An adaptive text message intervention to promote psychological well-being and reduce cardiac risk: The Text4Health controlled clinical pilot trial.

OBJECTIVE: In a two-arm pilot trial, we examined the feasibility, acceptability, and preliminary efficacy of a 12-week, adaptive text message intervention (TMI) to promote health behaviors and psychological well-being in 60 individuals with multiple cardiac risk conditions (i.e., hypertension, hyperlipidemia, and/or type 2 diabetes) and suboptimal adherence to exercise or dietary guidance. METHODS: Participants were allocated to receive the TMI or enhanced usual care (eUC). The TMI included daily adaptive text messages promoting health behaviors, twice-weekly messages to set goals and monitor progress, and monthly phone check-ins. Feasibility (primary outcome) and acceptability were measured by rates of successful text message delivery and daily participant ratings of message utility (0-10 Likert scale). We also assessed impact on health behavior adherence, psychological health, and functional outcomes. RESULTS: The TMI was feasible (99.3% of messages successfully sent) and well-accepted (mean utility = 7.4/10 [SD 2.6]). At 12 weeks, the TMI led to small-sized greater improvements in moderate to vigorous physical activity (d = 0.37), overall physical activity (d = 0.23), optimism (d = 0.20), anxiety (d = -0.36), self-efficacy (d = 0.22), and physical function (d = 0.20), compared to eUC. It did not impact other outcomes substantially at this time point. CONCLUSION: This 12-week, adaptive TMI was feasible, well-accepted, and associated with small-sized greater improvements in health behavior and psychological outcomes. Though larger studies are needed, it has the potential to be a scalable, low-intensity program that could be used in clinical practice. CLINICALTRIALS: govregistration:NCT04382521.

Relationships between gene expression and behavior in mice in response to systemic modulation of the O-GlcNAcylation pathway.

Enhancing protein O-GlcNAcylation by pharmacological inhibition of the enzyme O-GlcNAcase (OGA), which removes the O-GlcNAc modification from proteins, has been explored in mouse models of amyloid-beta and tau pathology. However, the O-GlcNAcylation-dependent link between gene expression and neurological behavior remains to be explored. Using chronic administration of Thiamet G (TG, an OGA inhibitor) in vivo, we used a protocol designed to relate behavior with the transcriptome and selected biochemical parameters from the cortex of individual animals. TG-treated mice showed improved working memory as measured using a Y-maze test. RNA sequencing analysis revealed 151 top differentially expressed genes with a Log2fold change >0.33 and adjusted p-value <0.05. Top TG-dependent upregulated genes were related to learning, cognition and behavior, while top downregulated genes were related to IL-17 signaling, inflammatory response and chemotaxis. Additional pathway analysis uncovered 3 pathways, involving gene expression including 14 cytochrome c oxidase subunits/regulatory components, chaperones or assembly factors, and 5 mTOR (mechanistic target of rapamycin) signaling factors. Multivariate Kendall correlation analyses of behavioral tests and the top TG-dependent differentially expressed genes revealed 91 statistically significant correlations in saline-treated mice and 70 statistically significant correlations in TG-treated mice. These analyses provide a network regulation landscape that is important in relating the transcriptome to behavior and the potential impact of the O-GlcNAC pathway.

Dynamic transcriptomic responses to divergent acute exercise stimuli in young adults.

Acute exercise elicits dynamic transcriptional changes that, when repeated, form the fundamental basis of health, resilience, and performance adaptations. While moderate-intensity endurance training combined with conventional resistance training (traditional, TRAD) is often prescribed and recommended by public health guidance, high-intensity training combining maximal-effort intervals with intensive, limited-rest resistance training is a time-efficient alternative that may be used tactically (HITT) to confer similar benefits. Mechanisms of action of these distinct stimuli are incompletely characterized and have not been directly compared. We assessed transcriptome-wide responses in skeletal muscle and circulating extracellular vesicles (EVs) to a single exercise bout in young adults randomized to TRAD (n = 21, 12 M/9 F, 22 ± 3 yr) or HITT (n = 19, 11 M/8 F, 22 ± 2 yr). Next-generation sequencing captured small, long, and circular RNA in muscle and EVs. Analysis identified differentially expressed transcripts (|log2FC|>1, FDR ≤ 0.05) immediately (h0, EVs only), h3, and h24 postexercise within and between exercise protocols. In aaddition, all apparently responsive transcripts (FDR < 0.2) underwent singular value decomposition to summarize data structures into latent variables (LVs) to deconvolve molecular expression circuits and interregulatory relationships. LVs were compared across time and exercise protocol. TRAD, a longer but less intense stimulus, generally elicited a stronger transcriptional response than HITT, but considerable overlap and key differences existed. Findings reveal shared and unique molecular responses to the exercise stimuli and lay groundwork toward establishing relationships between protein-coding genes and lesser-understood transcripts that serve regulatory roles following exercise. Future work should advance the understanding of these circuits and whether they repeat in other populations or following other types of exercise/stress.NEW & NOTEWORTHY We examined small and long transcriptomics in skeletal muscle and serum-derived extracellular vesicles before and after a single exposure to traditional combined exercise (TRAD) and high-intensity tactical training (HITT). Across 40 young adults, we found more consistent protein-coding gene responses to TRAD, whereas HITT elicited differential expression of microRNA enriched in brain regions. Follow-up analysis revealed relationships and temporal dynamics across transcript networks, highlighting potential avenues for research into mechanisms of exercise response and adaptation.

Repeat subconcussion in the adult rat gives rise to behavioral deficits similar to a single concussion but different depending upon sex.

Although concussions are a popular focus of neurotrauma research, subconcussions occur with higher frequency but are less well-studied. A subconcussion is an impact to the head that does not result in immediately diagnosable concussion but can result in later neurological consequences. Repeat subconcussions can produce behavioral impairments and neuropathology that is similar to or worse than those seen following a single concussion. The current study modified a previously established closed head injury model of concussion to create a subconcussion model and examines sex differences in behavioral responses to repeated subconcussion in the adult rat. Rats received a single concussion, single or repeat subconcussions, or no impact and behavior was monitored from 2 h through 31 days post-injury. A single concussion or repeat subconcussion resulted in deficits in locomotion, righting reflexes, and recognition memory. The degree of deficit induced by repeat subconcussions were either similar (righting reflexes) or greater/more persistent (locomotor deficits and recognition memory) than that of a concussion. Single subconcussion resulted in acute deficits that were mild and limited to righting reflexes and locomotion. Sex differences were observed in responses to repeat subconcussion: females showed greater deficits in righting reflexes, locomotion, and vestibular function, while males showed greater alterations in anxiety and depressive-like behavior. This study established a model of subconcussive impact where a single subconcussive impact resulted in minimal behavioral deficits but repeat subconcussions resulted in deficits similar to or worse than a single concussion. Our data also suggest sex differences in behavioral responses to both concussive and subconcussive impacts.

Development of the Residual Lesion Score for congenital heart surgery: the RAND Delphi methodology.

BACKGROUND AND OBJECTIVE: The Residual Lesion Score is a novel tool for assessing the achievement of surgical objectives in congenital heart surgery based on widely available clinical and echocardiographic characteristics. This article describes the methodology used to develop the Residual Lesion Score from the previously developed Technical Performance Score for five common congenital cardiac procedures using the RAND Delphi methodology. METHODS: A panel of 11 experts from the field of paediatric and congenital cardiology and cardiac surgery, 2 co-chairs, and a consultant were assembled to review and comment on validity and feasibility of measuring the sub-components of intraoperative and discharge Residual Lesion Score for five congenital cardiac procedures. In the first email round, the panel reviewed and commented on the Residual Lesion Score and provided validity and feasibility scores for sub-components of each of the five procedures. In the second in-person round, email comments and scores were reviewed and the Residual Lesion Score revised. The modified Residual Lesion Score was scored independently by each panellist for validity and feasibility and used to develop the "final" Residual Lesion Score. RESULTS: The Residual Lesion Score sub-components with a median validity score of ≥7 and median feasibility score of ≥4 that were scored without disagreement and with low absolute deviation from the median were included in the "final" Residual Lesion Score. CONCLUSION: Using the RAND Delphi methodology, we were able to develop Residual Lesion Score modules for five important congenital cardiac procedures for the Pediatric Heart Network's Residual Lesion Score study.

State of Knowledge on Molecular Adaptations to Exercise in Humans: Historical Perspectives and Future Directions.

For centuries, regular exercise has been acknowledged as a potent stimulus to promote, maintain, and restore healthy functioning of nearly every physiological system of the human body. With advancing understanding of the complexity of human physiology, continually evolving methodological possibilities, and an increasingly dire public health situation, the study of exercise as a preventative or therapeutic treatment has never been more interdisciplinary, or more impactful. During the early stages of the NIH Common Fund Molecular Transducers of Physical Activity Consortium (MoTrPAC) Initiative, the field is well-positioned to build substantially upon the existing understanding of the mechanisms underlying benefits associated with exercise. Thus, we present a comprehensive body of the knowledge detailing the current literature basis surrounding the molecular adaptations to exercise in humans to provide a view of the state of the field at this critical juncture, as well as a resource for scientists bringing external expertise to the field of exercise physiology. In reviewing current literature related to molecular and cellular processes underlying exercise-induced benefits and adaptations, we also draw attention to existing knowledge gaps warranting continued research effort. © 2021 American Physiological Society. Compr Physiol 12:3193-3279, 2022.

A Care Management Intervention for Noncardiac Chest Pain: Treatment Development and Feasibility Assessment.

ABSTRACT.Objective: Noncardiac chest pain is common and can cause distress, impair quality of life, and lead to recurrent evaluation. It is often multifactorial in etiology and influenced by psychological factors. The objective of this study was to describe the development, implementation, and preliminary feasibility of an 8-week multicomponent care management intervention.Methods: Participants with noncardiac chest pain were recruited from primary care clinics, ambulatory cardiac stress testing, and the emergency department (ED) at an urban academic hospital from March 2019 to November 2019. The care management team consisted of a nurse, cardiologist, and psychiatrist. Following a 1-time consultation visit with the cardiologist and nurse, evaluation and treatment recommendations were conveyed to the participant's primary care physician. The nurse completed 8 weekly phone calls with the participant to provide support, introduce therapeutic principles, and assist with care coordination under the supervision of a psychiatrist. Intervention feasibility was assessed on 7 domains. To examine preliminary efficacy, the number of ED visits was recorded, and participants completed pre-post measures of psychological health and health-related quality of life and Likert scales of chest pain symptom severity, frequency, and impact.Results: The intervention was developed and implemented in 3 patients who completed 100% of the consultation visits and a mean of 95.8% of study phone calls. There were no adverse events or ED visits. Mean scores for chest pain severity, chest pain frequency, chest pain impact, depression, anxiety, and somatization all improved. No other trends were observed.Conclusions: The findings suggest that a care management intervention may be feasible with potential to improve chest pain symptoms and psychological outcomes. A larger, randomized trial is needed to explore the efficacy of this intervention.Trial Registration: ClinicalTrials.gov identifier: NCT04904198.

Social Work's Response during the COVID-19 Pandemic: A Systematic Literature Review-Balancing Telemedicine with Social Work Self-Care during A Pandemic.

Before the COVID-19 pandemic, questions about the increased use of telemedicine had become common in conversations among medical providers. With the onset of the pandemic, these questions became more pronounced, and quick implementation became the key. New and historic barriers to telemedicine began to emerge at a dramatically increased rate during its rapid mobilization. However, considering how quickly telemedicine has been implemented, the impact on frontline workers, such as social workers, has not been specifically explored. We wondered how the change from face-to-face care to using digital platforms for care delivery has affected social work. Could social work ensure the fluid rollout of digital treatment platforms for care management? Could social work balance the increased number of digital treatment platforms with self-care for social workers during the COVID-19 crisis? What were some history social- work-preparedness plans used for other pandemics, and would those plans work for the COVID-19 pandemic? What were some of the self-care techniques employed by social workers? What were the emerging best practices of social workers at the Department of Veterans Affairs (VA) health care system in the U.S. South? We needed to explore these questions to formulate knowledge that could be beneficial for VA health care. This literature review assesses the current responses from the field of social work during the COVID-19 pandemic, leveraging telemedicine, social work self-care, and the fluidity of VA services.

Muscle transcriptional networks linked to resistance exercise training hypertrophic response heterogeneity.

The skeletal muscle hypertrophic response to resistance exercise training (RT) is highly variable across individuals. The molecular underpinnings of this heterogeneity are unclear. This study investigated transcriptional networks linked to RT-induced muscle hypertrophy, classified as 1) predictive of hypertrophy, 2) responsive to RT independent of muscle hypertrophy, or 3) plastic with hypertrophy. Older adults (n = 31, 18 F/13 M, 70 ± 4 yr) underwent 14-wk RT (3 days/wk, alternating high-low-high intensity). Muscle hypertrophy was assessed by pre- to post-RT change in mid-thigh muscle cross-sectional area (CSA) [computed tomography (CT), primary outcome] and thigh lean mass [dual-energy X-ray absorptiometry (DXA), secondary outcome]. Transcriptome-wide poly-A RNA-seq was performed on vastus lateralis tissue collected pre- (n = 31) and post-RT (n = 22). Prediction networks (using only baseline RNA-seq) were identified by weighted gene correlation network analysis (WGCNA). To identify Plasticity networks, WGCNA change indices for paired samples were calculated and correlated to changes in muscle size outcomes. Pathway-level information extractor (PLIER) was applied to identify Response networks and link genes to biological annotation. Prediction networks (n = 6) confirmed transcripts previously connected to resistance/aerobic training adaptations in the MetaMEx database while revealing novel member genes that should fuel future research to understand the influence of baseline muscle gene expression on hypertrophy. Response networks (n = 6) indicated RT-induced increase in aerobic metabolism and reduced expression of genes associated with spliceosome biology and type-I myofibers. A single exploratory Plasticity network was identified. Findings support that interindividual differences in baseline gene expression may contribute more than RT-induced changes in gene networks to muscle hypertrophic response heterogeneity. Code/Data: https://github.com/kallavin/MASTERS_manuscript/tree/master.

Unprecedented reduction in air pollution and corresponding short-term premature mortality associated with COVID-19 lockdown in Delhi, India.

Countries around the world introduced strict restrictions on movement and activities known as 'lockdowns' to restrict the spread of the novel coronavirus disease (COVID-19) from the end of 2019. A sudden improvement in air quality was observed globally as a result of these lockdowns. To provide insight into the changes in air pollution levels in response to the COVID-19 restrictions we have compared surface air quality data in Delhi during four phases of lockdown and the first phase of the restriction easing period (25 March to 30 June 2020) with data from a baseline period (2018-2019). Simultaneously, short-term exposure of PM2.5 and O3 attributed premature mortality were calculated to understand the health benefit of the change in air quality. Ground-level observations in Delhi showed that concentrations of PM10, PM2.5 and NO2 dropped substantially in 2020 during the overall study period compared with the same period in previous years, with average reductions of ~49%, ~39%, and ~39%, respectively. An overall lower reduction in O3 of ~19% was observed for Delhi. A slight increase in O3 was found in Delhi's industrial and traffic regions. The highest peak of the diurnal variation decreased substantially for all the pollutants at every phase. The decrease in PM2.5 and O3 concentrations in 2020, prevented 904 total premature deaths, a 60% improvement when compared to the figures for 2018-2019. The restrictions on human activities during the lockdown have reduced anthropogenic emissions and subsequently improved air quality and human health in one of the most polluted cities in the world.Implications: I am submitting herewith the manuscript entitled "Unprecedented Reduction in Air Pollution and Corresponding Short-term Premature Mortality Associated with COVID-19 Forced Confinement in Delhi, India" for potential publishing in your journal.The novelty of this research lies in: (1) we utilized ground-level air quality data in Delhi during four phases of lockdown and the first phase of unlocking period (25th March to 30th June) for 2020 as well as data from the baseline period (2018-2019) to provide an early insight into the changes in air pollution levels in response to the COVID-19 pandemic, (2) Chatarize the change of diurnal variation of the pollutants and (3) we assess the health risk due to PM2.5 and O3. Results from ground-level observations in Delhi showed that concentrations of PM10, PM2.5 and NO2 substantially dropped in 2020 during the overall study period compared to the similar period in previous years, with an average reduction of ~49%, ~39%, and ~39%, respectively. In the case of O3, the overall reduction was observed as ~19% in Delhi, while a slight increase was found in industrial and traffic regions. And consequently, the highest peak of the diurnal variation decreased substantially for all the pollutants. The health impact assessment of the changes in air quality indicated that 904 short-term premature deaths (~60%) were prevented due to the decline in PM2.5 and O3 concentrations in the study period. The restrictions on human activities during the lockdown have reduced the anthropogenic emissions and subsequently improved air quality and human health in one of the most polluted cities in the world.

Pelargonium sidoides root extract for the treatment of acute cough due to lower respiratory tract infection in adults: a feasibility double-blind, placebo-controlled randomised trial.

BACKGROUND: Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or "Kaloba®", is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries. STUDY DESIGN: Feasibility double-blind randomised placebo-controlled clinical trial. METHODS: We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2-4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial. RESULTS: Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18-21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex. CONCLUSIONS: It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition. TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .

Exploring regional differences in cyclist safety at roundabouts: A comparative study between the UK (based on Northumbria data) and Belgium.

The level of safety for cyclists at roundabouts may vary according to national differences not only in the design itself but also sociodemographic, cyclist and driver behaviour as well as environmental factors. This paper investigates the national influence on cyclist casualty severity at roundabouts by comparing the United Kingdom (using Northumbria as a representative sample) and Belgium. The data included speed limits, socio-demographic characteristics, environmental conditions and driver/cyclist behaviour-related contributory factors. First, a logistic regression analysis for the UK data, including 864 cyclist casualties, was carried out. Increasing the speed limit by ten units (for example 30mph to 40mph) increased the probability of a cyclist being killed or seriously injured by 10%. A cyclist casualty was more than three times more likely to be killed or seriously injured (the odds ratio is 3.02) where sudden braking was recorded as a contributory factor. Second, a separate logistic regression analysis for Belgium was conducted. Cyclists ignoring the priority at roundabouts increased the probability of a fatal or seriously injured collisions (the odds ratio is 2.71). Comparing the individual analysis for both countries, the influence of cyclist age was consistent. Each one-year increase in cyclist age increases chance of being killed or seriously injured as opposed to not being killed or seriously injured by 2 % (odds ratio is 1.02) in both UK and Belgium. A final comparative analysis was applied considering proxy variables for both countries. Three-way chi-square tests of independence showed that all non-behavioural variables (i.e. sociodemographic characteristics, speed limit, and environmental conditions) were found to be statistically different between UK and Belgium for both slight and killed and seriously injured casualties. This suggests that driver/cyclist interaction and behaviour in the two countries is generally similar whilst speed limits, the sociodemographic characteristics of cyclists and environmental conditions are specific for each country. The third part of the logistic regression analysis suggested that the country residual was highly statistically significant. This indicates that there are some statistically significant differences with respect to the characteristics of the two regional datasets used in the analysis.

Herbal medicine for acute bronchitis: A qualitative interview study of patients' and health professionals' views.

BACKGROUND: Antibiotics are widely prescribed for acute bronchitis in the UK. Herbal medicine could be used instead to provide symptom relief. AIM: To explore the views of patients and health professionals on using herbal medicine for acute bronchitis instead of antibiotics. DESIGN AND SETTING: This was a nested qualitative study, conducted alongside a feasibility randomised clinical trial which ran from July 2018 to May 2019 in 20 GP practices in Wessex, UK. METHOD: We conducted telephone semi-structured interviews with patients and with health professionals. The interview data were transcribed and analysed thematically. RESULTS: Overall, 40 interviews were conducted with 29 patients, six GPs and five nurses. While some patients believed antibiotics are more effective, most were aware of resistance and were keen to try an alternative, including herbal medicine. Several patients believed herbals would be "less intrusive" than antibiotics, whereas a few disliked the taste or experienced side-effects after taking a herbal. Professionals were concerned about potential interactions with conventional medicines. Many patients trusted herbals because of their long history of use, while some did not understand them. Availability of herbals without a prescription enables patients to use them for self-care, but their cost was a barrier for some. Many patients were willing to take a herbal if advised by their GP. Most GPs were happy to recommend a herbal, if endorsed by evidence-based guidelines. CONCLUSION: Many patients and health professionals would consider using herbal medicine for acute bronchitis, if based on trustworthy advice and evidence-based guidelines respectively.

REDUCE (Reviewing long-term antidepressant use by careful monitoring in everyday practice) internet and telephone support to people coming off long-term antidepressants: protocol for a randomised controlled trial.

BACKGROUND: Around one in ten adults take antidepressants for depression in England, and their long-term use is increasing. Some need them to prevent relapse, but 30-50% could possibly stop them without relapsing and avoid adverse effects and complications of long-term use. However, stopping is not always easy due to withdrawal symptoms and a fear of relapse of depression. When general practitioners review patients on long-term antidepressants and recommend to those who are suitable to stop the medication, only 6-8% are able to stop. The Reviewing long-term antidepressant use by careful monitoring in everyday practice (REDUCE) research programme aims to identify safe and cost-effective ways of helping patients taking long-term antidepressants taper off treatment when appropriate. METHODS: Design: REDUCE is a two-arm, 1:1 parallel group randomised controlled trial, with randomisation clustered by participating family practices. SETTING: England and north Wales. POPULATION: patients taking antidepressants for longer than 1 year for a first episode of depression or longer than 2 years for repeated episodes of depression who are no longer depressed and want to try to taper off their antidepressant use. INTERVENTION: provision of 'ADvisor' internet programmes to general practitioners or nurse practitioners and to patients designed to support antidepressant withdrawal, plus three patient telephone calls from a psychological wellbeing practitioner. The control arm receives usual care. Blinding of patients, practitioners and researchers is not possible in an open pragmatic trial, but statistical and health economic data analysts will remain blind to allocation. OUTCOME MEASURES: the primary outcome is self-reported nine-item Patient Health Questionnaire at 6 months for depressive symptoms. SECONDARY OUTCOMES: depressive symptoms at other follow-up time points, anxiety, discontinuation of antidepressants, social functioning, wellbeing, enablement, quality of life, satisfaction, and use of health services for costs. SAMPLE SIZE: 402 patients (201 intervention and 201 controls) from 134 general practices recruited over 15-18 months, and followed-up at 3, 6, 9 and 12 months. A qualitative process evaluation will be conducted through interviews with 15-20 patients and 15-20 practitioners in each arm to explore why the interventions were effective or not, depending on the results. DISCUSSION: Helping patients reduce and stop antidepressants is often challenging for practitioners and time-consuming for very busy primary care practices. If REDUCE provides evidence showing that access to internet and telephone support enables more patients to stop treatment without increasing depression we will try to implement the intervention throughout the National Health Service, publishing practical guidance for professionals and advice for patients to follow, publicised through patient support groups. TRIAL REGISTRATION: ISRCTN:12417565. Registered on 7 October 2019.

Sex-specific effects of developmental exposure to polychlorinated biphenyls on neuroimmune and dopaminergic endpoints in adolescent rats.

Exposure to environmental contaminants early in life can have long lasting consequences for physiological function. Polychlorinated biphenyls (PCBs) are a group of ubiquitous contaminants that perturb endocrine signaling and have been associated with altered immune function in children. In this study, we examined the effects of developmental exposure to PCBs on neuroimmune responses to an inflammatory challenge during adolescence. Sprague Dawley rat dams were exposed to a PCB mixture (Aroclor 1242, 1248, 1254, 1:1:1, 20 µg/kg/day) or oil control throughout pregnancy, and adolescent male and female offspring were injected with lipopolysaccharide (LPS, 50 µg/kg, ip) or saline control prior to euthanasia. Gene expression profiling was conducted in the hypothalamus, prefrontal cortex, striatum, and midbrain. In the hypothalamus, PCBs increased expression of genes involved in neuroimmune function, including those within the nuclear factor kappa b (NF-κB) complex, independent of LPS challenge. PCB exposure also increased expression of receptors for dopamine, serotonin, and estrogen in this region. In contrast, in the prefrontal cortex, PCB exposure blunted or induced irregular neuroimmune gene expression responses to LPS challenge. Moreover, neither PCB nor LPS exposure altered expression of neurotransmitter receptors throughout the mesocorticolimbic circuit. Almost all effects were present in males but not females, in agreement with the idea that male neuroimmune cells are more sensitive to perturbation and emphasizing the importance of studying both male and female subjects. Given that altered neuroimmune signaling has been implicated in mental health and substance abuse disorders that often begin during adolescence, these results highlight neuroimmune processes as another mechanism by which early life PCBs can alter brain function later in life.

Disrupting MLV integrase:BET protein interaction biases integration into quiescent chromatin and delays but does not eliminate tumor activation in a MYC/Runx2 mouse model.

Murine leukemia virus (MLV) integrase (IN) lacking the C-terminal tail peptide (TP) loses its interaction with the host bromodomain and extraterminal (BET) proteins and displays decreased integration at promoter/enhancers and transcriptional start sites/CpG islands. MLV lacking the IN TP via an altered open reading frame was used to infect tumorigenesis mouse model (MYC/Runx2) animals to observe integration patterns and phenotypic effects, but viral passage resulted in the restoration of the IN TP through small deletions. Mice subsequently infected with an MLV IN lacking the TP coding sequence (TP-) showed an improved median survival by 15 days compared to wild type (WT) MLV infection. Recombination with polytropic endogenous retrovirus (ERV), Pmv20, was identified in seven mice displaying both fast and slow tumorigenesis, highlighting the strong selection within the mouse to maintain the full-length IN protein. Mapping the genomic locations of MLV in tumors from an infected mouse with no observed recombination with ERVs, TP-16, showed fewer integrations at TSS and CpG islands, compared to integrations observed in WT tumors. However, this mouse succumbed to the tumor in relatively rapid fashion (34 days). Analysis of the top copy number integrants in the TP-16 tumor revealed their proximity to known MLV common insertion site genes while maintaining the MLV IN TP- genotype. Furthermore, integration mapping in K562 cells revealed an insertion preference of MLV IN TP- within chromatin profile states associated with weakly transcribed heterochromatin with fewer integrations at histone marks associated with BET proteins (H3K4me1/2/3, and H3K27Ac). While MLV IN TP- showed a decreased overall rate of tumorigenesis compared to WT virus in the MYC/Runx2 model, MLV integration still occurred at regions associated with oncogenic driver genes independently from the influence of BET proteins, either stochastically or through trans-complementation by functional endogenous Gag-Pol protein.

HATRIC: a study of Pelargonium sidoides root extract EPs®7630 (Kaloba®) for the treatment of acute cough due to lower respiratory tract infection in adults-study protocol for a double blind, placebo-controlled randomised feasibility trial.

BACKGROUND: Acute lower respiratory tract infection is a common acute infection managed in primary care. The current dominant management strategy in the UK is antibiotics, despite widespread publicity regarding antimicrobial resistance and evidence that the small benefits of antibiotics do not outweigh the harms. There is a need to address the rising problem of antibiotic resistance by providing credible alternative strategies, which reduce symptom burden. There is sufficient evidence to recommend the use of Pelargonium sidoides root extract in order to warrant undertaking an independent clinical trial.We propose a feasibility study to demonstrate our ability to recruit and retain patients and conduct a placebo-controlled trial of Pelargonium sidoides extract EPs®7630 in lower respiratory tract infection where pneumonia is not suspected. Both the tablet and liquid formulations will be included. METHODS: The HATRIC trial is a double-blind randomised placebo-controlled feasibility study aiming to determine the potential to conduct a fully powered trial of Pelargonium sidoides root extract as an alternative to the inappropriate use of antibiotics for acute bronchitis in UK primary care.Primary care sites will be equally randomised to one of two formulation groups (tablet or liquid preparation). Additionally, within each site, patients will be evenly randomised to active or placebo treatment. Antibiotic consumption will be monitored during the trial, but the use of a delayed prescription strategy is encouraged. The target sample size for this study is 160 patients overall or 40 per arm, recruited from approximately 20 primary care sites. The analysis will be descriptive focusing on estimation with no formal comparison of groups taking place. DISCUSSION: If this trial demonstrates the feasibility of recruitment and delivery, we will seek funding for a fully powered placebo-controlled trial of Pelargonium sidoides root extract for the treatment of lower respiratory tract infections in primary care. TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry (ISRCTN17672884) on 16 August 2018.

Adult skeletal muscle deletion of Mitofusin 1 and 2 impedes exercise performance and training capacity.

Endurance exercise has been shown to be a positive regulator of skeletal muscle metabolic function. Changes in mitochondrial dynamics (fusion and fission) have been shown to influence mitochondrial oxidative capacity. We therefore tested whether genetic disruption of mitofusins (Mfns) affected exercise performance in adult skeletal muscle. We generated adult-inducible skeletal muscle-specific Mfn1 (iMS-Mfn1KO), Mfn2 (iMS-Mfn2KO), and Mfn1/2 (iMS-MfnDKO) knockout mice. We assessed exercise capacity by performing a treadmill time to exhaustion stress test before deletion and up to 8 wk after deletion. Analysis of either the iMS-Mfn1KO or the iMS-Mfn2KO did not reveal an effect on exercise capacity. However, analysis of iMS-MfnDKO animals revealed a progressive reduction in exercise performance. We measured individual electron transport chain (ETC) complex activity and observed a reduction in ETC activity in both the subsarcolemmal and intermyofibrillar mitochondrial fractions specifically for NADH dehydrogenase (complex I) and cytochrome- c oxidase (complex IV), which was associated with a decrease in ETC subunit expression for these complexes. We also tested whether voluntary exercise training would prevent the decrease in exercise capacity observed in iMS-MfnDKO animals ( n = 10/group). However, after 8 wk of training we did not observe any improvement in exercise capacity or ETC subunit parameters in iMS-MfnDKO animals. These data suggest that the decrease in exercise capacity observed in the iMS-MfnDKO animals is in part the result of impaired ETC subunit expression and ETC complex activity. Taken together, these results provide strong evidence that mitochondrial fusion in adult skeletal muscle is important for exercise performance. NEW & NOTEWORTHY This study is the first to utilize an adult-inducible skeletal muscle-specific knockout model for Mitofusin (Mfn)1 and Mfn2 to assess exercise capacity. Our findings reveal a progressive decrease in exercise performance with Mfn1 and Mfn2 deletion. The decrease in exercise capacity was accompanied by impaired oxidative phosphorylation specifically for complex I and complex IV. Furthermore, voluntary exercise training was unable to rescue the impairment, suggesting that normal fusion is essential for exercise-induced mitochondrial adaptations.

Cyclist casualty severity at roundabouts - To what extent do the geometric characteristics of roundabouts play a part?

INTRODUCTION: In general, priority junctions are converted into roundabouts to increase capacity and reduce vehicle accidents. However, previous research has indicated that roundabouts are dangerous for vulnerable users, especially cyclists. METHOD: This paper investigates which design factors influence cyclist casualty severity at give way (non-signalized) roundabouts with mixed traffic, using the UK STATS19 National dataset of cyclist casualties. First, the correlation matrix was generated to observe the relationship between variables. Second, dimension reduction was applied to geometric design variables in order to reduce the number of variables and generate the factors. Finally, the binary logistic regression method, with serious and slight casualties as dependent variables, was applied in three steps. The first Binary Logistic Regression Model (BLRM) included speed limit, sociodemographic, and meteorological conditions. The variables in the second BLRM consisted of geometric design variables. The third BLRM included the factors that were generated by dimension reduction. RESULTS: The correlation matrix revealed that the number of lanes on approach and half width on approach were statistically significantly correlated, while the variables, such as geometric design (entry path radius, number of arms, number of flare lanes on approach, type of roundabout and number of circulating lanes), sociodemographic (casualty gender and age), speed limit and meteorologically related factors (daylight, weather and road surface condition), did not show any statistical significance. From the dimension reduction process, two main factors were identified, including Approach Capacity (Factor 1) and Size of Roundabout (Factor 2), and they were subsequently used as independent variables in the logistic regression analysis. The subsequent BLRMs showed that a higher speed limit reduces the safety for cyclists at roundabouts. The probability of a serious casualty increases by approximately five times (odds ratio 4.97) for each additional number of lanes on approach and by 4% (odds ratio 1.04) with a higher entry path radius. It was also found that Factor 2 (Approach Capacity) increases the casualty severity (odds ratio 1.86) for cyclists at roundabouts. Practical applications: While this research studied roundabouts in the UK, the methodological approach and statistical analysis techniques are applicable to other countries and the findings are likely to be of value to decision makers worldwide.

Sex differences in effects of gestational polychlorinated biphenyl exposure on hypothalamic neuroimmune and neuromodulator systems in neonatal rats.

Polychlorinated biphenyls (PCBs) are ubiquitous in the environment and exposure to them is associated with immune, endocrine and neural dysfunction. Effects of PCBs on inflammation and immunity are best described in spleen and blood, with fewer studies on neural tissues. This is an important gap in knowledge, as molecules typically associated with neuroinflammation also serve neuromodulatory roles and interact with hormones in normal brain development. The current study used Sprague-Dawley rats to assess whether gestational PCB exposure altered hypothalamic gene expression and serum cytokine concentration in neonatal animals given an immune challenge. Dams were fed wafers containing a mixture of PCBs at an environmentally relevant dose and composition (20 µg/kg, 1:1:1 Aroclor 1242:1248:1254) or oil vehicle control throughout their pregnancy. One day old male and female offspring were treated with an inflammatory challenge (lipopolysaccharide, LPS, 50 µg/kg, sc) or saline vehicle control approximately 3.5 h prior to tissue collection. Across both basal and activated inflammatory states, PCB exposure caused greater expression of a subset of inflammatory genes in the hypothalamus and lower expression of genes involved in dopamine, serotonin, and opioid systems compared to oil controls. PCB exposure also altered reactions to inflammatory challenge: it reversed the normal decrease in Esr2 hypothalamic expression and induced an abnormal increase in IL-1b and IL-6 serum concentration in response to LPS. Many of these effects were sex specific. Given the potential long-term consequences of neuroimmune disruption, our findings demonstrate the need for further research.