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AIM/HYPOTHESIS: The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. METHODS: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. RESULTS: A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. CONCLUSIONS/INTERPRETATION: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. FUNDING: This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. REGISTRATION: This systematic review is registered in PROSPERO (CRD42019120083).

In a clinical trial with a survival outcome, an interim analysis is often performed to allow for early stopping for efficacy. If the interim analysis is early in the trial, one might conclude that a new treatment is more effective (compared to e.g.\ a placebo) and stop the trial, whereas the survival curves in the trial arms are not mature for the research question under investigation, for example because the curves are still close to 1 at that time. This means that the decision is based on a small percentage of the events in the long run only; possibly the events of the more frail patients in the trial who may not be representative for the whole group of patients. It may not be sensible to conclude effectiveness based on so little information. Criteria to determine the moment the interim analysis will be performed, should be chosen with care, and include the maturity of the data at the time of the interim analysis. Here, the expected survival rates at the interim analysis play a role. In this paper we will derive the asymptotic distribution of the Kaplan-Meier curves at the (random) moment the interim analysis will be performed for a one and two arm clinical trial. Based on this distribution, an interval in which the Kaplan Meier curves will fall into (with probability 95\%) is derived and could be used to plan the moment of the interim analysis in the design stage of the trial, so before the trial starts., Comment: 21 pages, 2 figures, 3 tables

Background: Diltiazem is recommended and frequently prescribed in patients with angina and nonobstructive coronary artery disease (ANOCA), suspected of coronary vasomotor dysfunction (CVDys). However, studies substantiating its effect is this patient group are lacking. Objectives: The randomized, placebo-controlled EDIT-CMD (Efficacy of Diltiazem to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial) evaluated the effect of diltiazem on CVDys, as assessed by repeated coronary function testing (CFT), angina, and quality of life. Methods: A total of 126 patients with ANOCA were included and underwent CFT. CVDys, defined as the presence of vasospasm (after intracoronary acetylcholine provocation) and/or microvascular dysfunction (coronary flow reserve

Contains fulltext : 249454.pdf (Publisher’s version ) (Open Access) Repeated sessions of cerebellar anodal transcranial direct current stimulation (tDCS) have been suggested to modulate cerebellar-motor cortex (M1) connectivity and decrease ataxia severity. However, therapeutic trials involving etiologically homogeneous groups of ataxia patients are lacking. The objective of this study was to investigate if a two-week regimen of daily cerebellar tDCS sessions diminishes ataxia and non-motor symptom severity and alters cerebellar-M1 connectivity in individuals with spinocerebellar ataxia type 3 (SCA3). We conducted a randomized, double-blind, sham-controlled trial in which twenty mildly to moderately affected SCA3 patients received ten sessions of real or sham cerebellar tDCS (i.e., five days per week for two consecutive weeks). Effects were evaluated after two weeks, three months, six months, and twelve months. Change in Scale for the Assessment and Rating of Ataxia (SARA) score after two weeks was defined as the primary endpoint. Static posturography, SCA Functional Index tests, various patient-reported outcome measures, the cerebellar cognitive affective syndrome scale, and paired-pulse transcranial magnetic stimulation to examine cerebellar brain inhibition (CBI) served as secondary endpoints. Absolute change in SARA score did not differ between both trial arms at any of the time points. We observed significant short-term improvements in several motor, cognitive, and patient-reported outcomes after the last stimulation session in both groups but no treatment effects in favor of real tDCS. Nonetheless, some of the patients in the intervention arm showed a sustained reduction in SARA score lasting six or even twelve months, indicating interindividual variability in treatment response. CBI, which reflects the functional integrity of the cerebellothalamocortical tract, remained unchanged after ten tDCS sessions. Albeit exploratory, there was some indication for between-group differences in SARA speech score after six and twelve months and in the number of extracerebellar signs after three and six months. Taken together, our study does not provide evidence that a two-week treatment with daily cerebellar tDCS sessions reduces ataxia severity or restores cerebellar-M1 connectivity in early-to-middle-stage SCA3 patients at the group level. In order to potentially increase therapeutic efficacy, further research is warranted to identify individual predictors of symptomatic improvement. 14 p.

Aim/hypothesis: The physiological counterregulatory response to hypoglycaemia is reportedly hierarchically organized, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To more accurately compare thresholds for activation of these responses between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. Methods: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using methods for interval censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% confidence interval of the mean baseline measurement or euglycaemic control clamp. Results: A total of 63 articles were included. Compared to non-diabetic controls, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 (3.2-4.2) vs. 3.4 (2.8-3.9 mmol/l), noradrenaline (3.2 (3.2-3.7) vs. 3.0 (2.8-3.1) mmol/l), cortisol (3.5 (3.2-4.2) mmol/l vs. 2.8 (2.8-3.4) mmol/l), and growth hormone (3.8 (3.3-3.8) vs. 3.2 (3.0-3.3) mmol/l) all occurred at lower glucose levels in people with than in those without diabetes (all p ≤ 0.01). Similarly, although both autonomic (3.4 (3.4-3.4) vs. 3.0 (2.8-3.4) mmol/l) and neuroglycopenic (3.4 (2.8-∞ vs. 3.0 (3.0-3.1) mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. Conclusions/interpretation: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia.

Additional file 1: Estimated effects of ICPT as compared to CAU for completers (ICPT N = 38, CAU N = 21)

Supplemental material, 180914_WEBAPPENDIX_Sample_size_for_cRCT_stepped_wedge_trials_with_more_than_2_levels for Sample size calculation for stepped-wedge cluster-randomized trials with more than two levels of clustering by Steven Teerenstra, Monica Taljaard, Anja Haenen, Anita Huis, Femke Atsma, Laura Rodwell and Marlies Hulscher in Clinical Trials

Item does not contain fulltext AIMS: The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance. METHODS: The study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes - i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole - were retrieved from the Dutch Medicines Regulatory Authority. RESULTS: In most studies, the intrasubject variability in total and peak drug exposure was comparable for the brand-name [in the range 0.01-0.24 for area under the concentration-time curve (AUCt ) and 0.02-0.29 for peak plasma concentration (Cmax ) on a log scale] and generic (0.01-0.23 for AUCt and 0.08-0.33 for Cmax ) drugs, and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUCt and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction could be considered negligible (-0.069 to 0.047 for AUCt and -0.091 to 0.02 for Cmax ). CONCLUSION: In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name to a generic drug is comparable with that seen following repeated administration of the brand-name drug in the patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation-dependent variation in exposure is observed upon switching. Thus, our data support that, for the medicines that were included in the present investigation, from a clinical pharmacological perspective, the benefit-risk balance of a generic drug is comparable with that of the brand-name drug.

Mean scores and standard deviation of the outcome domains per group at baseline (T0), halfway (T1) and post treatment (T2) (DOCX 29 kb)

Regression coefficient table- Regression coefficients for the maximum likelihood model and the models built in accordance with the three winning strategies. (DOCX 15Â kb)

Data summary table- A summary of the predictor information in the four DVT data sets. (DOCX 15Â kb)

Calibration plots- Calibration plots of models developed in the Full Oudega data using the winning strategies, assessed in the Toll validation data. (DOCX 188Â kb)

Pubmed Search strategy. (DOCX 16 kb)

Calibration plots- Calibration plots of models developed in the Full Oudega data using the winning strategies, assessed in the Toll validation data. (DOCX 188Â kb)

Regression coefficient table- Regression coefficients for the maximum likelihood model and the models built in accordance with the three winning strategies. (DOCX 15Â kb)

Previous studies showed that decreased cerebral saturation during cardiac surgery is related to adverse postoperative outcome. Therefore, we investigated the influence of intraoperative events on cerebral tissue saturation in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). A total of 52 adult patients who underwent cardiac surgery using pulsatile CPB were included in this prospective explorative study. Cerebral tissue oxygen saturation (SctO2) was measured in both the left and right cerebral hemisphere. Intraoperative events, involving interventions performed by anesthesiologist, surgeon, and clinical perfusionist, were documented. Simultaneously, in-line hemodynamic parameters (partial oxygen pressure, partial carbon dioxide pressure, hematocrit, arterial blood pressure, and CPB flow rates) were recorded. Cerebral tissue saturation was affected by anesthetic induction (p < .001), placement of the sternal retractor (p < .001), and initiation (p < .001) as well as termination of CPB (p < .001). Placement (p < .001) and removal of the aortic cross-clamp (p = .026 for left hemisphere, p = .048 for right hemisphere) led to changes in cerebral tissue saturation. In addition, when placing the aortic cross-clamp, hematocrit (p < .001) as well as arterial (p = .007) and venous (p < .001) partial oxygen pressures changed. Cerebral tissue oximetry effectively identifies changes related to surgical events or vulnerable periods during cardiac surgery. Future studies are needed to identify methods of mitigating periods of reduced cerebral saturation.

Next to severely decreased pump flow, hypovolemia in extracorporeal life support (ELS) can result in subatmospheric venous line pressure. Such pressure may lead to degassing and resultant gaseous microemboli (GME), with potential changes in neurological clinical outcome. CME activity resulting from degassing was investigated in relation to subatmospheric venous line pressure, partial oxygen pressure (pO2), and hematocrit in a model of a centrifugal pump-based circuit for long-term ELS. Additionally, a device that provides instantaneous volume buffer capacity during hypovolemia was evaluated in relation to GME appearance. An exponential relationship was found between decreasing venous line pressure and GME downstream of the centrifugal pump (P=0.001). Arterial bubble activity appeared at subatmospheric venous line pressures of 200mmHg and less. A rising (pO2) increased formation of GME (P=0.05). A rise in hematocrit, in contrast, did not affect embolic activity (P=0.22). With simulated hypovolemia, volume buffer capacity added to the venous line dampened fluctuations of venous line pressure by approximately 40%, but a significant reduction in GME formation could not be found (P=0.22). Moreover, the device enabled a 14% higher support flow. With ELS flow being related to patient volume status, hypovolemia can diminish support. A coherent decrease of venous line pressure triggers degassing of blood-dissolved gases and causes arterial GME, which can become massive during persistent conditions of limited venous return. Incorporation of a volume buffer capacity device into the extracorporeal support circuit enables a higher and more stable support flow in critically low patient filling.

Background: The prognosis of rhabdomyosarcoma (RMS) in children and adolescents has improved since the introduction of multi-agent chemotherapy. However, outcome data of adults with RMS are scarce. This multicenter retrospective study investigated the effect of age on outcome of RMS. Patients and Methods: Data were collected from three Dutch University Medical Centers between 1977-2009. The effect of age and clinical prognostic factors on relapse-free and disease-specific survival (DSS) were analyzed. Results: Age as a continuous variable predicted poor survival in multivariate analysis. Five-year DSS was highest for non-metastatic embryonal RMS, followed by non-metastatic alveolar RMS and was poor in metastatic disease. Higher age correlated with unfavorable histological subtype (alveolar RMS) and with metastatic disease at presentation in embryonal RMS. In non-metastatic embryonal RMS and in all alveolar RMS, higher age was an adverse prognostic factor of outcome. Conclusion: This study indicates that age is a negative predictor of survival in patients with embryonal and alveolar RMS.

The response of colorectal tumours to chemotherapy is highly variable. Preclinical work has shown that the Kirsten ras (KRAS) oncogene sensitizes colorectal tumour cells to oxaliplatin and capecitabine in a wild-type tumour suppressor p53 (TP53)-dependent manner. Therefore, whether or not the combined mutation status of KRAS and TP53 could predict response to chemotherapy in metastatic colorectal cancer was tested. A subgroup of patients from the CAIRO2 study (randomized phase III study on capecitabine, oxaliplatin, bevacizumab with or without cetuximab in first-line advanced colorectal cancer) that received capecitabine plus oxaliplatin (CAPOX) treatment in combination with bevacizumab was selected. The tumours were analyzed for KRAS and TP53 mutations by PCR/sequencing. The relationship between tumour response and genotype was analyzed. The following KRAS/TP53 genotypes were identified: KRASmut/TP53mut n=21, KRASmut/TP53wt n=20, KRASwt/TP53mut n=25, KRASwt/TP53wt n=15. No genotype was associated with a significantly better or worse progression-free or overall survival. The combined mutation status of KRAS and TP53 does not predict response to CAPOX in patients with metastasized colorectal cancer

Point-of-care analyzers may benefit therapeutic decision making by reducing turn-around-time for samples. This is especially true when biochemical parameters exceed the clinical reference range, in which acute and effective treatment is essential. We therefore evaluated the analytical performance of the i-STAT point-of-care analyzer in two critically ill adult patient populations. During a 3-month period, 48 blood samples from patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) and 42 blood samples from non-cardiac patients who needed intensive care treatment were analyzed on both the i-STAT analyzer (CPB and non-CPB mode, respectively) and our laboratory analyzers (RapidLab 865/Sysmex XE-2100 instrument). The agreement analysis for quantitative data was used to compare i-STAT to RapidLab for blood gas/electrolytes and for hematocrit with the Sysmex instrument. Point-of-care electrolytes and blood gases had constant deviation, except for pH, pO2, and hematocrit. A clear linear trend in deviation of i-STAT from RapidLab was noticed for pH during CPB (r = 0.32, p = .03) and for pO2 > 10 kPa during CPB (r = −0.59, p < .0001 when 10 < pO2

BACKGROUND: The effectiveness of community-based geriatric intervention models for vulnerable older adults is controversial. We evaluated a problem-based multidisciplinary intervention targeting vulnerable older adults at home that promised efficacy through better timing and increased commitment of patients and primary care physicians. This study compared the effects of this new model to usual care. METHODS: Primary care physicians referred older people for problems with cognition, nutrition, behavior, mood, or mobility. One hundred fifty-one participants (mean age 82.2 years, 74.8% women) were included in a pseudocluster randomized trial with 6-month follow-up for the primary outcomes. Eighty-five participants received the new intervention, and 66 usual care. In the intervention arm, geriatric nurses visited patients at home for geriatric assessment and management in cooperation with primary care physicians and geriatricians. Modified intention-to-treat analyses focused on differences between treatment arms in functional abilities (Groningen Activity Restriction Scale-3) and mental well-being (subscale mental health Medical Outcomes Study [MOS]-20), using a mixed linear model. RESULTS: After 3 months, treatment arms showed significant differences in favor of the new intervention. Functional abilities improved 2.2 points (95% confidence interval [CI], 0.3-4.2) and well-being 5.8 points (95% CI, 0.1-11.4). After 6 months, the favorable effect increased for well-being (9.1; 95% CI, 2.4-15.9), but the effect on functional abilities was no longer significant (1.6; 95% CI, -0.7 to 3.9). CONCLUSIONS: This problem-based geriatric intervention improved functional abilities and mental well-being of vulnerable older people. Problem-based interventions can increase the effectiveness of primary care for this population. ispartof: Journals of Gerontology A, Biological Sciences and Medical Sciences vol:63 issue:3 pages:283-290 ispartof: location:United States status: published

SPIRIT checklist. (DOC 122 kb)

SPIRIT checklist. (DOC 122 kb)