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BackgroundThe traditional management of papillary thyroid cancer (PTC) is thyroidectomy (total or partial removal of the thyroid). Active surveillance (AS) may be considered as an alternative option for small, low risk PTC. AS involves close follow-up (including regularly scheduled clinical and radiological assessments), with the intention of intervening with surgery for disease progression or patient preference.MethodsThis is a protocol for a prospective, observational, long-term follow-up multi-centre Canadian cohort study. Consenting eligible adults with small, low risk PTC (< 2cm in maximal diameter, confined to the thyroid, and not immediately adjacent to critical structures in the neck) are offered the choice of AS or surgery for management of PTC. Patient participants are free to choose either option (AS or surgery) and the disease management course is thus not assigned by the investigators. Surgery is provided as usual care by a surgeon in an institution of the patient’s choice. Our primary objective is to determine the rate of ‘failure’ of disease management in respective AS and surgical arms as defined by: i) AS arm – surgery for progression of PTC, and ii) surgical arm - surgery or other treatment for disease persistence or progression after completing initial treatment. Secondary outcomes include long-term thyroid oncologic and treatment outcomes, as well as patient-reported outcomes.DiscussionThe results from this study will provide long-term clinical and patient reported outcome evidence regarding active surveillance or immediate surgery for management of small, low risk PTC. This will inform future clinical trials in disease management of small, low risk papillary thyroid cancer.Registration detailsThis prospective observational cohort study is registered on clinicaltrials.gov (NCT04624477), but it should not be considered a clinical trial as there is no assigned intervention and patients are free to choose either AS or surgery.

Newly synthesized small GTPases in the Ras and Rho families are prenylated by cytosolic prenyltransferases and then escorted by chaperones to membranes, the nucleus, and other sites where the GTPases participate in a variety of signaling cascades. Understanding how prenylation and trafficking are regulated will help define new therapeutic strategies for cancer and other disorders involving abnormal signaling by these small GTPases. A growing body of evidence indicates that splice variants of SmgGDS (gene name RAP1GDS1) are major regulators of the prenylation, post-prenylation processing, and trafficking of Ras and Rho family members. SmgGDS-607 binds pre-prenylated small GTPases, while SmgGDS-558 binds prenylated small GTPases. This review discusses the history of SmgGDS research and explains our current understanding of how SmgGDS splice variants regulate the prenylation and trafficking of small GTPases. We discuss recent evidence that mutant forms of RabL3 and Rab22a control the release of small GTPases from SmgGDS, and review the inhibitory actions of DiRas1, which competitively blocks the binding of other small GTPases to SmgGDS. We conclude with a discussion of current strategies for therapeutic targeting of SmgGDS in cancer involving splice-switching oligonucleotides and peptide inhibitors.

The purpose of this case series was to evaluate the presence of low Energy Availability (EA) and its impact on components of Relative Energy Deficiency in Sport (RED-S) in a population of female collegiate runners. Seven female NCAA Division I athletes (age: 22.3 ± 1.5 yrs; height: 169.7 ± 5.7 cm; weight: 58.3 ± 4.1 kg) were tracked from August until February, covering the beginning (Pre XC), end (Post XC) of their competitive cross country season, and beginning of the following track season (Pre Track). The athletes were assessed for female athlete triad (Triad) risk, energy availability, body composition, resting metabolic rate (RMR), nutritional intake, and blood markers (including vitamin D, ferritin, and triiodothyronine (T3)). From Pre XC to Post XC there were no significant differences in body mass, fat free mass or body fat percentage. At Pre XC, mean EA was 31.6 ± 13.3 kcal/kg FFM∙d-1. From Post XC to Pre Track, there was a significant increase in body mass (59.1 ± 5.1 to 60.6 ± 5.7 kg, p

Background: Change-of-direction (CoD) is a necessary physical ability of a field sport and may vary in youth players according to their maturation status.Objectives: The aim of this study is: to compare the effectiveness of a 6-week CoD training intervention on dynamic balance (CS-YBT), horizontal jump (5JT), speed (10 and 30-m linear sprint times), CoD with (15 m-CoD + B) and without (15 m-CoD) the ball, in youth male soccer players at different levels of maturity [pre- and post-peak height velocity (PHV)].Materials and Methods: Thirty elite male youth soccer players aged 10–17 years from the Tunisian first division participated in this study. The players were divided into pre- (G1, n = 15) and post-PHV (G2, n = 15) groups. Both groups completed a similar 6-week training program with two sessions per week of four CoD exercises. All players completed the following tests before and after intervention: CS-YBT; 5 JT; 10, 30, and 15 m-CoD; and 15 m-CoD + B, and data were analyzed using ANCOVA.Results: All 30 players completed the study according to the study design and methodology. Adherence rate was 100% across all groups, and no training or test-related injuries were reported. Pre-PHV and post-PHV groups showed significant amelioration post-intervention for all dependent variables (after test > before test; p < 0.01, d = 0.09–1.51). ANOVA revealed a significant group × time interaction only for CS-YBT (F = 4.45; p < 0.04; η2 = 0.14), 5JT (F = 6.39; p < 0.02; η2 = 0.18), and 15 m-CoD (F = 7.88; p < 0.01; η2 = 0.22). CS-YBT, 5JT, and 15 m-CoD improved significantly in the post-PHV group (+ 4.56%, effect size = 1.51; + 4.51%, effect size = 1.05; and -3.08%, effect size = 0.51, respectively), more than the pre-PHV group (+ 2.77%, effect size = 0.85; + 2.91%, effect size = 0.54; and -1.56%, effect size = 0.20, respectively).Conclusion: The CoD training program improved balance, horizontal jump, and CoD without the ball in male preadolescent and adolescent soccer players, and this improvement was greater in the post-PHV players. The maturity status of the athletes should be considered when programming CoD training for soccer players.

Background Immune checkpoint inhibitors (ICI) can achieve durable responses in a subset of patients with locally advanced or metastatic urothelial carcinoma (aUC). The use of tumor genomic profiling in clinical practice may help suggest biomarkers to identify patients most likely to benefit from ICI.Methods We undertook a retrospective analysis of patients treated with an ICI for aUC at a large academic medical center. Patient clinical and histopathological variables were collected. Responses to treatment were assessed for all patients with at least one post-baseline scan or clear evidence of clinical progression following treatment start. Genomic profiling information was also collected for patients when available. Associations between patient clinical/genomic characteristics and objective response were assessed by logistic regression; associations between the characteristics and progression-free survival (PFS) and overall survival (OS) were examined by Cox regression. Multivariable analyses were performed to identify independent prognostic factors.Results We identified 119 aUC patients treated with an ICI from December 2014 to January 2020. Genomic profiling was available for 78 patients. Overall response rate to ICI was 29%, and median OS (mOS) was 13.4 months. Favorable performance status at the start of therapy was associated with improved OS (HR 0.46, p=0.025) after accounting for other covariates. Similarly, the presence of a TERT promoter mutation was an independent predictor of improved PFS (HR 0.38, p=0.012) and OS (HR 0.32, p=0.037) among patients who had genomic profiling available. Patients with both a favorable performance status and a TERT promoter mutation had a particularly good prognosis with mOS of 21.1 months as compared with 7.5 months in all other patients (p=0.03).Conclusions The presence of a TERT promoter mutation was an independent predictor of improved OS in a cohort of aUC patients treated with an ICI who had genomic data available. Most of the clinical and laboratory variables previously shown to be prognostic in aUC patients treated with chemotherapy did not have prognostic value among patients treated with an ICI. Genomic profiling may provide important prognostic information and affect clinical decision making in this patient population. Validation of these findings in prospective patient cohorts is needed.

Background The aim of this study was to compare the effects of 8 weeks resistance training (RT) with two sessions versus four sessions per week under volume load-equated conditions on body composition, maximal strength, and explosive actions performance in recreationally trained men. Methods Thirty-five healthy young men participated in the study and were randomly divided into a two sessions per-week RT (RT2, n = 12), four sessions per-week RT (RT4, n = 13) or a control group (CG, n = 10). All subjects were evaluated for thigh, chest and arm circumference, countermovement jump (CMJ), medicine ball throw (MBT), 1-repetition maximum (1RM) leg press, bench press, arm curl, muscular endurance (i.e., 60% of 1RM to failure) for leg press, and bench press at pre, mid (week 4) and post an 8-week training intervention. Results A two-way analysis of variance with repeated measures (3 [group] × 3 [time]) revealed that both training groups increased chest and thigh circumferences, strength and explosive actions performance tests in comparison to CG following 8 weeks of training (p = 0.01 to 0.04). Group × time interactions were also noted in 1RM bench press (effects size [ES] = 1.07 vs. 0.89) and arm curl (ES = 1.15 vs. 0.89), with greater gains for RT4 than RT2 (p = 0.03). Conclusion RT improved muscle strength, explosive actions performance and markers of muscle size in recreationally trained men; however, four sessions of resistance training per week produced greater gains in muscular strength for the upper body measures (i.e., 1RM bench press and arm curl) when compared to two sessions per week under volume-equated conditions.

Abstract Understanding how automated insulin delivery (AID) algorithm features impact glucose control under full closed loop delivery represents a critical step toward reducing patient burden by eliminating the need for carbohydrate entries at mealtimes. Here, we use a pig model of diabetes to compare AndroidAPS and Loop open‐source AID systems without meal announcements. Overall time‐in‐range (70–180 mg/dl) for AndroidAPS was 58% ± 5%, while time‐in‐range for Loop was 35% ± 5%. The effect of the algorithms on time‐in‐range differed between meals and overnight. During the overnight monitoring period, pigs had an average time‐in‐range of 90% ± 7% when on AndroidAPS compared to 22% ± 8% on Loop. Time‐in‐hypoglycemia also differed significantly during the lunch meal, whereby pigs running AndroidAPS spent an average of 1.4% (+0.4/−0.8)% in hypoglycemia compared to 10% (+3/−6)% for those using Loop. As algorithm design for closed loop systems continues to develop, the strategies employed in the OpenAPS algorithm (known as oref1) as implemented in AndroidAPS for unannounced meals may result in a better overall control for full closed loop systems.

Objective Chronic diseases are associated with increased unplanned acute hospital use. Remote patient monitoring (RPM) can detect disease exacerbations and facilitate proactive management, possibly reducing expensive acute hospital usage. Current evidence examining RPM and acute care use mainly involves heart failure and omits automated invasive monitoring. This study aimed to determine if RPM reduces acute hospital use.Methods A systematic literature review of PubMed, Embase and CINAHL electronic databases was undertaken in July 2019 and updated in October 2020 for studies published from January 2015 to October 2020 reporting RPM and effect on hospitalisations, length of stay or emergency department presentations. All populations and disease conditions were included. Two independent reviewers screened articles. Quality analysis was performed using the Joanna Briggs Institute checklist. Findings were stratified by outcome variable. Subgroup analysis was undertaken on disease condition and RPM technology.Results From 2050 identified records, 91 studies were included. Studies were medium-to-high quality. RPM for all disease conditions was reported to reduce admissions, length of stay and emergency department presentations in 49% (n=44/90), 49% (n=23/47) and 41% (n=13/32) of studies reporting each measure, respectively. Remaining studies largely reported no change. Four studies reported RPM increased acute care use. RPM of chronic obstructive pulmonary disease (COPD) was more effective at reducing emergency presentation than RPM of other disease conditions. Similarly, invasive monitoring of cardiovascular disease was more effective at reducing hospital admissions versus other disease conditions and non-invasive monitoring.Conclusion RPM can reduce acute care use for patients with cardiovascular disease and COPD. However, effectiveness varies within and between populations. RPM’s effect on other conditions is inconclusive due to limited studies. Further analysis is required to understand underlying mechanisms causing variation in RPM interventions. These findings should be considered alongside other benefits of RPM, including increased quality of life for patients.PROSPERO registration number CRD42020142523.

Colorectal cancer (CRC), prostate cancer (PC) and breast cancer (BC) are among the most common cancers worldwide with well-established screening strategies. We aim to investigate the effectiveness and compliance of a one-stop screening service for CRC, PC and BC. Asymptomatic subjects aged 50–75 years were invited. Eligible subjects were offered fecal immunochemical test (FIT) for CRC screening. Serum prostate specific antigen (PSA) and Prostate Health Index (PHI) were offered for male PC screening and mammogram (MMG) for female BC screening as a one-stop service. Colonoscopy was offered to FIT+ subjects, prostate biopsy to PSA/PHI+ (PSA>10/PHI≥35) males and breast biopsy to MMG+ (Breast Imaging-Reporting and Data System, BI-RADS≥4) females. From August 2018 to April 2020, 3165 subjects were recruited. All participants (1372 men and 1793 women) were willing to accept FIT for CRC screening, and PSA/PHI test or MMG as second cancer screening. 102 subjects diagnosed advanced neoplasms after colonoscopy. Thirty-three males diagnosed PC after prostate biopsy and 15 females diagnosed BC after breast biopsy. No major complication reported in first tier screening tests. Subjects who were willing to undergo CRC screening were highly likely to accept other cancer screening when offered in a one-stop program. In conclusion, the effectiveness and compliance of a one-stop service for CRC, PC, and BC screening among asymptomatic subjects were high. Future studies should be conducted to test various ways of integrating cancer screening programs.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT04034953.

Background: Vasopressors are administered to critical care patients to avoid hypotension, which is associated with myocardial injury, kidney injury and death. However, they work by causing vasoconstriction, which may reduce blood flow and cause other adverse effects. A mean arterial pressure target typically guides administration. An individual patient data meta-analysis (Lamontagne F, Day AG, Meade MO, Cook DJ, Guyatt GH, Hylands M, et al. Pooled analysis of higher versus lower blood pressure targets for vasopressor therapy septic and vasodilatory shock. Intensive Care Med 2018;44:12–21) suggested that greater exposure, through higher mean arterial pressure targets, may increase risk of death in older patients. Objective: To estimate the clinical effectiveness and cost-effectiveness of reduced vasopressor exposure through permissive hypotension (i.e. a lower mean arterial pressure target of 60–65 mmHg) in older critically ill patients. Design: A pragmatic, randomised clinical trial with integrated economic evaluation. Setting: Sixty-five NHS adult general critical care units. Participants: Critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension. Interventions: Intervention – permissive hypotension (i.e. a mean arterial pressure target of 60–65 mmHg). Control (usual care) – a mean arterial pressure target at the treating clinician’s discretion. Main outcome measures: The primary clinical outcome was 90-day all-cause mortality. The primary cost-effectiveness outcome was 90-day incremental net monetary benefit. Secondary outcomes included receipt and duration of advanced respiratory and renal support, mortality at critical care and acute hospital discharge, and questionnaire assessment of cognitive decline and health-related quality of life at 90 days and 1 year. Results: Of 2600 patients randomised, 2463 (permissive hypotension, n = 1221; usual care, n = 1242) were analysed for the primary clinical outcome. Permissive hypotension resulted in lower exposure to vasopressors than usual care [mean duration 46.0 vs. 55.9 hours, difference –9.9 hours (95% confidence interval –14.3 to –5.5 hours); total noradrenaline-equivalent dose 31.5 mg vs. 44.3 mg, difference –12.8 mg (95% CI –18.0 mg to –17.6 mg)]. By 90 days, 500 (41.0%) patients in the permissive hypotension group and 544 (43.8%) patients in the usual-care group had died (absolute risk difference –2.85%, 95% confidence interval –6.75% to 1.05%; p = 0.154). Adjustment for prespecified baseline variables resulted in an odds ratio for 90-day mortality of 0.82 (95% confidence interval 0.68 to 0.98) favouring permissive hypotension. There were no significant differences in prespecified secondary outcomes or subgroups; however, patients with chronic hypertension showed a mortality difference favourable to permissive hypotension. At 90 days, permissive hypotension showed similar costs to usual care. However, with higher incremental life-years and quality-adjusted life-years in the permissive hypotension group, the incremental net monetary benefit was positive, but with high statistical uncertainty (£378, 95% confidence interval −£1347 to £2103). Limitations: The intervention was unblinded, with risk of bias minimised through central allocation concealment and a primary outcome not subject to observer bias. The control group event rate was higher than anticipated. Conclusions: In critically ill patients aged ≥ 65 years receiving vasopressors for vasodilatory hypotension, permissive hypotension did not significantly reduce 90-day mortality compared with usual care. The absolute treatment effect on 90-day mortality, based on 95% confidence intervals, was between a 6.8-percentage reduction and a 1.1-percentage increase in mortality. Future work: Future work should (1) update the individual patient data meta-analysis, (2) explore approaches for evaluating heterogeneity of treatment effect and (3) explore 65 trial conduct, including use of deferred consent, to inform future trials. Trial registration: Current Controlled Trials ISRCTN10580502. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 14. See the NIHR Journals Library website for further project information.

Introduction In 2013, a single-centre study reported the safe use of esmolol in patients with septic shock and tachycardia who required vasopressor therapy for more than 24 hours. Although not powered to detect a change in mortality, marked improvements were seen in survival (adjusted HR, 0.39; 95% CI, 0.26 to 0.59; p

The study examined Social media use by arable crop farmers for climate change adaptation communication in Imo State, Nigeria. Data were collected with the aid of structured questionnaire from 285 arable randomly selected crop farmers in the study area. Results showed that arable crop farmer use social media to seek knowledge about climate change, disseminate information to friends, seek climate change adaptation strategies and post-climate change adaptation strategies to farmer groups. However, the percentage of arable crop farmers’ use of social media types was low. Multiple regressions show that sex, educational level and age influenced utilization of social media for climate change adaptation communication. Based on the findings of the study it is recommended that farmers should be encouraged to raise concern, make posts and engage in discussions on social media so as to attract and raise awareness of issues of concern among them, other stakeholders and the public. Government, International Organizations and Non-governmental Organizations should organize training on use of smart phones, social media and Information and Communication Technologies for farmers, and farmer groups.

Testing and case identification are key strategies in controlling the COVID-19 pandemic. Contact tracing and isolation are only possible if cases have been identified. The effectiveness of testing should be assessed, but a single comprehensive metric is not available to assess testing effectiveness, and no timely estimates of case detection rate are available globally, making inter-country comparisons difficult. The purpose of this paper was to propose a single, comprehensive metric, called the COVID-19 Testing Index (CovTI) scaled from 0 to 100, derived from epidemiological indicators of testing, and to identify factors associated with this outcome. The index was based on case-fatality rate, test positivity rate, active cases, and an estimate of the detection rate. It used parsimonious modeling to estimate the true total number of COVID-19 cases based on deaths, testing, health system capacity, and government transparency. Publicly reported data from 165 countries and territories that had reported at least 100 confirmed cases by June 3, 2020 were included in the index. Estimates of detection rates aligned satisfactorily with previous estimates in literature (R2 = 0.44). As of June 3, 2020, the states with the highest CovTI included Hong Kong (93.7), Australia (93.5), Iceland (91.8), Cambodia (91.3), New Zealand (90.6), Vietnam (90.2), and Taiwan (89.9). Bivariate analyses showed the mean CovTI in countries with open public testing policies (66.9, 95% CI 61.0-72.8) was significantly higher than in countries with no testing policy (29.7, 95% CI 17.6-41.9) (p

Intravenous thrombolysis with alteplase within 4.5 hours from symptom onset is a well-established treatment of acute ischaemic stroke (AIS). The aim was to compare alteplase for AIS between patients aged >80 and ≤80 years in our registry data, from 2013 to 2018. Mechanical thrombectomy cases were excluded. We assessed clinical outcomes over the six-year period and between patients aged over 80 and ≤80 years, using measures including the discharge modified Rankin Scale (mRS), 24-hour National Institutes of Health Stroke Scale (NIHSS) improvement, and symptomatic intracerebral haemorrhage (sICH) rate. Of a total of 805 AIS patients who received intravenous alteplase, 278 (34.5%) were over 80 years old, and 527 (65%) were younger. 616 (76.5%) received thrombolysis≤3 hours after symptom onset and 189 (23.5%) within 3-4.5 hours. Median baseline mRS and NIHSS of the elderly cohort were 1 (IQR 0-5) and 13 (IQR 2-37), respectively, compared to the younger cohort 0 (IQR 0-5) and 9 (IQR 0-29). The sICH rate was 7.2% in the elderly and 4.6% in those ≤80 years, p=0.05. NIHSS improved within 24 hours in 34% of the elderly cohort compared to 35% in the younger cohort. At hospital discharge, the mortality rate was 9% in the elderly cohort compared to the 6% in the younger cohort, p=0.154. 25% of patients aged >80 years had mRS≤2 compared to 47% in the younger patients (p

During late embryonic development of the cerebral cortex, the major class of cortical output neurons termed subcerebral projection neurons (SCPN; including the predominant population of corticospinal neurons, CSN) and the class of interhemispheric callosal projection neurons (CPN) initially express overlapping molecular controls that later undergo subtype-specific refinements. Such molecular refinements are largely absent in heterogeneous, maturation-stalled, neocortical-like neurons (termed "cortical" here) spontaneously generated by established embryonic stem cell (ES) and induced pluripotent stem cell (iPSC) differentiation. Building on recently identified central molecular controls over SCPN development, we used a combination of synthetic modified mRNA (modRNA) for Fezf2, the central transcription factor controlling SCPN specification, and small molecule screening to investigate whether distinct chromatin modifiers might complement Fezf2 functions to promote SCPN-specific differentiation by mouse ES (mES)-derived cortical-like neurons. We find that the inhibition of a specific histone deacetylase, Sirtuin 1 (SIRT1), enhances refinement of SCPN subtype molecular identity by both mES-derived cortical-like neurons and primary dissociated E12.5 mouse cortical neurons. In vivo, we identify that SIRT1 is specifically expressed by CPN, but not SCPN, during late embryonic and postnatal differentiation. Together, these data indicate that SIRT1 has neuronal subtype-specific expression in the mouse cortex in vivo, and that its inhibition enhances subtype-specific differentiation of highly clinically relevant SCPN / CSN cortical neurons in vitro.

Abstract Introduction Radiolabeled ligands for fibrillar amyloid beta (Aβ) peptides are used in positron emission tomography (PET) for dementia diagnosis. Current ligands do not discriminate parenchymal amyloid plaques from cerebral amyloid angiopathy (CAA). Methods We undertook neuropathological examination of 65 older people (81.6 ± 7.96 (mean ± SD) years, 27F/38M): 15 with neuropathological diagnosis of AD, 25 with neuropathological diagnosis of other neurodegenerative dementias (Lewy body dementia and Parkinson disease dementia), and 25 without significant neurodegenerative pathology. Results We observed CAA in non‐Alzheimer's dementia (non‐AD dementia) and control brains, of comparable extent to those with neuropathologically confirmed AD. Aβ‐positive vessel density did not differ significantly between non‐AD dementia and control groups. Across all subjects there was a highly significant correlation between vessel Aβ40 density and vessel Aβ42 density (Spearman rho = 0.855, P < .001). CAA was absent or sparse in subcortical white matter across all patient groups. Conclusion Our data indicate that CAA can be abundant in non‐AD brains and raise a cautionary note regarding interpretation of amyloid PET imaging.

Abstract: Thirty-three-year-old Caucasian male underwent initiation of levetiracetam following witnessed generalized seizure activity at the same time presenting with a right MCA territory ischemic stroke. He then developed elevated CPK and myalgias are highly suspicious for rhabdomyolysis following levetiracetam. Subsequent improvement noted following complete cessation of medication. At follow-up patient reported complete resolution of hemiparesis and myalgias and no new neurological deficits while tolerating valproic acid. This case exemplifies potential rare adverse effect of levetiracetam. Levetiracetam is an antiepileptic medication effective for both generalized and focal types of epilepsy by affecting a broad spectrum of neurotransmitter release via calcium channels GABA receptors and synaptic vessel protein 2A (SV2A). Typical adverse effects include mild dizziness, headache, nausea, somnolence and sometimes hostility. This case provides further evidence of a rare and potentially life-threatening adverse effect of rhabdomyolysis. Further study is needed to possibly detect the exact mechanism resulting in this rare and dangerous adverse effect.

Signaling through the TNF-family receptor Fas/CD95 can trigger apoptosis or non-apoptotic cellular responses and is essential for protection from autoimmunity. Receptor clustering has been observed following interaction with Fas ligand (FasL), but the stoichiometry of Fas, particularly when triggered by membrane-bound FasL, the only form of FasL competent at inducing programmed cell death, is not known. Here we used super-resolution microscopy to study the behavior of single molecules of Fas/CD95 on the plasma membrane after interaction of Fas with FasL on planar lipid bilayers. We observed rapid formation of Fas protein superclusters containing more than 20 receptors after interactions with membrane-bound FasL. Fluorescence correlation imaging demonstrated recruitment of FADD dependent on an intact Fas death domain, with lipid raft association playing a secondary role. Flow-cytometric FRET analysis confirmed these results, and also showed that some Fas clustering can occur in the absence of FADD and caspase-8. Point mutations in the Fas death domain associated with autoimmune lymphoproliferative syndrome (ALPS) completely disrupted Fas reorganization and FADD recruitment, confirming structure-based predictions of the critical role that these residues play in Fas–Fas and Fas–FADD interactions. Finally, we showed that induction of apoptosis correlated with the ability to form superclusters and recruit FADD.

The objective of this study was to assess inactivated influenza vaccine effectiveness (VE) by time since vaccination in adults aged ≥ 18 years using a test-negative design. All data were obtained from the US Department of Defense Global Respiratory Pathogen Surveillance Program over four influenza seasons, from 2016–2017 through 2019–2020. Analyses were performed to estimate VE using a generalized linear mixed model with logit link and binomial distribution. The adjusted overall VE against any medically attended, laboratory-confirmed influenza decreased from 50% (95% confidence interval (CI): 41–58%) in adults vaccinated 14 to 74 days prior to the onset of influenza-like illness (ILI), to 39% (95% CI: 31–47%) in adults vaccinated 75 to 134 days prior to the onset of ILI, then to 17% (95% CI: 0–32%) in adults vaccinated 135 to 194 days prior to the onset of ILI. The pattern and magnitude of VE change with increasing time since vaccination differed by influenza (sub)types. Compared to VE against influenza A(H1N1)pdm09 and influenza B, the decrease of VE against influenza A(H3N2) was more pronounced with increasing time since vaccination. In conclusion, based on the analysis of 2536 influenza-positive cases identified from 7058 adults over multiple influenza seasons, the effectiveness of inactivated influenza vaccine wanes within 180 days after 14 days of influenza vaccination.

In the roadmaps of the automotive industry, the electric vehicle (EV) is regarded as a crucial technology for the future of automotive power systems. The EV has become a top priority of major global car manufacturers and is expected to disrupt the road transportation sector. In Malaysia and Indonesia, EVs just started as an important force. However, in Malaysia, the lack of EV infrastructure, along with its strong dependency on fossil fuels, poses an enormous challenge. The situation is very similar in Indonesia. Indonesia has huge potential as Southeast Asia’s largest vehicle market and a major nickel producer, an important EV battery ingredient. Therefore, this article addresses several critical issues in implementing EVs in Malaysia and Indonesia. In preparing this review, we have thoroughly selected very important EV keywords that are frequently asked. We have also interviewed some prominent figures in the field of EV to address the most critical aspects worth including in the paper. In doing so, we plan to provide content that will be beneficial not only to the academic world but also to the automotive industry in general. Firstly, a summary of the EV adoption scenario in each country was presented. Afterwards, the types of EVs and battery capacities available in both countries were explained. The next section focused on the adoption rate of EVs, followed by the discussion of EVs charging infrastructure. In addition to that, issues pertaining to vehicle tax credit were also addressed. The opportunities and challenges of EV were then addressed in depth before concluding remarks were given.

Phosphorus (P) fertilizers have a dramatic effect on agricultural productivity, but conventional methods of application result in only limited recovery of the applied P. Given the increasing volatility in rock phosphate prices, more efficient strategies for P fertilizer use would be of economic and environmental benefit in the drive for sustainable intensification. This study used a combination of controlled-environment experiments and radioisotopic labeling to investigate the fertilizer use efficiency of a combination of seed (grain) dressing and foliar applications of P to spring wheat (Triticum aestivum L.). Radioisotopic labeling showed that the application of foliar P in the presence of photosynthetic light substantially increased both P-uptake into the leaf and P-mobilization within the plant, especially when an adjuvant was used. When compared with soil application of inorganic P buried into the rooting zone, a combination of a 3 μmol seed dressing and three successive 46.3 μmol plant−1 foliar applications were far more efficient at providing P fertilization benefits in P-limiting conditions. We conclude that a combination of seed dressing and foliar applications of P is potentially a better alternative to conventional soil-based application, offering greater efficiency in use of applied P both in terms of P-uptake rate and grain yield. Further work is required to evaluate whether these results can be obtained under a range of field conditions.

ObjectiveWe investigated the effects of combined balance and strength training on measures of balance and muscle strength in older women with a history of falls.MethodsTwenty-seven older women aged 70.4 ± 4.1 years (age range: 65 to 75 years) were randomly allocated to either an intervention (IG, n = 12) or an active control (CG, n = 15) group. The IG completed 8 weeks combined balance and strength training program with three sessions per week including visual biofeedback using force plates. The CG received physical therapy and gait training at a rehabilitation center. Training volumes were similar between the groups. Pre and post training, tests were applied for the assessment of muscle strength (weight-bearing squat [WBS] by measuring the percentage of body mass borne by each leg at different knee flexions [0°, 30°, 60°, and 90°], sit-to-stand test [STS]), and balance. Balance tests used the modified clinical test of sensory interaction (mCTSIB) with eyes closed (EC) and opened (EO), on stable (firm) and unstable (foam) surfaces as well as spatial parameters of gait such as step width and length (cm) and walking speed (cm/s).ResultsSignificant group × time interactions were found for different degrees of knee flexion during WBS (0.0001 < p < 0.013, 0.441 < d < 0.762). Post hoc tests revealed significant pre-to-post improvements for both legs and for all degrees of flexion (0.0001 < p < 0.002, 0.697 < d < 1.875) for IG compared to CG. Significant group × time interactions were found for firm EO, foam EO, firm EC, and foam EC (0.006 < p < 0.029; 0.302 < d < 0.518). Post hoc tests showed significant pre-to-post improvements for both legs and for all degrees of oscillations (0.0001 < p < 0.004, 0.753 < d < 2.097) for IG compared to CG. This study indicates that combined balance and strength training improved percentage distribution of body weight between legs at different conditions of knee flexion (0°, 30°, 60°, and 90°) and also decreased the sway oscillation on a firm surface with eyes closed, and on foam surface (with eyes opened or closed) in the IG.ConclusionThe higher positive effects of training seen in standing balance tests, compared with dynamic tests, suggests that balance training exercises including lateral, forward, and backward exercises improved static balance to a greater extent in older women.

Introduction: As the world struggles to manage and move forward from the clinical effects of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the ability to test for viral genomic RNA in patient samples is critical. Currently, the development and performance of SARS-CoV-2 clinical tests is impaired by a diminished supply chain of reagents needed for the tests, compelling labs to seek alternative, readily-available reagents as substitutes. Aim: To evaluate the suitability of Phosphate-Buffered Saline (PBS) and RNAlater™ as substitutes for sample transport media, to preserve the fidelity of viral RNA for use in a SARSCoV-2 RT-PCR assay. Materials and Methods: This molecular study was conducted in Dayton, Ohio (USA) using synthetic materials and deidentified remnant patient specimens. Simulated standard clinical laboratory storage conditions were used, including prolonged storage up to 72 hours at 2-8°C and a freeze/thaw cycle. PCR amplification performance was measured for PBS and RNAlater™ against transport medium as a reference using purified viral RNA. Performance differences were determined using repeated-measures two-way ANOVA with a 5% false discovery rate. Results: Results indicate that both solutions were suitable for testing viral RNA in the short term, but the viral RNA stored in PBS began to degrade after just 24 hours at 2-8°C. In contrast, RNAlater™ preserved the viral RNA out to 72 hours when stored at 2-8°C, with no statistically significant decrease in the detection limits compared to freshly-prepared viral RNA dilutions. A single freeze/thaw cycle raised the lower limit of detection for RNAlater™-preserved viral RNA slightly. Conclusion: The current (as of April 2020) CDC sample guidelines permit the use of PBS, but have not published data to support this claim. These results offer an alternative to the transport options outlined in many Emergency Use Authorisations (EUA) currently authorised for use in diagnostic testing and may be used for possible long-term storage solutions for studies investigating SARS-CoV-2.

In November 2000, the Queensland Telepaediatric Service (QTS) was established in Brisbane, Australia, to support the delivery of telehealth services to patients and clinicians in regional and remote locations. The QTS was built on a centralized coordination model, where telehealth services could be effectively managed by a dedicated telehealth coordinator. In doing so, telehealth referral and consultation processes were efficient and clinicians felt better supported as they adjusted to new processes for engaging with patients. We have conducted a retrospective review of activity associated with the QTS and summarized key activities which have arisen from this extensive program of work. Telehealth service records and associated publications were used to describe the evolution of the QTS over a 15-year period. From November 2000 to March 2016, 23,054 telehealth consultations were delivered for 37 pediatric clinical specialties. The most common service areas included child and youth mental health, neurology, burns care, surgery, and ear nose and throat services. A range of different telehealth service models were developed to align with different clinical service needs and location of services. Whilst most work involved video consultation between hospitals, some services involved the delivery of telehealth services into the home, schools or community health centres. Despite its longevity, the QTS was not immune to the usual challenges associated with telehealth implementation, service redesign and sustainability. Experience reported from the QTS will be useful for other health services seeking to develop comprehensive telehealth services in a rapidly changing healthcare environment.

Rationale & Objective: Although end-stage kidney disease (ESKD) adversely affects fertility, pregnancies can occur among women receiving dialysis. ESKD increases the risk for adverse pregnancy outcomes and little is known about contraceptive use in women undergoing dialysis. Study Design: Retrospective cohort study. Setting & Participants: Using the US Renal Data System covering January 1, 2005, through December 31, 2014, we evaluated for each calendar year women who for the entire year were aged 15 to 44 years, receiving dialysis, and with Medicare as the primary payer. Predictors: Age, race/ethnicity, and calendar year of prevalent ESKD. Outcome: Contraceptive use. Analytic Approach: We determined rates of contraceptive use and used multivariable logistic regression to identify factors associated with contraceptive use. Results: The study cohort included 35,732 women and represented 115,713 person-years. The rate of contraceptive use was 5.30% of person-years (95% CI, 5.17%-5.42%). Overall, contraceptive use increased from 2005 to 2014 (4.21%; 95% CI, 3.84%-4.59% vs 6.54%, 95% CI, 6.10%-6.99%). Compared with women aged 25 to 29 years, contraceptive use was higher in women aged 15 to 24 years (OR, 1.30; 95% CI, 1.18-1.43) and lower in women aged 30 to 34 years (OR, 0.74; 95% CI, 0.68-0.81), 35 to 39 years (OR, 0.46; 95% CI, 0.42-0.50), and 40 to 44 years (OR, 0.30; 95% CI, 0.27-0.34). Compared with White women, contraceptive use was higher in Black (OR, 1.12; 95% CI, 1.02-1.24) and Native American women (OR, 1.60; 95% CI, 1.25-2.05). Women with ESKD due to glomerulonephritis had a higher likelihood of contraceptive use than women with ESKD due to diabetes (OR, 1.22; 95% CI, 1.06-1.42). Women receiving peritoneal dialysis had a lower likelihood of contraceptive use than women receiving hemodialysis (OR, 0.85; 95% CI, 0.78-0.93). Compared with women without predialysis nephrology care, contraceptive use was higher in women who received predialysis nephrology care for 12 or fewer months (OR, 1.22; 95% CI, 1.09-1.37) and more than 12 months (OR, 1.33; 95% CI, 1.20-1.47). Limitations: Retrospective design and use of administrative data. Conclusions: Among women with ESKD undergoing dialysis, contraceptive use remains low at 5.30%. Younger age, Native American and Black race/ethnicity, ESKD due to glomerulonephritis, hemodialysis, and predialysis nephrology care are associated with a higher likelihood of contraceptive use. The study highlights the importance of prepregnancy counseling for contraceptive use in women receiving dialysis.

Several religious and theological approaches to culture in African studies have assessed the idea of inculturation as a helpless incorporation of cultural values from one culture into another. We showed in this article that this is a limited perspective to the process of inculturation, and that this limitation is the reason for the failure of several attempts at inculturation. We assessed inculturation from the angle of marketisation of cultures, and we argued that the adoption or adaptation of cultural elements from one culture into another should be an agentic rationalisation process. The article demonstrated that the rationalisation process is validated by pre-adoption pragmatic experiences or expectations such that the feature(s) being adopted has either initially proven – or at least is expected – to be more useful than what it is meant to replace or enhance. We concluded that a rationalisation approach to inculturation is based on an initial recognition of conceptual entities and practices, the need to adopt them, and a follow-up justification for this need. Without such perspective, an inculturation effort will not be successfully completed, sustainable or mutually respectful. Contribution: Our primary contribution is that we tried to provide broad, agentic, rational approach to inculturation. This contribution is important in sub-fields of Christian Church History and Philosophy of Religion. It properly aligns with this journal’s focus on history of religions, as well as phenomenology, and philosophy of religion(s).

Background: The present study is a prospective observational single arm clinical investigation, with parallel bench test interrogation, aimed at investigating the technical feasibility, safety and clinical outcomes with the cone flare crush modified-T (CFCT) bifurcation stenting technique. Bifurcation percutaneous coronary intervention (PCI) remains an area of ongoing procedural evolution. More widely applicable and reproducible techniques are required. Methods: From April 2018 until March 2019, 20 consecutive patients underwent bifurcation PCI using the CFCT technique with a Pt-Cr everolimus drug-eluting stent with a bioresorbable polymer. Exercise stress echocardiography was performed at 12-month follow-up. The primary outcome was a composite of cardiac related mortality, myocardial infarction, target lesion/vessel revascularization and stroke. Safety secondary endpoints included bleeding, all-cause mortality and stent thrombosis. Results: All patients underwent a successful CFCT bifurcation procedure with no complications to 30-day follow-up. One patient met the primary endpoint requiring target lesion revascularization at 9 months for stable angina. There were no other primary or secondary outcome events in the cohort. There were no strokes, deaths, stent thrombosis or myocardial infarction during the follow-up period. The mean CCS score improved from 2.25 to 0.25 (p

Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. The wtf4 gene is a meiotic driver in Schizosaccharomyces pombe that uses a poison-antidote mechanism to selectively kill meiotic products (spores) that do not inherit wtf4. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species, Saccharomyces cerevisiae. The Wtf4poison protein forms dispersed, toxic aggregates. The Wtf4antidote can co-assemble with the Wtf4poison and promote its trafficking to vacuoles. We show that neutralization of the Wtf4poison requires both co-assembly with the Wtf4antidote and aggregate trafficking, as mutations that disrupt either of these processes result in cell death in the presence of the Wtf4 proteins. This work reveals that wtf parasites can exploit protein aggregate management pathways to selectively destroy spores.

Dyskinesia associated with chronic levodopa treatment in Parkinson’s disease is associated with maladaptive striatal plasticity. The objective of this study was to examine whether macroscale structural changes, as captured by magnetic resonance imaging (MRI) accompany this plasticity and to identify plausible cellular contributors in a rodent model of levodopa-induced dyskinesia. Adult male Sprague-Dawley rats were rendered hemi-parkinsonian by stereotaxic injection of 6-hydroxydopamine into the left medial forebrain bundle prior to chronic treatment with saline (control) or levodopa to induce abnormal involuntary movements (AIMs), reflective of dyskinesia. Perfusion-fixed brains underwent ex vivo structural MRI before sectioning and staining for cellular markers. Chronic treatment with levodopa induced significant AIMs (p < 0.0001 versus saline). The absolute volume of the ipsilateral, lesioned striatum was increased in levodopa-treated rats resulting in a significant difference in percentage volume change when compared to saline-treated rats (p < 0.01). Moreover, a significant positive correlation was found between this volume change and AIMs scores for individual levodopa-treated rats (r = 0.96; p < 0.01). The density of Iba1+ cells was increased within the lesioned versus intact striatum (p < 0.01) with no difference between treatment groups. Conversely, Iba1+ microglia soma size was significantly increased (p < 0.01) in the lesioned striatum of levodopa-treated but not saline-treated rats. Soma size was not, however, significantly correlated with either AIMs or MRI volume change. Although GFAP+ astrocytes were elevated in the lesioned versus intact striatum (p < 0.001), there was no difference between treatment groups. No statistically significant effects of either lesion or treatment on RECA1, a marker for blood vessels, were observed. Collectively, these data suggest chronic levodopa treatment in 6-hydroxydopamine lesioned rats is associated with increased striatal volume that correlates with the development of AIMs. The accompanying increase in number and size of microglia, however, cannot alone explain this volume expansion. Further multi-modal studies are warranted to establish the brain-wide effects of chronic levodopa treatment.

Background: Speech and language disorders in childhood have the potential to affect every aspect of a child’s day-to-day life and can potentially have negative long-term impacts. Aim: This scoping review seeks to collate the existing evidence to identify the long-term effects of childhood speech and language disorders. Methods: A systematic search of speechBITE, ERIC (Education Resources Information Center), Linguistics and Language Behaviour Abstracts, PubMed, MEDLINE, PsycINFO, SocINDEX and the Cochrane Library was conducted. Peer-reviewed English language publications reporting on the long-term (2+-year) outcomes of individuals with a childhood history of speech or language disorders were included. Data were extracted and the study quality assessed using a modified Newcastle–Ottawa scale. Results: Fifty-one studies met the inclusion criteria. These studies reported mixed results, the most common of which were suboptimal mental health, social and academic outcomes for persons with a history of speech or language disorders. We found an association between childhood speech or language disorders and psychiatric disability, behavioural problems, lower socio-economic status, relationship and living difficulties, and lower academic achievement compared to the general population. Conclusion: Individuals with a history of childhood speech or language disorders may experience long-term difficulties in mental health, social well-being and academic outcomes.

Microglia, the resident tissue macrophages of the brain, are increasingly implicated in the pathophysiology of psychiatric disorders with a neurodevelopmental origin, including schizophrenia. To date, however, our understanding of the potential role for these cells in schizophrenia has been informed by studies of aged post-mortem samples, low resolution in vivo neuroimaging and rodent models. Whilst these have provided important insights, including signs of the heterogeneous nature of microglia, we currently lack a validated human in vitro system to characterize microglia in the context of brain health and disease during neurodevelopment. Primarily, this reflects a lack of access to human primary tissue during developmental stages. In this review, we first describe microglia, including their ontogeny and heterogeneity and consider their role in brain development. We then provide an evaluation of the potential for differentiating microglia from human induced pluripotent stem cells (hiPSCs) as a robust in vitro human model system to study these cells. We find the majority of protocols for hiPSC-derived microglia generate cells characteristically similar to foetal stage microglia when exposed to neuronal environment-like cues. This may represent a robust and relevant model for the study of cellular and molecular mechanisms in schizophrenia. Each protocol however, provides unique benefits as well as shortcomings, highlighting the need for context-dependent protocol choice and cross-lab collaboration and communication to identify the most robust and translatable microglia model.

BackgroundThe regular assessment of hormonal and mood state parameters in professional soccer are proposed as good indicators during periods of intense training and/or competition to avoid overtraining.ObjectiveThe aim of this study was to analyze hormonal, psychological, workload and physical fitness parameters in elite soccer players in relation to changes in training and match exposure during a congested period of match play.MethodsSixteen elite soccer players from a team playing in the first Tunisian soccer league were evaluated three times (T1, T2, and T3) over 12 weeks. The non-congested period of match play was from T1 to T2, when the players played 6 games over 6 weeks. The congested period was from T2 to T3, when the players played 10 games over 6 weeks. From T1 to T3, players performed the Yo-Yo intermittent recovery test level 1 (YYIR1), the repeated shuttle sprint ability test (RSSA), the countermovement jump test (CMJ), and the squat jump test (SJ). Plasma Cortisol (C), Testosterone (T), and the T/C ratio were analyzed at T1, T2, and T3. Players had their mood dimensions (tension, depression, anger, vigor, fatigue, confusion, and a Total Mood Disturbance) assessed through the Profile of Mood State questionnaire (POMS). Training session rating of perceived exertion (sRPE) was also recorded on a daily basis in order to quantify internal training load and elements of monotony and strain.ResultsSignificant performance declines (T1 < T2 < T3) were found for SJ performance (p = 0.04, effect size [ES] ES1–2 = 0.15−0.06, ES2–3 = 0.24) from T1 to T3. YYIR1 performance improved significantly from T1 to T2 and declined significantly from T2 to T3 (p = 0.001, ES1–2 = 0.24, ES2–3 = −2.54). Mean RSSA performance was significantly higher (p = 0.019, ES1–2 = −0.47, ES2–3 = 1.15) in T3 compared with T2 and T1. Best RSSA performance was significantly higher in T3 when compared with T2 and T1 (p = 0.006, ES2–3 = 0.47, ES1–2 = −0.56), but significantly lower in T2 when compared with to T1. T and T/C were significantly lower in T3 when compared with T2 and T1 (T: p = 0.03, ES3–2 = −0.51, ES3–1 = −0.51, T/C: p = 0.017, ES3–2 = −1.1, ES3–1 = −1.07). Significant decreases were found for the vigor scores in T3 when compared to T2 and T1 (p = 0.002, ES1–2 = 0.31, ES3–2 = −1.25). A significant increase was found in fatigue scores in T3 as compared to T1 and T2 (p = 0.002, ES1–2 = 0.43, ES2–3 = 0.81). A significant increase was found from T1 < T2 < T3 intension score (p = 0.002, ES1–2 = 1.1, ES2–3 = 0.2) and anger score (p = 0.03, ES1–2 = 0.47, ES2–3 = 0.33) over the study period. Total mood disturbance increased significantly (p = 0.02, ES1–2 = 0.91, ES2–3 = 1.1) from T1 to T3. Between T1-T2, significant relationships were observed between workload and changes in T (r = 0.66, p = 0.003), and T/C ratio (r = 0.62, p = 0.01). There were significant relationships between performance in RSSAbest and training load parameters (workload: r = 0.52, p = 0.03; monotony: r = 0.62, p = 0.01; strain: r = 0.62, p = 0.009). Between T2-T3, there was a significant relationship between Δ% of total mood disturbance and Δ% of YYIR1 (r = −0.54; p = 0.04), RSSAbest (r = 0.58, p = 0.01), SJ (r = −0,55, p = 0.01), T (r = 0.53; p = 0.03), and T/C (r = 0.5; p = 0.04).ConclusionAn intensive period of congested match play significantly compromised elite soccer players’ physical and mental fitness. These changes were related to psychological but not hormonal parameters; even though significant alterations were detected for selected measures. Mood monitoring could be a simple and useful tool to determine the degree of preparedness for match play during a congested period in professional soccer.

If an artificial intelligence aims to maximize risk-adjusted return, then under mild conditions it is disproportionately likely to pick an unethical strategy unless the objective function allows sufficiently for this risk. Even if the proportion η of available unethical strategies is small, the probability pU of picking an unethical strategy can become large; indeed, unless returns are fat-tailed pU tends to unity as the strategy space becomes large. We define an unethical odds ratio, Υ (capital upsilon), that allows us to calculate pU from η, and we derive a simple formula for the limit of Υ as the strategy space becomes large. We discuss the estimation of Υ and pU in finite cases and how to deal with infinite strategy spaces. We show how the principle can be used to help detect unethical strategies and to estimate η. Finally we sketch some policy implications of this work.