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Spontaneous intracerebral hemorrhage (ICH) results in high rates of morbidity and mortality, with intraventricular hemorrhage (IVH) being associated with even worse outcomes. Therapeutic interventions in acute ICH have continued to emerge with focus on arresting hemorrhage expansion, clot volume reduction of both intraventricular and parenchymal hematomas, and targeting perihematomal edema and inflammation. Large randomized controlled trials addressing the effectiveness of rapid blood pressure lowering, hemostatic therapy with platelet transfusion, and other clotting complexes and hematoma volume reduction using minimally invasive techniques have impacted clinical guidelines. We review the recent evolution in the management of acute spontaneous ICH, discussing which interventions have been shown to be safe and which may potentially improve outcomes.

Intracerebral haemorrhage is an important public health problem leading to high rates of death and disability in adults. Although the number of hospital admissions for intracerebral haemorrhage has increased worldwide in the past 10 years, mortality has not fallen. Results of clinical trials and observational studies suggest that coordinated primary and specialty care is associated with lower mortality than is typical community practice. Development of treatment goals for critical care, and new sequences of care and specialty practice can improve outcome after intracerebral haemorrhage. Specific treatment approaches include early diagnosis and haemostasis, aggressive management of blood pressure, open surgical and minimally invasive surgical techniques to remove clot, techniques to remove intraventricular blood, and management of intracranial pressure. These approaches improve clinical management of patients with intracerebral haemorrhage and promise to reduce mortality and increase functional survival.

In this randomized trial involving patients with intracerebral hemorrhage, intensive reduction in systolic blood pressure to a target of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. An acute hypertensive response in patients with intracerebral hemorrhage is common 1 and may be associated with hematoma expansion and increased mortality. 2 , 3 , 4 The second Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial 5 (INTERACT2) included patients with spontaneous intracerebral hemorrhage who had a systolic blood pressure of 150 to 220 mm Hg within 6 hours after symptom onset. The rate of death or disability among patients randomly assigned to intensive reduction in the systolic blood-pressure level, with a target systolic blood pressure of less than 140 mm Hg within 1 hour, was nonsignificantly lower than the rate among those . . .

A care bundle is a small but crucial set of treatments that, when implemented together, can improve outcomes.1 Acute spontaneous intracerebral haemorrhage has few effective treatments and intracerebral haemorrhage-specific recommendations for care bundles.2,3 In clinical practice, intracerebral haemorrhage is often approached with negativity.4 Moreover, the synergistic benefits of specialised nursing care, neurointensive and neurosurgical care, blood pressure control, reversal of coagulopathy, and other interventions have not been ascertained.5 In The Lancet, Lu Ma and colleagues6 report the results of INTERACT3, a cluster randomised, pragmatic, multicentre, blinded endpoint, stepped wedge controlled trial performed in 144 hospitals in ten predominantly low-income and middle-income countries to investigate the efficacy and safety of a care bundle incorporating early intensive blood pressure lowering and management protocols for hyperglycaemia, pyrexia, and abnormal anticoagulation in patients with intracerebral haemorrhage presenting within 6 h of symptom onset. The percentage of patients with the early withdrawal of active life support was minimal (<1%), but patient location after hospital admission might have been a bias since intensive care unit admission was 5% higher in the care bundle group than the usual care group, as was the use of intravenous blood pressure lowering treatments on days 2–7, typically an intensive care unit intervention. [...]the absence of level 1 evidence for all bundle components might affect acceptance, especially for blood pressure control, where guidelines have differed.6–8 INTERACT 3 is promising, demonstrating that an intracerebral haemorrhage care bundle focused on physiological control interventions, whether synergistic or not, might promote better outcomes in hospitals where care has not previously optimised sustained interventions.

Anhydramnios secondary to anuria before 22 weeks of gestational age and congenital bilateral renal agenesis before 26 weeks of gestational age are collectively referred to as early-pregnancy renal anhydramnios. Early-pregnancy renal anhydramnios occurs in at least 1 in 2000 pregnancies and is considered universally fatal when left untreated because of severe pulmonary hypoplasia precluding ex utero survival The Renal Anhydramnios Fetal Therapy (RAFT) trial is a nonrandomized, nonblinded, multicenter clinical trial designed to assess the efficacy, safety, and feasibility of amnioinfusions for patients with pregnancies complicated by early-pregnancy renal anhydramnios. The primary objective of this study is to determine the proportion of neonates surviving to successful dialysis, defined as use of a dialysis catheter for ≥14 days. A consortium of 9 North American Fetal Therapy Network (NAFTNet) centers was formed, and the RAFT protocol was refined in collaboration with the NAFTNet Scientific Committee. Enrollment in the trial began in April 2020. Participants may elect to receive amnioinfusions or to join the nonintervention observational expectant management group. Eligible pregnant women must be at least 18 years of age with a fetal diagnosis of isolated early-pregnancy renal anhydramnios. In addition to the primary study objective stated above, secondary objectives include (1) to assess maternal safety and feasibility of the serial amnioinfusion intervention (2) to perform an exploratory study of the natural history of untreated early pregnancy renal anhydramnios (3) to examine correlations between prenatal imaging and lung specific factors in amniotic fluid as predictive of the efficacy of serial percutaneous amnioinfusions and (4) to determine short- and long-term outcomes and quality of life in surviving neonates and families enrolled in RAFT The RAFT trial is the first clinical trial to investigate the efficacy, safety, and feasibility of amnioinfusions to treat the survival-limiting pulmonary hypoplasia associated with anhydramnios. Although the intervention offers an opportunity to treat a condition known to be almost universally fatal in affected neonates, the potential burdens associated with end-stage kidney disease from birth must be acknowledged. ClinicalTrials.gov identifier: NCT03101891.

X-ray computed tomography (CT) imaging of the brain is commonly used in diagnostic settings. Although CT scans are primarily used in clinical practice, they are increasingly used in research. A fundamental processing step in brain imaging research is brain extraction — the process of separating the brain tissue from all other tissues. Methods for brain extraction have either been 1) validated but not fully automated, or 2) fully automated and informally proposed, but never formally validated. To systematically analyze and validate the performance of FSL's brain extraction tool (BET) on head CT images of patients with intracranial hemorrhage. This was done by comparing the manual gold standard with the results of several versions of automatic brain extraction and by estimating the reliability of automated segmentation of longitudinal scans. The effects of the choice of BET parameters and data smoothing is studied and reported. All images were thresholded using a 0–100Hounsfield unit (HU) range. In one variant of the pipeline, data were smoothed using a 3-dimensional Gaussian kernel (σ=1mm3) and re-thresholded to 0–100HU; in the other, data were not smoothed. BET was applied using 1 of 3 fractional intensity (FI) thresholds: 0.01, 0.1, or 0.35 and any holes in the brain mask were filled. For validation against a manual segmentation, 36 images from patients with intracranial hemorrhage were selected from 19 different centers from the MISTIE (Minimally Invasive Surgery plus recombinant-tissue plasminogen activator for Intracerebral Evacuation) stroke trial. Intracranial masks of the brain were manually created by one expert CT reader. The resulting brain tissue masks were quantitatively compared to the manual segmentations using sensitivity, specificity, accuracy, and the Dice Similarity Index (DSI). Brain extraction performance across smoothing and FI thresholds was compared using the Wilcoxon signed-rank test. The intracranial volume (ICV) of each scan was estimated by multiplying the number of voxels in the brain mask by the dimensions of each voxel for that scan. From this, we calculated the ICV ratio comparing manual and automated segmentation: ICVautomatedICVmanual. To estimate the performance in a large number of scans, brain masks were generated from the 6 BET pipelines for 1095 longitudinal scans from 129 patients. Failure rates were estimated from visual inspection. ICV of each scan was estimated and an intraclass correlation (ICC) was estimated using a one-way ANOVA. Smoothing images improves brain extraction results using BET for all measures except specificity (all p<0.01, uncorrected), irrespective of the FI threshold. Using an FI of 0.01 or 0.1 performed better than 0.35. Thus, all reported results refer only to smoothed data using an FI of 0.01 or 0.1. Using an FI of 0.01 had a higher median sensitivity (0.9901) than an FI of 0.1 (0.9884, median difference: 0.0014, p<0.001), accuracy (0.9971 vs. 0.9971; median difference: 0.0001, p<0.001), and DSI (0.9895 vs. 0.9894; median difference: 0.0004, p<0.001) and lower specificity (0.9981 vs. 0.9982; median difference: −0.0001, p<0.001). These measures are all very high indicating that a range of FI values may produce visually indistinguishable brain extractions. Using smoothed data and an FI of 0.01, the mean (SD) ICV ratio was 1.002 (0.008); the mean being close to 1 indicates the ICV estimates are similar for automated and manual segmentation. In the 1095 longitudinal scans, this pipeline had a low failure rate (5.2%) and the ICC estimate was high (0.929, 95% CI: 0.91, 0.945) for successfully extracted brains. BET performs well at brain extraction on thresholded, 1mm3 smoothed CT images with an FI of 0.01 or 0.1. Smoothing before applying BET is an important step not previously discussed in the literature. Analysis code is provided. •We present a fully automated brain extraction procedure for CT scans adapting the BET from FSL.•We investigated the effect smoothing the data before using BET; smoothing improves performance.•We varied the fractional intensity using 0.01, 0.1, and 0.35. FI of 0.01 and 0.1 performed best.•We validated against a gold standard — accuracy and Dice overlap of automated segmentation was high.

We present a new estimator of the restricted mean survival time in randomized trials where there is right censoring that may depend on treatment and baseline variables. The proposed estimator leverages prognostic baseline variables to obtain equal or better asymptotic precision compared to traditional estimators. Under regularity conditions and random censoring within strata of treatment and baseline variables, the proposed estimator has the following features: (i) it is interpretable under violations of the proportional hazards assumption; (ii) it is consistent and at least as precise as the Kaplan–Meier and inverse probability weighted estimators, under identifiability conditions; (iii) it remains consistent under violations of independent censoring (unlike the Kaplan–Meier estimator) when either the censoring or survival distributions, conditional on covariates, are estimated consistently; and (iv) it achieves the nonparametric efficiency bound when both of these distributions are consistently estimated. We illustrate the performance of our method using simulations based on resampling data from a completed, phase 3 randomized clinical trial of a new surgical treatment for stroke; the proposed estimator achieves a 12% gain in relative efficiency compared to the Kaplan–Meier estimator. The proposed estimator has potential advantages over existing approaches for randomized trials with time-to-event outcomes, since existing methods either rely on model assumptions that are untenable in many applications, or lack some of the efficiency and consistency properties (i)–(iv). We focus on estimation of the restricted mean survival time, but our methods may be adapted to estimate any treatment effect measure defined as a smooth contrast between the survival curves for each study arm. We provide R code to implement the estimator.

Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients.

[...]we urge caution in the combination of proxy responses and patient responses or in the isolated use of proxy reports to precisely characterize patient status until the sources of biases are fully understood. Health-related quality of life should be reported by those experiencing the life lived. [...]this is possible for patients with acute neurologic injury, who are unable to report their perspective, stating the limitations of data obtained from proxy reports and the impact of biases in any analysis is critical to the interpretation and use of such proxy data. Using and understanding the patient’s perspective may provide a more accurate representation of the potential value of recovery following brain injury and may allow for an informed shared decision-making process during the acute phase of injury that incorporates patients’ perspectives of their long-term health-related quality of life.