Study Protocol of a Randomized, Two-Arm, Phase I/II Trial Investigating the Feasibility, Safety, and Efficacy of Local Treatment with US-Guided High-Intensity Focused Ultrasound in Combination with Palliative Chemotherapy in Inoperable Pancreatic Cancer.

BACKGROUND: Pancreatic adenocarcinoma (PaC) still has a dismal prognosis, and despite medical advances, a bleak 5-year survival rate of only 8%, largely due to late diagnosis and limited curative surgical options for most patients. Frontline palliative treatment shows some survival advantages. However, the high disease mortality is accompanied by high morbidity including cancer-related pain and additional symptoms, which strongly impair patients' quality of life (QOL). At present, there is no established strategy for local therapy for PaC primarily aiming to manage local tumor growth and alleviate associated symptoms, particularly pain. In recent years, non-invasive high-intensity focused ultrasound (HIFU) has shown promising results in reducing cancer pain and tumor mass, improving patients' QOL with few side effects. STUDY DESIGN: This is the first randomized controlled trial worldwide including 40 patients with inoperable pancreatic adenocarcinoma randomized into two groups: group A undergoing standard chemotherapy; and group B undergoing standard chemotherapy plus local HIFU treatment. This study aims to establish a robust evidence base by examining the feasibility, safety, and efficacy of US-guided HIFU in combination with standard palliative systemic therapy for unresectable PaC. Primary endpoint assessments will focus on parameters including safety issues (phase I), and local response rates (phase II).

Prevention of cerebral thromboembolism by oral anticoagulation with dabigatran after pulmonary vein isolation for atrial fibrillation: the ODIn-AF trial.

BACKGROUND AND OBJECTIVES: Long-term oral anticoagulation (OAC) following successful catheter ablation of atrial fibrillation (AF) remains controversial. Prospective data are missing. The ODIn-AF study aimed to evaluate the effect of OAC on the incidence of silent cerebral embolic events and clinically relevant cardioembolic events in patients at intermediate to high risk for embolic events, free from AF after pulmonary vein isolation (PVI). METHODS: This prospective, randomized, multicenter, open-label, blinded endpoint interventional trial enrolled patients who were scheduled for PVI to treat paroxysmal or persistent AF. Six months after PVI, AF-free patients were randomized to receive either continued OAC with dabigatran or no OAC. The primary endpoint was the incidence of new silent micro- and macro-embolic lesions detected on brain MRI at 12 months of follow-up compared to baseline. Safety analysis included bleedings, clinically evident cardioembolic, and serious adverse events (SAE). RESULTS: Between 2015 and 2021, 200 patients were randomized into 2 study arms (on OAC: n = 99, off OAC: n = 101). There was no significant difference in the occurrence of new cerebral microlesions between the on OAC and off OAC arm [2 (2%) versus 0 (0%); P = 0.1517] after 12 months. MRI showed no new macro-embolic lesion, no clinical apparent strokes were present in both groups. SAE were more frequent in the OAC arm [on OAC n = 34 (31.8%), off OAC n = 18 (19.4%); P = 0.0460]; bleedings did not differ. CONCLUSION: Discontinuation of OAC after successful PVI was not found to be associated with an elevated risk of cerebral embolic events compared with continued OAC after a follow-up of 12 months.

Study Protocol of a Prospective, Monocentric, Single-Arm Study Investigating the Safety and Efficacy of Local Ablation of Symptomatic Uterine Fibroids with US-Guided High-Intensity Focused Ultrasound (HIFU).

Uterine fibroids are the most common benign tumors of the uterus. Approximately 20-50% of women with myomas experience a variety of symptoms such as vaginal bleeding, abdominal pain, pelvic pain and pressure, and urological problems, possibly interfering with fertility and pregnancy. Although surgery remains the standard treatment option for fibroids, non-invasive therapeutic options, such as high-intensity focused ultrasound (HIFU), have emerged over the last dec ade. During HIFU, ultrasound is focused on the target tissue causing coagulation necrosis. HIFU has, meanwhile, become an established method for treating uterine fibroids in many countries. Clinical data have shown that it effectively alleviates fibroid-related symptoms and reduces fibroid size with a very low rate of side effects. However, there is a lack of data on how this treatment affects laboratory parameters and structural features of uterine tissue. As our center is the only one in German-speaking countries where ultrasound-guided HIFU technology is currently established, the aim of this prospective, monocentric, single-arm trial is not only to evaluate the safety and efficacy of local US-guided HIFU in symptomatic uterine fibroid patients according to GCP standards but also to explore its effects on blood parameters and the structural integrity of uterine tissue using elastographic methods.

Dose Recommendations for Common Drugs in Patients with Liver Cirrhosis: A Systematic Literature Review.

BACKGROUND AND OBJECTIVES: The presence of liver cirrhosis affects the selection and dosing of drugs metabolised by the liver as doses have to be adjusted to the remaining liver function. This is a major challenge in clinical practice as specific guidelines are lacking. The aim of this study was to identify drugs for which recommendations on selection and dose adjustments for patients with cirrhosis exist by assessing the literature according to certain quality standards, paying particular attention to the suitability of these recommendations for clinical practice. METHODS: A systematic literature review included peer-reviewed publications that were published by October 2020 in PubMed in the English language and aimed to generate recommendations on dose adjustment in patients with liver cirrhosis. Subsequently, the identified publications were checked for reporting quality against the relevant reporting guidelines and the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Finally, all specific dose recommendations were extracted, compared with the specifications of the Summaries of Product Characteristics and mapped according to the Anatomical Therapeutic Chemical/Defined Daily Dose Index. RESULTS: Eighteen publications covering a total of 1145 dose recommendations for 481 active substances were identified. There were 706 recommendations for 316 substances sufficiently specific for application in clinical practice. For 22 active substances, the specific recommendations were consistent across multiple publications, of which only six were also consistent with the respective Summaries of Product Characteristics. CONCLUSIONS: As the majority of dose recommendations were not sufficiently specific or even contradictory, there is an urgent need for the definition of standard parameters for a uniform assessment of drugs in liver cirrhosis. In addition, dose recommendations should be aligned by suitable methods.

Levels of Alzheimer's disease blood biomarkers are altered after food intake-A pilot intervention study in healthy adults.

INTRODUCTION: Blood biomarkers accurately identify Alzheimer's disease (AD) pathophysiology and axonal injury. We investigated the influence of food intake on AD-related biomarkers in cognitively healthy, obese adults at high metabolic risk. METHODS: One-hundred eleven participants underwent repeated blood sampling during 3 h after a standardized meal (postprandial group, PG). For comparison, blood was sampled from a fasting subgroup over 3 h (fasting group, FG). Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), amyloid-beta (Aß) 42/40, phosphorylated tau (p-tau) 181 and 231, and total-tau were measured via single molecule array assays. RESULTS: Significant differences were found for NfL, GFAP, Aß42/40, p-tau181, and p-tau231 between FG and PG. The greatest change to baseline occurred for GFAP and p-tau181 (120 min postprandially, p < 0.0001). CONCLUSION: Our data suggest that AD-related biomarkers are altered by food intake. Further studies are needed to verify whether blood biomarker sampling should be performed in the fasting state. HIGHLIGHTS: Acute food intake alters plasma biomarkers of Alzheimer's disease in obese, otherwise healthy adults. We also found dynamic fluctuations in plasma biomarkers concentration in the fasting state suggesting physiological diurnal variations. Further investigations are highly needed to verify if biomarker measurements should be performed in the fasting state and at a standardized time of day to improve the diagnostic accuracy.

Vericiguat: A Randomized, Phase Ib, Placebo-Controlled, Double-Blind, QTc Interval Study in Patients with Chronic Coronary Syndromes.

BACKGROUND: Vericiguat is indicated for the treatment of symptomatic chronic heart failure in adult patients with reduced ejection fraction who are stabilized after a recent decompensation event. OBJECTIVE: To investigate the effects of vericiguat on QT interval in patients with chronic coronary syndromes (CCS). METHODS: This was a randomized, phase Ib, placebo-controlled, double-blind, double-dummy, multicenter study. Vericiguat once daily was up-titrated from 2.5 mg to 5 mg and then to 10 mg (treatments A, B, and C) at 14-day intervals. Positive control was moxifloxacin 400 mg (single dose on day 8 or day 50; placebo on other days [treatment D]). We evaluated the placebo-adjusted change from baseline of the Frederica-corrected QTc interval (QTcF), pharmacokinetics, safety, and tolerability of vericiguat. RESULTS: In total, 74 patients with CCS, with mean (standard deviation) age 63.4 (8.0) years, were included and 72 patients completed the study. At each timepoint up to 7 h after administration, mean placebo-corrected change in QTcF from baseline was < 6 ms and the upper limit of the two-sided 90% confidence interval of the mean was below the 10-ms threshold for clinical relevance. Moxifloxacin confirmed the assay sensitivity. Median time of maximum concentration of vericiguat was 4.5 h post-dose. The adverse event profile of vericiguat was consistent with its mechanism of action, and the findings did not indicate any safety concerns. CONCLUSIONS: As part of an integrative risk assessment, this study demonstrated no clinically relevant corrected QT prolongation with vericiguat 10 mg once daily at steady state. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03504982.

Vericiguat is approved for treating worsening heart failure with reduced ejection fraction. As part of the safety evaluation of vericiguat, this study assessed its effect on the QT interval of the electrocardiogram. An electrocardiogram measures electrical activity of the heart. The QT interval is the time from the start of the Q wave to the end of the T wave. A longer than normal QT interval indicates an increased chance for abnormal heart rhythms. Usually, a QT study is conducted at high doses in healthy volunteers. Previous studies indicated that high doses of vericiguat may cause increased changes in blood pressure in healthy volunteers. Therefore, this study was performed in patients at a normal therapeutic dose. Patients with chronic coronary syndromes were enrolled rather than patients with heart failure with reduced ejection fraction, because they have fewer electrocardiogram abnormalities. The starting dose of vericiguat was 2.5 mg once daily, and the dose was increased to 5 mg and then to 10 mg at 14-day intervals. Placebo was tested for comparison and moxifloxacin (400 mg), a drug known to increase the QT interval, was tested to confirm that the study could detect a change in the QT interval. An increase in the QT interval of more than 10 ms was considered clinically relevant. Of 74 patients included, 72 completed the study. At each timepoint (up to 7 h after dosing), the difference between the QT change for vericiguat and placebo was less than 10 ms; therefore, vericiguat does not prolong the QT interval to a clinically relevant extent.

[General practitioners' perception of integrated care using communication technologies: a secondary analysis of a focus group of the Horizon 2020 funded project POLYCARE]. / Einschätzung deutscher Hausärztinnen und Hausärzte zur integrierten Versorgung mittels Kommunikationstechnologien : Sekundäranalyse einer Fokusgruppe des Horizont-2020-geförderten Projektes POLYCARE.

BACKGROUND: Integrated healthcare models (IC) have the objective of reducing the costs of an increased use of health service as well as the strong sectoral fragmentation of the German health care system. However, no national approach has been implemented in primary care to date. METHOD: Ten GPs from the Cologne/Bonn district (60% male; Ø age = 52 years [35-65]) were invited to a focus group in 2016. The interview was part of the Horizon 2020 funded POLYCARE study. A semi-structured guideline was used to assess feasibility of the POLYCARE study protocol. GPs also provided information about previous experience with and attitudes toward IC models and the relevant information and communication technologies (ICT), such as home-monitoring or communication software. This information was analyzed using a transcending secondary analysis to evaluate conditions for their successful implementation. RESULTS: Participants reported little experience with IC and ICT. However, they reported being open to both and seeing potential for time savings, better networking opportunities, and increased quality of care for their patients. The integration of social services was considered as a chance of alleviating the burden of socio-medical tasks. Barriers to the introduction of IC and ICT were seen in the initial time investment, the lack of legal structures, the concern about overabundant data, and the susceptibility to failure. CONCLUSION: The nationwide expansion of social services as well as ICT that is easy to use, less susceptible to failure, and compatible with existing structures show great potential for relieving GPs. Future research should address the concerns - such as financial and time expenses of introducing IC and ICT - of GPs by systematic investigation in long-term studies. The provision of an additional legal basis that is regulating the respective remuneration models as well as the rights and obligations of all parties, IC and ICT can play a greater role in future patient care.

Influence on study outcomes of an inpatient study by the behavior of the study staff (PINgPOng): study protocol for a randomized clinical trial.

BACKGROUND: The placebo effect as the symptom improvement following inert treatments is a fixed component of RCTs to differentiate between specific effects of the tested pharmacological substance from other unspecific effects. The PINgPOng study was set up to analyze the influence of a study team trained to either minimize the placebo response and optimize drug-placebo differences or to maximize the placebo response to increase drug efficacy by unspecific factors on the study results of a RCT in a classical early clinical trial setting. METHODS/DESIGN: PINgPOng is a single-center, prospective, randomized, double-blind, placebo-controlled study in a 3-group, 2-sequence, 2-period cross-over design. The study is conducted according to the principles of ICH-GCP and the Declaration of Helsinki on the Phase I-Unit of the University Hospital Bonn. The primary endpoint is the pain intensity in the cold pressor test before and after the administration of 15 mg oxycodone or placebo. The pain intensity is compared between three study conditions: 32 healthy volunteers in each study arm will be treated either by an untrained study team (arm A), by a study team trained to maximize (arm B), or to minimize placebo responses (arm C). Neuroendocrine factors (alpha-amylase activity, salivary cortisol), characteristic traits (anxiety, depression, stress), and somatic reactions are analyzed as covariates of the pain perception. DISCUSSION: The PINgPOng study will allow to answer the question whether and to what extent the behavior of a trained study team (neutral vs. maximize vs. minimize placebo responses) will differentially affect placebo responses in a setting of a highly standardized early clinical trial. The results will help to control the placebo effects by education of the clinical study team and to avoid unnecessary high placebo effects in clinical development. TRIAL REGISTRATION: German Clinical Trials Register DRKS00013586 . Registered on December 22, 2017.

Dynamics, outcomes and prerequisites of the first SARS-CoV-2 superspreading event in Germany in February 2020: a cross-sectional epidemiological study.

OBJECTIVES: The first German SARS-CoV-2 outbreak was a superspreading event in Gangelt, North Rhine-Westphalia, during indoor carnival festivities called 'Kappensitzung' (15 February 2020). We determined SARS-CoV-2 RT-PCR positivity rate, SARS-CoV-2-specific antibodies, and analysed the conditions and dynamics of superspreading, including ventilation, setting dimensions, distance from infected persons and behavioural patterns. DESIGN: In a cross-sectional epidemiological study (51 days postevent), participants were asked to give blood, pharyngeal swabs and complete self-administered questionnaires. SETTING: The SARS-CoV-2 superspreading event took place during festivities in the small community of Gangelt in February 2020. This 5-hour event included 450 people (6-79 years of age) in a building of 27 m × 13.20 m × 4.20 m. PARTICIPANTS: Out of 450 event participants, 411 volunteered to participate in this study. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: infection status (determined by IgG ELISA). SECONDARY OUTCOME: symptoms (determined by questionnaire). RESULTS: Overall, 46% (n=186/404) of participants had been infected, and their spatial distribution was associated with proximity to the ventilation system (OR 1.39, 95% CI 0.86 to 2.25). Risk of infection was highly associated with age: children (OR 0.33, 95% CI 0.267 to 0.414) and young adults (age 18-25 years) had a lower risk of infection than older participants (average risk increase of 28% per 10 years). Behavioural differences were also risk associated including time spent outside (OR 0.55, (95% CI 0.33 to 0.91) or smoking (OR 0.32, 95% CI 0.124 to 0.81). CONCLUSIONS: Our findings underline the importance of proper indoor ventilation for future events. Lower susceptibility of children/young adults indicates their limited involvement in superspreading.

Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1.

Introduction: Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate, leading to kidney stones, nephrocalcinosis, kidney failure, and systemic oxalosis. In the 6-month double-blind period (DBP) of ILLUMINATE-A, a phase 3, randomized, placebo-controlled trial in patients with PH1 ≥6 years old, treatment with lumasiran, an RNA interference therapeutic, led to substantial reductions in urinary oxalate (UOx) levels. Methods: We report data to month 12 in the extension period (EP) of ILLUMINATE-A, including patients who continued lumasiran (lumasiran/lumasiran) or crossed over from placebo to lumasiran (placebo/lumasiran). Results: In the lumasiran/lumasiran group (n = 24), the reduction in 24-hour UOx level was sustained to month 12 (mean reduction from baseline, 66.9% at month 6; 64.1% at month 12). The placebo/lumasiran group (n = 13) had a similar time course and magnitude of 24-hour UOx reduction (mean reduction, 57.3%) after 6 months of lumasiran. Kidney stone event rates seemed to be lower after 6 months of lumasiran in both groups compared with the 12 months before consent, and this reduction was maintained at month 12 in the lumasiran/lumasiran group. At study start, 71% of patients in the lumasiran/lumasiran group and 92% in the placebo/lumasiran group had nephrocalcinosis. Nephrocalcinosis grade improved after 6 months of lumasiran in the lumasiran/lumasiran and placebo/lumasiran groups (13% and 8% of patients, respectively). After an additional 6 months of lumasiran, 46% of patients had improvement in nephrocalcinosis grade within the lumasiran/lumasiran group. Estimated glomerular filtration rate (eGFR) remained stable during the course of lumasiran treatment. The most common adverse events (AEs) related to lumasiran were mild, transient injection-site reactions (ISRs). Conclusion: Long-term lumasiran treatment enabled sustained lowering of UOx levels with acceptable safety and encouraging results on clinical outcomes.

Influence of a proinflammatory state on postprandial outcomes in elderly subjects with a risk phenotype for cardiometabolic diseases.

PURPOSE: Low-grade inflammation in obesity is associated with insulin resistance and other metabolic disturbances. In response to high-energy meal intake, blood concentrations of inflammatory markers, glucose and insulin rise. The aim of this study was to examine whether a basal inflammatory state influences postprandial responses. METHODS: A randomized crossover trial was performed in 60 participants with a cardiometabolic risk phenotype (age 70 ± 5 years; BMI 30.9 ± 3.1 kg/m2). Each participant consumed three different iso-energetic meals (4300 kJ): a Western diet-like high-fat meal (WDHF), a Western diet-like high-carbohydrate meal (WDHC) and a Mediterranean diet-like meal (MED). Blood samples were collected when fasted and hourly for 5 h postprandially and analyzed for glucose, insulin, interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and endothelial adhesion molecules. Based on fasting serum C-reactive protein (CRP) concentrations, participants were assigned to a high inflammation (CRP ≥ 2.0 mg/L; n = 30) or low inflammation (CRP < 2.0 mg/L; n = 30) group, and postprandial outcomes were compared. RESULTS: Plasma IL-6, glucose and serum insulin increased after all meals, while IL-1ß and endothelial adhesion molecules were unchanged. The high inflammation group had higher fasting and postprandial IL-6 concentrations than the low inflammation group, although the IL-6 response slope was similar between groups. In response to the WDHC meal, participants in the high inflammation group experienced a higher glycaemic response than those in the low inflammation group. CONCLUSION: A basal proinflammatory state results in higher absolute fasting and postprandial IL-6 concentrations, but the increase in IL-6 relative to basal levels is not different between high and low inflammation groups. Elevated glycaemic response in the high inflammation group may be due to inflammation-induced short-term insulin resistance. The trial was registered at http://www.germanctr.de and http://www.drks.de under identifier DRKS00009861 (registration date, January 22, 2016).

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria.

Primary hyperoxaluria (PH) is a family of ultra-rare autosomal recessive inherited disorders of hepatic glyoxylate metabolism characterized by oxalate overproduction. Nedosiran is an RNA interference agent that inhibits hepatic lactate dehydrogenase, the enzyme responsible for the common, final step of oxalate production in all three genetic subtypes of PH. Here, we assessed in a two-part, randomized, single-ascending-dose, phase 1 study (PHYOX1) the safety, pharmacokinetics, pharmacodynamics, and exposure-response of subcutaneous nedosiran in 25 healthy participants (Group A) and 18 patients with PH1 or PH2 (Group B). Group A received nedosiran (0.3, 1.5, 3.0, 6.0, then 12.0 mg/kg) or placebo, and Group B received open-label nedosiran (1.5, 3.0, or 6.0 mg/kg). No significant safety concerns were identified. Injection site reactions (four or more hours post dose) occurred in 13.3% of participants in Group A and 27.8% of participants in Group B. Mean maximum reduction in 24-hour urinary oxalate excretion from baseline to day 57 (end of study) across Group B dose cohorts was 55% (range: 22%-100%) after single-dose nedosiran, with 33% participants reaching normal 24-hour urinary oxalate excretion. Based on the available modeling and simulation data, a fixed monthly dose of nedosiran 160 mg (free acid; equivalent to 170 mg sodium salt) in adults was associated with the highest proportion of simulated individuals achieving normal or near-normal 24-hour urinary oxalate excretion and fewest fluctuations in urinary oxalate response. Thus, single-dose nedosiran demonstrated acceptable safety and evidence of a pharmacodynamic effect in both PH1 and PH2 subpopulations consistent with its mechanism of action.

Transcutaneous vagal nerve simulation to reduce a systemic inflammatory response syndrome and the associated intestinal failure: study protocol of a prospective, two-armed, sham-controlled, double-blinded trial in healthy subjects (the NeuroSIRS-Study).

PURPOSE: Surgery initiates pro-inflammatory mediator cascades leading to a variably pronounced sterile inflammation (SIRS). SIRS is associated with intestinal paralysis and breakdown of intestinal barrier and might result in abdominal sepsis. Technological progress led to the development of a neurostimulator for transcutaneous auricular vagal nerve stimulation (taVNS), which is associated with a decline in inflammatory parameters and peristalsis improvement in rodents and healthy subjects via activation of the cholinergic anti-inflammatory pathway. Therefore, taVNS might be a strategy for SIRS prophylaxis. METHODS: The NeuroSIRS-Study is a prospective, randomized two-armed, sham-controlled, double-blind clinical trial. The study is registered at DRKS00016892 (09.07.2020). A controlled endotoxemia is used as a SIRS-mimicking model. 2 ng/kg bodyweight lipopolysaccharide (LPS) will be administered after taVNS or sham stimulation. The primary objective is a reduction of clinical symptoms of SIRS after taVNS compared to sham stimulation. Effects of taVNS on release of inflammatory cytokines, intestinal function, and vital parameters will be analyzed. DISCUSSION: TaVNS is well-tolerated, with little to no side effects. Despite not fully mimicking postoperative inflammation, LPS challenge is the most used experimental tool to imitate SIRS and offers standardization and reproducibility. The restriction to healthy male volunteers exerts a certain bias limiting generalizability to the surgical population. Still, this pilot study aims to give first insights into taVNS as a prophylactic treatment in postoperative inflammation to pave the way for further clinical trials in patients at risk for SIRS. This would have major implications for future therapeutic approaches.

APOE ɛ4 Is Associated with Postprandial Inflammation in Older Adults with Metabolic Syndrome Traits.

The apolipoprotein E (APOE) polymorphism impacts blood lipids and biomarkers of oxidation and inflammation, contributing to an isoform-dependent disease risk. We investigated the effect of the APOE genotype on postprandial metabolism after consumption of three different isoenergetic (4200 kJ) meals in older adults with a CVD risk phenotype. In a randomized crossover study, participants with metabolic syndrome traits (APOE E3, n = 39; E4, n = 10; mean age, 70 ± 5 years; BMI 31.3 ± 3.0 kg/m2) consumed a Western-like diet high-fat (WDHF), Western-like diet high-carbohydrate (WDHC), or Mediterranean-like diet (MED) meal. Parameters of lipid and glucose metabolism, inflammatory, and oxidative parameters were analyzed in blood samples collected at fasting and 1-5 h postprandially. Data were analyzed by linear mixed models. The magnitude of the IL-6 increase after the WDHF meal was significantly higher in E4 than in E3 carriers (iAUC: E4 = 7.76 vs. E3 = 2.81 pg/mL × h). The time to detect the IL-6 increase was shorter in the E4 group. All meals produced postprandial glycemia, insulinemia, and lipidemia, without differences between the E3 and the E4 groups. IL-1ß and oxidized LDL levels did not change postprandially. In conclusion, APOE E4 carriers display increased postprandial inflammation, indicated by higher postprandial IL-6 increase, when compared to non-carriers.

Safety and Suitability of the SmartPill® after Abdominal Surgery: Results of the Prospective, Two-Armed, Open-Label PIDuSA Trial.

INTRODUCTION: Postoperative ileus (POI) is a common complication after abdominal surgery. Until today, an evidence-based treatment of prolonged POI is still lacking, which can be attributed to the poor quality of clinical trials. Various different surrogate markers used to define POI severity are considered to be the cause of low-quality trials making it impossible to derive treatment recommendation. The SmartPill®, which is able to record pH values, temperature and pressure after ingestion, could be an ideal tool to measure transit times and peristalsis and therefore analyze POI severity. Unfortunately, the device has no approval for postoperative use due to safety concerns. The primary objective of the study is to determine safety of the SmartPill® in patients undergoing surgery. Secondary objectives were the quality of the recorded data and the suitability of the SmartPill® for analyzing intestinal motility after different surgical procedures. METHODS: The PIDuSA Study is a prospective, 2-arm, open-label trial. At the end of surgery, the SmartPill® was applied to 49 patients undergoing abdominal surgery having a high risk for impaired intestinal motility and 15 patients undergoing extra-abdominal surgery. Patients were visited daily to access safety data of the SmartPill® on the basis of adverse and serious adverse events (AEs/SAEs). Suitability and data quality were investigated by analyzing data completeness and feasibility to determine transit times and peristalsis for all sections of the gastrointestinal tract. RESULTS: In total, 179 AEs and 8 SAEs were recorded throughout the study affecting 42 patients in the abdominal (158 AEs) and 9 patients in the extra-abdominal surgery group (21 AEs, p = 0.061); none of them were device related. Primary capsule failure was observed in 5 patients, ultimately resulting in an impossibility of data analysis in only 3 patients (4.4%). 9% of the recorded data were incomplete due to the patient's incompliance in keeping the receiver close to the body. In 3 patients (4.4%), isolated small bowel transit could not be determined due to pH alterations as a result of prolonged POI. DISCUSSION: Our study demonstrates that the use of the SmartPill® is safe after surgery but requires a reasonable patient compliance to deliver meaningful data. An objective analysis of transit times and peristalsis was possible irrespective of type and site of surgery in over 95% indicating that the SmartPill® has the potential to deliver objective parameters for POI severity in future clinical trials. However, in some patients with prolonged POI, analysis of small bowel transit could be challenging.

Depletion of LAG-3+ T Cells Translated to Pharmacology and Improvement in Psoriasis Disease Activity: A Phase I Randomized Study of mAb GSK2831781.

Activated T cells drive a range of immune-mediated inflammatory diseases. LAG-3 is transiently expressed on recently activated CD4+ and CD8+ T cells. We describe the engineering and first-in-human clinical study (NCT02195349) of GSK2831781 (an afucosylated humanized IgG1 monoclonal antibody enhanced with high affinity for Fc receptors and LAG-3 and antibody-dependent cellular cytotoxicity capabilities), which depletes LAG-3 expressing cells. GSK2831781 was tested in a phase I/Ib, double-blind, placebo-controlled clinical study, which randomized 40 healthy participants (part A) and 27 patients with psoriasis (part B) to single doses of GSK2831781 (up to 0.15 and 5 mg/kg, respectively) or placebo. Adverse events were generally balanced across groups, with no safety or tolerability concern identified. LAG-3+ cell depletion in peripheral blood was observed at doses ≥ 0.15 mg/kg and was dose-dependent. In biopsies of psoriasis plaques, a reduction in mean group LAG-3+ and CD3+ T-cell counts was observed following treatment. Downregulation of proinflammatory genes (IL-17A, IL-17F, IFNγ, and S100A12) and upregulation of the epithelial barrier integrity gene, CDHR1, was observed with the 5 mg/kg dose of GSK2831781. Psoriasis disease activity improved up to day 43 at all GSK2831781 doses (0.5, 1.5, and 5 mg/kg) compared with placebo. Depletion of LAG-3-expressing activated T cells is a novel approach, and this first clinical study shows that GSK2831781 is pharmacologically active and provides encouraging early evidence of clinical effects in psoriasis, which warrants further investigation in T-cell-mediated inflammatory diseases.

Infection fatality rate of SARS-CoV2 in a super-spreading event in Germany.

A SARS-CoV2 super-spreading event occurred during carnival in a small town in Germany. Due to the rapidly imposed lockdown and its relatively closed community, this town was seen as an ideal model to investigate the infection fatality rate (IFR). Here, a 7-day seroepidemiological observational study was performed to collect information and biomaterials from a random, household-based study population. The number of infections was determined by IgG analyses and PCR testing. We found that of the 919 individuals with evaluable infection status, 15.5% (95% CI:[12.3%; 19.0%]) were infected. This is a fivefold higher rate than the reported cases for this community (3.1%). 22.2% of all infected individuals were asymptomatic. The estimated IFR was 0.36% (95% CI:[0.29%; 0.45%]) for the community and 0.35% [0.28%; 0.45%] when age-standardized to the population of the community. Participation in carnival increased both infection rate (21.3% versus 9.5%, p < 0.001) and number of symptoms (estimated relative mean increase 1.6, p = 0.007). While the infection rate here is not representative for Germany, the IFR is useful to estimate the consequences of the pandemic in places with similar healthcare systems and population characteristics. Whether the super-spreading event not only increases the infection rate but also affects the IFR requires further investigation.

Acute Effects of Three Different Meal Patterns on Postprandial Metabolism in Older Individuals with a Risk Phenotype for Cardiometabolic Diseases: A Randomized Controlled Crossover Trial.

SCOPE: The aim of this study is to investigate acute postprandial responses to intake of meals typical for Mediterranean and Western diets. METHODS: In a randomized crossover design, overweight and obese participants with a risk phenotype for cardiometabolic diseases consumed three different isoenergetic meals: Western diet-like high-fat (WDHF), Western diet-like high-carbohydrate (WDHC), and Mediterranean diet (MED) meal. Blood samples are collected at fasting and 1, 2, 3, 4, 5 h postprandially and analyzed for parameters of lipid and glucose metabolism, inflammation, oxidation, and antioxidant status. RESULTS: Compared to MED and WDHF meals, intake of a WDHC meal results in prolonged and elevated increases in glucose and insulin. Elevations for triglycerides are enhanced after the WDHF meal compared to the MED and the WDHC meal. Glucagon-like peptide-1 and interleukin-6 increase postprandially without meal differences. Apart from vitamin C showing an increase after the MED meal and a decrease after WDHF and WDHC meals, antioxidant markers decrease postprandially without meal differences. Plasma interleukin-1ß is not affected by meal intake. CONCLUSIONS: Energy-rich meals induce hyperglycemia, hyperlipemia, an inflammatory response, and a decrease in antioxidant markers. A meal typical for the Mediterranean diet results in favorable effects on glycemic, insulinemic, and lipemic responses.

Interferon-beta-induced changes in neuroimaging phenotypes of appetitive motivation and reactivity to emotional salience.

Treatment with interferon (IFN) has been associated with depressive side effects. Previous neuroimaging studies have provided information about changes in brain activation patterns in patients under treatment with IFN-alpha, but the effect of other IFNs, or the role of the underlying disease, has yet to be clarified. In the present fMRI study, we looked at brain changes after 8 days of IFN-beta treatment in N = =17 healthy volunteers, thus avoiding the possible confound of the effects of underlying pathology in studies of IFN-treated patients with neurological or other medical disorders. We followed a symptom dimensional approach by simultaneously investigating two distinct symptom domains of depressiveness: negative affect (amygdala) and appetitive motivation (ventral striatum). In these early phases of IFN treatment we detected a selective change in neural substrates of appetitive motivation, consistent with the predominant symptomatic change recorded in psychopathology ratings. In contrast, the fMRI phenotype of negative affect, which is known to characterize disorders of affect involving anxiety and depressiveness as well as individual vulnerability to depression, was unchanged after treatment. These findings suggest that IFN may induce an affective syndrome through a mechanism involving down-regulation of appetitive motivation.

Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.

BACKGROUND: There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. METHODS: In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m2 per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m2 on day 1) plus temozolomide (100-200 mg/m2 per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. FINDINGS: Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. INTERPRETATION: Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. FUNDING: German Federal Ministry of Education and Research.