A study on the epidemiology of rosacea

Pharmacoepidemiology is the science of the use and the effects of drugs in large human populations. Although its original role was confined to post-marketing surveillance of rare or long-latency adverse drug events, the science is gaining increasing importance across different stages of drug development, where it has been applied to assess drug utilization patterns and cost-effectiveness, to characterize target populations of drugs in development, to evaluate undiscovered beneficial or detrimental drug effects, or to provide evidence of effectiveness when randomized controlled trials face ethical or practical barriers. Rosacea is a common but under-investigated inflammatory skin disease, characterized by relapses and remissions. The exact pathomechanism of the skin disease remains to be elucidated, but recent findings indicate a key etiologic role of the innate immune system. Evidence-based treatment options for the skin disease are sparse and greatly needed. The aim of the comprehensive rosacea project presented within this thesis was to contribute to the general understanding of the skin disease, thereby focusing on the impact of different drugs and diseases on incident rosacea. The project comprises six individual studies, set up in a case-control study design, using data from the General Practice Research Database (GPRD). This United Kingdom (UK)-based database contains longitudinal primary-care records of millions of patients, representative of the UK population. Information is recorded by general practitioners including demographics, lifestyle factors, medical diagnoses, referrals to secondary care, laboratory and diagnostic results, and a complete history of drug prescriptions. The study population consisted of 53,927 patients with an incident rosacea diagnosis between 1995 and 2009 and the same number of rosacea-free controls, matched on age, sex, index date, general practice, and history in the database. Study 3.1 builds the basis of the project, and describes the study population in terms of demographics, lifestyle characteristics, and ocular symptoms. An overall incidence rate of diagnosed rosacea in the UK of 1.65 / 1,000 person-years was calculated, and stratified by age, gender, calendar time, and geographic region. While cigarette smoking seemed to prevent patients from developing rosacea, alcohol consumption yielded a marginal risk increase. Studies 3.2 and Study 3.5 fathom the insufficiently supported notion regarding the association of rosacea with migraine (Study 3.2) and with psychiatric diseases (Study 3.5). Drug effects of triptans (Study 3.2) and of psychotropic drugs (Study 3.5) on incident rosacea were also studied. In contrast to previous findings, pre-existing migraine was not generally associated with incident rosacea, but post-menopausal women with severe migraine may be at a slightly increased risk of rosacea. Although mechanistically conceivable, triptans did not alter the risk of developing rosacea. Neither depression nor other affective disorders affected the relative risk of rosacea, but patients with diagnosed schizophrenia were diagnosed with rosacea less frequently. Although the latter finding is intriguing, it requires further investigation, as diagnostic bias cannot be ruled out. Of all psychotropic drugs, current lithium exposure may protect patients from developing the skin disease. Topical lithium has been proven to be effective in seborrheic dermatitis, and might be an interesting approach for rosacea therapy. Two further studies evaluate the effect of diuretics (focus spironolactone, Study 3.3) and of other antihypertensive drugs (including β-blockers and calcium channel blockers, Study 3.6) on incident rosacea. In line with one previous study, spironolactone yielded a significantly decreased rosacea risk, whereas no other diuretic drug class showed an effect. Despite a generally assumed detrimental effect of calcium channel blockers on rosacea, Study 3.6 did not reveal an increased risk of rosacea for users of this drug class. β-blockers, which have been suggested as an off-label treatment for erythematotelangiectatic rosacea, revealed a small risk decrease, which is probably larger in erythematotelangiectatic rosacea patients alone. Especially with abundantly used therapeutics, such as antihypertensive drugs, sound evidence is required in order for healthcare professionals to make the right decisions in clinical practice. Finally, Study 3.4 reports a previously uninvestigated decreased rosacea risk for patients with diabetes at an advanced disease stage, potentially due to impaired vasodilation. It remains to be clarified whether insulin enhances this effect. In summary, these large population-based studies contribute to the understanding of rosacea yielding important evidence and raising new hypotheses. While some results may directly support clinicians in their daily decisions on rosacea treatment, yet others might spark follow-up projects on potential new treatment approaches for rosacea as well as on pathomechanistic aspects of the skin disease

Recording of Chronic Diseases and Adverse Obstetric Outcomes during Hospitalizations for a Delivery in the National Swiss Hospital Medical Statistics Dataset between 2012 and 2018: An Observational Cross-Sectional Study.

The prevalence of chronic diseases during pregnancy and adverse maternal obstetric outcomes in Switzerland has been insufficiently studied. Data sources, which reliably capture these events, are scarce. We conducted a nationwide observational cross-sectional study (2012-2018) using data from the Swiss Hospital Medical Statistics (MS) dataset. To quantify the recording of chronic diseases and adverse maternal obstetric outcomes during delivery in hospitals or birthing centers (delivery hospitalization), we identified women who delivered a singleton live-born infant. We quantified the prevalence of 23 maternal chronic diseases (ICD-10-GM) and compared results to a nationwide Danish registry study. We further quantified the prevalence of adverse maternal obstetric outcomes (ICD-10-GM/CHOP) during the delivery hospitalization and compared the results to existing literature from Western Europe. We identified 577,220 delivery hospitalizations, of which 4.99% had a record for ≥1 diagnosis of a chronic disease (versus 15.49% in Denmark). Moreover, 13 of 23 chronic diseases seemed to be substantially under-recorded (8 of those were >10-fold more frequent in the Danish study). The prevalence of three of the chronic diseases was similar in the two studies. The prevalence of adverse maternal obstetric outcomes was comparable to other European countries. Our results suggest that chronic diseases are under-recorded during delivery hospitalizations in the MS dataset, which may be due to specific coding guidelines and aspects regarding whether a disease generates billable effort for a hospital. Adverse maternal obstetric outcomes seemed to be more completely captured

Early renal transplant dysfunction due to arterial kinking stenosis

The main differential diagnoses of early renal trans-plant dysfunction include ischaemic damage, cyclospo-rin toxicity, and rejection [1]. Rarer causes include bleeding, ureteral obstruction, urinary leak, venou

Dispensed drugs during pregnancy in outpatient care between 2015 and 2021 in Switzerland: a retrospective analysis of Swiss healthcare claims data.

AIM OF THE STUDY We aimed to evaluate the utilisation of all prescribed drugs during pregnancy dispensed in outpatient care in Switzerland between 2015 and 2021. METHODS We conducted a descriptive study using the Swiss Helsana claims database (2015-2021). We established a cohort of pregnancies by identifying deliveries and estimating the date of the last menstrual period. We analysed the drug burden during a 270-day pre-pregnancy period, during pregnancy (overall and by trimester), and during a 270-day postpartum period. Subsequently, we quantified 1) the median number of drug dispensations (total vs. unique drug claims); and 2) the prevalence of exposure to at least one dispensed drug and the number of dispensed drugs (0, 1, 2, 3, 4, and ≥5); and 3) the 15 most frequently dispensed drugs were identified during each period, overall and stratified by maternal age. RESULTS Among 34,584 pregnant women (5.6% of all successful pregnancies in Switzerland), 87.5% claimed at least one drug (not including vitamins, supplements, and vaccines), and 33.3% claimed at least five drugs during pregnancy. During trimester 1 alone, 8.2% of women claimed at least five distinct drugs. The proportion of women who claimed prescribed drugs was lower pre-pregnancy (69.1%) and similar postpartum (85.6%) when compared to during pregnancy (87.5%). The most frequently claimed drugs during pregnancy were meaningfully different during pregnancy than before and after. CONCLUSIONS This study suggests that 8 of 10 women in Switzerland are exposed to prescribed drugs during pregnancy. Most drugs dispensed during pregnancy are comparatively well investigated and are considered safe. However, the high drug burden in this vulnerable patient population underlines the importance of evidence on the benefit-risk profile of individual drugs taken during pregnancy

Mathematical model-driven deep learning enables personalized adaptive therapy

Standard-of-care treatment regimens have long been designed for maximal cell killing, yet these strategies often fail when applied to metastatic cancers due to the emergence of drug resistance. Adaptive treatment strategies have been developed as an alternative approach, dynamically adjusting treatment to suppress the growth of treatment-resistant populations and thereby delay, or even prevent, tumor progression. Promising clinical results in prostate cancer indicate the potential to optimize adaptive treatment protocols. Here, we applied deep reinforcement learning (DRL) to guide adaptive drug scheduling and demonstrated that these treatment schedules can outperform the current adaptive protocols in a mathematical model calibrated to prostate cancer dynamics, more than doubling the time to progression. The DRL strategies were robust to patient variability, including both tumor dynamics and clinical monitoring schedules. The DRL framework could produce interpretable, adaptive strategies based on a single tumor burden threshold, replicating and informing optimal treatment strategies. The DRL framework had no knowledge of the underlying mathematical tumor model, demonstrating the capability of DRL to help develop treatment strategies in novel or complex settings. Finally, a proposed five-step pathway, which combined mechanistic modeling with the DRL framework and integrated conventional tools to improve interpretability compared to traditional "black-box" DRL models, could allow translation of this approach to the clinic. Overall, the proposed framework generated personalized treatment schedules that consistently outperformed clinical standard-of-care protocols

Antidiabetic Medication Utilisation before and during Pregnancy in Switzerland between 2012 and 2019: An Administrative Claim Database from the MAMA Cohort.

BACKGROUND The incidence of diabetes mellitus (both pregestational and gestational) is increasing worldwide, and hyperglycemia during pregnancy is associated with adverse pregnancy outcomes. Evidence on the safety and efficacy of metformin during pregnancy has accumulated resulting in an increase in its prescription in many reports. AIMS We aimed to determine the prevalence of antidiabetic drug use (insulins and blood glucose-lowering drugs) before and during pregnancy in Switzerland and the changes therein during pregnancy and over time. METHODS We conducted a descriptive study using Swiss health insurance claims (2012-2019). We established the MAMA cohort by identifying deliveries and estimating the last menstrual period. We identified claims for any antidiabetic medication (ADM), insulins, blood glucose-lowering drugs, and individual substances within each class. We defined three groups of pattern use based on timing of dispensation: (1) dispensation of at least one ADM in the prepregnancy period and in or after trimester 2 (T2) (pregestational diabetes); (2) dispensation for the first time in or after T2 (GDM); and (3) dispensation in the prepregnancy period and no dispensation in or after T2 (discontinuers). Within the pregestational diabetes group, we further defined continuers (dispensation for the same group of ADM) and switchers (different ADM group dispensed in the prepregnancy period and in or after T2). RESULTS MAMA included 104,098 deliveries with a mean maternal age at delivery of 31.7. Antidiabetic dispensations among pregnancies with pregestational and gestational diabetes increased over time. Insulin was the most dispensed medication for both diseases. Between 2017 and 2019, less than 10% of pregnancies treated for pregestational diabetes continued metformin rather than switching to insulin. Metformin was offered to less than 2% of pregnancies to treat gestational diabetes (2017-2019). CONCLUSION Despite its position in the guidelines and the attractive alternative that metformin represents to patients who may encounter barriers with insulin therapy, there was reluctance to prescribe it

Rescue and Regrowth of Sensory Nerves Following Deafferentation by Neurotrophic Factors

Trauma and loss of cochlear inner hair cells causes a series of events that result first in the retraction of the peripheral processes of the auditory nerve, scar formation in the organ of Corti, and over the course of weeks to months (depending on the species) the loss of auditory nerve cell bodies (spiral ganglion cells). Neurotrophic factors play an important role in the mature nervous system as survival factors for maintenance and protection and also can play a role in regrowth. Studies in the cochlea now show that application of exogenous neurotrophic factors can enhance survival of spiral ganglion cells after deafness and induce regrowth of peripheral processes, perhaps by replacing lost endogenous factors. Combinations of factors may be most effective for achieving greatest survival and regrowth. Our studies find that brain-derived neurotrophic factor (BDNF) and glial-line-derived neurotrophic factor (GDNF) are very effective at enhancing spiral ganglion cell survival following deafness from ototoxic drugs or noise. It has also been found that BDNF plus fibroblast growth factor (FGF) is very effective at inducing process regrowth. Electrical stimulation also acts to enhance spiral ganglion cell survival, and the combination of electrical stimulation and neurotrophic factors could prove a most effective intervention.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73558/1/j.1749-6632.1999.tb08650.x.pd

The sensory epithelium and its innervation in the mole rat cochlea

The mole rat ( Spalax ehrenbergi ) burrows throughout its life in subterranean tunnels. Several structural and functional features which adapt the mole rat to its habitat have been discerned. The goal of this study was to elucidate the structural basis for adaptation of the auditory end-organ to an environment where low-frequency acoustical signals prevail. For this purpose, cochleae of adult mole rats were studied with light and electron microscopy. Inner hair cells throughout the cochlea, and outer hair cells in the basal (high-frequency) portion of the cochlea, were similar in structure to those seen in other mammals. In contrast, outer hair cells in the apical (low-frequency) portion displayed unique structural features. These features resembled the structure of inner hair cells or immature outer hair cells. The innervation of outer hair cells was most uncommon, in that classical medial efferent innervation was not found throughout the cochlear spiral.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50050/1/903140211_ftp.pd