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Supplementary Table 1. Hazard ratios of GI cancer overall by sex

Supplementary Table 2. Hazard ratios of GI cancer subsites by sex

Response to: 'Correspondence on 'Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study'' by Zheng We thank Dr Zheng for his comments on our recently published article in the Annals of the Rheumatic Diseases entitled 'Concom-itant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: a population-based cohort study'. 1 2 Our main goal in this study was to bring more clinical insight into the simultaneous use of these two common medications in patients with rheumatoid arthritis (RA), that is, oral glucocorticoids (GCs) and proton pump inhibitors (PPIs), using data from a large primary care database and pharmacoepidemiological methodologies. Our results showed that there was an interaction in the risk of osteoporotic (OP) fractures with concomitant use of oral GCs and PPIs in patients with RA. Based on the adjusted hazard ratios and according to the formula proposed by Rothman et al, 3 the relative excess risk due to interaction (RERI) was: 1.60-1.23 − 1.22 + 1 = 0.15. We now have also calculated the CIs and the statistical significance of this index using the method proposed by Hosmer and Lemeshow. 4 5 The lower and upper limits of the 95% CI of the RERI were −0.16 and 0.45, respectively, and the p value was 0.36. This means, although we observed a 15% more risk of OP fracture with concomitant use of oral GCs and PPIs in addition to the single use of each drug versus non-use of both, this additive interaction was not statistically significant. As we discussed in our paper, there is currently no proven biological mechanism for an action of PPIs on bone or falling, 6 while the effects of GCs on bone and the musculoskeletal system are quite established. Our secondary analyses (ie, lower fracture risk with long-term or higher daily doses of PPIs compared with short-term or lower daily doses) did not support the few proposed potential mechanisms, such as hypochlorhydria and calcium malabsorption, or an increased fall risk due to malab-sorption of magnesium or vitamin B 12. This is important to consider when interpreting a potential additive interaction between oral GCs and PPIs on fracture risk. Without this basic knowledge, it would be extremely difficult to confer any conclusions on a plausible synergistic action of these two drugs, since it would sound more as a methodological reasoning rather than a clinical explanation.

Summary: Oral glucocorticoids may increase major osteoporotic fracture risk (MOF) in myasthenia gravis patients. To assess this risk, we performed a case–control study including all Danish patients with a MOF between 1995 and 2011. We also pooled our data with data from another study. We found no increased risk. Osteoporosis prevention remains advisable. Purpose/introduction: The prolonged use of high doses of oral glucocorticoids (GCs), a common treatment in patients with myasthenia gravis (MG), may increase major osteoporotic fracture (MOF) risk. Previous epidemiological studies did not exclusively focus on patients with MG or had relatively few GC-exposed MG patients. Aims were to evaluate the risk of MOF in MG patients using oral GCs in a large study population and to perform a pooled analysis with data from previous work. Methods: A population-based case–control study (1995–2011) was conducted using the Danish National Health Service. Cases had sustained a MOF, and controls had not. All were aged ≥ 18 years. Multivariate conditional logistic regression estimated odds ratios (ORs) among MG patients using oral GCs versus non-users. Adjustments were made for comorbidities and comedications. In the pooled analysis, results were pooled by the use of generic inverse variance methods, assuming a random-effects model. Results: We identified 376,858 cases and 376,858 controls. MOF risk was not elevated in MG patients currently using oral GCs compared to MG patients not on oral GCs (ORadj.: 1.26 (95% CI 0.68–2.33)). The use of the highest cumulative dose of oral GCs (≥ 7 g) did not show an increased risk of MOF among MG patients (ORadj.: 2.00 (95% CI 0.90–4.44)). Our pooled analysis also showed no association between oral GC use and MOF risk. Conclusion: This study showed that oral GC use in patients with MG was not associated with increased risk of MOF in our case–control study and pooled analysis. Osteoporosis prevention in MG patients based on clinical guidelines remains advisable.

To develop a reliable 2-compartment population pharmacokinetic (PK) model for unbound ceftriaxone in a critically ill population and determine an optimal dosing regimen.This was a prospective, single-center, observational study of critically ill patients treated with ceftriaxone. Unbound serum ceftriaxone concentrations were measured using validated ultrafiltration and ultra-performance liquid chromatography-tandem mass spectrometry. PK analysis and dosing simulations were performed using an iterative 2-stage Bayesian fitting procedure and Monte Carlo simulations. The PK/pharmacodynamics (PD) target was attained when unbound serum ceftriaxone concentrations exceeded 4 times the minimum inhibitory concentration (MIC) for ≥ 60% of the dosing interval (ƒT91 patients were enrolled, and 173 unbound ceftriaxone concentrations were acquired. The population PK parameter estimates were hepatic clearance 5.2 ± 0.9 L/h/1.85mWe developed a reliable population PK model for unbound ceftriaxone in a critically ill population. Dosing simulations revealed ƒT

Risperidone and aripiprazole, commonly used antipsychotics in children with autism spectrum disorder (ASD), have previously been associated with elevated fracture risk in other populations. The aim of this study was to evaluate and compare the risk of fracture among children with ASD using risperidone or aripiprazole. This was a retrospective, propensity-score matched cohort study, set between January 2013 and December 2018. We used the MarketScan Medicaid insurance data, which covers multiple states of the United States. We included ASD children aged 2-18 years, who were new users of aripiprazole or risperidone and with no prior history of antipsychotic use or fractures. The main exposure was the continued use of aripiprazole or risperidone. The incidence rates of any fracture during follow-up were evaluated, and the risk between aripiprazole and risperidone was compared via Cox-proportional hazard models. Results were stratified by age, sex, duration of exposure and fracture site. In total, 3312 patients (78% male; mean [SD] age 11.0 [3.7] years) were identified for each cohort. Over the full duration of follow-up, fracture incidence rates per 1000 patient-years were 23.2 for risperidone and 38.4 for aripiprazole (hazard ratio and 95% confidence interval: 0.60 [0.44-0.83]). Risks were similar between cohorts throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. Extremity fractures drove most of the increased risk, with the biggest differences in lower leg and ankle fractures. Differences widened for children aged 10 years or younger (HR [95% CI]: 0.47 [0.30-0.74]). In conclusion, compared to aripiprazole, risperidone was associated with 40% lower risk of fracture. Further analysis on the mechanism and long-term bone health of antipsychotic-treated children with ASD is warranted.Lay summary We compared the risk of bone fractures among 6624 children with autism spectrum disorder (ASD), half of whom used risperidone and half of whom used aripiprazole. Taking other factors into account, risks were similar between the two groups throughout the first 180 days on treatment, but significantly higher in the aripiprazole group thereafter. The biggest differences were in lower leg and ankle fractures. Overall, compared with aripiprazole, risperidone was associated with 40% lower risk of fracture.

Introduction: People with diabetes could have an increased risk of falls as they show more complications, morbidity and use of medication compared to the general population. This study aimed to estimate the risk of falls and to identify risk factors associated with falls in people with diabetes. The second aim was to estimate fall-related injuries, such as lesions and fractures, including their anatomic localization in people with diabetes compared with the general population. Methods: From the Danish National Patient Register, we identified people with Type 1 Diabetes (T1D) (n=12,975) Type 2 Diabetes (T2D) (n=407,009). The cohort was divided into two groups, with respective control groups matched on age and sex (1:1). All episodes of people hospitalized with a first fall from 1996 to 2017 were analyzed using a Cox proportional-hazards model. Risk factors such as age, sex, diabetic complications, a history of alcohol abuse and the use of medication were included in an adjusted analysis. The incidence rate, incidence rate difference and incidence rate ratio (IRR) of falls and the anatomic localization of fall-related injuries as lesions and fractures were identified. Results and Discussion: The cumulative incidence, of falls requiring hospital treatment, was 13.3% in T1D, 11.9% in T2D. In the adjusted analysis, T1D and T2D were associated with a higher risk of falls [T1D, Hazard Ratio (HR): 1.33 (95% CI: 1.25 - 1.43), T2D, HR: 1.19 (95% CI:1.16 - 1.22), respectively]. Women [group 1, HR 1.21 (CI:95%:1.13 - 1.29), group 2, HR 1.61 (CI:95%:1.58-1.64)], aged >65 years [groups 1, HR 1.52 (CI:95%:1.39 - 1.61), group 2, HR 1.32 (CI:95%:1.58-1.64)], use of selective serotonin receptor inhibitors (SSRI) [group 1, HR 1.35 (CI:95%:1.1.30 - 1.40), group 2, HR 1.32 (CI:95%:1.27-1.38)], opioids [group 1, HR 1.15 (CI:95%:1.12 - 1.19), group 2, HR 1.09 (CI:95%:1.05-1.12)] and a history of alcohol abuse [group 1, HR 1.77 (CI:95%:1.17 - 2.15), group 2, HR 1.88 (CI:95%:1.65-2.15)] were significantly associated with an increased risk of falls in both groups. The IRR of fall-related injuries as hip, radius, humerus and skull/facial fractures were higher in people with T2D than controls [IRR 1.02 (CI:95%:1.01-1.04), IRR 1.39 (CI:95%: 1.18-1.61), IRR 1.24 (CI:95%: 1.12-1.37) and IRR 1.15 (CI:95%:1.07-1.24)]. People with T1D had a higher IRR of hip fractures than controls [IRR: 1.11 (CI:95%:1.02 – 1.23)]. Conclusion: People with diabetes have an increased risk of first fall and a higher incidence of fall- related injuries, including fractures. Advanced aging and sex are non-modifiable risk factors, whereas diabetes, the use of SSRIs and opioids and alcohol abuse could be potentially modifiable risk factors for falls. Gaining information on risk factors for falls could guide the management of diabetes treatment, i.e., choice of drugs, which enables us to improve treatment, particularly in people with a high risk of falls and fractures associated with high mortality.

AIMS: A diabetic foot ulcer (DFU) is a severe condition associated with morbidity and mortality. Population-based studies are rare and limited by access to reliable data. Without this data, efforts in primary prevention cannot be evaluated. Therefore, we examined the incidence and changes over time for the first DFU in people with diabetes. We also examined hospitalization and all-cause mortality and their changes over time.METHODS: From the UK primary care CPRD GOLD database (2007-2017), we identified 129,624 people with diabetes by a prescription for insulin or a non-insulin anti-diabetic drug. DFUs were identified using Read codes and expressed as incidence rates (IRs). Changes over time were described using Poisson and logistic regression and expressed as incidence rate ratios (IRRs) and odds ratios (ORs) respectively.RESULTS: The mean IR of first registered DFUs was 2.5 [95% CI: 2.1-2.9] per 1000 person-years for people with type 2 diabetes and 1.6 [1.3-1.9] per 1000 person-years for people with type 1. The IRs declined for people with type 2 diabetes (IRR per year: 0.97 [0.96-0.99]), while no changes were observed for people with type 1 diabetes (IRR per year: 0.96 [0.89-1.04]). Average hospitalization and 1-year mortality risk for people with type 2 diabetes were 8.2% [SD: 4.7] and 11.7% [SD: 2.2] respectively. Both declined over time (OR: 0.89 [0.84, 0.94] and 0.94 [0.89, 0.99]).CONCLUSION: The decline in all IRs, hospitalizations and mortality in people with type 2 diabetes suggests that prevention and care of the first DFU has improved for this group in primary care in the UK.

A previous chlamydia infection did not result in fewer pregnant women, but among women with a pregnancy intention, time to pregnancy was longer compared with women without a previous infection. Supplemental digital content is available in the text., Background A Chlamydia trachomatis infection (chlamydia) can result in tubal factor infertility in women. To assess if this association results in fewer pregnant women, we aimed to assess pregnancy incidences and time to pregnancy among women with a previous chlamydia infection compared with women without one and who were participating in the Netherlands Chlamydia Cohort Study (NECCST). Methods The NECCST is a cohort of women of reproductive age tested for chlamydia in a chlamydia screening trial between 2008 and 2011 and reinvited for NECCST in 2015 to 2016. Chlamydia status (positive/negative) was defined using chlamydia screening trial–nucleic acid amplification test results, chlamydia immunoglobulin G presence in serum, or self-reported chlamydia infections. Data on pregnancies were collected via questionnaires in 2015–2016 and 2017–2018. Overall pregnancies (i.e., planned and unplanned) and time to pregnancy (among women with a pregnancy intention) were compared between chlamydia-positive and chlamydia-negative women using Cox regressions. Results Of 5704 women enrolled, 1717 (30.1%; 95% confidence interval [CI], 28.9–31.3) women was chlamydia positive. Overall pregnancy proportions were similar in chlamydia-positive and chlamydia-negative women (49.0% [95% CI, 46.5–51.4] versus 50.5% [95% CI, 48.9–52.0]). Pregnancies per 1000 person-years were 53.2 (95% CI, 51.5–55.0) for chlamydia negatives and 83.0 (95% CI, 78.5–87.9) for chlamydia positives. Among women with a pregnancy intention, 12% of chlamydia-positive women had a time to pregnancy of >12 months compared with 8% of chlamydia negatives (P < 0.01). Conclusions Overall pregnancy rates were not lower in chlamydia-positive women compared with chlamydia-negative women, but among women with a pregnancy intention, time to pregnancy was longer and pregnancy rates were lower in chlamydia-positive women. Trial registration number: Dutch Trial Register NTR-5597.

Background Poor adherence to antihypertensives is associated with negative outcome of the disease as well as loss of health-care resources. Addressing the epidemic of poor adherence requires identifying factors associated with this behaviour. The aim of this study is to describe adherence to antihypertensive medication among Lebanese hypertensive patients and to evaluate the association between socio-economic, patient- and conditions-related factors and non-adherence. Methods A cross-sectional study was carried out on adherence to antihypertensive medications covering all governorates of Lebanon. This study was conducted between February 2018 and January 2019 on a random sample of 1497 hypertensive patients. A face-to-face questionnaire was used to assess adherence to antihypertensive medication and its determinants according to the five World Health Organization (WHO) main categories. Logistic regression analysis was performed to test the adjusted association between the multiple exposure factors, and drug adherence data were collected by trained interviewers. Results Adherence to antihypertensive medications was reported by 1253 (83.7%) of the patients. After multivariate analysis, patients who tried to control their stress level (OR = 0.77, 95% CI [0.38-0.95]), those who had normal BP readings (OR =0.49, 95% CI [0.18-0.97]), and those who believed in the effectiveness of their treatment (OR = 0.31, 95% CI [0.14-0.76]) had a significantly lower chance to exhibit non-adherence to their treatment. However, older patients (OR= 1.87, 95% CI [1.23-2.21]), divorced/separated patients (OR= 2.14, 95% CI [1.31-5.48]), married (OR=1.96, 95% CI [1.27-3.90]), widowed (OR=2.11, 95% CI [1.62-6.50]), obese patients (OR = 1.76, 95% CI [1.21-1.94]), and patients who smoked hookah and cigarettes (OR = 2.62, 95% CI [1.17-6.76]) were more likely to exhibit non-adherence. Conclusion Our study highlights the influence of factors such as old age, marital status, BMI and high level of emotional stress on non-adherence to medication in hypertensive patients. These determinants should be incorporated into adherence improving strategies.

Background and Aims Thiazolidinediones (TZDs) and glucagon-like peptide-1 (GLP-1) receptor agonists are potential pharmacological treatment options for patients at risk of NAFLD. Therefore, we examined the association between the risk of NAFLD and the use of TZDs and GLP-1 receptor agonists compared with the use of sulfonylureas (SUs) and insulins. Additionally, we calculated the incidence of HCC in users of TZDs and GLP-1 receptor agonists. Approach and Results We conducted a population-based cohort study using primary care data from the Clinical Practice Research Datalink database (2007-2018). All patients aged ≥18 with a prescription of an oral glucose-lowering agent or GLP-1 receptor agonist were included. The first prescription defined the start of follow-up. The primary outcome was a new diagnosis of NAFLD. Cox proportional hazards regression was used to estimate HRs and 95% CIs of the primary outcome. Incidence rates of HCC were determined per 1,000 person-years for all exposures. The study identified 207,367 adults with a prescription for a glucose-lowering agent. The risk of NAFLD was lower in patients prescribed a TZD than in those prescribed an SU (adjusted HR [aHR], 0.32; 95% CI, 0.20-0.51). No difference in risk of NAFLD was observed comparing GLP-1 receptor agonist use with insulin use (aHR, 1.22; 95% CI, 0.91-1.63). Conclusions Results of our study endorse the use of TZDs for selected patients at risk of NAFLD but do not support previous findings regarding the beneficial effect of GLP-1 receptor agonists. The low number of events in several subgroups may affect the generalizability of the current findings., Hepatology, 74 (5), ISSN:0270-9139, ISSN:1527-3350

Studies that generate real-world evidence on the effects of medical products through analysis of digital data collected in clinical practice provide key insights for regulators, payers, and other healthcare decision-makers. Ensuring reproducibility of such findings is fundamental to effective evidence-based decision-making. We reproduce results for 150 studies published in peer-reviewed journals using the same healthcare databases as original investigators and evaluate the completeness of reporting for 250. Original and reproduction effect sizes were positively correlated (Pearson’s correlation = 0.85), a strong relationship with some room for improvement. The median and interquartile range for the relative magnitude of effect (e.g., hazard ratiooriginal/hazard ratioreproduction) is 1.0 [0.9, 1.1], range [0.3, 2.1]. While the majority of results are closely reproduced, a subset are not. The latter can be explained by incomplete reporting and updated data. Greater methodological transparency aligned with new guidance may further improve reproducibility and validity assessment, thus facilitating evidence-based decision-making. Study registration number: EUPAS19636.

Background Medication is frequently thrown away after a patient’s discharge from hospital, with undesirable economic and environmental consequences. Because of the rising costs of healthcare, interventions to reduce medication wastage (and associated costs) are warranted. Using Patient’s Own Medication during hospitalisation might decrease medication wastage and associated costs. Objective To study the economic impact of patient’s own medication use on medication waste and hospital staff’s time spent during hospitalisation. Setting In seven Dutch hospitals, of which university, teaching, general, and specialised hospitals, eight different hospital wards, surgical and medical, were selected. Method In this prospective pre-post intervention study data on the economic value of medication waste and time spent by healthcare professionals were collected for a 2 months period each. The economic value of medication waste was defined as the value (€) of wasted medication per 100 patient days. For each ward, time spent on medication process activities was measured 10 times per staff member. The average time spent (in hours) on medication process steps (multiple activities) per staff member per 100 patients and associated salary costs were calculated for both periods. Main outcome measure The primary outcome of the study was the total economic value (€) of wasted medication per 100 patient days. Results Implementation of Patient’s Own Medication decreased the economic value of wasted medication by 39.5% from €3983 to €2411 per 100 patient days. The mean time spent on the total medication process was reduced with 5.2 h per 100 patients (from 112.7 to 104.4 h per 100 patients). We observed a shift in professional activities, as physicians and nurses spent less time on the medication process, whereas pharmacy technicians had a greater role in it. When time spent was expressed as salary; €1219 could be saved per 100 patients. Conclusions This study showed that ‘Patient’s Own Medication' implementation may have a positive economic impact, as the value of medication waste decreases, hospital staff devoted less time on the medication process, and staff deployment is more efficient.

Background: Reviews suggest that the ADO score is the most discriminatory prognostic score for predicting mortality among chronic obstructive pulmonary disease (COPD) patients, but a full evaluation and external validation within primary care settings is critical before implementation. Objectives: To validate the ADO score in prevalent and screen-detected primary care COPD cases at 3 years and at shorter time periods. Patients and methods: One thousand eight hundred and ninety-two COPD cases were recruited between 2012 and 2014 from 71 United Kingdom general practices as part of the Birmingham COPD Cohort study. Cases were either on the practice COPD register or screen-detected. We validated the ADO score for predicting 3-year mortality with 1-year and 2-year mortality as secondary endpoints using discrimination (area-under-the-curve (AUC)) and calibration plots. Results: One hundred and fifty-four deaths occurred within 3 years. The ADO score was discriminatory for predicting 3-year mortality (AUC= 0.74; 95% CI: 0.69-0.79). Similar performance was found for 1- (AUC= 0.73; 0.66-0.80) and 2-year mortality (0.72; 0.67-0.76). The ADO score showed reasonable calibration for predicting 3-year mortality (calibration slope 0.95; 0.70-1.19) but over-predicted in cases with higher predicted risks of mortality at 1 (0.79; 0.45-1.13) and 2-year (0.79; 0.57-1.01) mortality. Discussion: The ADO score showed promising discrimination in predicting 3-year mortality in a primary care population including screen-detected cases. It may need to be recalibrated if it is used to provide risk predictions for 1- or 2-year mortality since, in these time-periods, over-prediction was evident, especially in cases with higher predicted mortality risks.

The Autism impact measure (AIM) is a caregiver-reported questionnaire assessing autism symptom frequency and impact in children, previously shown to have good test–retest reliability, convergent validity and structural validity. This study extended previous work by exploring the AIM’s ability to discriminate between ‘known-groups’ of children, and estimating thresholds for clinically important responses. Data were collected online and electronically on computer and mobile devices; hence, it was also possible to confirm other psychometric properties of the AIM in this format. This study provides confirmatory and additional psychometric validation of the AIM. The AIM offers a valid, quick and inexpensive method for caregivers to report core symptoms of autism spectrum disorder (ASD) including communication deficits, difficulties with social interactions and repetitive behaviors. Electronic supplementary material The online version of this article (10.1007/s10803-019-04011-2) contains supplementary material, which is available to authorized users.

PURPOSE: It is not clear whether all deaths are recorded in the Clinical Practice Research Datalink (CPRD) or how accurate a recorded date of death is. Individual-level linkage with national data from the Office for National Statistics (ONS) and Hospital Episode Statistics (HES) in England offers the opportunity to compare death information across different data sources. METHODS: Age-standardised mortality rates (ASMRs) standardised to the European Standard Population (ESP) 2013 for CPRD were compared with figures published by the ONS, and crude mortality rates were calculated for a sample population with individual linkage between CPRD, ONS, and HES data. Agreement on the fact of death between CPRD and ONS was assessed and presented over time from 1998 to 2013. RESULTS: There were 33 997 patients with a record of death in the ONS data; 33 389 (98.2%) of these were also identified in CPRD. Exact agreement on the death date between CPRD and the ONS was 69.7% across the whole study period, increasing from 53.4% in 1998 to 78.0% in 2013. By 2013, 98.8% of deaths were in agreement within ±30 days. CONCLUSIONS: For censoring follow-up and calculating mortality rates, CPRD data are likely to be sufficient, as a delay in death recording of up to 1 month is unlikely to impact results significantly. Where the exact date of death or the cause is important, it may be advisable to include the individually linked death registration data from the ONS.

Objectives: Clinical trials have shown that low-dose glucocorticoid therapy in patients with rheumatoid arthritis (RA) reduces bone loss in hands or hip, but the effect on osteoporotic fractures is not yet clear. Therefore, we investigated the use of low-dose oral glucocorticoids and risk of osteoporotic fractures among patients with RA. Methods: This was a cohort study including patients with RA aged 50+ years from the Clinical Practice Research Datalink between 1997-2017. Exposure to oral glucocorticoids was stratified by the most recent prescription in current (1 year) use, and average daily and cumulative doses. Risk of incident osteoporotic fractures (including hip, vertebrae, humerus, forearm, pelvis, and ribs) were estimated by time-dependent Cox proportional-hazards models, adjusted for life-style parameters, comorbidities, and comedications. Secondary analyses assessed osteoporotic fracture risk with a combination of average daily and cumulative doses of oral glucocorticoids. Results: Among 15 123 patients with RA (mean age 68.8 years, 68% females), 1640 osteoporotic fractures occurred. Current low-dose oral glucocorticoid therapy (≤7.5 mg prednisolone equivalent/day) in patients with RA was not associated with overall risk of osteoporotic fractures (adjusted hazard ratio 1.14, 95% CI 0.98-1.33) compared with past glucocorticoid use, but was associated with an increased risk of clinical vertebral fracture (adjusted hazard ratio 1.59, 95% CI 1.11-2.29). Results remained unchanged regardless of a short-term or a long-term use of oral glucocorticoids., Rheumatology, 61 (4)

Oral glucocorticoids may increase major osteoporotic fracture risk (MOF) in myasthenia gravis patients. To assess this risk, we performed a case-control study including all Danish patients with a MOF between 1995 and 2011. We also pooled our data with data from another study. We found no increased risk. Osteoporosis prevention remains advisable.The prolonged use of high doses of oral glucocorticoids (GCs), a common treatment in patients with myasthenia gravis (MG), may increase major osteoporotic fracture (MOF) risk. Previous epidemiological studies did not exclusively focus on patients with MG or had relatively few GC-exposed MG patients. Aims were to evaluate the risk of MOF in MG patients using oral GCs in a large study population and to perform a pooled analysis with data from previous work.A population-based case-control study (1995-2011) was conducted using the Danish National Health Service. Cases had sustained a MOF, and controls had not. All were aged ≥ 18 years. Multivariate conditional logistic regression estimated odds ratios (ORs) among MG patients using oral GCs versus non-users. Adjustments were made for comorbidities and comedications. In the pooled analysis, results were pooled by the use of generic inverse variance methods, assuming a random-effects model.We identified 376,858 cases and 376,858 controls. MOF risk was not elevated in MG patients currently using oral GCs compared to MG patients not on oral GCs (ORThis study showed that oral GC use in patients with MG was not associated with increased risk of MOF in our case-control study and pooled analysis. Osteoporosis prevention in MG patients based on clinical guidelines remains advisable.

Background: Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic Drug Monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce. Objective: The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings. Methods: In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, the limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/Pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval. Result: The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation Conclusion: The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a non-insulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for lifestyle variables, comorbidities, and concomitant drug use. Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect..

Background Patients with obstructive sleep apnea (OSA) might be at risk of gout because of pathophysiological mechanisms that can lead to hyperuricemia and eventually gout or because of shared risk factors between both diseases. The objective of the present study was to investigate the risk of gout in patients with OSA. Methods A population-based case-control study using the UK Clinical Practice Research Datalink GOLD including all patients aged 40 years and older with a first diagnosis of gout between 1987 and 2014. Gout cases were matched by year of birth, sex, and practice to non-gout controls. Conditional logistic regression estimated the risk of gout with an earlier diagnosis of OSA. Analyses were adjusted for lifestyle factors, comorbidities, and recent drug use. Results One hundred eleven thousand five hundred nine cases were matched with 210,241 controls. Patients with OSA were at increased risk of gout (OR 1.86; 95%CI (1.71–2.02). However, this association disappeared (OR 1.05; 95% CI 0.96–1.16) after adjustment for smoking status, body mass index (BMI), alcohol use, a history of heart failure, diabetes mellitus, renal function, and recent use of diuretics and other medications. Among females with OSA and patients with OSA associated with heart failure, renal impairment, or higher BMI, the risk of gout was however still increased when compared to the total control population. Conclusion This study showed that the observed association between OSA and gout disappeared after adjustment.

Contains fulltext : 218134.pdf (Publisher’s version ) (Closed access) A new method for quantification of osimertinib (OSIM) in human plasma using a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated. Methanol was used for protein precipitation and pazopanib as internal standard. Separation was performed on a HyPURITY(R)C18 analytical column (50 x 2.1 mm; 3 mum) using a gradient elution of ammonium acetate in water and ammonium acetate in methanol, both acidified with formic acid 0.1%. Detection and quantification of OSIM and pazopanib was performed using a triple quadruple mass spectrometer after electrospray ionization. This method led to robust results, as the selectivity, carryover, precision and accuracy all met pre-specified requirements. OSIM was stable in human serum when stored at -80 degrees C. Reduced stability was found when stored at 2-4 degrees C or room temperature. Degradation of OSIM slowed down in EDTA-plasma and acidified human serum. The limited stability of OSIM at room temperature should be considered for transport and sample preparation. Plasma samples should be frozen as soon as possible and sample preparation should be performed on dry-ice. In the future, EDTA-plasma and sample acidification may be used to improve OSIM stability at room temperature. However, more research and validation of such an approach are required.

Dietary intake has been shown to affect bone health via both proinflammatory and anti- inflammatory mechanisms. Some dietary constituents such as zinc, magnesium and calcium have anti-inflammatory effect and are beneficial for the bone physiology. The aim was to analyze bone mineral density (BMD), bone remodeling markers, serum vitamin D values and overall intake of the dietary minerals (calcium, magnesium, zinc and sodium) with respect to the dietary inflammatory index (DII) score. Women (N = 400) included in this study were divided in subgroups according to the adherence to DII score. Q1 indicated participants having the lowest DII values and highest adherence to anti-inflammatory diet, while Q4 were participants having pro- inflammatory diet. Kruskal–Wallis test was used to analyze the adherence of the bone status parameters to the DII score as well as the adherence of dietary minerals to DII score. Multiple regression analyses was employed to test the relationship between BMD and bone remodeling markers with the DII score and age. P\0.05 was considered as statistically significant. Our results revealed that women whose dietary habits were more in anti- inflammatory quartiles, had significantly higher values of the lumbar spine BMD (P = 0.01), left hip BMD (P\0.01) and bone alkaline phosphatase (P\0.01). They also had significantly higher intakes of dietary calcium, magnesium and zinc, P\0.01, respectively. Multiple regression analyses revealed that age and DII were significantly and inversely correlated to left hip BMD, while deoxypyridinoline was just proportional to age and DII, P\0.01, respectively. Study results suggest that anti-inflammatory diet is associated with high BMD and younger age.

Introduction: Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow obstruction and respiratory symptoms. While short course systemic GCs are prescribed in patients with acute COPD exacerbations, little is known of the risk of fractures with intermittent exposure to high-dose GC and the effect of proxies of disease severity.Methods: A case-control study was conducted using the Danish National Hospital Discharge Registry (NHDR) between January 1996 to December 2011. Conditional logistics regression models were used to derive adjusted odds ratios (OR) risk of fractures in subjects with COPD stratified by intermittent high-dose, and proxies of disease severity.Result: A total of 635,536 cases and the same number of controls were identified (mean age 67.5 +/- 13.8, 65% female). COPD patients with intermittent use of high average daily dose oral glucocorticoids did not have an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fracture compared to non-COPD patients (adj. OR 0.65; 95% CI: 0.50-0.86, 0.70; 95% CI: 0.70-0.99, 1.17; 95% CI: 0.59-2.32, 1.98; 95% CI: 0.59-6.65 respectively). We identified an elevated risk of osteoporotic fracture among patients who visited the emergency unit (adj. OR 1.47; 95% CI 1.20-1.79) or were hospitalised in the past year for COPD (adj. OR 1.76; 95% CI 1.66-1.85). Current GC use among COPD patients was associated with an increased risk of osteoporotic, hip and clinically symptomatic vertebral fractures compared to patients without COPD.Conclusion: Intermittent high-dose GCs was not associated with an increased risk of any, osteoporotic, hip or clinically symptomatic vertebral fractures in patients with COPD. Current GC use was however associated with an increased risk of hip and clinically symptomatic vertebral fractures. Therefore, emphasis on prophylactic treatment of fractures may not be essential in patients with COPD receiving intermittent dose of GCs, whereas this should be considered for high-dose long-term users with advanced COPD disease stage, postmenopausal women and men over 40 years. (C) 2018 Elsevier Inc. All rights reserved.

We investigated the association between the current use of individual sulphonylureas and the risk of a first ever acute myocardial infarction (AMI) and all-cause mortality, in a population-based cohort study using primary care data from the Clinical Practice Research Datalink (CPRD) database (2004-2012). New users (N=121,869) with at least one prescription for a non-insulin antidiabetic agent, and aged ≥18 years were included. The first prescription defined start of follow-up. Time-dependent Cox proportional hazards models were used to estimate the risk of a first ever AMI and all-cause mortality associated with the use of individual sulphonylureas, and other non-insulin glucose-lowering drugs. No differences in risk of a first ever AMI (adjusted hazard ratio [HRadj]: 1.02, 95% Confidence Interval [CI]: 0.70-1.50) or all-cause mortality (HRadj: 0.97, 95% CI: 0.80-1.17) were observed comparing gliclazide use with non-gliclazide sulphonylurea use. Similar results were found for each individual sulphonylurea. As evidence is accumulating that gliclazide is no safer than other sulphonylureas, current guidelines suggesting superiority should be carefully evaluated.

Aims Nonvitamin K antagonist oral anticoagulants (NOACs) are now available for the prevention of stroke in patients with atrial fibrillation (AF) as an alternative to vitamin K antagonists (VKA) and aspirin. The comparative effectiveness and safety in daily practice of these different drug classes is still unclear. The objective of this study was to evaluate the risk of major bleeding and stroke in AF patients using NOACs, VKAs or aspirin. Methods A retrospective cohort study was conducted among AF patients using the UK Clinical Practice Research Datalink (March 2008–October 2014). New users of VKAs, NOACs and low dose aspirin were followed from the date of first prescription of an antithrombotic drug until the occurrence of stroke or major bleeding. Analyses were adjusted for a history of comorbidities and drug use with Cox regression analysis. Results A total of 31 497 patients were eligible for the study. The hazard ratio (HR) of major bleeding was 2.07 [95% confidence interval (CI) 1.27–3.38] for NOACs compared with VKAs, which was mainly attributed by the increased risk of gastrointestinal bleeding (HR 2.63, 95% CI 1.50–4.62). This increased bleeding risk was restricted to women (HR 3.14, 95% CI 1.76–5.60). Aspirin showed a similar bleeding risk as VKAs. NOACs showed equal effectiveness as VKA in preventing ischaemic stroke (HR 1.22, 95% CI 0.67–2.19). VKAs were more effective than aspirin (HR 2.18, 95% CI 1.83–2.59). Conclusions NOACs were associated with a higher risk on gastrointestinal bleeding, particularly in women. The use of NOACs in patients who are vulnerable for this type of bleeding should be carefully considered. NOACs and VKAs are equally effective in preventing stroke. Aspirin was not effective in the prevention of stroke in AF.

Aim Direct-acting oral anticoagulants (DOACs) have become available for the prevention of stroke in patients with atrial fibrillation (AF). Conflicting results have been published on the risk of acute myocardial infarction (AMI) with the use of DOACs in comparison with vitamin K antagonists (VKAs). The objective of the present study was to evaluate the risk of AMI in patients with AF who are exposed to either VKAs, DOACs or low-dose (< 325 mg) aspirin. Methods We conducted a population-based cohort study using data from the Clinical Practice Research Datalink (2008–2014). The study population (n = 30 146) consisted of all patients ≥18 years with a diagnosis of AF who were new users of VKAs, DOACs (rivaroxaban and dabigatran) or aspirin. Cox proportional hazards models were used to estimate the hazard ratio (HR) of AMI for users of DOACs or aspirin vs. VKA. Adjustments were made for age, gender, lifestyle, risk factors, comorbidity and other drugs. Results The risk of AMI was doubled when we compared current use of DOACs with current use of VKAs [adjusted HR 2.11; 95% confidence interval (CI) 1.08, 4.12] and for current users of aspirin vs. current VKA users (adjusted HR 1.91; 95% CI 1.45, 2.51). Conclusions There is a twofold increase in the risk of AMI for users of DOACs, in comparison with VKAs, in AF therapy. In addition, the results suggested that in patients with AF, the incidence of AMI is higher during aspirin monotherapy than during the use of VKAs.

Background As an alternative to vitamin K antagonist and low-dose aspirin ( 2). Conclusion Non vitamin K oral anticoagulants are associated with a higher risk on all-cause mortality, particularly in men and in patients with higher stroke risk., International Journal of Clinical Pharmacy, 41 (6), ISSN:2210-7703, ISSN:0928-1231, ISSN:2210-7711

Introduction and Background: Multiple domains of chronic obstructive pulmonary disease (COPD) contribute to its progression and thus must be taken into account when predicting outcomes. The ADO score (age, dyspnoea, and airflow obstruction) is a good predictor of mortality in COPD. However, it is not known how the ADO score changes over time and which factors are associated with any change. Aims and Objectives: To examine the change in ADO score over time and factors that affect this change. Methods: We followed 4,804 primary care COPD patients (mean FEV1% predicted: 59.3 +/- 19.7, 55.2 % males, mean age: 69.4 years +/- 9.3) from The Health Improvement Network (THIN) database from 2005 to 2014. The association between baseline patient factors and the change in ADO over time was assessed using linear mixed effect models. Results: The mean first recorded ADO score was 7.4 (range 0 to 14). The ADO score increased by an average of 0.19 points per year (95% CI: 0.18 to 0.20) although there was no significant change in score for 89% of patients. Patients who were either former smokers (β= 0.031; 95% CI: 0.004 to 0.059; P=0.025), current smokers (β= 0.052; 95% CI: 0.022 to 0.083; P=0.001) or were underweight (β= 0.065; 95% CI: 0.004 to 0.125; P=0.037) had more rapid progression. Overweight (β= -0.050; 95% CI: -0.071 to -0.029; P Discussion: Although the ADO score remains stable for the majority of THIN patients over time, patients who actively smoke or have lower BMI have more rapid progression.

The Autism impact measure (AIM) is a caregiver-reported questionnaire assessing autism symptom frequency and impact in children, previously shown to have good test-retest reliability, convergent validity and structural validity. This study extended previous work by exploring the AIM's ability to discriminate between 'known-groups' of children, and estimating thresholds for clinically important responses. Data were collected online and electronically on computer and mobile devices; hence, it was also possible to confirm other psychometric properties of the AIM in this format. This study provides confirmatory and additional psychometric validation of the AIM. The AIM offers a valid, quick and inexpensive method for caregivers to report core symptoms of autism spectrum disorder (ASD) including communication deficits, difficulties with social interactions and repetitive behaviors.

Purpose: β-Blockers (BBs) have been associated with a reduced cardiorespiratory fitness (CRF). This is possibly caused by inhibition of β2-receptors in the airways. However, there are limited data available on β-receptor selectivity and CRF. We therefore aimed to assess the association between BB use and CRF and to assess the association between β-receptor selectivity and CRF. Methods: Participants in the Maastricht Study were aged between 40 and 75 years. Exposure to BB use was determined by use of pharmacy records. General linear models were used to obtain adjusted means of 2 proxies for CRF: covered distance during the 6-minute walk test (6MWT) and estimated maximum power output adjusted for body mass ( Wmax kg−1) during the submaximal cycle ergometer test. Adjusted means were compared between current, past, and never BB users. Current users were subsequently stratified by β-receptor selectivity and dose. Results: Compared to never use, current use was associated with a lower CRF, based on the 6MWT (current use: 569.7 m; never use: 580.4 m [ P = .010]), but not based on the cycling test (current use: 2.14 W kg−1; never use: 2.13 W kg−1 [ P = .690]). There was no difference between current selective and current nonselective BB use. Conclusion: β-Blockers use was associated with CRF based on the 6MWT but not the cycling test. There was no difference between current selective and nonselective BB users, possibly due to the small number of nonselective BB users, differential underlying diseases, other pharmacological properties, and limitations related to the proxies of the outcome.

In epidemiology, one typically wants to estimate the risk of an outcome associated with an exposure after adjusting for confounders. Sometimes, outcome and exposure and maybe some confounders are available in a large data set, whereas some important confounders are only available in a validation data set that is typically a subset of the main data set. A generally applicable method in this situation is the two-stage calibration (TSC) method. We present a simplified easy-to-implement version of the TSC for the case where the validation data are a subset of the main data. We compared the simplified version to the standard TSC version for incidence rate ratios, odds ratios, relative risks, and hazard ratios using simulated data, and the simplified version performed better than our implementation of the standard version. The simplified version was also tested on real data and performed well.