Programme theories to describe how different general practitioner service models work in different contexts in or alongside emergency departments (GP-ED): realist evaluation.

BACKGROUND: Addressing increasing patient demand and improving ED patient flow is a key ambition for NHS England. Delivering general practitioner (GP) services in or alongside EDs (GP-ED) was advocated in 2017 for this reason, supported by £100 million (US$130 million) of capital funding. Current evidence shows no overall improvement in addressing demand and reducing waiting times, but considerable variation in how different service models operate, subject to local context. METHODS: We conducted mixed-methods analysis using inductive and deductive approaches for qualitative (observations, interviews) and quantitative data (time series analyses of attendances, reattendances, hospital admissions, length of stay) based on previous research using a purposive sample of 13 GP-ED service models (3 inside-integrated, 4 inside-parallel service, 3 outside-onsite and 3 with no GPs) in England and Wales. We used realist methodology to understand the relationship between contexts, mechanisms and outcomes to develop programme theories about how and why different GP-ED service models work. RESULTS: GP-ED service models are complex, with variation in scope and scale of the service, influenced by individual, departmental and external factors. Quantitative data were of variable quality: overall, no reduction in attendances and waiting times, a mixed picture for hospital admissions and length of hospital stay. Our programme theories describe how the GP-ED service models operate: inside the ED, integrated with patient flow and general ED demand, with a wider GP role than usual primary care; outside the ED, addressing primary care demand with an experienced streaming nurse facilitating the 'right patients' are streamed to the GP; or within the ED as a parallel service with most variability in the level of integration and GP role. CONCLUSION: GP-ED services are complex . Our programme theories inform recommendations on how services could be modified in particular contexts to address local demand, or whether alternative healthcare services should be considered.

Targeted accurate RNA consensus sequencing (tARC-seq) reveals mechanisms of replication error affecting SARS-CoV-2 divergence.

RNA viruses, like SARS-CoV-2, depend on their RNA-dependent RNA polymerases (RdRp) for replication, which is error prone. Monitoring replication errors is crucial for understanding the virus's evolution. Current methods lack the precision to detect rare de novo RNA mutations, particularly in low-input samples such as those from patients. Here we introduce a targeted accurate RNA consensus sequencing method (tARC-seq) to accurately determine the mutation frequency and types in SARS-CoV-2, both in cell culture and clinical samples. Our findings show an average of 2.68 × 10-5 de novo errors per cycle with a C > T bias that cannot be solely attributed to APOBEC editing. We identified hotspots and cold spots throughout the genome, correlating with high or low GC content, and pinpointed transcription regulatory sites as regions more susceptible to errors. tARC-seq captured template switching events including insertions, deletions and complex mutations. These insights shed light on the genetic diversity generation and evolutionary dynamics of SARS-CoV-2.

Accommodations for disabilities in dental education: A focus on technical standards and clinical skills.

Providing disability-based accommodations is a multifaceted process that must balance the needs of dental students and their institutions. Reasonable accommodations must not compromise patient safety or cause an undue burden on the student or institution. Therefore, more creative approaches must be considered as the number of individuals and the types of learning disabilities have increased in recent years. In the clinical setting, providing accommodations also requires detailed advanced planning and collaboration to maintain program quality. However, current technical standards (TS) may serve as a barrier to entry into the health professions for people with disabilities. These individuals remain substantially underrepresented in dentistry despite bringing unique perspectives and experiences that can contribute to a diverse workforce of culturally proficient practitioners. In response, many schools have adopted a "functional" approach to TS that emphasizes a student's abilities rather than their limitations. In addition, innovative assistive technologies coupled with the application of critical pedagogy and universal design learning practices that engage people with the widest possible range of capabilities allows equitable approaches for learning and assessment while maintaining professional standards.

Nutritional Considerations for Elite Golf: A Narrative Review.

Golf is predominantly a skill-based sport where technical aspects are regarded as a priority area for improving performance. At present, most of the existing literature has focused on improving a player's physicality, endurance and technical attributes in an effort to enhance performance. While important, the role of nutrition in elite golf has received little attention to date. The energy demands of the sport can vary depending on the level of the individual (recreational-professional), with distances of up to 20 km being covered and the time spent on the course ranging approximately 4-8 h each day. Like other sports, a focus on pre-game, during and post-game nutrition, including hydration, is integral to ensuring that individuals are adequately fuelled, hydrated and optimally recovered. For the elite athletes who travel extensively to international tournaments, it is important to understand the additional impact of travel on the body and consider the role nutrition can play in preventing illness and ensuring minimal disruption to golf performance. Lastly, the role of dietary supplements to enhance the performance of golfers is also important to consider. This review aims to consolidate the findings of the existing research focusing on nutrition strategies for golf performance and identify areas for potential future research.

Combined effects of exercise and different levels of acute hypoxic severity: A randomized crossover study on glucose regulation in adults with overweight.

Purpose: The aim of this study was to investigate the influence of manipulating hypoxic severity with low-intensity exercise on glucose regulation in healthy overweight adults. Methods: In a randomized crossover design, 14 males with overweight (age: 27 ± 5 years; body mass index (BMI) 27.1 ± 1.8 kg⋅m2) completed three exercise trials involving 60 min aerobic exercise cycling at 90% lactate threshold in normoxia (NM, FiO2 = 20.9%), moderate hypoxia (MH, FiO2 = 16.5%) and high hypoxia (HH, FiO2 = 14.8%). A post-exercise oral glucose tolerance test (OGTT) was performed. Venous blood samples were analyzed for incremental area under the curve (iAUC), plasma glucose and insulin, as well as exerkine concentrations (plasma apelin and fibroblast growth factor 21 [FGF-21]) pre- and post-exercise. A 24-h continuous glucose monitoring (CGM) was used to determine interstitial glucose concentrations. Heart rate, oxygen saturation (SpO2) and perceptual measures were recorded during exercise. Results: Post-exercise OGTT iAUC for plasma glucose and insulin concentrations were lower in MH vs. control (p = 0.02). Post-exercise interstitial glucose iAUC, plasma apelin and FGF-21 were not different between conditions. Heart rate was higher in HH vs. NM and MH, and MH vs. NM (p < 0.001), while SpO2 was lower in HH vs. NM and MH, and MH vs. NM (p < 0.001). Overall perceived discomfort and leg discomfort were higher in HH vs. NM and MH (p < 0.05), while perceived breathing difficulty was higher in HH vs. NM only (p = 0.003). Conclusion: Compared to higher hypoxic conditions, performing acute aerobic-based exercise under moderate hypoxia provided a more effective stimulus for improving post-exercise glucose regulation while concomitantly preventing excessive physiological and perceptual stress in healthy overweight adults.

Unpacking the renal system component of the "structure and function" core concept of physiology by an Australian team.

An Australia-wide consensus was reached on seven core concepts of physiology, one of which was "structure and function" with the descriptor "Structure and function are intrinsically related to all levels of the organism. In all physiological systems, the structure from a microscopic level to an organ level dictates its function." As a framework for the structure and function core concept, the renal system was unpacked by a team of 5 Australian Physiology educators from different universities with extensive teaching experience into hierarchical levels, with 5 themes and 25 subthemes up to 3 levels deep. Within theme 1, the structures that comprise the renal system were unpacked. Within theme 2, the physiological processes within the nephron such as filtration, reabsorption, and secretion were unpacked. Within theme 3, the processes involved in micturition were unpacked. In theme 4, the structures and processes involved in regulating renal blood flow and glomerular filtration were unpacked; and within theme 5, the role of the kidney in red blood cell production was unpacked. Twenty-one academics rated the difficulty and importance of each theme/subtheme, and results were analyzed using a one-way ANOVA. All identified themes were validated as "essential" to "important"/"moderately important" and rated between "difficult" to "not difficult." A similar framework consisting of structure, physiological processes, physical processes, and regulation can be used to unpack other body systems. Unpacking of the body systems will provide a list of what students should be taught in curricula across Australian universities and inform assessment and learning activities.NEW & NOTEWORTHY This is the first attempt to unpack and validate the "structure and function" core concept in physiology with all Australian educators. We unpacked the renal system into themes with hierarchical levels, which were validated by an experienced team of Australian physiology educators. Our unpacking of the "structure and function" core concept provides a specific framework for educators to apply this important concept in physiology education.

The potential use of skin and liver as biomarkers to estimate mercury in the brain, kidney, and muscle of bottlenose dolphins (Tursiops truncatus).

For marine cetaceans, Hg biomagnification can negatively affect neurological, hepatic, renal, and immune functions. To evaluate the use of biomarkers for Hg in dolphins, multiple tissues were analyzed from 127 stranded common bottlenose dolphins (Tursiops truncatus) from the estuarine and oceanic waters of Virginia, USA. Twenty-two percent of liver Hg concentrations exceeded the published observed effect level for liver abnormalities, and 26 % of cerebrum samples exceeded the published threshold for neurochemical changes, suggesting that Hg may have impacted dolphin health. Mercury tissue levels were similar to or lower than those reported from other locations (liver range: 1.4-943 µg/g-dw). Significant correlations were found between tissue types, indicating that skin or liver can be used as a biomarker to estimate the total Hg concentrations in the other tissue types (kidney, liver, cerebrum, cerebellum, pons). This is the first study to measure Hg concentrations in multiple brain regions of T. truncatus.

Establishing consensus for the core concepts of physiology in the Australian higher education context using the Delphi method.

A set of core concepts ("big ideas") integral to the discipline of physiology are important for students to understand and demonstrate their capacity to apply. We found poor alignment of learning outcomes in programs with physiology majors (or equivalent) from 17 Australian universities and the 15 core concepts developed by a team in the United States. The objective of this project was to reach Australia-wide consensus on a set of core concepts for physiology, which can be embedded in curricula across Australian universities. A four-phase Delphi method was employed, starting with the assembling of a Task Force of physiology educators with extensive teaching and curriculum development expertise from 25 Australian universities. After two online meetings and a survey, the Task Force reached agreement on seven core concepts of physiology and their descriptors, which were then sent out to the physiology educator community across Australia for agreement. The seven core concepts and their associated descriptions were endorsed through this process (n = 138). In addition, embedding the core concepts across the curriculum was supported by both Task Force members (85.7%) and educators (82.1%). The seven adopted core concepts of human physiology were Cell Membrane, Cell-Cell Communication, Movement of Substances, Structure and Function, Homeostasis, Integration, and Physiological Adaptation. The core concepts were subsequently unpacked into themes and subthemes. If adopted, these core concepts will result in consistency across curricula in undergraduate physiology programs and allow for future benchmarking.NEW & NOTEWORTHY This is the first time Australia-wide agreement has been reached on the core concepts of physiology with the Delphi method. Embedding of the core concepts will result in consistency in physiology curricula, improvements to teaching and learning, and benchmarking across Australian universities.

Conjugation's Toolkit: the Roles of Nonstructural Proteins in Bacterial Sex.

Bacterial conjugation, a form of horizontal gene transfer, relies on a type 4 secretion system (T4SS) and a set of nonstructural genes that are closely linked. These nonstructural genes aid in the mobile lifestyle of conjugative elements but are not part of the T4SS apparatus for conjugative transfer, such as the membrane pore and relaxosome, or the plasmid maintenance and replication machineries. While these nonstructural genes are not essential for conjugation, they assist in core conjugative functions and mitigate the cellular burden on the host. This review compiles and categorizes known functions of nonstructural genes by the stage of conjugation they modulate: dormancy, transfer, and new host establishment. Themes include establishing a commensalistic relationship with the host, manipulating the host for efficient T4SS assembly and function and assisting in conjugative evasion of recipient cell immune functions. These genes, taken in a broad ecological context, play important roles in ensuring proper propagation of the conjugation system in a natural environment.

Mechanisms for Combined Hypoxic Conditioning and Divergent Exercise Modes to Regulate Inflammation, Body Composition, Appetite, and Blood Glucose Homeostasis in Overweight and Obese Adults: A Narrative Review.

Obesity is a major global health issue and a primary risk factor for metabolic-related disorders. While physical inactivity is one of the main contributors to obesity, it is a modifiable risk factor with exercise training as an established non-pharmacological treatment to prevent the onset of metabolic-related disorders, including obesity. Exposure to hypoxia via normobaric hypoxia (simulated altitude via reduced inspired oxygen fraction), termed hypoxic conditioning, in combination with exercise has been increasingly shown in the last decade to enhance blood glucose regulation and decrease the body mass index, providing a feasible strategy to treat obesity. However, there is no current consensus in the literature regarding the optimal combination of exercise variables such as the mode, duration, and intensity of exercise, as well as the level of hypoxia to maximize fat loss and overall body compositional changes with hypoxic conditioning. In this narrative review, we discuss the effects of such diverse exercise and hypoxic variables on the systematic and myocellular mechanisms, along with physiological responses, implicated in the development of obesity. These include markers of appetite regulation and inflammation, body conformational changes, and blood glucose regulation. As such, we consolidate findings from human studies to provide greater clarity for implementing hypoxic conditioning with exercise as a safe, practical, and effective treatment strategy for obesity.

Examining the Influence of the Human Gut Microbiota on Cognition and Stress: A Systematic Review of the Literature.

The gut microbiota is seen as an emerging biotechnology that can be manipulated to enhance or preserve cognition and physiological outputs of anxiety and depression in clinical conditions. However, the existence of such interactions in healthy young individuals in both non-stressful and stressful environments is unclear. The aim of this systematic review was to examine the relationship between the human gut microbiota, including modulators of the microbiota on cognition, brain function and/or stress, anxiety and depression. A total of n = 25 eligible research articles from a possible 3853 published between October 2018 and August 2021 were identified and included. Two study design methods for synthesis were identified: cross-sectional or pre/post intervention. Few cross-sectional design studies that linked microbiota to cognition, brain activity/structure or mental wellbeing endpoints existed (n = 6); however, correlations between microbiota diversity and composition and areas of the brain related to cognitive functions (memory and visual processing) were observed. Intervention studies targeting the gut microbiota to improve cognition, brain structure/function or emotional well-being (n = 19) generally resulted in improved brain activity and/or cognition (6/8), and improvements in depression and anxiety scores (5/8). Despite inherit limitations in studies reviewed, available evidence suggests that gut microbiota is linked to brain connectivity and cognitive performance and that modulation of gut microbiota could be a promising strategy for enhancing cognition and emotional well-being in stressed and non-stressed situations.

The Effects of Intermittent Fasting and Continuous Energy Restriction with Exercise on Cardiometabolic Biomarkers, Dietary Compliance, and Perceived Hunger and Mood: Secondary Outcomes of a Randomised, Controlled Trial.

(1) Background: Excess weight in the form of adiposity plays a key role in the pathogenesis of cardiometabolic diseases. Lifestyle modifications that incorporate continuous energy restriction (CER) are effective at inducing weight loss and reductions in adiposity; however, prescribing daily CER results in poor long-term adherence. Over the past decade, intermittent fasting (IF) has emerged as a promising alternative to CER that may promote increased compliance and/or improvements in cardiometabolic health parameters independent of weight loss. (2) Methods: This paper presents a secondary analysis of data from a 12-week intervention investigating the effects of a twice-weekly fast (5:2 IF; IFT group) and CER (CERT group) when combined with resistance exercise in 34 healthy participants (17 males and 17 females, mean BMI: 27.0 kg/m2, mean age: 23.9 years). Specifically, changes in cardiometabolic blood markers and ratings of hunger, mood, energy and compliance within and between groups were analysed. Dietary prescriptions were hypoenergetic and matched for energy and protein intake. (3) Results: Both dietary groups experienced reductions in total cholesterol (TC; mean reduction, 7.8%; p < 0.001), low-density lipoprotein cholesterol (LDL-C; mean reduction, 11.1%; p < 0.001) and high-density lipoprotein cholesterol (mean reduction 2.6%, p = 0.049) over the 12 weeks. Reductions in TC and LDL-C were greater in the IFT group after adjustment for baseline levels and change in weight. No significant changes in markers of glucose regulation were observed. Both groups maintained high levels of dietary compliance (~80%) and reported low levels of hunger over the course of the intervention period. (4) Conclusions: Secondary data analysis revealed that when combined with resistance training, both dietary patterns improved blood lipids, with greater reductions observed in the IFT group. High levels of compliance and low reported levels of hunger throughout the intervention period suggest both diets are well tolerated in the short-to-medium term.

Effects of Intermittent Energy Restriction Alone and in Combination with Sprint Interval Training on Body Composition and Cardiometabolic Biomarkers in Individuals with Overweight and Obesity.

The popularity of intermittent fasting (IF) and high intensity (sprint) interval training (SIT) has increased in recent years amongst the general public due to their purported health benefits and feasibility of incorporation into daily life. The number of scientific studies investigating these strategies has also increased, however, very few have examined the combined effects, especially on body composition and cardiometabolic biomarkers, which is the primary aim of this investigation. A total of thirty-four male and female participants (age: 35.4 ± 8.4 y, body mass index (BMI): 31.3 ± 3.5 kg/m2, aerobic capacity (VO2peak) 27.7 ± 7.0 mL·kg−1·min−1) were randomized into one of three 16-week interventions: (1) 5:2 IF (2 non-consecutive days of fasting per week, 5 days on ad libitum eating), (2) supervised SIT (3 bouts per week of 20s cycling at 150% VO2peak followed by 40 s of active rest, total 10 min duration), and (3) a combination of both interventions. Body composition, haemodynamic and VO2peak were measured at 0, 8 and 16 weeks. Blood samples were also taken and analysed for lipid profiles and markers of glucose regulation. Both IF and IF/SIT significantly decreased body weight, fat mass and visceral fat compared to SIT only (p < 0.05), with no significant differences between diet and diet + exercise combined. The effects of diet and/or exercise on cardiometabolic biomarkers were mixed. Only exercise alone or with IF significantly increased cardiorespiratory fitness. The results suggest that energy restriction was the main driver of body composition enhancement, with little effect from the low volume SIT. Conversely, to achieve benefits in cardiorespiratory fitness, exercise is required.

RNA polymerase inaccuracy underlies SARS-CoV-2 variants and vaccine heterogeneity.

Both the SARS-CoV-2 virus and its mRNA vaccines depend on RNA polymerases (RNAP)1,2; however, these enzymes are inherently error-prone and can introduce variants into the RNA3. To understand SARS-CoV-2 evolution and vaccine efficacy, it is critical to identify the extent and distribution of errors introduced by the RNAPs involved in each process. Current methods lack the sensitivity and specificity to measure de novo RNA variants in low input samples like viral isolates3. Here, we determine the frequency and nature of RNA errors in both SARS-CoV-2 and its vaccine using a targeted Accurate RNA Consensus sequencing method (tARC-seq). We found that the viral RNA-dependent RNAP (RdRp) makes ~1 error every 10,000 nucleotides - higher than previous estimates4. We also observed that RNA variants are not randomly distributed across the genome but are associated with certain genomic features and genes, such as S (Spike). tARC-seq captured a number of large insertions, deletions and complex mutations that can be modeled through non-programmed RdRp template switching. This template switching feature of RdRp explains many key genetic changes observed during the evolution of different lineages worldwide, including Omicron. Further sequencing of the Pfizer-BioNTech COVID-19 vaccine revealed an RNA variant frequency of ~1 in 5,000, meaning most of the vaccine transcripts produced in vitro by T7 phage RNAP harbor a variant. These results demonstrate the extraordinary genetic diversity of viral populations and the heterogeneous nature of an mRNA vaccine fueled by RNAP inaccuracy. Along with functional studies and pandemic data, tARC-seq variant spectra can inform models to predict how SARS-CoV-2 may evolve. Finally, our results may help improve future vaccine development and study design as mRNA therapies continue to gain traction.

Heat Acclimation with or without Normobaric Hypoxia Exposure Leads to Similar Improvements in Endurance Performance in the Heat.

BACKGROUND: Combining the key adaptation of plasma volume (PV) expansion with synergistic physiological effects of other acclimation interventions to maximise endurance performance in the heat has potential. The current study investigated the effects of heat acclimation alone (H), combined with normobaric hypoxia exposure (H+NH), on endurance athletic performance. METHODS: Well-trained participants completed a heat-stress trial (30 °C, 80% relative humidity (RH), 20.8% fraction of inspired oxygen (FiO2)) of a 75 min steady-state cycling (fixed workload) and a subsequent 15 min cycling time trial for distance before and after intervention. Participants completed 12 consecutive indoor training days with either heat acclimation (H; 60 min·day-1, 30 °C, 80% RH; 20.8% FiO2) or heat acclimation and overnight hypoxic environment (H+NH; ~12 h, 60% RH; 16% FiO2 simulating altitude of ~2500 m). Control (CON) group trained outdoors with average maximum daily temperature of 16.5 °C and 60% RH. RESULTS: Both H and H+NH significantly improved time trial cycling distance by ~5.5% compared to CON, with no difference between environmental exposures. PV increased (+3.8%) and decreased (-4.1%) following H and H+NH, respectively, whereas haemoglobin concentration decreased (-2%) and increased (+3%) in H and H+NH, respectively. CONCLUSION: Our results show that despite contrasting physiological adaptations to different environmental acclimation protocols, heat acclimation with or without hypoxic exposure demonstrated similar improvements in short-duration exercise performance in a hot environment.

Dietary Assessment Tools and Metabolic Syndrome: Is It Time to Change the Focus?

Metabolic syndrome (MS) is associated with a range of chronic diseases, for which lifestyle interventions are considered the cornerstone of treatment. Dietary interventions have primarily focused on weight reduction, usually via energy restricted diets. While this strategy can improve insulin sensitivity and other health markers, weight loss alone is not always effective in addressing all risk factors associated with MS. Previous studies have identified diet quality as a key factor in reducing the risk of MS independent of weight loss. Additionally, supporting evidence for the use of novel strategies such as carbohydrate restriction and modifying the frequency and timing of meals is growing. It is well established that dietary assessment tools capable of identifying dietary patterns known to increase the risk of MS are essential for the development of personalised, targeted diet and lifestyle advice. The American Heart Association (AHA) recently evaluated the latest in a variety of assessment tools, recommending three that demonstrate the highest evidence-based and clinical relevance. However, such tools may not assess and thus identify all dietary and eating patterns associated with MS development and treatment, especially those which are new and emerging. This paper offers a review of current dietary assessment tools recommended for use by the AHA to assess dietary and eating patterns associated with MS development. We discuss how these recommendations align with recent and novel evidence on the benefits of restricting ultra-processed food and refined carbohydrates and modifying timing and frequency of meals. Finally, we provide recommendations for future redevelopment of these tools to be deployed in health care settings.

Search strategy analysis of Tg4-42 Alzheimer Mice in the Morris Water Maze reveals early spatial navigation deficits.

Spatial disorientation is one of the earliest symptoms in Alzheimer's disease and allocentric deficits can already be detected in the asymptomatic preclinical stages of the disease. The Morris Water Maze (MWM) is used to study spatial learning in rodent models. Here we investigated the spatial memory of female 3, 7 and 12 month-old Alzheimer Tg4-42 mice in comparison to wild-type control animals. Conventional behavior analysis of escape latencies and quadrant preference revealed spatial memory and reference memory deficits in female 7 and 12 month-old Tg4-42 mice. In contrast, conventional analysis of the MWM indicated an intact spatial memory in 3 month-old Tg4-42 mice. However, a detailed analysis of the swimming strategies demonstrated allocentric-specific memory deficits in 3 month-old Tg4-42 mice before the onset of severe memory deficits. Furthermore, we could show that the spatial reference memory deficits in aged Tg4-42 animals are caused by the lack of allocentric and spatial strategies. Analyzing search strategies in the MWM allows to differentiate between hippocampus-dependent allocentric and hippocampus-independent egocentric search strategies. The spatial navigation impairments in young Tg4-42 mice are well in line with the hypometabolism and synaptic deficits in the hippocampus. Therefore, analyzing search strategies in the Tg4-42 model can be a powerful tool for preclinical drug testing and identifying early therapeutic successes.

Intermittent fasting and continuous energy restriction result in similar changes in body composition and muscle strength when combined with a 12 week resistance training program.

PURPOSE: The objective of this study was to compare the effects of 12 weeks of resistance training combined with either 5:2 intermittent fasting or continuous energy restriction on body composition, muscle size and quality, and upper and lower body strength. METHODS: Untrained individuals undertook 12 weeks of resistance training plus either continuous energy restriction [20% daily energy restriction (CERT)] or 5:2 intermittent fasting [~ 70% energy restriction 2 days/week, euenergetic consumption 5 days/week (IFT)], with both groups prescribed a mean of ≥ 1.4 g of protein per kilogram of body weight per day. Participants completed 2 supervised resistance and 1 unsupervised aerobic/resistance training combination session per week. Changes in lean body mass (LBM), thigh muscle size and quality, strength and dietary intake were assessed. RESULTS: Thirty-four participants completed the study (CERT = 17, IFT = 17). LBM was significantly increased (+ 3.7%, p < 0.001) and body weight (- 4.6%, p < 0.001) and fat (- 24.1%, p < 0.001) were significantly reduced with no significant difference between groups, though results differed by sex. Both groups showed improvements in thigh muscle size and quality, and reduced intramuscular and subcutaneous fat assessed by ultrasonography and peripheral quantitative computed tomography (pQCT), respectively. The CERT group demonstrated a significant increase in muscle surface area assessed by pQCT compared to the IFT group. Similar gains in upper and lower body strength and muscular endurance were observed between groups. CONCLUSION: When combined with resistance training and moderate protein intake, continuous energy restriction and 5:2 intermittent fasting resulted in similar improvements in body composition, muscle quality, and strength. ACTRN: ACTRN12620000920998, September 2020, retrospectively registered.

Patients' experiences of attending emergency departments where primary care services are located: qualitative findings from patient and clinician interviews from a realist evaluation.

BACKGROUND: Patient experience is an important outcome and indicator of healthcare quality, and patient reported experiences are key to improving quality of care. While patient experience in emergency departments (EDs) has been reported in research, there is limited evidence about patients' specific experiences with primary care services located in or alongside EDs. We aim to identify theories about patient experience and acceptability of being streamed to a primary care clinician in an ED. METHODS: Using theories from a rapid realist review as a basis, we interviewed 24 patients and 106 staff members to generate updated theories about patient experience and acceptability of streaming to primary care services in EDs. Feedback from 56 stakeholders, including clinicians, policymakers and patient and public members, as well as observations at 13 EDs, also contributed to the development of these theories, which we present as a programme theory. RESULTS: We found that patients had no expectations or preferences for which type of clinician they were seen by, and generally found being streamed to a primary care clinician in the ED acceptable. Clinicians and patients reported that patients generally found primary care streaming acceptable if they felt their complaint was dealt with suitably, in a timely manner, and when clinicians clearly communicated the need for investigations, and how these contributed to decision-making and treatment plans. CONCLUSIONS: From our findings, we have developed a programme theory to demonstrate that service providers can expect that patients will be generally satisfied with their experience of being streamed to, and seen by, primary care clinicians working in these services. Service providers should consider the potential advantages and disadvantages of implementing primary care services at their ED. If primary care services are implemented, clear communication is needed between staff and patients, and patient feedback should be sought.

Global transgenic upregulation of KCC2 confers enhanced diazepam efficacy in treating sustained seizures.

Reduced anticonvulsant efficacy of benzodiazepines is a problem in the treatment of status epilepticus, with up to 50% of patients failing to respond to their first dose. KCC2 is a neuronal K+ -Cl- co-transporter that helps set and maintain intracellular Cl- concentrations. KCC2 functional downregulation is a potential contributor to benzodiazepine resistance. We tested this idea using male and female doxycycline-inducible, conditional transgenic mice to increase the functional expression of KCC2 in pyramidal neurons. We administered mice with two doses of the chemoconvulsant kainic acid (5 mg/kg, i.p.) 60 min apart and quantified the resultant seizures with electroencephalography (EEG) recordings. Overexpression of KCC2 prior to the chemoconvulsant challenge did not affect seizure latency or other measures of seizure severity, but it did increase diazepam's efficacy in stopping EEG seizures. Spike rate, time in seizure, and EEG spectral power following diazepam (5 mg/kg, i.p) were all significantly lower in KCC2 overexpression mice as compared to control mice. Our results indicate that, in the context of benzodiazepine resistance during sustained seizures, addressing impaired Cl- homeostasis alone appreciably improves the efficacy of γ-aminobutyric acid (GABA)ergic inhibition. We therefore suggest the simultaneous targeting of KCC2 and GABAA receptors as a pathway for improving current anticonvulsant therapeutic strategies.