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We have discovered that the determination of CD4 effector and memory fates after infection is regulated not only by initial signals from antigen and pathogen recognition, but also by a second round of such signals at a checkpoint during the effector response. Signals to effectors determine their subsequent fate, inducing further progression to tissue-restricted follicular helpers, cytotoxic CD4 effectors, and long-lived memory cells. The follicular helpers help the germinal center B-cell responses that give rise to high-affinity long-lived antibody responses and memory B cells that synergize with T-cell memory to provide robust long-lived protection. We postulate that inactivated vaccines do not provide extended signals from antigen and pathogen beyond a few days, and thus elicit ineffective CD4 T- and B-cell effector responses and memory. Defining the mechanisms that underlie effective responses should provide insights necessary to develop vaccine strategies that induce more effective and durable immunity., (Copyright © 2021 Cold Spring Harbor Laboratory Press; all rights reserved.)

Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype-phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty-nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non-LoF variants. This study identifies genotype-phenotype correlations as well as race-facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long-term outcomes in individuals with WSS., (© 2021 Wiley Periodicals LLC.)

Context: Strong evidence throughout the literature highlights burnout as a significant and increasing problem among medical students, impacting students' ability to effectively care for and empathize with patients., Objectives: To examine how involvement in extracurricular activities and attendance at burnout lectures can impact burnout among medical students., Methods: An anonymous digital survey including the Maslach Burnout Inventory (MBI) was sent to all students (n=765) at Rowan University School of Osteopathic Medicine. The survey included questions regarding the number of burnout/wellness lectures respondents had attended, the number of clubs in which the respondents participated, the number of hours spent in these clubs, and any leadership positions held by the respondents., Results: Of the 765 students enrolled, 597 completed the survey. Results indicated that women participated in significantly more clubs than men ( t [456]=-4.30; p<0.001). Men had higher scores on the depersonalization subscale of the MBI than women ( t [463)=2.98; p<0.01]. There were no gender differences in emotional exhaustion or personal accomplishment. Linear regression analyses including gender and club participation as predictors of each of the burnout subscales indicated a significant interaction between gender and number of clubs ( β =0.34; p<0.05), in that more club participation was associated with higher depersonalization scores for women, but lower depersonalization scores for men. The number of wellness/burnout prevention lectures attended was not predictive of scores on any of the burnout subscales., Conclusions: Our results indicate the importance of understanding what drives burnout on the individual level and adapting interventions to suit the needs of individual students, rather than the student body as a whole., (© 2021 Jennifer C. Sepede et al., published by De Gruyter, Berlin/Boston.)

Background: Endometriosis (where endometrial-like tissue is found outside the uterus) affects ~ 176 million women worldwide and can lead to debilitating pelvic pain. There is an unmet need for new medical treatment options for endometriosis. Pelvic peritoneal mesothelial cells of women with endometriosis exhibit detrimental metabolic reprogramming that creates an environment favouring the formation and survival of endometriosis lesions. We have generated powerful preclinical proof-of-concept data to show that it is possible to correct this metabolic phenotype using dichloroacetate (DCA), a non-hormonal compound previously used to treat rare metabolic disorders in children. We plan a single-arm, open-label, single site exploratory clinical trial to inform the design of a future randomised controlled trial (RCT) to determine the efficacy of DCA for the treatment of endometriosis-associated pain., Methods: We will recruit 30 women with endometriosis-associated pain over a 6-month period. All participants will receive approximately 6.25 mg/kg oral DCA capsules twice daily for 6 weeks, with a dose increase to approximately 12.5 mg/kg twice daily for a further 6 weeks if their pain has not been adequately controlled on this dose regime and side-effects are acceptable. If pain is adequately controlled with minimal side-effects, the lower dose will be continued for a further 6 weeks. The primary objective is to determine whether it is possible to achieve acceptable recruitment and retention rates within the defined exclusion and inclusion criteria. Secondary objectives are to determine the acceptability of the trial to participants, including the proposed methods of recruitment, treatment, follow-up frequency and number of questionnaires. The recruitment rate will be determined by the proportion of patients recruited from the pool of eligible women. The retention rate will be determined by the proportion of participants who attended the final trial visit., Discussion: This is a feasibility study to explore effectiveness and acceptability of the proposed field methodology (recruitment, retention, study processes and compliance with treatment). The results will be used to inform the design of a future RCT., Trial Registration: ClinicalTrials.gov, NCT04046081 Registered 6 August 2019.

Cell migration in 3D microenvironments is a complex process which depends on the coordinated activity of leading edge protrusive force and rear retraction in a push-pull mechanism. While the potentiation of protrusions has been widely studied, the precise signalling and mechanical events that lead to retraction of the cell rear are much less well understood, particularly in physiological 3D extra-cellular matrix (ECM). We previously discovered that rear retraction in fast moving cells is a highly dynamic process involving the precise spatiotemporal interplay of mechanosensing by caveolae and signalling through RhoA. To further interrogate the dynamics of rear retraction, we have adopted three distinct mathematical modelling approaches here based on (i) Boolean logic, (ii) deterministic kinetic ordinary differential equations (ODEs) and (iii) stochastic simulations. The aims of this multi-faceted approach are twofold: firstly to derive new biological insight into cell rear dynamics via generation of testable hypotheses and predictions; and secondly to compare and contrast the distinct modelling approaches when used to describe the same, relatively under-studied system. Overall, our modelling approaches complement each other, suggesting that such a multi-faceted approach is more informative than methods based on a single modelling technique to interrogate biological systems. Whilst Boolean logic was not able to fully recapitulate the complexity of rear retraction signalling, an ODE model could make plausible population level predictions. Stochastic simulations added a further level of complexity by accurately mimicking previous experimental findings and acting as a single cell simulator. Our approach highlighted the unanticipated role for CDK1 in rear retraction, a prediction we confirmed experimentally. Moreover, our models led to a novel prediction regarding the potential existence of a 'set point' in local stiffness gradients that promotes polarisation and rapid rear retraction., Competing Interests: The authors have declared that no competing interests exist.

Background: Nurse staffing impacts patient outcomes, but little is known about the relationship between nurse staffing and outcomes for lung cancer patients undergoing pulmonary lobectomy., Objectives: To examine the association between nurse staffing and outcomes following lobectomy for lung cancer., Methods: Patients (N = 16,994) with lung cancer between who underwent lobectomy between 2008-2011 were identified in the National Inpatient Sample. Nurse staffing was quantified using registered nurse full-time equivalents per adjusted patient days. Multivariable models were used to estimate the effect of RN FTEs on mortality, length of stay, and costs, controlling for covariates., Results: Patients treated at hospitals using 5.6 or more RN FTEs had shorter hospitals stays by 0.37 days (p = 0.008), had 36% lower odds of mortality (OR = 0.64, p = 0.014), but incurred $4,388 (p < 0.0001) in additional costs., Conclusions: Hospital administrators face a troubling trade-off between costs and outcomes in decisions about nurse staffing mix for pulmonary lobectomy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Electronic health records (EHRs) are increasingly being used to support public health surveillance, including in cancer, where many population-based registries can now accept electronic case reporting. Using EHRs to supplement cancer registry data provides the opportunity to examine in more detail emerging issues in cancer control, such as the increasing incidence rates of early onset colorectal cancer (CRC). The purpose of this study was to evaluate the feasibility of a public health organization partnering with a health system to examine risk factors for early-onset CRC in a community cancer setting, and to further understand challenges with using EHRs to address emerging topics in cancer control. We conducted a mixed-methods evaluation using key informant interviews with public health practitioners, researchers, and registry staff to generate insights on how using EHRs and partnering with health systems can improve chronic disease surveillance and cancer control. A data quality assessment of variables representing risk factors for CRC and other clinical characteristics was conducted on all CRC patients diagnosed in 2016 at the participating cancer center. The quantitative assessment of the EHR data revealed that, while most chronic health conditions were well documented, around 25% of CRC patients were missing information on body mass index, alcohol, and tobacco use. Key informants offered ideas and ways to overcome challenges with using EHR data to support chronic disease surveillance. Their recommendations included the following activities: engaging EHR vendors in the development of standards, taking leadership roles on workgroups to address emerging technological issues, participating in pilot studies and task forces, and negotiating with EHR vendors so that clinical decision support tools built to support public health initiatives are freely available to all users of those EHRs. Although using EHR data to support public health efforts is not without its challenges, it soon could be an important part of chronic disease surveillance and cancer control.

Background: Technosphere Insulin (TI) is an inhaled insulin. Studies comparing TI with short-acting insulin analogues provide important insights on efficacy, dosing, and time course of action., Methods: Planned enrollment of 230 subjects was limited to 138 due to premature study discontinuation. The primary efficacy endpoint was a noninferiority of glycosylated hemoglobin (HbA1c) of 0.4% for TI compared with insulin lispro (LIS) in a 16-week phase 3 randomized clinical trial in type 1 diabetes mellitus., Results: HbA1c values were similar in the TI and LIS groups at the beginning of the trial (7.8% and 7.6%, respectively) and at trial endpoint (7.7% and 7.6%, respectively). Least squares mean changes from baseline were similar between study groups. Glucose values after a standard meal were significantly lower with TI in the first 90 minutes post meal compared with LIS. Mild or moderate hypoglycemia event rates were also significantly lower with TI compared with LIS (5.97 vs 8.01, respectively; P = .0269). Cough was the most commonly reported adverse event with TI. Pulmonary function as measured by forced expiratory volume in 1 second was not different between groups at baseline, 16 weeks, or 4 weeks off study drug., Conclusions: HbA1c was unchanged and overall glucose control was comparable between groups. Treatment with TI resulted in improved post-meal glucose and a lower risk of hypoglycemia compared with LIS., (© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Improving the quality and efficiency of healthcare is an international priority. A range of complex ward based quality initiatives have been developed over recent years, perhaps the most influential programme has been Productive Ward: Releasing Time to Care. The programme aims to improve work processes and team efficiency with the aim of 'releasing time', which would be used to increase time with patients ultimately improving patient care, although this does not form a specific part of the programme. This study aimed to address this and evaluate the impact using recent methodological advances in complex intervention evaluation design., Method: The objective of this study was to assess the impact of an augmented version of The Productive Ward: Releasing Time to Care on staff and patient outcomes. The design was a naturalistic stepped-wedge trial. The setting included fifteen wards in two acute hospitals in a Scottish health board region. The intervention was the Productive Ward: Releasing Time to Care augmented with practice development transformational change methods that focused on staff caring behaviours, teamwork and patient feedback. The primary outcomes included nurses' shared philosophy of care, nurse emotional exhaustion, and patient experience of nurse communication. Secondary outcomes covered additional key dimensions of staff and patient experience and outcomes and frequency of emergency admissions for same diagnosis within 6 months of discharge., Results: We recruited 691 patients, 177 nurses and 14 senior charge nurses. We found statistically significant improvements in two of the study's three primary outcomes: patients' experiences of nurse communication (Effect size=0.15, 95% CI; 0.05 to 0.24), and nurses' shared philosophy of care (Effect size =0.42, 95% CI; 0.14 to 0.70). There were also significant improvements in secondary outcomes: patients' overall rating of ward quality; nurses' positive affect; and items relating to nursing team climate. We found no change in frequency of emergency admissions within six months of discharge., Conclusions: We found evidence that the augmented version of The Productive Ward: Releasing Time to Care Intervention was successful in improving a number of dimensions of nurse experience and ward culture, in addition to improved patient experience and evaluations of the quality of care received. Despite these positive summary findings across all wards, intervention implementation appeared to vary between wards. By addressing the contextual factors, which may influence these variations, and tailoring some elements of the intervention, it is likely that greater improvements could be achieved., Trial Registration Number: UKCRN 14195., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To compare glycemic efficacy of Technosphere insulin (TI) versus that of insulin aspart (IA), each added to basal insulin, in type 2 diabetes., Methods: This randomized, 24-week trial included subjects aged from 18 to 80 years who were treated with subcutaneous insulin for 3 months and had glycated hemoglobin (HbA1C) levels of 7.0% to 11.5%. After receiving stabilized insulin glargine doses during a 4-week lead in, the subjects were randomized to TI or IA. The primary end point was an HbA1C change from baseline, with the differences analyzed by equivalence analyses., Results: In the overall cohort (N = 309; males, 23.3%), mean (SD) age was 58.5 (8.4) years, body mass index was 30.8 (4.7) kg/m 2 , weight was 82.2 (13.6) kg, and duration of diabetes was 12.2 (7.1) years. An intention-to-treat cohort had 150 subjects randomized to TI (mean [SD] HbA1C: 8.9% [1.1%]) and 154 randomized to IA (mean [SD] HbA1C: 9.0% [1.3%]). At 24 weeks, mean (SD) HbA1C value declined to 7.9% (1.3%) and 7.7% (1.1%) in the TI and IA cohorts, respectively. A treatment difference of 0.26% was not statistically significant, but the predefined equivalency margin was not met. Subjects receiving TI lost 0.78 kg compared to baseline; subjects receiving IA gained 0.23 kg (P =.0007). The incidence of mild/moderate hypoglycemia was lower for the TI cohort, though not statistically significant., Conclusion: Both TI and IA resulted in significant and clinically meaningful HbA1C reductions. TI also resulted in significant and clinically meaningful weight reductions. These data support the use of inhaled insulin as a treatment option for individuals with type 2 diabetes., (Copyright © 2020 AACE. Published by Elsevier Inc. All rights reserved.)

Coronavirus disease 2019 (COVID-19) can progress to cytokine storm that is associated with organ dysfunction and death. The purpose of the present study is to determine clinical characteristics associated with 28 day in-hospital survival in patients with coronavirus disease 2019 (COVID-19) that received tocilizumab. This was a retrospective observational cohort study conducted at a five hospital health system in Michigan, United States. Adult patients with confirmed COVID-19 that were admitted to the hospital and received tocilizumab for cytokine storm from March 1, 2020 through April 3, 2020 were included. Patients were grouped into survivors and non-survivors based on 28 day in-hospital mortality. Study day 0 was defined as the day tocilizumab was administered. Factors independently associated with in-hospital survival at 28 days after tocilizumab administration were assessed. Epidemiologic, demographic, laboratory, prognostic scores, treatment, and outcome data were collected and analyzed. Clinical response was collected and defined as a decline of two levels on a six-point ordinal scale of clinical status or discharged alive from the hospital. Of the 81 patients included, the median age was 64 (58-71) years and 56 (69.1%) were male. The 28 day in-hospital mortality was 43.2%. There were 46 (56.8%) patients in the survivors and 35 (43.2%) in the non-survivors group. On study day 0 no differences were noted in demographics, clinical characteristics, severity of illness scores, or treatments received between survivors and non-survivors. C-reactive protein was significantly higher in the non-survivors compared to survivors. Compared to non-survivors, recipients of tocilizumab within 12 days of symptom onset was independently associated with survival (adjusted OR: 0.296, 95% CI: 0.098-0.889). SOFA score ≥8 on day 0 was independently associated with mortality (adjusted OR: 2.842, 95% CI: 1.042-7.753). Clinical response occurred more commonly in survivors than non-survivors (80.4% vs. 5.7%; p < 0.001). Improvements in the six-point ordinal scale and SOFA score were observed in survivors after tocilizumab. Early receipt of tocilizumab in patients with severe COVID-19 was an independent predictor for in-hospital survival at 28 days., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The development and transformation of nursing within professional tertiary education have exerted a great pressure and challenge upon nursing students. Stress experienced by nursing students is a common precursor of psychological distress and attrition. However, no scale is specifically used to evaluate the sources of stress experienced by nursing students in Mainland China. Aims and Objective . This study is aimed at testing and comparing the reliability and validity including sensitivity and specificity of two nursing students' stress instruments, the Chinese version of Student Nurse Stress Index Scale (SNSI-CHI), and the Stressors in Student Nursing Scale (SINS-CN) in Chinese nursing students, and describing the stress status of nursing students in China., Methods: A cross-sectional survey was conducted in two nursing schools in Henan Province from August 2017 to January 2018. Data were collected by using a questionnaire comprising the Chinese version of SNSI (SNSI-CHI), the Chinese version of SINS (SINS-CN), and the Chinese Perceived Stress Scale (CPSS). Homogeneity and stability, content, construct and concurrent validity, and sensitivity and specificity were assessed., Results: The Cronbach's alpha ( α ) of SNSI-CHI was 0.90, and the item-to-total correlations ranged from 0.35 to 0.66. The Cronbach's α of SINS-CN was 0.93, and the item-to-total correlations ranged from 0.19 to 0.61. The findings of exploratory factor analysis (EFA) confirmed a good construct validity of SNSI-CHI and SINS-CN. The Pearson's rank correlation coefficients, between total scores of SNSI-CHI and CPSS and SINS-CN and CPSS, were assessed to 0.38 ( P < 0.01) and 0.39 ( P < 0.01), respectively. Regarding the CPSS, as the criterion, the cut-points of SNSI-CHI and SINS-CN for the area under the receiver operator characteristic (ROC) curve were 0.77and 0.66, respectively., Conclusion: Both scales are valid and reliable for evaluating the source of stress of student nurses in China. Each has its own characteristics, but the SNSI-CHI demonstrated marginal advantage over the SINS-CN. The SNSI-CHI is short, is easily understood, and with clear dimension for the nursing students, and the SNSI-CHI is more acceptable for the users in China., Competing Interests: The authors declare that they have no competing interests and no conflict of interest., (Copyright © 2020 Yiru Zhu et al.)

Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain significance (c.442A > T; p.Thr148Ser). This report expands the presenting phenotype of patients with PPA2 variants. It also highlights the utility of dried blood spots for postmortem molecular diagnosis., (© 2020 Sanford et al.; Published by Cold Spring Harbor Laboratory Press.)

Objective: Two glenoid bone loss calculations are compared across a range of anatomic glenoid sizes., Methods: 20 cadaveric paired glenoid diameters were measured to create glenoid models with bone loss calculated in 1 mm linear increments up to 50% bone loss comparing the linear measurement percentage (LMP) to the circle line method (CLM) gold standard., Results: The LMP overestimates glenoid bone loss at every potential 1 mm increment across each glenoid model until bone loss reaches 50%., Conclusion: The widely-used LMP method overestimates bone loss compared to a gold standard potentially misguiding surgeons towards bony reconstruction in shoulder instability during preoperative planning., Competing Interests: The authors declare that they have no competing interests., (© 2020 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

Extracellular vesicles (EVs) are emerging as promising nanoscale therapeutics due to their intrinsic role as mediators of intercellular communication, regulating tissue development and homeostasis. The low immunogenicity and natural cell-targeting capabilities of EVs has led to extensive research investigating their potential as novel acellular tools for tissue regeneration or for the diagnosis of pathological conditions. However, the clinical use of EVs has been hindered by issues with yield and heterogeneity. From the modification of parental cells and naturally-derived vesicles to the development of artificial biomimetic nanoparticles or the functionalisation of biomaterials, a multitude of techniques have been employed to augment EVs therapeutic efficacy. This review will explore various engineering strategies that could promote EVs scalability and therapeutic effectiveness beyond their native utility. Herein, we highlight the current state-of-the-art EV-engineering techniques with discussion of opportunities and obstacles for each. This is synthesised into a guide for selecting a suitable strategy to maximise the potential efficacy of EVs as nanoscale therapeutics.

Anomalously low winter sea ice extent and early retreat in CE 2018 and 2019 challenge previous notions that winter sea ice in the Bering Sea has been stable over the instrumental record, although long-term records remain limited. Here, we use a record of peat cellulose oxygen isotopes from St. Matthew Island along with isotope-enabled general circulation model (IsoGSM) simulations to generate a 5500-year record of Bering Sea winter sea ice extent. Results show that over the last 5500 years, sea ice in the Bering Sea decreased in response to increasing winter insolation and atmospheric CO 2 , suggesting that the North Pacific is highly sensitive to small changes in radiative forcing. We find that CE 2018 sea ice conditions were the lowest of the last 5500 years, and results suggest that sea ice loss may lag changes in CO 2 concentrations by several decades., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

This work presents a new technique for evaluating the solid-liquid phase transformations in complex diesel fuel blends and diesel surrogates under high-pressure conditions intended to simulate those occurring in vehicle fuel injectors. A high-pressure apparatus based on a visual identification of freezing and thawing has been designed and built to monitor phase behavior and determine the crystallization temperature of complex fuels to predict wax precipitation. The proposed methodology was validated using pure substances-n-hexadecane (C 16 H 34 ), cyclohexane (C 6 H 12 ), and a mixture of 0.5848 mol fraction n-hexadecane in cyclohexane. The crystallization temperatures of these compounds were measured from atmospheric pressure to 400 MPa for temperatures varying from 290 K to 363 K and compared to those reported in the literature. The standard error of the estimated temperatures for the experimental data obtained in this work, based on a given pressure, was compared to data from the literature. This methodology will be extended to investigate the properties of more complex fuel mixtures.

Recent studies suggest that the tetracycline antibiotic minocycline, or its cousins, hold therapeutic potential for affective and psychotic disorders. This is proposed on the basis of a direct effect on microglia-mediated frontocortical synaptic pruning (FSP) during adolescence, perhaps in genetically susceptible individuals harboring risk alleles in the complement component cascade that is involved in this normal process of CNS circuit refinement. In reviewing this field, it is argued that minocycline is actually probing and modulating a deeply evolved and intricate system wherein psychosocial stimuli sculpt the circuitry of the "social brain" underlying adult behavior and personality. Furthermore, this system can generate psychiatric morbidity that is not dependent on genetic variation. This view has important ramifications for understanding "pathologies" of human social behavior and cognition as well as providing long-sought potential mechanistic links between social experience and susceptibility to mental and physical disease., (© 2020 Wiley Periodicals LLC.)

Background: Individuals with Cystic fibrosis (CF) are the most vulnerable population for pulmonary infection with nontuberculous mycobacteria (NTM). Screening, diagnosis, and assessment of treatment response currently depend on traditional culture techniques, but sputum analysis for NTM in CF is challenging, and associated with a low sensitivity. The cell wall lipoarabinomannan (LAM), a lipoglycan found in all mycobacterial species, and has been validated as a biomarker in urine for active Mycobacterium tuberculosis infection., Methods: Urine from a CF cohort (n = 44) well-characterized for NTM infection status by airway cultures was analyzed for LAM by gas chromatography/mass spectrometry. All subjects with positive sputum cultures for NTM had varying amounts of LAM in their urine. No LAM was detected in subjects who never had a positive culture (14/45). One individual initially classified as NTM sputum negative subsequently developed NTM disease 657 days after the initial urine LAM testing. Repeat urine LAM testing turned positive, correlating to her positive NTM status. Subjects infected with subspecies of M. abscessus had greater LAM quantities than those infected with M. avium complex (MAC). There was no correlation with disease activity or treatment status and LAM quantity. A TB Capture ELISA using anti-LAM antibodies demonstrated very poor sensitivity in identifying individuals with positive NTM sputum cultures., Conclusion: These findings support the conclusion that urine LAM related to NTM infection may be a useful screening test to determine patients at low risk for having a positive NTM sputum culture, as part of a lifetime screening strategy in the CF population., Competing Interests: Declaration of Competing Interest Authors have no competing interests., (Copyright © 2020. Published by Elsevier B.V.)

Integrin adhesion complexes (IACs) bridge the extracellular matrix to the actin cytoskeleton and transduce signals in response to both chemical and mechanical cues. The composition, interactions, stoichiometry, and topological organization of proteins within IACs are not fully understood. To address this gap, we used multiplexed proximity biotinylation (BioID) to generate an in situ, proximity-dependent adhesome in mouse pancreatic fibroblasts. Integration of the interactomes of 16 IAC-associated baits revealed a network of 147 proteins with 361 proximity interactions. Candidates with underappreciated roles in adhesion were identified, in addition to established IAC components. Bioinformatic analysis revealed five clusters of IAC baits that link to common groups of prey, and which therefore may represent functional modules. The five clusters, and their spatial associations, are consistent with current models of IAC interaction networks and stratification. This study provides a resource to examine proximal relationships within IACs at a global level., (© 2020 Chastney et al.)

Two robust and efficient mechanochemical protocols for the synthesis of an array of N-arylamides have been developed. This was achieved by a C-N cross-coupling between O-pivaloyl hydroxamic acids and aryl iodides or aryl boronic acids, in the presence of a stoichiometric amount of a copper mediator. The effectiveness of this method is highlighted by the high-yielding (up to 94 %), scalable (up to 8 mmol), and rapid (20 minutes) synthesis of N-aryl amides (15 examples), using a variety of deactivated and sterically encumbered substrates, whilst employing mild conditions and in the absence of solvents. In addition, it was determined that whilst the O-pivaloyl hydroxamic acid precursors can be synthesised mechanochemically, iron contamination originating from the steel jars was found to occur which can hinder the efficacy of this process. Furthermore, 3D printing was used to produce custom milling jars that could successfully accommodate a scaled-up version of the two protocols., (© 2020 Wiley-VCH GmbH.)

Hypertension (HTN) is a leading cause of death and disability throughout the world. Yet, despite widely available treatment options, blood pressure (BP) control rates have remained relatively stagnant. One approach to address this issue is through collaborative care models, particularly those employing pharmacists. Numerous randomized controlled trials (RCT) have demonstrated the effectiveness of pharmacist interventions to improve BP control across primary care, community-based, and telemedicine models. A meta-analysis of 39 RCTs has demonstrated that pharmacist interventions significantly reduce both systolic and diastolic BP compared with controls across diverse patient populations. Pharmacists can contribute to HTN management in a variety of ways, including assisting with out-of-office monitoring, providing education, identifying and resolving nonadherence, and titrating antihypertensive therapy to achieve BP control. In this review, we discuss key trials conducted in recent years that support the role of pharmacists in HTN management and provide guidance on practical considerations for working collaboratively with pharmacists to improve BP control.

As the world struggles through the COVID-19 pandemic, we should also be asking what systems-level measures will be needed to prevent this or even worse disasters from happening in the future. We argue that the pandemic is merely one of potentially myriad and pleiomorphic future global disasters generated by the same underlying dynamical system. We explain that there are four broad but easily identifiable systemic, pathologically networked conditions that are hurtling civilization toward potential self-destruction. As long as these conditions are not resolved, we should consider catastrophe as an inevitable emergent endpoint from the dynamics. All four conditions can be reversed with collective action to begin creating an enduring and thriving post- COVID-19 world. This will require maximal application of the precautionary principle., (© 2020 WILEY Periodicals, Inc.)

Topical administration of corticosteroids is the cornerstone treatment of anterior uveitis, but poor corneal penetration and retention cause hindrance in their therapeutic utility. The conventional eye drops are less valuable in conditions where inflammation reaches deeper regions of the eye. Therefore, there is a clear need for an effective drug delivery system, which can increase corticosteroid penetration after topical application. To address this, cationic nanostructured lipid carriers of the drug triamcinolone acetonide (cTA-NLC) were prepared. The cTA-NLC were prepared by a hot microemulsion method and evaluated for drug release, permeation, cell uptake, cytotoxicity, anti-inflammatory activity and ocular irritancy. The cTA-NLC are nanometric in size (< 200 nm), with a zeta potential of about +35 mv and % drug EE of 88 %. The nanocarriers exhibited slow and sustained release of around 84 % in 24 h and transcorneal drug permeation of 51 % in 8 h. The nanocarriers exhibited no cytotoxicity (% cell viability of>90 %). The cell uptake study showed that nanocarriers could retain inside the cells for 24 h. The developed formulation could significantly reduce the TNF-α level in LPS induced inflamed cells. The studies indicated that cTA-NLC could be a promising option for the topical treatment of uveitis., Competing Interests: Declaration of Competing Interest All the authors declare that this article content has no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Achondroplasia is the most common short-stature skeletal dysplasia, additionally marked by rhizomelia, macrocephaly, midface hypoplasia, and normal cognition. Potential medical complications associated with achondroplasia include lower extremity long bone bowing, middle-ear dysfunction, obstructive sleep apnea, and, more rarely, cervicomedullary compression, hydrocephalus, thoracolumbar kyphosis, and central sleep apnea. This is the second revision to the original 1995 health supervision guidance from the American Academy of Pediatrics for caring for patients with achondroplasia. Although many of the previously published recommendations remain appropriate for contemporary medical care, this document highlights interval advancements in the clinical methods available to monitor for complications associated with achondroplasia. This document is intended to provide guidance for health care providers to help identify individual patients at high risk of developing serious sequelae and to enable intervention before complications develop., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Parts of the Southwestern United States report arsenic levels in water resources that are above the United States Environmental Protection Agency's current drinking water limits. Prolonged exposure to arsenic through food and drinking water can contribute to significant health problems including cancer, developmental effects, cardiovascular disease, neurotoxicity, and diabetes. In order to understand exposure risks, water sampling and testing has been conducted throughout Arizona. This information is available to the public through often non-overlapping databases that are difficult to access and in impracticable formats. The current study utilized a systemic compilation of online databases to compile a spreadsheet containing over 33,000 water samples. The reported arsenic concentrations from these databases were collected from 1990-2017. Using ArcGIS software, these data were converted into a map shapefile and overlaid onto a map of Arizona. This visual representation shows that arsenic levels in surface and ground water exceed the United States Environmental Protection Agency's drinking water limits for many sites in several counties in Arizona, and there is an underrepresentation of sampling in several tribal jurisdictions. This information is useful for water managers and private well owners throughout the State for determining safe drinking water sources and limiting exposure to arsenic.

The density power divergence, indexed by a single tuning parameter α , has proved to be a very useful tool in minimum distance inference. The family of density power divergences provides a generalized estimation scheme which includes likelihood-based procedures (represented by choice α = 0 for the tuning parameter) as a special case. However, under data contamination, this scheme provides several more stable choices for model fitting and analysis (provided by positive values for the tuning parameter α ). As larger values of α necessarily lead to a drop in model efficiency, determining the optimal value of α to provide the best compromise between model-efficiency and stability against data contamination in any real situation is a major challenge. In this paper, we provide a refinement of an existing technique with the aim of eliminating the dependence of the procedure on an initial pilot estimator. Numerical evidence is provided to demonstrate the very good performance of the method. Our technique has a general flavour, and we expect that similar tuning parameter selection algorithms will work well for other M-estimators, or any robust procedure that depends on the choice of a tuning parameter., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2020 Informa UK Limited, trading as Taylor & Francis Group.)

From 2008 to 2013, we sampled freshwater turtle populations at 66 sites in south, central, and west Texas, USA. Sampling sites included ponds, lakes, resacas (oxbow lakes), canals, and rivers. We sampled turtle populations using baited hoop nets (66 sites) and basking traps (3 sites), and captured turtles by hand opportunistically in terrestrial habitat. We measured carapace length and width, plastron length and width, body depth, and weight of captured turtles. Excluding recaptures, we measured 356 Apalone spinifera emoryi (Texas Spiny Softshell), 24 Chelydra serpentina (Snapping Turtle), 20 Kinosternon flavescens (Yellow Mud Turtle), 47 Trachemys gaigeae (Big Bend Slider), and 1070 Trachemys scripta elegans (Red-eared Slider). Carapace length of Apalone spinifera emoryi ranged from 85 to 426 mm (mean = 182 mm). Carapace length of Chelydra serpentina ranged from 74 to 320 mm (mean = 233 mm). Carapace length of Kinosternon flavescens ranged from 64 to 147 mm (mean = 114 mm). Carapace length of Trachemys gaigeae ranged from 54 to 203 mm (mean = 141 mm). Carapace length of Trachemys scripta elegans ranged from 30 to 328 mm (mean = 171 mm). These data are useful for assessing spatial and temporal variation in size and body condition of freshwater turtles., (© 2020 The Author(s).)

In two independent ongoing next-generation sequencing projects for individuals with holoprosencephaly and individuals with disorders of sex development, and through international research collaboration, we identified twelve individuals with de novo loss-of-function (LoF) variants in protein phosphatase 1, regulatory subunit 12a (PPP1R12A), an important developmental gene involved in cell migration, adhesion, and morphogenesis. This gene has not been previously reported in association with human disease, and it has intolerance to LoF as illustrated by a very low observed-to-expected ratio of LoF variants in gnomAD. Of the twelve individuals, midline brain malformations were found in five, urogenital anomalies in nine, and a combination of both phenotypes in two. Other congenital anomalies identified included omphalocele, jejunal, and ileal atresia with aberrant mesenteric blood supply, and syndactyly. Six individuals had stop gain variants, five had a deletion or duplication resulting in a frameshift, and one had a canonical splice acceptor site loss. Murine and human in situ hybridization and immunostaining revealed PPP1R12A expression in the prosencephalic neural folds and protein localization in the lower urinary tract at critical periods for forebrain division and urogenital development. Based on these clinical and molecular findings, we propose the association of PPP1R12A pathogenic variants with a congenital malformations syndrome affecting the embryogenesis of the brain and genitourinary systems and including disorders of sex development., (Published by Elsevier Inc.)

Background: Ivacaftor shows benefit in patients with cystic fibrosis (CF) and CFTR mutations associated with residual CF transmembrane conductance regulator (CFTR) function. Here we further assess the effect of ivacaftor in such patients using an N-of-1 study design., Methods: Patients aged ≥12 years with CF with clinical or molecular evidence of residual CFTR function were randomized to 1 of 4 treatment sequences for two 4-week, double-blind crossover cycles (each divided into 2 weeks of ivacaftor treatment and placebo) followed by 8 weeks of open-label ivacaftor treatment. The primary endpoint was absolute change from cycle baseline of percent predicted forced expiratory volume in 1 s (ppFEV 1 ) after 2 weeks of treatment with ivacaftor relative to placebo., Results: Absolute change (SD) from study baseline in ppFEV 1 favored ivacaftor by 2.3 (1.0) percentage points (95% credible interval, 0.4-4.1) after 2 weeks of treatment. Absolute mean change (SD) from open-label baseline (defined as day 1 of the open-label ivacaftor treatment period) in ppFEV 1 after 8 weeks of treatment was 4.7 (4.2) percentage points (P<.0001). Safety of ivacaftor was consistent with that observed in prior studies., Conclusions: Ivacaftor improved lung function during the double-blind and open-label treatment periods in patients with CF and CFTR mutations associated with residual CFTR function (ClinicalTrials.gov, NCT01685801)., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Clonal Mycobacterium mucogenicum isolates (determined by molecular typing) were recovered from 19 bronchoscopic specimens from 15 patients. None of these patients had evidence of mycobacterial infection. Laboratory culture materials and bronchoscopes were negative for Mycobacteria. This pseudo-outbreak was caused by contaminated ice used to provide bronchoscopic lavage. Control was achieved by transitioning to sterile ice.

Lloyd Jones, MC, Morris, MG, and Jakeman, JR. Effect of work: Rest ratio on cycling performance following sprint interval training: A randomized control trial. J Strength Cond Res 33(12): 3263-3268, 2019-Sprint interval training (SIT) has been shown to improve performance measures in a range of individuals, and it is understood that different responses can be elicited from different training protocols. However, consideration of changes in work to rest ratios could offer important insight into optimizing training programs. The purpose of this study was to investigate the effect of 3 different work to rest ratios on exercise performance. Thirty-six male and female subjects were randomly allocated to 1 of 3 training groups or a nontraining control group. Training consisted of 10 × 6 second "all-out" sprints on a cycle ergometer, with a 1:8, 1:10, or 1:12 work-to-rest ratio. Performance data, including peak power output, performance decrement, and 10-km time trial performance data were collected before and after 2 weeks of SIT. There were significant (p ≤ 0.05) improvements in all parameters for the training groups, but no changes were observed in the control condition. Peak power increased by 57.2, 50.7, and 53.7 W in the 1:8, 1:10 and 1:12 groups, respectively, with no significant differences in response between conditions. Time trial performance improved significantly in all 3 training conditions (29.4, 8.7, and 25.1 seconds in the 1:8, 1:10, and 1:12 groups), while worsening in the control group. All training conditions resulted in significant improvements in performance, but there were no significant differences in improvement for any of the groups. Any of the 3 stated that work to rest ratios would be appropriate for use with athletes and allow some level of personal preference for those interested in using the protocol.

Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder caused by biallelic variants in UBE3B. Kaufman oculocerebrofacial syndrome is characterized by a recognizable pattern of malformations including moderate to severe intellectual disability, growth deficiency, microcephaly and a distinctive facial gestalt. Common craniofacial features include short upslanting palpebral fissures, blepharophimosis or ptosis, ear anomalies, hearing loss, palate anomalies and stridor/laryngomalacia. The aim of this study was to describe the phenotypic features and the genotype of five new individuals from three unrelated families, and to review systematically the published information of 26 cases. The main features are summarized contributing to further characterize the natural history of the disease. Novel phenotypic features and two novel pathogenic variants in UBE3B are reported: A splice site variant (c.2569-1G > C) and a nonsense variant (c.518C > A, p.Ser173Ter). Kaufman oculocerebrofacial syndrome is likely an underdiagnosed disorder which can be clinically recognized based on its distinctive facial gestalt and relatively homogenous natural history.

Cell division, the purpose of which is to enable cell replication, and in particular to distribute complete, accurate copies of genetic material to daughter cells, is essential for the propagation of life. At a morphological level, division not only necessitates duplication of cellular structures, but it also relies on polar segregation of this material followed by physical scission of the parent cell. For these fundamental changes in cell shape and positioning to be achieved, mechanisms are required to link the cell cycle to the modulation of cytoarchitecture. Outside of mitosis, the three main cytoskeletal networks not only endow cells with a physical cytoplasmic skeleton, but they also provide a mechanism for spatio-temporal sensing via integrin-associated adhesion complexes and site-directed delivery of cargoes. During mitosis, some interphase functions are retained, but the architecture of the cytoskeleton changes dramatically, and there is a need to generate a mitotic spindle for chromosome segregation. An economical solution is to re-use existing cytoskeletal molecules: transcellular actin stress fibres remodel to create a rigid cortex and a cytokinetic furrow, while unipolar radial microtubules become the primary components of the bipolar spindle. This remodelling implies the existence of specific mechanisms that link the cell-cycle machinery to the control of adhesion and the cytoskeleton. In this article, we review the intimate three-way connection between microenvironmental sensing, adhesion signalling and cell proliferation, particularly in the contexts of normal growth control and aberrant tumour progression. As the morphological changes that occur during mitosis are ancient, the mechanisms linking the cell cycle to the cytoskeleton/adhesion signalling network are likely to be primordial in nature and we discuss recent advances that have elucidated elements of this link. A particular focus is the connection between CDK1 and cell adhesion. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS., (© 2019 Wiley Periodicals, Inc.)

Sediment cores from Florida Bay, Everglades National Park were examined to determine ecosystem response to relative sea-level rise (RSLR) over the Holocene. High-resolution multiproxy analysis from four sites show freshwater wetlands transitioned to mangrove environments 4-3.6 ka, followed by estuarine environments 3.4-2.8 ka, during a period of enhanced climate variability. We calculate a RSLR rate of 0.67 ± 0.1 mm yr -1 between ~4.2-2.8 ka, 4-6 times lower than current rates. Despite low RSLR rates, the rapid mangrove to estuarine transgression was facilitated by a period of prolonged droughts and frequent storms. These findings suggest that with higher and accelerating RSLR today, enhanced climate variability could further hasten the loss of mangrove-lined coastlines, compounded by the reductions in natural flow to the coast caused by water management. Climate variability is nonlinear, and when superimposed on increases in RSLR, can complicate estimated trajectories of coastal inundation for resource management and urban planning.

An understanding of the mechanisms whereby cell adhesion complexes (ACs) relay signals bidirectionally across the plasma membrane is necessary to interpret the role of adhesion in regulating migration, differentiation, and growth. A range of AC types has been defined, but to date all have similar compositions and are dependent on a connection to the actin cytoskeleton. Recently, a new class of AC has been reported that normally lacks association with both the cytoskeleton and integrin-associated adhesome components, but is rich in components of the clathrin-mediated endocytosis machinery. The characterization of this new type of adhesion structure, which is emphasized by mitotic cells and cells in long-term culture, identifies a hitherto underappreciated link between the adhesion machinery and clathrin structures at the plasma membrane. While this discovery has implications for how ACs are assembled and disassembled, it raises many other issues. Consequently, to increase awareness within the field, and stimulate research, we explore a number of the most significant questions below., (© 2019 Lock et al.)

Recent waves of controversies surrounding genetic engineering have spilled into popular science in Twitter battles between reputable scientists and their followers. Here, a cautionary perspective on the possible blind spots and risks of CRISPR and related biotechnologies is presented, focusing in particular on the stochastic nature of cellular control processes., (© 2019 WILEY Periodicals, Inc.)

While the physical dimensions of climate change are now routinely assessed through multimodel intercomparisons, projected impacts on the global ocean ecosystem generally rely on individual models with a specific set of assumptions. To address these single-model limitations, we present standardized ensemble projections from six global marine ecosystem models forced with two Earth system models and four emission scenarios with and without fishing. We derive average biomass trends and associated uncertainties across the marine food web. Without fishing, mean global animal biomass decreased by 5% (±4% SD) under low emissions and 17% (±11% SD) under high emissions by 2100, with an average 5% decline for every 1 °C of warming. Projected biomass declines were primarily driven by increasing temperature and decreasing primary production, and were more pronounced at higher trophic levels, a process known as trophic amplification. Fishing did not substantially alter the effects of climate change. Considerable regional variation featured strong biomass increases at high latitudes and decreases at middle to low latitudes, with good model agreement on the direction of change but variable magnitude. Uncertainties due to variations in marine ecosystem and Earth system models were similar. Ensemble projections performed well compared with empirical data, emphasizing the benefits of multimodel inference to project future outcomes. Our results indicate that global ocean animal biomass consistently declines with climate change, and that these impacts are amplified at higher trophic levels. Next steps for model development include dynamic scenarios of fishing, cumulative human impacts, and the effects of management measures on future ocean biomass trends., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Jacobsen syndrome (OMIM #147791) is a rare contiguous gene disorder caused by deletions in distal 11q. The clinical phenotype is variable and can include dysmorphic features, varying degrees of intellectual disability, behavioral problems including autism and attention deficit hyperactivity disorder, congenital heart defects, structural kidney defects, genitourinary problems, immunodeficiency, and a bleeding disorder due to impaired platelet production and function. Previous studies combining both human and animal systems have implicated several disease-causing genes in distal 11q that contribute to the Jacobsen syndrome phenotype. One gene, ETS1 , has been implicated in causing congenital heart defects, structural kidney defects, and immunodeficiency. We performed a comprehensive phenotypic analysis on a patient with congenital heart disease previously found to have a de novo frameshift mutation in ETS1 , resulting in the loss of the DNA-binding domain of the protein. Our results suggest that loss of Ets1 causes a "partial Jacobsen syndrome phenotype" including congenital heart disease, facial dysmorphism, intellectual disability, and attention deficit hyperactivity disorder., (© 2019 Tootleman et al.; Published by Cold Spring Harbor Laboratory Press.)

Parrondo's paradox, in which losing strategies can be combined to produce winning outcomes, has received much attention in mathematics and the physical sciences; a plethora of exciting applications has also been found in biology at an astounding pace. In this review paper, the authors examine a large range of recent developments of Parrondo's paradox in biology, across ecology and evolution, genetics, social and behavioral systems, cellular processes, and disease. Intriguing connections between numerous works are identified and analyzed, culminating in an emergent pattern of nested recurrent mechanics that appear to span the entire biological gamut, from the smallest of spatial and temporal scales to the largest-from the subcellular to the complete biosphere. In analyzing the macro perspective, the pivotal role that the paradox plays in the shaping of biological life becomes apparent, and its identity as a potential universal principle underlying biological diversity and persistence is uncovered. Directions for future research are also discussed in light of this new perspective., (© 2019 WILEY Periodicals, Inc.)

Background: Currently, relatively little is known regarding the sources and levels of stress experienced by nursing students in China. This is largely because there is no reliable and valid, culturally appropriate measure of student nurse' stress. A culturally acceptable, Chinese Version of the Student Nurse Stress Index Scale (SNSI-CHI), with established reliability and validity, is needed to identify sources of stress in Chinese nursing students., Methods: This validation study used a cross-sectional descriptive survey design. Stratified cluster random sampling was used to collect data from August 2017 to January, 2018 from 1100 nursing students in Henan Province, China. A demographic questionnaire, SNSI-CHI and Perceived Stress Scale (PSS-14) were administered. Exploratory and confirmatory factor analysis was carried out on two randomly selected samples (each N = 538) from the overall return. The content, construct, predictive and concurrent validity of the translated SNSI-CHI were examined., Results: 1076 nursing students returned the survey (97.82% response rate). The average total score of SNSI-CHI was 58.455 ± 13.903. The internal consistency, test-retest reliability and content validity of the SNSI-CHI was excellent with a content validity index of 0.954. A four factor simple structure was revealed and confirmed using exploratory (explaining 75% of the variance) and confirmatory factor analysis (x 2 /df = 1.347, GFI = 0.956, AGFI = 0.945, RMR = 0.032, RMSEA = 0.025, NFI = 0.974, IFI = 0.993, TLI = 0.992, CFI = 0.993). This structure, i.e. academic load, clinical concerns, interface worries and personal problems compared well with the original SNSI. The SNSI-CHI totals and subscales showed good concurrent and predictive validity with the PSS-14 as comparator or criterion. A score of higher than 65 on the SNSI-CHI indicates high levels of perceived stress symptoms. Some 10.5% of respondents experience high levels of stressful demand. Sensitivity and specificity values of 71.7% and 75.1% respectively, demonstrated good predictive validity., Limitations: This study sample was confined to the Henan Province, which may limit its generalizability. A larger and more diverse sample is needed in the future research., Conclusions: The SNSI-CHI is both reliable and valid and culturally appropriate for use in China and its structure enables cross-cultural comparison., (Copyright © 2019. Published by Elsevier B.V.)

Background: One of the striking regularities of human behavior is that a prolonged physical, cognitive, or emotional activity leads to feelings of fatigue. Fatigue could be due to (1) depletion of a finite resource of physical and/or psychological energy or (2) changes in motivation, attention, and goal-directed effort (e.g. motivational control theory)., Purpose: To contrast predictions from these two views in a real-time study of subjective fatigue in nurses while working., Methods: One hundred nurses provided 1,453 assessments over two 12-hr shifts. Nurses rated fatigue, demand, control, and reward every 90 min. Physical energy expenditure was measured objectively using Actiheart. Hypotheses were tested using multilevel models to predict fatigue from (a) the accumulated values of physical energy expended, demand, control, and reward over the shift and (b) from distributed lag models of the same variables over the previous 90 min., Results: Virtually all participants showed increasing fatigue over the work period. This increase was slightly greater when working overnight. Fatigue was not dependent on physical energy expended nor perceived work demands. However, it was related to perceived control over work and perceived reward associated with work., Conclusions: Findings provide little support for a resource depletion model; however, the finding that control and reward both predicted fatigue is consistent with a motivational account of fatigue., (© Society of Behavioral Medicine 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The present study investigates whether nurses working for a national medical telephone helpline show evidence of "decision fatigue," as measured by a shift from effortful to easier and more conservative decisions as the time since their last rest break increases., Method: In an observational, repeated-measures study, data from approximately 4,000 calls to 150 nurses working for the Scottish NHS 24 medical helpline (37% of the national workforce) were modeled to determine whether the likelihood of a nurse's decision to refer a patient to another health professional the same day (the clinically safest but most conservative and resource inefficient decision) varied according to the number of calls taken/time elapsed since a nurse's last rest break and/or since the start of shift. Analyses used mixed-effect logistic regression., Results: For every consecutive call taken since last rest break, the odds of nurses making a conservative management decision (i.e., arranging for callers to see another health professional the same day) increased by 5.5% (p = .001, 95% confidence interval [CI: 2.2, 8.8]), an increase in odds of 20.5% per work hour (p < .001, 95% CI [9.1, 33.2]) or 49.0% (on average) from immediately after 1 break to immediately before the next. Decision-making was not significantly related to general or cumulative workload (calls or time elapsed since start of shift)., Conclusions: Every consecutive decision that nurses make since their last break produces a predictable shift toward more conservative, and less resource-efficient, decisions. Theoretical models of cognitive fatigue can elucidate how and why this shift occurs, helping to identify potentially modifiable determinants of patient care. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Glacial-interglacial variations in CO 2 and methane in polar ice cores have been attributed, in part, to changes in global wetland extent, but the wetland distribution before the Last Glacial Maximum (LGM, 21 ka to 18 ka) remains virtually unknown. We present a study of global peatland extent and carbon (C) stocks through the last glacial cycle (130 ka to present) using a newly compiled database of 1,063 detailed stratigraphic records of peat deposits buried by mineral sediments, as well as a global peatland model. Quantitative agreement between modeling and observations shows extensive peat accumulation before the LGM in northern latitudes (>40°N), particularly during warmer periods including the last interglacial (130 ka to 116 ka, MIS 5e) and the interstadial (57 ka to 29 ka, MIS 3). During cooling periods of glacial advance and permafrost formation, the burial of northern peatlands by glaciers and mineral sediments decreased active peatland extent, thickness, and modeled C stocks by 70 to 90% from warmer times. Tropical peatland extent and C stocks show little temporal variation throughout the study period. While the increased burial of northern peats was correlated with cooling periods, the burial of tropical peat was predominately driven by changes in sea level and regional hydrology. Peat burial by mineral sediments represents a mechanism for long-term terrestrial C storage in the Earth system. These results show that northern peatlands accumulate significant C stocks during warmer times, indicating their potential for C sequestration during the warming Anthropocene., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)