IncidencePrevalence: An R package to calculate population-level incidence rates and prevalence using the OMOP common data model.

PURPOSE: Real-world data (RWD) offers a valuable resource for generating population-level disease epidemiology metrics. We aimed to develop a well-tested and user-friendly R package to compute incidence rates and prevalence in data mapped to the observational medical outcomes partnership (OMOP) common data model (CDM). MATERIALS AND METHODS: We created IncidencePrevalence, an R package to support the analysis of population-level incidence rates and point- and period-prevalence in OMOP-formatted data. On top of unit testing, we assessed the face validity of the package. To do so, we calculated incidence rates of COVID-19 using RWD from Spain (SIDIAP) and the United Kingdom (CPRD Aurum), and replicated two previously published studies using data from the Netherlands (IPCI) and the United Kingdom (CPRD Gold). We compared the obtained results to those previously published, and measured execution times by running a benchmark analysis across databases. RESULTS: IncidencePrevalence achieved high agreement to previously published data in CPRD Gold and IPCI, and showed good performance across databases. For COVID-19, incidence calculated by the package was similar to public data after the first-wave of the pandemic. CONCLUSION: For data mapped to the OMOP CDM, the IncidencePrevalence R package can support descriptive epidemiological research. It enables reliable estimation of incidence and prevalence from large real-world data sets. It represents a simple, but extendable, analytical framework to generate estimates in a reproducible and timely manner.

Calculating daily dose in the Observational Medical Outcomes Partnership Common Data Model.

PURPOSE: We aimed to develop a standardized method to calculate daily dose (i.e., the amount of drug a patient was exposed to per day) of any drug on a global scale using only drug information of typical observational data in the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) and a single reference table from Observational Health Data Sciences And Informatics (OHDSI). MATERIALS AND METHODS: The OMOP DRUG_STRENGTH reference table contains information on the strength or concentration of drugs, whereas the OMOP DRUG_EXPOSURE table contains information on patients' drug prescriptions or dispensations/claims. Based on DRUG_EXPOSURE data from the primary care databases Clinical Practice Research Datalink GOLD (United Kingdom) and Integrated Primary Care Information (IPCI, The Netherlands) and healthcare claims from PharMetrics® Plus for Academics (USA), we developed four formulas to calculate daily dose given different DRUG_STRENGTH reference table information. We tested the dose formulas by comparing the calculated median daily dose to the World Health Organization (WHO) Defined Daily Dose (DDD) for six different ingredients in those three databases and additional four international databases representing a variety of healthcare settings: MAITT (Estonia, healthcare claims and discharge summaries), IQVIA Disease Analyzer Germany (outpatient data), IQVIA Longitudinal Patient Database Belgium (outpatient data), and IMASIS Parc Salut (Spain, hospital data). Finally, in each database, we assessed the proportion of drug records for which daily dose calculations were possible using the suggested formulas. RESULTS: Applying the dose formulas, we obtained median daily doses that generally matched the WHO DDD definitions. Our dose formulas were applicable to >85% of drug records in all but one of the assessed databases. CONCLUSION: We have established and implemented a standardized daily dose calculation in OMOP CDM providing reliable and reproducible results.

Effects of Short-Term Potassium Chloride Supplementation in Patients with CKD.

BACKGROUND: Observational studies suggest that adequate dietary potassium intake (90-120 mmol/day) may be renoprotective, but the effects of increasing dietary potassium and the risk of hyperkalemia are unknown. METHODS: This is a prespecified analysis of the run-in phase of a clinical trial in which 191 patients (age 68±11 years, 74% males, 86% European ancestry, eGFR 31±9 ml/min per 1.73 m2, 83% renin-angiotensin system inhibitors, 38% diabetes) were treated with 40 mmol potassium chloride (KCl) per day for 2 weeks. RESULTS: KCl supplementation significantly increased urinary potassium excretion (72±24 to 107±29 mmol/day), plasma potassium (4.3±0.5 to 4.7±0.6 mmol/L), and plasma aldosterone (281 [198-431] to 351 [241-494] ng/L), but had no significant effect on urinary sodium excretion, plasma renin, BP, eGFR, or albuminuria. Furthermore, KCl supplementation increased plasma chloride (104±3 to 105±4 mmol/L) and reduced plasma bicarbonate (24.5±3.4 to 23.7±3.5 mmol/L) and urine pH (all P<0.001), but did not change urinary ammonium excretion. In total, 21 participants (11%) developed hyperkalemia (plasma potassium 5.9±0.4 mmol/L). They were older and had higher baseline plasma potassium. CONCLUSIONS: In patients with CKD stage G3b-4, increasing dietary potassium intake to recommended levels with potassium chloride supplementation raises plasma potassium by 0.4 mmol/L. This may result in hyperkalemia in older patients or those with higher baseline plasma potassium. Longer-term studies should address whether cardiorenal protection outweighs the risk of hyperkalemia.Clinical trial number: NCT03253172.

Incidence, risk factors and re-exacerbation rate of severe asthma exacerbations in a multinational, multidatabase pediatric cohort study.

BACKGROUND: There are sparse real-world data on severe asthma exacerbations (SAE) in children. This multinational cohort study assessed the incidence of and risk factors for SAE and the incidence of asthma-related rehospitalization in children with asthma. METHODS: Asthma patients 5-17 years old with ≥1 year of follow-up were identified in six European electronic databases from the Netherlands, Italy, the UK, Denmark and Spain in 2008-2013. Asthma was defined as ≥1 asthma-specific disease code within 3 months of prescriptions/dispensing of asthma medication. Severe asthma was defined as high-dosed inhaled corticosteroids plus a second controller. SAE was defined by systemic corticosteroids, emergency department visit and/or hospitalization all for reason of asthma. Risk factors for SAE were estimated by Poisson regression analyses. RESULTS: The cohort consisted of 212 060 paediatric asthma patients contributing to 678 625 patient-years (PY). SAE rates ranged between 17 and 198/1000 PY and were higher in severe asthma and highest in severe asthma patients with a history of exacerbations. Prior SAE (incidence rate ratio 3-45) and younger age increased the SAE risk in all countries, whereas obesity, atopy and GERD were a risk factor in some but not all countries. Rehospitalization rates were up to 79% within 1 year. CONCLUSIONS: In a real-world setting, SAE rates were highest in children with severe asthma with a history of exacerbations. Many severe asthma patients were rehospitalized within 1 year. Asthma management focusing on prevention of SAE is important to reduce the burden of asthma.

Use of azithromycin and risk of ventricular arrhythmia.

BACKGROUND: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia. METHODS: We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders. RESULTS: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis. INTERPRETATION: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.

Combining evidence from multiple electronic health care databases: performances of one-stage and two-stage meta-analysis in matched case-control studies.

PURPOSE: Clustering of patients in databases is usually ignored in one-stage meta-analysis of multi-database studies using matched case-control data. The aim of this study was to compare bias and efficiency of such a one-stage meta-analysis with a two-stage meta-analysis. METHODS: First, we compared the approaches by generating matched case-control data under 5 simulated scenarios, built by varying: (1) the exposure-outcome association; (2) its variability among databases; (3) the confounding strength of one covariate on this association; (4) its variability; and (5) the (heterogeneous) confounding strength of two covariates. Second, we made the same comparison using empirical data from the ARITMO project, a multiple database study investigating the risk of ventricular arrhythmia following the use of medications with arrhythmogenic potential. In our study, we specifically investigated the effect of current use of promethazine. RESULTS: Bias increased for one-stage meta-analysis with increasing (1) between-database variance of exposure effect and (2) heterogeneous confounding generated by two covariates. The efficiency of one-stage meta-analysis was slightly lower than that of two-stage meta-analysis for the majority of investigated scenarios. Based on ARITMO data, there were no evident differences between one-stage (OR = 1.50, CI = [1.08; 2.08]) and two-stage (OR = 1.55, CI = [1.12; 2.16]) approaches. CONCLUSIONS: When the effect of interest is heterogeneous, a one-stage meta-analysis ignoring clustering gives biased estimates. Two-stage meta-analysis generates estimates at least as accurate and precise as one-stage meta-analysis. However, in a study using small databases and rare exposures and/or outcomes, a correct one-stage meta-analysis becomes essential.

The need to scale up HIV indicator condition-guided testing for early case-finding: a case-control study in primary care.

BACKGROUND: European guidelines recommend offering an HIV test to individuals who display HIV indicator conditions (ICs). We aimed to investigate the incidence of ICs in primary care reported in medical records prior to HIV diagnosis. METHODS: We did a cross-sectional search in an electronic general practice database using a matched case-control design to identify which predefined ICs registered by Dutch GPs were most associated with an HIV-positive status prior to the time of diagnosis. RESULTS: We included 224 HIV cases diagnosed from 2009 to 2013, which were matched with 2,193 controls. Almost two thirds (n = 136, 60.7%) of cases were diagnosed with one or more ICs in the period up to five years prior to the index date compared to 18.7% (n = 411) of controls. Cases were more likely to have an IC than controls: in the one year prior to the index date, the odds ratio (OR) for at least one condition was 11.7 (95% CI: 8.3 to 16.4). No significant differences were seen in the strength of the association between HIV diagnosis and ICs when comparing genders, age groups or urbanisation levels. There is no indication that subgroups require a different testing strategy. CONCLUSIONS: Our study shows that there are opportunities for IC-guided testing in primary care. We recommend that IC-guided testing be more integrated in GPs' future guidelines and that education strategies be used to facilitate its implementation in daily practice.

Risk of upper gastrointestinal bleeding from different drug combinations.

BACKGROUND & AIMS: Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and low-dose aspirin increases the risk of upper gastrointestinal bleeding (UGIB). Guidelines suggest avoiding certain drug combinations, yet little is known about the magnitude of their interactions. We estimated the risk of UGIB during concomitant use of nonselective (ns)NSAIDs, cyclooxygenase -2 selective inhibitors (COX-2 inhibitors), and low-dose aspirin with other drugs. METHODS: We performed a case series analysis of data from 114,835 patients with UGIB (930,888 person-years of follow-up) identified from 7 population-based health care databases (approximately 20 million subjects). Each patient served as his or her own control. Drug exposure was determined based on prescriptions of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin, alone and in combination with other drugs that affect the risk of UGIB. We measured relative risk (incidence rate ratio [IRR] during drug exposure vs nonexposure) and excess risk due to concomitant drug exposure (relative excess risk due to interaction [RERI]). RESULTS: Monotherapy with nsNSAIDs increased the risk of diagnosis of UGIB (IRR, 4.3) to a greater extent than monotherapy with COX-2 inhibitors (IRR, 2.9) or low-dose aspirin (IRR, 3.1). Combination therapy generally increased the risk of UGIB; concomitant nsNSAID and corticosteroid therapies increased the IRR to the greatest extent (12.8) and also produced the greatest excess risk (RERI, 5.5). Concomitant use of nsNSAIDs and aldosterone antagonists produced an IRR for UGIB of 11.0 (RERI, 4.5). Excess risk from concomitant use of nsNSAIDs with selective serotonin reuptake inhibitors (SSRIs) was 1.6, whereas that from use of COX-2 inhibitors with SSRIs was 1.9 and that for use of low-dose aspirin with SSRIs was 0.5. Excess risk of concomitant use of nsNSAIDs with anticoagulants was 2.4, of COX-2 inhibitors with anticoagulants was 0.1, and of low-dose aspirin with anticoagulants was 1.9. CONCLUSIONS: Based on a case series analysis, concomitant use of nsNSAIDs, COX-2 inhibitors, or low-dose aspirin with SSRIs significantly increases the risk of UGIB. Concomitant use of nsNSAIDs or low-dose aspirin, but not COX-2 inhibitors, with corticosteroids, aldosterone antagonists, or anticoagulants produces significant excess risk of UGIB.

Time trends in the incidence, prevalence and age at diagnosis of asthma in children.

BACKGROUND: Current knowledge on the prevalence of asthma is mainly based on cross-sectional questionnaire data. Current population-based data on the incidence of asthma in children are scarce. OBJECTIVE: To study the incidence, prevalence, and age at diagnosis of asthma in children in the Netherlands over the study period 2000-2012. METHODS: A population-based cohort study was conducted in the Integrated Primary Care Information database. The cohort consisted of 176,516 children (379,536 personyears (PY) of follow-up), aged 5-18 years between 2000 and 2012. All medical records of children with physician diagnosed asthma were validated. Incidence rates, annual percent change (APC), and prevalence for asthma were calculated. Influence of age and gender on incidence rates and change in age at diagnosis were studied. RESULTS: We identified an asthma cohort of 14,303 children with 35,118 PY. The overall incidence rate was 6.7/1000 PY (95% CI, 6.45-6.97). Until 2008, the incidence rate was significantly increasing (APC 5.79 (95% CI 1.43-10.34); from 2008 onwards, a non-significant decrease was observed (APC -12.16 (95% CI -23.07 to 0.28). Incidence for girls was lower than for boys, this difference decreased with increasing age. (p < 0.001) Overall, the age at diagnosis increased over calendar time and was lower for boys. (linear trend p < 0.001). CONCLUSION: Our population-based cohort study observed an incidence rate of 6.7 per 1000 PY of physician-diagnosed asthma in children in the Netherlands over 2000-2012. The asthma incidence rate was increasing until 2008. Further studies are needed to confirm the decrease in asthma incidence rate from 2008 onwards.

Health-related quality of life and problem behaviour after GH cessation in adults born SGA: a 12-year follow-up study.

CONTEXT: Long-term data regarding HRQoL and problem behaviour in adults born SGA who were treated with GH during childhood are lacking. OBJECTIVE: To investigate longitudinal changes in HRQoL and problem behaviour in adults born SGA during 12 years after cessation of childhood GH-treatment (SGA-GH), and compare these with 3 control groups at age around 30 years. PARTICIPANTS: 176 SGA-GH adults and 3 untreated age-matched control groups: 50 born SGA with short stature (SGA-S), 77 born SGA with spontaneous catch-up growth to normal height (SGA-CU) and 99 born appropriate-for-gestational-age with normal height (AGA). MAIN OUTCOME MEASURES: HRQoL and problem behavior were assessed using TNO-AZL Adults Quality of Life questionnaire (TAAQoL) and Adolescent Behavior Check List (ABCL) at 6 months, 2, 5 and 12 years after GH-cessation. Data at 12-years after GH-cessation were compared with 3 control groups. RESULTS: During 12 years after GH-cessation, HRQoL remained similar on 9 subscales in SGA-GH adults, but decreased on 3 subscales (gross motor functioning, pain, sleep). Externalizing problem behaviour decreased significantly and internalizing problem behaviour tended to decrease. SGA-GH and SGA-S adults had similar HRQoL and problem behaviour. SGA-GH adults had, compared to AGA adults, similar HRQoL on 7 subscales, lower HRQoL on 5 subscales and more internalizing and externalizing problem behaviour. All SGA adults had lower HRQoL and more internalizing problem behaviour than AGA adults. Adult height associated negatively with externalizing problem behaviour, but the influence was small. CONCLUSIONS: During 12 years after GH-cessation, HRQoL remained mostly similar and problem behaviour decreased in SGA-GH adults. SGA-GH and SGA-S adults had similar HRQoL and problem behaviour. All SGA adults had lower HRQoL and more internalizing problem behaviour than AGA adults.

Clinical Relevance of Resection Margins in Patients with Total Laryngectomy or Laryngopharyngectomy.

BACKGROUND: Laryngeal and hypopharyngeal cancer is complex and resection margins are therefore constrained. The aim of this study was to investigate the clinical relevance of resection margins in laryngeal and hypopharyngeal surgery. METHODS: A retrospective cohort study was performed for patients treated with a total laryngectomy (TL) or laryngopharyngectomy (TLP) for laryngeal or hypopharyngeal squamous cell carcinoma (LSCC and HSCC, respectively). Within the groups primary LSCC, recurrent LSCC, primary HSCC, and recurrent HSCC the relationship between the status of the resection margin according to the Royal Collage of Pathology and the recurrence and survival rates were investigated. RESULTS: Positive resection margins were found in 54% for primary LSCC, 29% for recurrent LSCC, 62% for primary HSCC, and 44% for recurrent HSCC. For primary and recurrent LSCC, there was a linear association between total recurrence and narrowing margins (p = 0.007 resp. p = 0.008). Multivariate survival analysis for primary and recurrent LSCC showed a significantly worse disease free and disease-specific survival in case of positive margins compared to clear margins. CONCLUSION: Similar survival rates were recorded for close and clear margins for primary and recurrent LSCC. This may suggest that a margin > 5 mm is not clinically relevant in terms of survival. Therefore, a margin of 1-5 mm should be accepted in certain subsites. Margins < 1 mm are related to significantly worse outcomes and should be avoided.

Circulating maternal cytokines influence fetal growth in pregnant women with rheumatoid arthritis.

BACKGROUND: High rheumatoid arthritis (RA) disease activity during pregnancy is associated with a lower birth weight. Active RA is characterised by high circulating levels of cytokines, which can mediate placental growth and remodelling. OBJECTIVES: To assess the influence of maternal serum cytokine levels on birth weight in RA pregnancy. METHODS: This study is embedded in the PARA Study, a prospective study on RA and pregnancy. In the present study, 161 pregnant women with RA and 32 healthy pregnant women were studied. The main outcome measures were birth weight SD score (birth weight SDS) in relation to maternal serum levels of interleukin-10 (IL-10), interleukin-6 (IL-6) and tumour necrosis factor-α (TNFα) at three different time points: preconception and during the first and third trimester. Single-nucleotide polymorphisms (SNPs) in the corresponding cytokine genes were also studied. RESULTS: During the first trimester, IL-10 was detectable in 16% of patients with RA, IL-6 in 71%, and TNFα in all patients with RA. Mean birth weight SDS of children born to mothers with RA was higher when IL-10 level was high compared with low (difference=0.75; p=0.04), and lower when IL-6 was high compared with low (difference=0.50; p<0.01) in the first trimester. No correlation was seen at the other time points studied or with TNFα. Cytokine levels were not related to their corresponding SNPs. CONCLUSIONS: Maternal IL-10 and IL-6 levels are associated with fetal growth in RA. In the first trimester, high IL-10 levels are associated with higher birth weight SDS, and high IL-6 levels are associated with lower birth weight SDS, even after correction for disease activity.

Skinfold-based-equations to assess longitudinal body composition in children from birth to age 5 years.

BACKGROUND & AIMS: In order to identify children at risk for excess adiposity, it is important to determine body composition longitudinally throughout childhood. However, most frequently used techniques in research are expensive and time-consuming and, therefore, not feasible for use in general clinical practice. Skinfold measurements can be used as proxy for adiposity, but current anthropometry-based-equations have random and systematic errors, especially when used longitudinally in pre-pubertal children. We developed and validated skinfold-based-equations to estimate total fat mass (FM) longitudinally in children aged 0-5 years. METHODS: This study was embedded in the Sophia Pluto study, a prospective birth cohort. In 998 healthy term-born children, we longitudinally measured anthropometrics, including skinfolds and determined FM using Air Displacement Plethysmography (ADP) by PEA POD and Dual energy X-ray Absorptiometry (DXA) from birth to age 5 years. Of each child one random measurement was used in the determination cohort, others for validation. Linear regression was used to determine the best fitting FM-prediction model based on anthropometric measurements using ADP and DXA as reference methods. For validation, we used calibration plots to determine predictive value and agreement between measured and predicted FM. RESULTS: Three skinfold-based-equations were developed for adjoined age ranges (0-6 months, 6-24 months and 2-5 years), based on FM-trajectories. Validation of these prediction equations showed significant correlations between measured and predicted FM (R: 0.921, 0.779 and 0.893, respectively) and good agreement with small mean prediction errors of 1, 24 and -96 g, respectively. CONCLUSIONS: We developed and validated reliable skinfold-based-equations which may be used longitudinally from birth to age 5 years in general practice and large epidemiological studies.

Oral corticosteroid use and sarcopenia-related traits in older people with chronic airway disease: a population-based study.

Background: Sarcopenia is characterised by two major phenotypic components: low handgrip strength (HGS) and appendicular skeletal muscle index (ASMI). Oral corticosteroid (OCS) use is an important medication for acute respiratory exacerbations in patients with COPD and asthma. However, the association of OCS and sarcopenia components in older people is largely unexplored. The aim of this study was to examine the association between OCS use and HGS or ASMI in the general population and explore interactions with chronic airway diseases. Methods: From the population-based Rotterdam Study, 5054 participants (age 69.0±8.8 years; 56% females) were included in the cross-sectional analysis and 1324 in the longitudinal analysis. Associations between OCS and muscle strength and mass were analysed using linear regression models adjusted for age, sex, fat %, height, kidney function, smoking and comorbidities. Results: At baseline, ever-OCS users had lower handgrip strength (ß= -0.48, 95% CI -0.84- -0.12) than never-OCS users, with cumulative frequency (≥10 OCS prescriptions)-dependent effects (ß= -1.25, 95% CI -2.16- -0.33). COPD ever-OCS users, but not asthma, had lower handgrip strength (ß= -0.98, 95% CI -1.91- -0.06) and lower lean mass (ß= -0.14, 95% CI -0.27- -0.01) than never-OCS users. After 5.6 years of follow-up in those free of sarcopenia traits at baseline, COPD ever-OCS users developed lower handgrip strength (ß= -1.64, 95% CI -2.87- -0.40) with frequency (ß= -3.64, 95% CI -6.57- -0.72) and duration (ß= -1.51, 95% CI -2.87- -0.15) association compared to never-OCS users. Conclusions: OCS use is associated with a decline in handgrip strength in people with COPD in a cumulative frequency and duration-dependent manner. Routine muscle examination may be necessary for patients with COPD.

Drug Utilisation Patterns of Alternatives to Ranitidine-Containing Medicines in Patients Treated with Ranitidine: A Network Analysis of Data from Six European National Databases.

INTRODUCTION: Ranitidine, a histamine H2-receptor antagonist (H2RA), is indicated in the management of gastric acid-related disorders. In 2020, the European Medicines Agency (EMA) recommended suspension of all ranitidine-containing medicines in the European Union (EU) due to the presence of N-nitrosodimethylamine (NDMA) impurities, which were considered to be carcinogenic. The aim of this study was to investigate the impact of regulatory intervention on use patterns of ranitidine-containing medicines and their therapeutic alternatives. OBJECTIVES: The aim was to study drug utilisation patterns of ranitidine and report discernible trends in treatment discontinuation and switching to alternative medications. METHODS: This retrospective, population-based cohort study was conducted using primary care records from six European countries between 2017 and 2023. To explore drug utilisation patterns, we calculated (1) incident use of ranitidine, other H2RAs, and other alternative drugs for the treatment of gastric ulcer and/or gastric bleeding; (2) ranitidine discontinuation; and (3) switching from ranitidine to alternative drugs (H2RAs, proton-pump inhibitors [PPIs], and other medicinal products for acid-related disorders). RESULTS: During the study period, 385,273 new ranitidine users were observed, with most users being female and aged 18-74 years. Ranitidine was the most commonly prescribed H2RA in the pre-referral period (September 2017-August 2019), with incidence rates between 0.8 and 9.0/1000 person years (PY). A steep decline to 0.3-3.8/1000 PY was observed in the referral period (September 2019-March 2020), eventually dropping to 0.0-0.4/1000 PY in the post-referral period (April 2020-March 2022). Switching from ranitidine to alternative drugs increased in the post-referral period, with the majority of patients switching to PPIs. Discontinuation of ranitidine use ranged from 270 to 380/1000 users in 2017 and decreased over time. CONCLUSIONS: Ranitidine was commonly used prior to referral, but it was subsequently discontinued and replaced primarily with PPIs.

Comorbidity in incident osteoarthritis cases and matched controls using electronic health record data.

BACKGROUND: Comorbidities are common in patients with osteoarthritis (OA). This study aimed to determine the association of a wide range of previously diagnosed comorbidities in adults with newly diagnosed OA compared with matched controls without OA. METHODS: A case-control study was conducted. The data were derived from an electronic health record database that contains the medical records of patients from general practices throughout the Netherlands. Incident OA cases were defined as patients with one or more diagnostic codes recorded in their medical records that correspond to knee, hip, or other/peripheral OA. Additionally, the first OA code had to be recorded between January 1, 2006, and December 31, 2019. The date of cases' first OA diagnosis was defined as the index date. Cases were matched (by age, sex, and general practice) to up to 4 controls without a recorded OA diagnosis. Odds ratios were derived for each 58 comorbidities separately by dividing the comorbidity prevalence of cases by that of their matched controls at the index date. RESULTS: 80,099 incident OA patients were identified of whom 79,937 (99.8%) were successfully matched with 318,206 controls. OA cases had higher odds for 42 of the 58 studied comorbidities compared with matched controls. Musculoskeletal diseases and obesity showed large associations with incident OA. CONCLUSIONS: Most of the comorbidities under study had higher odds in patients with incident OA at the index date. While previously known associations were confirmed in this study, some associations were not described earlier.

Chronic Cough-Related Differences in Brain Morphometry in Adults: A Population-Based Study.

BACKGROUND: Individuals with cough hypersensitivity have increased central neural responses to tussive stimuli, which may result in maladaptive morphometric changes in the central cough processing systems. RESEARCH QUESTION: Are the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough? STUDY DESIGN AND METHODS: Between 2009 and 2014, participants in the Rotterdam Study, a population-based cohort, underwent brain MRI and were interviewed for chronic cough, which was defined as daily coughing for at least 3 months. Regional brain volumes were quantified with the use of parcellation software. Based on literature review, we identified and studied seven brain regions that previously had been associated with altered functional brain activity in chronic cough. The relationship between chronic cough and regional brain volumes was investigated with the use of multivariable regression models. RESULTS: Chronic cough was prevalent in 9.6% (No. = 349) of the 3,620 study participants (mean age, 68.5 ± 9.0 years; 54.6% female). Participants with chronic cough had significantly smaller anterior cingulate cortex volume than participants without chronic cough (mean difference, -126.16 mm3; 95% CI, -245.67 to -6.66; P = .039). Except for anterior cingulate cortex, there were no significant difference in the volume of other brain regions based on chronic cough status. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere (mean difference, -88.11 mm3; 95% CI, -165.16 to -11.06; P = .025) and in male participants (mean difference, -242.58 mm3; 95% CI, -428.60 to -56.55; P = .011). INTERPRETATION: Individuals with chronic cough have a smaller volume of the anterior cingulate cortex, which is a brain region involved in cough suppression. CLINICAL TRIAL REGISTRATION: The Netherlands National Trial Registry (NTR; www.trialregister.nl) and the World Health Organization's International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under the joint catalogue number NTR6831.

Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post-Fracture Treatment, and All-Cause Mortality.

In this international study, we examined the incidence of hip fractures, postfracture treatment, and all-cause mortality following hip fractures, based on demographics, geography, and calendar year. We used patient-level healthcare data from 19 countries and regions to identify patients aged 50 years and older hospitalized with a hip fracture from 2005 to 2018. The age- and sex-standardized incidence rates of hip fractures, post-hip fracture treatment (defined as the proportion of patients receiving anti-osteoporosis medication with various mechanisms of action [bisphosphonates, denosumab, raloxifene, strontium ranelate, or teriparatide] following a hip fracture), and the all-cause mortality rates after hip fractures were estimated using a standardized protocol and common data model. The number of hip fractures in 2050 was projected based on trends in the incidence and estimated future population demographics. In total, 4,115,046 hip fractures were identified from 20 databases. The reported age- and sex-standardized incidence rates of hip fractures ranged from 95.1 (95% confidence interval [CI] 94.8-95.4) in Brazil to 315.9 (95% CI 314.0-317.7) in Denmark per 100,000 population. Incidence rates decreased over the study period in most countries; however, the estimated total annual number of hip fractures nearly doubled from 2018 to 2050. Within 1 year following a hip fracture, post-hip fracture treatment ranged from 11.5% (95% CI 11.1% to 11.9%) in Germany to 50.3% (95% CI 50.0% to 50.7%) in the United Kingdom, and all-cause mortality rates ranged from 14.4% (95% CI 14.0% to 14.8%) in Singapore to 28.3% (95% CI 28.0% to 28.6%) in the United Kingdom. Males had lower use of anti-osteoporosis medication than females, higher rates of all-cause mortality, and a larger increase in the projected number of hip fractures by 2050. Substantial variations exist in the global epidemiology of hip fractures and postfracture outcomes. Our findings inform possible actions to reduce the projected public health burden of osteoporotic fractures among the aging population. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Trends in the conduct and reporting of clinical prediction model development and validation: a systematic review.

OBJECTIVES: This systematic review aims to provide further insights into the conduct and reporting of clinical prediction model development and validation over time. We focus on assessing the reporting of information necessary to enable external validation by other investigators. MATERIALS AND METHODS: We searched Embase, Medline, Web-of-Science, Cochrane Library, and Google Scholar to identify studies that developed 1 or more multivariable prognostic prediction models using electronic health record (EHR) data published in the period 2009-2019. RESULTS: We identified 422 studies that developed a total of 579 clinical prediction models using EHR data. We observed a steep increase over the years in the number of developed models. The percentage of models externally validated in the same paper remained at around 10%. Throughout 2009-2019, for both the target population and the outcome definitions, code lists were provided for less than 20% of the models. For about half of the models that were developed using regression analysis, the final model was not completely presented. DISCUSSION: Overall, we observed limited improvement over time in the conduct and reporting of clinical prediction model development and validation. In particular, the prediction problem definition was often not clearly reported, and the final model was often not completely presented. CONCLUSION: Improvement in the reporting of information necessary to enable external validation by other investigators is still urgently needed to increase clinical adoption of developed models.

The interrelationship of chronic cough and depression: a prospective population-based study.

Background: Chronic cough is a debilitating medical condition that is often complicated by psychomorbidities such as depressive symptoms. Nevertheless, little is known about the impact of chronic cough on the risk of developing depression. Therefore, we investigated the association between chronic cough and prevalent, incident and recurrent depression in a population-based sample of middle-aged and older persons. Methods: Within the Rotterdam Study, a population-based cohort, we defined chronic cough as reporting daily coughing for ⩾3 months. Depression was assessed using the Center for Epidemiologic Studies Depression scale, clinical interviews and medical records. Associations between chronic cough and depression were determined with linear, logistic and Cox regression analyses. Results: The study included 5877 participants (mean±sd age 72±8 years, 59% female) who contributed 37 287 person-years of follow-up. At baseline, participants with chronic cough reported more depressive symptoms (adjusted standardised mean difference 0.15, 95% CI 0.07-0.22) compared to those without chronic cough. Over time, chronic cough was associated with an increased risk of depression in participants with a history of depression (hazard ratio (HR) 1.45, 95% CI 1.13-1.84), but not in those without a history of depression (HR 0.91, 95% CI 0.68-1.22). Conclusions: Adults with chronic cough have a disproportionate burden of depressive symptoms and an increased risk of recurrent depression. This highlights the importance of screening for depression in patients with chronic cough.