Proteomics couples electrical remodelling to inflammation in a murine model of heart failure with sinus node dysfunction.

AIMS: In patients with heart failure (HF), concomitant sinus node dysfunction (SND) is an important predictor of mortality, yet its molecular underpinnings are poorly understood. Using proteomics, this study aimed to dissect the protein and phosphorylation remodelling within the sinus node in an animal model of HF with concurrent SND. METHODS AND RESULTS: We acquired deep sinus node proteomes and phosphoproteomes in mice with heart failure and SND and report extensive remodelling. Intersecting the measured (phospho)proteome changes with human genomics pharmacovigilance data, highlighted downregulated proteins involved in electrical activity such as the pacemaker ion channel, Hcn4. We confirmed the importance of ion channel downregulation for sinus node physiology using computer modelling. Guided by the proteomics data, we hypothesized that an inflammatory response may drive the electrophysiological remodeling underlying SND in heart failure. In support of this, experimentally induced inflammation downregulated Hcn4 and slowed pacemaking in the isolated sinus node. From the proteomics data we identified proinflammatory cytokine-like protein galectin-3 as a potential target to mitigate the effect. Indeed, in vivo suppression of galectin-3 in the animal model of heart failure prevented SND. CONCLUSION: Collectively, we outline the protein and phosphorylation remodeling of SND in heart failure, we highlight a role for inflammation in electrophysiological remodelling of the sinus node, and we present galectin-3 signalling as a target to ameliorate SND in heart failure.

Near-infrared spectroscopy to measure brain oxygenation: A comparison of measurements on the skin, skull and dura mater.

BACKGROUND: The reliability of near-infrared spectroscopy (NIRS) for measuring cerebral oxygenation (ScO2 ) is controversial due to the possible contamination from extracranial tissues. We compared ScO2 measured with the NIRS optode on the forehead, the skull and the dura mater in anaesthetised patients undergoing craniotomy. We hypothesised that ScO2 measured directly on the skull and the dura mater would differ from ScO2 measured on the skin. METHODS: This prospective observational study included 17 adult patients scheduled for elective craniotomy. After induction of general anaesthesia, ScO2 was measured on the forehead skin, as well as on the skull and on the dura mater in the surgical field. The primary comparison was the difference in ScO2 measured on the dura mater and on ScO2 measured on the skin; secondary comparisons were the differences in ScO2 on the skull and ScO2 on the skin and the dura mater, respectively. Data were described with median (5%-95% range) and analysed with the Wilcoxon signed-rank test. RESULTS: ScO2 values on the dura mater were obtained in 11 patients, and median ScO2 (48%, 29%-95%) did not differ significantly from ScO2 on the skin (73%, 49%-92%; p = .052), median difference -25% (-35.6% to -1.2%). ScO2 on the skull (N = 16) was lower than that on the skin (63% [43%-79%] vs. 75% [61%-94%]; p = .0002), median difference -10% (-20.8 to -3.0). CONCLUSION: In adults undergoing craniotomy, NIRS-based ScO2 measured on the dura mater did not reach statistically significantly lower values than ScO2 measured on the skin, whereas values on the skull were lower than on the skin, indicating a contribution from scalp tissue to the signal.

Impact of hyperoxia and phenylephrine on cerebral oxygenation: An experimental clinical study.

BACKGROUND: Oxygen supply to the brain is of special importance during intracranial surgery because it may be compromised by intracranial pathology. A high arterial blood pressure (mean arterial pressure above 80 mmHg) and a high arterial oxygen tension (PaO2 above 12 kPa) is therefore often targeted in these patients, when for example intracranial pressure is increased or when a mass effect on brain tissue from a tumour is present, and it is pursued by administering vasopressors such as phenylephrine and by increasing inspiratory oxygen fraction (FiO2 ). However, whether these interventions increase cerebral oxygenation remains uncertain. We aimed to investigate the effect of hyperoxia and phenylephrine on brain tissue oxygen tension (PbtO2 ) in patients undergoing craniotomy. METHODS: In this experimental study, we included 17 adult patients scheduled for elective craniotomy. After securing a stable baseline of the oxygen probe, PbtO2 was measured in white matter peripherally in the surgical field during general anaesthesia. Primary comparisons were PbtO2 before versus after an increase in FiO2 from 0.30 to 0.80 as well as before versus after a bolus dose of phenylephrine (0.1-0.2 mg depending on patient haemodynamics). Data were analysed with the Wilcoxon signed rank test. RESULTS: We obtained complete data sets in 11 patients undergoing the FiO2 increase and six patients receiving the phenylephrine bolus. PbtO2 was 22 (median; 5%-95% range, 4.6-54) mmHg during 30% oxygen, 68 (8.4-99) mmHg during 80% oxygen (p = .004 compared to 30% oxygen), 21 (4.5-81) mmHg before phenylephrine, and 19 (4.2-56) mmHg after phenylephrine (p = .56 compared to before phenylephrine). CONCLUSION: In patients undergoing craniotomy under general anaesthesia, brain tissue oxygen tension increased with a high inspiratory oxygen fraction but remained unchanged after a bolus dose of phenylephrine.

Loss of Nuclear Envelope Integrity and Increased Oxidant Production Cause DNA Damage in Adult Hearts Deficient in PKP2: A Molecular Substrate of ARVC.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by high propensity to life-threatening arrhythmias and progressive loss of heart muscle. More than 40% of reported genetic variants linked to ARVC reside in the PKP2 gene, which encodes the PKP2 protein (plakophilin-2). METHODS: We describe a comprehensive characterization of the ARVC molecular landscape as determined by high-resolution mass spectrometry, RNA sequencing, and transmission electron microscopy of right ventricular biopsy samples obtained from patients with ARVC with PKP2 mutations and left ventricular ejection fraction >45%. Samples from healthy relatives served as controls. The observations led to experimental work using multiple imaging and biochemical techniques in mice with a cardiac-specific deletion of Pkp2 studied at a time of preserved left ventricular ejection fraction and in human induced pluripotent stem cell-derived PKP2-deficient myocytes. RESULTS: Samples from patients with ARVC present a loss of nuclear envelope integrity, molecular signatures indicative of increased DNA damage, and a deficit in transcripts coding for proteins in the electron transport chain. Mice with a cardiac-specific deletion of Pkp2 also present a loss of nuclear envelope integrity, which leads to DNA damage and subsequent excess oxidant production (O2.- and H2O2), the latter increased further under mechanical stress (isoproterenol or exercise). Increased oxidant production and DNA damage is recapitulated in human induced pluripotent stem cell-derived PKP2-deficient myocytes. Furthermore, PKP2-deficient cells release H2O2 into the extracellular environment, causing DNA damage and increased oxidant production in neighboring myocytes in a paracrine manner. Treatment with honokiol increases SIRT3 (mitochondrial nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-3) activity, reduces oxidant levels and DNA damage in vitro and in vivo, reduces collagen abundance in the right ventricular free wall, and has a protective effect on right ventricular function. CONCLUSIONS: Loss of nuclear envelope integrity and subsequent DNA damage is a key substrate in the molecular pathology of ARVC. We show transcriptional downregulation of proteins of the electron transcript chain as an early event in the molecular pathophysiology of the disease (before loss of left ventricular ejection fraction <45%), which associates with increased oxidant production (O2.- and H2O2). We propose therapies that limit oxidant formation as a possible intervention to restrict DNA damage in ARVC.

Medication-related osteonecrosis of the jaws: a single centre, Far North Queensland case series.

Medication-related osteonecrosis of the jaws (MRONJ) is a painful debilitating condition which is considered rare in the medical literature available to prescribers. Dentists, however, are likely to trigger this condition through extractions and implants. Anecdotally MRONJ appears more common than first thought. This paper presents 13 cases of MRONJ diagnosed and treated by a single oral and maxillofacial surgeon based in Cairns, Far North Queensland, in a 2-year period. The management of these cases is presented. The two cases where MRONJ resulted in the loss of dental implants are highlighted. © 2022 Australian Dental Association.

Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability.

BACKGROUND: Ibrutinib is a protein kinase inhibitor that has been widely successful in treating multiple common variations of B-cell cancers. However, an unfortunate side effect of ibrutinib is that it predisposes patients to development of atrial fibrillation. OBJECTIVES: The purpose of this study was to assess other commonly prescribed protein kinase inhibitors for similar pro-arrhythmic liability. METHODS: This study comprehensively evaluated data from the U.S. Food and Drug Administration adverse events reporting system and determined the reporting of cardiac arrhythmia attributed to kinase inhibitor therapy using a multivariable logistic regression model. We evaluated 3,663,300 case reports containing 23,067 cases of atrial fibrillation and 66,262 cases of cardiac arrhythmia. In total, 32 protein kinase inhibitors were evaluated, almost all of which are oncotherapeutics. RESULTS: Seven protein kinase inhibitors were associated with a significant increase in the odds of atrial fibrillation (ibrutinib, ponatinib, nilotinib, ribociclib, trametinib, osimertinib, and idelalisib). Assessment of broader pro-arrhythmic toxicity suggested a ventricular-specific liability for nilotinib and a bradyarrhythmia risk with alectinib and crizotinib. CONCLUSIONS: Compounds that result in the inhibition of a number of protein kinases are associated with an increased risk of cardiac rhythm disturbances. The mechanisms driving the arrhythmogenic effects remain to be discovered, but this study presents an important step in identifying and prioritizing the study of these protein kinase signaling pathways.

Educational attainment and work disability in cancer survivors: Do diagnosis and comorbidity affect this association?

OBJECTIVES: To study whether educational attainment had less impact on work disability in cancer survivors than in individuals without cancer. To study whether comorbidity had a higher impact on work disability in low-educated cancer survivors than in high-educated and whether this impact differed when compared with individuals without cancer. METHODS: Linkage of population-based public health survey data and the Danish Cancer Registry formed two groups: cancer survivors (n = 3,514) and cancer-free individuals (n = 171,262). In logistic regression models, the risk of experiencing an 8-week sick leave spell and the granting of disability pension within a 3-year follow-up period was studied in three educational levels and whether these associations were modified by history of cancer and comorbidity. Odds ratios (OR) with 95% confidence intervals (CI) are reported. RESULTS: Non-stratified adjusted risk of experiencing an 8-week sick leave spell (OR: 1.41, 95% CI (1.33-1.49)) or being granted a disability pension (OR: 1.61, 95% CI (1.31-1.97)) was significantly higher in low-educated than in high-educated respondents. Cancer or comorbidity did not significantly interact with education on the risk of work disability. CONCLUSIONS: A moderate impact of low education on future work disability was found for all respondents, neither history of cancer nor comorbidity modified this association.

Improvements in Clinical Outcomes in Children with Cystic Fibrosis aged Six and 16 years.

Aims Our aim was to assess if outcomes for cystic fibrosis (CF) patients at six & sixteen years of age have improved in the last 17 years looking at FEV1, BMI and death. Methods A retrospective observational study using a prospectively maintained database of CF patients at Cork University Hospital. Results 84 patients were included in the 16-year-old data and 89 patients were included in the six-year-old data. The mean FEV1 and BMI (16 years) for the 2002-2007 group was 72.9±21.0% and 18.9±2.53 respectively, 2008-2013 group was 75.4±27.2% and 19.8±2.7 and for the 2014-2018 group was 95.2±16.0% and 22.9±4.1. The percentage of patients (16 years) with chronic pseudomonas status was 37.9% (11/30) in the 2002-2007 group, 51.6 % (16/31) in the 2008-2013 group and 4.2% (1/24) in the 2014-2018 group. The relationship between FEV1 and FVC with BMI remained significant in multivariate analysis (P <0.001). The mean FEV1 (six years) for the 2002-2007 group was 90.7±16.1%, 2008-2013 group was 99.3±17.9% and for the 2014-2018 group was 100.9±15.8%. Conclusions Improvements in FEV1 and BMI aged six and 16 years are notable as well as a significant decline in the number of patients with chronic pseudomonas.

Development of an Insulin-Prescribing Chart for Paediatric Diabetes

Aim Our aim was to design a new insulin prescribing tool in compliance with the Irish Medicines Safety Network recommendations. Methods In 2015, we undertook a review of the existing paediatric subcutaneous insulin-prescribing sheet introduced to Cork University Hospital in 2013. This involved a retrospective analysis of 15 consecutive in-patient insulin prescribing charts and a questionnaire distributed to health professionals. Following this a new insulin prescribing chart was designed and implemented in 2016 and a re-audit was performed in 2017. Results The 2017 re-audit demonstrated that the new insulin chart was viewed as easier (95% of previous users n=18) and safer (n=16) to use. There was less confusion (2017: 28%, n=11/39 vs 2015: 50%, n=17/34 2015) and the ALERT system helped staff standardise hypo/hyperglycaemia management (71%, n=28). Conclusion The new paediatric insulin prescribing chart has improved safety and ease of prescribing insulin. The colour coded quasi graph and ALERT system has made it easier to appreciate capillary blood glucose trends and manage them safely.

High Rates of Diabetic Ketoacidosis in Patients with New and Known Type 1 Diabetes over a Six-Year Period

Aims To analyse all paediatric patients who presented with diabetic ketoacidosis (DKA) from 2012 to 2017. Methods A retrospective observational study was carried out analysing all cases of diabetic ketoacidosis admitted to a regional centre from 2012-2017. Results We identified 133 cases of DKA, 81 (61%) were newly diagnosed patients and 52 (39%) were patients with known T1DM. There were 215 new diagnoses of T1DM during the study period giving a DKA rate at diagnosis of 38%. Among the 52 cases with established T1DM, 13 cases (25%) presented in severe DKA and 37 cases (71%) occurred in adolescents aged over 12 years. Precipitating factors included chronic suboptimal control and psychosocial factors (28/52), acute illness (16/52), and pump technical failure (5/52). There were two cases treated for suspected cerebral oedema and one case each of subarachnoid haemorrhage and cardiac arrhythmia. Conclusion The current proportion of new T1DM presenting in DKA is higher than international data. The high frequency of DKA in known T1DM indicates a need for particular focus on adolescents.

Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms.

A non-myeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive non-myeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low risk (n=36); and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 for three days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary end point was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. The primary end point was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with non-myeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease non-relapse mortality, especially among patients with high-risk disease. Trial registered under clinicaltrials.gov identifier: NCT00397813.

Two-piece ALIF cage optimizes the bone-implant interface in a 360° setting.

INTRODUCTION: Clinical research has documented that cage subsidence and the loss of balance correction is a significant complication related to spinal fusion. Subsidence is a multifactorial complication, where implant design is one important element. The aim of the study is to compare the rigidity and bone-implant relative motion of segments treated with either a conventional one-piece ALIF cage versus a two-piece ALIF cage, which adapts in situ and permits 7°-21° of lordosis. METHODS: Seven lumbosacral (L3-S1) human cadaver specimens were tested in a universal spine tester in the intact condition, the specimens instrumented with a two-piece ALIF cage (Statur®-L, FBC Device, Denmark) and a one-piece ALIF cage (Pezo™-A, Ulrich GmbH & Co. KG., Germany), both supplemented with a pedicle screw system using pure moments of ±7.5 Nm in three principal motion directions. For assessment of the bone-implant interface, fluoroscopic videos were captured during motion and 3D motion was measured using an optical motion capturing system. RESULTS: Significantly less motion at the implant-endplate interface was found for the two-piece cage (1.0° ± 0.6°) in comparison to the one-piece cage (4.2° ± 1.7°) in flexion/extension. No significant differences in segment rigidity were found between the one-piece and two-piece cages in the 360° setup, while both configurations significantly reduced the range of motion compared to the intact condition (p < 0.05). CONCLUSION: In comparison to the traditional one-piece ALIF cages, the two-piece cage concept reduced the relative motion at the bone-implant interface without compromising stability.

The effect of multiple reminders on response patterns in a Danish health survey.

BACKGROUND: Reminders are routinely applied in surveys to increase response rates and reduce the possibility of bias. This study examines the effect of multiple reminders on the response rate, non-response bias, prevalence estimates and exposure-outcome relations in a national self-administered health survey. METHODS: Data derive from the Danish National Health Survey 2010, in which 298,550 individuals (16 years of age or older) were invited to participate in a cross-sectional survey using a mixed-mode approach (paper and web questionnaires). At least two reminders were sent to non-respondents, and 177,639 individuals completed the questionnaire (59.5%). Response patterns were compared between four groups of individuals (first mailing respondents, second mailing respondents, third mailing respondents and non-respondents). RESULTS: Multiple reminders led to an increase in response rate from 36.7 to 59.5%; however, the inclusion of second and third mailing respondents did not change the overall characteristics of respondents compared with non-respondents. Furthermore, only small changes in prevalence estimates and exposure-outcome relationships were observed when including second and third mailing respondents compared with only first mailing respondents. CONCLUSIONS: Multiple reminders were an effective way to increase the response rate in a national Danish health survey. However, when differences do exist between respondents and non-respondents, the results suggest that second and third mailings are unlikely to eliminate these differences. Overall, multiple reminders seemed to have only minor effect on response patterns and study conclusions in the present study.

Lifestyle factors associated with type 2 diabetes and use of different glucose-lowering drugs: cross-sectional study.

AIMS: To examine the lifestyle profile among persons with and without Type 2 diabetes mellitus (DM) and among users of different glucose-lowering drugs. METHODS: We used questionnaire data from a Danish health survey and identified presence of Type 2 DM and use of medications through medical databases. We calculated age- and gender-standardized prevalence ratios (PRs) of lifestyle factors according to Type 2 DM and different glucose-lowering drugs. RESULTS: Of 21,637 survey participants aged 25-79 years, 680 (3%) had Type 2 DM (median age 63 years) with a median diabetes duration of 5 years. Participants with Type 2 DM had a substantially higher prevalence of obesity (36% vs. 13%, PR: 3.1, 95% confidence interval (CI): 2.8-3.6), yet more reported to eat a very healthy diet (25% vs. 21%, PR: 1.2, 95% CI: 1.0-1.4) and to exercise regularly (67% vs. 53%, PR: 1.3, 95% CI: 1.2-1.4). Also, fewer were current smokers or had high alcohol intake. When compared with metformin users, obesity was substantially less prevalent in users of sulfonylurea (PR: 0.5, 95% CI: 0.4-0-8), and insulin and analogues (PR: 0.4, 95% CI: 0.3-0.7). Tobacco smoking was more prevalent in sulfonylurea users (PR: 1.4, 95% CI: 0.9-2.1) compared with metformin users. We found no material differences in physical exercise, diet or alcohol intake according to type of glucose-lowering drug. CONCLUSIONS: Type 2 DM patients are substantially more obese than other individuals, but otherwise report to have a healthier lifestyle. Metformin use is strongly associated with obesity, whereas sulfonylurea use tends to be associated with tobacco smoking.

A randomized phase II trial of tacrolimus, mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation.

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

Energy drink consumption and the relation to socio-demographic factors and health behaviour among young adults in Denmark. A population-based study.

BACKGROUND: The objective of this study is to estimate the prevalence of energy drink consumption and examine the associations of socio-demographic factors and health behaviour with energy drink consumption among young adults in Denmark. METHODS: The study is based on a public health survey from 2010 (n = 3923). Multiple logistic regression analyses were used to analyse the association between weekly consumption of energy drink and the potential explanatory factors of interest. RESULTS: In total, 15.8 % of the young adults drink energy drinks on a weekly basis. Men have higher odds of weekly energy drink consumption than women. The study also shows that young age, being employed and having a low educational level are associated with weekly energy drink consumption. According to health behaviour, daily smoking, high amounts of alcohol consumption, alcoholic binge drinking and being overweight are associated with weekly energy drink consumption. CONCLUSION: Compared with other European countries the prevalence of energy drink consumption is relatively low in Denmark. In Denmark energy drink consumption is typically a male phenomenon and there is a clear social gradient in the prevalence of energy drink consumption where the intake is far more common among people with low levels of education than among people with higher levels of education. This study also shows that there is some kind of 'add on' effect of energy drinks, meaning that people who also use other stimulants-such as alcohol and cigarettes-are more inclined to consume energy drinks.

Lifestyle factors among proton pump inhibitor users and nonusers: a cross-sectional study in a population-based setting.

PURPOSE: Lifestyle factors may influence observed associations between proton pump inhibitor (PPI) usage and health outcomes. The aim of the study reported here was to examine characteristics and differences in lifestyle among PPI users and nonusers. METHODS: This cross-sectional study utilized data from a 2006 population-based health survey of 21,637 persons in the Central Danish Region. All persons using prescribed PPIs were identified through linkage to a population-based prescription database. Biometric measures and prevalence of smoking, excessive alcohol consumption, diet, and physical exercise were analyzed, comparing PPI users with nonusers. RESULTS: Among 10,129 (46.8%) male and 11,508 (53.2%) female survey respondents, 1,356 (13.4%) males and 1,691 (14.7%) females reported ever use of PPIs. PPI users were more obese (16.7%) than nonusers (13.1%), with an age- and sex-standardized prevalence ratio (PR) of 1.3 (95% confidence interval [CI]: 1.2-1.4). The prevalence of smokers was also higher in the PPI group (26.2% vs 22.3% [PR =1.2, 95% CI: 1.1-1.3]), as was the prevalence of ex-smokers (41.0% vs 32.0% [PR =1.2, 95% CI: 1.1-1.2]). Unhealthy diet was slightly more common among PPI users than among nonusers (15.4% vs 13.0%), with a PR of 1.2 (95% CI: 1.1-1.3). Physical exercise level and alcohol consumption were similar in the two groups. Hospital-diagnosed comorbidity was observed in 35% of PPI users (a Charlson Comorbidity Index score of 1 or more) compared with only 15% among nonusers. CONCLUSION: PPI users are more obese, smoke more, and have significantly more comorbidities than PPI nonusers. These data are important when evaluating unmeasured confounding in observational studies of PPI effects.