Background. The COVID-19 pandemic has altered the context for antimicrobial stewardship in primary care. Aim: To assess the effect of the pandemic on antibiotic prescribing, accounting for changes in consultations for respiratory and urinary tract infections (RTIs/UTIs). Design and Setting: Population-based cohort study using the UK Clinical Practice Research Datalink (CPRD) (January 2017 to September 2020). Method: Interrupted time series analysis evaluated changes in antibiotic prescribing and RTI/UTI consultations adjusting for age, gender, season and secular trends. We assessed the proportion of COVID-19 episodes associated with antibiotic prescribing. Results: There were 253,655 registered patients in 2017 and 232,218 in 2020 with 559,461 antibiotic prescriptions, 216,110 RTI consultations and 36,402 UTI consultations. Compared to pre-pandemic months, March 2020 was associated with higher prescribing (adjusted rate ratio 1.13; 95% confidence interval 1.11 to 1.16). Prescribing fell below predicted rates between April and August 2020, reaching a minimum in May (0.73, 0.71 to 0.75). Pandemic months were associated with lower rates of RTI/UTI consultations, particularly in April for RTIs (0.23; 0.22 to 0.25). There were small reductions in the proportion of RTI consultations with antibiotic prescribed and no reduction for UTIs. Among 25,889 COVID-19 patients, 2,942 (11%) had antibiotics within a COVID-19 episode. Conclusion: Pandemic months were initially associated with increased antibiotic prescribing which then fell below expected levels during the national lockdown. Findings are reassuring that antibiotic stewardship priorities have not been neglected due to COVID-19. Research is required into the effects of reduced RTI/UTI consultations on incidence of serious bacterial infection.

Background: There is substantial variation in use of urgent suspected cancer referral (two week wait/2WW) between practices. Aim: To examine change in use of 2WW referrals in England over ten years (2009/10 to 2018/19) and practice and population factors associated with cancer detection. Design and Setting: Retrospective cross-sectional study of English general practices and their 2WW referral and cancer waiting times (CWT) detection data (all cancers other than non melanoma skin cancers) 2009/10 to 2018/19. Methods: Descriptive statistics of changes over ten years in 2WW referral data. Yearly linear regression models to determine the association between cancer detection rates and quintiles of practice and population characteristics. Predicted cancer detection rates were calculated and the difference between lowest (Q1) to highest (Q5) quintiles. Results: Over the ten years studied there were 14.89m 2WW referrals (2.2m 2018/19), 2.68m new cancer diagnoses of which 1.26m were detected following 2WW. The detection rate increased from 41% to 52%. In 2018/19 an additional 66,172 cancers were detected via 2WW compared to 2009/10. Higher cancer detection via 2WW referrals was associated with larger practices and those with younger GPs. From 2016/17 onwards more deprived practice populations were associated with decreased cancer detection. Conclusions: From 2009/10 to 2018/19 2WW referrals increased on average by 10% year on year. Higher cancer detection was found in larger practices, with relatively younger GPs and more recently, less deprived populations. COVID-19 has led to significant impacts on 2WW referral activity and the impact on patient outcomes will need to be studied.

Insulin sensitivity and age are independently associated with an insulin-induced change in functional microvascular dilator capacity in individuals with central adiposity at risk of CVD. Dilator capacity is not improved by six months high dose statin treatment.

Physiological adaptation to high-altitude living in native Andeans is unlikely to compensate for the significant differences we observed between diurnal and nocturnal oxyhemoglobin saturation, most marked in infancy. This vulnerability to sleep-related hypoxia in early childhood has potential lifespan implications. Future studies should characterize the sleep- related respiratory physiology underpinning our observations.

New Findings• What is the central question of this study?Autonomic nervous dysfunction is implicated in complications of sickle cell anaemia (SCA). In healthy adults, a deep inspiratory breath hold (IBH) elicits rapid transient SNS- mediated vasoconstriction detectable using Laser Doppler Flux (LDF) assessment of the finger-tip cutaneous micovasculature.• What is the main finding and its importance?We demonstrate significantly increased resting peripheral blood flow and sympathetic activity in African children with SCA compared to sibling controls and increased sympathetic stimulation in response to vasoprovocation with DIG.This study is the first to observe an inverse association between resting peripheral blood flow and haemoglobin oxygen saturation (SpO2). These phenomena may be an adaptive response to the hypoxic exposure in SCA.There is increasing evidence that autonomic dysfunction in adults with homozygous sickle cell (haemoglobin SS) disease is associated with enhanced autonomic nervous system-mediated control of microvascular perfusion. However, it is unclear whether such differences are detectable in children with SS disease. We studied 65 children with SS disease [38 boys; median age 7.2 (interquartile range 5.1–10.6) years] and 20 control children without symptoms of SS disease [8 boys; 8.7 (5.5–10.8) years] and recorded mean arterial blood pressure (ABP) and daytime haemoglobin oxygen saturation (). Cutaneous blood flux at rest (RBF) and during the sympathetically activated vasoconstrictor response to inspiratory breath hold (IBH) were measured in the finger pulp of the non-dominant hand using laser Doppler fluximetry. Local factors mediating flow motion were assessed by power spectral density analysis of the oscillatory components of the laser Doppler signal. The RBF measured across the two study groups was negatively associated with age (r=−0.25, P < 0.0001), ABP (r=−0.27, P= 0.02) and daytime (r=−0.30, P= 0.005). Children with SS disease had a higher RBF (P= 0.005) and enhanced vasoconstrictor response to IBH (P= 0.002) compared with control children. In children with SS disease, higher RBF was associated with an increase in the sympathetic interval (r=−0.28, P= 0.022). The SS disease status, daytime and age explained 22% of the variance in vasoconstrictor response to IBH (P < 0.0001). Our findings suggest that blood flow and blood flow responses in the skin of young African children with SS disease differ from those of healthy control children, with increased resting peripheral blood flow and increased sympathetic stimulation from a young age in SS disease. They further suggest that the laser Doppler flowmetry technique with inspiratory breath hold manoeuvre appears to be robust for use in young children with SS disease, to explore interactions between , ABP and autonomic function with clinical complications, e.g. skin ulceration.