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

<h3>Introduction</h3> Inflammatory bowel disease is increasingly common among patients (pts) aged ≥60 years (y), who tend to have more comorbidities than pts &lt;60y. This True North study (NCT02435992) post hoc analysis examined the efficacy and safety of ozanimod (OZA) in pts aged &lt;60y and ≥60y with UC. <h3>Methods</h3> Pts were randomized to double-blind OZA 0.92mg or placebo (PBO; cohort 1) or open-label OZA (cohort 2) during a 10-week (wk) induction period (IP). Pts with clinical response to OZA at wk 10 were re-randomized to double-blind OZA or PBO for maintenance through wk 52. Clinical remission and response, endoscopic improvement, and mucosal healing at wk 10 and 52, and adjusted treatment (tx) differences for OZA vs PBO (Cochran-Mantel-Haenszel test) were evaluated. Safety was assessed. <h3>Results</h3> 562 pts &lt;60y (OZA, n=376; PBO, n=186) and 83 pts ≥60y (OZA, n=53; PBO, n=30) in cohort 1 and 315 pts &lt;60y and 52 pts ≥60y in cohort 2 were analyzed. During maintenance, 196 pts &lt;60y and 34 pts ≥60y continued on OZA; 196 pts &lt;60y and 31 pts ≥60y were re-randomized to PBO. Baseline characteristics were generally well balanced; pts ≥60y had less-extensive disease, lower fecal calprotectin levels, and more polypharmacy. Adjusted tx differences favored OZA vs PBO and were similar between age groups across all efficacy endpoints at wk 10 and 52. PBO response rates were higher in pts ≥60y vs &lt;60y. During IP, rates of tx-emergent adverse events (TEAEs) with OZA in cohort 1/2 were lower in pts ≥60y (36%/31%) vs &lt;60y (41%/41%). Rates of serious TEAEs (≥60y, 6%/4%; &lt;60y, 4%/7%) and TEAEs leading to tx discontinuation were comparable (≥60y, 2%/6%; &lt;60y, 3.5%/3.5%) in cohort 1/2. During maintenance, TEAEs were more frequent in pts ≥60y (56%) vs &lt;60y (48%), serious TEAEs were less common (3% vs 6%), and TEAEs leading to tx discontinuation were similar (3% vs 1%). AEs of special interest rates were low; the most common were infection (≥60y, 2 pts vs &lt;60y, 3 pts), hepatic effects (0 vs 2), macular edema (1 vs 0), malignancy (0 vs 2), and pulmonary effects (0 vs 1). One death from acute respiratory distress syndrome due to viral pneumonia occurred during IP in a 64y-old pt but was deemed unrelated to OZA. <h3>Conclusions</h3> OZA was well tolerated and efficacious in both younger (&lt;60y) and older (≥60y) pts with UC. This study was previously presented at UEGW 2022. 

P100 Efficacy and safety of ozanimod in older patients with ulcerative colitis (UC): post hoc analysis of the True North study

Two Strikes but Not Out: Deep Remission of Ulcerative Colitis with Ustekinumab After Primary Non-response to Infliximab and Vedolizumab.

Background: Limited guidance exists for the post-discharge care of ulcerative colitis (UC) patients hospitalized for moderate-severe flares. Methods: RAND methodology was used to establish appropriateness of inpatient and post-discharge steroid dosing, discharge criteria, follow-up, and post-discharge biologic or small molecule initiation. A literature review informed the panels voting, which occurred anonymously during two rounds before and after a moderated virtual session. Results: Methylprednisolone 40-60mg IV every 24 hours or hydrocortisone 300mg IV three times daily are appropriate for inpatient management, with methylprednisolone 40mg being appropriate if intolerant of higher doses. It is appropriate to discharge patients once rectal bleeding has resolved (Mayo sub score 0-1) and/or stool frequency has returned to baseline frequency and form (Mayo sub score 0-1). It is appropriate to discharge patients on 40mg of prednisone after observing patients for 24 hours in-hospital to ensure stability prior to discharge. For patients being discharged on steroids without in-hospital biologic or small molecule therapy initiation, it is appropriate to start anti-TNF therapy after discharge for anti-TNF naive patients. For anti-TNF exposed patients it is appropriate to start vedolizumab or ustekinumab for all patients, and tofacitinib for those with a low risk of adverse events. It is appropriate to follow up patients clinically within 2 weeks, and with lower endoscopy within 4-6 months after discharge. Conclusion: We provide guidance on the inpatient and post-discharge management of UC patients hospitalized for moderate-severe flares.

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Appropriate management of steroids and discharge planning during and after hospital admission for moderate-severe ulcerative colitis


 
 
 Variation in clinical response to 5-aminosalicylic acid (5-ASA) has been attributed in part to its inactivation by gut microbes. Recently, in the Inflammatory Bowel Disease (IBD) Multi’omics Database (IBDMDB), a multicenter year-long cohort of 100+ participants with IBD, we identified 12 gut microbial enzymes from two protein families that convert 5-ASA to N-acetyl 5-ASA, a compound that lacks anti-inflammatory effects. Within the IBDMDB, we then found that a subset of these enzymes was cross-sectionally linked with greater risk of treatment failure, defined by corticosteroid use. The aim of this study was to prospectively associate these drug-degrading gut microbial enzymes with treatment failure and to confirm in vitro conversion of 5-ASA by these enzymes.
 
 
 
 We examined the prospective association between gut microbial acetyltransferases with risk of 5-ASA treatment failure in the ongoing “Study of a Prospective Adult Research Cohort with IBD” (SPARC IBD). We included 208 participants who at study entry 1) gave a stool sample at baseline, 2) were on 5-ASA, and 3) were steroid-free. Fecal metagenomic data was processed by the same analysis pipeline (biobakery3) as in the IBDMDB. Exposure was defined identically as in the IBDMDB as metagenomic carriage of 3-4 drug-degrading acetyltransferases compared to 0-2 acetyltransferases. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) of incident steroid use using multivariable generalized estimating equations, adjusting for age and sex. For biochemical characterization, the 12 enzymes identified in the IBDMDB were heterologously expressed by E. coli. A representative enzyme was selected from each protein family for purification, and then incubated with 5-ASA and acetyl CoA for 6 hr at 37C with 1 mM of each substrate and 50 μM enzyme. Using a custom LC–MS assay, we then detected N-acetyl 5-ASA production.
 
 
 
 Over a median follow-up of 8 months, we identified 60 cases of corticosteroid use. Consistent with data from the IBDMDB, we found that metagenomic carriage of 3 or more microbial acetyltransferase genes in SPARC IBD (compared to 2 or fewer) was associated with treatment failure (OR 2.77, 95% CI 1.03-7.43). In a random effects meta-analysis of the two cohorts, we observed a three-fold increased risk of drug failure (OR 3.12, 95% CI 1.41-6.89) (Fig 1). In vitro biochemical experiments confirmed the ability of a thiolase and an acyl-CoA N-acetyltransferase to acetylate 5-ASA, generating product at levels consistent with >25% conversion (Fig 2).
 
 
 
 
 
 We characterized two gut microbial protein families that are directly involved in 5-ASA metabolism and, in turn, are prospectively associated with 5-ASA treatment failure. These findings advance the possibility of microbiome-based personalized medicine for patients with IBD.


/pdf/gut-microbial-metabolism-of-5-asa-is-prospectively-1s1ma3zp.pdf

Gut microbial metabolism of 5-asa is prospectively associated with treatment failure in patients with ibd


 
 
 This retrospective study gathered medical/pharmacy claims data on patients with IBD between 01/01/2000 and 03/31/2019 from the IBM® MarketScan® commercial claims database to assess the real-world impact of fatigue on healthcare costs in patients newly diagnosed with inflammatory bowel disease (IBD).
 
 
 
 Eligible participants were ≥18 years, newly diagnosed with IBD (≥2 separate claims) and had ≥12 months of continuous database enrollment before and after fatigue diagnosis. The date of fatigue diagnosis was the index date; participants were followed for 12 months post-index. Patients with (cases) or without (controls) fatigue were matched 1:1 by propensity score matching. Patients with evidence of prior IBD diagnosis/treatment, or those with a chronic disease other than IBD wherein fatigue is the primary symptom, were excluded. Healthcare resource utilization (HCRU), including hospitalizations, inpatient and outpatient visits, and associated costs was compared between cases and controls.
 
 
 
 Matched IBD cohorts (21,321 cases/21,321 controls) were identified (42% CD and 58% UC) with similar baseline characteristics (average age: 46 years; 60% female). Cases versus controls had significantly more all-cause outpatient visits (incidence rate ratio [IRR], 95% confidence intervals [95% CI]: 1.64 [1.61, 1.67], P<0.001) and all-cause hospitalizations (IRR [95% CI]: 1.92 [1.81, 2.04], P<0.001); as well as significantly higher all-cause total direct healthcare costs (mean: $24,620 vs $15,324; P<0.001). Similar findings were observed for IBD-related outcomes, as well as in CD- and UC-specific subgroups.
 
 
 
 Presence of fatigue is associated with an increase in HCRU and total medical costs among patients newly diagnosed with IBD.


Ashwin N. Ananthakrishnan

Papers

P100 Efficacy and safety of ozanimod in older patients with ulcerative colitis (UC): post hoc analysis of the True North study

Two Strikes but Not Out: Deep Remission of Ulcerative Colitis with Ustekinumab After Primary Non-response to Infliximab and Vedolizumab.

Appropriate management of steroids and discharge planning during and after hospital admission for moderate-severe ulcerative colitis

Gut microbial metabolism of 5-asa is prospectively associated with treatment failure in patients with ibd

Economic Burden Of Fatigue In Inflammatory Bowel Disease