Monotone return to steady nonequilibrium

We propose and analyze a new candidate Lyapunov function for relaxation towards general nonequilibrium steady states. The proposed functional is obtained from the large time asymptotics of time-symmetric fluctuations. For driven Markov jump or diffusion processes it measures an excess in dynamical activity rates. We present numerical evidence and we report on a rigorous argument for its monotonous time-dependence close to the steady nonequilibrium or in general after a long enough time. This is in contrast with the behavior of approximate Lyapunov functions based on entropy production that when driven far from equilibrium often keep exhibiting temporal oscillations even close to stationarity.Comment: Accepted for publication in Phys. Rev. Let

Development of a quality indicator set to measure and improve quality of ICU care for patients with traumatic brain injury.

BACKGROUND: We aimed to develop a set of quality indicators for patients with traumatic brain injury (TBI) in intensive care units (ICUs) across Europe and to explore barriers and facilitators for implementation of these quality indicators. METHODS: A preliminary list of 66 quality indicators was developed, based on current guidelines, existing practice variation, and clinical expertise in TBI management at the ICU. Eight TBI experts of the Advisory Committee preselected the quality indicators during a first Delphi round. A larger Europe-wide expert panel was recruited for the next two Delphi rounds. Quality indicator definitions were evaluated on four criteria: validity (better performance on the indicator reflects better processes of care and leads to better patient outcome), feasibility (data are available or easy to obtain), discriminability (variability in clinical practice), and actionability (professionals can act based on the indicator). Experts scored indicators on a 5-point Likert scale delivered by an electronic survey tool. RESULTS: The expert panel consisted of 50 experts from 18 countries across Europe, mostly intensivists (N = 24, 48%) and neurosurgeons (N = 7, 14%). Experts agreed on a final set of 42 indicators to assess quality of ICU care: 17 structure indicators, 16 process indicators, and 9 outcome indicators. Experts are motivated to implement this finally proposed set (N = 49, 98%) and indicated routine measurement in registries (N = 41, 82%), benchmarking (N = 42, 84%), and quality improvement programs (N = 41, 82%) as future steps. Administrative burden was indicated as the most important barrier for implementation of the indicator set (N = 48, 98%). CONCLUSIONS: This Delphi consensus study gives insight in which quality indicators have the potential to improve quality of TBI care at European ICUs. The proposed quality indicator set is recommended to be used across Europe for registry purposes to gain insight in current ICU practices and outcomes of patients with TBI. This indicator set may become an important tool to support benchmarking and quality improvement programs for patients with TBI in the future

A multifaceted feedback strategy alone does not improve the adherence to organizational guideline-based standards: a cluster randomized trial in intensive care

Organizational data such as bed occupancy rate and nurse-to-patient ratio are related to clinical outcomes and to the efficient use of intensive care unit (ICU) resources. Standards for these performance indicators are provided in guidelines. We studied the effects of a multifaceted feedback strategy to improve the adherence to these standards. In a cluster randomized controlled study design the intervention ICUs received extensive monthly feedback reports, they received outreach visits and initiated a quality improvement team. The control ICUs received limited quarterly feedback reports only. We collected primary data prospectively within the setting of a Dutch national ICU registry over a 14-month study period. The target indicators were bed occupancy rate (aiming at 80 % or below) and nurse-to-patient ratio (aiming at 0.5 or higher). Data were collected per 8-h nursing shift. Logistic regression analysis was performed. For both study end points, the odds ratios (OR) for improvements at follow-up versus at baseline were calculated separately for control and intervention ICUs. We analyzed data on 67,237 nursing shifts. The bed occupancy rate did not improve in the intervention group compared to baseline (adjusted OR 0.88; 95 % confidence interval (CI), 0.62-1.27) or compared to control group (OR 0.67; 95 % CI 0.39-1.15). The nurse-to-patient ratio did not improve (OR 0.72; 95 % CI 0.41-1.26 compared to baseline and OR 0.65; 95 % CI 0.35-1.19 compared to control group). A multifaceted feedback intervention did not improve the adherence to guideline-based standards on the organizational issues bed occupancy rate and nurse-to-patient ratio in the ICU. The reasons may be a limited confidence in data quality, the lack of practical tools for improvement, and the relatively short follow-up. ISRCTN5054214

A human vitamin D receptor mutation causes rickets and impaired Th1/Th17 responses

We present a brother and sister with severe rickets, alopecia and highly elevated serum levels of 1,25-dihydroxyvitamin D (1,25-(OH)2D3). Genomic sequencing showed a homozygous point mutation (A133G) in the vitamin D receptor gene, leading to an amino acid change in the DNA binding domain (K45E), which was described previously. Hereditary vitamin D resistant rickets (HVDRR) was diagnosed. Functional studies in skin biopsy fibroblasts confirmed this. 1,25-(OH)2D3 reduced T helper (Th) cell population-specific cytokine expression of interferon γ (Th1), interleukins IL-17A (Th17) and IL-22 (Th17/Th22) in peripheral blood mononuclear cells (PBMCs) from the patient's parents, whereas IL-4 (Th2) levels were higher, reflecting an immunosuppressive condition. None of these factors were regulated by 1,25-(OH)2D3 in PBMCs from the boy. At present, both patients (boy is 23years of age, girl is 7) have not experienced any major immune-related disorders. Although both children developed alopecia, the girl did so earlier than the boy. The boy showed complete recovery from the rickets at the age of 17 and does not require any vitamin D supplementations to date.In conclusion, we characterized two siblings with HVDRR, due to a mutation in the DNA binding domain of VDR. Despite a defective T cell response to vitamin D, no signs of any inflammatory-related abnormalities were seen, thus questioning an essential role of vitamin D in the immune system. Despite the fact that currently medicine is not required, close monitoring in the future of these patients is warranted for potential recurrence of vitamin D dependence and diagnosis of (chronic) inflammatory-related diseases

Clinical verification of 18F-DCFPyL PET-detected lesions in patients with biochemically recurrent prostate cancer

PURPOSE: Radiolabeled Prostate-Specific Membrane Antigen (PSMA) PET/CT is the current standard-of-care for lesion detection in patients with biochemically recurrent (BCR) prostate cancer (PCa). However, rigorous verification of detected lesions is not always performed in routine clinical practice. To aid future 18F-radiolabeled PSMA PET/CT interpretation, we aimed to identify clinical/imaging characteristics that increase the likelihood that a PSMA-avid lesion is malignant. MATERIALS AND METHODS: 262 patients with BCR, who underwent 18F-DCFPyL PSMA PET/CT, were retrospectively analyzed. The malignant nature of 18F-DCFPyL PET-detected lesions was verified through any of the following metrics: (1) positive histopathological examination; (2) additional positive imaging; (3) a ≥50% decrease in Prostate-Specific Antigen (PSA) following irradiation of the lesion(s). RESULTS: In 226/262 PET scans (86.3%) at least one lesion suspicious for recurrent PCa was detected ('positive scan'). In 84/226 positive scans (37.2%), at least one independent verification metric was available. PSMA PET-detected lesions were most often confirmed to be malignant (PCa) in the presence of a CT-substrate (96.5% vs. 55.6% without CT-substrate), with SUVpeak ≥3.5 (91.4% vs. 60.0% with SUVpeak2 PET-positive lesions (94.1% vs. 64.2% in patients with 1-2 PET-positive lesions; p<0.001-0.03). CONCLUSIONS: In this study, the clinical verification of 18F-DCFPyL PET-positive lesions in patients with BCR was performed. Diagnostic certainty of PET-detected lesions increases in the presence of characteristic abnormalities on CT, when SUVpeak is ≥3.5, when PSA-levels exceed 2.0 ng/mL or in patients with more than two PET-positive lesions