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Background Propensity score (PS) methods are increasingly used, even when sample sizes are small or treatments are seldom used. However, the relative performance of the two mainly recommended PS methods, namely PS-matching or inverse probability of treatment weighting (IPTW), have not been studied in the context of small sample sizes. Methods We conducted a series of Monte Carlo simulations to evaluate the influence of sample size, prevalence of treatment exposure, and strength of the association between the variables and the outcome and/or the treatment exposure, on the performance of these two methods. Results Decreasing the sample size from 1,000 to 40 subjects did not substantially alter the Type I error rate, and led to relative biases below 10%. The IPTW method performed better than the PS-matching down to 60 subjects. When N was set at 40, the PS matching estimators were either similarly or even less biased than the IPTW estimators. Including variables unrelated to the exposure but related to the outcome in the PS model decreased the bias and the variance as compared to models omitting such variables. Excluding the true confounder from the PS model resulted, whatever the method used, in a significantly biased estimation of treatment effect. These results were illustrated in a real dataset. Conclusion Even in case of small study samples or low prevalence of treatment, PS-matching and IPTW can yield correct estimations of treatment effect unless the true confounders and the variables related only to the outcome are not included in the PS model.

In patients with convulsive status epilepticus, the addition of cooling to 32 to 34°C for 24 hours did not have a significant effect on the percentage of patients with good outcomes at 90 days as compared with standard seizure treatment alone. Convulsive status epilepticus is among the most challenging life-threatening neurologic emergencies. 1 Antiepileptic drug treatment is initiated rapidly and adjusted in response to clinical and electroencephalographic (EEG) findings. 2 The in-hospital mortality associated with this condition is approximately 20% and, if status epilepticus remains refractory to treatment, can be as high as 40%. 3 – 7 Functional impairments after status epilepticus may be due to the effect of seizures on cortical neurons or to cerebral damage due to the underlying process that caused the seizures. In a prospective, multicenter study, 50% of survivors of convulsive status epilepticus who were admitted to an intensive care . . .

The best catecholamine regimen for cardiogenic shock has been poorly evaluated. When a vasopressor is required to treat patients with the most severe form of cardiogenic shock, whether inodilators should be added or whether inopressors can be used alone has not been established. The purpose of this study was to compare the impact of these two strategies on short-term mortality in patients with severe cardiogenic shocks. Three observational cohorts of patients with decompensated heart failure were pooled to comprise a total of 1,272 patients with cardiogenic shocks. Of these 1,272 patients, 988 were considered to be severe because they required a vasopressor during the first 24 hours. We developed a propensity-score (PS) model to predict the individual probability of receiving one of the two regimens (inopressors alone or a combination) conditionally on baseline-measured covariates. The benefit of the treatment regimen on the mortality rate was estimated by fitting a weighted Cox regression model. A total of 643 patients (65.1%) died within the first 30 days (inopressors alone: 293 (72.0%); inopressors and inodilators: 350 (60.0%)). After PS weighting, we observed that the use of an inopressor plus an inodilator was associated with an improved short-term mortality (HR: 0.66 [0.55-0.80]) compared to inopressors alone. In the most severe forms of cardiogenic shock where a vasopressor is immediately required, adding an inodilator may improve short-term mortality. This result should be confirmed in a randomized, controlled trial.

Background Multiple imputation by chained equations (MICE) requires specifying a suitable conditional imputation model for each incomplete variable and then iteratively imputes the missing values. In the presence of missing not at random (MNAR) outcomes, valid statistical inference often requires joint models for missing observations and their indicators of missingness. In this study, we derived an imputation model for missing binary data with MNAR mechanism from Heckman’s model using a one-step maximum likelihood estimator. We applied this approach to improve a previously developed approach for MNAR continuous outcomes using Heckman’s model and a two-step estimator. These models allow us to use a MICE process and can thus also handle missing at random (MAR) predictors in the same MICE process. Methods We simulated 1000 datasets of 500 cases. We generated the following missing data mechanisms on 30% of the outcomes: MAR mechanism, weak MNAR mechanism, and strong MNAR mechanism. We then resimulated the first three cases and added an additional 30% of MAR data on a predictor, resulting in 50% of complete cases. We evaluated and compared the performance of the developed approach to that of a complete case approach and classical Heckman’s model estimates. Results With MNAR outcomes, only methods using Heckman’s model were unbiased, and with a MAR predictor, the developed imputation approach outperformed all the other approaches. Conclusions In the presence of MAR predictors, we proposed a simple approach to address MNAR binary or continuous outcomes under a Heckman assumption in a MICE procedure.

Charles Chiu and colleagues analyze the gut viromes of recipients of hematopoietic stem cell transplantation and identify characteristics associated with the severity of graft-versus-host disease in the gut. Much attention has been focused on the role of the bacterial microbiome in human health, but the virome is understudied. Although previously investigated in individuals with inflammatory bowel diseases or solid-organ transplants 1 , 2 , virome dynamics in allogeneic hematopoietic stem cell transplantation (HSCT) and enteric graft-versus-host disease (GVHD) remain unexplored. Here we characterize the longitudinal gut virome in 44 recipients of HSCT using metagenomics. A viral 'bloom' was identified, and significant increases were demonstrated in the overall proportion of vertebrate viral sequences following transplantation ( P = 0.02). Increases in both the rates of detection ( P < 0.0001) and number of sequences ( P = 0.047) of persistent DNA viruses (anelloviruses, herpesviruses, papillomaviruses and polyomaviruses) over time were observed in individuals with enteric GVHD relative to those without, a finding accompanied by a reduced phage richness ( P = 0.01). Picobirnaviruses were detected in 18 individuals (40.9%), more frequently before or within a week after transplant than at later time points ( P = 0.008). In a time-dependent Cox proportional-hazards model, picobirnaviruses were predictive of the occurrence of severe enteric GVHD (hazard ratio, 2.66; 95% confidence interval (CI) = 1.46–4.86; P = 0.001), and correlated with higher fecal levels of two GVHD severity markers, calprotectin and α1-antitrypsin. These results reveal a progressive expansion of vertebrate viral infections over time following HSCT, and they suggest an unexpected association of picobirnaviruses with early post-transplant GVHD.

Background Intensive care unit (ICU) survivors have reduced long-term survival compared to the general population. Identifying parameters at ICU discharge that are associated with poor long-term outcomes may prove useful in targeting an at-risk population. The main objective of the study was to identify clinical and biological determinants of death in the year following ICU discharge. Methods FROG-ICU was a prospective, observational, multicenter cohort study of ICU survivors followed 1 year after discharge, including 21 medical, surgical or mixed ICUs in France and Belgium. All consecutive patients admitted to intensive care with a requirement for invasive mechanical ventilation and/or vasoactive drug support for more than 24 h following ICU admission and discharged from ICU were included. The main outcome measure was all-cause mortality at 1 year after ICU discharge. Clinical and biological parameters on ICU discharge were measured, including the circulating cardiovascular biomarkers N-terminal pro-B type natriuretic peptide, high-sensitive troponin I, bioactive-adrenomedullin and soluble-ST2. Socioeconomic status was assessed using a validated deprivation index (FDep). Results Of 1570 patients discharged alive from the ICU, 333 (21%) died over the following year. Multivariable analysis identified age, comorbidity, red blood cell transfusion, ICU length of stay and abnormalities in common clinical factors at the time of ICU discharge (low systolic blood pressure, temperature, total protein, platelet and white cell count) as independent factors associated with 1-year mortality. Elevated biomarkers of cardiac and vascular failure independently associated with 1-year death when they are added to multivariable model, with an almost 3-fold increase in the risk of death when combined (adjusted odds ratio 2.84 (95% confidence interval 1.73–4.65), p  < 0.001). Conclusions The FROG-ICU study identified, at the time of ICU discharge, potentially actionable clinical and biological factors associated with poor long-term outcome after ICU discharge. Those factors may guide discharge planning and directed interventions. Trial registration ClinicalTrials.gov NCT01367093 . Registered on 6 June 2011.

Although the treatment of iatrogenic and HIV-related Kaposi sarcoma is well defined and mostly based on restoring immune function, the treatment of classic and endemic Kaposi sarcoma is less well established. Chemotherapy or interferon α is used for patients with extensive cutaneous or visceral Kaposi sarcoma, but tolerance might be poor and long-term remission is rare. We aimed to evaluate the activity of pembrolizumab in classic and endemic Kaposi sarcoma with cutaneous extension requiring systemic treatment. We did a multicentre, single-arm, proof-of-concept, phase 2 trial in adults aged 18 years or older with histologically proven classic or endemic Kaposi's sarcoma with progressive cutaneous extension requiring systemic treatment and an Eastern Cooperative Oncology Group performance status of 0–1 in three hospitals in France. The patients were treated with 200 mg pembrolizumab intravenously every 3 weeks for 6 months (eight cycles) or until severe toxicity. The primary endpoint was the best overall response rate within the 6-month timeframe, defined by the occurrence of a complete response or partial response and assessed by an investigator using the modified AIDS Clinical Trial Group (ACTG) criteria. Three or more responses among a total 17 patients were needed for the primary endpoint to be met, using a Simon's two-stage optimal design assuming a 30% response rate as desirable. For this final study analysis, all patients were included following the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT03469804, and is closed to new participants. 30 patients were screened for eligibility and 17 patients (eight [47%] with classic and nine [53%] with endemic Kaposi's sarcoma) were enrolled between July 2, 2018, and Dec 16, 2019. The median follow-up was 20·4 months (IQR 18·1–24·1). Two (12%) patients had a complete response, ten (59%) had a partial response, and five (29%) had stable disease as the best response within the 6-month treatment timeframe, with a best overall response rate of 71% (95% CI 44–90), meeting the predefined primary outcome (ie, exceeding a response rate of 30%). Treatment-related adverse events occurred in 13 (76%) of 17 patients, including two grade 3 adverse events (one [6%] acute cardiac decompensation and one [6%] granulomatous reaction). Treatment was prematurely discontinued in two (12%) patients due to grade 3 acute reversible cardiac decompensation and grade 2 pancreatitis, and one other patient had a grade 3 granulomatous reaction in mediastinal lymph nodes requiring steroids and methotrexate treatment. There were no serious adverse events or treatment-related deaths. In this prospective trial, which to our knowledge is the first to assess the role of PD-1 blockade in patients with classic and endemic Kaposi's sarcoma, pembrolizumab showed promising anti-tumour activity with an acceptable safety profile. If this result is supported by further studies, treatment with anti-PD-1 could be part of the therapeutic armamentarium for patients with classic and endemic Kaposi's sarcoma. MSD France.

BACKGROUND:In contrast to benign meningiomas, malignant meningiomas (MM) are rare and associated with an unfavourable prognosis. Reports on MM concern fairly small cohorts, often comprising less than 30 cases. OBJECTIVE:To describe the outcome MM and identify factors that may influence survival. METHODS:Pathology reports and clinical data of 178 patients treated between 1989 and 2017 for a MM at 6 different international institutions were retrospectively reviewed. Seventy-six patients (42.7%) had a previous history of grade I or grade II meningioma. The patients underwent a total of 380 surgical resections and 72.5% received radiotherapy. Median follow-up was 4.5 yr. RESULTS:At data collection, 111 patients were deceased (63.4%) and only 23 patients (13.7%) were alive without any residual tumor on the most recent scan. Median overall survival was 2.9 yr, 95% confidence interval [CI; 2.4, 4.5]. Overall survival rates at 1, 5, and 10 yr, respectively, were77.7%, 95% CI [71.6, 84.3], 40%, 95% CI [32.7, 49], and 27.9%, 95% CI [20.9, 37.3]. In the multivariable analysis, age at MM surgery <65 yr (hazard ratio [HR] = 0.44, 95% CI [0.29, 0.67], P < .001), previous benign or atypical meningioma surgery (HR = 1.9, 95% CI [1.23, 2.92], P = .004), completeness of resection (HR = 0.51, 95% CI [0.34, 0.78], P = .002), and adjuvant radiotherapy (HR = 0.64, 95% CI [0.42, 0.98], P = .039) were established as independent prognostic factors for survival. CONCLUSION:This large series confirms the poor prognosis associated with MM, the treatment of which remains challenging. Patients under 65-yr-old with primary MM may live longer after complete resection and postoperative radiotherapy. Even with aggressive treatments, local control remains difficult to achieve.

Metastatic melanoma can be treated with anti-PD-1 monotherapy or in combination with anti-CTLA-4 or anti-Lag3. However, combination therapy is associated with a high risk of toxicity. Recently, we reported that high plasma soluble CD27 (sCD27) levels reflect the intratumoral interaction of CD70-CD27 and dysfunctional T cells in the tumor microenvironment of renal cell carcinoma. In this study, we first characterized the intratumoral expression of CD70 and CD27 in melanoma tumors and their interaction in vivo. We then reported a significant association between baseline sCD27 and anti-PD-1 resistance as assessed by progression-free survival, overall survival, or 12-month complete response in two prospective cohorts of melanoma patients. Multivariate analysis confirmed that sCD27 was independently associated with clinical outcomes. Notably, sCD27 did not predict clinical response to combination therapy in either cohort. This differential predictive value of sCD27 for the two therapeutic options was later confirmed by propensity score analysis. Our results suggest that high plasma sCD27 levels predict poorer efficacy of anti-PD1 monotherapy in metastatic melanoma, justifying therapeutic escalation with a combination of anti-PD1 and anti-CTLA-4. Synopsis Predictive biomarkers of immunotherapy response are critical for clinical practice. In this study, baseline plasma sCD27 was identified as a reliable biomarker discriminating response to anti-PD-1 versus anti-PD-1 + anti-CTLA-4 in two independent melanoma patient cohorts. In the melanoma tumor microenvironment, CD27 interacts more with CD70-expressing non-tumor cells than with CD70-expressing tumor cells. Elevated baseline plasma sCD27 predicts poor outcome in melanoma patients treated with anti-PD-1, while no difference in response is observed in patients treated with anti-PD-1 plus anti-CTLA-4. The predictive value of sCD27 is independent of other clinical parameters as shown by multivariate analysis. The differential value of sCD27 in predicting response to anti-PD-1 and combination therapy was confirmed by propensity score analysis. Predictive biomarkers of immunotherapy response are critical for clinical practice. In this study, baseline plasma sCD27 was identified as a reliable biomarker discriminating response to anti-PD-1 versus anti-PD-1 + anti-CTLA-4 in two independent melanoma patient cohorts.

Background Diffuse alveolar hemorrhage (DAH) occurs during the course of autoimmune disease and may be life threatening. The objective was to assess characteristics and prognosis factors of DAH who required intensive care unit (ICU) admission in patients with autoimmune diseases. Methods French multicenter retrospective study including patients presenting DAH related to autoimmune diseases requiring ICU admission from 2000 to 2016. Results One hundred four patients (54% of men) with median age of 56 [32–68] years were included with 79 (76%) systemic vasculitis and 25 (24%) connective tissue disorders. All patients received steroids, and 72 (69%), 12 (11.5%), and 57 (55%) patients had cyclophosphamide, rituximab, and plasma exchanges, respectively. During ICU stay, 52 (50%), 36 (35%), and 55 (53%) patients required mechanical ventilation, vasopressor use, and renal replacement therapy, respectively. Factors associated with mechanical ventilation weaning were age (HR [95%CI] 0.97 [0.96–0.99] per 10 years, p  < 0.0001), vasculitis-related DAH (0.52 [0.27–0.98], p  = 0.04), and time from dyspnea onset to ICU admission (0.99 [0.99–1] per day, p  = 0.03). ICU mortality was 15%. Factors associated with alive status at ICU discharge were chronic cardiac failure (HR [95%CI] 0.37 [0.15–0.94], p  = 0.04), antiphospholipid syndrome-related DAH (3.17 [1.89–5.32], p  < 0.0001), SAPS II (0.98 [0.97–0.99], p  = 0.007), and oxygen flow at ICU admission (0.95 [0.91–0.99] per liter/min, p  = 0.04). Conclusion DAH in autoimmune diseases is a life-threatening complication which requires mechanical ventilation in half of the cases admitted to ICU.