SFX-01 in hospitalised patients with community-acquired pneumonia during the COVID-19 pandemic: a double-blind, randomised, placebo-controlled trial.

Introduction: Sulforaphane can induce the transcription factor, Nrf2, promoting antioxidant and anti-inflammatory responses. In this study, hospitalised patients with community-acquired pneumonia (CAP) were treated with stabilised synthetic sulforaphane (SFX-01) to evaluate impact on clinical status and inflammation. Methods: Double-blind, randomised, placebo-controlled trial of SFX-01 (300 mg oral capsule, once daily for 14 days) conducted in Dundee, UK, between November 2020 and May 2021. Patients had radiologically confirmed CAP and CURB-65 (confusion, urea >7 mmol·L-1, respiratory rate ≥30 breaths·min-1, blood pressure <90 mmHg (systolic) or ≤60 mmHg (diastolic), age ≥65 years) score ≥1. The primary outcome was the seven-point World Health Organization clinical status scale at day 15. Secondary outcomes included time to clinical improvement, length of stay and mortality. Effects on Nrf2 activity and inflammation were evaluated on days 1, 8 and 15 by measurement of 45 serum cytokines and mRNA sequencing of peripheral blood leukocytes. Results: The trial was terminated prematurely due to futility with 133 patients enrolled. 65 patients were randomised to SFX-01 treatment and 68 patients to placebo. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was the cause of CAP in 103 (77%) cases. SFX-01 treatment did not improve clinical status at day 15 (adjusted OR 0.87, 95% CI 0.41-1.83; p=0.71), time to clinical improvement (adjusted hazard ratio (aHR) 1.02, 95% CI 0.70-1.49), length of stay (aHR 0.84, 95% CI 0.56-1.26) or 28-day mortality (aHR 1.45, 95% CI 0.67-3.16). The expression of Nrf2 targets and pro-inflammatory genes, including interleukin (IL)-6, IL-1ß and tumour necrosis factor-α, was not significantly changed by SFX-01 treatment. At days 8 and 15, respectively, 310 and 42 significant differentially expressed genes were identified between groups (false discovery rate adjusted p<0.05, log2FC >1). Conclusion: SFX-01 treatment did not improve clinical status or modulate key Nrf2 targets in patients with CAP primarily due to SARS-CoV-2 infection.

Photodynamic Diagnosis-guided Transurethral Resection of Bladder Tumour in Participants with a First Suspected Diagnosis of Intermediate- or High-risk Non-muscle-invasive Bladder Cancer: Cost-effectiveness Analysis Alongside a Randomised Controlled Trial.

Background: Recurrence of non-muscle-invasive bladder cancer (NMIBC) is common after transurethral resection of bladder tumour (TURBT). Photodynamic diagnosis (PDD) may reduce recurrence. PDD uses a photosensitiser in the bladder that causes the tumour to fluoresce to guide resection. PDD provides better diagnostic accuracy and allows more complete tumour resection. Objective: To estimate the economic efficiency of PDD-guided TURBT (PDD-TURBT) in comparison to white light-guided TURNT (WL-TURBT) in individuals with a suspected first diagnosis of NMIBC at intermediate or high risk of recurrence on the basis of routine visual assessment before being scheduled for TURBT. Design setting and participants: This is a health economic evaluation alongside a pragmatic, open-label, parallel-group randomised trial from a societal perspective. A total of 493 participants (aged ≥16 yr) were randomly allocated to PDD-TURBT (n = 244) or WL-TURBT (n = 249) in 22 UK National Health Service hospitals. Outcome measurements and statistical analysis: Cost effectiveness ratios were based on the use of health care resources associated with PDD-TURBT and WL-TURBT and quality-adjusted life years (QALYs) gained within the trial. Uncertainties in key parameters were assessed using sensitivity analyses. Results and limitations: On the basis of the use of resources driven by the trial protocol, the incremental cost effectiveness of PDD-TURBT in comparison to WL-TURBT was not cost saving. At 3 yr, the total cost was £12 881 for PDD-TURBT and £12 005 for WL-TURBT. QALYs at three years were 2.087 for PDD-TURBT and 2.094 for WL-TURBT. The probability that PDD-TURBT is cost effective was never >30% above the range of societal cost-effectiveness thresholds. Conclusions: There was no evidence of a difference in either costs or QALYs over 3-yr follow-up between PDD-TURBT and WL-TURBT in individuals with suspected intermediate- or high-risk NMIBC. PDD-TURBT is not supported for the management of primary intermediate- or high-risk NMIBC. Patient summary: We assessed overall costs for two approaches for removal of bladder tumours in noninvasive cancer and measured quality-adjusted life years gained for each. We found that use of a photosensitiser in the bladder was not more cost effective than use of white light only during tumour removal.

Photodynamic versus white-light-guided resection of first-diagnosis non-muscle-invasive bladder cancer: PHOTO RCT.

BACKGROUND: Around 7500 people are diagnosed with non-muscle-invasive bladder cancer in the UK annually. Recurrence following transurethral resection of bladder tumour is common, and the intensive monitoring schedule required after initial treatment has associated costs for patients and the NHS. In photodynamic diagnosis, before transurethral resection of bladder tumour, a photosensitiser that is preferentially absorbed by tumour cells is instilled intravesically. Transurethral resection of bladder tumour is then conducted under blue light, causing the photosensitiser to fluoresce. Photodynamic diagnosis-guided transurethral resection of bladder tumour offers better diagnostic accuracy than standard white-light-guided transurethral resection of bladder tumour, potentially reducing the chance of subsequent recurrence. OBJECTIVE: The objective was to assess the clinical effectiveness and cost-effectiveness of photodynamic diagnosis-guided transurethral resection of bladder tumour. DESIGN: This was a multicentre, pragmatic, open-label, parallel-group, non-masked, superiority randomised controlled trial. Allocation was by remote web-based service, using a 1 : 1 ratio and a minimisation algorithm balanced by centre and sex. SETTING: The setting was 22 NHS hospitals. PARTICIPANTS: Patients aged ≥ 16 years with a suspected first diagnosis of high-risk non-muscle-invasive bladder cancer, no contraindications to photodynamic diagnosis and written informed consent were eligible. INTERVENTIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour and standard white-light cystoscopy transurethral resection of bladder tumour. MAIN OUTCOME MEASURES: The primary clinical outcome measure was the time to recurrence from the date of randomisation to the date of pathologically proven first recurrence (or intercurrent bladder cancer death). The primary health economic outcome was the incremental cost per quality-adjusted life-year gained at 3 years. RESULTS: We enrolled 538 participants from 22 UK hospitals between 11 November 2014 and 6 February 2018. Of these, 269 were allocated to photodynamic diagnosis and 269 were allocated to white light. A total of 112 participants were excluded from the analysis because of ineligibility (n = 5), lack of non-muscle-invasive bladder cancer diagnosis following transurethral resection of bladder tumour (n = 89) or early cystectomy (n = 18). In total, 209 photodynamic diagnosis and 217 white-light participants were included in the clinical end-point analysis population. All randomised participants were included in the cost-effectiveness analysis. Over a median follow-up period of 21 months for the photodynamic diagnosis group and 22 months for the white-light group, there were 86 recurrences (3-year recurrence-free survival rate 57.8%, 95% confidence interval 50.7% to 64.2%) in the photodynamic diagnosis group and 84 recurrences (3-year recurrence-free survival rate 61.6%, 95% confidence interval 54.7% to 67.8%) in the white-light group (hazard ratio 0.94, 95% confidence interval 0.69 to 1.28; p = 0.70). Adverse event frequency was low and similar in both groups [12 (5.7%) in the photodynamic diagnosis group vs. 12 (5.5%) in the white-light group]. At 3 years, the total cost was £12,881 for photodynamic diagnosis-guided transurethral resection of bladder tumour and £12,005 for white light. There was no evidence of differences in the use of health services or total cost at 3 years. At 3 years, the quality-adjusted life-years gain was 2.094 in the photodynamic diagnosis transurethral resection of bladder tumour group and 2.087 in the white light group. The probability that photodynamic diagnosis-guided transurethral resection of bladder tumour was cost-effective was never > 30% over the range of society's cost-effectiveness thresholds. LIMITATIONS: Fewer patients than anticipated were correctly diagnosed with intermediate- to high-risk non-muscle-invasive bladder cancer before transurethral resection of bladder tumour and the ratio of intermediate- to high-risk non-muscle-invasive bladder cancer was higher than expected, reducing the number of observed recurrences and the statistical power. CONCLUSIONS: Photodynamic diagnosis-guided transurethral resection of bladder tumour did not reduce recurrences, nor was it likely to be cost-effective compared with white light at 3 years. Photodynamic diagnosis-guided transurethral resection of bladder tumour is not supported in the management of primary intermediate- to high-risk non-muscle-invasive bladder cancer. FUTURE WORK: Further work should include the modelling of appropriate surveillance schedules and exploring predictive and prognostic biomarkers. TRIAL REGISTRATION: This trial is registered as ISRCTN84013636. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 40. See the NIHR Journals Library website for further project information.

Around 7500 people are diagnosed with early-stage bladder cancer in the UK each year. Early bladder cancer is contained within the bladder and has not yet invaded the bladder's muscle wall or spread elsewhere in the body. The cancer will return (recur) in around half of people after initial treatment and they have to attend hospital for regular check-ups, with costs to both them and the NHS. The first step in treating early bladder cancer is surgery to remove the tumour. This surgery is normally performed under white light. Photodynamic diagnosis is a new technique in which a liquid is put into the patient's bladder before surgery and a blue light is used during the operation. This causes the bladder cancer to fluoresce so that it can be seen more easily by the surgeon. The Photodynamic versus white-light-guided resection of first diagnosis non-muscle-invasive bladder cancer ( PHOTO ) trial aimed to find out whether or not using photodynamic diagnosis at initial surgery would reduce how often the cancer recurred and whether or not this could reduce the cost of treating early bladder cancer. A total of 538 people with early bladder cancer who had a medium to high chance of their cancer returning after treatment were enrolled in the PHOTO trial. They were included in one of two treatment groups, at random: 269 had photodynamic surgery and 269 had standard white-light surgery. People in both groups were monitored regularly for any recurrences, with further treatment as appropriate. After 3 years, 4 out of 10 people in each group had a recurrence of their bladder cancer. We found no difference between the treatment groups in the number of people with recurrences. We found no evidence of a benefit to patients, and the total costs of photodynamic surgery were higher than those of standard white light. We therefore recommend that it is no longer used in the treatment of this group of patients.

Dipeptidyl peptidase-1 inhibition in patients hospitalised with COVID-19: a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial.

BACKGROUND: Neutrophil serine proteases are involved in the pathogenesis of COVID-19 and increased serine protease activity has been reported in severe and fatal infection. We investigated whether brensocatib, an inhibitor of dipeptidyl peptidase-1 (DPP-1; an enzyme responsible for the activation of neutrophil serine proteases), would improve outcomes in patients hospitalised with COVID-19. METHODS: In a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial, across 14 hospitals in the UK, patients aged 16 years and older who were hospitalised with COVID-19 and had at least one risk factor for severe disease were randomly assigned 1:1, within 96 h of hospital admission, to once-daily brensocatib 25 mg or placebo orally for 28 days. Patients were randomly assigned via a central web-based randomisation system (TruST). Randomisation was stratified by site and age (65 years or ≥65 years), and within each stratum, blocks were of random sizes of two, four, or six patients. Participants in both groups continued to receive other therapies required to manage their condition. Participants, study staff, and investigators were masked to the study assignment. The primary outcome was the 7-point WHO ordinal scale for clinical status at day 29 after random assignment. The intention-to-treat population included all patients who were randomly assigned and met the enrolment criteria. The safety population included all participants who received at least one dose of study medication. This study was registered with the ISRCTN registry, ISRCTN30564012. FINDINGS: Between June 5, 2020, and Jan 25, 2021, 406 patients were randomly assigned to brensocatib or placebo; 192 (47·3%) to the brensocatib group and 214 (52·7%) to the placebo group. Two participants were excluded after being randomly assigned in the brensocatib group (214 patients included in the placebo group and 190 included in the brensocatib group in the intention-to-treat population). Primary outcome data was unavailable for six patients (three in the brensocatib group and three in the placebo group). Patients in the brensocatib group had worse clinical status at day 29 after being randomly assigned than those in the placebo group (adjusted odds ratio 0·72 [95% CI 0·57-0·92]). Prespecified subgroup analyses of the primary outcome supported the primary results. 185 participants reported at least one adverse event; 99 (46%) in the placebo group and 86 (45%) in the brensocatib group. The most common adverse events were gastrointestinal disorders and infections. One death in the placebo group was judged as possibly related to study drug. INTERPRETATION: Brensocatib treatment did not improve clinical status at day 29 in patients hospitalised with COVID-19. FUNDING: Sponsored by the University of Dundee and supported through an Investigator Initiated Research award from Insmed, Bridgewater, NJ; STOP-COVID19 trial.

Introducing NICE guidelines for intravenous fluid therapy into a district general hospital.

BACKGROUND: National Institute for Health and Care Excellence (NICE) guidelines on intravenous fluid prescribing for adults in hospital, issued in 2013, advised less use of 0.9% sodium chloride than current practice, provided a logical system for prescribing and suggested further study of electrolyte abnormalities. AIMS: To describe the steps taken to establish and monitor guideline introduction and to assess effects on clinical biochemistry results, in a general hospital setting. METHODS: We used established principles of change to modify education, teaching, record keeping and audit throughout the hospital, changed the availability of intravenous fluid preparations in the wards and monitored the use of intravenous fluids. We anonymously linked local clinical chemistry records to nationally available patient records (NHS Scotland SMR01). We chose specified medical emergencies, and major emergency and elective general and orthopaedic surgery, where management would require intravenous fluids, for a two-phase cross-sectional study between 2007 and 2017, spanning the change in prescribing. Primary outcomes were abnormal bicarbonate, sodium, potassium and incidence of acute kidney injury (AKI), and secondary outcomes were mortality and length of stay. RESULTS: Over the study period, sodium chloride 0.9% use decreased by 75%, and overall intravenous fluid use decreased from 0.65 to 0.40 L/occupied bed day. The incidence of acidosis decreased from 7.4% to 4.8% of all admissions (difference -2.7%, 95% CI -2.1 to -3.0). No important changes in other electrolytes were noted; in particular, plasma sodium values showed no adverse effects. Stage 1 AKI increased from 6.7% to 9.0% (difference 2.3%, 95% CI 1.6 to 3.0), but other causes for this cannot be excluded. Mortality and length of stay showed no adverse effects. CONCLUSIONS AND IMPLICATIONS: Effective implementation of the guidelines required substantial time, effort and resource. NICE suggestions of fluid types for maintenance appear appropriate, but prescribed volumes continue to require careful clinical judgement.

A Randomized Trial of PHOTOdynamic Surgery in Non-Muscle-Invasive Bladder Cancer.

PDD or WL Resection of Tumors in NMIBCIn this open-label trial, patients with intermediate- or high-risk non-muscle-invasive bladder cancer at diagnosis were randomly assigned to photodynamic diagnosis or white light-guided transurethral resection of bladder tumor. Three-year recurrence-free rates were 57.8% and 61.6% in the PDD and WL groups, respectively, with no difference in quality-adjusted life years between the treatment groups at 3 years.

Provision of the progestogen-only pill by community pharmacies as bridging contraception for women receiving emergency contraception: the Bridge-it RCT.

INTRODUCTION: Unless women start effective contraception after using emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies that are unable to provide ongoing contraception (apart from barrier methods which have high failure rates). This means that women need an appointment with a general practitioner or at a sexual and reproductive health clinic. We conducted a pragmatic cluster randomised cohort crossover trial to determine whether or not pharmacist provision of a bridging supply of a progestogen-only pill plus the invitation to attend a sexual and reproductive health clinic resulted in increased subsequent use of effective contraception (hormonal or intrauterine). METHODS: Twenty-nine pharmacies in three UK cities recruited women receiving emergency contraception (levonorgestrel). In the intervention, women received a 3-month supply of the progestogen-only pill (75 µg of desogestrel) plus a card that provided rapid access to a local sexual and reproductive health clinic. In the control arm, pharmacists advised women to attend their usual contraceptive provider. The primary outcome was reported use of an effective contraception (hormonal and intrauterine methods) at 4 months. Process evaluation was also conducted to inform any future implementation. RESULTS: The study took place December 2017 and June 2019 and recruited 636 women to the intervention (n = 316) and control groups (n = 320). There were no statistically significant differences in demographic characteristics between the groups. Four-month follow-up data were available for 406 participants: 63% (198/315) of the control group and 65% (208/318) of the intervention group. The proportion of participants reporting use of effective contraception was 20.1% greater (95% confidence interval 5.2% to 35.0%) in the intervention group (58.4%, 95% confidence interval 48.6% to 68.2%) than in the control group (40.5%, 95% confidence interval 29.7% to 51.3%) (adjusted for recruitment period, treatment arm and centre; p = 0.011). The proportion of women using effective contraception remained statistically significantly larger, when adjusted for age, current sexual relationship and history of past use of effective contraception, and was robust to the missing data. There were no serious adverse events. CONCLUSION: Provision of a bridging supply of the progestogen-only pill with emergency contraception from a pharmacist and the invitation to a sexual and reproductive health clinic resulted in a significant increase in self-reported subsequent use of effective contraception. This simple intervention has the potential to prevent more unintended pregnancies for women after emergency contraception. TRIAL REGISTRATION: Current Controlled Trials ISRCTN70616901. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 27. See the NIHR Journals Library website for further project information.

The emergency contraceptive pill can prevent pregnancy following unprotected sex or a burst condom; however, unless women start a regular method of contraception they remain at risk of pregnancy. Most women obtain emergency contraception from a community pharmacy (chemist), but then require an appointment with a general practitioner or at a sexual and reproductive health clinic for ongoing contraception. Getting an appointment can take time and unintended pregnancies can occur during this time. If a pharmacist could give women a small supply of a progestogen-only pill or 'mini-pill' with their emergency contraception, together with help to get an appointment at a clinic, then this might help more women to start effective contraception. We undertook a study in 29 pharmacies in Lothian, Tayside and London among women receiving emergency contraception. Pharmacists provided either their standard advice about contraception (control group) or the intervention. The intervention was a 3-month supply of the progestogen-only pill plus a rapid-access card, which, if presented at a sexual and reproductive health clinic, would help women get an appointment for contraception. The order in which the pharmacy provided either control or intervention was randomised. We conducted telephone interviews with the women 4 months later to find out what contraception they were using. A total of 636 women took part in the study, 316 in the intervention group and 320 in the control group. The proportion who said that they were using an effective method of contraception was around 20% larger in the intervention group. In addition, fewer women in this group said that they had used emergency contraception again. This study shows that community pharmacy provision of a small supply of progestogen-only pills and the invitation to attend a sexual and reproductive health clinic results in a large increase in the use of effective contraception after emergency contraception. If this became routine practice then it could help prevent unintended pregnancies.

Use of effective contraception following provision of the progestogen-only pill for women presenting to community pharmacies for emergency contraception (Bridge-It): a pragmatic cluster-randomised crossover trial.

BACKGROUND: Unless women start effective contraception after oral emergency contraception, they remain at risk of unintended pregnancy. Most women in the UK obtain emergency contraception from community pharmacies. We hypothesised that pharmacist provision of the progestogen-only pill as a bridging interim method of contraception with emergency contraception plus an invitation to a sexual and reproductive health clinic, in which all methods of contraception are available, would result in increased subsequent use of effective contraception. METHODS: We did a pragmatic cluster-randomised crossover trial in 29 UK pharmacies among women receiving levonorgestrel emergency contraception. Women aged 16 years or older, not already using hormonal contraception, not on medication that could interfere with the progestogen-only pill, and willing to give contact details for follow-up were invited to participate. In the intervention group, women received a 3-month supply of the progestogen-only pill (75 µg desogestrel) plus a rapid access card to a participating sexual and reproductive health clinic. In the control group, pharmacists advised women to attend their usual contraceptive provider. The order in which each pharmacy provided the intervention or control was randomly assigned using a computer software algorithm. The primary outcome was the use of effective contraception (hormonal or intrauterine) at 4 months. This study is registered, ISRCTN70616901 (complete). FINDINGS: Between Dec 19, 2017, and June 26, 2019, 636 women were recruited to the intervention group (316 [49·6%], mean age 22·7 years [SD 5·7]) or the control group (320 [50·3%], 22·6 years [5·1]). Three women (one in the intervention group and two in the control group) were excluded after randomisation. 4-month follow-up data were available for 406 (64%) participants, 25 were lost to follow-up, and two participants no longer wanted to participate in the study. The proportion of women using effective contraception was 20·1% greater (95% CI 5·2-35·0) in the intervention group (mean 58·4%, 48·6-68·2), than in the control group (mean 40·5%, 29·7-51·3 [adjusted for recruitment period, treatment group, and centre]; p=0·011).The difference remained significant after adjusting for age, current sexual relationship, and history of effective contraception use, and was robust to the effect of missing data (assuming missingness at random). No serious adverse events occurred. INTERPRETATION: Provision of a supply of the progestogen-only pill with emergency contraception from a community pharmacist, along with an invitation to a sexual and reproductive health clinic, results in a clinically meaningful increase in subsequent use of effective contraception. Widely implemented, this practice could prevent unintended pregnancies after use of emergency contraception. FUNDING: National Institute for Health Research (Health Technology Assessment Programme project 15/113/01).

Cardiovascular Effects of Switching From Tobacco Cigarettes to Electronic Cigarettes.

BACKGROUND: E-cigarette (EC) use is increasing exponentially worldwide. The early cardiovascular effects of switching from tobacco cigarettes (TC) to EC in chronic smokers is unknown. Meta-analysis of flow-mediated dilation (FMD) studies indicate 13% lower pooled, adjusted relative risks of cardiovascular events with every 1% improvement in FMD. OBJECTIVES: This study sought to determine the early vascular impact of switching from TC to EC in chronic smokers. METHODS: The authors conducted a prospective, randomized control trial with a parallel nonrandomized preference cohort and blinded endpoint of smokers ≥18 years of age who had smoked ≥15 cigarettes/day for ≥2 years and were free from established cardiovascular disease. Participants were randomized to EC with nicotine or EC without nicotine for 1 month. Those unwilling to quit continued with TC in a parallel preference arm. A propensity score analysis was done to adjust for differences between the randomized and preference arms. Vascular function was assessed by FMD and pulse wave velocity. Compliance with EC was measured by carbon monoxide levels. RESULTS: Within 1 month of switching from TC to EC, there was a significant improvement in endothelial function (linear trend ß = 0.73%; 95% confidence interval [CI]: 0.41 to 1.05; p < 0.0001; TC vs. EC combined: 1.49%; 95% CI: 0.93 to 2.04; p < 0.0001) and vascular stiffness (-0.529 m/s; 95% CI: -0.946 to -0.112; p = 0.014). Females benefited from switching more than males did in every between-group comparison. Those who complied best with EC switch demonstrated the largest improvement. There was no difference in vascular effects between EC with and without nicotine within the study timeframe. CONCLUSIONS: TC smokers, particularly females, demonstrate significant improvement in vascular health within 1 month of switching from TC to EC. Switching from TC to EC may be considered a harms reduction measure. (Vascular Effects of Regular Cigarettes Versus Electronic Cigarette Use [VESUVIUS]; NCT02878421; ISRCTN59133298).

Increased mortality and morbidity in patients with chronic hypoparathyroidism: A population-based study.

OBJECTIVES: A population-based study was undertaken to determine the mortality and morbidity for people with hypoparathyroidism compared to the general population. METHODS: In this study, patients identified with chronic hypoparathyroidism using data linkage from regional datasets were compared with five age- and gender-matched controls from the general population. Data from biochemistry, hospital admissions, prescribing and the demographic dataset were linked. Outcomes for mortality and specified conditions were examined for all patients and subdivided into post-surgical and non-surgical cases of hypoparathyroidism. RESULTS: All patients had an increased risk of epilepsy (HR 1.65 [95% CI 1.12-2.44]) and cataracts (HR 2.10 [1.30-3.39]) but no increased fracture risk. Only non-surgical hypoparathyroid patients also had increased mortality (HR 2.11 [1.49-2.98]), cardiovascular disease (HR 2.18 [1.41-3.39]), cerebrovascular disease (HR 2.95 [1.46-5.97]), infection (HR 1.87 [1.2-2.92]) and mental illness (HR 1.59 [1.21-2.11]). There was an increased risk of renal failure (HR 10.05 [95% CI 4.71-21.43]) during the first 2000 days (5.5 years) of follow-up. Renal failure and death were associated with increasing serum calcium concentrations. CONCLUSION: Patients with hypoparathyroidism have an increased risk of cataract and epilepsy. Non-surgical hypoparathyroidism is associated with increased mortality and additional morbidities.

Amputation-free survival in 17,353 people at high risk for foot ulceration in diabetes: a national observational study.

AIMS/HYPOTHESIS: Our aim was to investigate amputation-free survival in people at high risk for foot ulceration in diabetes ('high-risk foot'), and to compare different subcategories of high-risk foot. METHODS: Overall, 17,353 people with diabetes and high-risk foot from January 2008 to December 2011 were identified from the Scotland-wide diabetes register (Scottish Care Information-Diabetes: N = 247,278). Participants were followed-up for up to 2 years from baseline and were categorised into three groups: (1) those with no previous ulcer, (2) those with an active ulcer or (3) those with a healed previous ulcer. Participants with prior minor or major amputation were excluded. Accelerated failure time models were used to compare amputation-free survival up to 2 years between the three exposure groups. RESULTS: The 2 year amputation-free survival rate in all people with diabetes with high-risk foot was 84.5%. In this study group, 270 people (10.0%) had an amputation and 2424 (90.0%) died during the 2 year follow-up period. People who had active and healed previous ulcers at baseline had significantly lower 2 year amputation-free survival compared with those who had no previous ulcer (both p < 0.0001). The percentage of people who died within 2 years for those with healed ulcer, active ulcer or no baseline ulcer was 22.8%, 16% and 12.1%, respectively. CONCLUSIONS/INTERPRETATION: In people judged to be at high risk of foot ulceration, the risk of death was up to nine times the risk of amputation. Death rates were higher for people with diabetes who had healed ulcers than for those with active ulcers. However, people with active ulcers had the highest risk of amputation.

Association Between Objectively Measured Physical Activity and Opioid, Hypnotic, or Anticholinergic Medication Use in Older People: Data from the Physical Activity Cohort Scotland Study.

BACKGROUND: Centrally acting medications cause cognitive slowing and incoordination, which could reduce older people's physical activity levels. This association has not been studied previously. OBJECTIVES: The aim of this study was to examine the association between opioid, hypnotic and anticholinergic medication, and objectively measured physical activity, in a cohort of older people. METHODS: We used data from the Physical Activity Cohort Scotland, a representative cohort of community-dwelling older people aged 65 years and over who were assessed at baseline and again 2-3 years later. Objective physical activity was measured using Stayhealthy RT3 accelerometers over 7 days. Baseline medication use (opioid use, hypnotic use, modified Anticholinergic Risk Scale [mARS]) was obtained from linked, routinely collected community prescribing records. Cross-sectional and longitudinal associations between baseline medication use and both baseline activity and change in activity over time were analysed using unadjusted and adjusted linear regression models. RESULTS: Overall, 310 participants were included in the analysis; mean age 77 years (standard deviation 7). No association was seen between baseline use of any medication class and baseline physical activity levels in unadjusted or adjusted models. For change in activity over time, there was no difference between users and non-users of hypnotics or opioids. Higher anticholinergic burden was associated with a steeper decline in activity over the follow-up period (mARS 0: - 7051 counts/24 h/year; mARS 1-2: - 15,942 counts/24 h/year; mARS ≥ 3: - 19,544 counts/24 h/year; p = 0.03) and this remained robust to multiple adjustments. CONCLUSION: Anticholinergic burden is associated with greater decline in objectively measured physical activity over time in older people, a finding not seen with hypnotic or opioid use.

A Population-Based Study of the Epidemiology of Chronic Hypoparathyroidism.

There are very few reports on the epidemiology of chronic hypoparathyroidism. A population-based study was undertaken to describe the prevalence and incidence of hypoparathyroidism in Tayside, Scotland. Data on biochemistry, hospital admissions, prescribing, and death records in Tayside, Scotland, from 1988 to 2015 were linked electronically. Patients with at least three serum albumin-corrected calcium concentrations below the reference range that were taken in an outpatient setting were included in the study. Patients with severe chronic kidney disease before low calcium were excluded from the study. Patients with hypocalcemia were included if they had either previous neck surgery/irradiation, a low serum parathyroid hormone (PTH), or were treated with vitamin D. Patients were identified as having either a postsurgical or a nonsurgical cause or had secondary hypoparathyroidism, eg, hypomagnesemia. Overall, 18,955 patients were identified with hypocalcemia. Of these, 222 patients had primary hypoparathyroidism, 116 with postsurgical and 106 with nonsurgical chronic hypoparathyroidism. In 2015, the prevalence of primary hypoparathyroidism was 40 per 100,000, with a rate of 23 and 17 per 100,000, respectively, for postsurgical and nonsurgical. Eighty percent of the former and 64% of the latter were female. The mean serum calcium at diagnosis was 1.82 mmol/L (SD ± 0.24) and the annual incidence varied from 1-4 per 100,000. Overall, 71% of patients were prescribed vitamin D and/or calcium, whereas activated vitamin D was used in 48% of postsurgical cases and 43% of nonsurgical cases. Thyroxine and/or hydrocortisone were prescribed in more than 90% of postsurgical and 64% of nonsurgical cases. In conclusion, the prevalence of nonsurgical chronic hypoparathyroidism was greater than previously reported using this population-based approach. Many had mild hypocalcemia and did not receive any treatment. © 2017 American Society for Bone and Mineral Research.

Has primary care antimicrobial use really been increasing? Comparison of changes in different prescribing measures for a complete geographic population 1995-2014.

Objectives: To elucidate how population trends in total antimicrobials dispensed in the community translate into individual exposure. Methods: Retrospective, population-based observational study of all antimicrobial prescribing in a Scottish region in financial years 1995, 2000 and 2005-14. Analysis of temporal changes in all antimicrobials and specific antimicrobials measured in: WHO DDD per 1000 population; prescriptions per 1000 population; proportion of population with ≥1 prescription; mean number of prescriptions per person receiving any; mean DDD per prescription. Results: Antimicrobial DDD increased between 1995 and 2014, from 5651 to 6987 per 1000 population [difference 1336 (95% CI 1309-1363)]. Prescriptions per 1000 fell (from 821 to 667, difference -154, -151 to -157), as did the proportion prescribed any antimicrobial [from 39.3% to 30.8% (-8.5, -8.4 to -8.6)]. Rising mean DDD per prescription, from 6.88 in 1995 to 10.47 in 2014 (3.59, 3.55-3.63), drove rising total DDD. In the under-5s, every measure fell over time (68.2% fall in DDD per 1000; 60.7% fall in prescriptions per 1000). Among 5-64 year olds, prescriptions per 1000 were lowest in 2014 but among older people, despite a reduction since 2010, the 2014 rate was still higher than in 2000. Trends in individual antimicrobials provide some explanation for overall trends. Conclusions: Rising antimicrobial volumes up to 2011 were mainly due to rising DDD per prescription. Trends in dispensed drug volumes do not readily translate into information on individual exposure, which is more relevant for adverse consequences including emergence of resistance.

Factors associated with change in objectively measured physical activity in older people - data from the physical activity cohort Scotland study.

BACKGROUND: Cross-sectional relationships between physical activity and health have been explored extensively, but less is known about how physical activity changes with time in older people. The aim of this study was to assess baseline predictors of how objectively measured physical activity changes with time in older people. METHODS: Longitudinal cohort study using data from the Physical Activity Cohort Scotland. A sample of community-dwelling older people aged 65 and over were recruited in 2009-2011, then followed up 2-3 years later. Physical activity was measured using Stayhealthy RT3 accelerometers over 7 days. Other data collected included baseline comorbidity, health-related quality of life (SF-36), extended Theory of Planned Behaviour Questionnaire and Social Capital Module of the General Household Survey. Associations between follow-up accelerometer counts and baseline predictors were analysed using a series of linear regression models, adjusting for baseline activity levels and follow-up time. RESULTS: Follow up data were available for 339 of the original 584 participants. The mean age was 77 years, 185 (55%) were female and mean follow up time was 26 months. Mean activity counts fell by between 2% per year (age < =80, deprivation decile 5-10) and 12% per year (age > 80, deprivation decile 5-10) from baseline values. In univariate analysis age, sex, deprivation decile, most SF-36 domains, most measures of social connectedness, most measures from the extended Theory of Planned Behaviour, hypertension, diabetes mellitus, chronic pain and depression score were significantly associated with adjusted activity counts at follow-up. In multivariate regression age, satisfactory friend network, SF-36 physical function score, and the presence of diabetes mellitus were independent predictors of activity counts at follow up after adjustment for baseline count and duration of follow up. CONCLUSIONS: Health status and social connectedness, but not extended Theory of Planned Behaviour measures, independently predicted changes in physical activity in community dwelling older people.

Risk of postoperative acute kidney injury in patients undergoing orthopaedic surgery--development and validation of a risk score and effect of acute kidney injury on survival: observational cohort study.

STUDY QUESTION: What is the predicted risk of acute kidney injury after orthopaedic surgery and does it affect short term and long term survival? METHODS: The cohort comprised adults resident in the National Health Service Tayside region of Scotland who underwent orthopaedic surgery from 1 January 2005 to 31 December 2011. The model was developed in 6220 patients (two hospitals) and externally validated in 4395 patients from a third hospital. Several preoperative variables were selected for candidate predictors, based on literature, clinical expertise, and availability in the orthopaedic surgery setting. The main outcomes were the development of any severity of acute kidney injury (stages 1-3) within the first postoperative week, and 90 day, one year, and longer term survival. STUDY ANSWER AND LIMITATIONS: Using logistic regression analysis, independent predictors of acute kidney injury were older age, male sex, diabetes, number of prescribed drugs, lower estimated glomerular filtration rate, use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers, and American Society of Anesthesiologists grade. The model's predictive performance for discrimination was good (C statistic 0.74 in development cohort, 0.70 in validation cohort). Calibration was good in the development cohort and after recalibration in the validation cohort. Only the highest risks were over-predicted. Survival was worse in patients with acute kidney injury compared with those without (adjusted hazard ratio 1.53, 95% confidence interval 1.38 to 1.70). This was most noticeable in the short term (adjusted hazard ratio: 90 day 2.36, 1.94 to 2.87) and diminished over time (90 day-one year 1.40, 1.10 to 1.79; >1 year 1.28, 1.10 to 1.48). The model used routinely collected data in the orthopaedic surgery setting therefore some variables that could potentially improve predictive performance were not available. However, the readily available predictors make the model easily applicable. WHAT THIS STUDY ADDS: A preoperative risk prediction model consisting of seven predictors for acute kidney injury was developed, with good predictive performance in patients undergoing orthopaedic surgery. Survival was significantly poorer in patients even with mild (stage 1) postoperative acute kidney injury. FUNDING, COMPETING INTERESTS, DATA SHARING: SB received grants from Tenovus Tayside, Chief Scientist Office, and the Royal College of Physicians and Surgeons of Glasgow; PT receives grants from Novo Nordisk, GlaxoSmithKline, and the New Drugs Committee of the Scottish Medicines Consortium. No additional data are available.

Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS).

OBJECTIVE: The aim of this study was to determine the extent of drug interactions affecting levothyroxine, using study drugs often co-administered to patients on long-term levothyroxine therapy. DESIGN: A retrospective population analysis linking biochemistry and prescription data between 1 January 1993 and 31 December 2012 was used. PATIENTS: The study population was Tayside residents prescribed levothyroxine on at least three occasions, within a six-month period, prior to the start of a study drug. Individuals acted as their own controls pre- and postinitiation of study drug. Overall, 10 999 patients (mean age 58 years, 82% female) being treated with thyroxine were included in the study. MEASUREMENTS: Changes in TSH following initiation of study drug. RESULTS: Iron, calcium, proton pump inhibitors and oestrogen all increased serum TSH concentration: an increase of 0·22 mU/l (P < 0.001), 0·27 mU/l (P < 0·001), 0·12 mU/l (P < 0·01), and 0·08 mU/l (P < 0·007), respectively. For these four study drugs, there was a clinically significant increase of over 5 mU/l in serum TSH, in 7·5%, 4·4%, 5·6% and 4·3% patients, respectively. There was a decrease of 0·17 mU/l (P-value 0.01) in the TSH concentration for those patients on statins. The TSH decreased by 5 mU/l in 3·7% of patients. There was no effect with H2 receptor antagonists or glucocorticoids. CONCLUSION: This large population-based study demonstrates significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, statins and oestrogens. These drugs may reduce the effectiveness of levothyroxine, and patients' TSH concentrations should be carefully monitored.

Dog ownership and physical activity in later life: a cross-sectional observational study.

OBJECTIVE: To examine whether dog ownership amongst community dwelling older adults (≥ 65 years) is associated with objectively measured physical activity (PA). METHODS: We used data from the Physical Activity Cohort Scotland (PACS) which consists of 547 people aged 65 and over, resident in the community in Tayside, Scotland. The data was collected in 2009-2011. We assessed whether dog ownership is associated with objectively measured physical activity (accelerometry counts). RESULTS: The physical activity (PA) counts of 547 older people (mean age 79 (standard deviation (SD) 8 years, 54% female) were analysed. Linear mixed models showed that dog ownership was positively related to higher PA levels. This positive relationship remained after controlling for a large number of individual and contextual variables, including attitude towards exercise, physical activity intention and history of physical activity. Dog owners were found to be 12% more active (21,875 counts, 95% Confidence Interval (CI): 2810 to 40,939, p<0.05) than non-dog owners. CONCLUSION: Dog ownership is associated with physical activity in later life. Interventions to increase activity amongst older people might usefully attempt to replicate elements of the dog ownership experience.

Risk of AKI with gentamicin as surgical prophylaxis.

In 2009, the Scottish government issued a target to reduce Clostridium difficile infection by 30% in 2 years. Consequently, Scottish hospitals changed from cephalosporins to gentamicin for surgical antibiotic prophylaxis. This study examined rates of postoperative AKI before and after this policy change. The study population comprised 12,482 adults undergoing surgery (orthopedic, urology, vascular, gastrointestinal, and gynecology) with antibiotic prophylaxis between October 1, 2006, and September 30, 2010 in the Tayside region of Scotland. Postoperative AKI was defined by the Kidney Disease Improving Global Outcomes criteria. The study design was an interrupted time series with segmented regression analysis. In orthopedic patients, change in policy from cefuroxime to flucloxacillin (two doses of 1 g) and single-dose gentamicin (4 mg/kg) was associated with a 94% increase in AKI (P=0.04; 95% confidence interval, 93.8% to 94.3%). Most patients who developed AKI after prophylactic gentamicin had stage 1 AKI, but some patients developed persistent stage 2 or stage 3 AKI. The antibiotic policy change was not associated with a significant increase in AKI in the other groups. Regardless of antibiotic regimen, however, rates of AKI were high (24%) after vascular surgery, and increased steadily after gastrointestinal surgery. Rates could only be ascertained in 52% of urology patients and 47% of gynecology patients because of a lack of creatinine testing. These results suggest that gentamicin should be avoided in orthopedic patients in the perioperative period. Our findings also raise concerns about the increasing prevalence of postoperative AKI and failures to consistently measure postoperative renal function.