Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.

/pdf/biological-insights-from-108-schizophrenia-associated-3rfvth8dm9.pdf

Biological insights from 108 schizophrenia-associated genetic loci

To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008. A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a Pao
 2/Fio
 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a Pao
 2/Fi
 o
 2 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5–10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency (2C). Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

/pdf/surviving-sepsis-campaign-international-guidelines-for-229kg8suph.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012

Prospective Cohort Study

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

/pdf/integrative-analysis-of-111-reference-human-epigenomes-4bavnjaon6.pdf

Integrative analysis of 111 reference human epigenomes

Understanding protein function and discovering molecular therapies require deciphering the cell types in which proteins act as well as the interactions between proteins. However, modeling protein interactions across diverse biological contexts, such as tissues and cell types, remains a significant challenge for existing algorithms. We introduce Pinnacle, a flexible geometric deep learning approach that is trained on contextualized protein interaction networks to generate context-aware protein representations. Leveraging a human multiorgan single-cell transcriptomic atlas, Pinnacle provides 394,760 protein representations split across 156 cell type contexts from 24 tissues and organs. Pinnacle’s contextualized representations of proteins reflect cellular and tissue organization and Pinnacle’s tissue representations enable zero-shot retrieval of the tissue hierarchy. Pretrained Pinnacle protein representations can be adapted for downstream tasks: to enhance 3D structure-based protein representations (PD-1/PD-L1 and B7-1/CTLA-4) at cellular resolution and to study the genomic effects of drugs across cellular contexts. Pinnacle outperforms state-of-the-art, yet context-free, models in nominating therapeutic targets for rheumatoid arthritis and inflammatory bowel diseases, and can pinpoint cell type contexts that are more predictive of therapeutic targets than context-free models (29 out of 156 cell types in rheumatoid arthritis; 13 out of 152 cell types in inflammatory bowel diseases). Pinnacle is a network-based contextual AI model that dynamically adjusts its outputs based on biological contexts in which it operates.

Contextualizing protein representations using deep learning on protein networks and single-cell data

LINKED CONTENT This article is linked to Woelfel et al papers. To view these articles, visit https://doi.org/10.1111/apt.17264

Editorial: immunosuppression and SARS‐CoV‐2 vaccination—where do we stand?

Mo1548: RISK OF INFECTIONS WITH USTEKINUMAB AND TOFACITINIB COMPARED TO TUMOR NECROSIS FACTOR ANTANOGISTS IN INFLAMMATORY BOWEL DISEASES

EDITORS, We thank Drs. Logan and colleagues for taking an interest in our paper and raising an important point regarding data on faecal calprotectin. Only 1 study in our systematic review contained information regarding faecal calprotectin. Levine et al measured faecal calprotectin at baseline and at end of treatment in patients induced with exclusive enteral nutrition and corticosteroids. Among those induced with exclusive enteral nutrition, 22 of 72 had normalisation of faecal calprotectin. Only 3 of 23 treated with corticosteroids had normalisation of faecal calprotectin. Although the difference was not statistically significant, the trend was towards greater improvement in the exclusive enteral nutrition group (OR 2.93, [CI 95% 0.7910.90]). Because only 1 study met our inclusion criteria, we did not feel it met the threshold to be included in the final manuscript, but failed to update the abstract. We agree that the absence of statistical benefit does not imply an absence of benefit, but simply that the literature we reviewed was not mature enough to have enough studies with which to base any conclusions. Logan et al do provide data on improvement in faecal from studies which did not meet our inclusion criteria. We agree that biomarkers have taken on a large importance in the management of Crohn’s disease, and that future rigorous comparison studies of Crohn’s nutritional therapy should include biomarker and mucosal healing data as part of their design.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/apt.14360

Letter: reproducible evidence shows that exclusive enteral nutrition significantly reduces faecal calprotectin concentrations in children with active Crohn's disease-Authors' reply.

Ashwin N. Ananthakrishnan

Papers

Contextualizing protein representations using deep learning on protein networks and single-cell data

Editorial: immunosuppression and SARS‐CoV‐2 vaccination—where do we stand?

Mo1548: RISK OF INFECTIONS WITH USTEKINUMAB AND TOFACITINIB COMPARED TO TUMOR NECROSIS FACTOR ANTANOGISTS IN INFLAMMATORY BOWEL DISEASES

Letter: reproducible evidence shows that exclusive enteral nutrition significantly reduces faecal calprotectin concentrations in children with active Crohn's disease-Authors' reply.

Reply: To PMID 23912083.