Prevalence and prescribing patterns of oral corticosteroids in the United States, Taiwan, and Denmark, 2009-2018.

Oral corticosteroids (OCS) are commonly prescribed for acute, self-limited conditions, despite studies demonstrating toxicity. Studies evaluating longitudinal OCS prescribing in the general population are scarce and do not compare use across countries. This study investigated and compared OCS prescription patterns from 2009 to 2018 in the general populations of the United States, Taiwan, and Denmark. This international population-based longitudinal cohort study used nationwide claims databases (United States: Optum Clinformatics Data Mart; de-identified; Taiwan: National Health Insurance Research Database; and Denmark: National Prescription and Patient Registries/Danish National Patient Registry) to evaluate OCS prescribing. We classified annual OCS duration as short-term (1-29 days), medium-term (30-89 days), or long-term (≥90 days). Longitudinal change in annual prevalence of OCS use and physician prescribing patterns were reported. Among 54,630,437 participants, average annual percentage of overall OCS use was 6.8% in the United States, 17.5% in Taiwan, and 2.2% in Denmark during 2009-2018. Prevalence of OCS prescribing increased at an average annual rate of 0.1%-0.17%, mainly driven by short-term prescribing to healthy adults. One-quarter to one-fifth of OCS prescribing was associated with a diagnosis of respiratory infection. Family practice and internal medicine physicians were among the highest OCS prescribers across countries and durations. Age- and sex-stratified trends mirrored unstratified trends. This study provides real-world evidence of an ongoing steady increase in OCS use in the general populations of the United States, Taiwan, and Denmark. This increase is largely driven by short-term OCS prescribing to healthy adults, a practice previously viewed as safe but recently shown to incur substantial population-level risk.

Performance of a Support Vector Machine Learning Tool for Diagnosing Diabetic Retinopathy in Clinical Practice.

PURPOSE: To examine the real-world performance of a support vector machine learning software (RetinaLyze) in order to identify the possible presence of diabetic retinopathy (DR) in patients with diabetes via software implementation in clinical practice. METHODS: 1001 eyes from 1001 patients-one eye per patient-participating in the Danish National Screening Programme were included. Three independent ophthalmologists graded all eyes according to the International Clinical Diabetic Retinopathy Disease Severity Scale with the exact level of disease being determined by majority decision. The software detected DR and no DR and was compared to the ophthalmologists' gradings. RESULTS: At a clinical chosen threshold, the software showed a sensitivity, specificity, positive predictive value and negative predictive value of 84.9% (95% CI: 81.8-87.9), 89.9% (95% CI: 86.8-92.7), 92.1% (95% CI: 89.7-94.4), and 81.0% (95% CI: 77.2-84.7), respectively, when compared to human grading. The results from the routine screening were 87.0% (95% CI: 84.2-89.7), 85.3% (95% CI: 81.8-88.6), 89.2% (95% CI: 86.3-91.7), and 82.5% (95% CI: 78.5-86.0), respectively. AUC was 93.4%. The reference graders Conger's Exact Kappa was 0.827. CONCLUSION: The software performed similarly to routine grading with overlapping confidence intervals, indicating comparable performance between the two groups. The intergrader agreement was satisfactory. However, evaluating the updated software alongside updated clinical procedures is crucial. It is therefore recommended that further clinical testing before implementation of the software as a decision support tool is conducted.

A cohort follow-up study for diabetic retinopathy screening incidence in the North Denmark Region.

AIMS: To evaluate diabetic retinopathy (DR) screening incidence in a universal healthcare system. METHODS: Registry-based cohort study based on a Danish regional population from 2009 to 2018. Individuals with diabetes were identified by medication. Screening attendance was estimated by surrogate measures using local and nationwide databases reported by cumulative incidence. RESULTS: 18,832 patients were included. By the end of the first year, the cumulative incidence of screening for DR was 60.2% and by the end of the second year 74.2%. The cumulative incidence was 93.9% overall, 97.7% for patients with type 1 diabetes (T1D) and 93.4% for patients with type 2 diabetes. Screening proportions per 1, 2 and 5 years were calculated. Females, patients with T1D, and patients attending screening at hospitals had a higher Hazard Ratio of 1.084, 1.157, and 1.573, respectively. The Cochran-Armitage trend test indicated increased screening frequency from 2009 to 2018. Validation of DR screening was done at hospitals with a mean positive predictive value of 86.78%. Cumulative incidence curves showed a small right shift when censoring the first, second and third screening visits. CONCLUSIONS: Nearly all patients were screened for DR over a 5-year timespan. Female patients with T1D who attended screening at hospitals were significantly more likely to be screened. Validation of screening visits at hospitals was reported with a high mean positive predictive value. Most other studies, to the best of our knowledge, only report screening attendance for patients already enrolled in a DR screening programme. This study describes the overall screening attendance for the total eligible diabetes population.

Hormonal Contraceptives Are Associated With an Increase in Incidence of Asthma in Women.

BACKGROUND: Use of exogenous female sex hormones is associated with the development of asthma, but the question of whether the effect is protective or harmful remains unresolved. OBJECTIVE: To investigate whether initiation of hormonal contraceptive (HC) treatment was associated with development of asthma. METHODS: We performed a register-based, exposure-matched cohort study including women who initiated HC treatment of any kind between 10 and 40 years of age and compared the incidence of asthma with women who did not initiate HCs. Asthma was defined as 2 redeemed prescriptions of inhaled corticosteroids within 2 years. Data were analyzed using Cox regression models adjusted for income and urbanization. RESULTS: We included 184,046 women with a mean age of 15.5 years (SD 1.5 y), in which 30,669 initiated HC treatment and 153,377 did not. We found that initiation of HCs was associated with an increased hazard ratio (HR) of developing new asthma by 1.78 (95% CI 1.58-2.00; P < .001). The cumulative risk of new asthma was 2.7% after 3 years among users of HCs compared with 1.5% in nonusers. In the different subtypes of HCs, second- and third-generation contraceptives carried significant associations (second-generation HR 1.76; 95% CI 1.52-2.03; P < .001; third-generation HR 1.62 95% CI 1.23-2.12; P < .001). The association with increased incidence was seen only in women younger than 18 years. CONCLUSIONS: In this study, first-time users of HCs had an increased incidence of asthma compared with nonusers. Clinicians prescribing HCs should be aware that airway symptoms may develop.

A register-based study: cough - a frequent phenomenon in the adult population.

BACKGROUND: Chronic cough, more than 8 weeks, can either be without co-morbidity called unexplained chronic cough (UCC) or with co-morbidity called refractory chronic cough (RCC). Using datasets from the Danish National Prescription Registry (Prescription Registry) and Danish National Patient Registry (Patient Registry) we wanted to investigate the prevalence and factors of importance of cough in a Nationwide registry. MATERIAL AND METHODS: Inclusion criteria were patients 18-90 years with at least one final cough diagnosis (ICD-10 DR05/DR059) in Patient registry or patients who have redeemed ≥2 prescriptions for relevant cough-medication within a 90-day harvest in the Prescription registry from 2008 to 2017. To validate this study's chosen proxy on chronic cough an analysis of the Patient registry sub-population with a contact of ≥8 weeks and then final diagnosis code DR05/DR059 was also performed. The population was divided into UCC and RCC. RESULTS: Of the 104,216 patients from the Prescription registry, 52,727 were classified as having UCC and 51,489 were classified with RCC. From the Patient registry 34,260 were included, of whom 12,278 had UCC and 21,982 had RCC. Cough were frequently found among females (p < 0.0001). Both genders were around 2 years older in RCC than UCC (p < 0.0001) Spirometry was performed in 69 and 57%, X-ray in 73 and 58% and asthma challenge test performed in 13 and 5% (UCC and RCC, respectively, p < 0.0001). The frequency of co-morbidities such as heart failure, rheumatologic disease, pulmonary embolism, and diabetes was < 10%. CONCLUSION: Many patients suffer from chronic cough or cough requiring medications, with or without co-morbidity; frequently found among menopausal women. Most patients had a substantial work-up performed. The high frequency and the resources consuming work-up program call for systematic coding of disease, systematic patient evaluation and more specific treatment options. The study was approved (ID: no. P-2019-191).

Inhaled anti-asthma therapies following hormone therapy in women: a nationwide cohort study.

Research question: Does menopausal hormone therapy (HT) with exogenous oestrogens and progestogens change the use of inhaled anti-asthma medications in women with asthma? Methods: In a population-based matched cohort study using the Danish registries, we included women with asthma aged 45-65 years from 1 June 1995 to 30 June 2018. We investigated whether HT with oestrogen and/or progestogens was associated with changes in use of inhaled anti-asthma therapies in the 12 months following initiation. We used exposure density matching to match exposed subjects with unexposed subjects on age, household income and level of education. An exposed subject was defined as receiving HT. We calculated mean dose of medications and odds ratios of increases in the 12 months following HT initiation. Results: We included 139 483 women with asthma, of whom 116 014 (83.2%) were unexposed subjects and 23 469 (16.8%) exposed subjects. Mean±sd age was 53.0±5.2 years. Initiation of HT was not consistently associated with increased mean doses of inhaled corticosteroids (ICS), or long- and short-acting ß2-agonists. Women receiving systemic oestrogens had increased odds ratios of large increases (>100 µg) in ICS at 6 months (OR 1.09; 95% CI 1.04-1.13; p<0.001) and 9 months (OR 1.07; 95% CI 1.03-1.12; p<0.001). Progestogens were protective against increases in ICS at 6 and 9 months (OR 0.87; 95% CI 0.82-0.93; p<0.001; and OR 0.86; 95% CI 0.81-0.91; p<0.001). Conclusion: Initiation of HT did not change the use of inhaled medications in asthma. However, detrimental effects of oestrogen, as well as beneficial effects of progestogens, cannot be excluded.

Desloratadine Exposure and Incidence of Seizure: A Nordic Post-authorization Safety Study Using a New-User Cohort Study Design, 2001-2015.

INTRODUCTION: A small number of adverse events of seizure in patients using desloratadine (DL) have been reported. The European Medicines Agency requested a post-authorization safety study to investigate whether there is an association between DL exposure and seizure. OBJECTIVE: The aim was to study the association between DL exposure and incidence of first seizure. METHODS: A new-user cohort study of individuals redeeming a first-ever prescription of DL in Denmark, Finland, Norway, and Sweden in 2001-2015 was conducted. DL exposure was defined as days' supply plus a 4-week grace period. DL unexposed periods were initiated 27 weeks after DL prescription redemption. Poisson regression was used to estimate the adjusted incidence rate and adjusted incidence rate ratio (aIRR) of incident seizure. RESULTS: A total of 1,807,347 first-ever DL users were included in the study, with 49.3% male and a mean age of 29.5 years at inclusion; 20.3% were children aged 0-5 years. The adjusted incidence rates of seizure were 21.7 and 31.6 per 100,000 person-years during DL unexposed and exposed periods, respectively. A 46% increased incidence rate of seizure was found during DL exposed periods (aIRR = 1.46, 95% confidence interval [CI] 1.34-1.59). The aIRR ranged from 1.85 (95% CI 1.65-2.08) in children aged 0-5 years to 1.01 in adults aged 20 years or more (95% CI 0.85-1.19). CONCLUSION: This study found an increased incidence rate of seizure during DL exposed periods as compared to unexposed periods among individuals younger than 20 years. No difference in incidence rate of seizure was observed in adults between DL exposed and unexposed.

Risk of Stroke, Myocardial Infarction, and Death Among Patients With Retinal Artery Occlusion and the Effect of Antithrombotic Treatment.

Purpose: To evaluate the risk of future stroke, myocardial infarction (MI), and death of patients with retinal artery occlusion (RAO) and the effect of various antithrombotic treatments as secondary prevention. Methods: This cohort study was based on nationwide health registries and included the entire Danish population from 2000 to 2018. All patients with RAO were identified and their adjusted risks of stroke, MI, or death in time periods since RAO were compared with those of the Danish population. Furthermore, antithrombotic treatment of patients with RAO was determined by prescription claims, and the association with the risk of stroke, MI, or death was assessed using multivariate Poisson regression models and expressed as rate ratios (RR) with 95% confidence intervals (95% CIs). Results: After inclusion, 6628 individuals experienced a first-time RAO, of whom 391 had a stroke, 66 had a MI, and 402 died within the first year after RAO. RAO was associated with an increased risk of stroke, MI, or death which persisted for more than 1 year for all three outcomes but was highest on days 3 to 14 after RAO for stroke, with an adjusted RR of 50.71 (95% CI, 41.55-61.87), and on days 14 to 90 after RAO for MI and death, with adjusted RRs of 1.98 (95% CI, 1.25-3.15) and 1.64 (95% CI, 1.28-189), respectively. Overall, antithrombotic treatment was not associated with any protective effect the first year. Conclusions: Patients with RAO had an increased risk of stroke, MI, or death. No protective effect of antithrombotic treatment was shown. Translational Relevance: These findings are relevant to the management of patients with RAO.

Hormone Replacement Therapy and Development of New Asthma.

BACKGROUND: Hormone replacement therapy (HRT) is prescribed to millions of women worldwide. Previous studies have suggested that HRT has both protective and harmful effects in asthma. RESEARCH QUESTION: Is HRT in menopause associated with new development of asthma? STUDY DESIGN AND METHODS: We undertook a nested case-control study based on the Danish registers from June 1, 1995, through December 31, 2018. A diagnosis of asthma was defined as two redeemed prescriptions of inhaled corticosteroids within 2 years. HRT was defined as two redeemed prescriptions of female sex hormones within 6 months. Data were analyzed using a conditional logistic regression model. RESULTS: We included 34,533 women with asthma vs 345,116 women without asthma between 40 and 65 years of age. In a multivariate analysis adjusted for age, household income, and educational level, active HRT resulted in a hazard ratio (HR) of 1.63 (95% CI, 1.55-1.71; P < .001) of new asthma development. Women with asthma who terminated HRT were likely to discontinue their asthma treatment subsequently (HR, 2.12; 95% CI, 1.94-2.33; P < .001). INTERPRETATION: HRT seems to play a role in the development of asthma in mature women. Clinicians prescribing HRT and women receiving HRT should be aware that new airway symptoms can develop, and discontinuation of HRT should be considered.

Biologic Therapy and Treatment Options in Diabetic Retinopathy with Diabetic Macular Edema.

Proliferative diabetic retinopathy and diabetic macular edema can be a potentially sightthreatening disease if not treated correctly. It is directly correlated to the duration of diabetes and how well managed the patients' diabetes is. In the last 15 years, the treatment of diabetic eye disease has taken a quantum leap in methodology due to the group of biological agents named antivascular endothelial growth factor (anti-VEGF). The introduction of the first biological agent has revolutionized the treatment, not only in diabetic eye disease but also across most inflammatory eye diseases, causing leakage of fluid from the blood vessels i.e., in age-related macular degeneration. The availability of these biological agents, despite their considerable costs, have significantly improved the outcomes measured in visual acuity compared to more traditional treatments of diabetic retinopathy in the form of sole laser treatment and glycemic control. The agents demonstrate a favorable safety profile, but if the rarest and most severe side effects occur, there is a potential total loss of vision. This review aims to make an overview of the current pharmaceutical therapeutic options in the treatment of diabetic macular edema. This includes laser therapy, intravitreal steroids, and a primary focus on intravitreal antivascular endothelial growth factors.

Correction to: Benefits and harm of systemic steroids for short- and long-term use in rhinitis and rhinosinusitis: an EAACI position paper.

[This corrects the article DOI: 10.1186/s13601-019-0303-6.].

Risk of Developing Hypokalemia in Patients With Hypertension Treated With Combination Antihypertensive Therapy.

Little is known about the occurrence of hypokalemia due to combination therapy for hypertension. Using data from Danish administrative registries, we investigated the association between different combinations of antihypertensive therapy and risk of developing hypokalemia. Using incidence density matching, 2 patients without hypokalemia were matched to a patient with hypokalemia (K, <3.5 mmol/L) on age, sex, renal function, and time between index date and date of potassium measurement. Combination therapies were subdivided into 10 groups including ß-blockers (BB)+thiazides (BB+thiazides), calcium channel blockers (CCB)+renin angiotensin system inhibitors (RASi)+thiazides (CCB+RASi+Thiazides), calcium channel blockers+thiazides (CCB+thiazides), and ß-blockers+renin angiotensin system inhibitors+thiazides (BB+RASi+thiazides). We used conditional logistic regression to estimate the odds of developing hypokalemia for different combinations of antihypertensive drugs within 90 days of combination therapy initiation. We matched 463 patients with hypokalemia to 926 patients with normal potassium concentrations. The multivariable analysis showed 5.82× increased odds of developing hypokalemia if administered CCB+thiazides (95% CI, 3.06-11.08) compared with CCB+RASi. Other combinations significantly associated with increased hypokalemia odds were BB+thiazides (odds ratio, 3.34 [95% CI, 1.67-6.66]), CCB+RASi+thiazides (odds ratio, 3.07 [95% CI, 1.72-5.46]), and BB+RASi+thiazides (odds ratio, 2.78 [95% CI, 1.41-5.47]). Combinations of thiazides with CCB, RASi, or BB were strongly associated with increased hypokalemia risk within 90 days of treatment initiation.

Benefits and harm of systemic steroids for short- and long-term use in rhinitis and rhinosinusitis: an EAACI position paper.

Because of the inflammatory mechanisms of most chronic upper airway diseases such as rhinitis and chronic rhinosinusitis, systemic steroids have been used for their treatment for decades. However, it has been very well documented that-potentially severe-side-effects can occur with the accumulation of systemic steroid courses over the years. A consensus document summarizing the benefits of systemic steroids for each upper airway disease type, as well as highlighting the potential harms of this treatment is currently lacking. Therefore, a panel of international experts in the field of Rhinology reviewed the available literature with the aim of providing recommendations for the use of systemic steroids in treating upper airway disease.

Risk of diabetes among related and unrelated family members.

AIMS: The aim was to explore familial aggregation of diabetes in genetically related and unrelated individuals. METHODS: We included citizens from Danish nationwide registries between 1995 and 2018 and calculated rate ratios (RR) of diabetes based on family relation using Poisson regression. RESULTS: Of 7.3 million individuals eligible for inclusion, we identified 343,237 (4.7%) with diabetes. The RR of diabetes was 2.02 (95% CI: 1.99-2.05; p < 0.0001) if any relative had diabetes, 1.79 (95% CI: 1.76-1.83) if a father had diabetes, and 2.06 (95% CI: 2.02-2.10) if a mother had diabetes. If both parents had diabetes, the RR was 3.40 (95% CI: 3.24-3.56). Among full siblings, the RR for developing diabetes was 2.77 (95% CI: 2.71-2.84) and 5.76 (95% CI: 5.00-6.63) for twins. For second-degree relatives, half siblings with a common mother had a RR of 2.35 (95% CI: 2.15-2.56), and with a common father 1.99 (95% CI: 1.81-2.17). Furthermore, the RR was 1.60 (95% CI: 1.56-1.64) if a wife had diabetes, and 1.41 (95% CI: 1.38-1.44) if a husband had diabetes. A subgroup analysis of individuals receiving insulin only treatment (N = 23,054) demonstrated a similar risk pattern, although with slightly higher risk estimates. CONCLUSIONS/INTERPRETATION: Family aggregation of diabetes is associated with genetic disposition with maternal status being the predominant factor. Furthermore, we observed increased risk of diabetes in second-degree relatives, and between unrelated spouses, indicating that environmental factors influence diabetes risk substantially.

Prehospital time and mortality in patients requiring a highest priority emergency medical response: a Danish registry-based cohort study.

OBJECTIVE: To examine the association between time from emergency medical service vehicle dispatch to hospital arrival and 1-day and 30-day mortality. DESIGN: Register-based cohort study. SETTING: North Denmark Region (≈8000 km2, catchment population ≈600 000). PARTICIPANTS: We included all highest priority dispatched ambulance transports in North Denmark Region in 2006-2012. INTERVENTIONS: Using logistic regression and the g-formula approach, we examined the association between time from emergency dispatch to hospital arrival and mortality for presumed heart, respiratory, cerebrovascular and other presumed medical conditions, as well as traffic or other accidents, as classified by emergency dispatch personnel. MAIN OUTCOME MEASURES: 1-day and 30-day mortality. RESULTS: Among 93 167 individuals with highest priority ambulances dispatched, 1948 (2.1%) were dead before the ambulance arrived and 19 968 (21.4%) were transported to the hospital under highest priority (median total prehospital time from dispatch to hospital arrival 47 min (25%-75%: 35-60 min); 95th percentile 84 min). Among 18 709 with population data, 1-day mortality was 10.9% (n=2038), and was highest for patients with dyspnoea (20.4%) and lowest for patients with traffic accidents (2.8%). Thirty-day mortality was 18.3% and varied between 36.6% (patients with dyspnoea) and 3.7% (traffic accidents). One-day mortality was not associated with total prehospital time, except for presumed heart conditions, where longer prehospital time was associated with decreased mortality: adjusted OR for >60 min vs 0-30 min was 0.61 (95% CI 0.40 to 0.91). For patients with dyspnoea, OR for >60 min vs 0-30 min was 0.90 (95% CI 0.56 to 1.45), for presumed cerebrovascular conditions OR 1.41 (95% CI 0.53 to 3.78), for other presumed medical conditions OR 0.84 (95% CI 0.70 to 1.02), for traffic accidents OR 0.65 (95% CI 0.29 to 1.48) and for other accidents OR 0.84 (95% CI 0.47 to 1.51). Similar findings were found for 30-day mortality. CONCLUSIONS: In this study, where time from emergency dispatch to hospital arrival mainly was <80 min, there was no overall relation between this prehospital time measure and mortality.

Animal Models Used to Simulate Retinal Artery Occlusion: A Comprehensive Review.

PURPOSE: To present an overview of animal models of retinal artery occlusion (RAO). METHODS: Through a systematic literature search in PubMed and Embase, papers describing methods of inducing RAO in animal models were included. The identified methodologic approaches were presented in a narrative synthesis and compared with RAO in humans. RESULTS: In total, 83 papers reporting on 88 experiments were included. Six different species were used with rodents and monkeys being the most common, and a minority were performed using cats, dogs, rabbits, or pigs. The anatomy of pigs and monkeys resemble that of humans most closely. The two most frequently used methods were laser-induced occlusion or ligation of the arteries. Other methods included raised intraocular pressure, arterial clamping, administration of vasoconstricting agents, the use of an occluder, embolization, and endovascular approaches to induce occlusion. In general, occlusions lasted for only 30 to 90 minutes, often followed by reperfusion. CONCLUSIONS: Although a broad range of methods have previously been used, they all have limitations. Preferably, the methods should imitate the human disease as closely as possible and avoid damaging other structures. Therefore, monkeys followed by pigs are to be preferred and ligation or clamping may be a suitable model in larger animals as there is a potential to isolate and occlude the retinal artery only. Being less invasive, laser-induced occlusion is another suitable approach. TRANSLATIONAL RELEVANCE: This review aims at assisting researchers in deciding on the most ideal experimental setting, and thereby increase the translational value to human disease.

Familial Clustering of Cardiac Conduction Defects and Pacemaker Insertion.

BACKGROUND: The etiopathogenesis of electrocardiographic bundle branch and atrioventricular blocks is not fully understood. We investigated familial clustering of cardiac conduction defects and pacemaker insertion in the FHS (Framingham Heart Study). Additionally, we assessed familial clustering of pacemaker insertion in the Danish general population. METHODS: In FHS, we used multivariable-adjusted logistic regression models to investigate the association of parental atrioventricular block (PR interval, ≥0.2 s), complete bundle branch block (QRS, ≥0.12 s), or pacemaker insertion with the occurrence of cardiac conduction abnormalities in their offspring. The Danish nationwide administrative registries were interrogated to assess the relations of parental pacemaker insertion with offspring pacemaker insertion. RESULTS: In FHS (n=371 cases with first-degree atrioventricular block, complete bundle branch block, or pacemaker insertion, and 1471 age- and sex-matched controls), individuals with at least 1 affected parent with a conduction defect had a 1.65-fold odds (odds ratio, 95% CI, 1.32-2.07) for manifesting an atrioventricular block and a 1.62-fold odds (95% CI, 1.08-2.42) for developing a complete bundle branch block. If at least 1 parent had any electrocardiographic conduction defect or pacemaker insertion, the offspring had a 1.62-fold odds (95% CI, 1.31-2.00) for experiencing any of these conditions. In Denmark (n=2 824 199 individuals; 5397 incident pacemaker implantations), individuals with at least 1 first-degree relative with history of pacemaker insertion had a multivariable-adjusted 1.68-fold (incidence rate ratio, 95% CI, 1.49-1.89) risk of undergoing a pacemaker insertion. If the affected relative was ≤45 years of age, the incidence rate ratio was markedly increased to 51.0 (95% CI, 32.7-79.9). CONCLUSIONS: Cardiac conduction blocks and risk for pacemaker insertion cluster within families. A family history of conduction system disturbance or pacemaker insertion should trigger increased awareness of a similar propensity in other family members, especially so when the conduction system disease occurs at a younger age.

Comparison of Survival After Aortic Valve Replacement With Mitroflow or Perimount Prostheses.

Bioprosthetic aortic valves degenerate over time, and differences between brands could be expected. We compared 2 brands implanted in 3 different centers serving 3.3 million people. Between 2000 and 2014, we identified 1241 bioprosthetic aortic valve replacements using Mitroflow (Sorin, Milan, Italy) and 3212 using Perimount (Edwards Lifesciences, Irvine, CA) covering 88% of all aortic valve replacements in the region. Average differences in t-year mortality were derived from Cox regression. The complete case analyses included 881 Mitroflow replacements and 2488 Perimount replacements. The median follow-up time and 25/75 percentiles were 5.0 years (3.3-7.2) and 8.4 years (5.1-10.6) for Perimount and Mitroflow, respectively. Multiple Cox regression analyses demonstrated significantly higher mortality with Mitroflow valves compared with Perimount (hazard ratio 1.27; 95% CI: 1.1-1.5; P < 0.001). Average risk of death within 5 years was 25.0% with Mitroflow and 20.4% with Perimount. Average difference in 5-year mortality based on Cox regression was 4.60% in favor of Perimount (95% CI: 1.02-8.02%; P = 0.01) and the number needed to harm was 21.9 (95% CI: 12.7-80.5) within 5 years. Propensity matching confirmed 2-year survival differences 4.6% in favor of Perimount (95% CI: 1.2-7.9%; P = 0.004), and further confirmed in a series of subgroups and a double robust analysis that takes into account both propensity for treatment and covariate relation to outcome. Mitroflow valves were associated with a significantly increased risk of death when compared to Perimount valves.

Pulmonary safety of ophthalmic beta-blockers: a nationwide registry-based cohort study.

PURPOSE: Ophthalmic beta-blockers, used in the treatment of increased intraocular pressure, are known to cause pulmonary adverse effects. Few, if any, studies have quantified the extent of the problem in a real-life population. In this nationwide study, we assess the pulmonary safety of patients initiating treatment with ophthalmic beta-blockers. METHODS: Using the Danish Nationwide Registries from 1995 to 2012, we identified all individuals aged 20-90 years who initiated monotherapy with an intraocular pressure-lowering drug, with or without concomitant obstructive pulmonary disease. Risks of (i) switching to another drug and (ii) new onset of obstructive pulmonary disease during a 90-day follow-up were examined by cumulative risk and logistic regression models adjusted for available covariates. RESULTS: The cohort consisted of 97 463 individuals. Odds ratios for drug switch in individuals without concomitant obstructive pulmonary disease (n = 86 568) were as follows: 1.47 for beta-blockers (95% confidence interval (CI): 1.35-1.61; p < 0.001), 2.68 for parasympathomimetics (95% CI: 2.32-3.10; p < 0.001) and 4.80 for alfa-2-agonists (95% CI: 4.17-5.53; p < 0.001). Odds ratios in individuals with concomitant obstructive pulmonary disease (n = 10 895) were as follows: 2.61 for parasympathomimetics (95% CI: 1.83-3.72; p < 0.001), 2.96 for beta-blockers (95% CI: 2.31-3.78; p < 0.001) and 3.54 for alfa-2-agonists (95% CI: 2.56-4.88; p < 0.001). There was no significant association between treatment class and new onset of obstructive pulmonary disease (p = 0.30). CONCLUSION: Ophthalmic beta-blockers were associated with an increased risk of drug switch. However, the absolute risk was very small. No increased risk of new onset of obstructive pulmonary disease was found. Our data suggest that more patients might be eligible for ophthalmic beta-blockers.

Increased Mortality and Comorbidity Associated With Leber's Hereditary Optic Neuropathy: A Nationwide Cohort Study.

Purpose: Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease in which optic neuropathy is considered a key feature. Several other manifestations of LHON have been reported; however, only little is known of their incidence and the life expectancy in LHON patients. Methods: This study, based on Danish nationwide health registries, included 141 patients diagnosed with LHON and 297 unaffected family members in the maternal line. The incidence of comorbidities and mortality for patients with LHON and unaffected family members was compared with that in the general population. Results: Having LHON was associated with an almost 2-fold risk of mortality with a rate ratio (RR) of 1.95 (95% confidence interval [CI]: 1.47-2.59; P < 0.001). The incidence of several diseases was increased for LHON patients, but not for family members. The incidence of stroke was 5.73 per 1000 patient-years for LHON patients compared to 2.33 for the general population, and the RR was 2.38 (95% CI: 1.58-3.58; P < 0.001). The incidence of demyelinating disorders was 2.24 compared to 0.21 for the general population; RR was 12.89 (95% CI: 6.70-24.77; P < 0.001). A 4-fold risk of dementia was seen for LHON patients (RR: 4.26, 95% CI: 1.91-9.48; P < 0.001), incidence 1.45 for LHON and 0.37 for the general population. Moreover, LHON patients had an increased risk of epilepsy, atherosclerosis, nerve symptoms, neuropathy, and alcohol-related disorders. Conclusions: The manifestation of LHON was associated with increased mortality and increased incidence of several disorders including stroke, demyelinating disorder, dementia, and epilepsy.