Delivering effective, comprehensive, multi-exercise component cardiac rehabilitation (CR) for chronic heart failure patients in low resource settings in sub-Saharan Africa: Queen Elizabeth Central Hospital-(QECH-CR) randomised CR study, Malawi.

BACKGROUND: The delivery of Cardiac Rehabilitation (CR) and attaining evidence-based treatment goals are challenging in developing countries, such as Malawi. The aims of this study were to (i) assess the effects of exercise training/ CR programme on cardiorespiratory and functional capacity of patients with chronic heart failure (CHF), and (ii) examine the effectiveness of a novel, hybrid CR delivery using integrated supervised hospital- and home-based caregiver approaches. METHODS: A pre-registered (UMIN000045380), randomised controlled trial of CR exercise therapy in patients with CHF was conducted between September 2021 and May 2022. Sixty CHF participants were randomly assigned into a parallel design-exercise therapy (ET) (n = 30) or standard of care (n = 30) groups. Resting hemodynamics, oxygen saturation, distance walked in six-minutes (6MWD) and estimated peak oxygen consumption (VO2 peak) constituted the outcome measures. The exercise group received supervised, group, circuit-based ET once weekly within the hospital setting and prescribed home-based exercise twice weekly for 12 weeks. Participants in both arms received a group-based, health behaviour change targeted education (usual care) at baseline, 8-, 12- and 16-weeks. RESULTS: Most of the participants were female (57%) with a mean age of 51.9 ±15.7 years. Sixty-five percent (65%) were in New York Heart Association class III, mostly with preserved left ventricular ejection fraction (HFpEF) (mean Left Ventricular Ejection Fraction 52.9 ±10.6%). The 12-weeks ET led to significant reductions in resting haemodynamic measures (all P <0.05). The ET showed significantly higher improvements in the 6MWD (103.6 versus 13.9 m, p<0.001) and VO2 peak (3.0 versus 0.4 ml·kg-1·min-1, p <0.001). Significant improvements in 6MWD and VO2 peak (both p<0.001), in favour of ET, were also observed across all follow-up timepoints. CONCLUSION: This novel, randomised, hybrid ET-based CR, delivered to mainly HFpEF patients using an integrated hospital- and home-based approach effectively improved exercise tolerance, cardiorespiratory fitness capacities and reduced perceived exertion in a resource-limited setting.

Confirming the attainment of maximal oxygen uptake within special and clinical groups: A systematic review and meta-analysis of cardiopulmonary exercise test and verification phase protocols.

BACKGROUND AND AIM: A plateau in oxygen uptake ([Formula: see text]) during an incremental cardiopulmonary exercise test (CPET) to volitional exhaustion appears less likely to occur in special and clinical populations. Secondary maximal oxygen uptake ([Formula: see text]) criteria have been shown to commonly underestimate the actual [Formula: see text]. The verification phase protocol might determine the occurrence of 'true' [Formula: see text] in these populations. The primary aim of the current study was to systematically review and provide a meta-analysis on the suitability of the verification phase for confirming 'true' [Formula: see text] in special and clinical groups. Secondary aims were to explore the applicability of the verification phase according to specific participant characteristics and investigate which test protocols and procedures minimise the differences between the highest [Formula: see text] values attained in the CPET and verification phase. METHODS: Electronic databases (PubMed, Web of Science, SPORTDiscus, Scopus, and EMBASE) were searched using specific search strategies and relevant data were extracted from primary studies. Studies meeting inclusion criteria were systematically reviewed. Meta-analysis techniques were applied to quantify weighted mean differences (standard deviations) in peak [Formula: see text] from a CPET and a verification phase within study groups using random-effects models. Subgroup analyses investigated the differences in [Formula: see text] according to individual characteristics and test protocols. The methodological quality of the included primary studies was assessed using a modified Downs and Black checklist to obtain a level of evidence. Participant-level [Formula: see text] data were analysed according to the threshold criteria reported by the studies or the inherent measurement error of the metabolic analysers and displayed as Bland-Altman plots. RESULTS: Forty-three studies were included in the systematic review, whilst 30 presented quantitative information for meta-analysis. Within the 30 studies, the highest mean [Formula: see text] values attained in the CPET and verification phase protocols were similar (mean difference = -0.00 [95% confidence intervals, CI = -0.03 to 0.03] L·min-1, p = 0.87; level of evidence, LoE: strong). The specific clinical groups with sufficient primary studies to be meta-analysed showed a similar [Formula: see text] between the CPET and verification phase (p > 0.05, LoE: limited to strong). Across all 30 studies, [Formula: see text] was not affected by differences in test protocols (p > 0.05; LoE: moderate to strong). Only 23 (53.5%) of the 43 reviewed studies reported how many participants achieved a lower, equal, or higher [Formula: see text] value in the verification phase versus the CPET or reported or supplied participant-level [Formula: see text] data for this information to be obtained. The percentage of participants that achieved a lower, equal, or higher [Formula: see text] value in the verification phase was highly variable across studies (e.g. the percentage that achieved a higher [Formula: see text] in the verification phase ranged from 0% to 88.9%). CONCLUSION: Group-level verification phase data appear useful for confirming a specific CPET protocol likely elicited [Formula: see text], or a reproducible [Formula: see text], for a given special or clinical group. Participant-level data might be useful for confirming whether specific participants have likely elicited [Formula: see text], or a reproducible [Formula: see text], however, more research reporting participant-level data is required before evidence-based guidelines can be given. TRIAL REGISTRATION: PROSPERO (CRD42021247658) https://www.crd.york.ac.uk/prospero.

Intensive support does not improve positive-airway pressure use in spinal cord injury/disease: a randomized clinical trial.

STUDY OBJECTIVE: Treatment of sleep-disordered breathing (SDB) with positive airway pressure (PAP) therapy has unique clinical challenges in individuals living with spinal cord injuries and diseases (spinal cord injury [SCI]/D). Interventions focused on increasing PAP use have not been studied in this population. We aimed to evaluate the benefits of a program to increase PAP use among Veterans with SCI/D and SDB. METHODS: Randomized controlled trial comparing a behavioral Intervention (n = 32) and educational control (n = 31), both including one face-to-face and five telephone sessions over 3 months. The intervention included education about SDB and PAP, goal setting, troubleshooting, and motivational enhancement. The control arm included non-directive sleep education only. RESULTS: Primary outcomes were objective PAP use (nights ≥4 hours used within 90 days) and sleep quality (Pittsburgh Sleep Quality Index [PSQI] at 3 months). These did not differ between intervention and control (main outcome timepoint; mean difference 3.5 [-9.0, 15.9] nights/week for PAP use; p = .578; -1.1 [-2.8, 0.6] points for PSQI; p = .219). Secondary outcomes included fatigue, depression, function, and quality of life. Only fatigue improved significantly more in the intervention versus the control group (p = .025). Across groups, more PAP use was associated with larger improvements in sleep quality, insomnia, sleepiness, fatigue, and depression at some time points. CONCLUSIONS: PAP use in Veterans with SCI/D and SDB is low, and a 3-month supportive/behavioral program did not show significant benefit compared to education alone. Overall, more PAP use was associated with improved symptoms suggesting more intensive support, such as in-home assistance, may be required to increase PAP use in these patients. CLINICAL TRIALS INFORMATION: Title: "Treatment of Sleep Disordered Breathing in Patients with SCI." Registration number: NCT02830074. Website: https://clinicaltrials.gov/study/NCT02830074?cond=Sleep%20Apnea&term=badr&rank=5.

Food & You: A digital cohort on personalized nutrition.

Nutrition is a key contributor to health. Recently, several studies have identified associations between factors such as microbiota composition and health-related responses to dietary intake, raising the potential of personalized nutritional recommendations. To further our understanding of personalized nutrition, detailed individual data must be collected from participants in their day-to-day lives. However, this is challenging in conventional studies that require clinical measurements and site visits. So-called digital or remote cohorts allow in situ data collection on a daily basis through mobile applications, online services, and wearable sensors, but they raise questions about study retention and data quality. "Food & You" is a personalized nutrition study implemented as a digital cohort in which participants track food intake, physical activity, gut microbiota, glycemia, and other data for two to four weeks. Here, we describe the study protocol, report on study completion rates, and describe the collected data, focusing on assessing their quality and reliability. Overall, the study collected data from over 1000 participants, including high-resolution data of nutritional intake of more than 46 million kcal collected from 315,126 dishes over 23,335 participant days, 1,470,030 blood glucose measurements, 49,110 survey responses, and 1,024 stool samples for gut microbiota analysis. Retention was high, with over 60% of the enrolled participants completing the study. Various data quality assessment efforts suggest the captured high-resolution nutritional data accurately reflect individual diet patterns, paving the way for digital cohorts as a typical study design for personalized nutrition.

High-intensity interval training in patients with intermittent claudication.

OBJECTIVE: Provision, uptake, adherence, and completion rates for supervised exercise programs (SEP) for intermittent claudication (IC) are low. A shorter, more time-efficient, 6-week, high-intensity interval training (HIIT) program may be an effective alternative that is more acceptable to patients and easier to deliver. The aim of this study was to determine the feasibility of HIIT for patients with IC. METHODS: A single arm proof-of-concept study, performed in secondary care, recruiting patients with IC referred to usual-care SEPs. Supervised HIIT was performed three times per week for 6 weeks. The primary outcome was feasibility and tolerability. Potential efficacy and potential safety were considered, and an integrated qualitative study was undertaken to consider acceptability. RESULTS: A total of 280 patients were screened: 165 (59%) were eligible, and 40 (25%) were recruited. The majority (n = 31; 78%) of participants completed the HIIT program. The remaining nine patients were withdrawn or chose to withdraw. Completers attended 99% of training sessions, completed 85% of sessions in full, and performed 84% of completed intervals at the required intensity. There were no related serious adverse events. Maximum walking distance (+94 m; 95% confidence interval, 66.6-120.8 m) and the SF-36 physical component summary (+2.2; 95% confidence interval, 0.3-4.1) were improved following completion of the program. CONCLUSIONS: Uptake to HIIT was comparable to SEPs in patients with IC, but completion rates were higher. HIIT appears feasible, tolerable, and potentially safe and beneficial for patients with IC. It may provide a more readily deliverable, acceptable form of SEP. Research comparing HIIT with usual-care SEPs appears warranted.

Serum transthyretin and aminotransferases are associated with lean mass in people with coronary heart disease: Further insights from the CARE-CR study.

Background: Low muscle mass disproportionately affects people with coronary heart disease compared to healthy controls but is under-researched and insufficiently treated. Inflammation, poor nutrition, and neural decline might contribute to low muscle mass. This study aimed to assess circulatory biomarkers related to these mechanisms [albumin, transthyretin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and C-terminal agrin fragment] and their relationship with muscle mass in people with coronary heart disease. Our findings could be beneficial to indicate mechanisms of sarcopenia, detect sarcopenia, and evaluate treatment. Methods: Serum blood samples from people with coronary heart disease were analysed for biomarker concentrations using enzyme-linked immunosorbent assays. Skeletal muscle mass was estimated using dual X-ray absorptiometry derived appendicular lean mass and reported as skeletal muscle index (SMI; kg m-2), and as a proportion of total body mass [appendicular skeletal mass (ASM%)]. Low muscle mass was defined as a SMI <7.0 and <6.0 kg m-2, or ASM% <25.72 and <19.43% for men and women, respectively. Associations between biomarkers and lean mass were adjusted for age and inflammation. Results: Sixty-four people were assessed; 14 (21.9%) had low muscle mass. People with low muscle mass had lower transthyretin (effect size 0.34, p = 0.007), ALT (effect size 0.34, p = 0.008), and AST (effect size 0.26, p = 0.037) concentrations, compared to those with normal muscle mass. SMI was associated with inflammation-corrected ALT (r = 0.261, p = 0.039) and with inflammation- and age-adjusted AST/ALT ratio (r = -0.257, p = 0.044). Albumin and C-terminal agrin fragment were not associated with muscle mass indices. Conclusion: Circulatory transthyretin, ALT and AST were associated with low muscle mass in people with coronary heart disease. Low concentrations of these biomarkers might indicate that low muscle mass is partially explained by poor nutrition and high inflammation in this cohort. Targeted treatments to address these factors could be considered for people with coronary heart disease.

Insomnia severity predicts depression, anxiety, and posttraumatic stress disorder in veterans with spinal cord injury or disease: a cross-sectional observational study.

STUDY OBJECTIVES: To assess the association of insomnia symptoms and psychiatric symptoms in patients with spinal cord injury or disease (SCI/D). METHODS: In this cross-sectional observational study, veterans with SCI/D (n = 72; mean = 59.85 ± 10.4 years; 92% male) completed baseline measures, including the Insomnia Severity Index (ISI) during the baseline phase of a clinical trial on treatment of sleep disorders in veterans with SCI/D. Depression severity was measured by the Patient Health Questionnaire (PHQ-9; sleep items excluded), anxiety severity was measured by the Generalized Anxiety Disorder screener (GAD-7), and probable posttraumatic stress disorder (PTSD) was measured by the Primary Care PTSD screener. Blocked regression was used to evaluate the impact of insomnia symptoms (ISI) on mental health measures after accounting for demographics and level of spinal cord injury/disease. RESULTS: On average, participants scored in the mild range for depression (PHQ-9 = 7.4 ± 5.9) and anxiety severity (GAD-7 = 6.1 ± 6.1). In total, 36.1% (n = 26) screened positive for probable PTSD. ISI explained 19% of the variance in PHQ-9 and 20% of the variance in GAD-7 (P < .001) over and above demographics and SCI/D level of injury/disease. Odds of probable PTSD were increased 1.22-fold for each 1 unit increase in ISI (P = .001) after accounting for demographics and level of injury/disease. CONCLUSIONS: In veterans with SCI/D, insomnia severity was linked to depression and anxiety symptom severity and risk of PTSD. Study results warrant further research to evaluate the impact of insomnia treatment on depression, anxiety, and PTSD in patients with SCI/D. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Treatment of Sleep-disordered Breathing in Patients With SCI; URL: https://clinicaltrials.gov/ct2/show/NCT02830074; Identifier: NCT02830074. CITATION: Kelly MR, Zeineddine S, Mitchell MN, et al. Insomnia severity predicts depression, anxiety, and posttraumatic stress disorder in veterans with spinal cord injury or disease: a cross-sectional observational study. J Clin Sleep Med. 2023;19(4):695-701.

Intensive hands-on microsurgery course provides a solid foundation for performing clinical microvascular surgery.

PURPOSE: Microvascular surgery requires highly specialized and individualized training; most surgical residency training programs are not equipped with microsurgery teaching expertise and/or facilities. The aim of this manuscript was to describe the methodology and clinical effectiveness of an international microsurgery course, currently taught year-round in eight countries. METHODS: In the 5-day microsurgery course trainees perform arterial and venous end-to-end, end-to-side, one-way-up, and continuous suture anastomoses and vein graft techniques in live animals, supported by video demonstrations and hands-on guidance by a full-time instructor. To assess and monitor each trainee's progress, the course's effectiveness is evaluated using "in-course" evaluations, and participant satisfaction and clinical relevance are assessed using a "post-course" survey. RESULTS: Between 2007 and 2017, more than 600 trainees participated in the microsurgery course. "In-course" evaluations of patency rates revealed 80.3% (arterial) and 39% (venous) performed in end-to-end, 82.7% in end-to-side, 72.6% in continuous suture, and 89.5% (arterial) and 62.5% (venous) one-way-up anastomoses, and 58.1% in vein graft technique. "Post-course" survey results indicated that participants considered the most important components of the microcourse to be "practicing on live animals", followed by "the presence of a full-time instructor". In addition, almost all respondents indicated that they were more confident performing clinical microsurgery cases after completing the course. CONCLUSIONS: Microvascular surgery requires highly specialized and individualized training to achieve the competences required to perform and master the delicate fine motor skills necessary to successfully handle and anastomose very small and delicate microvascular structures. The ever-expanding clinical applications of microvascular procedures has led to an increased demand for training opportunities. By teaching time-tested basic motor skills that form the foundation of microsurgical technique this international microsurgery-teaching course is helping to meet this demand.

A novel broad spectrum venom metalloproteinase autoinhibitor in the rattlesnake Crotalus atrox evolved via a shift in paralog function.

The complexity of snake venom composition reflects adaptation to the diversity of prey and may be driven at times by a coevolutionary arms race between snakes and venom-resistant prey. However, many snakes are also resistant to their own venom due to serum-borne inhibitors of venom toxins, which raises the question of how snake autoinhibitors maintain their efficacy as venom proteins evolve. To investigate this potential three-way arms race among venom, prey, and autoinhibitors, we have identified and traced the evolutionary origin of serum inhibitors of snake venom metalloproteinases (SVMPs) in the Western Diamondback rattlesnake Crotalus atrox which possesses the largest known battery of SVMP genes among crotalids examined. We found that C. atrox expresses five members of a Fetuin A-related metalloproteinase inhibitor family but that one family member, FETUA-3, is the major SVMP inhibitor that binds to approximately 20 different C. atrox SVMPs and inhibits activities of all three SVMP classes. We show that the fetua-3 gene arose deep within crotalid evolution before the origin of New World species but, surprisingly, fetua-3 belongs to a different paralog group than previously identified SVMP inhibitors in Asian and South American crotalids. Conversely, the C. atrox FETUA-2 ortholog of previously characterized crotalid SVMP inhibitors shows limited activity against C. atrox SVMPs. These results reveal that there has been a functional evolutionary shift in the major SVMP inhibitor in the C. atrox lineage as the SVMP family expanded and diversified in the Crotalus lineage. This broad-spectrum inhibitor may be of potential therapeutic interest.

Tetraplegia is associated with increased hypoxic ventilatory response during nonrapid eye movement sleep.

People with cervical spinal cord injury (SCI) are likely to experience chronic intermittent hypoxia while sleeping. The physiological effects of intermittent hypoxia on the respiratory system during spontaneous sleep in individuals with chronic cervical SCI are unknown. We hypothesized that individuals with cervical SCI would demonstrate higher short- and long-term ventilatory responses to acute intermittent hypoxia (AIH) exposure than individuals with thoracic SCI during sleep. Twenty participants (10 with cervical SCI [9 male] and 10 with thoracic SCI [6 male]) underwent an AIH and sham protocol during sleep. During the AIH protocol, each participant experienced 15 episodes of isocapnic hypoxia using mixed gases of 100% nitrogen (N2 ) and 40% carbon dioxide (CO2 ) to achieve an oxygen saturation of less than 90%. This was followed by two breaths of 100% oxygen (O2 ). Measurements were collected before, during, and 40 min after the AIH protocol to obtain ventilatory data. During the sham protocol, participants breathed room air for the same amount of time that elapsed during the AIH protocol and at approximately the same time of night. Hypoxic ventilatory response (HVR) during the AIH protocol was significantly higher in participants with cervical SCI than those with thoracic SCI. There was no significant difference in minute ventilation (V.E. ), tidal volume (V.T. ), or respiratory frequency (f) during the recovery period after AIH in cervical SCI compared to thoracic SCI groups. Individuals with cervical SCI demonstrated a significant short-term increase in HVR compared to thoracic SCI. However, there was no evidence of ventilatory long-term facilitation following AIH in either group.

Metabolic risk is associated with sociodemographic characteristics in adolescents from both rural and urban regions from southern Brazil.

BACKGROUND: The prevalence of several cardiovascular metabolic disorders are increasingly cause for concern in adolescents worldwide. Given the complex interrelations between metabolic risk (MR) and sociodemographic variables, the present study aims to examine the association between the presence of MR with sociodemographic characteristics (sex, skin color, residential area, and parental socioeconomic status) in adolescents from Southern Brazil. METHODS: Cross-sectional study conducted with 1,152 adolescents (507 males) aged between 12 and 17 years. MR was assessed using a continuous score (cMetS; sum of Z-scores of the following variables: waist circumference, systolic blood pressure (SBP), glucose, high-density lipoprotein cholesterol [HDL-C, inverse], triglycerides [TG], and estimated cardiorespiratory fitness [CRF, inverse]). Poisson regression was used to examine associations between sociodemographic variables with the dichotomized cMetS and separate metabolic variables. The results were expressed with prevalence ratios (PR) and 95% confidence intervals (CI). RESULTS: The presence of MR (evaluated by the cMetS) was observed in 8.7% of adolescents. Higher MR was less prevalent among non-white adolescents (PR: 0.96; 95% CI: 0.93; 0.99). Adolescents living in rural areas had a lower prevalence of the following metabolic variables; low HDL-C (PR: 0.95; 95% CI: 0.94; 0.97), elevated TG (PR: 0.95; 95% CI: 0.92; 0.99), elevated glucose (PR: 0.96; 95% CI: 0.95; 0.98), and low CRF levels (PR: 0.88; 95% CI: 0.85; 0.92). Whereas, SBP was higher in those living in rural areas (PR: 1.11; 95% CI: 1.05; 1.17). In girls, there was a higher prevalence of raised TG (PR: 1.06; 95% CI: 1.02; 1.10) and lower levels of CRF (PR: 1.20; 95% CI: 1.16; 1.24), but a lower prevalence of elevated glucose (PR: 0.97; 95% CI: 0.97; 0.99). CONCLUSION: Higher MR prevalence was lower in those self-reporting non-white skin color and selected MR factors were less prevalent in those living in rural areas. The identification of groups at higher MR is important for early prevention and monitoring strategies for both Type 2 diabetes and later cardiovascular disease. Future studies should be conducted to assess the socio-cultural aspects of the relationships between MR and socio-cultural and lifestyle variables.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

Although midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

Moderating Role of Physical Fitness in the Association Between TV Time and Adiposity Parameters in Adolescents.

PURPOSE: To identify whether physical fitness (PF) components play a moderating role in the relationship between TV time and adiposity levels. DESIGN: Cross-sectional study. SETTING: Few studies have examined if different PF levels modify the association between TV time and adiposity in adolescents. Studies often focus on the isolated relationships between obesity and TV time, or obesity and PF levels. SUBJECTS: 1071 adolescents (617 girls), aged 12 to 17 years. MEASURES: Cardiorespiratory fitness (CRF), abdominal muscular endurance, and lower limb strength were evaluated using the protocols of the Projeto Esporte Brasil fitness testing battery. TV time was obtained using a self-reported questionnaire. Body mass index (BMI) and waist circumference (WC) were also assessed. Moderation analyses were conducted through multiple linear regression models with the following associations tested in different models: PF components, TV time, and interaction (PF component x TV time) with adiposity parameters (BMI and WC). RESULTS: A significant interaction term was found for CRF and TV time in the association with both WC (ß: -.005; 95% CI: -.009; -.001; P = .012) and BMI (ß: -.002; 95% CI: -.004; -.001; P = .009). CONCLUSION: CRF moderates the relationship between TV time and adiposity measures in this cross-sectional analysis. These data support strategies looking at increasing physical activity levels to improve CRF and avoid the development of excess abdominal obesity and excess weight.

Randomized Mechlorethamine/Chlormethine Induced Dermatitis Assessment Study (MIDAS) Establishes Benefit of Topical Triamcinolone 0.1% Ointment Cotreatment in Mycosis Fungoides.

INTRODUCTION: Treatment of early-stage mycosis fungoides (MF) requires safe, skin-directed therapies. Medication side effects can lead to underutilization of effective therapies. The objective of this study was to assess the use of topical triamcinolone 0.1% ointment as a means of reducing contact dermatitis associated with topical mechlorethamine/chlormethine gel for the treatment of MF. METHODS: This prospective, randomized, open-label study evaluated 28 adults with mycosis fungoides who were eligible for treatment with topical mechlorethamine/chlormethine gel from December 17, 2017 to December 23, 2020. Patients were treated for 4 months with clinical follow-up through 12 months. Patients had half of their lesions also treated with topical triamcinolone 0.1% ointment (while the other half were treated with mechlorethamine/chlormethine alone). The study was self-controlled with separate lesions in the same patient receiving each treatment arm. Treatment arms were determined by the flip of a coin. RESULTS: Twenty-eight patients enrolled (17 men (61%) and 11 women (39%)). Demographics included 25 White, 2 African Americans, and 1 Asian patient. Twenty-five completed the 12-month follow-up. Triamcinolone 0.1% ointment led to increased tolerability of mechlorethamine/chlormethine gel but did not change the efficacy of mechlorethamine/chlormethine. There was a statistically significant 50% decrease in dermatitis (SCORD score) at month 2 in the triamcinolone-treated arm. CONCLUSIONS: Topical triamcinolone ointment is a helpful adjuvant therapy when treating patients with topical mechlorethamine/chlormethine gel. It diminishes inflammation and does not reduce efficacy. The peak incidence of dermatitis in the study occurred in the second and third months. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03380026.

Outcomes following coronary artery bypass surgery in diabetic treatment sub-groups. A propensity matched analysis of >7000 patients over 18 years.

BACKGROUND: European System for Cardiac Operative Risk Evaluation II incorporates insulin-controlled diabetes whilst omitting tablet-controlled diabetes. Differences in adverse clinical outcomes following coronary artery bypass graft between these groups are poorly established. Therefore, a propensity matched comparison of short and longer term mortality and morbidity in insulin-controlled diabetes, tablet-controlled diabetes and non-diabetic patients was undertaken. METHODS: Isolated first-time coronary artery bypass graft surgeries between April 1999 and April 2017 were propensity score matched by pre- and intra-operative variables. RESULTS: 8241 patients; 23.5% diabetics and 76.5% non-diabetics. The groups' demographical and clinical characteristics were comparable after matching. Insulin-controlled diabetes patients had significantly higher in-hospital mortality (3.8% vs. 1.7%, p < 0.05), multisystem failure (2.6% vs. 1.8%, p < 0.05), sternal wound infections requiring debridement (3.6% vs. 1.3%, p < 0.05), respiratory complications (25.6% vs. 21.9%, p < 0.05), new dialysis (4.7% vs. 0.9%, p < 0.05) and longer hospital stays (13.5 ± 13.3 vs. 10.6 ± 8.0, p < 0.05) compared to non-diabetic patients.Tablet-controlled diabetes patients had significantly higher strokes (2.9% vs. 1.2, p < 0.05), superficial sternal wound infections (6.7% vs. 5.4%, p < 0.05), respiratory complications (25.7% vs. 22.7%, p < 0.05), new dialysis (1.7% vs. 0.6%, p < 0.05), post-operative atrial fibrillation (37.1% vs. 33.9%, p < 0.05) and readmission with myocardial infarction (22.4% vs. 19.6%, p < 0.05) compared to non-diabetic patients. CONCLUSION: Diabetic treatment sub-groups are an independent risk factor for sternal wound infection, new dialysis requirement, multisystem failure and readmission with myocardial infarction after isolated first coronary artery bypass graft surgery. The findings suggest the need for better risk stratification of diabetic groups prior to cardiac surgery and for improved cardiovascular risk management post-surgery in tablet-controlled diabetes patients.

Love is in the hair: arginine methylation of human hair proteins as novel cardiovascular biomarkers.

Cardiovascular disease is the major cause of death worldwide. Extensive cardiovascular biomarkers are available using blood tests but very few, if any, investigations have described non-invasive tests for cardiovascular biomarkers based on readily available hair samples. Here we show, first, that human hair proteins are post-translationally modified by arginine methylation (ArgMe). Using western blot, proteomic data mining and mass spectrometry, we identify several ArgMe events in hair proteins and we show that keratin-83 is extensively modified by ArgMe in the human hair. Second, using a preliminary cohort (n = 18) of heterogenous healthy donors, we show that the levels of protein ArgMe in hair correlate with serum concentrations of a well-established cardiovascular biomarker, asymmetric dimethylarginine (ADMA). Compared to blood collection, hair sampling is cheaper, simpler, requires minimal training and carries less health and safety and ethical risks. For these reasons, developing the potential of hair protein ArgMe as clinically useful cardiovascular biomarkers through further research could be useful in future prevention and diagnosis of cardiovascular disease.

Translating Psychedelic Therapies From Clinical Trials to Community Clinics: Building Bridges and Addressing Potential Challenges Ahead.

Research exploring the potential of psychedelic-assisted therapies to treat a range of mental illnesses is flourishing, after the problematic sociopolitical history of psychedelics led to the shutdown of clinical research for almost 40 years. Encouraged by positive results, clinicians and patients are now hopeful that further interruptions to research will be avoided, so that the early promise of these therapies might be fulfilled. At this early stage of renewed interest, researchers are understandably focusing more on clinical trials to investigate safety and efficacy, than on longer-term goals such as progression to community practice. Looking to identify and avoid potential pitfalls on the path to community clinics, the authors, a group of Australian clinicians and researchers, met to discuss possible obstacles. Five broad categories of challenge were identified: 1) inherent risks; 2) poor clinical practice; 3) inadequate infrastructure; 4) problematic perceptions; and 5) divisive relationships and fractionation of the field. Our analysis led us to propose some strategies, including public sector support of research and training to establish best practice and optimize translation, and funding to address issues of equitable access to treatment. Above all, we believe that strategic planning and professional cohesion will be crucial for success. Accordingly, our key recommendation is the establishment of a multidisciplinary advisory body, broadly endorsed and representing all major stakeholders, to guide policy and implementation of psychedelic-assisted therapies in Australia. Although these challenges and strategies are framed within the Australian context, we sense that they may generalize to other parts of the world. Wherever they apply, we believe that anticipation of potential difficulties, and creative responses to address them, will be important to avoid roadblocks in the future and keep the "psychedelic renaissance" on track.

FTO gene polymorphism and longitudinal changes in nutritional/obesity status in children and adolescents: Schoolchildren's health cohort study.

The fat mass and obesity-associated gene (FTO) has been extensively reported in the literature related to nutritional status, but there has been limited description of the genetic contribution to obesity risk during childhood and adolescence, especially in Latin Americans. This study aims to associate the rs9939609 polymorphism, of the FTO gene, with changes in nutritional status in Brazilian schoolchildren followed for 3 years. A longitudinal study was conducted with 355 schoolchildren, aged 7-15 years in 2011/2012 and subsequently re-evaluated in 2014/2015. Nutritional (obesity) status was classified by identifying those exceeding recommended thresholds for waist circumference (WC), waist-to-height ratio (WHtR), body mass index (BMI), and body fat percentage (BF%). The rs9939609 polymorphism was genotyped by a real-time polymerase chain reaction. Relative risk (RR with 95% confidence interval) of obesity status by FTO gene polymorphism was calculated by Poisson regression. The risk group was determined for genotypes with the allele A polymorphism, and regression models were adjusted for age, sex, height, ethnicity, and geographical location. Considering the longitudinal changes in status over the 3-year follow-up, the RR of developing a WC exceeding the threshold recommended (WC >75th age and sex-standardized percentile), or remaining with this condition, was higher in children with AT/AA genotype. For WC, the RR was 1.66 (1.07; 2.58) in crude analysis and 1.17 (1.01; 1.35) following adjustment for age (years), gender, ethnicity, and geographical location. The comparative risk of abdominal obesity, assessed by WHtR (not recommended threshold ≥0.50), was 53% and 8%, respectively, higher in AT/AA compared to TT genotype.Conclusion: This is one of the first longitudinal investigations to show a significant association between the A allele of the rs9939609 polymorphism and individuals with higher than recommended WC and WHtR measures in Brazilian children and adolescents. What is known: • The FTO has an effect on increases in body mass index (BMI) among children and adolescents. • It established the association between FTO and overweight/obesity in Caucasians. What is new: • The presence of the risk allele of rs9939609 (FTO gene) polymorphism is associated with increased abdominal fat in Brazilian schoolchildren. • Was detected an association between FTO gene polymorphism (rs9939609) with WC in follow-up cohort and changes in WC and WHtR follow-up over 3 years, during childhood and adolescence growth.

Is a verification phase useful for confirming maximal oxygen uptake in apparently healthy adults? A systematic review and meta-analysis.

BACKGROUND: The 'verification phase' has emerged as a supplementary procedure to traditional maximal oxygen uptake (VO2max) criteria to confirm that the highest possible VO2 has been attained during a cardiopulmonary exercise test (CPET). OBJECTIVE: To compare the highest VO2 responses observed in different verification phase procedures with their preceding CPET for confirmation that VO2max was likely attained. METHODS: MEDLINE (accessed through PubMed), Web of Science, SPORTDiscus, and Cochrane (accessed through Wiley) were searched for relevant studies that involved apparently healthy adults, VO2max determination by indirect calorimetry, and a CPET on a cycle ergometer or treadmill that incorporated an appended verification phase. RevMan 5.3 software was used to analyze the pooled effect of the CPET and verification phase on the highest mean VO2. Meta-analysis effect size calculations incorporated random-effects assumptions due to the diversity of experimental protocols employed. I2 was calculated to determine the heterogeneity of VO2 responses, and a funnel plot was used to check the risk of bias, within the mean VO2 responses from the primary studies. Subgroup analyses were used to test the moderator effects of sex, cardiorespiratory fitness, exercise modality, CPET protocol, and verification phase protocol. RESULTS: Eighty studies were included in the systematic review (total sample of 1,680 participants; 473 women; age 19-68 yr.; VO2max 3.3 ± 1.4 L/min or 46.9 ± 12.1 mL·kg-1·min-1). The highest mean VO2 values attained in the CPET and verification phase were similar in the 54 studies that were meta-analyzed (mean difference = 0.03 [95% CI = -0.01 to 0.06] L/min, P = 0.15). Furthermore, the difference between the CPET and verification phase was not affected by any of the potential moderators such as verification phase intensity (P = 0.11), type of recovery utilized (P = 0.36), VO2max verification criterion adoption (P = 0.29), same or alternate day verification procedure (P = 0.21), verification-phase duration (P = 0.35), or even according to sex, cardiorespiratory fitness level, exercise modality, and CPET protocol (P = 0.18 to P = 0.71). The funnel plot indicated that there was no significant publication bias. CONCLUSIONS: The verification phase seems a robust procedure to confirm that the highest possible VO2 has been attained during a ramp or continuous step-incremented CPET. However, given the high concordance between the highest mean VO2 achieved in the CPET and verification phase, findings from the current study would question its necessity in all testing circumstances. PROSPERO REGISTRATION ID: CRD42019123540.

Ratings of perceived exertion at the ventilatory anaerobic threshold in people with coronary heart disease: A CARE CR study.

BACKGROUND: Exercise prescription guidelines for individuals undergoing cardiovascular rehabilitation (CR) are often based on heart rate training zones and rating of perceived exertion (RPE). United Kingdom guidelines indicate that patients should exercise at an intensity of RPE 11 to 14. OBJECTIVES: We aimed to determine the accuracy of this approach by comparing this RPE range with an objectively measured marker of exercise intensity, the ventilatory anaerobic threshold (VAT), and examine whether baseline directly determined cardiorespiratory fitness (CRF) affects the association between VAT and RPE. METHODS: Participants underwent a maximal cardiopulmonary exercise test before an 8-week community-based CR programme. Peak oxygen uptake (V̇O2peak) and VAT were recorded, and RPE at the workload at which VAT was identified was recorded. Data were then split into tertiles, based on VO2peak, to determine whether RPE at the VAT differed in participants with low, moderate or higher CRF. RESULTS: We included 70 individuals [mean (SD) age 63.1 (10.0) years; body mass index 29.4 (4.0) kg/m2; 86% male]. At baseline, the mean RPE at the VAT (RPE@VAT) was 11.8 (95% confidence interval 11.0-12.6) and significantly differed between low and high CRF groups (P<0.001). The mean RPE@VAT was 10.1 (8.7-11.5), 11.8 (10.5-13.0), and 13.7 (12.5-14.9) for low, moderate and high CRF groups, respectively. CONCLUSIONS: When using RPE to guide exercise intensity in CR populations, one must consider the effect of baseline CRF. Mean RPEs of ∼10, 12 and 14 correspond to the VAT in low, moderate and higher-fit patients, respectively.