METHODS: Principal components analysis identified five types of intended responses. K-means cluster analysis was then used to develop profiles of nurses' intended responses across these five responses. Multinomial logit regression was utilised to examine psychosocial variables that distinguished different profiles RESULTS: Cluster analysis resulted in five profiles that reflect different patterns of intended responses by nurses - Facilitator, Complier, Expediter, Objector, and Detached. Logit regressions of explanatory variables indicated that nurses' attitude toward assisted dying, ethical beliefs, and social norms predicted nurses' membership in intended response profiles. The overall model was statistically significant, χ2(20) = 106.527, p < .001, and the predictors accounted for 25.3% of the variance in the profiles (Cox and Snell test: Pseudo R2 = 0.253). CONCLUSION: Nurses intended responses have been usefully constructed as five patterns or profiles of multiple responses. These profiles represent different types and levels of engagement with requests. Further, attitude and social expectations distinguish profiles with stronger intentions to engage positively. Using a cluster analysis methodology provides a more holistic understanding of nurses' intended responses to assisted dying requests by focusing on various responses and demonstrating that nurses have distinctive patterns of responses.

Cheminformatics-Based Identification of Potential Novel Anti-SARS-CoV-2 Natural Compounds of African Origin.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2) has impacted negatively on public health and socioeconomic status, globally. Although, there are currently no specific drugs approved, several existing drugs are being repurposed, but their successful outcomes are not guaranteed. Therefore, the search for novel therapeutics remains a priority. We screened for inhibitors of the SARS-CoV-2 main protease and the receptor-binding domain of the spike protein from an integrated library of African natural products, compounds generated from machine learning studies and antiviral drugs using AutoDock Vina. The binding mechanisms between the compounds and the proteins were characterized using LigPlot+ and molecular dynamics simulations techniques. The biological activities of the hit compounds were also predicted using a Bayesian-based approach. Six potential bioactive molecules NANPDB2245, NANPDB2403, fusidic acid, ZINC000095486008, ZINC0000556656943 and ZINC001645993538 were identified, all of which had plausible binding mechanisms with both viral receptors. Molecular dynamics simulations, including molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) computations revealed stable protein-ligand complexes with all the compounds having acceptable free binding energies <-15 kJ/mol with each receptor. NANPDB2245, NANPDB2403 and ZINC000095486008 were predicted as antivirals; ZINC000095486008 as a membrane permeability inhibitor; NANPDB2403 as a cell adhesion inhibitor and RNA-directed RNA polymerase inhibitor; and NANPDB2245 as a membrane integrity antagonist. Therefore, they have the potential to inhibit viral entry and replication. These drug-like molecules were predicted to possess attractive pharmacological profiles with negligible toxicity. Novel critical residues identified for both targets could aid in a better understanding of the binding mechanisms and design of fragment-based de novo inhibitors. The compounds are proposed as worthy of further in vitro assaying and as scaffolds for the development of novel SARS-CoV-2 therapeutic molecules.

A critical interpretive synthesis of the roles of midwives in health systems.

BACKGROUND: Midwives' roles in sexual and reproductive health and rights continues to evolve. Understanding the profession's role and how midwives can be integrated into health systems is essential in creating evidence-informed policies. Our objective was to develop a theoretical framework of how political system factors and health systems arrangements influence the roles of midwives within the health system. METHODS: A critical interpretive synthesis was used to develop the theoretical framework. A range of electronic bibliographic databases (CINAHL, EMBASE, Global Health database, HealthSTAR, Health Systems Evidence, MEDLINE and Web of Science) was searched through to 14 May 2020 as were policy and health systems-related and midwifery organisation websites. A coding structure was created to guide the data extraction. RESULTS: A total of 4533 unique documents were retrieved through electronic searches, of which 4132 were excluded using explicit criteria, leaving 401 potentially relevant records, in addition to the 29 records that were purposively sampled through grey literature. A total of 100 documents were included in the critical interpretive synthesis. The resulting theoretical framework identified the range of political and health system components that can work together to facilitate the integration of midwifery into health systems or act as barriers that restrict the roles of the profession. CONCLUSIONS: Any changes to the roles of midwives in health systems need to take into account the political system where decisions about their integration will be made as well as the nature of the health system in which they are being integrated. The theoretical framework, which can be thought of as a heuristic, identifies the core contextual factors that governments can use to best leverage their position when working to improve sexual and reproductive health and rights.

Understanding the Role of Values in Health Policy Decision-Making From the Perspective of Policy-Makers and Stakeholders: A Multiple-Case Embedded Study in Chile and Colombia.

BACKGROUND: Chile and Colombia are examples of Latin American countries with health systems shaped by similar values. Recently, both countries have crafted policies to regulate the participation of private for-profit insurance companies in their health systems, but through very different mechanisms. This study asks: what values are important in the decision-making processes that crafted these policies? And how and why are they used? METHODS: An embedded multiple-case study design was carried out for 2 specific decisions in each country: (1) in Chile, the development of the Universal Plan of Explicit Entitlements -AUGE/GES - and mandating universal coverage of treatments for high-cost diseases; and (2) in Colombia, the declaration of health as a fundamental right and a mechanism to explicitly exclude technologies that cannot be publicly funded. We interviewed key informants involved in one or more of the decisions and/or in the policy analysis and development process that contributed to the eventual decision. The data analysis involved a constant comparative approach and thematic analysis for each case study. RESULTS: From the 40 individuals who were invited, 28 key informants participated. A tension between 2 important values was identified for each decision (eg, solidarity vs. individualism for the AUGE/GES plan in Chile; human dignity vs. sustainability for the declaration of the right to health in Colombia). Policy-makers used values in the decisionmaking process to frame problems in meaningful ways, to guide policy development, as a pragmatic instrument to make decisions, and as a way to legitimize decisions. In Chile, values such as individualism and free choice were incorporated in decision-making because attaining private health insurance was seen as an indicator of improved personal economic status. In Colombia, human dignity was incorporated as the core value because the Constitutional Court asserted its importance in its use of judicial activism as a check on the power of the executive and legislative branches. CONCLUSION: There is an opportunity to open further exploration of the role of values in different health decisions, political sectors besides health, and even other jurisdictions.

A SARS-CoV-2 serological assay to determine the presence of blocking antibodies that compete for human ACE2 binding.

As SARS-CoV-2 continues to spread around the world, there is an urgent need for new assay formats to characterize the humoral response to infection. Convalescent serum is being used for treatment and for isolation of patient-derived antibodies. However, currently there is not a simple means to estimate serum bulk neutralizing capability. Here we present an efficient competitive serological assay that can simultaneously determine an individual's seropositivity against the SARS-CoV-2 Spike protein and estimate the neutralizing capacity of anti-Spike antibodies to block interaction with the human angiotensin converting enzyme 2 (ACE2) required for viral entry. In this ELISA-based assay, we present natively-folded viral Spike protein receptor binding domain (RBD)-containing antigens via avidin-biotin interactions. Sera are then supplemented with soluble ACE2-Fc to compete for RBD-binding serum antibodies, and antibody binding quantified. Comparison of signal from untreated serum and ACE2-Fc-treated serum reveals the presence of antibodies that compete with ACE2 for RBD binding, as evidenced by loss of signal with ACE2-Fc treatment. In our test cohort of nine convalescent SARS-CoV-2 patients, we found all patients had developed anti-RBD antibodies targeting the epitope responsible for ACE2 engagement. This assay provides a simple and high-throughput method to screen patient sera for potentially neutralizing anti-Spike antibodies to enable identification of candidate sera for therapeutic use.

Miniaturization optimized weapon killing power during the social stress of late pre-contact North America (AD 600-1600).

Before Europeans arrived to Eastern North America, prehistoric, indigenous peoples experienced a number of changes that culminated in the development of sedentary, maize agricultural lifeways of varying complexity. Inherent to these lifeways were several triggers of social stress including population nucleation and increase, intergroup conflict (warfare), and increased territoriality. Here, we examine whether this period of social stress co-varied with deadlier weaponry, specifically, the design of the most commonly found prehistoric archery component in late pre-contact North America: triangular stone arrow tips (TSAT). The examination of modern metal or carbon projectiles, arrows, and arrowheads has demonstrated that smaller arrow tips penetrate deeper into a target than do larger ones. We first experimentally confirm that this relationship applies to arrow tips made from stone hafted onto shafts made from wood. We then statistically assess a large sample (n = 742) of late pre-contact TSAT and show that these specimens are extraordinarily small. Thus, by miniaturizing their arrow tips, prehistoric people in Eastern North America optimized their projectile weaponry for maximum penetration and killing power in warfare and hunting. Finally, we verify that these functional advantages were selected across environmental and cultural boundaries. Thus, while we cannot and should not rule out stochastic, production economizing, or non-adaptive cultural processes as an explanation for TSAT, overall our results are consistent with the hypothesis that broad, socially stressful demographic changes in late pre-contact Eastern North America resulted in the miniaturization-and augmented lethality-of stone tools across the region.

Understanding the conditions that influence the roles of midwives in Ontario, Canada's health system: an embedded single-case study.

BACKGROUND: Despite the significant variability in the role and integration of midwifery across provincial and territorial health systems, there has been limited scholarly inquiry into whether, how and under what conditions midwifery has been assigned roles and integrated into Canada's health systems. METHODS: We use Yin's (2014) embedded single-case study design, which allows for an in-depth exploration to qualitatively assess how, since the regulation of midwives in 1994, the Ontario health system has assigned roles to and integrated midwives as a service delivery option. Kingdon's agenda setting and 3i + E theoretical frameworks are used to analyze two recent key policy directions (decision to fund freestanding midwifery-led birth centres and the Patients First primary care reform) that presented opportunities for the integration of midwives into the health system. Data were collected from key informant interviews and documents. RESULTS: Nineteen key informant interviews were conducted, and 50 documents were reviewed in addition to field notes taken during the interviews. Our findings suggest that while midwifery was created as a self-regulated profession in 1994, health-system transformation initiatives have restricted the profession's integration into Ontario's health system. The policy legacies of how past decisions influence the decisions possible today have the most explanatory power to understand why midwives have had limited integration into interprofessional maternity care. The most important policy legacies to emerge from the analyses were related to payment mechanisms. In the medical model, payment mechanisms privilege physician-provided and hospital-based services, while payment mechanisms in the midwifery model have imposed unintended restrictions on the profession's ability to practice in interprofessional environments. CONCLUSIONS: This is the first study to explain why midwives have not been fully integrated into the Ontario health system, as well as the limitations placed on their roles and scope of practice. The study also builds a theoretical understanding of the integration process of healthcare professions within health systems and how policy legacies shape service delivery options.

Impact of Urgent Care Openings on Emergency Department Visits to Two Academic Medical Centers Within an Integrated Health Care System.

STUDY OBJECTIVE: The effect of urgent cares on local emergency department (ED) patient volumes is presently unknown. In this paper, we aimed to assess the change in low-acuity ED utilization at 2 academic medical centers in relation to patient proximity to an affiliated urgent care. METHODS: We created a geospatial database of ED visits occurring between April 2016 and March 2018 to 2 academic medical centers in an integrated health care system, geocoded by patient home address. We used logistic regression to characterize the relationship between the likelihood of patients visiting the ED for a low-acuity condition, based on ED discharge diagnosis, and urgent care center proximity, defined as living within 1 mile of an open urgent care center, for each of the academic medical centers in the system, adjusting for spatial, temporal, and patient factors. RESULTS: We identified a statistically significant reduction in the likelihood of ED visits for low-acuity conditions by patients living within 1 mile of an urgent care center at 1 of the 2 academic medical centers, with an adjusted odds ratio of 0.87 (95% confidence interval 0.78 to 0.98). There was, however, no statistically significant reduction at the other affiliated academic medical center. Further analysis showed a statistically significant temporal relationship between time since urgent care center opening and likelihood of a low-acuity ED visit, with approximately a 1% decrease in the odds of a low-acuity visit for every month that the proximal urgent care center was open (odds ratio 0.99; 95% confidence interval 0.985 to 0.997). CONCLUSION: Although further research is needed to assess the factors driving urgent care centers' variable influence on low-acuity ED use, these findings suggest that in similar settings urgent care center development may be an effective strategy for health systems hoping to decrease ED utilization for low-acuity conditions at academic medical centers.

Sugar beet hemoglobins: reactions with nitric oxide and nitrite reveal differential roles for nitrogen metabolism.

In contrast with human hemoglobin (Hb) in red blood cells, plant Hbs do not transport oxygen, instead research points towards nitrogen metabolism. Using comprehensive and integrated biophysical methods we characterized three sugar beet Hbs: BvHb1.1, BvHb1.2 and BvHb2. Their affinities for oxygen, CO, and hexacoordination were determined. Their role in nitrogen metabolism was studied by assessing their ability to bind NO, to reduce nitrite (NiR, nitrite reductase), and to form nitrate (NOD, NO dioxygenase). Results show that BvHb1.2 has high NOD-like activity, in agreement with the high nitrate levels found in seeds where this protein is expressed. BvHb1.1, on the other side, is equally capable to bind NO as to form nitrate, its main role would be to protect chloroplasts from the deleterious effects of NO. Finally, the ubiquitous, reactive, and versatile BvHb2, able to adopt 'open and closed forms', would be part of metabolic pathways where the balance between oxygen and NO is essential. For all proteins, the NiR activity is relevant only when nitrite is present at high concentrations and both NO and oxygen are absent. The three proteins have distinct intrinsic capabilities to react with NO, oxygen and nitrite; however, it is their concentration which will determine the BvHbs' activity.

ATP redirects cytokine trafficking and promotes novel membrane TNF signaling via microvesicles.

Cellular stress or injury induces release of endogenous danger signals such as ATP, which plays a central role in activating immune cells. ATP is essential for the release of nonclassically secreted cytokines such as IL-1ß but, paradoxically, has been reported to inhibit the release of classically secreted cytokines such as TNF. Here, we reveal that ATP does switch off soluble TNF (17 kDa) release from LPS-treated macrophages, but rather than inhibiting the entire TNF secretion, ATP packages membrane TNF (26 kDa) within microvesicles (MVs). Secretion of membrane TNF within MVs bypasses the conventional endoplasmic reticulum- and Golgi transport-dependent pathway and is mediated by acid sphingomyelinase. These membrane TNF-carrying MVs are biologically more potent than soluble TNF in vivo, producing significant lung inflammation in mice. Thus, ATP critically alters TNF trafficking and secretion from macrophages, inducing novel unconventional membrane TNF signaling via MVs without direct cell-to-cell contact. These data have crucial implications for this key cytokine, particularly when therapeutically targeting TNF in acute inflammatory diseases.-Soni, S., O'Dea, K. P., Tan, Y. Y., Cho, K., Abe, E., Romano, R., Cui, J., Ma, D., Sarathchandra, P., Wilson, M. R., Takata, M. ATP redirects cytokine trafficking and promotes novel membrane TNF signaling via microvesicles.

Components in Lentinus edodes mushroom with anti-biofilm activity directed against bacteria involved in caries and gingivitis.

The present study investigated the compounds present in the low molecular mass fraction of Lentinus edodes mushroom (shiitake) extract and their anti-virulence activity against oral pathogens (reference and clinical Streptococcus mutans, Actinomyces naeslundii, and Prevotella intermedia strains). Oxalic, succinic, and quinic acids, and adenine, inosine, and uridine were identified by HPLC-DAD-ESI-MS/MS. Their anti-biofilm production and preformed biofilm disaggregation activities were studied using commercial standard compounds at different concentrations. As regards S. mutans, the highest activity was shown by adenine at 5 mg mL-1 both in the biofilm inhibition (BI 50%) and biofilm disaggregation tests (BD 20%). Considering A. naeslundii, BI values close to 80% were registered for oxalic acid at 1 mg mL-1 and 2 mg mL-1 and BD 50% for quinic acid at 3 mg mL-1. A weaker activity was found against P. intermedia. Furthermore, different mixtures of the commercial standards were tested showing that the activity of a compound can be strongly and sometimes negatively affected by the presence of the other compounds.

Noninvasive Ventilation in Patients With Do-Not-Intubate and Comfort-Measures-Only Orders: A Systematic Review and Meta-Analysis.

OBJECTIVES: To assess the effectiveness of noninvasive ventilation in patients with acute respiratory failure and do-not-intubate or comfort-measures-only orders. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science from inception to January 1, 2017. STUDY SELECTION: Studies of all design types that enrolled patients in the ICU or hospital ward who received noninvasive ventilation and had preset do-not-intubate or comfort-measures-only orders. DATA EXTRACTION: Data abstraction followed Meta-analysis of Observational Studies in Epidemiology guidelines. Data quality was assessed using a modified Newcastle-Ottawa Scale. DATA SYNTHESIS: Twenty-seven studies evaluating 2,020 patients with do-not-intubate orders and three studies evaluating 200 patients with comfort-measures-only orders were included. In patients with do-not-intubate orders, the pooled survival was 56% (95% CI, 49-64%) at hospital discharge and 32% (95% CI, 21-45%) at 1 year. Hospital survival was 68% for chronic obstructive pulmonary disease, 68% for pulmonary edema, 41% for pneumonia, and 37% for patients with malignancy. Survival was comparable for patients treated in a hospital ward versus an ICU. Quality of life of survivors was not reduced compared with baseline, although few studies evaluated this. No studies evaluated quality of dying in nonsurvivors. In patients with comfort-measures-only orders, a single study showed that noninvasive ventilation was associated with mild reductions in dyspnea and opioid requirements. CONCLUSIONS: A large proportion of patients with do-not-intubate orders who received noninvasive ventilation survived to hospital discharge and at 1 year, with limited data showing no decrease in quality of life in survivors. Provision of noninvasive ventilation in a well-equipped hospital ward may be a viable alternative to the ICU for selected patients. Crucial questions regarding quality of life in survivors, quality of death in nonsurvivors, and the impact of noninvasive ventilation in patients with comfort-measures-only orders remain largely unanswered.