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Abstract Background Chronic pain is a major health issue and rapid population ageing exacerbates the burden to health systems in countries like Germany. Nonpharmacological interventions (NPIs) are essential in pain care and the prioritization of active NPIs is emphasized in guidelines. This paper examines the utilization of NPIs for chronic pain management in community-dwelling older adults with a certified need of care in Berlin, Germany. Methods Cross-sectional data was collected through standardized face-to-face surveys with older adults (≥65 years), using validated instruments (e.g., Brief Pain Inventory), and structured lists for NPI utilization. Categorization into active and passive NPIs was performed through a literature-based, iterative process by an interdisciplinary team. For not normally distributed data, non-parametric tests were used as appropriate. Logistic regression was conducted for multivariate analysis. Results In total, 250 participants were included in this analysis (aged 65-104, x̅ = 81.8, 68.8% female). Most (92%) use NPIs for chronic pain management: 85.6% use active NPIs, 50.4% active movement and only 5.6% use solely passive approaches. Most common NPIs are distraction, thermotherapy/compresses, and physiotherapy. The odds of utilizing physiotherapy are three times higher for those with high educational status when compared to those with low education while those with low educational status had higher odds of using thermotherapy/compresses. Conclusions In our sample, most community-dwelling older adults with a certified need of care use active NPIs for chronic pain management with about half using active movement approaches. Considering the high vulnerability of this population, physiotherapy (in the form of therapeutic exercise) is a particularly appropriate intervention, and it was the third most frequent NPI in our sample. However, there is a social gradient in the utilization of physiotherapy for chronic pain management which might be rooted in issues around awareness, appeal, and access to such measures. It is important to take socioeconomic differences into account when planning the care for older chronic pain patients but also when designing research or user-friendly guidelines for this target group. Trial registration Ethical approval from the Ethics Committee of Charité - Universitätsmedizin Berlin (EA1/368/14) and study registration with the Central Study Register (ZSR no. 20009093).

Abstract Classic psychedelics and MDMA have a colorful history of recreational use, and both have recently been re-evaluated as tools for the treatment of psychiatric disorders. Several studies have been carried out to assess potential long-term effects of a regular use on cognition, delivering distinct results for psychedelics and MDMA. However, to date knowledge is scarce on cognitive performance during acute effects of those substances. In this systematic review and meta-analysis, we investigate how cognitive functioning is affected by psychedelics and MDMA during the acute drug effects and the sub-acute (“afterglow”) window. Our quantitative analyses suggest that acute cognitive performance is differentially affected by psychedelics when compared to MDMA: psychedelics impair attention and executive function, whereas MDMA primarily affects memory, leaving executive functions and attention unaffected. Our qualitative analyses reveal that executive functioning and creativity may be increased during a window of at least 24 h after the acute effects of psychedelics have subsided, whereas no such results have been observed for MDMA. Our findings may contribute to inform recommendations on harm reduction for recreational settings and to help fostering differential approaches for the use of psychedelics and MDMA within a therapeutic framework.

Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70–95%]) than MRA (20% [10–30%]), SGLT2i (30% [20–50%]) or (GLP1-RA (10% [5–15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15–40%) vs 18% [10%–25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5–5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers’ dosage reduction was the usual management.

AbstractBackground Healthcare providers are faced with an increasing number of patients with obesity and arterial hypertension. Preventing obesity-associated hypertension and appropriately managing patients with established disease are both important. Hence, the aim of our study was to evaluate the clinical care of patients with obesity and hypertension among ESH Excellence Centres (ECs).Methods We conducted a cross-sectional, international 30-item survey through e-mails.Results In total, 70 representatives of ECs participated (78% men) with 66% of them practicing medicine for more than 30 years and working in well-equipped clinics. Most were internists (41%) and cardiologists (37%) and 73% reported training on the management of obese patients with hypertension. A majority weigh their patients (77%) and evaluate patients for sleep disorders (93%). However, only 47% spend more than 5min to advise for lifestyle modification in general, 59% for weight loss, 56% for salt intake and 64% for exercise. Finally, a minority of participants ask patients if they like their body (6%) or about previous attempts to lose weight (28%), evaluate 24h urinary sodium excretion rate (22%) and provide written (15%) or personalized (10%) dietary advices. If the patient suffers also from type 2 diabetes mellitus, 66% switch treatment to GLP1 receptor agonists and 60% to SGLT2 inhibitors.Conclusion Most clinicians in ESH ECs are well educated regarding obesity-associated hypertension, and clinics are sufficiently equipped to manage these patients, as well. However, several deficits were reported regarding efforts to address and implement obesity specific aspects and interventions to improve care in patients with obesity and hypertension.

Background Patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are at high risk for both thromboembolism and bleeding events. The latter induces a potential reason for withholding oral anticoagulation (OAC) despite an indication for prophylaxis of thromboembolic events.

Purpose To describe the history of the Excellence Centre (EC) programme of the European Society of Hypertension (ESH) since the beginning in 2006, its achievements, and its future developments. Materials and Methods We list the number of ECs per country, the research projects performed so far, and the organisational steps needed to reshape the EC programme for the future. Results In August 2023, the ESH EC programme includes 118 registered ECs in 21 European and 7 non-European countries. Updates about the formal steps for application, re-application, transfer of EC and retirement of EC heads are given. Conclusions The EC programme of the ESH has been a success from the beginning. Further refinements will make it fit for the next decades.

The prevalence of hypertension is rising, and the majority of patients are managed by General Physicians (GPs). GPs workload influences their capacity to follow and implement hypertension guidelines adequately. The time needed to treat (TNT) each patient at the GP level should be taken into consideration in hypertension practice guidelines.

Background: Glomerular hyperfiltration (GH) is an important mechanism in the development of albuminuria in hypertension. The Munich Wistar Frömter (MWF) rat is a non-diabetic model of chronic kidney disease (CKD) with GH due to inherited low nephron number resulting in spontaneous albuminuria and podocyte injury. In MWF rats, we identified prostaglandin (PG) E2 (PGE2) signaling as a potential causative mechanism of albuminuria in GH.Method: For evaluation of the renal PGE2 metabolic pathway, time-course lipidomic analysis of PGE2 and its downstream metabolites 15-keto-PGE2 and 13-14-dihydro-15-keto-PGE2 was conducted in urine, plasma and kidney tissues of MWF rats and albuminuria-resistant spontaneously hypertensive rats (SHR) by liquid chromatography electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS).Results: Lipidomic analysis revealed no dysregulation of plasma PGs over the time course of albuminuria development, while glomerular levels of PGE2 and 15-keto-PGE2 were significantly elevated in MWF compared to albuminuria-resistant SHR. Overall, averaged PGE2 levels in glomeruli were up to ×150 higher than the corresponding 15-keto-PGE2 levels. Glomerular metabolic ratios of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were significantly lower, while metabolic ratios of prostaglandin reductases (PTGRs) were significantly higher in MWF rats with manifested albuminuria compared to SHR, respectively.Conclusion: Our data reveal glomerular dysregulation of the PGE2 metabolism in the development of albuminuria in GH, resulting at least partly from reduced PGE2 degradation. This study provides first insights into dynamic changes of the PGE2 pathway that support a role of glomerular PGE2 metabolism and signaling for early albuminuria manifestation in GH.

The 2023 hypertension guidelines of the European Society of Hypertension (ESH) have been published in the December issue of the official Journal of the Society (Journal of Hypertension),1 where they are freely available online. Compared to the guidelines published 5 years ago,2 the new guidelines address issues never or only marginally addressed before, including a large number of comorbidities to hypertension that may change the approach to antihypertensive management. [...]

Abstract Transmembrane protein 14A (TMEM14A) is a relatively unknown protein that is now identified to be required for maintaining the integrity of the glomerular filtration barrier. It is an integral transmembrane protein of 99 amino acids with three transmembrane domains. TMEM14A has been implied to suppress Bax‐mediated apoptosis in other studies. Other than that, little is currently known of its function. Here, we show that its expression is diminished before onset of proteinuria in a spontaneously proteinuric rat model. Knocking down tmem14a mRNA translation results in proteinuria in zebrafish embryos without affecting tubular reabsorption. Also, it is primarily expressed by podocytes. Lastly, an increase in glomerular TMEM14A expression is exhibited in various proteinuric renal diseases. Overall, these results suggest that TMEM14A is a novel factor in the protective mechanisms of the nephron to maintain glomerular filtration barrier integrity.

Perirenal adipose tissue (PRAT) surrounding the kidney is emerging as a player and novel independent risk factor in diabetic kidney disease (DKD); DKD is a complication of diabetes and is a major cause of increased cardiovascular (CV) risk and CV mortality in affected patients. We determined the effect of diabetes induction on (i) kidney and CV damage and (ii) on the expression of proinflammatory and profibrotic factors in both the PRAT and the mesenteric adipose tissue (MAT) of Munich Wistar Frömter (MWF) rats. The 16-week-old male MWF rats (n = 10 rats/group) were fed standard chow (MWF-C) or a high-fat/high-sucrose diet for 6 weeks together with low-dose streptozotocin (15 mg/kg i.p.) at the start of dietary exposure (MWF-D). Phenotyping was performed at the end of treatment through determining water intake, urine excretion, and oral glucose tolerance; use of the homeostatic model assessment–insulin resistance index (HOMA-IR) evidenced the development of overt diabetes manifestation in MWF-D rats. The kidney damage markers Kim-1 and Ngal were significantly higher in MWF-D rats, as were the amounts of PRAT and MAT. A diabetes-induced upregulation in IL-1, IL-6, Tnf-α, and Tgf-β was observed in both the PRAT and the MAT. Col1A1 was increased in the PRAT but not in the MAT of MWF-D, whereas IL-10 was lower and higher in the PRAT and the MAT, respectively. Urinary albumin excretion and blood pressure were not further increased by diabetes induction, while heart weight was higher in the MWF-D. In conclusion, our results show a proinflammatory and profibrotic in vivo environment in PRAT induced by diabetes which might be associated with kidney damage progression in the MWF strain.

BackgroundAtrial fibrillation (AF) is a common arrhythmia with increasing prevalence with respect to age and comorbidities. AF may influence the prognosis in patients hospitalized with Coronavirus disease 2019 (COVID-19). We aimed to assess the prevalence of AF among patients hospitalized due to COVID-19 and the association of AF and in-hospital anticoagulation treatment with prognosis.Methods and resultsWe assessed the prevalence of AF among patients hospitalized due to COVID-19 and the association of AF and in-hospital anticoagulation treatment with prognosis. Data of all COVID-19 patients hospitalized in the University Hospital in Krakow, Poland, between March 2020 and April 2021, were analyzed. The following outcomes: short-term (30-days since hospital admission) and long-term (180-days after hospital discharge) mortality, major cardiovascular events (MACEs), pulmonary embolism, and need for red blood cells (RBCs) transfusion, as a surrogate for major bleeding events during hospital stay were assessed. Out of 4,998 hospitalized patients, 609 had AF (535 pre-existing and 74 de novo). Compared to those without AF, patients with AF were older and had more cardiovascular disorders. In adjusted analysis, AF was independently associated with an increased risk of short-term {p = 0.019, Hazard Ratio [(HR)] 1.236; 95% CI: 1.035–1.476} and long-term mortality (Log-rank p

Introduction: Epidemiological studies in children suggested that in utero exposure to chlorpyrifos (CPF), an organophosphate insecticide, may cause developmental neurotoxicity (DNT). We applied quantitative in vitro–in vivo extrapolation (QIVIVE) based on in vitro concentration and non-choline esterase-dependent effects data combined with Benchmark dose (BMD) modelling to predict oral maternal CPF exposure during pregnancy leading to fetal brain effect concentration. By comparing the results with data from epidemiological studies, we evaluated the contribution of the in vitro endpoints to the mode of action (MoA) for CPF-induced DNT.Methods: A maternal-fetal PBK model built in PK-Sim® was used to perform QIVIVE predicting CPF concentrations in a pregnant women population at 15 weeks of gestation from cell lysate concentrations obtained in human induced pluripotent stem cell-derived neural stem cells undergoing differentiation towards neurons and glia exposed to CPF for 14 days. The in vitro concentration and effect data were used to perform BMD modelling.Results: The upper BMD was converted into maternal doses which ranged from 3.21 to 271 mg/kg bw/day. Maternal CPF blood levels from epidemiological studies reporting DNT findings in their children were used to estimate oral CPF exposure during pregnancy using the PBK model. It ranged from 0.11 to 140 μg/kg bw/day.Discussion: The effective daily intake doses predicted from the in vitro model were several orders of magnitude higher than exposures estimated from epidemiological studies to induce developmental non-cholinergic neurotoxic responses, which were captured by the analyzed in vitro test battery. These were also higher than the in vivo LOEC for cholinergic effects. Therefore, the quantitative predictive value of the investigated non-choline esterase-dependent effects, although possibly relevant for other chemicals, may not adequately represent potential key events in the MoA for CPF-associated DNT.

Purpose Little is known on the beliefs, perceptions and practices of hypertension specialists in addressing non-adherence to therapy. Therefore, a survey was undertaken amongst healthcare professionals (HCPs) managing hypertension in the European Society of Hypertension (ESH) Centres of Excellence. Materials and methods Cross-sectional data were obtained between December 2020 and April 2021 using an online anonymous structured questionnaire including 26 questions/136 items, that was sent to all ESH Excellence centres. Results Overall 67 from 187 centres (37.3%) responded and 200 HCPs from 30 countries answered the questionnaire. Participants (60% men) were mainly physicians (91%) and nurses (8%) from University hospitals (77%). Among physicians, 83% had >10 years professional experience. Average time dedicated to discuss medications was 1-5 min in 48% and 6-10 min in 29% of cases. Interviews with patients about adherence were the most frequently used assessment method. Chemical detection of medications in urine was available in 36% of centres. One third of physicians involved their patients regularly in treatment decisions. The most frequent methods to improve adherence included simplification of medication therapy, more frequent visits, and home blood pressure monitoring. Conclusions The level of implementation of tools to detect and improve adherence in hypertension management by HCPs in ESH excellence centres is low. Structured educational activities focussing on adherence management and access to the newest objective measures to detect non-adherence might improve these deficits.

Infants of mothers treated for tuberculosis might be exposed to drugs via breast milk. The existing information on the exposure of breastfed infants lacks a critical review of the published data. We aimed to evaluate the quality of the existing data on antituberculosis (anti-TB) drug concentrations in the plasma and milk as a methodologically sound basis for the potential risk of breastfeeding under therapy. We performed a systematic search in PubMed for bedaquiline, clofazimine, cycloserine/terizidone, levofloxacin, linezolid, pretomanid/pa824, pyrazinamide, streptomycin, ethambutol, rifampicin and isoniazid, supplemented with update references found in LactMed®. We calculated the external infant exposure (EID) for each drug and compared it with the recommended WHO dose for infants (relative external infant dose) and assessed their potential to elicit adverse effects in the breastfed infant. Breast milk concentration data were mainly not satisfactory to properly estimate the EID. Most of the studies suffer from limitations in the sample collection, quantity, timing and study design. Infant plasma concentrations are extremely scarce and very little data exist documenting the clinical outcome in exposed infants. Concerns for potential adverse effects in breastfed infants could be ruled out for bedaquiline, cycloserine/terizidone, linezolid and pyrazinamide. Adequate studies should be performed covering the scenario in treated mothers, breast milk and infants.

Abstract Background The XALIA and XALIA‐LEA prospective, noninterventional studies investigated the safety and effectiveness of rivaroxaban versus standard anticoagulation for venous thromboembolism (VTE) treatment in routine clinical practice across global regions. Objectives This pooled analysis combined their data to determine the incidence of thromboembolic and bleeding events in both treatment groups and addressed specific bleeding patterns in a broad range of patients. Methods Patients with objectively confirmed VTE and an indication for ≥3 months’ anticoagulation treatment received rivaroxaban or standard anticoagulation (eg, initial treatment with heparin/fondaparinux, followed by a vitamin K antagonist [VKA]). Treatment choice, dose, management, and duration were at the physician’s discretion. Primary outcomes (major bleeding, recurrent VTE, and all‐cause mortality) were compared between the two treatment groups. Propensity score stratification, and matching were used to reduce bias due to confounding variables. Results Overall, 7129 patients were enrolled from 36 countries; 6445 and 2714 patients were included in the propensity score–stratified and –matched analyses, respectively. Major bleeding and incidences of recurrent VTE were similar between treatment groups; all‐cause mortality was lower with rivaroxaban than with standard anticoagulation. The incidences of genitourinary bleeding were higher with rivaroxaban than with standard anticoagulation therapy (46 and 23 events in the matched analysis, respectively). VKA management in real‐world practice was suboptimal. Conclusion XALIA and XALIA‐LEA show similar safety and effectiveness profiles of rivaroxaban and standard anticoagulation for VTE treatment in routine practice in many parts of the world. The observations are consistent with results from the phase III EINSTEIN randomized controlled trials.

Introduction: Transmembrane protein (TMEM) 63C is a member of the TMEM gene family and was recently linked to glomerular filtration barrier function and albuminuria. Its molecular function and expression regulation are largely unknown. Objective: In this study, we set out to characterize the regulating impact of microRNAs (miRNAs) such as miRNA-564 (miR-564) on TMEM63C expression in renal cells. Also, we examined the influence of transforming growth factor beta (TGF-ß) on TMEM63C expression and the potential impact of TMEM63C inhibition on epithelial-mesenchymal transition (EMT) in renal cells and on cell viability in human embryonic kidney 293 cells (HEK 293). Methods: Expression analyses were done using real-time PCR and Western blot. Dual luciferase assay was performed to determine the miRNA-mediated expression control. Cell viability was assessed via trypan blue exclusion staining. Results and Conclusions: MiR-564 reduced TMEM63C expression in HEK 293 and human podocytes (hPC). The treatment of renal cells with TGF-ß led to an increased expression of TMEM63C. Moreover, a reduced TMEM63C expression was associated with a changed ratio of EMT marker proteins such as α-smooth muscle actin versus E-cadherin in HEK 293 and decreased nephrin expression in hPC. In addition, cell viability was reduced upon inhibition of TMEM63C expression in HEK 293. This study demonstrates first mechanisms involved in TMEM63C expression regulation and a link to EMT in renal cells.

Inter-individual differences in antidepressant drug concentrations attained in blood may limit the efficacy of pharmacological treatment of depressive disorders. Therapeutic drug monitoring (TDM) enables to determine drug concentrations in blood and adjust antidepressant dosage accordingly. However, research on the underlying assumption of TDM, association between concentration and clinical effect, has yielded ambiguous results for antidepressants. It has been proposed that this ambiguity may be caused by methodological shortcomings in studies investigating the concentration-effect relationship. Guidelines recommend the use of TDM in antidepressant treatment as expert opinion. This reflects the lack of research, particularly systematic reviews and meta-analyses of randomized controlled trials, on the relationship between concentration and effect as well as on the benefits of the use of TDM in clinical practice. In this study, a systematic review and meta-analysis of randomized controlled trials has been performed to investigate the relationship between antidepressant concentration, efficacy, and side effects. It is the first meta-analytical approach to this subject and additionally considers methodological properties of primary studies as moderators of effect in quantitative analysis. Our results identified methodological shortcomings, namely the use of a flexible dose design and the exclusion of concentrations in lower- or subtherapeutic ranges, which significantly moderate the relationship between antidepressant concentration and efficacy. Such shortcomings obscure the evidence base of using TDM in clinical practice to guide antidepressant drug therapy. Further research should consider these findings to determine the relationship between concentration and efficacy and safety of antidepressant treatments, especially for newer antidepressants.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=246149, identifier: CRD42021246149.

Arterial stiffness is a major vascular complication of chronic kidney disease (CKD). The development of renal damage, hypertension, and increased pulse wave velocity (PWV) in CKD might be associated with an imbalance in bone morphogenetic proteins (BMP)-2 and BMP-7. Plasma BMP-2 and BMP-7 were determined by ELISA in CKD patients (stages I–III; n = 95) and Munich Wistar Frömter (MWF) rats. Age-matched Wistar rats were used as a control. The expression of BMP-2, BMP-7, and profibrotic and calcification factors was determined in kidney and perivascular adipose tissues (PVAT). BMP-2 was higher in stage III CKD patients compared to control subjects. BMP-7 was lower at any CKD stage compared to controls, with a significant further reduction in stage III patients. A similar imbalance was observed in MWF rats together with the increase in systolic (SBP) and diastolic blood pressure (DBP), or pulse wave velocity (PWV). MWF exhibited elevated urinary albumin excretion (UAE) and renal expression of BMP-2 or kidney damage markers, Kim-1 and Ngal, whereas renal BMP-7 was significantly lower than in Wistar rats. SBP, DBP, PWV, UAE, and plasma creatinine positively correlated with the plasma BMP-2/BMP-7 ratio. Periaortic and mesenteric PVAT from MWF rats showed an increased expression of BMP-2 and profibrotic and calcification markers compared to Wistar rats, together with a reduced BMP-7 expression. BMP-2 and BMP-7 imbalance in plasma, kidney, and PVATs is associated with vascular damage, suggesting a profibrotic/pro-calcifying propensity associated with progressive CKD. Thus, their combined analysis stratified by CKD stages might be of clinical interest to provide information about the degree of renal and vascular damage in CKD.

Background: Serotonergic psychedelics (SPs) like LSD, psilocybin, DMT, and mescaline are a heterogeneous group of substances that share agonism at 5-HT2a receptors. Besides the ability of these substances to facilitate profoundly altered states of consciousness, persisting psychological effects have been reported after single administrations, which outlast the acute psychedelic effects. In this review and meta-analysis, we investigated if repeated SP use associates with a characteristic neuropsychological profile indicating persisting effects on neuropsychological function.Methods: We conducted a systematic review of studies investigating the neuropsychological performance in SP users, searching studies in Medline, Web of Science, embase, ClinicalTrials.gov, and EudraCT. Studies were included if they reported at least one neuropsychological measurement in users of SPs. Studies comparing SP users and non-users that reported mean scores and standard deviations were included in an exploratory meta-analysis.Results: 13 studies (N = 539) published between 1969 and 2020 were included in this systematic review. Overall, we found that only three SPs were specifically investigated: ayahuasca (6 studies, n = 343), LSD (5 studies, n = 135), and peyote (1 study, n = 61). However, heterogeneity of the methodological quality was high across studies, with matching problems representing the most important limitation. Across all SPs, no uniform pattern of neuropsychological impairment was identified. Rather, the individual SPs seemed to be associated with distinct neuropsychological profiles. For instance, one study (n = 42) found LSD users to perform worse in trials A and B of the Trail-Making task, whereas meta-analytic assessment (5 studies, n = 352) of eleven individual neuropsychological measures indicated a better performance of ayahuasca users in the Stroop incongruent task (p = 0.03) and no differences in the others (all p > 0.05).Conclusion: The majority of the included studies were not completely successful in controlling for confounders such as differences in non-psychedelic substance use between SP-users and non-users. Our analysis suggests that LSD, ayahuasca and peyote may have different neuropsychological consequences associated with their use. While LSD users showed reduced executive functioning and peyote users showed no differences across domains, there is some evidence that ayahuasca use is associated with increased executive functioning.

Aim: To measure the extent of polypharmacy, multimorbidity and potential medication-related problems in elderly patients with chronic pain receiving home care.Methods: Data of 355 patients aged ≥65 years affected by chronic pain in home care who were enrolled in the ACHE study in Berlin, Germany, were analyzed. History of chronic diseases, diagnoses, medications including self-medication were collected for all patients. Multimorbidity was defined as the presence of ≥2 chronic conditions and levels were classified by the Charlson-Comorbidity-Index. Polypharmacy was defined as the concomitant intake of ≥5 medications. Potentially clinically relevant drug interactions were identified and evaluated; underuse of potentially useful medications as well as overprescription were also assessed.Results: More than half of the patients (55.4%) had moderate to severe comorbidity levels. The median number of prescribed drugs was 9 (range 0–25) and polypharmacy was detected in 89.5% of the patients. Almost half of them (49.3%) were affected by excessive polypharmacy (≥10 prescribed drugs). Polypharmacy and excessive polypharmacy occurred at all levels of comorbidity. We detected 184 potentially relevant drug interactions in 120/353 (34.0%) patients and rated 57 (31.0%) of them as severe. Underprescription of oral anticoagulants was detected in 32.3% of patients with atrial fibrillation whereas potential overprescription of loop diuretics was observed in 15.5% of patients.Conclusion: Multimorbidity and polypharmacy are highly prevalent in elderly outpatients with chronic pain receiving home care. Medication-related problems that could impair safety of drug treatment in this population are resulting from potentially relevant drug interactions, overprescribing as well as underuse.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential conflict of interest is reported on the websites of the ESH and the ESC.

Left ventricular hypertrophy (LVH) is a major risk factor for adverse cardiovascular events. Recently, a novel candidate gene encoding the carboxypeptidase X member 2 (CPXM2) was found to be associated with hypertension-induced LVH. CPXM2 belongs to the M14 family of metallocarboxypeptidases, yet it lacks detectable enzyme activity, and its function remains unknown. Here, we investigated the impact of micro (mi)RNA-29b, miRNA-195, and miRNA-497 on the posttranscriptional expression control of CPXM2. Candidate miRNAs for CPXM2 expression control were identified in silico. CPXM2 expression in rat cardiomyocytes (H9C2) was characterized via real-time PCR, Western blotting, and immunofluorescence. Direct miRNA/target mRNA interaction was analysed by dual luciferase assay. CPXM2 was expressed in H9C2 and co-localised with z-disc associated protein PDZ and LIM domain 3 (Pdlim3). Transfection of H9C2 with miRNA-29b, miRNA-195, and miRNA-497 led to decreased levels of CPXM2 mRNA and protein, respectively. Results of dual luciferase assays revealed that miRNA-29b and miRNA-497, but not miRNA-195, directly regulated CPXM2 expression on a posttranscriptional level via binding to the 3′UTR of CPXM2 mRNA. We identified two miRNAs capable of the direct posttranscriptional expression control of CPXM2 expression in rat cardiomyocytes. This novel data may help to shed more light on the—so far—widely unexplored expression control of CPXM2 and its potential role in LVH.

Background and Objective: Agranulocytosis is a rare and potentially life-threatening complication of metamizole (dipyrone) intake that is characterized by a loss of circulating neutrophil granulocytes. While the mechanism underlying this adverse drug reaction is not well understood, involvement of the immune system has been suggested. In addition, associations between genetic variants in the Human Leukocyte Antigen (HLA) region and agranulocytosis induced by other drugs have been reported. The aim of the present study was to assess whether genetic variants in classical HLA genes are associated with the susceptibility to metamizole-induced agranulocytosis (MIA) in a European population by targeted resequencing of eight HLA genes.Design: A case-control cohort of Swiss patients with a history of neutropenia or agranulocytosis associated with metamizole exposure (n = 53), metamizole-tolerant (n = 39) and unexposed controls (n = 161) was recruited for this study. A high-throughput resequencing (HTS) and high-resolution typing method was used to sequence and analyze eight HLA loci in a discovery subset of this cohort (n = 31 cases, n = 38 controls). Identified candidate alleles were investigated in the full Swiss cohort as well as in two independent cohorts from Germany and Spain using HLA imputation from genome-wide SNP array data. In addition, variant calling based on HTS data was performed in the discovery subset for the class I genes HLA-A, -B, and -C using the HLA-specific mapper hla-mapper.Results: Eight candidate alleles (p < 0.05) were identified in the discovery subset, of which HLA-C∗04:01 was associated with MIA in the full Swiss cohort (p < 0.01) restricted to agranulocytosis (ANC < 0.5 × 109/L) cases. However, no candidate allele showed a consistent association in the Swiss, German and Spanish cohorts. Analysis of individual sequence variants in class I genes produced consistent results with HLA typing but did not reveal additional small nucleotide variants associated with MIA.Conclusion: Our results do not support an HLA-restricted T cell-mediated immune mechanism for MIA. However, we established an efficient high-resolution (three-field) eight-locus HTS HLA resequencing method to interrogate the HLA region and demonstrated the feasibility of its application to pharmacogenetic studies.

OBJECTIVE:To analyze the pattern and appropriateness of pain medications in older adults receiving home care. METHODS:We performed a prospective cross-sectional study in patients ≥65 years old having chronic pain and receiving home care in Berlin, Germany. Data on prescribed pain medications were collected using self-reported information, nursing documents, and medication plans during interviews at home. Pain intensity was determined with the numeric rating scale (NRS) and the Pain Assessment In Advanced dementia (PAINAD) scale. The Pain Medication Appropriateness Scale score (SPMAS) was applied to evaluate inappropriateness (i.e. a score ≤67) of pain medication. RESULTS:Overall 322 patients with a mean age of 82.1 ± 7.4 years (71.4% females) were evaluated. The average pain intensity scores during the last 24 hours were 5.3 ± 2.1 and 2.3 ± 2.3 on NRS and PAINAD scale (range 0-10, respectively). Sixty (18.6%) patients did not receive any pain medication. Among the treated patients, dipyrone was the most frequently prescribed analgesic (71.4%), while 50.8% and 19.1% received systemic treatment with opioids and non-steroidal anti-inflammatory drugs, respectively. The observed median SPMAS was 47.6 (range 0-100) with 58 (18.0%) of patients achieving appropriate values. Half of the patients were treated with scheduled, while 29.9% were only treated with on-demand medications. Cognitive status had no effect on appropriateness of pain treatment. CONCLUSIONS:We observed substantial deficits in dosing patterns and appropriateness of pain medication in older adults with pain receiving home care. This applied to both patients with and without severe cognitive impairment.

Abstract Background Hazardous and harmful alcohol use and high blood pressure are central risk factors related to premature non-communicable disease (NCD) mortality worldwide. A reduction in the prevalence of both risk factors has been suggested as a route to reach the global NCD targets. This study aims to highlight that screening and interventions for hypertension and hazardous and harmful alcohol use in primary healthcare can contribute substantially to achieving the NCD targets. Methods A consensus conference based on systematic reviews, meta-analyses, clinical guidelines, experimental studies, and statistical modelling which had been presented and discussed in five preparatory meetings, was undertaken. Specifically, we modelled changes in blood pressure distributions and potential lives saved for the five largest European countries if screening and appropriate intervention rates in primary healthcare settings were increased. Recommendations to handle alcohol-induced hypertension in primary healthcare settings were derived at the conference, and their degree of evidence was graded. Results Screening and appropriate interventions for hazardous alcohol use and use disorders could lower blood pressure levels, but there is a lack in implementing these measures in European primary healthcare. Recommendations included (1) an increase in screening for hypertension (evidence grade: high), (2) an increase in screening and brief advice on hazardous and harmful drinking for people with newly detected hypertension by physicians, nurses, and other healthcare professionals (evidence grade: high), (3) the conduct of clinical management of less severe alcohol use disorders for incident people with hypertension in primary healthcare (evidence grade: moderate), and (4) screening for alcohol use in hypertension that is not well controlled (evidence grade: moderate). The first three measures were estimated to result in a decreased hypertension prevalence and hundreds of saved lives annually in the examined countries. Conclusions The implementation of the outlined recommendations could contribute to reducing the burden associated with hypertension and hazardous and harmful alcohol use and thus to achievement of the NCD targets. Implementation should be conducted in controlled settings with evaluation, including, but not limited to, economic evaluation.

Warfarin has been associated with renovascular calcification and worsening renal function, whereas rivaroxaban may provide a degree of renopreservation by decreasing vascular inflammation. We sought to compare rivaroxaban and warfarin’s impact on renal decline in patients with nonvalvular atrial fibrillation (NVAF) treated in routine practice. Using US MarketScan claims data from January 2012 to December 2017, we identified patients with NVAF newly initiated on rivaroxaban or warfarin with ≥12 months of continuous insurance coverage prior to initiation. Patients with stage 5 chronic kidney disease (CKD) or receiving hemodialysis at baseline were excluded. Outcomes included rates (events/100 person-years) of hospital or emergency department admission for acute kidney injury (AKI) or progression to stage 5 CKD or need for hemodialysis. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weights based on propensity scores (absolute standardized differences

Unraveling the genetic susceptibility of complex diseases such as chronic kidney disease remains challenging. Here, we used inbred rat models of kidney damage associated with elevated blood pressure for the comprehensive analysis of a major albuminuria susceptibility locus detected in these models. We characterized its genomic architecture by congenic substitution mapping, targeted next-generation sequencing, and compartment-specific RNA sequencing analysis in isolated glomeruli. This led to prioritization of transmembrane protein Tmem63c as a novel potential target. Tmem63c is differentially expressed in glomeruli of allele-specific rat models during onset of albuminuria. Patients with focal segmental glomerulosclerosis exhibited specific TMEM63C loss in podocytes. Functional analysis in zebrafish revealed a role for tmem63c in mediating the glomerular filtration barrier function. Our data demonstrate that integrative analysis of the genomic architecture of a complex trait locus is a powerful tool for identification of new targets such as Tmem63c for further translational investigation.

INTRODUCTION:Multimorbidity in advanced age and the need for drug treatment may lead to polypharmacy, while pharmacokinetic and pharmacodynamic changes may increase the risk of adverse drug events (ADEs). OBJECTIVE:The aim of this study was to determine the proportion of subjects using potentially inappropriate medication (PIM) in a cohort of older and predominantly healthy adults in relation to polypharmacy and morbidity. METHODS:Cross-sectional data were available from 1,382 study participants (median age 69 years, IQR 67-71, 51.3% females) of the Berlin Aging Study II (BASE-II). PIM was classified according to the EU(7)-PIM and German PRISCUS (representing a subset of the former) list. Polypharmacy was defined as the concomitant use of at least five drugs. A morbidity index (MI) largely based on the Charlson Index was applied to evaluate the morbidity burden. RESULTS:Overall, 24.1% of the participants were affected by polypharmacy. On average, men used 2 (IQR 1-4) and women 3 drugs (IQR 1-5). According to PRISCUS and EU(7)-PIM, 5.9% and 22.6% of participants received at least one PIM, while use was significantly more prevalent in females (25.5%) compared to males (19.6%) considering EU(7)-PIM (p = 0.01). In addition, morbidity in males receiving PIM according to EU(7)-PIM was higher (median MI 1, IQR 1-3) compared to males without PIM use (median MI 1, IQR 0-2, p

Abstract Background Overall, 30 to 50% of lower-limb deep-vein thrombosis (DVT) cases are isolated distal DVT (IDDVT). The recurrent venous thromboembolism (VTE) risk is unclear, leaving uncertainty over optimal IDDVT treatment. We present data on patients with IDDVT and proximal DVT (PDVT) from the prospective, noninterventional XALIA study of rivaroxaban for acute and extended VTE treatment. Methods Patients aged ≥18 years scheduled to receive ≥3 months' anticoagulation with rivaroxaban or standard anticoagulation were eligible, with follow-up for ≥12 months. We describe baseline characteristics, management strategies, and incidence proportions of VTE recurrence, major bleeding, and all-cause mortality in patients with IDDVT or PDVT, with or without distal vein involvement. Findings Overall, 1,004 patients with IDDVT and 3,098 with PDVT were enrolled; 641 (63.8%) and 1,683 (54.3%) received rivaroxaban, respectively. Patients with IDDVT were younger and had lower incidences of renal impairment, cancer, and unprovoked VTE than those with PDVT. On-treatment recurrence incidences for IDDVT versus PDVT were 1.0 versus 2.4% (adjusted hazard ratio [HR]: 0.56; 95% confidence interval [CI]: 0.29–1.08), and incidences posttreatment cessation were 1.1 versus 2.1% (adjusted HR: 0.65; 95% CI: 0.32–1.35), respectively. On-treatment major bleeding incidences were 0.9 versus 1.4% and mortality was 0.8 versus 2.2%, respectively. Median treatment duration in patients with IDDVT was shorter than in those with PDVT (102 vs. 192 days, respectively). Interpretation Patients with IDDVT had fewer comorbidities and were more frequently treated with rivaroxaban than those with PDVT. On-treatment and posttreatment recurrences were less frequent in patients with IDDVT. Trial registration number: NCT01619007.

Albuminuria is an early marker of renovascular damage associated to an increase in oxidative stress. The Munich Wistar Frömter (MWF) rat is a model of chronic kidney disease (CKD), which exhibits endothelial dysfunction associated to low nitric oxide availability. We hypothesize that the new highly selective, non-steroidal mineralocorticoid receptor (MR) antagonist, finerenone, reverses both endothelial dysfunction and microalbuminuria. Twelve-week-old MWF (MWF-C; MWF-FIN) and aged-matched normoalbuminuric Wistar (W-C; W-FIN) rats were treated with finerenone (FIN, 10 mg/kg/day p.o.) or vehicle (C) for 4-week. Systolic blood pressure (SBP) and albuminuria were determined the last day of treatment. Finerenone lowered albuminuria by >40% and significantly reduced SBP in MWF. Aortic rings of MWF-C showed higher contractions to either noradrenaline (NA) or angiotensin II (Ang II), and lower relaxation to acetylcholine (Ach) than W-C rings. These alterations were reversed by finerenone to W-C control levels due to an upregulation in phosphorylated Akt and eNOS, and an increase in NO availability. Apocynin and 3-amino-1,2,4-triazole significantly reduced contractions to NA or Ang II in MWF-C, but not in MWF-FIN rings. Accordingly, a significant increase of Mn-superoxide dismutase (SOD) and Cu/Zn-SOD protein levels were observed in rings of MWF-FIN, without differences in p22phox, p47phox or catalase levels. Total SOD activity was increased in kidneys from MWF-FIN rats. In conclusion, finerenone improves endothelial dysfunction through an enhancement in NO bioavailability and a decrease in superoxide anion levels due to an upregulation in SOD activity. This is associated with an increase in renal SOD activity and a reduction of albuminuria.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10−7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41–6.68, p = 1.01 × 10−7) and rs4427239 (OR = 5.47, 95%CI: 2.81–10.65, p = 5.75 × 10−7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

Glomerular hyperfiltration is an important mechanism in the development of albuminuria. During hyperfiltration, podocytes are exposed to increased fluid flow shear stress (FFSS) in Bowman’s space. Elevated Prostaglandin E2 (PGE2) synthesis and upregulated cyclooxygenase 2 (Cox2) are associated with podocyte injury by FFSS. We aimed to elucidate a PGE2 autocrine/paracrine pathway in human podocytes (hPC). We developed a modified liquid chromatography tandem mass spectrometry (LC/ESI-MS/MS) protocol to quantify cellular PGE2, 15-keto-PGE2, and 13,14-dihydro-15-keto-PGE2 levels. hPC were treated with PGE2 with or without separate or combined blockade of prostaglandin E receptors (EP), EP2, and EP4. Furthermore, the effect of FFSS on COX2, PTGER2, and PTGER4 expression in hPC was quantified. In hPC, stimulation with PGE2 led to an EP2- and EP4-dependent increase in cyclic adenosine monophosphate (cAMP) and COX2, and induced cellular PGE2. PTGER4 was downregulated after PGE2 stimulation in hPC. In the corresponding LC/ESI-MS/MS in vivo analysis at the tissue level, increased PGE2 and 15-keto-PGE2 levels were observed in isolated glomeruli obtained from a well-established rat model with glomerular hyperfiltration, the Munich Wistar Frömter rat. COX2 and PTGER2 were upregulated by FFSS. Our data thus support an autocrine/paracrine COX2/PGE2 pathway in hPC linked to concerted EP2 and EP4 signaling.

For venous thromboembolism (VTE) treatment, patient satisfaction was shown to improve with rivaroxaban versus standard anticoagulation in the phase III EINSTEIN DVT and EINSTEIN PE trials. This substudy of the prospective, noninterventional XALIA study of rivaroxaban for deep-vein thrombosis treatment assessed if this was also observed in routine clinical practice. Patients enrolled in XALIA who received rivaroxaban or standard anticoagulation treatment were eligible for inclusion in this substudy. Treatment decisions were at the physician's discretion. Patients completed the 17-item Anti-Clot Treatment Scale (ACTS, comprising a 12-item Burdens subscale, a 3-item Benefits subscale and one global item per subscale) during follow-up. The propensity score-matched set (PMS) was used for the main analysis; the adjusted safety analysis (ASAF) set was used for confirmatory purposes. Analyses by follow-up visit and subgroup, including age, sex, and previous VTE, were also conducted. The PMS-ACTS analysis included 458 rivaroxaban-treated and 434 standard anticoagulation-treated patients. Baseline demographic and clinical characteristics were generally similar across treatment arms. ACTS Burdens scores significantly improved with rivaroxaban versus standard anticoagulation (least-squares mean difference of 2.4 ± 0.4 points; p

Cytochrome P450 17A1 (CYP17A1) catalyses the formation and metabolism of steroid hormones. They are involved in blood pressure (BP) regulation and in the pathogenesis of left ventricular hypertrophy. Therefore, altered function of CYP17A1 due to genetic variants may influence BP and left ventricular mass. Notably, genome wide association studies supported the role of this enzyme in BP control. Against this background, we investigated associations between single nucleotide polymorphisms (SNPs) in or nearby the CYP17A1 gene with BP and left ventricular mass in patients with arterial hypertension and associated cardiovascular organ damage treated according to guidelines. Patients (n = 1007, mean age 58.0 ± 9.8 years, 83% men) with arterial hypertension and cardiac left ventricular ejection fraction (LVEF) ≥40% were enrolled in the study. Cardiac parameters of left ventricular mass, geometry and function were determined by echocardiography. The cohort comprised patients with coronary heart disease (n = 823; 81.7%) and myocardial infarction (n = 545; 54.1%) with a mean LVEF of 59.9% ± 9.3%. The mean left ventricular mass index (LVMI) was 52.1 ± 21.2 g/m2.7 and 485 (48.2%) patients had left ventricular hypertrophy. There was no significant association of any investigated SNP (rs619824, rs743572, rs1004467, rs11191548, rs17115100) with mean 24 h systolic or diastolic BP. However, carriers of the rs11191548 C allele demonstrated a 7% increase in LVMI (95% CI: 1%–12%, p = 0.017) compared to non-carriers. The CYP17A1 polymorphism rs11191548 demonstrated a significant association with LVMI in patients with arterial hypertension and preserved LVEF. Thus, CYP17A1 may contribute to cardiac hypertrophy in this clinical condition.

Abstract Background The noninterventional XALIA study compared rivaroxaban with standard anticoagulation for deep vein thrombosis treatment. This substudy describes the demographics, clinical characteristics, and outcomes of the patients with cancer. Methods Therapy type, dose, and duration were at the physician's discretion. The cohorts identified were rivaroxaban (rivaroxaban alone or after heparin or fondaparinux for ≤48 hours); early switchers (rivaroxaban after heparin or fondaparinux for >48 hours to 14 days and/or a vitamin K antagonist [VKA] for 1–14 days); standard anticoagulation (heparin or fondaparinux and a VKA); low-molecular-weight heparin (LMWH) alone; and miscellaneous (other heparins, fondaparinux alone, VKA alone). Primary outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Results In XALIA, 587 patients (11.4% of the XALIA cohort) were with cancer: 146 (24.9%) rivaroxaban, 30 (5.1%) early switchers, 141 (24.0%) standard anticoagulation, 223 (38.0%) LMWH, and 47 (8.0%) miscellaneous. Patients with gastrointestinal or lung cancer more commonly received LMWH than rivaroxaban; the opposite occurred in patients with breast or genitourinary cancer. Rates of primary outcome in the rivaroxaban group were as follows: major bleeding, 1.4% (n = 2); recurrent venous thromboembolism, 3.4% (n = 5); and all-cause mortality, 4.8% (n = 7). Conclusion In XALIA, physicians treated cancer-associated thrombosis with various anticoagulant regimens, most commonly LMWH. In addition, the choice of anticoagulant varied with cancer type. In rivaroxaban-treated patients, rates for the primary outcomes were low, suggesting that patients administered rivaroxaban were a good prognosis group.

Reactivation of fetal gene expression patterns has been implicated in common cardiac diseases in adult life including left ventricular (LV) hypertrophy (LVH) in arterial hypertension. Thus, increased wall stress and neurohumoral activation are discussed to induce the return to expression of fetal genes after birth in LVH. We therefore aimed to identify novel potential candidates for LVH by analyzing fetal-adult cardiac gene expression in a genetic rat model of hypertension, i.e. the stroke-prone spontaneously hypertensive rat (SHRSP). To this end we performed genome-wide transcriptome analysis in SHRSP to identify differences in expression patterns between day 20 of fetal development (E20) and adult animals in week 14 in comparison to a normotensive rat strain with contrasting low LV mass, i.e. Fischer (F344). 15232 probes were detected as expressed in LV tissue obtained from rats at E20 and week 14 (p < 0.05) and subsequently screened for differential expression. We identified 24 genes with SHRSP specific up-regulation and 21 genes with down-regulation as compared to F344. Further bioinformatic analysis presented Efcab6 as a new candidate for LVH that showed only in the hypertensive SHRSP rat differential expression during development (logFC = 2.41, p < 0.001) and was significantly higher expressed in adult SHRSP rats compared with adult F344 (+ 76%) and adult normotensive Wistar-Kyoto rats (+ 82%). Thus, it represents an interesting new target for further functional analyses and the elucidation of mechanisms leading to LVH. Here we report a new approach to identify candidate genes for cardiac hypertrophy by combining the analysis of gene expression differences between strains with a contrasting cardiac phenotype with a comparison of fetal-adult cardiac expression patterns.

UnlabelledTreatment of hypertension in hemodialysis (HD) patients is characterised by lack of evidence for both the blood pressure (BP) target goal and the recommended drug class to use. Telmisartan, an Angiotensin receptor blocker (ARB) that is metabolised in the liver and not excreted via HD extracorporeal circuit might be particularly suitable for HD patients. We designed and conducted a randomised, placebo-controlled, double-blind and cross-over trial for treatment of dialysis-associated hypertension with telmisartan 80 mg once daily or placebo on top of standard antihypertensive treatment excluding other Renin-Angiotensin-System (RAS) blockers. In 29 patients after randomization we analysed BP after a treatment period of 8 weeks, while 13 started with telmisartan and 16 with placebo; after 8 weeks 11 continued with telmisartan and 12 with placebo after cross-over, respectively. Patients exhibited a significant reduction of systolic pre-HD BP from 141.9±21.8 before to 131.3±17.3 mmHg after the first treatment period with telmisartan or placebo. However, no average significant influence of telmisartan was observed compared to placebo. The latter may be due to a large inter-individual variability of BP responses reaching from a 40 mmHg decrease under placebo to 40 mmHg increase under telmisartan. Antihypertensive co-medication was changed for clinical reasons in 7 out of 21 patients with no significant difference between telmisartan and placebo groups. Our starting hypothesis, that telmisartan on top of standard therapy lowers systolic office BP in HD patients could not be confirmed. In conclusion, this small trial indicates that testing antihypertensive drug efficacy in HD patients is challenging due to complicated standardization of concomitant medication and other confounding factors, e.g. volume status, salt load and neurohormonal activation, that influence BP control in HD patients.Trial registrationClinicaltrialsregister.eu 2005-005021-60.

Herb-induced liver injury (HILI) has recently attracted attention due to increasing reports of hepatotoxicity associated with use of phytotherapeutics. Here, we present data on HILI from the Berlin Case-Control Surveillance Study. The study was initiated in 2000 to investigate the serious toxicity of drugs including herbal medicines. Potential cases of liver injury were ascertained in more than 180 Departments of all 51 Berlin hospitals from October 2002 to December 2011. Drug or herb intake was assessed through a standardized face-to-face interview. Drug or herbal aetiology was assessed based on the updated Council for International Organizations of Medical Sciences scale. In ten of all 198 cases of hepatotoxicity included in the study, herbal aetiology was assessed as probable (once ayurvedic herb) or possible (Valeriana five times, Mentha piperita once, Pelargonium sidoides once, Hypericum perforatum once, Eucalyptus globulus once). Mean age was 56.4 ± 9.7 years, and the predominant pattern of liver injury was hepatocellular. No cases of acute liver failure or death were observed. This case series corroborates known risks for ayurvedic herbs, supports the suspected association between Valeriana use and liver injury, and indicates a hepatotoxic potential for herbs such as Pelargonium sidoides, Hypericum perforatum or Mentha piperita that were rarely associated with liver injury before. However, given that possible causality does not prove clinical significance, further studies in this field are needed.

We report the first case of a pregnant renal transplant patient with H1N1/09 infection. The woman showed a mild clinical course after diagnosis of H1N1/09 infection and therapy with oseltamivir (2×45 mg per day). After delivery by cesarean section, the neonate exhibited moderate respiratory and circulatory dysregulation, which spontaneously normalised a few days postpartum. In conclusion, rapid diagnosis of H1N1/09 and dose-adapted therapy with oseltamivir resulted in successful delivery of a healthy infant in our renal transplanted patient but emphasized the need for consequent vaccination strategies in pregnant transplant recipients for new influenza A pandemics in the future.