Large socioeconomic gap in period life expectancy and life years spent with complications of diabetes in the Scottish population with type 1 diabetes, 2013-2018.

BACKGROUND: We report the first study to estimate the socioeconomic gap in period life expectancy (LE) and life years spent with and without complications in a national cohort of individuals with type 1 diabetes. METHODS: This retrospective cohort study used linked healthcare records from SCI-Diabetes, the population-based diabetes register of Scotland. We studied all individuals aged 50 and older with a diagnosis of type 1 diabetes who were alive and residing in Scotland on 1 January 2013 (N = 8591). We used the Scottish Index of Multiple Deprivation (SIMD) 2016 as an area-based measure of socioeconomic deprivation. For each individual, we constructed a history of transitions by capturing whether individuals developed retinopathy/maculopathy, cardiovascular disease, chronic kidney disease, and diabetic foot, or died throughout the study period, which lasted until 31 December 2018. Using parametric multistate survival models, we estimated total and state-specific LE at an attained age of 50. RESULTS: At age 50, remaining LE was 22.2 years (95% confidence interval (95% CI): 21.6 - 22.8) for males and 25.1 years (95% CI: 24.4 - 25.9) for females. Remaining LE at age 50 was around 8 years lower among the most deprived SIMD quintile when compared with the least deprived SIMD quintile: 18.7 years (95% CI: 17.5 - 19.9) vs. 26.3 years (95% CI: 24.5 - 28.1) among males, and 21.2 years (95% CI: 19.7 - 22.7) vs. 29.3 years (95% CI: 27.5 - 31.1) among females. The gap in life years spent without complications was around 5 years between the most and the least deprived SIMD quintile: 4.9 years (95% CI: 3.6 - 6.1) vs. 9.3 years (95% CI: 7.5 - 11.1) among males, and 5.3 years (95% CI: 3.7 - 6.9) vs. 10.3 years (95% CI: 8.3 - 12.3) among females. SIMD differences in transition rates decreased marginally when controlling for time-updated information on risk factors such as HbA1c, blood pressure, BMI, or smoking. CONCLUSIONS: In addition to societal interventions, tailored support to reduce the impact of diabetes is needed for individuals from low socioeconomic backgrounds, including access to innovations in management of diabetes and the prevention of complications.

Flash monitor initiation is associated with improvements in HbA1c levels and DKA rates among people with type 1 diabetes in Scotland: a retrospective nationwide observational study.

AIMS/HYPOTHESIS: We assessed the real-world effect of flash monitor (FM) usage on HbA1c levels and diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH) rates among people with type 1 diabetes in Scotland and across sociodemographic strata within this population. METHODS: This study was retrospective, observational and registry based. Using the national diabetes registry, 14,682 individuals using an FM at any point between 2014 and mid-2020 were identified. Within-person change from baseline in HbA1c following FM initiation was modelled using linear mixed models accounting for within-person pre-exposure trajectory. DKA and SHH events were captured through linkage to hospital admission and mortality data. The difference in DKA and SHH rates between FM-exposed and -unexposed person-time was assessed among users, using generalised linear mixed models with a Poisson likelihood. In a sensitivity analysis, we tested whether changes in these outcomes were seen in an age-, sex- and baseline HbA1c-matched sample of non-users over the same time period. RESULTS: Prevalence of ever-FM use was 45.9% by mid-2020, with large variations by age and socioeconomic status: 64.3% among children aged <13 years vs 32.7% among those aged ≥65 years; and 54.4% vs 36.2% in the least-deprived vs most-deprived quintile. Overall, the median (IQR) within-person change in HbA1c in the year following FM initiation was -2.5 (-9.0, 2.5) mmol/mol (-0.2 [-0.8, 0.2]%). The change varied widely by pre-usage HbA1c: -15.5 (-31.0, -4.0) mmol/mol (-1.4 [-2.8, -0.4]%) in those with HbA1c > 84 mmol/mol [9.8%] and 1.0 (-2.0, 5.5) mmol/mol (0.1 [-0.2, 0.5]%) in those with HbA1c < 54 mmol/mol (7.1%); the corresponding estimated fold change (95% CI) was 0.77 (0.76, 0.78) and 1.08 (1.07, 1.09). Significant reductions in HbA1c were found in all age bands, sexes and socioeconomic strata, and regardless of prior/current pump use, completion of a diabetes education programme or early FM adoption. Variation between the strata of these factors beyond that driven by differing HbA1c at baseline was slight. No change in HbA1c in matched non-users was observed in the same time period (median [IQR] within-person change = 0.5 [-5.0, 5.5] mmol/mol [0.0 (-0.5, 0.5)%]). DKA rates decreased after FM initiation overall and in all strata apart from the adolescents. Estimated overall reduction in DKA event rates (rate ratio) was 0.59 [95% credible interval (CrI) 0.53, 0.64]) after FM vs before FM initiation, accounting for pre-exposure trend. Finally, among those at higher risk for SHH, estimated reduction in event rates was rate ratio 0.25 (95%CrI 0.20, 0.32) after FM vs before FM initiation. CONCLUSIONS/INTERPRETATION: FM initiation is associated with clinically important reductions in HbA1c and striking reduction in DKA rate. Increasing uptake among the socioeconomically disadvantaged offers considerable potential for tightening the current socioeconomic disparities in glycaemia-related outcomes.

Rising Rates and Widening Socioeconomic Disparities in Diabetic Ketoacidosis in Type 1 Diabetes in Scotland: A Nationwide Retrospective Cohort Observational Study.

OBJECTIVE: Whether advances in the management of type 1 diabetes are reducing rates of diabetic ketoacidosis (DKA) is unclear. We investigated time trends in DKA rates in a national cohort of individuals with type 1 diabetes monitored for 14 years, overall and by socioeconomic characteristics. RESEARCH DESIGN AND METHODS: All individuals in Scotland with type 1 diabetes who were alive and at least 1 year old between 1 January 2004 and 31 December 2018 were identified using the national register (N = 37,939). DKA deaths and hospital admissions were obtained through linkage to Scottish national death and morbidity records. Bayesian regression was used to test for DKA time trends and association with risk markers, including socioeconomic deprivation. RESULTS: There were 30,427 DKA admissions and 472 DKA deaths observed over 393,223 person-years at risk. DKA event rates increased over the study period (incidence rate ratio [IRR] per year 1.058 [95% credibility interval 1.054-1.061]). Males had lower rates than females (IRR male-to-female 0.814 [0.776-0.855]). DKA incidence rose in all age-groups other than 10- to 19-year-olds, in whom rates were the highest, but fell over the study. There was a large socioeconomic differential (IRR least-to-most deprived quintile 0.446 [0.406-0.490]), which increased during follow-up. Insulin pump use or completion of structured education were associated with lower DKA rates, and antidepressant and methadone prescription were associated with higher DKA rates. CONCLUSIONS: DKA incidence has risen since 2004, except in 10- to 19-year-olds. Of particular concern are the strong and widening socioeconomic disparities in DKA outcomes. Efforts to prevent DKA, especially in vulnerable groups, require strengthening.

Divergence-time estimates for hominins provide insight into encephalization and body mass trends in human evolution.

Quantifying speciation times during human evolution is fundamental as it provides a timescale to test for the correlation between key evolutionary transitions and extrinsic factors such as climatic or environmental change. Here, we applied a total evidence dating approach to a hominin phylogeny to estimate divergence times under different topological hypotheses. The time-scaled phylogenies were subsequently used to perform ancestral state reconstructions of body mass and phylogenetic encephalization quotient (PEQ). Our divergence-time estimates are consistent with other recent studies that analysed extant species. We show that the origin of the genus Homo probably occurred between 4.30 and 2.56 million years ago. The ancestral state reconstructions show a general trend towards a smaller body mass before the emergence of Homo, followed by a trend towards a greater body mass. PEQ estimations display a general trend of gradual but accelerating encephalization evolution. The obtained results provide a rigorous temporal framework for human evolution.

Marked improvements in glycaemic outcomes following insulin pump therapy initiation in people with type 1 diabetes: a nationwide observational study in Scotland.

AIMS/HYPOTHESIS: Our aim was to assess the use of continuous subcutaneous insulin infusion (CSII) in people with type 1 diabetes in Scotland and its association with glycaemic control, as measured by HbA1c levels, frequency of diabetic ketoacidosis (DKA) and severe hospitalised hypoglycaemia (SHH), overall and stratified by baseline HbA1c. METHODS: We included 4684 individuals with type 1 diabetes from the national Scottish register, who commenced CSII between 2004 and 2019. We presented crude within-person differences from baseline HbA1c over time since initiation, crude DKA and SHH event-rates pre-/post-CSII exposure. We then used mixed models to assess the significance of CSII exposure, taking into account: (1) the diffuse nature of the intervention (i.e. structured education often precedes initiation); (2) repeated within-person measurements; and (3) background time-trends occurring pre-intervention. RESULTS: HbA1c decreased after CSII initiation, with a median within-person change of -5.5 mmol/mol (IQR -12.0, 0.0) (-0.5% [IQR -1.1, 0.0]). Within-person changes were most substantial in those with the highest baseline HbA1c, with median -21.0 mmol/mol (-30.0, -11.0) (-1.9% [-2.7, -1.0]) change in those with a baseline >84 mmol/mol (9.8%) within a year of exposure, that was sustained: -19.0 mmol/mol (-27.6, -6.5) (-1.7% [-2.5, -0.6]) at ≥5 years. Statistical significance and magnitude of change were supported by the mixed models results. The crude DKA event-rate was significantly lower in post-CSII person-time compared with pre-CSII person-time: 49.6 events (95% CI 46.3, 53.1) per 1000 person-years vs 67.9 (64.1, 71.9); rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.61 (95% credible interval [CrI] 0.47, 0.77; posterior probability of reduction pp = 1.00). The crude overall SHH event-rate in post-CSII vs pre-CSII person-time was also lower: 17.8 events (95% CI 15.8, 19.9) per 1000 person-years post-exposure vs 25.8 (23.5, 28.3) pre-exposure; rate ratio from Bayesian mixed models adjusting for pre-exposure trend: 0.67 (95% CrI 0.45, 1.01; pp = 0.97). CONCLUSIONS/INTERPRETATION: CSII therapy was associated with marked falls in HbA1c especially in those with high baseline HbA1c. CSII was independently associated with reduced DKA and SHH rates. CSII appears to be an effective option for intensive insulin therapy in people with diabetes for improving suboptimal glycaemic control.

The association of polypharmacy and high-risk drug classes with adverse health outcomes in the Scottish population with type 1 diabetes.

AIMS/HYPOTHESIS: The aim of this work was to map the number of prescribed drugs over age, sex and area-based socioeconomic deprivation, and to examine the association between the number of drugs and particular high-risk drug classes with adverse health outcomes among a national cohort of individuals with type 1 diabetes. METHODS: Utilising linked healthcare records from the population-based diabetes register of Scotland, we identified 28,245 individuals with a diagnosis of type 1 diabetes on 1 January 2017. For this population, we obtained information on health status, predominantly reflecting diabetes-related complications, and information on the total number of drugs and particular high-risk drug classes prescribed. We then studied the association of these baseline-level features with hospital admissions for falls, diabetic ketoacidosis (DKA), and hypoglycaemia or death within the subsequent year using multivariate Cox proportional hazards models. RESULTS: Not considering insulin and treatment for hypoglycaemia, the mean number of prescribed drugs was 4.00 (SD 4.35). The proportion of individuals being prescribed five or more drugs at baseline consistently increased with age (proportion [95% CI]: 0-19 years 2.04% [1.60, 2.49]; 40-49 years 28.50% [27.08, 29.93]; 80+ years 76.04% [67.73, 84.84]). Controlling for age, sex, area-based socioeconomic deprivation and health status, each additional drug at baseline was associated with an increase in the hazard for hospitalisation for falls, hypoglycaemia and death but not for DKA admissions (HR [95% CI]: falls 1.03 [1.01, 1.06]; DKA 1.01 [1.00, 1.03]; hypoglycaemia 1.05 [1.02, 1.07]; death 1.04 [1.02, 1.06]). We found a number of drug classes to be associated with an increased hazard of one or more of these adverse health outcomes, including antithrombotic/anticoagulant agents, corticosteroids, opioids, antiepileptics, antipsychotics, hypnotics and sedatives, and antidepressants. CONCLUSIONS: Polypharmacy is common among the Scottish population with type 1 diabetes and is strongly patterned by sociodemographic factors. The number of prescribed drugs and the prescription of particular high-risk drug classes are strong markers of an increased risk of adverse health outcomes, including acute complications of diabetes.

Risks of and risk factors for COVID-19 disease in people with diabetes: a cohort study of the total population of Scotland.

BACKGROUND: We aimed to ascertain the cumulative risk of fatal or critical care unit-treated COVID-19 in people with diabetes and compare it with that of people without diabetes, and to investigate risk factors for and build a cross-validated predictive model of fatal or critical care unit-treated COVID-19 among people with diabetes. METHODS: In this cohort study, we captured the data encompassing the first wave of the pandemic in Scotland, from March 1, 2020, when the first case was identified, to July 31, 2020, when infection rates had dropped sufficiently that shielding measures were officially terminated. The participants were the total population of Scotland, including all people with diabetes who were alive 3 weeks before the start of the pandemic in Scotland (estimated Feb 7, 2020). We ascertained how many people developed fatal or critical care unit-treated COVID-19 in this period from the Electronic Communication of Surveillance in Scotland database (on virology), the RAPID database of daily hospitalisations, the Scottish Morbidity Records-01 of hospital discharges, the National Records of Scotland death registrations data, and the Scottish Intensive Care Society and Audit Group database (on critical care). Among people with fatal or critical care unit-treated COVID-19, diabetes status was ascertained by linkage to the national diabetes register, Scottish Care Information Diabetes. We compared the cumulative incidence of fatal or critical care unit-treated COVID-19 in people with and without diabetes using logistic regression. For people with diabetes, we obtained data on potential risk factors for fatal or critical care unit-treated COVID-19 from the national diabetes register and other linked health administrative databases. We tested the association of these factors with fatal or critical care unit-treated COVID-19 in people with diabetes, and constructed a prediction model using stepwise regression and 20-fold cross-validation. FINDINGS: Of the total Scottish population on March 1, 2020 (n=5 463 300), the population with diabetes was 319 349 (5·8%), 1082 (0·3%) of whom developed fatal or critical care unit-treated COVID-19 by July 31, 2020, of whom 972 (89·8%) were aged 60 years or older. In the population without diabetes, 4081 (0·1%) of 5 143 951 people developed fatal or critical care unit-treated COVID-19. As of July 31, the overall odds ratio (OR) for diabetes, adjusted for age and sex, was 1·395 (95% CI 1·304-1·494; p<0·0001, compared with the risk in those without diabetes. The OR was 2·396 (1·815-3·163; p<0·0001) in type 1 diabetes and 1·369 (1·276-1·468; p<0·0001) in type 2 diabetes. Among people with diabetes, adjusted for age, sex, and diabetes duration and type, those who developed fatal or critical care unit-treated COVID-19 were more likely to be male, live in residential care or a more deprived area, have a COVID-19 risk condition, retinopathy, reduced renal function, or worse glycaemic control, have had a diabetic ketoacidosis or hypoglycaemia hospitalisation in the past 5 years, be on more anti-diabetic and other medication (all p<0·0001), and have been a smoker (p=0·0011). The cross-validated predictive model of fatal or critical care unit-treated COVID-19 in people with diabetes had a C-statistic of 0·85 (0·83-0·86). INTERPRETATION: Overall risks of fatal or critical care unit-treated COVID-19 were substantially elevated in those with type 1 and type 2 diabetes compared with the background population. The risk of fatal or critical care unit-treated COVID-19, and therefore the need for special protective measures, varies widely among those with diabetes but can be predicted reasonably well using previous clinical history. FUNDING: None.

Switching antipsychotic medication to reduce sexual dysfunction in people with psychosis: the REMEDY RCT.

BACKGROUND: Sexual dysfunction is common among people who are prescribed antipsychotic medication for psychosis. Sexual dysfunction can impair quality of life and reduce treatment adherence. Switching antipsychotic medication may help, but the clinical effectiveness and cost-effectiveness of this approach is unclear. OBJECTIVE: To examine whether or not switching antipsychotic medication provides a clinically effective and cost-effective method to reduce sexual dysfunction in people with psychosis. DESIGN: A two-arm, researcher-blind, pilot randomised trial with a parallel qualitative study and an internal pilot phase. Study participants were randomised to enhanced standard care plus a switch of antipsychotic medication or enhanced standard care alone in a 1 : 1 ratio. Randomisation was via an independent and remote web-based service using dynamic adaptive allocation, stratified by age, gender, Trust and relationship status. SETTING: NHS secondary care mental health services in England. PARTICIPANTS: Potential participants had to be aged ≥ 18 years, have schizophrenia or related psychoses and experience sexual dysfunction associated with the use of antipsychotic medication. We recruited only people for whom reduction in medication dosage was ineffective or inappropriate. We excluded those who were acutely unwell, had had a change in antipsychotic medication in the last 6 weeks, were currently prescribed clozapine or whose sexual dysfunction was believed to be due to a coexisting physical or mental disorder. INTERVENTIONS: Switching to an equivalent dose of one of three antipsychotic medications that are considered to have a relatively low propensity for sexual side effects (i.e. quetiapine, aripiprazole or olanzapine). All participants were offered brief psychoeducation and support to discuss their sexual health and functioning. MAIN OUTCOME MEASURES: The primary outcome was patient-reported sexual dysfunction, measured using the Arizona Sexual Experience Scale. Secondary outcomes were researcher-rated sexual functioning, mental health, side effects of medication, health-related quality of life and service utilisation. Outcomes were assessed 3 and 6 months after randomisation. Qualitative data were collected from a purposive sample of patients and clinicians to explore barriers to recruitment. SAMPLE SIZE: Allowing for a 20% loss to follow-up, we needed to recruit 216 participants to have 90% power to detect a 3-point difference in total Arizona Sexual Experience Scale score (standard deviation 6.0 points) using a 0.05 significance level. RESULTS: The internal pilot was discontinued after 12 months because of low recruitment. Ninety-eight patients were referred to the study between 1 July 2018 and 30 June 2019, of whom 10 were randomised. Eight (80%) participants were followed up 3 months later. Barriers to referral and recruitment included staff apprehensions about discussing side effects, reluctance among patients to switch medication and reticence of both staff and patients to talk about sex. LIMITATIONS: Insufficient numbers of participants were recruited to examine the study hypotheses. CONCLUSIONS: It may not be possible to conduct a successful randomised trial of switching antipsychotic medication for sexual functioning in people with psychosis in the NHS at this time. FUTURE WORK: Research examining the acceptability and effectiveness of adjuvant phosphodiesterase inhibitors should be considered. TRIAL REGISTRATION: Current Controlled Trials ISRCTN12307891. 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. 24, No. 44. See the NIHR Journals Library website for further project information.

Antipsychotic medications can improve the mental health of people with psychosis but may also cause side effects. These include sexual side effects, such as reduced desire for sex or less pleasure from having sex. One way to try to tackle this problem is to switch the medicine people take to one that is thought less likely to cause these problems. However, it is unclear if this helps, and switching medication could potentially harm mental health or cause new side effects. We conducted a study to compare the effect of switching with not switching the medication of people with psychosis experiencing sexual side effects. We collected information about sexual functioning, mental health, quality of life and use of services at the start of the study and 6 months later. We also interviewed nurses, doctors and patients to get their views about the study. We recruited 10 patients over a 12-month period and conducted interviews with 51 clinicians and four patients. Many clinicians said that they found it difficult to talk to their patients about sex. Some thought that these problems occurred rarely and that other side effects mattered more to patients. Many patients were concerned about switching their medication, especially when it had improved their mental health. Others felt that these side effects were not very important, and some were not prepared to take part in a trial that could delay a change being made to their medication. We did not collect enough information to be able to find out if switching medication helps people who experience sexual side effects of antipsychotic drugs. It is important that clinicians ask about sexual side effects of antipsychotic medication and that further efforts are made to find ways to help patients who experience them.

Disparities in the analysis of morphological disparity.

Analyses of morphological disparity have been used to characterize and investigate the evolution of variation in the anatomy, function and ecology of organisms since the 1980s. While a diversity of methods have been employed, it is unclear whether they provide equivalent insights. Here, we review the most commonly used approaches for characterizing and analysing morphological disparity, all of which have associated limitations that, if ignored, can lead to misinterpretation. We propose best practice guidelines for disparity analyses, while noting that there can be no 'one-size-fits-all' approach. The available tools should always be used in the context of a specific biological question that will determine data and method selection at every stage of the analysis.

Real-World Use of Oritavancin for the Treatment of Osteomyelitis.

Osteomyelitis is a difficult-to-treat disease that can require both surgical debridement and a prolonged course of antimicrobial therapy. Current standard of care for the antimicrobial treatment of osteomyelitis is fraught with multiple challenges and limitations. Patients typically require the insertion of an indwelling catheter for single or multiple daily intravenous antibiotic infusions for up to 6 weeks. Currently, there are treatment guidelines for only vertebral osteomyelitis, indicating the complexity of the condition. Oritavancin is a long-acting, second-generation lipoglycopeptide, administered intravenously once per week, which has potential to be a useful alternative in the treatment of osteomyelitis. This article reviews occurrence and outcomes of off-label oritavancin use for treatment of osteomyelitis as described in case reports. Analysis included 23 patients treated for osteomyelitis with single- or multiple-dose oritavancin. Overall, clinical cure or improvement was achieved in 87% of patients, and adverse events were mild and reported in only two patients. Clinical efficacy was demonstrated in 81.8% of methicillin-resistant Staphylococcus aureus (MRSA), 71.4% of methicillin-sensitive S. aureus (MSSA), 50% of vancomycin-resistant Enterococcus (VRE), and in the single case of Streptococcus pyogenes. Oritavancin has shown efficacy against Gram-positive pathogens in osteomyelitis, and offers a possible outpatient treatment option for osteomyelitis patients. Future studies are needed to determine dosing frequency in osteomyelitis patients.

Expediting Discharge in Hospitalized, Adult Patients with Skin and Soft Tissue Infections Who Received Empiric Vancomycin Therapy with Oritavancin: Description of Findings from an Institutional Pathway.

BACKGROUND: An internal quality assurance review at AtlantiCare Regional Medical Center (ARMC) revealed that patients admitted with skin and soft tissue infections (SSTIs) remained in hospital post-resolution of acute symptoms and demonstrated a delayed transition to step-down oral antibiotic therapy. A non-mandatory institutional pathway was developed and implemented in 2016 to expedite hospital discharge in hemodynamically stable SSTI patients by utilizing oritavancin. OBJECTIVE: To describe the outcomes associated with use of single-dose oritavancin therapy to expedite hospital discharge in hemodynamically stable inpatients with SSTIs. METHODS: A retrospective, descriptive cohort was evaluated for outcomes of patients with SSTIs who received either oritavancin to expedite discharge or were discharged on oral step-down antibiotics. Patients were included in this analysis if they were: ≥ 18 years old; hospitalized; received empiric vancomycin; not pregnant or nursing; hemodynamically stable at the time of assessment; and received either oritavancin or oral step-down antibiotics to facilitate discharge. The primary outcomes were index hospital length of stay (LOS), 30-day SSTI-related readmissions, and 30-day SSTI progression. RESULTS: Overall, 199 patients met the study criteria (oritavancin = 99 and oral step-down antibiotics = 100). Groups were well matched at baseline. Patients who received oritavancin had a shorter mean index hospital LOS than those in the oral step-down antibiotic group (3.5 days vs. 5.6 days). Patients receiving oritavancin also had lower SSTI 30-day readmission and SSTI-progression rates. CONCLUSIONS: An institutional pathway that used oritavancin to expedite hospital discharge of hemodynamically stable SSTI patients resulted in shorter hospital LOS, less 30-day SSTI-related hospital readmissions, and decreased SSTI progression relative to those discharged on conventional oral step-down therapy.

Clinical Experience with Telavancin for the Treatment of Patients with Bacteremia and Endocarditis: Real-World Results from the Telavancin Observational Use Registry (TOUR™).

BACKGROUND: Bacteremia and endocarditis caused by Staphylococcus aureus (S. aureus), particularly methicillin-resistant S. aureus (MRSA), are challenging to treat and are associated with high morbidity and mortality. Telavancin is a lipoglycopeptide antibacterial active against susceptible Gram-positive pathogens, including MRSA. OBJECTIVE: This registry study assessed the real-world use and clinical outcomes of telavancin in patients with bacteremia or endocarditis enrolled in the Telavancin Observation Use Registry (TOUR™). METHODS: The subset of patients enrolled in TOUR who were diagnosed with endocarditis and/or bacteremia with a known or unknown primary source (N = 151) were analyzed. Data including demographics, infection type, baseline pathogens, prior or concomitant antimicrobial therapy, dosing regimen, clinical response, treatment-emergent adverse events (TEAEs) of interest, and mortality were collected by retrospective medical chart review. RESULTS: Telavancin was primarily used as a second-line or greater therapy (n = 132, 87.4%). MRSA was present in 87 (57.6%) patients. Median telavancin dose was 740.6 mg (interquartile range (IQR) 206.0 mg) and median duration of therapy was 9.0 days (IQR 24.0 days). Of the 132/151 (87.4%) patients with an available assessment at the end of telavancin therapy, a positive clinical response was achieved in 98/132 (74.2%), while 14/132 (10.6%) failed therapy and 20/132 (15.2%) had an indeterminant outcome. TEAEs occurred in 24 (15.9%) patients. The most frequent TEAE was renal failure (n = 12, 7.9%); seven of these patients were receiving concomitant nephrotoxic medications. There was no change in creatinine clearance for 67/89 (75.3%) patients with values recorded at the beginning and the end of telavancin therapy. CONCLUSIONS: In real-world clinical practice, overall positive clinical outcomes are observed in patients with bacteremia or endocarditis treated with telavancin, including in those patients infected with MRSA or another S. aureus pathogen. Telavancin may be an alternative treatment option for these patients. TRIAL REGISTRATION: This trial was registered with clinicaltrials.gov (NCT02288234) on 11 November 2014.

Time trends in deaths before age 50 years in people with type 1 diabetes: a nationwide analysis from Scotland 2004-2017.

AIMS/HYPOTHESIS: We aimed to examine whether crude mortality and mortality relative to the general population below 50 years of age have improved in recent years in those with type 1 diabetes. METHODS: Individuals with type 1 diabetes aged below 50 and at least 1 year old at any time between 2004 and 2017 in Scotland were identified using the national register. Death data were obtained by linkage to Scottish national death registrations. Indirect age standardisation was used to calculate sex-specific standardised mortality ratios (SMRs). Poisson regression was used to test for calendar-time effects as incidence rate ratios (IRRs). RESULTS: There were 1138 deaths in 251,143 person-years among 27,935 people with type 1 diabetes. There was a significant decline in mortality rate over time (IRR for calendar year 0.983 [95% CI 0.967, 0.998], p = 0.03), but the SMR remained approximately stable at 3.1 and 3.6 in men and 4.09 and 4.16 in women for 2004 and 2017, respectively. Diabetic ketoacidosis or coma (DKAoC) accounted for 22% of deaths and the rate did not decline significantly (IRR 0.975 [95% CI 0.94, 1.011], p = 0.168); 79.3% of DKAoC deaths occurred out of hospital. Circulatory diseases accounted for 27% of deaths and did decline significantly (IRR 0.946 [95% CI 0.914, 0.979], p = 0.002). CONCLUSIONS/INTERPRETATION: Absolute mortality has fallen, but the relative impact of type 1 diabetes on mortality below 50 years has not improved. There is scope to improve prevention of premature circulatory diseases and DKAoC and to develop more effective strategies for enabling people with type 1 diabetes to avoid clinically significant hyper- or hypoglycaemia. Graphical abstract.

The Effect of Fossil Sampling on the Estimation of Divergence Times with the Fossilized Birth-Death Process.

Timescales are of fundamental importance to evolutionary biology as they facilitate hypothesis tests of historical evolutionary processes. Through the incorporation of fossil occurrence data, the fossilized birth-death (FBD) process provides a framework for estimating divergence times using more paleontological data than traditional node calibration approaches have allowed. The inclusion of more data can refine evolutionary timescale estimates, but for many taxonomic groups it is computationally infeasible to include all available fossil occurrence data. Here, we utilize both empirical data and a simulation framework to identify approaches to subsampling fossil occurrence data that result in the most accurate estimates of divergence times. To achieve this we assess the performance of the FBD-Skyline model when implementing multiple approaches to incorporating subsampled fossil occurrence data. Our results demonstrate that it is necessary to account for all available fossil occurrence data to achieve the most accurate estimates of clade age. We show that this can be achieved if an empirical Bayes approach, accounting for fossil sampling through time, is applied to the FBD process. Random subsampling of occurrence data can lead to estimates of clade age that are incompatible with fossil evidence if no control over the affinities of fossil occurrences is enforced. Our results call into question the accuracy of previous divergence time studies incorporating the FBD process that have used only a subsample of all available fossil occurrence data.

A bespoke smoking cessation service compared with treatment as usual for people with severe mental ill health: the SCIMITAR+ RCT.

BACKGROUND: There is a high prevalence of smoking among people with severe mental ill health (SMI). Helping people with SMI to quit smoking could improve their health and longevity, and reduce health inequalities. However, those with SMI are less likely to access and engage with routine smoking cessation services than the general population. OBJECTIVES: To compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual stop smoking services for people with SMI. DESIGN: A pragmatic, two-arm, individually randomised controlled trial. SETTING: Primary care and secondary care mental health services in England. PARTICIPANTS: Smokers aged ≥ 18 years with SMI who would like to cut down on or quit smoking. INTERVENTIONS: A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual care. MAIN OUTCOME MEASURES: The primary outcome was self-reported, CO-verified smoking cessation at 12 months. Smoking-related secondary outcomes were self-reported smoking cessation, the number of cigarettes smoked per day, the Fagerström Test for Nicotine Dependence and the Motivation to Quit questionnaire. Other secondary outcomes were Patient Health Questionnaire-9 items, Generalised Anxiety Disorder Assessment-7 items and 12-Item Short-Form Health Survey, to assess mental health and body mass index measured at 6 and 12 months post randomisation. RESULTS: The trial randomised 526 people (265 to the intervention group, 261 to the usual-care group) aged 19 to 72 years (mean 46 years). About 60% of participants were male. Participants smoked between 3 and 100 cigarettes per day (mean 25 cigarettes per day) at baseline. The intervention group had a higher rate of exhaled CO-verified smoking cessation at 6 and 12 months than the usual-care group [adjusted odds ratio (OR) 12 months: 1.6, 95% confidence interval (CI) 0.9 to 2.8; adjusted OR 6 months: 2.4, 95% CI 1.2 to 4.7]. This was not statistically significant at 12 months (p = 0.12) but was statistically significant at 6 months (p = 0.01). In total, 111 serious adverse events were reported (69 in the BSC group and 42 in the usual-care group); the majority were unplanned hospitalisations due to a deterioration in mental health (n = 98). The intervention is likely (57%) to be less costly but more effective than usual care; however, this result was not necessarily associated with participants' smoking status. LIMITATIONS: Follow-up was not blind to treatment allocation. However, the primary outcome included a biochemically verified end point, less susceptible to observer biases. Some participants experienced difficulties in accessing nicotine replacement therapy because of changes in service provision. Efforts were made to help participants access nicotine replacement therapy, but this may have affected participants' quit attempt. CONCLUSIONS: People with SMI who received the intervention were more likely to have stopped smoking at 6 months. Although more people who received the intervention had stopped smoking at 12 months, this was not statistically significant. FUTURE WORK: Further research is needed to establish how quitting can be sustained among people with SMI. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72955454. 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. 23, No. 50. See the NIHR Journals Library website for further project information.

Smoking is an important health issue, especially among people who have experienced mental ill health such as schizophrenia or bipolar disorder. This is because people with severe mental ill health (SMI) are more likely to smoke than the general population. Despite this, they are less likely to get help to stop smoking, and it may be that people with mental ill health problems need greater support to help them stop smoking. To address this problem, we developed and tested a 'bespoke smoking cessation' (BSC) service tailored to people with SMI. People aged ≥ 18 years who said that they would like to stop smoking were randomly allocated to either a BSC service or the usual stop smoking services. Those in the BSC service were allocated a mental health professional who had been trained to deliver smoking cessation interventions. The mental health professional worked with the participant and their care team to advise on stop smoking medication and provide information, support and motivation. Usual-care participants were signposted to local smoking services, but their subsequent care was not directly provided or supervised by trial smoking cessation advisors. Between October 2015 and December 2016, 526 people with SMI were recruited into the study: 265 of these people were randomly assigned to the BSC service and 261 were randomly assigned to usual care. At 6 and 12 months after randomisation, participants completed questionnaires that asked about their smoking status and health. Participants had their smoking status tested by measuring the amount of carbon monoxide in their breath. After 6 months, more people who received the BSC intervention had stopped smoking than those who had received usual care. At 12 months, the results were less clear in terms of the difference in the number of people who had stopped smoking. The BSC service cost less than or similar to usual care, when considering the overall health-care services. The improvement in health of people who received the BSC service remains uncertain. In addition, we do not know whether or not this was related to people stopping smoking.

Real-world use of telavancin in the treatment of osteomyelitis.

This is a retrospective analysis of patients with osteomyelitis who received telavancin at some time during their treatment course. The primary outcome was the percent of patients cured or improved at the end of telavancin therapy (EOTT). The secondary outcome was the percent of patients cured or improved three months after discontinuation of telavancin therapy. There were 32 cases of osteomyelitis with methicillin-resistant Staphylococcus aureus identified in 17 (56.7%), methicillin-sensitive Staphylococcus aureus 2(6.6%), coagulase negative staphylococci 6 (20.0%) and other pathogens, 5 (16.7%). At EOTT, 87.5% of patients had their osteomyelitis cured and 94.6% had the infection cured at three months after telavancin was completed. The most common adverse events associated with telavancin were gastrointestinal in nature (nausea (25.8%), vomiting (9.7%) and diarrhea (3.2%)) followed by metallic taste (6.5%). A favorable outcome was achieved for many patients receiving the antimicrobial regimen that included telavancin for the treatment of osteomyelitis.

Lamotrigine for people with borderline personality disorder: a RCT.

BACKGROUND: No drug treatments are currently licensed for the treatment of borderline personality disorder (BPD). Despite this, people with this condition are frequently prescribed psychotropic medications and often with considerable polypharmacy. Preliminary studies have indicated that mood stabilisers may be of benefit to people with BPD. OBJECTIVE: To examine the clinical effectiveness and cost-effectiveness of lamotrigine for people with BPD. DESIGN: A two-arm, double-blind, placebo-controlled individually randomised trial of lamotrigine versus placebo. Participants were randomised via an independent and remote web-based service using permuted blocks and stratified by study centre, the severity of personality disorder and the extent of hypomanic symptoms. SETTING: Secondary care NHS mental health services in six centres in England. PARTICIPANTS: Potential participants had to be aged ≥ 18 years, meet diagnostic criteria for BPD and provide written informed consent. We excluded people with coexisting psychosis or bipolar affective disorder, those already taking a mood stabiliser, those who spoke insufficient English to complete the baseline assessment and women who were pregnant or contemplating becoming pregnant. INTERVENTIONS: Up to 200 mg of lamotrigine per day or an inert placebo. Women taking combined oral contraceptives were prescribed up to 400 mg of trial medication per day. MAIN OUTCOME MEASURES: Outcomes were assessed at 12, 24 and 52 weeks after randomisation. The primary outcome was the total score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. The secondary outcomes were depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment and adverse events. Higher scores on all measures indicate poorer outcomes. RESULTS: Between July 2013 and October 2015 we randomised 276 participants, of whom 195 (70.6%) were followed up 52 weeks later. At 52 weeks, 49 (36%) of those participants prescribed lamotrigine and 58 (42%) of those prescribed placebo were taking it. At 52 weeks, the mean total ZAN-BPD score was 11.3 [standard deviation (SD) 6.6] among those participants randomised to lamotrigine and 11.5 (SD 7.7) among those participants randomised to placebo (adjusted mean difference 0.1, 95% CI -1.8 to 2.0; p = 0.91). No statistically significant differences in secondary outcomes were seen at any time. Adjusted costs of direct care for those prescribed lamotrigine were similar to those prescribed placebo. LIMITATIONS: Levels of adherence in this pragmatic trial were low, but greater adherence was not associated with better mental health. CONCLUSIONS: The addition of lamotrigine to the usual care of people with BPD was not found to be clinically effective or provide a cost-effective use of resources. FUTURE WORK: Future research into the treatment of BPD should focus on improving the evidence base for the clinical effectiveness and cost-effectiveness of non-pharmacological treatments to help policy-makers make better decisions about investing in specialist treatment services. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90916365. FUNDING: Funding for this trial was provided by the Health Technology Assessment programme of the National Institute for Health Research (NIHR) and will be published in full in Health Technology Assessment; Vol. 22, No. 17. See the NIHR Journals Library website for further project information. The Imperial Biomedical Research Centre Facility, which is funded by NIHR, also provided support that has contributed to the research results reported within this paper. Part of Richard Morriss' salary during the project was paid by NIHR Collaboration for Leadership in Applied Health Research and Care East Midlands.

The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial.

OBJECTIVE: The authors examined whether lamotrigine is a clinically effective and cost-effective treatment for people with borderline personality disorder. METHOD: This was a multicenter, double-blind, placebo-controlled randomized trial. Between July 2013 and November 2016, the authors recruited 276 people age 18 or over who met diagnostic criteria for borderline personality disorder. Individuals with coexisting bipolar affective disorder or psychosis, those already taking a mood stabilizer, and women at risk of pregnancy were excluded. A web-based randomization service was used to allocate participants randomly in a 1:1 ratio to receive either an inert placebo or up to 400 mg/day of lamotrigine. The primary outcome measure was score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. Secondary outcome measures included depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, and adverse events. RESULTS: A total of 195 (70.6%) participants were followed up at 52 weeks, at which point 49 (36%) of those in the lamotrigine group and 58 (42%) of those in the placebo group were taking study medication. The mean ZAN-BPD score was 11.3 (SD=6.6) among those in the lamotrigine group and 11.5 (SD=7.7) among those in the placebo group (adjusted difference in means=0.1, 95% CI=-1.8, 2.0). There was no evidence of any differences in secondary outcomes. Costs of direct care were similar in the two groups. CONCLUSIONS: The results suggest that treating people with borderline personality disorder with lamotrigine is not a clinically effective or cost-effective use of resources.