Yokohama City Seibu Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

PURPOSE: Sepsis is recognized as a global public health problem, but the proportion due to hospital-acquired infections remains unclear. We aimed to summarize the epidemiological evidence related to the burden of hospital-acquired (HA) and ICU-acquired (ICU-A) sepsis. METHODS: We searched MEDLINE, Embase and the Global Index Medicus from 01/2000 to 03/2018. We included studies conducted hospital-wide or in intensive care units (ICUs), including neonatal units (NICUs), with data on the incidence/prevalence of HA and ICU-A sepsis and the proportion of community and hospital/ICU origin. We did random-effects meta-analyses to obtain pooled estimates; inter-study heterogeneity and risk of bias were assessed. RESULTS: Of the 13,239 studies identified, 51 met the inclusion criteria; 22 were from low- and middle-income countries. Twenty-eight studies were conducted in ICUs, 13 in NICUs, and ten hospital-wide. The proportion of HA sepsis among all hospital-treated sepsis cases was 23.6% (95% CI 17-31.8%, range 16-36.4%). In the ICU, 24.4% (95% CI 16.7-34.2%, range 10.3-42.5%) of cases of sepsis with organ dysfunction were acquired during ICU stay and 48.7% (95% CI 38.3-59.3%, range 18.7-69.4%) had a hospital origin. The pooled hospital incidence of HA sepsis with organ dysfunction per 1000 patients was 9.3 (95% CI 7.3-11.9, range 2-20.6)). In the ICU, the pooled incidence of HA sepsis with organ dysfunction per 1000 patients was 56.5 (95% CI 35-90.2, range 9.2-254.4) and it was particularly high in NICUs. Mortality of ICU patients with HA sepsis with organ dysfunction was 52.3% (95% CI 43.4-61.1%, range 30.1-64.6%). There was a significant inter-study heterogeneity. Risk of bias was low to moderate in ICU-based studies and moderate to high in hospital-wide and NICU studies. CONCLUSION: HA sepsis is of major public health importance, and the burden is particularly high in ICUs. There is an urgent need to improve the implementation of global and local infection prevention and management strategies to reduce its high burden among hospitalized patients.

PAD peripheral arterial disease PCI percutaneous coronary intervention peak V O2 peak oxygen uptake PH pulmonary hypertension PVCs premature ventricular contraction QOL quality of life RCT randomized controlled trial RPE rating of perceived exertion SGA Subjective Global Assessment STEMI ST elevation myocardial infarction TG triglyceride TAVI transcatheter aortic valve implantation VAD ventricular assist device V CO2 carbon dioxide output V E minute ventilation V E/V CO2 ventilatory equivalent for carbon dioxide V E vs. V CO2 slope minute ventilation vs. carbon dioxide output slope V O2 oxygen uptake V O2/HR oxygen pulse capacity is assessed by cardiopulmonary exercise testing (CPX), an exercise prescription is prepared based on the risk in terms of severity of illness, and then a treatment and CR plan is established. If CPX cannot be performed due to complications, low physical fitness, or low left ventricular function, exercise capacity should be confirmed by the 6-minute walk test.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

IMPORTANCE: The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive. OBJECTIVE: To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTS: The ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONS: The immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURES: The primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, -1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS: Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group. CONCLUSIONS AND RELEVANCE: Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support-free days. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02735707.

OBJECTIVES: Interventional endoscopic ultrasonography (EUS) procedures are gaining popularity and the most commonly performed procedures include EUS-guided drainage of pancreatic pseudocyst, EUS-guided biliary drainage, EUS-guided pancreatic duct drainage and EUS-guided celiac plexus ablation. The aim of this paper is to formulate a set of practice guidelines addressing various aspects of the above procedures. METHODS: Formulation of the guidelines was based on the best scientific evidence available. The RAND/UCLA appropriateness methodology (RAM) was used. Panellists recruited comprised experts in surgery, interventional EUS, interventional radiology and oncology from 11 countries. Between June 2014 and October 2016, the panellists met in meetings to discuss and vote on the clinical scenarios for each of the interventional EUS procedures in question. RESULTS: A total of 15 statements on EUS-guided drainage of pancreatic pseudocyst, 15 statements on EUS-guided biliary drainage, 12 statements on EUS-guided pancreatic duct drainage and 14 statements on EUS-guided celiac plexus ablation were formulated. The statements addressed the indications for the procedures, technical aspects, pre- and post-procedural management, management of complications, and competency and training in the procedures. All statements except one were found to be appropriate. Randomised studies to address clinical questions in a number of aspects of the procedures are urgently required. CONCLUSIONS: The current guidelines on interventional EUS procedures are the first published by an endoscopic society. These guidelines provide an in-depth review of the current evidence and standardise the management of the procedures.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

BACKGROUND: Lymphoid neoplasm with 18q21.3/BCL2 and 8q24/MYC translocation to immunoglobulin (IG) genes as dual-hit lymphoma/leukemia is very rare and known to have a poor clinical outcome. DESIGN AND METHODS: To clarify the clinicopathological characteristics of this malignancy, we analyzed 27 cases of cytogenetically proven dual-hit lymphoma/leukemia. RESULTS: Dual-hit lymphoma/leukemia was diagnosed at presentation in 22 cases and at relapse or disease progression in 5 cases. At the time of diagnosis of dual-hit lymphoma/leukemia, extranodal involvement was found in 25 cases (93%) and central nervous system involvement occurred in 15 cases (56%). The median survival and 1-year survival rate of the 27 cases were only 6 months and 22%, respectively, after diagnosis of the dual-hit lymphoma/leukemia. Seven cases of triple-hit lymphoma/leukemia (dual-hit lymphoma/leukemia with 3q27/BCL6 translocation) were included; the median survival of these patients was only 4 months from the diagnosis of the dual-hit lymphoma/leukemia. The duration of survival of the patients with a triple-hit malignancy was shorter than that of the other 20 cases of dual-hit lymphoma/leukemia (p=0.02). The translocation partner of MYC subdivided the dual-hit cases into two groups; 14 cases of IGH and 13 cases of IGK/L. The MIB-1 index was investigated in 14 cases with aggressive B-cell lymphoma, and was higher in the group with MYC-IGH translocation (n=7) than in the MYC-IGK/L group (n=7) (p=0.02). Overall survival was not different between the MYC-IGH translocation group (n=14) and the MYC-IGK or MYC-IGL translocation group (n=13). CONCLUSIONS: Dual-hit lymphoma/leukemia is a rare but distinct mature B-cell neoplasm with an extremely poor prognosis characterized by frequent extranodal involvement and central nervous system progression with either of the translocation partners of MYC.

BACKGROUND: It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. METHODS: The PubMed database was examined (1989-2017) for studies published in English language regarding the prospective follow-up results for the development of HCC in various liver diseases. A meta-analysis was performed for each liver disease. RESULTS: The annual incidence (%) of HCC in the non-cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non-cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73-fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07-fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88-fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79-fold), and (e) NASH (0.03%→1.35%, 45.00-fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow-up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. CONCLUSIONS: When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.

BACKGROUND: Gastrointestinal paralysis, nausea and vomiting and pain are major clinical problems following abdominal surgery. Anaesthetic and analgesic techniques that reduce pain and postoperative nausea and vomiting (PONV), while preventing or reducing postoperative ileus, may reduce postoperative morbidity, duration of hospitalization and hospital costs. This review was first published in 2001 and was updated by new review authors in 2016. OBJECTIVES: To compare effects of postoperative epidural analgesia with local anaesthetics versus postoperative systemic or epidural opioids in terms of return of gastrointestinal transit, postoperative pain control, postoperative vomiting, incidence of anastomotic leak, length of hospital stay and costs after abdominal surgery. SEARCH METHODS: We identified trials by conducting computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 12), MEDLINE (from 1950 to December 2014) and EMBASE (from 1974 to December 2014) and by checking the reference lists of trials retained. When we reran the search in February 2016, we added 16 potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate these studies into formal review findings during the next review update. SELECTION CRITERIA: We included parallel randomized controlled trials comparing effects of postoperative epidural local anaesthetic versus regimens based on systemic or epidural opioids. DATA COLLECTION AND ANALYSIS: We rated the quality of studies by using the Cochrane 'Risk of bias' tool. Two review authors independently extracted data and judged the quality of evidence according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation Working Group) scale. MAIN RESULTS: We included 128 trials with 8754 participants in the review, and 94 trials with 5846 participants in the analysis. Trials included in the review were funded as follows: charity (n = 19), departmental resources (n = 8), governmental sources (n = 15) and industry (in part or in total) (n = 15). The source of funding was not specified for the other studies.Results of 22 trials including 1138 participants show that an epidural containing a local anaesthetic will decrease the time required for return of gastrointestinal transit as measured by time to first flatus after an abdominal surgery (standardized mean difference (SMD) -1.28, 95% confidence interval (CI) -1.71 to -0.86; high quality of evidence; equivalent to 17.5 hours). The effect is proportionate to the concentration of local anaesthetic used. A total of 28 trials including 1559 participants reported a decrease in time to first faeces (stool) (SMD -0.67, 95% CI -0.86 to -0.47; low quality of evidence; equivalent to 22 hours). Thirty-five trials including 2731 participants found that pain on movement at 24 hours after surgery was also reduced (SMD -0.89, 95% CI -1.08 to -0.70; moderate quality of evidence; equivalent to 2.5 on scale from 0 to 10). From findings of 22 trials including 1154 participants we did not find a difference in the incidence of vomiting within 24 hours (risk ratio (RR) 0.84, 95% CI 0.57 to 1.23; low quality of evidence). From investigators in 17 trials including 848 participants we did not find a difference in the incidence of gastrointestinal anastomotic leak (RR 0.74, 95% CI 0.41 to 1.32; low quality of evidence). Researchers in 30 trials including 2598 participants noted that epidural analgesia reduced length of hospital stay for an open surgery (SMD -0.20, 95% CI -0.35 to -0.04; very low quality of evidence; equivalent to one day). Data on costs were very limited. AUTHORS' CONCLUSIONS: An epidural containing a local anaesthetic, with or without the addition of an opioid, accelerates the return of gastrointestinal transit (high quality of evidence). An epidural containing a local anaesthetic with an opioid decreases pain after abdominal surgery (moderate quality of evidence). We did not find a difference in the incidence of vomiting or anastomotic leak (low quality of evidence). For open surgery, an epidural containing a local anaesthetic would reduce the length of hospital stay (very low quality of evidence).

BACKGROUND: The aim of this review was to compare the effects of postoperative epidural analgesia with local anesthetics to postoperative systemic or epidural opioids in terms of return of gastrointestinal transit, postoperative pain control, postoperative vomiting, incidence of gastrointestinal anastomotic leak, hospital length of stay, and cost after abdominal surgery. METHODS: Trials were identified by computerized searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 12), Medical Literature Analysis and Retrieval System Online (MEDLINE) (from 1950 to December, 2014) and Excerpta Medica dataBASE (EMBASE) (from 1974 to December 2014) and by checking the reference lists of trials retained. We included parallel randomized controlled trials comparing the effects of postoperative epidural local anesthetic with regimens based on systemic or epidural opioids. The quality of the studies was rated according to the Cochrane tool. Two authors independently extracted data. We judged the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) working group scale. RESULTS: Based on 22 trials including 1138 participants, an epidural containing a local anesthetic will decrease the time required for return of gastrointestinal transit as measured by time required to observe the first flatus after an abdominal surgery standardized mean difference (SMD) -1.28 (95% confidence interval [CI], -1.71 to -0.86; high quality of evidence; equivalent to 17.5 hours). The effect is proportional to the concentration of local anesthetic used. Based on 28 trials including 1559 participants, we also found a decrease in time to first feces (stool): SMD -0.67 (95% CI, -0.86 to -0.47; low quality of evidence; equivalent to 22 hours). Based on 35 trials including 2731 participants, pain on movement at 24 hours after surgery is also reduced: SMD -0.89 (95% CI, -1.08 to -0.70; moderate quality of evidence; equivalent to 2.5 on a scale from 0 to 10). Based on 22 trials including 1154 participants, we did not find a difference in the incidence of vomiting within 24 hours: risk ratio 0.84 (95% CI, 0.57-1.23); low quality of evidence. Based on 17 trials including 848 participants we did not find a difference in the incidence of gastrointestinal anastomotic leak: risk ratio 0.74 (95% CI, 0.41-1.32; low quality of evidence). Based on 30 trials including 2598 participants, epidural analgesia reduces length of hospital stay for an open surgery: SMD -0.20 (95% CI, -0.35 to -0.04; very low quality of evidence; equivalent to 1 day). Data on cost were very limited. CONCLUSIONS: An epidural containing a local anesthetic, with or without the addition of an opioid, accelerates the return of the gastrointestinal transit (high quality of evidence). An epidural containing a local anesthetic with an opioid decreases pain after an abdominal surgery (moderate quality of evidence). An epidural containing a local anesthetic does not affect the incidence of vomiting or anastomotic leak (low quality of evidence). For an open surgery, an epidural containing a local anesthetic would reduce the length of hospital stay (very low quality of evidence).

Importance: The efficacy of antiplatelet therapy in critically ill patients with COVID-19 is uncertain. Objective: To determine whether antiplatelet therapy improves outcomes for critically ill adults with COVID-19. Design, Setting, and Participants: In an ongoing adaptive platform trial (REMAP-CAP) testing multiple interventions within multiple therapeutic domains, 1557 critically ill adult patients with COVID-19 were enrolled between October 30, 2020, and June 23, 2021, from 105 sites in 8 countries and followed up for 90 days (final follow-up date: July 26, 2021). Interventions: Patients were randomized to receive either open-label aspirin (n = 565), a P2Y12 inhibitor (n = 455), or no antiplatelet therapy (control; n = 529). Interventions were continued in the hospital for a maximum of 14 days and were in addition to anticoagulation thromboprophylaxis. Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of intensive care unit-based respiratory or cardiovascular organ support) within 21 days, ranging from -1 for any death in hospital (censored at 90 days) to 22 for survivors with no organ support. There were 13 secondary outcomes, including survival to discharge and major bleeding to 14 days. The primary analysis was a bayesian cumulative logistic model. An odds ratio (OR) greater than 1 represented improved survival, more organ support-free days, or both. Efficacy was defined as greater than 99% posterior probability of an OR greater than 1. Futility was defined as greater than 95% posterior probability of an OR less than 1.2 vs control. Intervention equivalence was defined as greater than 90% probability that the OR (compared with each other) was between 1/1.2 and 1.2 for 2 noncontrol interventions. Results: The aspirin and P2Y12 inhibitor groups met the predefined criteria for equivalence at an adaptive analysis and were statistically pooled for further analysis. Enrollment was discontinued after the prespecified criterion for futility was met for the pooled antiplatelet group compared with control. Among the 1557 critically ill patients randomized, 8 patients withdrew consent and 1549 completed the trial (median age, 57 years; 521 [33.6%] female). The median for organ support-free days was 7 (IQR, -1 to 16) in both the antiplatelet and control groups (median-adjusted OR, 1.02 [95% credible interval {CrI}, 0.86-1.23]; 95.7% posterior probability of futility). The proportions of patients surviving to hospital discharge were 71.5% (723/1011) and 67.9% (354/521) in the antiplatelet and control groups, respectively (median-adjusted OR, 1.27 [95% CrI, 0.99-1.62]; adjusted absolute difference, 5% [95% CrI, -0.2% to 9.5%]; 97% posterior probability of efficacy). Among survivors, the median for organ support-free days was 14 in both groups. Major bleeding occurred in 2.1% and 0.4% of patients in the antiplatelet and control groups (adjusted OR, 2.97 [95% CrI, 1.23-8.28]; adjusted absolute risk increase, 0.8% [95% CrI, 0.1%-2.7%]; 99.4% probability of harm). Conclusions and Relevance: Among critically ill patients with COVID-19, treatment with an antiplatelet agent, compared with no antiplatelet agent, had a low likelihood of providing improvement in the number of organ support-free days within 21 days. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Sakuma H, Awaya Y, Shiomi M, Yamanouchi H, Takahashi Y, Saito Y, Sugai K, Sasaki M. Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis. Acta Neurol Scand: 2010: 121: 251–256.© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – We conducted a nationwide multicenter study in Japan to elucidate the clinical and laboratory characteristics of acute encephalitis with refractory, repetitive partial seizures (AERRPS). Materials and methods – Clinical and laboratory features, treatment, and outcome were assessed using a structured questionnaire. Results – Twenty-nine children were enrolled in the study. Refractory and repetitive partial seizures accompanied by fever were the cardinal clinical features. Partial seizures consisted principally of eye deviation or facial twitching, being periodically repeated during the acute phase. These seizures were refractory to conventional anticonvulsants and were only suppressed by high-dose intravenous barbiturate administration. Rhythmic activities on electroencephalography and non-specific cerebral atrophy on neuroimaging were common. Serum or cerebrospinal antibodies against GluRε2 were positive in six patients. General prognosis was unfavorable due to intractable epilepsy and cognitive deficits. Conclusion – Based on the peculiar and homogenous features, AERRPS can be regarded as a distinct clinical entity.

CONTEXT: Although primary aldosteronism (PA) is the most common cause of endocrine hypertension, histopathological methods to reveal the presence and sites of aldosterone overproduction remain to be established. OBJECTIVE: The objective of the study was to investigate the significance of immunohistochemical staining to detect CYP11B2 and CYP11B1 in adrenal tissue of patients with PA. DESIGN AND PATIENTS: Thirty-two patients with PA who underwent unilateral adrenalectomy were studied. Immunohistochemical staining was performed using anti-CYP11B2 and anti-CYP11B1 antibodies on paraffin-embedded sections. We analyzed the expression of each enzyme semiquantitatively by scoring staining intensity and correlating it with clinical findings. RESULTS: Twenty-two patients showed positive CYP11B2 immunostaining in their tumors (aldosterone producing adenoma, APA). Four patients with CYP11B2-negative unilateral adenomas and 4 patients without tumors on computed tomography showed aldosterone-producing cell clusters (APCCs) with CYP11B2 immunostaining in the zona glomerulosa (multiple APCCs). The remaining 2 patients had unilateral multiple adrenocortical micronodules and diffuse adrenocortical hyperplasia, respectively. In APA, CYP11B2 score adjusted for tumor volume was positively correlated with plasma aldosterone and negatively correlated with serum potassium. The APA group was divided into 3 subgroups based on relative CYP11B2 and CYP11B1 immunostaining levels. The CYP11B2/CYP11B1-equivalent and CYP11B1-dominant APA groups showed significantly higher serum cortisol after 1 mg dexamethasone and larger tumor size than the CYP11B2-dominant APA group. CONCLUSIONS: The present study clearly demonstrates that CYP11B2 immunostaining is a powerful tool for histopathological diagnosis of aldosterone overproduction in PA and for subtype classification of APA, multiple APCCs, unilateral multiple adrenocortical micronodules, and diffuse hyperplasia.

Investigating the role of host genetic factors in COVID-19 severity and susceptibility can inform our understanding of the underlying biological mechanisms that influence adverse outcomes and drug development 1 , 2 . Here we present a second updated genome-wide association study (GWAS) on COVID-19 severity and infection susceptibility to SARS-CoV-2 from the COVID-19 Host Genetic Initiative (data release 7). We performed a meta-analysis of up to 219,692 cases and over 3 million controls, identifying 51 distinct genome-wide significant loci—adding 28 loci from the previous data release 2 . The increased number of candidate genes at the identified loci helped to map three major biological pathways that are involved in susceptibility and severity: viral entry, airway defence in mucus and type I interferon.

Practical guidelines for the diagnosis of acute pancreatitis are presented so that a rapid and adequate diagnosis can be made. When acute pancreatitis is suspected in patients with acute onset of abdominal pain and tenderness mainly in the upper abdomen, the diagnosis of acute pancreatitis is made on the basis of elevated levels of pancreatic enzymes in the blood and/or urine. Furthermore, other acute abdominal diseases are ruled out if local findings associated with pancreatitis are confirmed by diagnostic imaging. According to the diagnostic criteria established in Japan, patients who present with two of the following three manifestations are diagnosed as having acute pancreatitis: characteristic upper abdominal pain, elevated levels of pancreatic enzymes, and findings of ultrasonography (US), CT or MRI suggesting acute pancreatitis. Detection of elevated levels of blood pancreatic enzymes is crucial in the diagnosis of acute pancreatitis. Measurement of blood lipase is recommended, because it is reported to be superior to all other pancreatic enzymes in terms of sensitivity and specificity. For measurements of the blood amylase level widely used in Japan, it should be cautioned that, because of its low specificity, abnormal high values are also often obtained in diseases other than pancreatitis. The cut-off level of blood pancreatic enzymes for the diagnosis of acute pancreatitis is not able to be set because of lack of sufficient evidence and consensus to date. CT study is the most appropriate procedure to confirm image findings of acute pancreatitis. Elucidation of the etiology of acute pancreatitis should be continued after a diagnosis of acute pancreatitis. In the process of the etiologic elucidation of acute pancreatitis, judgment whether it is gallstone-induced or not is most urgent and crucial for deciding treatment policy including the assessment of whether endoscopic papillary treatment should be conducted or not. The diagnosis of gallstone-induced acute pancreatitis can be made by combining detection of elevated levels of bilirubin, transamylase (ALT, AST) and ALP detected by hematological examination and the visualization of gallstones by US.

Importance: Palmoplantar pustulosis (PPP) is a recalcitrant skin disease with no biologics currently approved for treatment. The involvement of interleukin 23 (IL-23) and cytokines of the type 17 helper T cell lineage in the pathogenesis of PPP has been recently postulated. Objective: To evaluate the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. Design, Setting, and Participants: This double-blind, randomized, placebo-controlled, parallel-group, 24-week trial was conducted between May 14, 2013, and September 27, 2014, at 11 centers in Japan. Participants were patients with moderate to severe PPP that did not respond adequately to conventional treatments. Interventions: Patients were randomized 1:1 to receive guselkumab, 200 mg, by subcutaneous injection or matching placebo at weeks 0 and 4. Main Outcomes and Measures: Changes in total scores of skin-related outcomes from baseline at the end of week 16 (primary clinical cutoff) and through week 24 were measured. Serum biomarker analyses were performed at baseline, week 4, and week 16, and safety was monitored through week 24. Results: Of 49 randomized patients (35 [71%] women; median [range] age, 52 [28-77] years), 41 completed the study at week 24. Mean (SD) PPP severity index total scores (primary end point) improved significantly from baseline in guselkumab-treated patients (-3.3 [2.43]) vs placebo (-1.8 [2.09]) (least squares mean difference, -1.5; 95% CI, -2.9 to -0.2; P = .03). At week 16, PPP area and severity index scores (least squares mean difference, -5.65; 95% CI, -9.80 to -1.50; P = .009) and proportion of patients achieving 50% reduction in these scores (difference in proportion, 39.2; 95% CI, 14.0-64.3; P = .009) improved significantly. A numerically higher proportion of patients had a physician's global assessment score of 1 or less in the guselkumab group vs placebo. Improvement in efficacy scores was maintained through week 24 in the guselkumab group. Significant reductions from baseline in serum IL-17A and IL-17F cytokine levels were observed at weeks 4 and 16. Frequency of treatment-emergent adverse events was comparable between the guselkumab group (19 of 25 patients [76%]) and the placebo group (18 of 24 patients [75%]). Frequent adverse effects included nasopharyngitis (14 patients [29%]), headache (3 patients [6%]), contact dermatitis (3 patients [6%]), and injection site erythema (3 patients [6%]). No major safety concerns emerged during the study. Conclusions and Relevance: Targeting IL-23 and its associated immune cascade with guselkumab may be a safe and useful therapeutic option for treatment of PPP. Trial Registration: clinicaltrials.gov Identifier: NCT01845987.

Transforming growth factor alpha (TGF-alpha) is thought to be involved in liver regeneration, cellular proliferation, and hepatocarcinogenesis. We have looked at the relationship between TGF-alpha and it's receptor, and have attempted to relate the expression of TGF-alpha and it's receptor to the differentiation of hepatocellular carcinoma (HCC) on serial sections of HCC. We examined immunohistochemically the expression of the TGF-alpha and of epidermal growth factor receptor (EGFR) proteins in the same area of 53 nodules (< 5 cm in diameter) of HCC obtained from patients. Immunoreactive proteins were visualized by using a biotin-streptoavidin system (LSAB Kil, Dako). TGF-alpha was strongly expressed in 29 of 53 (54.7%) nodules. Specimens strongly positive for TGF-alpha were found mainly in well-differentiated HCC, while specimens positive for EGFR were found mainly in poorly differentiated HCC (p < 0.05). In the tissues that stained weakly positive for TGF-alpha, the expression of EGFR differed significantly, according to the degree of HCC histologic differentiation (p < 0.05). These results led us to speculate that the expression of TGF-alpha and EGFR might be related to the pattern of histologic differentiation of HCC.

This clinical practice guideline of the diagnosis and treatment of adrenal insufficiency (AI) including adrenal crisis was produced on behalf of the Japan Endocrine Society. This evidence-based guideline was developed by a committee including all authors, and was reviewed by a subcommittee of the Japan Endocrine Society. The Japanese version has already been published, and the essential points have been summarized in this English language version. We recommend diagnostic tests, including measurement of basal cortisol and ACTH levels in combination with a rapid ACTH (250 μg corticotropin) test, the CRH test, and for particular situations the insulin tolerance test. Cut-off values in basal and peak cortisol levels after the rapid ACTH or CRH tests are proposed based on the assumption that a peak cortisol level ≥18 μg/dL in the insulin tolerance test indicates normal adrenal function. In adult AI patients, 15-25 mg hydrocortisone (HC) in 2-3 daily doses, depending on adrenal reserve and body weight, is a basic replacement regime for AI. In special situations such as sickness, operations, pregnancy and drug interactions, cautious HC dosing or the correct choice of glucocorticoids is necessary. From long-term treatment, optimal diurnal rhythm and concentration of serum cortisol are important for the prevention of cardiovascular disease and osteoporosis. In maintenance therapy during the growth period of patients with 21-hydroxylase deficiency, proper doses of HC should be used, and long-acting glucocorticoids should not be used. Education and carrying an emergency card are essential for the prevention and rapid treatment of adrenal crisis.