IMPORTANCE: Results of studies on use of prophylactic haloperidol in critically ill adults are inconclusive, especially in patients at high risk of delirium. OBJECTIVE: To determine whether ...prophylactic use of haloperidol improves survival among critically ill adults at high risk of delirium, which was defined as an anticipated intensive care unit (ICU) stay of at least 2 days. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled investigator-driven study involving 1789 critically ill adults treated at 21 ICUs, at which nonpharmacological interventions for delirium prevention are routinely used in the Netherlands. Patients without delirium whose expected ICU stay was at least a day were included. Recruitment was from July 2013 to December 2016 and follow-up was conducted at 90 days with the final follow-up on March 1, 2017. INTERVENTIONS: Patients received prophylactic treatment 3 times daily intravenously either 1 mg (n = 350) or 2 mg (n = 732) of haloperidol or placebo (n = 707), consisting of 0.9% sodium chloride. MAIN OUTCOME AND MEASURES: The primary outcome was the number of days that patients survived in 28 days. There were 15 secondary outcomes, including delirium incidence, 28-day delirium-free and coma-free days, duration of mechanical ventilation, and ICU and hospital length of stay. RESULTS: All 1789 randomized patients (mean, age 66.6 years SD, 12.6; 1099 men 61.4%) completed the study. The 1-mg haloperidol group was prematurely stopped because of futility. There was no difference in the median days patients survived in 28 days, 28 days in the 2-mg haloperidol group vs 28 days in the placebo group, for a difference of 0 days (95% CI, 0-0; P = .93) and a hazard ratio of 1.003 (95% CI, 0.78-1.30, P=.82). All of the 15 secondary outcomes were not statistically different. These included delirium incidence (mean difference, 1.5%, 95% CI, −3.6% to 6.7%), delirium-free and coma-free days (mean difference, 0 days, 95% CI, 0-0 days), and duration of mechanical ventilation, ICU, and hospital length of stay (mean difference, 0 days, 95% CI, 0-0 days for all 3 measures). The number of reported adverse effects did not differ between groups (2 0.3% for the 2-mg haloperidol group vs 1 0.1% for the placebo group). CONCLUSIONS AND RELEVANCE: Among critically ill adults at high risk of delirium, the use of prophylactic haloperidol compared with placebo did not improve survival at 28 days. These findings do not support the use of prophylactic haloperidol for reducing mortality in critically ill adults. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01785290
IMPORTANCE: One-year outcomes in patients who have had COVID-19 and who received treatment in the intensive care unit (ICU) are unknown. OBJECTIVE: To assess the occurrence of physical, mental, and ...cognitive symptoms among patients with COVID-19 at 1 year after ICU treatment. DESIGN, SETTING, AND PARTICIPANTS: An exploratory prospective multicenter cohort study conducted in ICUs of 11 Dutch hospitals. Patients (N = 452) with COVID-19, aged 16 years and older, and alive after hospital discharge following admission to 1 of the 11 ICUs during the first COVID-19 surge (March 1, 2020, until July 1, 2020) were eligible for inclusion. Patients were followed up for 1 year, and the date of final follow-up was June 16, 2021. EXPOSURES: Patients with COVID-19 who received ICU treatment and survived 1 year after ICU admission. MAIN OUTCOMES AND MEASURES: The main outcomes were self-reported occurrence of physical symptoms (frailty Clinical Frailty Scale score ≥5, fatigue Checklist Individual Strength—fatigue subscale score ≥27, physical problems), mental symptoms (anxiety Hospital Anxiety and Depression {HADS} subscale score ≥8, depression HADS subscale score ≥8, posttraumatic stress disorder mean Impact of Event Scale score ≥1.75), and cognitive symptoms (Cognitive Failure Questionnaire—14 score ≥43) 1 year after ICU treatment and measured with validated questionnaires. RESULTS: Of the 452 eligible patients, 301 (66.8%) patients could be included, and 246 (81.5%) patients (mean SD age, 61.2 9.3 years; 176 men 71.5%; median ICU stay, 18 days IQR, 11 to 32) completed the 1-year follow-up questionnaires. At 1 year after ICU treatment for COVID-19, physical symptoms were reported by 182 of 245 patients (74.3% 95% CI, 68.3% to 79.6%), mental symptoms were reported by 64 of 244 patients (26.2% 95% CI, 20.8% to 32.2%), and cognitive symptoms were reported by 39 of 241 patients (16.2% 95% CI, 11.8% to 21.5%). The most frequently reported new physical problems were weakened condition (95/244 patients 38.9%), joint stiffness (64/243 patients 26.3%) joint pain (62/243 patients 25.5%), muscle weakness (60/242 patients 24.8%) and myalgia (52/244 patients 21.3%). CONCLUSIONS AND RELEVANCE: In this exploratory study of patients in 11 Dutch hospitals who survived 1 year following ICU treatment for COVID-19, physical, mental, or cognitive symptoms were frequently reported.
Hypoxia is prevalent in atherosclerotic plaques, promoting plaque aggravation and subsequent cardiovascular disease (CVD). Transmembrane protein carbonic anhydrase IX (CAIX) is hypoxia-induced and ...can be shed into the circulation as soluble CAIX (sCAIX). As plaque macrophages are hypoxic, we hypothesized a role for CAIX in macrophage function, and as biomarker of hypoxic plaque burden and CVD. As tumor patients with probable CVD are treated with CAIX inhibitors, this study will shed light on their safety profile. CAIX co-localized with macrophages (CD68) and hypoxia (pimonidazole), and correlated with lipid core size and pro-inflammatory iNOS+ macrophages in unstable human carotid artery plaques. Although elevated pH and reduced lactate levels in culture medium of CAIX knock-out (CAIXko) macrophages confirmed its role as pH-regulator, only spare respiratory capacity of CAIXko macrophages was reduced. Proliferation, apoptosis, lipid uptake and expression of pro- and anti-inflammatory genes were not altered. Plasma sCAIX levels and plaque-resident CAIX were below the detection threshold in 50 and 90% of asymptomatic and symptomatic cases, respectively, while detectable levels did not associate with primary or secondary events, or intraplaque hemorrhage. Initial findings show that CAIX deficiency interferes with macrophage metabolism. Despite a correlation with inflammatory macrophages, plaque-resident and sCAIX expression levels are too low to serve as biomarkers of future CVD.
Objectives
To assess the associations of folate, homocysteine and vitamin B12 levels of children at birth and their methylenetetrahydrofolate reductase (MTHFR) variants with asthma and eczema in ...childhood.
Methods
This study was embedded in a population‐based prospective cohort study (n = 2,001). Neonatal cord blood folate, homocysteine and vitamin B12 levels were measured, and MTHFR C677T and A1298C genotyped. Wheezing and physician‐diagnosed eczema were annually obtained by questionnaire until 4 years. At 6 years, we collected information on physician‐diagnosed asthma ever and self‐reported eczema ever, measured fractional exhaled nitric oxide (FeNO), and interrupter resistance (Rint). Data were analysed with generalized estimating equations or logistic regression: continuous outcomes with linear regression models.
Results
Folate, homocysteine and vitamin B12 levels of children at birth were not associated with wheezing or eczema until 4 years, asthma and eczema ever, or FeNO or Rint at 6 years. In children carrying C677T mutations in MTHFR, higher folate levels were associated with an increased risk of eczema (repeated eczema until 4 years: OR 1.40 (95% CI 1.09–1.80) (SD change) P‐interaction = 0.003, eczema ever at 6 years: OR 1.41 (0.97–2.03) P‐interaction = 0.011). No interactions between MTHFR and child folate and homocysteine levels were observed for wheezing and asthma.
Conclusions
Folate, homocysteine and vitamin B12 levels of children at birth did not affect asthma‐ and eczema‐related outcomes up to the age of 6 years. Further studies are warranted to establish the role of MTHFR variants in these associations.
Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the ...resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer.
This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy.
If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Case series suggest that laparoscopic peritoneal lavage might be a promising alternative to sigmoidectomy in patients with perforated diverticulitis. We aimed to assess the ...superiority of laparoscopic lavage compared with sigmoidectomy in patients with purulent perforated diverticulitis, with respect to overall long-term morbidity and mortality. Methods We did a multicentre, parallel-group, randomised, open-label trial in 34 teaching hospitals and eight academic hospitals in Belgium, Italy, and the Netherlands (the Ladies trial). The Ladies trial is split into two groups: the LOLA group comparing laparoscopic lavage with sigmoidectomy and the DIVA group comparing Hartmann's procedure with sigmoidectomy plus primary anastomosis. The DIVA section of this trial is still underway but here we report the results of the LOLA section. Patients with purulent perforated diverticulitis were enrolled for LOLA, excluding patients with faecal peritonitis, aged older than 85 years, with high-dose steroid use (≥20 mg daily), and haemodynamic instability. Patients were randomly assigned (2:1:1; stratified by age <60 years vs ≥60 years) using secure online computer randomisation to laparoscopic lavage, Hartmann's procedure, or primary anastomosis in a parallel design after diagnostic laparoscopy. Patients were analysed according to a modified intention-to-treat principle and were followed up after the index operation at least once in the outpatient setting and after sigmoidoscopy and stoma reversal, according to local protocols. The primary endpoint was a composite endpoint of major morbidity and mortality within 12 months. This trial is registered with ClinicalTrials.gov , number NCT01317485. Findings Between July 1, 2010, and Feb 22, 2013, 90 patients were randomly assigned in the LOLA section of the Ladies trial when the study was terminated by the data and safety monitoring board because of an increased event rate in the lavage group. Two patients were excluded for protocol violations. The primary endpoint occurred in 30 (67%) of 45 patients in the lavage group and 25 (60%) of 42 patients in the sigmoidectomy group (odds ratio 1·28, 95% CI 0·54–3·03, p=0·58). By 12 months, four patients had died after lavage and six patients had died after sigmoidectomy (p=0·43). Interpretation Laparoscopic lavage is not superior to sigmoidectomy for the treatment of purulent perforated diverticulitis. Funding Netherlands Organisation for Health Research and Development.
This paper presents a community effort to develop good practice guidelines for the validation of global coarse-scale satellite soil moisture products. We provide theoretical background, a review of ...state-of-the-art methodologies for estimating errors in soil moisture data sets, practical recommendations on data pre-processing and presentation of statistical results, and a recommended validation protocol that is supplemented with an example validation exercise focused on microwave-based surface soil moisture products. We conclude by identifying research gaps that should be addressed in the near future.
•Satellite soil moisture validation methods are reviewed•Community-agreed validation good practice guidelines are presented•A standardized satellite soil moisture validation protocol is provided
To study the long-term effect of 16 weeks of etanercept treatment on disease activity and radiographic changes in patients with suspected non-radiographic axial spondyloarthritis (nr-axSpA).
Eighty ...patients with inflammatory back pain and suspected nr-axSpA, with a Bath Ankylosing Disease Activity Index (BASDAI) ≥ 4, received etanercept (n = 40) 25 mg twice weekly or placebo (n = 40) for 16 weeks. They were followed without treatment restrictions after 24 weeks, for up to 3 years. Comparisons were made between patients who received etanercept or placebo in the first period, and changes in BASDAI, Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Metrology Index (BASMI), function, and radiographic changes in the spine according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and sacroiliac joints (Bath Ankylosing Spondylitis Radiology Index (BASRI).
After 3 years of follow-up, 84% of the patients were diagnosed with SpA, predominantly axSpA. Biological treatment was started after 24 weeks in 30% of patients. Disease activity scores after 3 years did not reveal significant differences between the initial randomization groups in mean BASDAI scores (mean difference 0.9, 95% CI -1.1;0.7, p = 0.6) and ASDAS (mean ASDAS 0.3, 95% CI 0.6;3.1, p = 0.5). BASMI and function scores remained stable over 3 years. No differences in radiographic changes of the sacroiliac joints or spine were observed over 3 years between the two groups.
A short course of etanercept in patients with suspected nr-axSpA did not affect disease activity, the chance of biological treatment, or radiographic progression after 3 years of follow-up.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Aims/hypothesis
The hyperglycaemic clamp technique and the frequently sampled IVGTT are unsuitable techniques to assess beta cell function (BCF) in large cohorts. Therefore, the aim of this study was ...to evaluate the discriminatory ability of simple OGTT-based BCF indices for prediction of prediabetes (meaning impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes.
Methods
Glucose metabolism status was assessed by 2 h 75 g OGTT at baseline (
n
= 476, mean age 59.2 years, 38.7% women) and after 7 years of follow-up (
n
= 416) in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (1999–2009). Baseline plasma glucose, insulin and C-peptide values during OGTTs were used to calculate 21 simple indices of BCF. Disposition indices (BCF index × Matsuda index), to compensate for the prevailing level of insulin resistance, were calculated for the BCF indices with the best discriminatory abilities. The discriminatory ability of the BCF indices was estimated by the area under the receiver operating characteristics curve (ROC AUC) with an outcome of incident prediabetes (
n
= 73) or type 2 diabetes (
n
= 60 and
n
= 18 cases, respectively, in individuals who were non-diabetic or had normal glucose metabolism at baseline).
Results
For incident prediabetes (
n
= 73), all ROC AUCs were less than 70%, whereas for incident type 2 diabetes, I
30
/I
0
, CP
30
/CP
0
, ΔI
30
/ΔG
30
, ΔCP
30
/ΔG
30
(where I, CP and G are the plasma concentrations of insulin, C-peptide and glucose, respectively, at the times indicated), and corrected insulin response at 30 min had ROC AUCs over 70%. In at-baseline non-diabetic individuals, disposition indices ΔI
30
/ΔG
30
, ΔCP
30
/ΔG
30
and corrected insulin response at 30 min had ROC AUCs of over 80% for incident type 2 diabetes. Moreover, these BCF disposition indices had significantly better discriminatory abilities for incident type 2 diabetes than the Matsuda index alone.
Conclusions/interpretation
BCF indices reflecting early-phase insulin secretion have the best ability to discriminate individuals who will develop prediabetes and type 2 diabetes. Of these, ΔCP
30
/ΔG
30
, often referred to as the C-peptidogenic index, performed consistently well.
Biofilm accumulation in nanofiltration and reverse osmosis membrane elements results in a relative increase of normalised pressure drop (ΔNPD). However, an increase in ΔNPD is not exclusively linked ...to biofouling. In order to quantify biofouling, the biomass parameters adenosine triphosphate (ATP), total cell count and heterotrophic plate count in membrane elements were investigated during membrane autopsies and compared with ΔNPD in test rigs and 15 full scale investigations with different types of feed water. The combination of biomass related parameters ATP and total cell count in membrane elements seem to be suitable parameters for diagnosis of biofouling, whereas plate counts were not appropriate to assess biofouling. The applied ΔNPD measurement was too insensitive for early detection of fouling. Measurements of biological parameters in the water were shown to be not appropriate in quantifying biofouling. Evidently, there is a need for a practical tool, sensitive pressure drop data and systematic research.
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