Caloric restriction disrupts the microbiota and colonization resistance.

Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet-microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.

Hyponatremia in the emergency department: an overview of diagnostic and therapeutic approach.

INTRODUCTION: Hyponatremia, defined as a serum sodium concentration <135 mmol/l, is a frequent electrolyte disorder in patients presenting to an emergency department (ED). In this context, appropriate diagnostic and therapeutic management is rarely performed and challenging due to complex pathophysiologic mechanisms and a variety of underlying diseases. OBJECTIVE: To implement a feasible pathway of central diagnostic and therapeutic steps in the setting of an ED. METHODS: We conducted a narrative review of the literature, considering current practice guidelines on diagnosis and treatment of hyponatremia. Underlying pathophysiologic mechanisms and management of adverse treatment effects are outlined. We also report four cases observed in our ED. RESULTS: Symptoms associated with hyponatremia may appear unspecific and range from mild cognitive deficits to seizures and coma. The severity of hyponatremia-induced neurological manifestation and the risk of poor outcome is mainly driven by the rapidity of serum sodium decrease. Therefore, emergency treatment of hyponatremia should be guided by symptom severity and the assumed onset of hyponatremia development, distinguishing acute (<48 hours) versus chronic hyponatremia (>48 hours). CONCLUSIONS: Especially in moderately or severely symptomatic patients presenting to an ED, the application of a standard management approach appears to be critical to improve overall outcome. Furthermore, an adequate work-up in the ED enables further diagnostic and therapeutic evaluation during hospitalization.

Analysis of acute COVID-19 including chronic morbidity: protocol for the deep phenotyping National Pandemic Cohort Network in Germany (NAPKON-HAP).

BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. METHODS: In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. RESULTS: Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8-5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. CONCLUSIONS: The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

Endoscopic ultrasound-guided ethanol ablation versus surgical resection of insulinomas.

PURPOSE: Insulinoma is a rare tumor of the pancreas that can lead to hypoglycemia. To date, the standard therapy is surgical resection. After the first case report of successful endoscopic ultrasound-guided (EUS) ethanol injection 16 years ago, the need for establishing an alternative treatment method remains unchanged given the high morbidity rates of surgery and its unsuitability in some patients. MATERIALS AND METHODS: Here, we provide retrospective data from 33 insulinoma patients that were treated at our center between 2010 and 2021. Of these, 9 patients were treated with EUS-guided ethanol injection and 24 underwent pancreatic surgery. RESULTS: The ethanol group was older (ethanol: mean ± SE 67.8±11.2 years vs. surgery: 52.3±15.7, p=0.014) with a higher Charlson Comorbidity Index (3.0 (1.0;4.0) vs. 1.0 (0.0;2.0), p=0.008). The lowest glucose values were similar between groups before (ethanol: 2.09±0.17 mmol/l vs. surgery: 1.81±0.08, p=0.158) and after (4.95±0.74 vs. 5.41±0.28, p=0.581) the respective treatments. Complications occurred more frequently in the surgery group (11 % vs. 54 %, p=0.026). One patient after prior partial pancreatectomy died postoperatively. The hospitalization time was significantly shorter in the ethanol group (4.78±0.78 days vs. 19.88±4.07, p<0.001). CONCLUSION: EUS-guided ethanol injection can be similarly effective for the treatment of hyperinsulinemic hypoglycemia compared with pancreatic surgery but seems to be associated with less severe complications. This implies the need for prospective randomized trials in insulinoma patients with a low risk for malignancy.

Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma.

BACKGROUND: International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. METHODS: We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. PRIMARY ENDPOINT: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. RESULTS: In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT20-49Gy, tTTP was significantly longer for cRT50-60Gy (multivariate adjusted HR 0.10; 95% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. CONCLUSIONS: This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.

Metastases to the pituitary gland: insights from the German pituitary tumor registry.

Metastatic involvement of the pituitary gland is a rare but clinically significant phenomenon, that often poses diagnostic and therapeutic challenges. The aim of this study was to provide a comprehensive analysis of the origin of pituitary metastases using data from the German Pituitary Tumor Registry, one of the globally largest collections of pituitary pathology specimens. Here, we report data from a retrospective analysis of patients with metastases to the pituitary registered between 1990 and 2022. Out of 17,896 pituitary cases in the registry during this period, a total of 96 metastases to the pituitary gland were identified, accounting for 0.5% of all pituitary tumors in the registry. The mean age of the patients was 64 years. Breast cancer was identified as the primary tumor in 25% of total cases (n = 24/96) and in 50% of female patients. The second most prevalent primary tumor was lung cancer (18.75%, n = 18/96), followed by renal cell carcinoma (14.58%, n = 14/96). In comparison to current meta-analyses, this cohort shows a higher prevalence of metastases originating from the kidney. Furthermore, in contrast to the existing literature, no case of primary thyroid tumor was identified. Our study highlights the importance of pituitary metastases as a differential diagnosis in patients presenting with pituitary tumors.

Hepatic Energy Metabolism under the Local Control of the Thyroid Hormone System.

The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics.

Combined Oral Triglyceride and Glucose Tolerance Test After Acute Ischemic Stroke to Predict Recurrent Vascular Events: The Berlin "Cream&Sugar" Study.

BACKGROUND: Elevated triglyceride and glucose levels are associated with an increased cardiovascular disease risk including ischemic stroke. It is not known whether the response to a combined oral triglyceride and glucose challenge after ischemic stroke improves identification of patients with increased risk for recurrent vascular events. METHODS: The prospective, observational Berlin "Cream&Sugar" study was conducted at 3 different university hospital sites of the Charité-Universitätsmedizin Berlin, Germany, between January 24, 2009 and July 31, 2017. Patients with first-ever ischemic stroke were recruited 3 to 7 days after stroke. An oral triglyceride tolerance test (OTTT) and consecutive blood tests before (t0) as well as 3 (t1), 4 (t2), and 5 hours (t3) after OTTT were performed in fasting patients. An oral glucose tolerance test was performed in all nondiabetic patients 3 hours after the start of OTTT. Outcomes of the study were recurrent fatal or nonfatal stroke as well as a composite vascular end point including stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death assessed 1 year after stroke. Cox regression models were used to estimate hazard ratios and corresponding 95% CIs between patients with high versus low levels of triglyceride and glucose levels. RESULTS: Overall 755 patients were included; 523 patients completed OTTT and 1-year follow-up. Patients were largely minor strokes patients with a median National Institutes of Health Stroke Scale score of 1 (0-3). Comparing highest versus lowest quartiles of triglyceride levels, neither fasting (adjusted hazard ratiot0, 1.24 [95% CI, 0.45-3.42]) nor postprandial triglyceride levels (adjusted hazard ratiot3, 0.44 [95% CI, 0.16-1.25]) were associated with recurrent stroke. With regard to recurrent vascular events, results were similar for fasting triglycerides (adjusted hazard ratiot0, 1.09 [95% CI, 0.49-2.43]), however, higher postprandial triglyceride levels were significantly associated with a lower risk for recurrent vascular events (adjusted hazard ratiot3, 0.42 [95% CI, 0.18-0.95]). No associations were observed between fasting and post-oral glucose tolerance test blood glucose levels and recurrent vascular risk. All findings were irrespective of the diabetic status of patients. CONCLUSIONS: In this cohort of patients with first-ever' minor ischemic stroke, fasting triglyceride or glucose levels were not associated with recurrent stroke at one year after stroke. However, higher postprandial triglyceride levels were associated with a lower risk of recurrent vascular events which requires further validation in future studies. Overall, our results do not support the routine use of a combined OTTT/oral glucose tolerance test to improve risk prediction for recurrent stroke.

Weight loss-induced improvement of body weight and insulin sensitivity is not amplified by a subsequent 12-month weight maintenance intervention but is predicted by adaption of adipose atrial natriuretic peptide system: 48-month results of a randomized controlled trial.

BACKGROUND: Behavioral weight loss interventions are frequently hampered by long-term inefficacy. As metabolic improvements and health-related quality of life (HRQoL) are diminished by weight regain, effective long-term strategies are highly desirable. We aimed to analyze whether an additional weight maintenance intervention could delay body weight regain and can induce a long-term improvement of metabolism and HRQoL for up to 48 months in humans. Given the short-term metabolic effects of natriuretic peptides (NP), we also investigated the role of the adipose atrial NP (ANP) system in this long-term context. METHODS: After a successful 12-week weight reduction program 143 subjects (age>18; BMI≥27 kg/m2) were randomized (1:1) to a control group or a 12-month multimodal weight maintenance intervention focusing on nutritional counseling and physical exercises. Secondary trial outcomes including course of BMI, HOMA-IR, glucose response after oGTT (glucoseAUC), and HRQoL (SF-36) were analyzed yearly for 48 months. Adipose ANP receptor mRNA expression was analyzed during weight loss. RESULTS: Initial weight loss (- 4.7±1.5 kg/m2) improved glucoseAUC, HOMA-IR, and HRQoL. Although BMI was still reduced after 48 months (-1.98 [95% CI -2.61, -1.35] kg/m2), benefits on HOMA-IR, glucoseAUC, and mental health disappeared after 36 (-0.49 [-1.00, 0.02]), 18 (0.61 [-9.57, 10.79] mg dl-1 min-1), and 18 months (2.06 [-0.08, 4.20]), respectively, while improved physical health persisted up to months 48 (2.95 [0.49, 5.40]). Weight maintenance intervention inhibited weight regain and delayed impairment of HOMA-IR and glucoseAUC (but not HRQoL) for up to 12 months. However, no metabolic long-term effect was seen beyond the intervention period. Lower adipose NPR-C and higher NPR-A mRNA expression after weight loss predicted smaller regain of weight (r=0.398; p<0.05)/fat mass (FM) (r=0.391; p<0.05) and longer improvement of HOMA-IR (r=-0.422; p<0.05), respectively. CONCLUSIONS: Additional benefits of a behavioral 12-month weight maintenance intervention after weight loss regarding body weight regain and metabolic improvement does not persist beyond the intervention period. However, weight loss-induced modulation of the adipose ANP system is probably involved in the long-term control of body weight regain and insulin sensitivity. TRIAL REGISTRATION: ClinicalTrials.gov NCT00850629 . Registered on February 25, 2009.

Association between Subcutaneous Adipose Tissue Inflammation, Insulin Resistance, and Calorie Restriction in Obese Females.

The worldwide epidemic of overweight and obesity has led to an increase in associated metabolic comorbidities. Obesity induces chronic low-grade inflammation in white adipose tissue (WAT). However, the function and regulation of both innate and adaptive immune cells in human WAT under conditions of obesity and calorie restriction (CR) is not fully understood yet. Using a randomized interventional design, we investigated postmenopausal overweight or obese female subjects who either underwent CR for 3 mo followed by a 4-wk phase of weight maintenance or had to maintain a stable weight over the whole study period. A comprehensive immune phenotyping protocol was conducted using validated multiparameter flow cytometry analysis in blood and s.c. WAT (SAT). The TCR repertoire was analyzed by next-generation sequencing and cytokine levels were determined in SAT. Metabolic parameters were determined by hyperinsulinemic-euglycemic clamp. We found that insulin resistance correlates significantly with a shift toward the memory T cell compartment in SAT. TCR analysis revealed a diverse repertoire in SAT of overweight or obese individuals. Additionally, whereas weight loss improved systemic insulin sensitivity in the intervention group, SAT displayed no significant improvement of inflammatory parameters (cytokine levels and leukocyte subpopulations) compared with the control group. Our data demonstrate the accumulation of effector memory T cells in obese SAT and an association between systemic glucose homeostasis and inflammatory parameters in obese females. The long-standing effect of obesity-induced changes in SAT was demonstrated by preserved immune cell composition after short-term CR-induced weight loss.

Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients.

BACKGROUND: The objective was to investigate the role of gene expression and plasma levels of the muscular protein myostatin in intensive care unit-acquired weakness (ICUAW). This was performed to evaluate a potential clinical and/or pathophysiological rationale of therapeutic myostatin inhibition. METHODS: A retrospective analysis from pooled data of two prospective studies to assess the dynamics of myostatin plasma concentrations (day 4, 8 and 14) and myostatin gene (MSTN) expression levels in skeletal muscle (day 15) was performed. Associations of myostatin to clinical and electrophysiological outcomes, muscular metabolism and muscular atrophy pathways were investigated. RESULTS: MSTN gene expression (median [IQR] fold change: 1.00 [0.68-1.54] vs. 0.26 [0.11-0.80]; p = 0.004) and myostatin plasma concentrations were significantly reduced in all critically ill patients when compared to healthy controls. In critically ill patients, myostatin plasma concentrations increased over time (median [IQR] fold change: day 4: 0.13 [0.08/0.21] vs. day 8: 0.23 [0.10/0.43] vs. day 14: 0.40 [0.26/0.61]; p < 0.001). Patients with ICUAW versus without ICUAW showed significantly lower MSTN gene expression levels (median [IQR] fold change: 0.17 [0.10/0.33] and 0.51 [0.20/0.86]; p = 0.047). Myostatin levels were directly correlated with muscle strength (correlation coefficient 0.339; p = 0.020) and insulin sensitivity index (correlation coefficient 0.357; p = 0.015). No association was observed between myostatin plasma concentrations as well as MSTN expression levels and levels of mobilization, electrophysiological variables, or markers of atrophy pathways. CONCLUSION: Muscular gene expression and systemic protein levels of myostatin are downregulated during critical illness. The previously proposed therapeutic inhibition of myostatin does therefore not seem to have a pathophysiological rationale to improve muscle quality in critically ill patients. TRIAL REGISTRATION: ISRCTN77569430 -13th of February 2008 and ISRCTN19392591 17th of February 2011.

Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study.

BACKGROUND: After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. METHODS: In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. RESULTS: Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). CONCLUSIONS: Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.

Hypoxia and exercise interactions on skeletal muscle insulin sensitivity in obese subjects with metabolic syndrome: results of a randomized controlled trial.

BACKGROUND: Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome. METHODS: In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO2 conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO2 21%) conditions or hypoxia (n = 12; FiO2 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual V̇O2max. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues. RESULTS: The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISIClamp: 0.035 (IQR 0.016-0.075) vs. 0.037 (IQR 0.026-0.056) mg* kg-1 *min-1/(mU* l-1); p = 0.767). In contrast, ISIClamp improved during hypoxia training (0.028 (IQR 0.018-0.035) vs. 0.038 (IQR 0.024-0.060) mg * kg-1 *min-1/(mU *l-1); p < 0.05). Between group comparison of ISIClamp change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISIClamp during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISIClamp during hypoxic training. CONCLUSIONS: Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.

Interactions between neural decision-making circuits predict long-term dietary treatment success in obesity.

Although dietary decision-making is regulated by multiple interacting neural controllers, their impact on dietary treatment success in obesity has only been investigated individually. Here, we used fMRI to test how well interactions between the Pavlovian system (automatically triggering urges of consumption after food cue exposure) and the goal-directed system (considering long-term consequences of food decisions) predict future dietary success achieved in 39 months. Activity of the Pavlovian system was measured with a cue-reactivity task by comparing perception of food versus control pictures, activity of the goal-directed system with a food-specific delay discounting paradigm. Both tasks were applied in 30 individuals with obesity up to five times: Before a 12-week diet, immediately thereafter, and at three annual follow-up visits. Brain activity was analyzed in two steps. In the first, we searched for areas involved in Pavlovian processes and goal-directed control across the 39-month study period with voxel-wise linear mixed-effects (LME) analyses. In the second, we computed network parameters reflecting the covariation of longitudinal voxel activity (i.e. principal components) in the regions identified in the first step and used them to predict body mass changes across the 39 months with LME models. Network analyses testing the link of dietary success with activity of the individual systems as reference found a moderate negative link to Pavlovian activity primarily in left hippocampus and a moderate positive association to goal-directed activity primarily in right inferior parietal gyrus. A cross-paradigm network analysis that integrated activity measured in both tasks revealed a strong positive link for interactions between visual Pavlovian areas and goal-directed decision-making regions mainly located in right insular cortex. We conclude that adaptation of food cue processing resources to goal-directed control activity is an important prerequisite of sustained dietary weight loss, presumably since the latter activity can modulate Pavlovian urges triggered by frequent cue exposure in everyday life.

Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist.

Patients with rare defects in the gene encoding proopiomelanocortin (POMC) have extreme early-onset obesity, hyperphagia, hypopigmentation, and hypocortisolism, resulting from the lack of the proopiomelanocortin-derived peptides melanocyte-stimulating hormone and corticotropin. In such patients, adrenal insufficiency must be treated with hydrocortisone early in life. No effective pharmacologic treatments have been available for the hyperphagia and obesity that characterize the condition. In this investigator-initiated, open-label study, two patients with proopiomelanocortin deficiency were treated with setmelanotide, a new melanocortin-4 receptor agonist. The patients had a sustainable reduction in hunger and substantial weight loss (51.0 kg after 42 weeks in Patient 1 and 20.5 kg after 12 weeks in Patient 2).

Caloric Restriction in Older Adults-Differential Effects of Weight Loss and Reduced Weight on Brain Structure and Function.

Dietary modifications such as caloric restriction (CR) have been suggested as a means to improve memory and prevent age-related decline. However, it is unclear whether those effects remain stable over time or are related specifically to negative energy balance during the weight loss phase of CR. Using a randomized interventional design, we investigated changes in recognition memory and neural correlates in postmenopausal obese women (n = 19): 1) after intense weight loss in the course of a 12-week low-caloric diet (reduced body weight and negative energy balance) and 2) after having sustained the reduced weight over 4 more weeks (reduced body weight, but energy balance equilibrium). Participants were contrasted to a control group (n = 18) instructed not to change dietary habits. In the CR group, we found improved recognition memory, paralleled by increased gray matter volume in inferior frontal gyrus and hippocampus, and augmented hippocampal resting-state functional connectivity to parietal areas. Moreover, effects were specific for transient negative energy balance and could not be detected after subsequent weight maintenance. Our data demonstrate for the first time in humans that beneficial effects of CR on brain structure and function are due to weight loss rather than an overall reduced weight.

Mobile electronic versus paper case report forms in clinical trials: a randomized controlled trial.

BACKGROUND: Regulations, study design complexity and amounts of collected and shared data in clinical trials render efficient data handling procedures inevitable. Recent research suggests that electronic data capture can be key in this context but evidence is insufficient. This randomized controlled parallel group study tested the hypothesis that time efficiency is superior when electronic (eCRF) instead of paper case report forms (pCRF) are used for data collection. We additionally investigated predictors of time saving effects and data integrity. METHODS: This study was conducted on top of a clinical weight loss trial performed at a clinical research facility over six months. All study nurses and patients participating in the clinical trial were eligible to participate and randomly allocated to enter cross-sectional data obtained during routine visits either through pCRF or eCRF. A balanced randomization list was generated before enrolment commenced. 90 and 30 records were gathered for the time that 27 patients and 2 study nurses required to report 2025 and 2037 field values, respectively. The primary hypothesis, that eCRF use is faster than pCRF use, was tested by a two-tailed t-test. Analysis of variance and covariance were used to evaluate predictors of entry performance. Data integrity was evaluated by descriptive statistics. RESULTS: All randomized patients were included in the study (eCRF group n = 13, pCRF group n = 14). eCRF, as compared to pCRF, data collection was associated with significant time savings  across all conditions (8.29 ± 5.15 min vs. 10.54 ± 6.98 min, p = .047). This effect was not defined by participant type, i.e. patients or study nurses (F(1,112) = .15, p = .699), CRF length (F(2,112) = .49, p = .609) or patient age (Beta = .09, p = .534). Additional 5.16 ± 2.83 min per CRF were saved with eCRFs due to data transcription redundancy when patients answered questionnaires directly in eCRFs. Data integrity was superior in the eCRF condition (0 versus 3 data entry errors). CONCLUSIONS: This is the first study to prove in direct comparison that using eCRFs instead of pCRFs increases time efficiency of data collection in clinical trials, irrespective of item quantity or patient age, and improves data quality. TRIAL REGISTRATION: Clinical Trials NCT02649907 .

Whole-body vibration to prevent intensive care unit-acquired weakness: safety, feasibility, and metabolic response.

BACKGROUND: Intensive care unit (ICU)-acquired weakness in critically ill patients is a common and significant complication affecting the course of critical illness. Whole-body vibration is known to be effective muscle training and may be an option in diminishing weakness and muscle wasting. Especially, patients who are immobilized and not available for active physiotherapy may benefit. Until now whole-body vibration was not investigated in mechanically ventilated ICU patients. We investigated the safety, feasibility, and metabolic response of whole-body vibration in critically ill patients. METHODS: We investigated 19 mechanically ventilated, immobilized ICU patients. Passive range of motion was performed prior to whole-body vibration therapy held in the supine position for 15 minutes. Continuous monitoring of vital signs, hemodynamics, and energy metabolism, as well as intermittent blood sampling, took place from the start of baseline measurements up to 1 hour post intervention. We performed comparative longitudinal analysis of the phases before, during, and after intervention. RESULTS: Vital signs and hemodynamic parameters remained stable with only minor changes resulting from the intervention. No application had to be interrupted. We did not observe any adverse event. Whole-body vibration did not significantly and/or clinically change vital signs and hemodynamics. A significant increase in energy expenditure during whole-body vibration could be observed. CONCLUSIONS: In our study the application of whole-body vibration was safe and feasible. The technique leads to increased energy expenditure. This may offer the chance to treat patients in the ICU with whole-body vibration. Further investigations should focus on the efficacy of whole-body vibration in the prevention of ICU-acquired weakness. TRIAL REGISTRATION: Applicability and Safety of Vibration Therapy in Intensive Care Unit (ICU) Patients. ClinicalTrials.gov NCT01286610 . Registered 28 January 2011.

Impulse control in the dorsolateral prefrontal cortex counteracts post-diet weight regain in obesity.

A variety of studies suggest that efficient treatments to induce short-term dietary success in obesity exist. However, sustained maintenance of reduced weight is rare as a large proportion of patients start to regain weight when treatment is discontinued. Thus, from a clinical perspective, it would be desirable to identify factors that counteract post-diet weight regain across longer time-scales. To address this question, we extended our previous work on neural impulse control mechanisms of short-term dietary success in obesity and now investigated the mechanisms counteracting long-term weight regain after a diet. Specifically, we measured neural impulse control during a delay discounting task with fMRI at two time points, i.e. the beginning ('T0') and the end ('T12') of a one-year follow-up interval after a 12-week diet. Then, we tested whether activity in the dorsolateral prefrontal cortex (DLPFC) at T0 and whether activity changes across the follow-up period (T0-T12) are linked to success in weight maintenance. The analyses conducted show that control-related DLPFC activity at T0 was coupled to the degree of success in weight maintenance. Consistently, also behavioral measures of control were linked to the degree of success in maintenance. A direct comparison of neural and behavioral control parameters for prognostic weight change modeling revealed that neural signals were more informative. Taken together, neural impulse control in the DLPFC measured with fMRI directly after a diet predicts real-world diet success in obese patients across extended time periods.