The Effect of Nabiximols on Driving Ability in Adults with Chronic Tic Disorders: Results of a Substudy Analysis of the Double-Blind, Randomized, Placebo-Controlled CANNA-TICS Trial.

Background: The multicenter, randomized, double-blind, parallel-group, phase IIIb CANNA-TICS (CANNAbinoids in the treatment of TICS) trial showed clear trends for improvement of tics, depression, and quality of life with nabiximols versus placebo in adult patients with Gilles de la Tourette syndrome and other chronic tic disorders. Although in general nabiximols was well tolerated, it is unclear whether treatment using this cannabis extract influences driving skills in patients with chronic tic disorders. Methods: Here we report results of the "Fitness to Drive" substudy of the CANNA-TICS trial. The key endpoint was fitness to drive as a binary criterion with a computerized assessment at baseline and after 9 weeks of stable treatment (week 13) with nabiximols or placebo. A patient was considered unfit to drive according to the German Federal Highway Research Institute guidelines. Results: In the substudy, a total of 64 patients (76.6% men, mean±standard deviation of age: 36.8±13.9) were recruited at two study sites. The number of patients who were fit to drive increased from 24 (55.8%) at baseline to 28 (71.8%) at week 13 among 43 patients treated with nabiximols, and decreased from 14 (66.7%) to 10 (52.6%) among 21 patients who received placebo. The risk difference (nabiximols - placebo) was 0.17 (95% confidence interval=-0.08 to 0.43) in favor of nabiximols. Specifically, only 2 of 24 (8.3%) patients in the nabiximols, but 4 of 14 (28.6%) patients in the placebo group changed for the worse from fit (at baseline) to unfit (at week 13) to drive, whereas 8 of 19 (42.1%) patients in the nabiximols, and only 2 of 7 (28.6%) patients in the placebo group improved from unfit to fit. Conclusion: Treatment with nabiximols does not impair skills relevant to driving in those patients with tic disorders who were fit to drive at baseline and even improved fitness to drive in a subset of patients who were unfit to drive before start of treatment. EudraCT number: 2016-000564-42.

Sex-Specific Risk Factors of Nonstenotic Carotid Plaque in Embolic Stroke of Unknown Source: A Case-Control Study.

BACKGROUND: Many ischemic strokes are diagnosed as embolic strokes of undetermined source (ESUS). Recent evidence suggests that nonstenotic carotid plaque (nsCP) may be a substantial contributor to the risk for ESUS. We aimed to investigate the risk factor profile associated with nsCP in ESUS and defined stroke etiologies. METHODS: In this retrospective case-control study, we investigated consecutive patients with acute ischemic stroke due to ESUS, small-vessel disease, or cardioembolism proven by magnetic resonance imaging. The association of vascular risk factors age, arterial hypertension, diabetes, dyslipoproteinemia, body mass index, alcohol consumption, tobacco use, kidney failure, and history of stroke with the presence of nsCP was investigated using binary logistic regression analysis and further stratified by stroke etiology and sex. RESULTS: In total, 609 patients (median age, 76 years; 46% women) who were treated from 2018 to 2020 were considered. In patients with ESUS, sex played a more important role for the prevalence of nsCP than in defined etiologies. Female patients with ESUS had lower odds of exhibiting nsCP compared with male patients with ESUS (adjusted odds ratio, 0.36 [95% CI, 0.15-0.86]). In male patients with ESUS, we observed that age (adjusted odds ratio per 10-year increase, 2.55 [95% CI, 1.26-5.17]) and hypertension (adjusted odds ratio, 2.49 [95% CI, 0.56-11.1]) were the main risk factors for nsCP, whereas in female patients with ESUS also tobacco use was particularly relevant (adjusted odds ratio, 3.71 [95% CI, 0.61-22.5]). These results were in line with a sensitivity analysis in nsCP located ipsilateral to the infarct. CONCLUSIONS: Sex differences play an important role in nsCP prevalence in patients with ESUS. These findings may have important implications for the management in targeted secondary prevention following ESUS.

Diagnostic value of carotid intima-media thickness and clinical risk scores in determining etiology of ischemic stroke.

BACKGROUND: In the general population, carotid intima-media thickness (CIMT) is associated with atherosclerosis as well as atrial fibrillation (AF). However, the extent to which CIMT might be of diagnostic value in clarifying stroke etiology is currently unclear. METHODS: In this retrospective cohort study, we included 800 consecutive patients with acute ischemic stroke. We compared CIMT-values between stroke etiologies. The association between CIMT and cardioembolic stroke was investigated via logistic regression analysis adjusting for vascular risk factors. Receiver operating characteristic analyses were conducted to investigate the diagnostic value of CIMT in comparison to vascular risk factors and clinical AF risk scores (CHA2DS2VASc, HAVOC, and AS5F). RESULTS: CIMT-values were highest in patients with cardioembolic or atherosclerotic stroke origin. CIMT was associated with newly diagnosed AF compared against cryptogenic strokes (crude odds ratio (OR) per 0.1 mm-increase of CIMT: 1.26 (95% confidence interval (CI): 1.13-1.41)). After adjustment for vascular risk factors, the effect of CIMT on AF-diagnosis, however, was weakened (adjusted OR: 1.10 (95% CI: 0.97-1.25)). The diagnostic value of CIMT for detection of AF (AUC: 0.60, 95% CI: 0.54-0.65) was outperformed by AF risk scores. Among the scores investigated, the AS5F-score yielded best accuracy and calibration to predict newly diagnosed AF (AUC: 0.71, 95% CI: 0.65-0.78). CONCLUSIONS: CIMT may help in the diagnosis of stroke etiology. However, compared with vascular risk factors or clinical AF risk scores, CIMT does not provide substantial additional information on the risk of newly detected AF. Thus, stratification of AF risk based on scores, such as the AS5F, is advisable.

How to avoid concerns with the interpretation of two primary endpoints if significant superiority in one is sufficient for formal proof of efficacy.

Formal proof of efficacy of a drug requires that in a prospective experiment, superiority over placebo, or either superiority or at least non-inferiority to an established standard, is demonstrated. Traditionally one primary endpoint is specified, but various diseases exist where treatment success needs to be based on the assessment of two primary endpoints. With co-primary endpoints, both need to be "significant" as a prerequisite to claim study success. Here, no adjustment of the study-wise type-1-error is needed, but sample size is often increased to maintain the pre-defined power. Studies that use an at-least-one concept have been proposed where study success is claimed if superiority for at least one of the endpoints is demonstrated. This is sometimes also called the dual primary endpoint concept, and an appropriate adjustment of the study-wise type-1-error is required. This concept is not covered in the European Guideline on multiplicity because study success can be claimed if one endpoint shows significant superiority, despite a possible deterioration in the other. In line with Röhmel's strategy, we discuss an alternative approach including non-inferiority hypotheses testing that avoids obvious contradictions to proper decision-making. This approach leads back to the co-primary endpoint assessment, and has the advantage that minimum requirements for endpoints can be modeled flexibly for several practical needs. Our simulations show that, if planning assumptions are correct, the proposed additional requirements improve interpretation with only a limited impact on power, that is, on sample size.

BISCIT: Biliary interventions in critically ill patients with secondary sclerosing cholangitis-a study protocol for a multicenter, randomized, controlled parallel group trial.

BACKGROUND: Progress of cholangitis to cholangiosepsis is a frequent observation in patients with secondary sclerosing cholangitis in critically ill patients (SSC-CIP). Adequate biliary drainage may reduce episodes of cholangiosepsis and therefore stabilize liver function and improve survival. The primary objective of the BISCIT study is to demonstrate that scheduled biliary interventions will reduce incidence of cholangiosepsis, liver transplantation, or death in patients with SSC-CIP. METHODS: A total of 104 patients will be randomized at ten study sites. Patients with SSC-CIP, confirmed by endoscopic retrograde cholangiography (ERC), will be randomized 1:1 either in the intervention group which will be treated with scheduled biliary interventions (i.e., therapeutic ERC) every 8 weeks for 6 months or in the control group which will receive standard of care. The randomization will be stratified by center. The composite primary efficacy endpoint is defined as (1) occurrence of death, (2) necessity of liver transplantation, or (3) occurrence of cholangiosepsis within 6 months following randomization. DISCUSSION: Prospective evaluation of endoscopic treatment procedures is urgently needed to establish an evidence-based therapeutic treatment algorithm in SSC-CIP. A positive trial result could change the current standard of care for patients with SSC-CIP. The results of this study will be disseminated through presentations at international congresses, workshops, and peer-reviewed publications. TRIAL REGISTRATION: The trial was registered at ClinicalTrials.gov (NCT05396755, date of registration: May 31, 2022, last update: May 31, 2022).

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial.

BACKGROUND: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the randomized, double-blinded DIGIT-HF trial. METHODS AND RESULTS: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age ≥ 75 years, eGFR < 50 ml/min/1.73 m2, and BMI < 27 kg/m2 each were assigned one point for the digitoxin dosing score. A score of ≥ 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. CONCLUSION: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m2, BMI < 27 kg/m2, or age ≥ 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

CANNA-TICS: Efficacy and safety of oral treatment with nabiximols in adults with chronic tic disorders - Results of a prospective, multicenter, randomized, double-blind, placebo controlled, phase IIIb superiority study.

Preliminary data suggest that cannabis-based medicines might be a promising new treatment for patients with Tourette syndrome (TS)/chronic tic disorders (CTD) resulting in an improvement of tics, comorbidities, and quality of life. This randomized, multicenter, placebo-controlled, phase IIIb study aimed to examine efficacy and safety of the cannabis extract nabiximols in adults with TS/CTD (n = 97, randomized 2:1 to nabiximols:placebo). The primary efficacy endpoint was defined as a tic reduction of ≥ 25% according to the Total Tic Score of the Yale Global Tic Severity Scale after 13 weeks of treatment. Although a much larger number of patients in the nabiximols compared to the placebo group (14/64 (21·9%) vs. 3/33 (9·1%)) met the responder criterion, superiority of nabiximols could formally not be demonstrated. In secondary analyses, substantial trends for improvements of tics, depression, and quality of life were observed. Additionally exploratory subgroup analyses revealed an improvement of tics in particular in males, patients with more severe tics, and patients with comorbid attention deficit/hyperactivity disorder suggesting that these subgroups may benefit better from treatment with cannabis-based medication. There were no relevant safety issues. Our data further support the role of cannabinoids in the treatment of patients with chronic tic disorders.

MUC-FIRE: Study protocol for a randomized multicenter open-label controlled trial to show that MUCous FIstula REfeeding reduces the time from enterostomy closure to full enteral feeds.

Background: After enterostomy creation, the distal bowel to the ostomy is excluded from the physiologic passage of stool, nutrient uptake, and growth of this intestinal section. Those infants frequently require long-term parenteral nutrition, continued after enterostomy reversal due to the notable diameter discrepancy of the proximal and distal bowel. Previous studies have shown that mucous fistula refeeding (MFR) results in faster weight gain in infants. The aim of the randomized multicenter open-label controlled MUCous FIstula REfeeding ("MUC-FIRE") trial is to demonstrate that MFR between enterostomy creation and reversal reduces the time to full enteral feeds after enterostomy closure compared to controls, resulting in shorter hospital stay and less adverse effects of parenteral nutrition. Methods/Design: A total of 120 infants will be included in the MUC-FIRE trial. Following enterostomy creation, infants will be randomized to either an intervention or a non-intervention group.In the intervention group, perioperative MFR between enterostomy creation and reversal will be performed. The control group receives standard care without MFR.The primary efficacy endpoint of the study is the time to full enteral feeds. Secondary endpoints include first postoperative bowel movement after stoma reversal, postoperative weight gain, and days of postoperative parenteral nutrition. In addition adverse events will be analyzed. Discussion: The MUC-FIRE trial will be the first prospective randomized trial to investigate the benefits and disadvantages of MFR in infants. The results of the trial are expected to provide an evidence-based foundation for guidelines in pediatric surgical centers worldwide. Trial registration: The trial has been registered at clinicaltrials.gov (number: NCT03469609, date of registration: March 19, 2018; last update: January 20, 2023, https://clinicaltrials.gov/ct2/show/NCT03469609?term=NCT03469609&draw=2&rank=1).

Implications for blinding in clinical trials with THC-containing cannabinoids based on the CANNA-TICS trial.

Randomized double-blind placebo-controlled trials (RCTs) are regarded as the gold standard for clinical trials. While there are established standards to avoid unblinding, in RCTs using tetrahydrocannabinol (THC) containing cannabinoids, however, accidental unblinding and intentional self-unbinding must be considered as a particular issue, since THC tests are widely available. To investigate unblinding rates in an RCT using a THC-containing cannabinoid, we re-contacted 54 out of 97 participants of the CANNA-TICS trial who had participated in our study center in Hannover. Of the 54 participants, 53 could be reached. Of these, one participant (2%) stated that she had unblinded herself intentionally during the treatment phase, and another three patients (6%) reported intentional unblinding after the end of the treatment. Noteworthy, two patients provided discrepant information and denied self-unblinding during the interview, although during study/clinic visits they had reported having done so. Thus, based on all available information, three participants (6%) unblinded themselves intentionally during the treatment phase and another three (6%) after the end of the treatment. Accidental unblinding during the treatment phase was reported by 4/54 participants (7%) (during study visits). Since one participant reported both intentional self-unblinding (during the interview) and accidental unblinding (during a study visit), the total unblinding rate was 17% (n = 9). Of these, seven participants (13%) reported unblinding during the treatment phase. When asked in the interview whether they knew that self-unblinding would have been possible, only 34% (n = 18/53) of participants stated that they had been aware of this possibility. Thus, altogether 33% (n = 6/18) of those being informed about the possibility of self-unblinding did so and half of them (3/18, 17 %) during the treatment phase. It can be expected that in parallel to increasing knowledge of medicinal and recreational use of cannabinoids, more and more people will also be informed about the availability of THC tests. Hence, in future RCTs using THC-containing cannabinoids, researchers have to take the possibility of accidental and intentional unblinding into consideration, when designing the study.

Heterozygous BRCA1 and BRCA2 and Mismatch Repair Gene Pathogenic Variants in Children and Adolescents With Cancer.

BACKGROUND: Genetic predisposition is has been identified as a cause of cancer, yet little is known about the role of adult cancer predisposition syndromes in childhood cancer. We examined the extent to which heterozygous pathogenic germline variants in BRCA1, BRCA2, PALB2, ATM, CHEK2, MSH2, MSH6, MLH1, and PMS2 contribute to cancer risk in children and adolescents. METHODS: We conducted a meta-analysis of 11 studies that incorporated comprehensive germline testing for children and adolescents with cancer. ClinVar pathogenic or likely pathogenic variants (PVs) in genes of interest were compared with 2 control groups. Results were validated in a cohort of mainly European patients and controls. We employed the Proxy External Controls Association Test to account for different pipelines. RESULTS: Among 3975 children and adolescents with cancer, statistically significant associations with cancer risk were observed for PVs in BRCA1 and 2 (26 PVs vs 63 PVs among 27 501 controls, odds ratio = 2.78, 95% confidence interval = 1.69 to 4.45; P < .001) and mismatch repair genes (19 PVs vs 14 PVs among 27 501 controls, odds ratio = 7.33, 95% confidence interval = 3.64 to 14.82; P <.001). Associations were seen in brain and other solid tumors but not in hematologic neoplasms. We confirmed similar findings in 1664 pediatric cancer patients primarily of European descent. CONCLUSION: These data suggest that heterozygous PVs in BRCA1 and 2 and mismatch repair genes contribute with reduced penetrance to cancer risk in children and adolescents. No changes to predictive genetic testing and surveillance recommendations are required.

Effectiveness of Trainings of General Practitioners on Antibiotic Stewardship: Methods of a Pragmatic Quasi-Experimental Study in a Controlled Before-After Design in South-East-Lower Saxony, Germany (WASA).

Introduction: Antibiotic resistance is a serious threat to global public health. It reduces the effectiveness of treatments for serious bacterial infections and thus increases the risk of fatal outcomes. Antibiotic prescriptions are often not in line with clinical evidence-based guidelines. The process of emergence of resistant bacteria can be slowed down by adherence to guidelines. Yet this adherence seems to be lacking in primary health care. Methods and Analysis: This pragmatic quasi-experimental study using a controlled before-after design was carried out in South-East-Lower Saxony in 2018-2020. The voluntary attendance of interactive trainings with condensed presentation of current guidelines for general practitioners (GP) on antibiotic management for urinary and respiratory tract infections is regarded as intervention. Those GP not attending the trainings constitute the control group. Data were collected via questionnaires; routine health records are provided by a statutory health insurance. The primary outcome is the proportion of (guideline-based) prescriptions in relation to the relevant ICD-10 codes as well as daily defined doses and the difference in proportion of certain prescriptions according to guidelines before and after the intervention as compared to the control group. Further outcomes are among others the subjectively perceived risk of antibiotic resistance and the attitude toward the guidelines. The questionnaires to assess this are based on theory of planned behavior (TPB) and health action process approach (HAPA). Variations over time and effects caused by measures other than WASA (Wirksamkeit von Antibiotika-Schulungen in der niedergelassenen Aerzteschaft-Effectiveness of antibiotic management training in the primary health care sector) training are taken into account by including the control group and applying interrupted time series analysis. Ethics and Dissemination: The study protocol and the data protection concept respectively were reviewed and approved by the Ethics Committee of the Hannover Medical School and the Federal Commissioner for Data Protection and Freedom of Information. Trial Registration: https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00013951, identifier DRKS00013951.

Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial.

BACKGROUND: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. METHODS: In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. RESULTS: In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. CONCLUSIONS: Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912.

COVID-19 hits a trial: Arguments against hastily deviating from the plan.

The COVID-19 pandemic has substantially impacted the conduct of clinical trials. While initially preparing for a period of time, where it would likely be impossible to supervise trials in the usual way and precautionary measures had to be implemented to care for medication supply and general safety of study participants it is now important to consider, how the impact of the pandemic on trial outcome can be assessed, which measures are needed to decide, how to proceed with the trial and what is needed to compensate to irregularity introduced by the pandemic situation. Obviously not all trials will suffer to the same degree: some trials may be close to finalizing recruitment, others may not yet have started. Similarly not all clinical trials investigate vulnerable patient populations, but some will and may in addition have recruited to an extent that beneficial effects achieved in the initial phase of the trial may be outweighed by an increase e.g. in mortality that impacts both treatment groups. The situation is further complicated by the fact that the pandemic reached different countries in the world and even cities in one country at different points in time with different severity. Our example is a randomized and double-blind clinical trial comparing digitoxin and placebo in patients with advanced chronic heart failure. This trial has recruited roughly 1/3 of the overall 2200 patients when the disease outbreak reached Germany. We discuss how simulations and theoretical considerations can be used to address questions about the need to increase the overall sample-size to be recruited to compensate for a potential shrinkage of the treatment effect caused by the COVID-19 pandemic and what role the degree of consistency could play when comparing pre-, during- and post- COVID-19 periods of trial conduct regarding the question, whether the treatment effect can be considered consistent and with this generalizable. This is dependent on the size of the treatment effect and the impact of the pandemic. We argue, that in case of doubt, it may be wise to proceed with the original study plan.

The PNPLA3 rs738409 GG genotype is associated with poorer prognosis in 239 patients with autoimmune hepatitis.

BACKGROUND: Fibrosis progression in autoimmune hepatitis can be attenuated by immunosuppressive treatment; however, some patients progress despite therapy. Single nucleotide polymorphisms (SNPs) such as PNPLA3-rs738409, TM6SF2-rs58542926 and MBOAT7-rs641738 are associated with non-alcoholic fatty liver disease and fibrosis progression, whereas a splice variant in HSD17B13-rs72613567:TA has been shown to be protective. AIM: To analyse the impact of different SNPs on the long-term outcome of patients with autoimmune hepatitis. METHODS: We included 239 patients into this study who had been treated between 1983 and 2018 for autoimmune hepatitis. Genomic DNA was isolated from whole blood and SNPs were determined by PCR analysis. Liver biopsies were available for 215/239 patients (90%). Clinical and laboratory patient data were assessed by chart review. RESULTS: Mean age at baseline was 42.1 years with 74.1% being female. The median follow-up was 9.4 years (IQR 3.5-15.0), 11.7% of the patients (n = 28) died or required liver transplantation. In the Kaplan-Meier analysis of the combined endpoint time to liver transplantation or death, we observed that patients with the PNPLA3-rs738409 GG variant met more frequently the primary endpoint (P = 0.005). In Cox regression analysis PNPLA3-rs738409 GG as well as liver cirrhosis were identified as strong predictors for time to liver transplantation or death (HR 4.5 [CI 1.48-13.72], P = 0.008 and HR 9.24 [CI 2.11-40.44], P = 0.003, respectively). Neither steatosis, diabetes mellitus nor obesity were associated with outcome. CONCLUSIONS: PNPLA3-rs738409 variant GG is a predictor for time to liver transplantation or death and may help to identify autoimmune hepatitis patients at risk for disease progression.

Ultrafine particles and ozone perturb norepinephrine clearance rather than centrally generated sympathetic activity in humans.

Cardiovascular risk rapidly increased following exposure to air pollution. Changes in human autonomic regulation have been implicated based on epidemiological associations between exposure estimates and indirect autonomic nervous system measurements. We conducted a mechanistic study to test the hypothesis that, in healthy older individuals, well-defined experimental exposure to ultrafine carbon particles (UFP) increases sympathetic nervous system activity and more so with added ozone (O3). Eighteen participants (age >50 years, 6 women) were exposed to filtered air (Air), UFP, and UFP + O3 combination for 3 hours during intermittent bicycle ergometer training in a randomized, crossover, double-blind fashion. Two hours following exposure, respiration, electrocardiogram, blood pressure, and muscle sympathetic nerve activity (MSNA) were recorded at supine rest, during deep breathing, and during a Valsalva manoeuvre. Catechols and inflammatory marker levels were measured in venous blood samples. Induced sputum was obtained 3.5 h after exposure. Combined exposure to UFP + O3 but not UFP alone, caused a significant increase in sputum neutrophils and circulating leucocytes. Norepinephrine was modestly increased while the ratio between plasma dihydroxyphenylglycol (DHPG) and norepinephrine levels, a marker for norepinephrine clearance, was reduced with UFP + O3. Resting MSNA was not different (47 ± 12 with Air, 47 ± 14 with UFP, and 45 ± 14 bursts/min with UFP + O3). Indices of parasympathetic heart rate control were unaffected by experimental air pollution. Our study suggests that combined exposure to modest UFP and O3 levels increases peripheral norepinephrine availability through decreased clearance rather than changes in central autonomic activity. Pulmonary inflammatory response may have perturbed pulmonary endothelial norepinephrine clearance.

Cholemic Nephropathy Causes Acute Kidney Injury and Is Accompanied by Loss of Aquaporin 2 in Collecting Ducts.

Impairment of renal function often occurs in patients with liver disease. Hepatorenal syndrome is a significant cause of acute kidney injury (AKI) in patients with cirrhosis (HRS-AKI, type 1). Causes of non-HRS-AKI include cholemic nephropathy (CN), a disease that is characterized by intratubular bile casts and tubular injury. As data on patients with CN are obtained primarily from case reports or autopsy studies, we aimed to investigate the frequency and clinical course of CN. We identified 149 patients who underwent kidney biopsy between 2000 and 2016 at the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School. Of these, 79 had a history of liver disease and deterioration of renal function. When applying recent European Association for the Study of the Liver criteria, 45 of 79 patients (57%) presented with AKI, whereas 34 patients (43%) had chronic kidney disease (CKD). Renal biopsy revealed the diagnosis of CN in 8 of 45 patients with AKI (17.8%), whereas none of the patients with CKD was diagnosed with CN. Univariate analysis identified serum bilirubin, alkaline phosphatase, and urinary bilirubin and urobilinogen as predictive factors for the diagnosis of CN. Histological analysis of AKI patients with normal bilirubin, elevated bilirubin, and the diagnosis of CN revealed loss of aquaporin 2 (AQP2) expression in collecting ducts in patients with elevated bilirubin and CN. Biopsy-related complications requiring medical intervention occurred in 4 of 79 patients (5.1%). Conclusion: CN is a common finding in patients with liver disease, AKI, and highly elevated bilirubin. Loss of AQP2 in AKI patients with elevated bilirubin and CN might be the result of toxic effects of cholestasis and in part be responsible for the impairment of renal function.

Manual therapy applied by general practitioners for nonspecific low back pain: results of the ManRück pilot-study.

Background: Nonspecific acute low back pain (LBP) is a common reason for accessing primary care. German guidelines recommend non-steroidal anti-inflammatory drugs and physical activity as evidence-based treatments. Manual Therapy (MT) remains controversial. To increase evidence-based treatment options for general practitioners (GPs), a Pilot-Study was set up to gather information about the required conditions and setting for an RCT. Methods: The open pilot-study assesses recruitment methods for GPs and patients, timelines, data collection and outcomes of treatment immediately (T0) and 1, 6 and 12 weeks after consultation (T1, T2, T3). Inclusion criteria for GPs were: no experience of MT; for patients: adults between 18 and 50 suffering from LBP for less than 14 days.Study process: Patients' control-group (CG) was consecutively recruited first and received standard care. After GPs received a single training session in MT lasting two and a half hours, they consecutively recruited patients with LBP to the intervention group (IG). These patients received add-on MT.Primary outcomes: (A): timelines and recruitment success, (B): assessment tools and sample size evaluation, (C) clinical findings: pain intensity change from baseline to day 3 and time till (a) analgesic use stopped and (b) 2-point pain reduction on an 11-point scale occurred.Secondary outcomes: functional capacity, referral rate, use of other therapies, sick leave, patient satisfaction. Results: 14 GPs participated, recruiting 42 patients for the CG and 45 for the IG; 49% (56%) of patients were women. Average baseline pain was 5.98 points, SD: ±2.3 (5.98, SD ±1.8).For an RCT an extended timeline and enhanced recruitment procedures are required. The assessment tools seem appropriate and provided relevant findings: additional MT led to faster pain reduction. IG showed reduced analgesic use and reduced pain at T1 and improved functional capacity by T2. Conclusions: Before verifying the encouraging findings that additional MT may lead to faster pain reduction and reduced analgesic use via an RCT, the setting, patients' structure, and inclusion criteria should be considered more closely. Trial registration: Number: DRKS00003240 Registry: German Clinical Trials Registry (DRKS) URL: https://www.drks.de/drks_web/. Registration date: 14.11.2011. First patient: March 2012. Funding: the Rut and Klaus Bahlsen Stiftung, Hannover.

Short-Term Effects of a Multimodal 3-Week Inpatient Pulmonary Rehabilitation Programme for Patients with Sarcoidosis: The ProKaSaRe Study.

BACKGROUND: Real-world data on the effects of a multicomponent pulmonary rehabilitation (PR) for patients with sarcoidosis are scarce. OBJECTIVE: To describe characteristics of patients with sarcoidosis referred for a 3-week inpatient PR, to assess the effects of PR on their quality of life (QoL) and clinical outcomes, and to investigate whether there are specific subgroups who particularly benefit from PR. METHODS: Using a prospective multicentre study design, data regarding 6-min walking distance (6MWD), QoL (Saint George's Respiratory Questionnaire, SGRQ), and the secondary outcomes of dyspnoea and psychological burden (fatigue, anxiety, and depression) were collected. RESULTS: We included 296 patients in the study (average age 49.1 ± 9.7 years, 47% female, average vital capacity 3.5 ± 1.0 L [87.0 ± 20.6 predicted]). The 6MWD improved by the end of the rehabilitation by 39.8 m on average (p < 0.0001; standardised response mean, SRM = 0.61), SGRQ showed significant improvements in all 3 domains, and the total score (p < 0.001) improved by 5.69-8.28 points (SRM 0.46-0.62). For the secondary outcomes, significant improvement (p < 0.001) was seen for all measured parameters, e.g., dyspnoea (modified Medical Research Council Scale, mMRC), fatigue (Fatigue Assessment Scale [FAS]; SRM = -0.71), anxiety and depression (Hospital Anxiety and Depression Scale [HADS]; SRM -0.58/-0.38), and generic QoL (measured by the SF-36 scales of physical and mental health; SRM 0.31/0.55). CONCLUSIONS: Our results provide the first documented evidence that PR is a promising complementary therapy option for sarcoidosis patients who remain subjectively symptomatic despite optimised outpatient medical treatment.