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A large Scandinavian randomized trial showed no important outcome differences between hemoglobin levels of 7 g per deciliter and 9 g per deciliter as transfusion thresholds in patients with septic shock. Blood transfusions are frequently given to patients with septic shock. 1 – 4 Some of these transfusions are given to patients who are bleeding, but many nonbleeding patients also undergo transfusion. 5 The recommendations of the Surviving Sepsis Campaign regarding blood transfusion in patients with septic shock are complex and include a recommendation for transfusion to maintain a hematocrit of more than 30% in the presence of hypoperfusion in the first 6 hours. 6 After that, the transfusion threshold should be a hemoglobin level of less than 7 g per deciliter, aiming at levels between 7 g and 9 g per deciliter in patients . . .

In this study, patients with severe sepsis were assigned to fluid resuscitation with starch (HES 130/0.4) or Ringer's acetate. The starch group had an increased risk of death at day 90 and increased use of renal-replacement therapy, as compared with the Ringer's acetate group. Intravenous fluids are the mainstay of treatment for patients with hypovolemia due to severe sepsis. Colloid solutions are used to obtain rapid and lasting circulatory stabilization, but there are limited data to support this practice. 1 The Surviving Sepsis Campaign guidelines recommend the use of either colloids or crystalloids, 2 but high-molecular-weight hydroxyethyl starch (HES) may cause acute kidney failure in patients with severe sepsis, as observed in two randomized trials. 3 , 4 Those trials had substantial limitations, and participants received HES solutions with a molecular weight of 200 kD and a substitution ratio (the number of hydroxyethyl groups per glucose molecule) of . . .

Intravenous fluids are recommended for the treatment of patients who are in septic shock, but higher fluid volumes have been associated with harm in patients who are in the intensive care unit (ICU). In this international, randomized trial, we assigned patients with septic shock in the ICU who had received at least 1 liter of intravenous fluid to receive restricted intravenous fluid or standard intravenous fluid therapy; patients were included if the onset of shock had been within 12 hours before screening. The primary outcome was death from any cause within 90 days after randomization. We enrolled 1554 patients; 770 were assigned to the restrictive-fluid group and 784 to the standard-fluid group. Primary outcome data were available for 1545 patients (99.4%). In the ICU, the restrictive-fluid group received a median of 1798 ml of intravenous fluid (interquartile range, 500 to 4366); the standard-fluid group received a median of 3811 ml (interquartile range, 1861 to 6762). At 90 days, death had occurred in 323 of 764 patients (42.3%) in the restrictive-fluid group, as compared with 329 of 781 patients (42.1%) in the standard-fluid group (adjusted absolute difference, 0.1 percentage points; 95% confidence interval [CI], -4.7 to 4.9; P = 0.96). In the ICU, serious adverse events occurred at least once in 221 of 751 patients (29.4%) in the restrictive-fluid group and in 238 of 772 patients (30.8%) in the standard-fluid group (adjusted absolute difference, -1.7 percentage points; 99% CI, -7.7 to 4.3). At 90 days after randomization, the numbers of days alive without life support and days alive and out of the hospital were similar in the two groups. Among adult patients with septic shock in the ICU, intravenous fluid restriction did not result in fewer deaths at 90 days than standard intravenous fluid therapy. (Funded by the Novo Nordisk Foundation and others; CLASSIC ClinicalTrials.gov number, NCT03668236.).

The characterization of baseline microbial and functional diversity in the human microbiome has enabled studies of microbiome-related disease, diversity, biogeography, and molecular function. The National Institutes of Health Human Microbiome Project has provided one of the broadest such characterizations so far. Here we introduce a second wave of data from the study, comprising 1,631 new metagenomes (2,355 total) targeting diverse body sites with multiple time points in 265 individuals. We applied updated profiling and assembly methods to provide new characterizations of microbiome personalization. Strain identification revealed subspecies clades specific to body sites; it also quantified species with phylogenetic diversity under-represented in isolate genomes. Body-wide functional profiling classified pathways into universal, human-enriched, and body site-enriched subsets. Finally, temporal analysis decomposed microbial variation into rapidly variable, moderately variable, and stable subsets. This study furthers our knowledge of baseline human microbial diversity and enables an understanding of personalized microbiome function and dynamics. Updates from the Human Microbiome Project analyse the largest known body-wide metagenomic profile of human microbiome personalization. Delving deeper into the human microbiome The National Institutes of Health Human Microbiome Project, published in 2012, provided a broad overview of the baseline microbiome in healthy individuals using samples from 18 different body sites. In this second installment, the authors expand this dataset with new whole-metagenome sequences and additional time points to assess the diversity and spatiotemporal distributions of the microbiota at six of these body sites. Using a combination of strain profiling, species-level metagenomic functional profiling and longitudinal analyses, this study delivers deeper insights into human microbial communities and provides an important resource for understanding what constitutes a 'healthy' microbiota.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) characterized by abnormal extracellular matrix (ECM) remodeling. We hypothesized that ECM remodeling might result in a plasma profile of proteins specific for IPF that could distinguish patients with IPF from other idiopathic ILDs. To identify biomarkers that might assist in distinguishing IPF from non-IPF ILD. We developed a panel of 35 ECM, ECM-related, and lung-specific analytes measured in plasma from 86 patients with IPF (derivation cohort) and in 63 patients with IPF (validation cohort). Comparison groups included patients with rheumatoid arthritis-associated ILD (RA-ILD; n = 33), patients with alternative idiopathic ILDs (a-ILD; n = 41), and healthy control subjects (n = 127). Univariable and multivariable logistic regression models identified biomarkers that differentiated patients with IPF from those with a-ILD. Both continuous and diagnostic threshold versions of biomarkers were considered; thresholds were chosen to maximize summed diagnostic sensitivity and specificity in univariate receiver-operating characteristic curve analysis. A diagnostic score was created from the most promising analytes. Plasma surfactant protein (SP)-D > 31 ng/ml, matrix metalloproteinase (MMP)-7 > 1.75 ng/ml, and osteopontin > 6 ng/ml each significantly distinguished patients with IPF from patients with a-ILD, both individually and in a combined index. The odds ratio for IPF when at least one analyte in the index exceeded the threshold was 4.4 (95% confidence interval, 2.0-9.7; P = 0.0003). When at least two analytes were elevated, the odds ratio for IPF increased to 5.0 (95% confidence interval, 2.2-11.5; P = 0.0002). A biomarker index of SP-D, MMP-7, and osteopontin enhanced diagnostic accuracy in patients with IPF compared with those with non-IPF ILD. Our data suggest that this biomarker index may improve diagnostic confidence in IPF.

Patients with stable coronary disease were randomly assigned to an initial invasive strategy with angiography and revascularization if appropriate or to medical therapy alone. At 3.2 years, there was no significant difference between the groups with respect to the estimated rate of ischemic events. The findings were sensitive to the definition of myocardial infarction.

Deborah Mackay and colleagues identify mutations in ZFP57 , encoding a zinc-finger transcription factor, in families with transient neonatal diabetes and additional clinical features. Affected individuals have a variable pattern of DNA hypomethylation at multiple imprinted loci. We have previously described individuals presenting with transient neonatal diabetes and showing a variable pattern of DNA hypomethylation at imprinted loci throughout the genome. We now report mutations in ZFP57 , which encodes a zinc-finger transcription factor expressed in early development, in seven pedigrees with a shared pattern of mosaic hypomethylation and a conserved range of clinical features. This is the first description of a heritable global imprinting disorder that is compatible with life.

Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes. CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer

We have applied \"whole-genome shotgun sequencing\" to microbial populations collected en masse on tangential flow and impact filters from seawater samples collected from the Sargasso Sea near Bermuda. A total of 1.045 billion base pairs of nonredundant sequence was generated, annotated, and analyzed to elucidate the gene content, diversity, and relative abundance of the organisms within these environmental samples. These data are estimated to derive from at least 1800 genomic species based on sequence relatedness, including 148 previously unknown bacterial phylotypes. We have identified over 1.2 million previously unknown genes represented in these samples, including more than 782 new rhodopsin-like photoreceptors. Variation in species present and stoichiometry suggests substantial oceanic microbial diversity.