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

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

Risk of hand osteoarthritis in new users of hormone replacement therapy: a nested case-control analysis

Objective To estimate the risk of hand osteoarthritis (HOA) associated with hormone replacement therapy (HRT). Methods We conducted a nested case-control study using data from the UKbased Clinical Practice Research Datalink (1998–2017). In the study inception cohort comprised women at age 45. We matched women with incident HOA during follow-up (cases) to osteoarthritisfree controls on age and calendar date (index date, ID), in a ratio of 1:4. We applied conditional logistic regression to calculate odds ratios (OR) with 95 % confidence intervals (CI) of HOA associated with new HRT use compared with non-use overall, and for women with recorded menopause we calculated separate ORs according to the time between menopause and HRT initiation (current users), and the time between HRT cessation and the ID (past users), versus non-users. Results There were 3440 cases and 13,760 controls (mean age: 50.9 ± 4.1 years). We observed an adjusted OR (aOR) of HOA of 1.32 (95 % CI 1.17–1.48) in HRT users (versus nonusers), which attenuated to 0.98 (95 % CI 0.85–1.14) in women with recorded menopause. Current users (versus nonusers) who initiated HRT 3 months before or after menopause had an aOR of 0.72 (95 % CI 0.55–0.96), while aORs increased with later HRT initiation. Among past users (versus non-users), we observed an aOR of 1.25 (95 % CI 0.86–1.81) when HRT use was stopped ≤18 months before the ID, approaching the null with increasing duration between HRT cessation and the ID. Conclusion Current HRT use was associated with a decreased risk of HOA if initiated around menopause, but the risk reduction disappeared after HRT cessation

Changes in the Use of Hydrochlorothiazide and Other Antihypertensive Drugs in Switzerland in Association With the Swissmedic Safety Alert Regarding Non-melanoma Skin Cancer:An Interrupted Time-Series Analysis Using Swiss Claims Data

Purpose: Long-term use of hydrochlorothiazide increases the risk of non-melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. Methods: We performed interrupted time-series analyses using a large Swiss healthcare claims database (2015–2021). Within monthly intervals, we quantified the total number of claims and the total dispensed ‘defined daily doses’ (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers (ARB), (3) calcium-channel blockers (CCB) and (4) thiazide-like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre-DHPC trend, the immediate change and the post-DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. Results: ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300–400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. Conclusion: Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre-existing decline in the use of hydrochlorothiazide in Switzerland.</p

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 &gt;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

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

Molecular regulation of auditory hair cell death and approaches to protect sensory receptor cells and/or stimulate repair following acoustic trauma

International audienceLoss of auditory sensory hair cells (HCs) is the most common cause of hearing loss. This review addresses the signaling pathways that are involved in the programmed and necrotic cell death of auditory HCs that occur in response to ototoxic and traumatic stressor events. The roles of inflammatory processes, oxidative stress, mitochondrial damage, cell death receptors, members of the mitogen-activated protein kinase (MAPK) signal pathway and pro- and anti-cell death members of the Bcl-2 family are explored. The molecular interaction of these signal pathways that initiates the loss of auditory HCs following acoustic trauma is covered and possible therapeutic interventions that may protect these sensory HCs from loss via apoptotic or non-apoptotic cell death are explored