Objective:This is the first double-blind, randomized, controlled trial evaluating the efficacy and safety of intravenous immunoglobulin (IVIg) versus placebo in patients with idiopathic small fiber neuropathy (I-SFN).Methods:Between July 2016 and November 2018, 60 Dutch patients with skin-biopsy proven idiopathic SFN randomly received a starting dose of IVIg (2 g/kg body weight) or matching placebo (0.9% saline). Subsequently, 3 additional infusions of IVIg (1 g/kg) or placebo were administered at 3-weekly intervals. The primary outcome was a 1-point change in Pain Intensity Numerical Rating Scale (PI-NRS) at 12 weeks compared to baseline.Results:Thirty patients received IVIg, and 30 received placebo. In both groups, 29 patients completed the trial. In 40% of patients receiving IVIg, the mean average pain was decreased with at least 1 point, compared to 30% of the patients receiving placebo (p-value 0.588, OR 1.56, 95%CI 0.53-4.53). No significant differences were found on any of the other pre-specified outcomes including general wellbeing, autonomic symptoms, and overall functioning and disability.Conclusions:This RCT showed that IVIg treatment had no significant effect on pain in patients with painful idiopathic SFN.

Managing traumatic brain injury (TBI) patients with a cerebral perfusion pressure (CPP) near to the cerebral autoregulation (CA)-guided ''optimal'' CPP (CPPopt) value is associated with improved outcome and might be useful to individualize care, but has never been prospectively evaluated. This study evaluated the feasibility and safety of CA-guided CPP management in TBI patients requiring intracranial pressure monitoring and therapy (TBIicp patients). The CPPopt Guided Therapy: Assessment of Target Effectiveness (COGiTATE) parallel two-arm feasibility trial took place in four tertiary centers. TBIicp patients were randomized to either the Brain Trauma Foundation (BTF) guideline CPP target range (control group) or to the individualized CA-guided CPP targets (intervention group). CPP targets were guided by six times daily software-based alerts for up to 5 days. The primary feasibility end-point was the percentage of time with CPP concordant (-5 mm Hg) with the set CPP targets. The main secondary safety endpoint was an increase in therapeutic intensity level (TIL) between the control and intervention group. Twenty-eight patients were randomized to the control and 32 patients to the intervention group. CPP in the intervention group was in the target range for 46.5% (interquartile range, 41.2-58) of the monitored time, significantly higher than the feasibility target specified in the published protocol (36%; p < 0.001). There were no significant differences between groups for TIL or for other safety end-points. Conclusively, targeting an individual and dynamic CA-guided CPP is feasible and safe in TBIicp patients. This encourages a prospective trial powered for clinical outcomes.

A statistical hypothesis is a statement that can be tested by collecting data and making observations. Before you start data collection and perform your research, you need to formulate your hypothesis. An example hypothesis could be for instance: "If I increase the prescribed radiation dose to the tumor, this will also lead to an increase of side-effects in surrounding healthy tissues". The purpose of statistical hypothesis testing is to find out whether the observations are meaningful or can be attributed to noise or chance.

Topical imiquimod could be an alternative, noninvasive, treatment modality for high-grade cervical intraepithelial neoplasia (CIN). However, evidence is limited, and there are no studies that compared treatment effectiveness and side effects of topical imiquimod cream to standard large loop excision of the transformation zone (LLETZ) treatment. A multi-center, nonrandomized controlled trial was performed among women with a histologic diagnosis of CIN 2/3. Women were treated with either vaginal imiquimod (6.25 mg 3 times weekly for 8 to 16 wk) or LLETZ according to their own preference. Successful treatment was defined as the absence of high-grade dysplasia at the first follow-up interval after treatment (at 20 wk for the imiquimod group and at 26 wk for the LLETZ group). Secondary outcome measures were high-risk human papillomavirus (hrHPV) clearance, side effects, and predictive factors for successful imiquimod treatment. Imiquimod treatment was successful in 60% of women who completed imiquimod treatment and 95% of women treated with LLETZ. hrHPV clearance occurred in 69% and 67% in the imiquimod group and LLETZ group, respectively. This study provides further evidence on topical imiquimod cream as a feasible and safe treatment modality for high-grade CIN. Although the effectiveness is considerably lower than LLETZ treatment, imiquimod treatment could prevent initial surgical treatment in over 40% of women and should be offered to a selected population of women who wish to avoid (repeated) surgical treatment of high-grade CIN.

Cognition in absence epilepsy (AE) is generally considered undisturbed. However, reports on cognitive deficits in AE in recent years have suggested otherwise. This review systematically assesses current literature on cognitive performance in children with AE. A systematic literature search was performed in Pubmed, Embase, Cochrane and Web of Science. All studies reporting on cognitive performance in children with AE were considered. In total 33 studies were eligible for inclusion. Neuropsychological tests were classified into the following domains: intelligence; executive function; attention; language; motor & sensory-perceptual examinations; visuoperceptual/visuospatial/visuoconstructional function; memory and learning; achievement. Random-effect meta-analyses were conducted by estimating the pooled mean and/or pooling the mean difference in case-control studies. Full-scale IQ in children with AE was estimated at 96.78 (95%CI:94.46–99.10) across all available studies and in case-control studies IQ was on average 8.03 (95%CI:-10.45- -5.61) lower. Verbal IQ was estimated at 97.98 (95%CI:95.80–100.16) for all studies and 9.01 (95%CI:12.11- -5.90) points lower in case-control studies. Performance IQ was estimated at 97.23 (93.24–101.22) for all available studies and 5.32 (95%CI:-8.27–2.36) points lower in case-control studies. Lower performance was most often reported in executive function (cognitive flexibility, planning, and verbal fluency) and attention (sustained, selective and divided attention). Reports on school difficulties, neurodevelopmental problems, and attentional problems were high. In conclusion, in contrast to common beliefs, lower than average neurocognitive performance was noted in multiple cognitive domains, which may influence academic and psychosocial development.Electronic supplementary materialThe online version of this article (10.1007/s11065-019-09419-2) contains supplementary material, which is available to authorized users.

Preeclampsia is often preceded by abnormal hemodynamic changes with heterogeneous patterns in the first half of pregnancy. We assessed the effect of timely tailored correction of nonphysiological hemodynamic changes on preventing preeclampsia in a high-risk population. Primiparous women with a history of preeclampsia were invited to participate in a longitudinal program in their next pregnancy, including repeated hemodynamic assessments at 12-, 16-, 20- and 30-week gestation additional to regular pregnancy checkups. When at least 2 of the hemodynamic variables were not within physiological reference values, the hemodynamic imbalance between cardiac output and peripheral vascular resistance was counteracted with either labetalol, methyldopa, or nifedipine using a simple treatment algorithm. Normogram-guided women (n=157) were matched to 157 women receiving care as usual (power, 80%; α=0.05). Risk of recurrent preeclampsia was analyzed with logistic regression adjusted for daily low-dose aspirin or calcium supplementation. Hemodynamic changes were considered nonphysiological in 90% of women in the normogram-guided group. Twelve percent of these women developed recurrent preeclampsia compared with 22% in the care-as-usual group (adjusted odds ratio, 0.47 [95% CI, 0.25–0.88]). There were no differences between groups in gestational age at delivery (38 1 and 38 2 weeks in the normogram-guided and care-as-usual groups, respectively) and neonatal birth weight (3148 and 3180 g in the normogram-guided and care-as-usual groups, respectively). Tailored circulatory normalization of nonphysiological hemodynamic changes during pregnancy halves the risk of recurrent preeclampsia, without disadvantageous effects on offspring outcome. This simple and innovative treatment strategy may also be beneficial to other women at increased risk for preeclampsia in pregnancy. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04216706.

OBJECTIVES: Data about inhospital outcomes in bleeding complications during extracorporeal life support (ECLS) have been poorly investigated. DESIGN: Retrospective observational study. SETTING: Patients reported in Extracorporeal Life Support Organization Registry. PATIENTS: Data of 53.644 adult patients (greater than or equal to 18 yr old) mean age 51.4 ± 15.9 years, 33.859 (64.5%) male supported with single ECLS run between 01.01.2000 and 31.03.2020, and 19.748 cannulated for venovenous (V-V) ECLS and 30.696 for venoarterial (V-A) ECLS. INTERVENTIONS: Trends in bleeding complications, bleeding risk factors, and mortality. MEASUREMENT AND MAIN RESULTS: Bleeding complications were reported in 14.786 patients (27.6%), more often in V-A ECLS compared with V-V (30.0% vs 21.9%; p < 0.001). Hospital survival in those who developed bleeding complications was lower in both V-V ECLS (49.6% vs 66.6%; p < 0.001) and V-A ECLS (33.9 vs 44.9%; p < 0.001). Steady decrease in bleeding complications in V-V and V-A ECLS was observed over the past 20 years (coef., –1.124; p < 0.001 and –1.661; p < 0.001). No change in mortality rates was reported over time in V-V or V-A ECLS (coef., –0.147; p = 0.442 and coef., –0.195; p = 0.139). Multivariate regression revealed advanced age, ecls duration, surgical cannulation, renal replacement therapy, prone positioning as independent bleeding predictors in v-v ecls and female gender, ecls duration, pre-ecls arrest or bridge to transplant, therapeutic hypothermia, and surgical cannulation in v-a ecls. CONCLUSIONS: A steady decrease in bleeding over the last 20 years, mostly attributable to surgical and cannula-site–related bleeding has been found in this large cohort of patients receiving ECLS support. However, there is not enough data to attribute the decreasing trends in bleeding to technological refinements alone. Especially reduction in cannulation site bleeding is also due to changes in timing, patient selection, and ultrasound guided percutaneous cannulation. Other types of bleeding, such as CNS, have remained stable, and overall bleeding remains associated with a persistent increase in mortality.

Background The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism. Methods In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants. Results Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of − 0.9 g/L (95% CI: − 1.6 – − 0.1) and lower average ferritin concentration of − 1045 μg/L (95% CI: − 1983 – − 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 μg/L (− 6212–7334) and 27 mg/L (− 32–86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer. Conclusion Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels.