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Aims: To examine the associations of substituting sedentary behaviour (SB) for sleep, light physical activity (LPA) or moderate-to-vigorous physical activity (MVPA) with physical function and wellbeing., Methods: Cross-sectional data from 808 adults with Type 2 Diabetes Mellitus, (T2DM) were included. 24-hour behaviours were ascertained through accelerometery. Isotemporal substitution was used to estimate the theoretical substitution of SB for other 24-hour behaviours on associations with physical function and wellbeing markers., Results: Reallocating 30 min of SB to sleep was beneficially associated with 1.0% (95% CI: 0.1-1.9) higher sit-to-stand-60 (STS60) and 1.2% (0.1-2.3) Duke Activity Status Index (DASI) scores, 3.6% (1.5-5.5) lower Patient Hospital Questionnaire-9 (PHQ9) and 1.9% lower (0.1-3.7) Diabetes Distress scores. Whilst substituting SB with MVPA was associated with 3.8% (2.2-5.4) higher STS60 and 3.9% (2.0-5.9) DASI scores, and 4.7% (0.3-9.0) lower PHQ9 score. Replacing SB with LPA was associated with 4.1% (1.0-7.1) lower PHQ9 score., Conclusion: In adults with T2DM, theoretically replacing SB with sleep and physical activity, particularly MVPA is beneficially associated with markers of physical function and wellbeing. For wellbeing, associations for sleep were comparable (depression), or greater (diabetes distress), than for MVPA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Genital skin conditions are rare and pose a diagnostic challenge due to their diverse pathology. Patient anxiety and referral decisions add complexity for primary caregivers. Demographics and overlapping symptoms complicate diagnosis, causing anxiety for both patients and clinicians. Social stigma and apprehension to seek healthcare might delay treatment. Accurate differentiation between benign and potentially serious conditions is crucial., Objective: We aim to provide clinicians with a clear and concise framework to assist them in risk stratification, treatment decisions and referral pathways for common genital skin conditions., Discussion: Differentiating normal variations is crucial to minimise unnecessary investigations and alleviate patient anxiety. Circumcision status, pigmentation and genetics influence disease presentation. We highlight benign conditions for reassurance. Inflammatory genital lesions might arise from various causes. Biopsies remain essential for accurately diagnosing uncertain cases. Sexually transmitted infections (STIs) should be promptly diagnosed and treated. Neoplastic conditions can evolve rapidly, requiring an urgent specialist referral.

Aims: To explore the 5-year incidence and relative rates of sleep disorders in younger (16-≤40 years) and middle-older (=>40 years) age adults with and without newly diagnosed type 2 diabetes., Methods: This retrospective, observational cohort study utilised data from the US Collaborative Network within the TriNetX database. We compared 5-year cumulative incidence of sleep disorders in younger (n = 110,088) and middle-older populations (n = 1,185,961)., Results: The absolute risk of developing any type of sleep disorder was greater in individuals with type 2 diabetes vs. those without. Over the 5-year follow-up period, 14.2 % of younger adults and 18.5 % of middle-older age adults with newly diagnosed type 2 diabetes developed any form of sleep disorder, compared to 4.5 % and 7.9 % propensity matched individuals without diabetes. We observed a more pronounced relative rate across the observed sleep disorders in younger adults., Conclusions: The 5-year risk of sleep disorders is higher in those with newly diagnosed type 2 diabetes vs. those without. A higher absolute risk was seen in middle-older adults, but relative rates were consistently higher in younger adults with type 2 diabetes. Sleep should be regularly discussed as part of a holistic approach to diabetes care, particularly in those aged ≤40., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [TY has received research funding from AstraZeneca and Abbott. KK has served as a consultant, speaker or received research grants/support from AstraZeneca, Boehringer Ingelheim, Lilly, and Novo Nordisk. MJD has acted as consultant, advisory board member and speaker for Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Pfizer, Medtronic and ShouTi Pharma Inc and as a speaker for Napp Pharmaceuticals, Novartis and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen. The other authors have no conflicts of interest to declare]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Nighttime aircraft noise may affect people's sleep, yet large-scale evidence using objective and subjective measures remains limited., Objective: Our aim was to investigate associations between nighttime aircraft noise exposure and objectively measured sleep disturbance using a large UK cohort., Methods: We used data from 105,770 UK Biobank cohort participants exposed and unexposed to aircraft noise who lived in 44 local authority districts near 4 international airports in England. We used a generalized linear regression model to examine cross-sectional associations between aircraft noise L night (23:00 hours-07:00 hours) and 7-d actimetric measures collected 2013-2015 ( n = 22,102 ). We also used Logit and generalized estimating equations models to examine associations between L night and self-reported sleep measures at enrollment (2006-2010) and follow-up (2012-2013). This approach allowed us to compare and contrast the results and support potential future meta-analyses on noise-related sleep disturbance., Results: Cross-sectional analyses of actimetric data suggested sleep disturbance associated with L night , showing higher level of movements during the least active continuous 8-h time period [ β : 0.12 milligravitational units; 95% confidence interval (CI): 0.013, 0.23]. We also saw disrupted sleep-wake cycles as indicated by index scores of lower relative amplitude ( β : - 0.006 ; 95% CI: - 0.007 , - 0.005 ), poorer interdaily stability ( β : - 0.010 ; 95% CI: - 0.014 , - 0.006 ), and greater intradaily variability ( β : 0.021; 95% CI: 0.019, 0.023), comparing L night ≥ 55 dB with < 45 dB. Repeated cross-sectional analyses found a 52% higher odds of more frequent daytime dozing [odds ratio (OR) = 1.52 ; 95% CI: 1.32, 1.75] for L night ≥ 55 dB in comparison with < 45 dB, whereas the likelihood for more frequent sleeplessness was more uncertain ( OR = 1.13 ; 95% CI: 0.92, 1.39). Higher effect sizes were seen in preidentified vulnerable groups, including individuals > 65 y of age and those with diabetes or dementia., Conclusion: Individuals exposed to higher levels of aircraft noise experienced objectively higher levels of sleep disturbance and changes in sleep-wake cycle. https://doi.org/10.1289/EHP14156.

Background: The updated European Working Group on Sarcopenia in Older People (EWGSOP2) recommends handgrip strength (HGS) and the chair stand test (CST) to assess muscle strength, with the CST being a convenient proxy for lower limb strength. However, adiposity may differentially influence these strength criteria and produce discrepant sarcopenia prevalence., Objective: To determine the prevalence of sarcopenia using HGS or the CST, and to investigate the associations between these strength criteria and adiposity in adults with type 2 diabetes mellitus., Methods: The EWGSOP2 definition was used to assess the prevalence of probable (low muscle strength), confirmed (plus low muscle mass) and severe (plus poor physical performance) sarcopenia. Linear regression models were used to study the association between different measures of muscle strength and adiposity., Results: We used data from 732 adults with type 2 diabetes mellitus (35.7% female, aged 64 ± 8 years, body mass index 30.7 ± 5.0 kg/m2). Using the CST compared with HGS produced a higher prevalence of probable (31.7% vs. 7.1%), confirmed (5.6% vs. 1.6%) and severe (1.0% vs. 0.3%) sarcopenia, with poor agreement between strength criteria to identify probable sarcopenia. CST performance, but not HGS, was significantly associated with all measures of adiposity in unadjusted and adjusted models., Conclusions: Higher levels of adiposity may impact CST performance, but not HGS, resulting in a higher prevalence of sarcopenia in adults with type 2 diabetes mellitus. Consideration should be paid to the most appropriate measure of muscle function in this population., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Aim: To investigate how 24-h physical behaviours differ across type 2 diabetes (T2DM) subtypes., Materials and Methods: We included participants living with T2DM, enrolled as part of an ongoing observational study. Participants wore an accelerometer for 7 days to quantify physical behaviours across 24 h. We used routinely collected clinical data (age at onset of diabetes, glycated haemoglobin level, homeostatic model assessment index of beta-cell function, homeostatic model assessment index of insulin resistance, body mass index) to replicate four previously identified subtypes (insulin-deficient diabetes [INS-D], insulin-resistant diabetes [INS-R], obesity-related diabetes [OB] and age-related diabetes [AGE]), via k-means clustering. Differences in physical behaviours across the diabetes subtypes were assessed using generalized linear models, with the AGE cluster as the reference., Results: A total of 564 participants were included in this analysis (mean age 63.6 ± 8.4 years, 37.6% female, mean age at diagnosis 53.1 ± 10.0 years). The proportions in each cluster were as follows: INS-D: n = 35, 6.2%; INS-R: n = 88, 15.6%; OB: n = 166, 29.4%; and AGE: n = 275, 48.8%. Compared to the AGE cluster, the OB cluster had a shorter sleep duration (-0.3 h; 95% confidence interval [CI] -0.5, -0.1), lower sleep efficiency (-2%; 95% CI -3, -1), lower total physical activity (-2.9 mg; 95% CI -4.3, -1.6) and less time in moderate-to-vigorous physical activity (-6.6 min; 95% CI -11.4, -1.7), alongside greater sleep variability (17.9 min; 95% CI 8.2, 27.7) and longer sedentary time (31.9 min; 95% CI 10.5, 53.2). Movement intensity during the most active continuous 10 and 30 min of the day was also lower in the OB cluster., Conclusions: In individuals living with T2DM, the OB subtype had the lowest levels of physical activity and least favourable sleep profiles. Such behaviours may be suitable targets for personalized therapeutic lifestyle interventions., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

For the first time, the latest American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus guidelines have incorporated a growing body of evidence linking health outcomes associated with type 2 diabetes to the movement behavior composition over the whole 24-h day. Of particular note, the importance of sleep as a key lifestyle component in the management of type 2 diabetes is promulgated and presented using three key constructs: quantity, quality, and timing (i.e., chronotype). In this narrative review we highlight some of the key evidence justifying the inclusion of sleep in the latest consensus guidelines by examining the associations of quantity, quality, and timing of sleep with measures of glycemia, cardiovascular disease risk, and mortality. We also consider potential mechanisms implicated in the association between sleep and type 2 diabetes and provide practical advice for health care professionals about initiating conversations pertaining to sleep in clinical care. In particular, we emphasize the importance of measuring sleep in a free-living environment and provide a summary of the different methodologies and targets. In summary, although the latest ADA/EASD consensus report highlights sleep as a central component in the management of type 2 diabetes, placing it, for the first time, on a level playing field with other lifestyle behaviors (e.g., physical activity and diet), the evidence base for improving sleep (beyond sleep disorders) in those living with type 2 diabetes is limited. This review should act as a timely reminder to incorporate sleep into clinical consultations, ongoing diabetes education, and future interventions., (© 2024 by the American Diabetes Association.)

Chronotype studies investigating dietary intake, eating occasions (EO) and eating windows (EW) are sparse in people with type 2 Diabetes mellitus (T2DM). This analysis reports data from the CODEC study. The Morningness-Eveningness questionnaire (MEQ) assessed chronotype preference. Diet diaries assessed dietary intake and temporal distribution. Regression analysis assessed whether dietary intake, EW, or EO differed by chronotype. 411 participants were included in this analysis. There were no differences in energy, macronutrient intake or EW between chronotypes. Compared to evening chronotypes, morning and intermediate chronotypes consumed 36.8 (95% CI: 11.1, 62.5) and 20.9 (95% CI: -2.1, 44.1) fewer milligrams of caffeine per day, respectively. Evening chronotypes woke up over an hour and a half later than morning (01:36 95% CI: 01:09, 02:03) and over half an hour later than intermediate chronotypes (00:45 95% CI: 00:21; 01:09. Evening chronotypes went to sleep over an hour and a half later than morning (01:48 95% CI: 01:23; 02:13) and an hour later than intermediate chronotypes (01:07 95% CI: 00:45; 01:30). Evening chronotypes' EOs and last caffeine intake occurred later but relative to their sleep timings. Future research should investigate the impact of chronotype and dietary temporal distribution on glucose control to optimise T2DM interventions.

High physical activity levels during wake are beneficial for health, while high movement levels during sleep are detrimental to health. Our aim was to compare the associations of accelerometer-assessed physical activity and sleep disruption with adiposity and fitness using standardized and individualized wake and sleep windows. People (N = 609) with type 2 diabetes wore an accelerometer for up to 8 days. Waist circumference, body fat percentage, Short Physical Performance Battery (SPPB) test score, sit-to-stands, and resting heart rate were assessed. Physical activity was assessed via the average acceleration and intensity distribution (intensity gradient) over standardized (most active 16 continuous hours (M16h)) and individualized wake windows. Sleep disruption was assessed via the average acceleration over standardized (least active 8 continuous hours (L8h)) and individualized sleep windows. Average acceleration and intensity distribution during the wake window were beneficially associated with adiposity and fitness, while average acceleration during the sleep window was detrimentally associated with adiposity and fitness. Point estimates for the associations were slightly stronger for the standardized than for individualized wake/sleep windows. In conclusion, standardized wake and sleep windows may have stronger associations with health due to capturing variations in sleep durations across individuals, while individualized windows represent a purer measure of wake/sleep behaviors.

To evaluate the criterion validity of an automated sleep detection algorithm applied to data from three research-grade accelerometers worn on each wrist with concurrent laboratory-based polysomnography (PSG). A total of 30 healthy volunteers (mean [SD] age 31.5 [7.2] years, body mass index 25.5 [3.7] kg/m 2 ) wore an Axivity, GENEActiv and ActiGraph accelerometer on each wrist during a 1-night PSG assessment. Sleep estimates (sleep period time window [SPT-window], sleep duration, sleep onset and waking time, sleep efficiency, and wake after sleep onset [WASO]) were generated using the automated sleep detection algorithm within the open-source GGIR package. Agreement of sleep estimates from accelerometer data with PSG was determined using pairwise 95% equivalence tests (±10% equivalence zone), intraclass correlation coefficients (ICCs) with 95% confidence intervals and limits of agreement (LoA). Accelerometer-derived sleep estimates except for WASO were within the 10% equivalence zone of the PSG. Reliability between data from the accelerometers worn on either wrist and PSG was moderate for SPT-window duration (ICCs ≥ 0.65), sleep duration (ICCs ≥ 0.54), and sleep onset (ICCs ≥ 0.61), mostly good for waking time (ICCs ≥ 0.80), but poor for sleep efficiency (ICCs ≥ 0.08) and WASO (ICCs ≥ 0.08). The mean bias between all accelerometer-derived sleep estimates worn on either wrist and PSG were low; however, wide 95% LoA were observed for all sleep estimates, apart from waking time. The automated sleep detection algorithm applied to data from Axivity, GENEActiv and ActiGraph accelerometers, worn on either wrist, provides comparable measures to PSG for SPT-window and sleep duration, sleep onset and waking time, but a poor measure of wake during the sleep period., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Objective: To investigate the association between age at diagnosis of type 2 diabetes and depressive symptoms, diabetes-specific distress, and self-compassion among adults with type 2 diabetes., Research Design and Methods: This analysis used data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycemic Control (CODEC) cross-sectional study. Information was collected on depressive symptoms, diabetes-specific distress, and self-compassion, measured using validated self-report questionnaires, in addition to sociodemographic and clinical data. Multivariable regression models, adjusted for diabetes duration, sex, ethnicity, deprivation status, prescription of antidepressants (selective serotonin reuptake inhibitors), and BMI were used to investigate the association between age at diagnosis of type 2 diabetes and each of the three psychological outcomes., Results: A total of 706 participants were included; 64 (9.1%) were diagnosed with type 2 diabetes at <40 years, 422 (59.8%) between 40 and 59 years, and 220 (31.2%) at ≥60 years of age. After adjustment for key confounders, including diabetes duration, younger age at diagnosis was significantly associated with higher levels of depressive symptoms (βadj: -0.18 [95% CI -0.25 to -0.10]; P < 0.01) and diabetes-specific distress (βadj: -0.03 [95% CI -0.04 to -0.02]; P < 0.01) and lower levels of self-compassion (βadj: 0.01 [95% CI 0.00 to 0.02]; P < 0.01)., Conclusions: Diagnosis of type 2 diabetes at a younger age is associated with lower psychological well-being, suggesting the need for clinical vigilance and the availability of age-appropriate psychosocial support., (© 2023 by the American Diabetes Association.)

Introduction: Higher levels of physical activity are associated with lower cardiometabolic risk. However, the relative contribution of overall activity and the intensity of activity are unclear. Our aim was to determine the relative contribution of overall activity and intensity distribution of activity to cardiometabolic risk in a cross-sectional analysis of apparently healthy office workers and in people with one or more chronic disease., Methods: Clustered cardiometabolic risk score was calculated from mean arterial pressure, high-density lipoprotein cholesterol, triglycerides and HbA1c. Open-source software (GGIR) was used to generate average acceleration and intensity gradient from wrist-worn accelerometer data for two data sets: office-workers who did not have a self-reported medical condition ( n = 399, 70% women) and adults with one or more chronic disease ( n = 1137, 34% women). Multiple linear regression analyses were used to assess the relative contribution of overall activity and intensity of activity to cardiometabolic risk., Results: When mutually adjusted, both overall activity and intensity of activity were independently associated with cardiometabolic risk in the healthy group ( P < 0.05). However, for the CD group, although mutually adjusted associations for average acceleration were significantly associated with cardiometabolic risk ( P < 0.001), intensity was not. In healthy individuals, cardiometabolic risk was lower in those with high overall activity and/or intensity of activity, and who also undertook at least 10 min brisk walking. In those with a chronic disease, risk was lower in those who undertook at least 60 min slow walking., Conclusions: These findings suggest interventions aiming to optimize cardiometabolic health in healthy adults could focus on increasing both intensity and amount of physical activity. However, in those with chronic disease, increasing the amount of activity undertaken, regardless of intensity, may be more appropriate., (Copyright © 2022 by the American College of Sports Medicine.)

Introduction: Low self-compassion and poor sleep quality have been identified as potential key predictors of distress in type 2 diabetes (T2D). This study investigated relationships between sleep behaviors (sleep duration, social jetlag and daytime sleepiness), diabetes-related distress (DRD) and self-compassion in people with T2D., Research Design and Methods: This cross-sectional study used data from 467 people with T2D derived from self-report questionnaires, accelerometer-assessed sleep measures and demographic information (clinicaltrials.gov registration: NCT02973412). All participants had a diagnosis of T2D and no comorbid sleep disorder (excluding obstructive sleep apnea). Hierarchical multiple regression and mediation analysis were used to quantify relationships between self-compassion, sleep variables and DRD., Results: Significant predictors of DRD included two negative subscales of the Self-Compassion Scale (SCS), and daytime sleepiness. The 'overidentified' and 'isolation' SCS subscales were particularly important in predicting distress. Daytime sleepiness also partially mediated the influence of self-compassion on DRD, potentially through self-care around sleep., Conclusions: Daytime sleepiness and negative self-compassion have clear associations with DRD for people with T2D. The specific negative subscale outcomes suggest that strengthening individuals' ability to mindfully notice thoughts and experiences without becoming enmeshed in them, and reducing a sense of separateness and difference, might be key therapeutic targets for improving well-being in T2D. Psychological interventions should include approaches focused on reducing negative self-compassion and improving sleep behavior. Equally, reducing DRD may carry beneficial outcomes for sleep and self-compassion. Further work is however crucial to establish causation and long-term impact, and for development of relevant clinical resources., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To examine the independent associations between relative protein intake (g kg -1  day 1 ) and markers of physical function in those with type 2 diabetes, while also comparing with current guidelines for protein intake., Methods: This analysis reports data from the ongoing Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control (CODEC) study. Functional assessments included: Short Physical Performance Battery (SPPB), 60 s sit-to-stand (STS-60), 4-m gait speed, time to rise from a chair (×5) and handgrip strength. Participants also completed a self-reported 4 day diet diary. Regression analyses assessed whether relative protein intake was associated with markers of physical function. Interaction terms assessed whether the associations were modified by sex, age, HbA1c or body mass index (BMI)., Results: 413 participants were included (mean ± SD:age = 65.0 ± 7.7 years, 33% female, BMI = 30.6 ± 5.1 kg/m 2 ). The average total protein intake was 0.88 ± 0.31 g kg -1  day -1 . 33% of individuals failed to meet the reference nutrient intake for the United Kingdom (≥0.75 g kg -1  day -1 ), and 87% for European recommendations (≥1.2 g kg -1  day -1 ). After adjustment, each 0.5 g/kg of protein intake was associated with an 18.9% (95% CI: 2.3, 35.5) higher SPPB score, 22.7% (1.1, 44.3) more repetitions in STS-60, 21.1% (4.5, 37.7) faster gait speed and 33.2% (16.9, 49.5) lower chair rise time. There were no associations with handgrip strength or any interactions., Conclusions: Relative protein intake was positively associated with physical function outcomes, even after consideration of total energy intake. As a number of individuals were below the current guidelines, protein intake may be a modifiable factor of importance for people with type 2 diabetes., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: The number of individuals recovering from severe COVID-19 is increasing rapidly. However, little is known about physical behaviours that make up the 24-h cycle within these individuals. This study aimed to describe physical behaviours following hospital admission for COVID-19 at eight months post-discharge including associations with acute illness severity and ongoing symptoms., Methods: One thousand seventy-seven patients with COVID-19 discharged from hospital between March and November 2020 were recruited. Using a 14-day wear protocol, wrist-worn accelerometers were sent to participants after a five-month follow-up assessment. Acute illness severity was assessed by the WHO clinical progression scale, and the severity of ongoing symptoms was assessed using four previously reported data-driven clinical recovery clusters. Two existing control populations of office workers and individuals with type 2 diabetes were comparators., Results: Valid accelerometer data from 253 women and 462 men were included. Women engaged in a mean ± SD of 14.9 ± 14.7 min/day of moderate-to-vigorous physical activity (MVPA), with 12.1 ± 1.7 h/day spent inactive and 7.2 ± 1.1 h/day asleep. The values for men were 21.0 ± 22.3 and 12.6 ± 1.7 h /day and 6.9 ± 1.1 h/day, respectively. Over 60% of women and men did not have any days containing a 30-min bout of MVPA. Variability in sleep timing was approximately 2 h in men and women. More severe acute illness was associated with lower total activity and MVPA in recovery. The very severe recovery cluster was associated with fewer days/week containing continuous bouts of MVPA, longer total sleep time, and higher variability in sleep timing. Patients post-hospitalisation with COVID-19 had lower levels of physical activity, greater sleep variability, and lower sleep efficiency than a similarly aged cohort of office workers or those with type 2 diabetes., Conclusions: Those recovering from a hospital admission for COVID-19 have low levels of physical activity and disrupted patterns of sleep several months after discharge. Our comparative cohorts indicate that the long-term impact of COVID-19 on physical behaviours is significant., (© 2022. The Author(s).)

While limited evidence suggests that longer sleep durations can improve metabolic health in habitual short sleepers, there is no consensus on how sustained sleep extension can be achieved. A total of 18 men (mean [SD] age 41 [ 9] years), who were overweight/obese (mean [SD] body mass index 30 [3] kg/m 2 ) and short sleepers at increased risk of type 2 diabetes were randomised to a 6-week sleep-extension programme based on cognitive behavioural principles (n = 10) or a control (n = 8) group. The primary outcome was 6-week change in actigraphic total sleep time (TST). Fasting plasma insulin, insulin resistance (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR]), blood pressure, appetite-related hormones from a mixed-meal tolerance test, and continuous glucose levels were also measured. Baseline to 6-week change in TST was greater in the sleep-extension group, at 79 (95% confidence interval [CI] 68.90, 88.05) versus 6 (95% CI -4.43, 16.99) min. Change in the sleep-extension and control groups respectively also showed: lower fasting insulin (-11.03 [95% CI -22.70, 0.65] versus 7.07 [95% CI -4.60, 18.74] pmol/L); lower systolic (-11.09 [95% CI -17.49, -4.69] versus 0.76 [95% CI -5.64, 7.15] mmHg) and diastolic blood pressure (-12.16 [95% CI -17.74, -6.59] versus 1.38 [95% CI -4.19, 6.96] mmHg); lower mean amplitude of glucose excursions (0.34 [95% CI -0.57, -0.12] versus 0.05 [95% CI -0.20, 0.30] mmol/L); lower fasting peptide YY levels (-18.25 [95%CI -41.90, 5.41] versus 21.88 [95% CI -1.78, 45.53] pg/ml), and improved HOMA-IR (-0.51 [95% CI -0.98, -0.03] versus 0.28 [95% CI -0.20, 0.76]). Our protocol increased TST and improved markers of metabolic health in male overweight/obese short sleepers., (© 2021 European Sleep Research Society.)

Background: The diagnosis of type 2 diabetes (T2D) in younger adults, an increasingly common public health issue, is associated with a higher risk of cardiovascular complications and mortality, which may be due to a more adverse cardiovascular risk profile in individuals diagnosed at a younger age., Aim: To investigate the association between age at diagnosis and the cardiovascular risk profile in adults with T2D., Methods: A pooled dataset was used, comprised of data from five previous studies of adults with T2D, including 1409 participants of whom 196 were diagnosed with T2D under the age of 40 years. Anthropometric and blood biomarker measurements included body weight, body mass index (BMI), waist circumference, body fat percentage, glycaemic control (HbA1c), lipid profile and blood pressure. Univariable and multivariable linear regression models, adjusted for diabetes duration, sex, ethnicity and smoking status, were used to investigate the association between age at diagnosis and each cardiovascular risk factor., Results: A higher proportion of participants diagnosed with T2D under the age of 40 were female, current smokers and treated with glucose-lowering medications, compared to participants diagnosed later in life. Participants diagnosed with T2D under the age of 40 also had higher body weight, BMI, waist circumference and body fat percentage, in addition to a more adverse lipid profile, compared to participants diagnosed at an older age. Modelling results showed that each one year reduction in age at diagnosis was significantly associated with 0.67 kg higher body weight [95% confidence interval (CI): 0.52-0.82 kg], 0.18 kg/m 2 higher BMI (95%CI: 0.10-0.25) and 0.32 cm higher waist circumference (95%CI: 0.14-0.49), after adjustment for duration of diabetes and other confounders. Younger age at diagnosis was also significantly associated with higher HbA1c, total cholesterol, low-density lipoprotein cholesterol and triglycerides., Conclusion: The diagnosis of T2D earlier in life is associated with a worse cardiovascular risk factor profile, compared to those diagnosed later in life., Competing Interests: Conflict-of-interest statement: Barker MM, Zaccardi F, Brady EM, Gulsin GS, Hall AP, Henson J, Htike ZZ, McCann GP, Redman EL, Webb DR and Yeo J report no conflicts of interest. Khunti K has acted as consultant, advisory board member and speaker for Abbott, Amgen, Astrazeneca, Bayer, NAPP, Lilly, Merck Sharp and Dohme, Novartis, Novo Nordisk, Roche, Berlin-Chemie AG/Menarini Group, Sanofi-Aventis, Servier, Boehringer Ingelheim, EACME grants from Boehringer Ingelheim, AstraZeneca, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme. Yates T and Sargeant JA are supported by the NIHR Leicester BRC and have received project funding in the form an investigator-initiated grant from AstraZeneca. EGW has received personal fees from Abbott Diabetes Care, Dexcom, Eli lilly, Insulet, Medtronic, Novo Nordisk, Sanofi Aventis. Davies MJ has acted as consultant, advisory board member and speaker for Novo Nordisk, Sanofi, Lilly and Boehringer Ingelheim, an advisory board member and speaker for AstraZeneca, an advisory board member for Janssen, Lexicon, Servier and Gilead Sciences Ltd and as a speaker for Napp Pharmaceuticals, Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, AstraZeneca and Janssen., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Aims: 'Chronotype' describes an individual's sleep-wake schedule, and can be classified into morning, intermediate or evening types. Evening chronotype has been widely associated with increased cardiometabolic risk and mortality in people with type 2 diabetes. We explored associations between chronotype and markers of well-being in people with type 2 diabetes., Methods: Participants of the 'Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control' (CODEC) observational study completed questionnaires to determine chronotype (Morningness-Eveningness Questionnaire, MEQ) and concurrent measures of well-being (Diabetes-related Distress scale, Patient Health Questionnaire-9 to measure depression, and Self-Compassion Scale), as a secondary endpoint of the study. Adjusted generalised linear models were used to compare well-being between chronotype subgroups in this cohort., Results: Of the 808 individuals included in the CODEC study, from convenience sampling, 476 individuals completed the psychosocial questionnaire substudy. Of these, 67% (n = 321) were male, and 86% (n = 408) were white European. From the MEQ, 24% (n = 114) were morning chronotype, 24% (n = 113) were evening and 52% (n = 249) were intermediate chronotype. Diabetes-related distress was significantly higher in evening chronotypes (exponentiated adjusted coefficient = 1.18 (CI: 1.05-1.32)), compared to morning (p adjusted  = 0.005) and intermediate chronotypes (p adjusted  = 0.039). Similarly, depression was significantly higher in evening chronotypes (exponentiated adjusted coefficient = 1.84 (CI: 1.28-2.65)) compared to morning (p adjusted  = 0.001) and intermediate chronotypes (p adjusted  = 0.016)., Discussion: Evening chronotype in people with type 2 diabetes may be associated with higher levels of diabetes-related distress and depression. These findings warrant further investigation to establish causality and evidence-based interventions that negate the effects of evening chronotype in people with type 2 diabetes., (© 2021 Diabetes UK.)

Aim: To quantify how differences in metrics characterizing physical activity and sedentary behaviour in type 2 diabetes are associated with physical function., Methods: This analysis included participants' data from the Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control (CODEC) cross-sectional study. Data were stratified into two groups according to their short physical performance battery (SPPB) score (impaired physical function = SPPB < 10 and normal physical function = SPPB ≥ 10). Hand-grip strength, sit-to-stand 60 (STS-60) and the Duke Activity Status Index (DASI) score were used to assess functional capacity, while physical activity metrics were measured with a wrist-worn accelerometer. The associations between physical activity metrics and measures of functional capacity were analysed using generalized linear modelling., Results: Some 635 adults (median age 66 years, 34% female) were included in this analysis. Overall, 29% of the cohort scored < 10 in the SPPB test indicating impaired physical function. This group spent more time in prolonged sedentary behaviour (600.7 vs. 572.5 min) and undertook less-intense physical activity. Each sd increase in physical activity volume and intensity gradients for those with impaired physical function was associated with 17% more repetitions for STS-60 with similar associations seen for DASI score. Each sd in sedentary time was associated with 15% fewer repetitions in STS-60 and 16% lower DASI score in those with impaired physical function, whereas in normal physical function group it was 2% and 1%, respectively., Conclusions: The strength of the associations for physical activity measures and functional capacity were modified by physical function status, with the strongest association seen in those with impaired physical function., (© 2020 Diabetes UK.)

This paper presents a review of the nature, range, and incidences of background pathology findings in the respiratory tract of cynomolgus monkeys and rats. Data were collected from 81 inhalation studies and 133 non-inhalation studies evaluated at 3 geographically distinct contract research organization facilities. The inhalation studies were comprised of 44 different small molecule pharmaceuticals or chemicals which were also analyzed in order to understand the patterns of induced changes within the respiratory tract. The lung was the most frequently affected organ in both species, with increased alveolar macrophages being the most common background and test article-related finding. In the upper respiratory tract (URT), inflammatory cell infiltrates were the most common background findings in the nasal cavity in monkeys. Induced URT findings were more frequent in rats than monkeys, with squamous metaplasia in the larynx, and goblet cell hyperplasia in the nasal cavity being the most common. Overall, the data revealed a limited pattern of response to inhaled molecules in the respiratory tract, with background and test article-related findings often occurring in the same regions. It is hoped that these data will assist in the interpretation of findings in the respiratory tract induced by novel inhaled small molecule entities.

The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple ("uncomplicated") increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators.

Treatment of nonhuman primates and mice with a humanized antigen-binding fragment (Fab) antibody (UCBFab) inhibiting transforming growth factor β via daily inhalation for up to 13 weeks resulted in low systemic exposure but high local exposure in the lung. Target engagement was demonstrated by reduced levels of signal transducers, phosphoSMAD and plasminogen activator inhibitor-1 in the bronchoalveolar lavage fluid (BALF). Treatment was associated with a high frequency and titer of antidrug antibodies, indicating high local immunogenicity, and local pathology within the lung and draining lymph nodes. Microscopic changes were characterized by perivascular (PV) and peribronchiolar (PB) mononuclear inflammatory cell (MIC) infiltrates that were principally lymphocytic in nature and mixed inflammatory cell infiltrates and/or inflammation within the alveoli. Immunohistochemical investigation revealed a predominantly CD68-positive macrophage and CD3- and CD8>CD4-positive T-cell response in the alveoli, whereas within the airways, there was a variable mixture of CD3-positive T cells, CD20-positive B cells, and CD68-positive macrophages. Increased cellularity of the draining lymph nodes was also noted, indicating the presence of an immune response to the inhaled test article. Morphologic changes did not progress over time, and all changes partially recovered. Increased leukocytes (principally macrophages) in BALF cytology correlated with the changes seen by histopathology.

Introduction: Previous investigations have suggested that evening chronotypes may be more susceptible to obesity-related metabolic alterations. However, whether device-measured physical behaviors differ by chronotype in those with type 2 diabetes (T2DM) remains unknown., Research Design and Methods: This analysis reports data from the ongoing Chronotype of Patients with Type 2 Diabetes and Effect on Glycaemic Control (CODEC) observational study. Eligible participants were recruited from both primary and secondary care settings in the Midlands area, UK. Participants were asked to wear an accelerometer (GENEActiv, ActivInsights, Kimbolton, UK) on their non-dominant wrist for 7 days to quantify different physical behaviors (sleep, sedentary, light, moderate-to-vigorous physical activity (MVPA), intensity gradient, average acceleration and the acceleration above which the most active continuous 2, 10, 30 and 60 min are accumulated). Chronotype preference (morning, intermediate or evening) was assessed using the Morningness-Eveningness Questionnaire. Multiple linear regression analyses assessed whether chronotype preference was associated with physical behaviors and their timing. Evening chronotypes were considered as the reference group., Results: 635 participants were included (age=63.8±8.4 years, 34.6% female, body mass index=30.9±5.1 kg/m 2 ). 25% (n=159) of the cohort were morning chronotypes, 52% (n=330) intermediate and 23% (n=146) evening chronotypes. Evening chronotypes had higher sedentary time (28.7 min/day, 95% CI 8.6 to 48.3) and lower MVPA levels (-9.7 min/day, -14.9 to -4.6) compared to morning chronotypes. The intensity of the most active continuous 2-60 min of the day, average acceleration and intensity gradient were lower in evening chronotypes. The timing of physical behaviors also differed across chronotypes, with evening chronotypes displaying a later sleep onset and consistently later physical activity time., Conclusions: People with T2DM lead a lifestyle characterized by sedentary behaviors and insufficient MVPA. This may be exacerbated in those with a preference for 'eveningness' (ie, go to bed late and get up late)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: A person's chronotype is their entrained preference for sleep time within the 24 hours clock. It is described by the well-known concept of the 'lark' (early riser) and 'owl' (late sleeper). Evidence suggests that the 'owl' is metabolically disadvantaged due to the standard organisation of our society which favours the 'lark' and places physiological stresses on this chronotype. The aim of this study is to explore cardiometabolic health between the lark and owl in a population with an established metabolic condition - type 2 diabetes., Methods: This cross-sectional, multisite study aims to recruit 2247 participants from both secondary and primary care settings. The primary objective is to compare glycaemic control between late and early chronotypes. Secondary objectives include determining if late-chronotype is associated with poorer cardiometabolic health and other lifestyle factors, including well-being, compared with early-chronotype; describing the prevalence of the five different chronotypes in this cohort and examining the trends in glycaemic control, cardiometabolic health, well-being and lifestyle factors across chronotype., Analysis: The primary outcome (glycated haemoglobin (HbA1c)), linear regression analysis will compare HbA1c between early and late chronotypes, with and without adjustment for confounding variables. Chronotype will be modelled as a categorical variable with all five levels (from extreme-morning to extreme-late type), and as a continuous variable to calculate p for trend across the five categories. A number of models will be created; unadjusted through to adjusted with age, sex, ethnicity, body mass index, duration of diabetes, family history of diabetes, current medication and dietary habits. All secondary outcomes will be analysed using the same method., Ethics: Ethical approval from the West Midlands - Black Country Research Ethics Committee (16/WM/0457)., Dissemination: The results will be disseminated through publication in peer-reviewed medical journal, relevant medical/health conferences and a summary report sent to patients., Trial Registration Number: NCT02973412 (Pre-Results)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Investigating the association between sleep duration, obesity, adipokines and insulin resistance (via Leptin:Adiponectin ratio (LAR)), in those at high risk of type 2 diabetes mellitus (T2DM)., Methods: Adults with impaired glucose regulation (IGR) were included. Fasting bloods for inflammatory biomarkers and glycaemic status, 2-h glucose, anthropometrics, objective physical activity, and self-reported sleep were collected. The average number of hours slept in a 24 h period was categorised as ≤5.5, 6-6.5, 7-7.5, 8-8.5, and ≥9 h. Regression models were fitted with sleep (linear and quadratic) and logistic regression used for IGR and adjusted for age, sex, ethnicity, body mass index, waist circumference and objective physical activity., Results: 2848 participants included (593 with inflammatory marker data). Short sleep and long sleep duration were significantly independently associated with higher body mass index (P < 0.001), body weight (P < 0.01), and waist circumference (P < 0.001). 6-7 h of sleep/24 h is associated with the lowest obesity measures. Fasting insulin and LAR were positively associated with sleep duration. Adiponectin levels were negatively associated with sleep duration., Conclusions: These results support the evidence of an association between short and long sleep duration and indices of obesity. We demonstrate an independent relationship between long sleep duration and insulin resistance., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background/objectives: Male genital dermatoses are a common and underappreciated cause of morbidity. Its prevalence and the characteristics of patients presenting with these conditions are poorly understood. The aim of the study was to ascertain which dermatoses were referred to the Male Genital Dermatology Clinic in Melbourne, Australia and to determine whether circumcision and atopy are associated with male genital skin disease., Method: This was a retrospective review of 331 new patients who attended the clinic from 2004 to 2012. Descriptive statistics were obtained to determine the frequency of diagnoses made in the clinic and to record the proportions of circumcised and atopic patients., Results: The most common primary diagnoses were irritant contact dermatitis (n = 67), dysaesthesia (n = 60), psoriasis (n = 31), lichen sclerosus (n = 28), unknown (n = 19), genital warts (n = 18), normal anatomic variant (n = 17), other infection (n = 17), eczema (n = 16) and lichen planus (n = 16). For the 10 most commonly observed conditions, more than 70% of patients were uncircumcised and more than 69% of these patients had a history of atopy., Conclusions: The diagnoses made were described, including their associations with non-circumcision and atopy. Several of these observations have not been recognised before in the literature. We discuss lessons learned in the management of male genital disease and its psychosocial impact., (© 2016 The Australasian College of Dermatologists.)

Purpose of Review: To provide a basic understanding of sleep physiology, the pathophysiology of sleep-disordered breathing and the processes applied in undertaking and assessing sleep studies., Recent Findings: It has become increasingly apparent that obstructive sleep apnoea is associated with heightened perioperative risk. Furthermore, the condition still remains under-diagnosed in patients presenting for surgery., Summary: This review describes the physiology of sleep including sleep stages, sleep monitoring, the normal hypnogram and investigation from simple overnight pulse oximetry to full polysomnography. The pathophysiology of sleep-disordered breathing is discussed; from simple snoring through obstructive sleep apnoea to obesity hypoventilation syndrome. The relationship to metabolic syndrome is explored.Salient points in the interpretation of sleep study reports are presented.

Epiphyseal growth plate dysplasia (chondrodysplasia) might be considered as the pathognomonic feature of antiangiogenic treatment in preclinical species as it is reliably and dose-responsively induced in rodents and monkeys with vascular endothelial growth factor receptor (VEGFR) inhibitors, fibroblast growth factor (FGF) receptor inhibitors, matrix metalloproteinase inhibitors, and vascular targeting agents. Here we report epiphyseal growth plate dysplasia in juvenile rabbits treated with an oral spleen tyrosine kinase inhibitor induced by off-target antiangiogenic inhibition of VEGF and FGF family kinase receptors. Epiphyseal growth plate dysplasia resulted in weakening and fracturing of the femoral head physis in 6 of 10 male and 1 of 10 female animals as well as microfracturing and dysplasia of the distal femoral articular cartilage in 1 male animal. Fracture lines ran through the zone of hypertrophic cartilage (as well as adjacent zones), were orientated parallel to the physeal plane, and often involved displacement of the femoral head. We would suggest that the high prevalence of growth plate fracture in the rabbit may represent a potential additional adverse risk to those already established for children treated with antiangiogenic therapy., (© 2016 by The Author(s) 2016.)

The growth plate, ovary, adrenal gland, and rodent incisor tooth are sentinel organs for antiangiogenic effects since they respond reliably, quantitatively, and sensitively to inhibition of the vascular endothelial growth factor receptor (VEGFR). Here we report that treatment of rats with platelet-derived growth factor receptor beta (PDGFRβ) inhibitors that target pericytes results in severe ovarian hemorrhage with degeneration and eventual rupture of the corpus luteum. Evaluation of the growth plate, adrenal gland, and incisor tooth that are typical target organs for antiangiogenic treatment in the rodent revealed no abnormalities. Histologically, the changes in the ovary were characterized by sinusoidal dilatation, increased vessel fragility, and hemorrhage into the corpus luteum. Immunocytochemical staining of vessels with alpha smooth muscle actin and CD31 that recognize pericytes and vascular endothelium, respectively, demonstrated that this effect was due to selective pericyte deficiency within corpora lutea. Further experiments in which rats were treated concurrently with both PDGFRβ and VEGFR inhibitors ablated the hemorrhagic response, resulting instead in corpus luteum necrosis. These changes are consistent with the notion that selective pericyte loss in the primitive capillary network resulted in increased vessel fragility and hemorrhage, whereas concomitant VEGFR inhibition resulted in vessel regression and reduced vascular perfusion that restricted development of the hemorrhagic vessels. These results also highlight the utility of the rodent ovary to respond differentially to VEGFR and PDGFR inhibitors, which may provide useful information during routine safety assessment for determining target organ toxicity., (© The Author(s) 2015.)

Dental caries, one of the most globally widespread infectious diseases, is intimately linked to pH dynamics. In supragingival plaque, after the addition of a carbohydrate source, bacterial metabolism decreases the pH which then subsequently recovers. Molecular mechanisms supporting this important homeostasis are poorly characterized in part due to the fact that there are hundreds of active species in dental plaque. Only a few mechanisms (for example, lactate fermentation, the arginine deiminase system) have been identified and studied in detail. Here, we conducted what is to our knowledge, the first full transcriptome and metabolome analysis of a diverse oral plaque community by using a functionally and taxonomically robust in vitro model system greater than 100 species. Differential gene expression analyses from the complete transcriptome of 14 key community members revealed highly varied regulation of both known and previously unassociated pH-neutralizing pathways as a response to the pH drop. Unique expression and metabolite signatures from 400 detected metabolites were found for each stage along the pH curve suggesting it may be possible to define healthy and diseased states of activity. Importantly, for the maintenance of healthy plaque pH, gene transcription activity of known and previously unrecognized pH-neutralizing pathways was associated with the genera Lactobacillus, Veillonella and Streptococcus during the pH recovery phase. Our in vitro study provides a baseline for defining healthy and disease-like states and highlights the power of moving beyond single and dual species applications to capture key players and their orchestrated metabolic activities within a complex human oral microbiome model.

AZD7969 is a potent inhibitor of glycogen synthase kinase 3 (GSK3β), which is a multifunctional serine/threonine kinase that negatively regulates the Wnt/β-catenin signaling pathway. Treatment of rats and dogs with AZD7969 for periods of up to 4 weeks resulted in a number of changes, the most significant of which was a dose-dependent, and treatment-related, increase in proliferation in a number of tissues that was thought to arise from derepression of Wnt/β-catenin signaling in the stem cell compartment. Phenotypically, this resulted in hyperplasia that either maintained normal tissue architecture in the gastrointestinal tract, liver, kidney, and adrenals or effaced normal tissue architecture within the bones, incisor teeth, and femorotibial joint. In addition to these changes, we noted a treatment-related increase in iron loading in the liver and proximal small intestines. This off-target effect was robust, potent, and occurred in both dogs and rats suggesting that AZD7969 might be a useful tool compound to study iron storage disorders in the laboratory., (© 2014 by The Author(s).)

The candidate phylum TM7 is globally distributed and often associated with human inflammatory mucosal diseases. Despite its prevalence, the TM7 phylum remains recalcitrant to cultivation, making it one of the most enigmatic phyla known. In this study, we cultivated a TM7 phylotype (TM7x) from the human oral cavity. This extremely small coccus (200-300 nm) has a distinctive lifestyle not previously observed in human-associated microbes. It is an obligate epibiont of an Actinomyces odontolyticus strain (XH001) yet also has a parasitic phase, thereby killing its host. This first completed genome (705 kb) for a human-associated TM7 phylotype revealed a complete lack of amino acid biosynthetic capacity. Comparative genomics analyses with uncultivated environmental TM7 assemblies show remarkable conserved gene synteny and only minimal gene loss/gain that may have occurred as TM7x adapted to conditions within the human host. Transcriptomic and metabolomic profiles provided the first indications, to our knowledge, that there is signaling interaction between TM7x and XH001. Furthermore, the induction of TNF-α production in macrophages by XH001 was repressed in the presence of TM7x, suggesting its potential immune suppression ability. Overall, our data provide intriguing insights into the uncultivability, pathogenicity, and unique lifestyle of this previously uncharacterized oral TM7 phylotype.

Accumulating evidence suggests benefit of extracorporeal cardiopulmonary resuscitation (E-CPR) in patients with refractory cardiac arrest by using venoarterial extracorporeal membrane oxygenation. Appropriate patient selection for E-CPR is cumbersome and still debated. We describe a 56-year-old male who developed refractory ventricular fibrillation upon arrival at the emergency department and was successfully treated by urgent E-CPR. Patient selection, complications and the need to adapt the chain of survival are discussed.

Background: Our knowledge of microbial diversity in the human oral cavity has vastly expanded during the last two decades of research. However, much of what is known about the behavior of oral species to date derives from pure culture approaches and the studies combining several cultivated species, which likely does not fully reflect their function in complex microbial communities. It has been shown in studies with a limited number of cultivated species that early oral biofilm development occurs in a successional manner and that continuous low pH can lead to an enrichment of aciduric species. Observations that in vitro grown plaque biofilm microcosms can maintain similar pH profiles in response to carbohydrate addition as plaque in vivo suggests a complex microbial community can be established in the laboratory. In light of this, our primary goal was to develop a robust in vitro biofilm-model system from a pooled saliva inoculum in order to study the stability, reproducibility, and development of the oral microbiome, and its dynamic response to environmental changes from the community to the molecular level., Results: Comparative metagenomic analyses confirmed a high similarity of metabolic potential in biofilms to recently available oral metagenomes from healthy subjects as part of the Human Microbiome Project. A time-series metagenomic analysis of the taxonomic community composition in biofilms revealed that the proportions of major species at 3 hours of growth are maintained during 48 hours of biofilm development. By employing deep pyrosequencing of the 16S rRNA gene to investigate this biofilm model with regards to bacterial taxonomic diversity, we show a high reproducibility of the taxonomic carriage and proportions between: 1) individual biofilm samples; 2) biofilm batches grown at different dates; 3) DNA extraction techniques and 4) research laboratories., Conclusions: Our study demonstrates that we now have the capability to grow stable oral microbial in vitro biofilms containing more than one hundred operational taxonomic units (OTU) which represent 60-80% of the original inoculum OTU richness. Previously uncultivated Human Oral Taxa (HOT) were identified in the biofilms and contributed to approximately one-third of the totally captured 16S rRNA gene diversity. To our knowledge, this represents the highest oral bacterial diversity reported for an in vitro model system so far. This robust model will help investigate currently uncultivated species and the known virulence properties for many oral pathogens not solely restricted to pure culture systems, but within multi-species biofilms.

Purpose: To systematically evaluate the impact of diet, exercise and lifestyle modification programmes on indices of obesity, Obstructive Sleep Apnoea (OSA) parameters and quality of life (QoL) in adults with OSA., Methods: Electronic databases were searched to identify randomised controlled trials published in English with an intervention based on dietary weight loss, exercise and/or lifestyle programme in adults with OSA. Meta-analyses were conducted using random-effects models., Results: Twelve studies met the inclusion criteria with nine comparing similar interventions. Diet and diet plus continuous positive airway pressure (CPAP) therapy were compared in three studies (n = 261), and intensive lifestyle programmes and routine care were compared in six studies (n = 483). Diet with CPAP therapy reduced weight by -2.64 kg (95 % Confidence Interval (CI) -3.98, -1.30, I (2) = 0 %) compared with diet alone. No differences were observed for QoL or Epworth Sleepiness Scale. A significant reduction in weight was seen in participants receiving an intensive lifestyle intervention of -5.65 kg (95 % CI -10.91, -0.40, I(2) = 95.7 %) compared with controls. Reductions were also observed for waist circumference (-5.80 cm, 95 % CI -8.64, -2.96, I(2) = 77.7 %), body mass index (BMI) (-2.33 kg/m(2), 95 % CI -3.41, -1.24, I(2) = 78.8 %) and the Apnoea Hypopnoea Index (AHI) (-4.55 events/h, 95 % CI -7.12, -1.98, I(2) = 54.4 %) but with high levels of heterogeneity., Conclusions: Intensive lifestyle management can significantly reduce obesity indices and improve AHI. Future research is required to investigate this effect due to a limited number of studies identified.