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Background The aim of this study was to characterize severe immune-related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death. Methods Patients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected. Results In total, 450 admissions were classified as irAE admissions and represent the study's cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA-4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA-4 plus PD-1 combination therapy recipients (OR, 1.88; p < .001), relative to PD-1/PD-L1 monotherapy recipients, and patients with multiple toxicity had a 5-fold increase in inpatient mortality. Conclusion This study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA-4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi-organ involvement is common and those patients are at highest risk of inpatient mortality. Implications for Practice The number of patients admitted to Massachusetts General Hospital for immune-related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.

The surge in cases of severe COVID-19 has resulted in clinicians triaging intensive care unit (ICU) admissions in places where demand has exceeded capacity. In order to assist difficult triage decisions, clinicians require clear guidelines on how to prioritise patients. Existing guidelines show significant variability in their development, interpretation, implementation and an urgent need for a robust synthesis of published guidance. To understand how to manage which patients are admitted to ICU, and receive mechanical ventilatory support, during periods of high demand during the COVID-19 pandemic, a systematic review was performed. Databases of indexed literature (Medline, Embase, Web of Science, and Global Health) and grey literature (Google.com and MedRxiv), published from 1 January until 2 April 2020, were searched. Search terms included synonyms of COVID-19, ICU, ventilation, and triage. Only formal written guidelines were included. There were no exclusion criteria based on geographical location or publication language. Quality appraisal of the guidelines was performed using the Appraisal of Guidelines for Research and Evaluation Instrument II (AGREE II) and the Appraisal of Guidelines for Research and Evaluation Instrument Recommendation EXcellence (AGREE REX) appraisal tools, and key themes related to triage were extracted using narrative synthesis. Of 1902 unique records identified, nine relevant guidelines were included. Six guidelines were national or transnational level guidance (UK, Switzerland, Belgium, Australia and New Zealand, Italy, and Sri Lanka), with one state level (Kansas, USA), one international (Extracorporeal Life Support Organization) and one specific to military hospitals (Department of Defense, USA). The guidelines covered several broad themes: use of ethical frameworks, criteria for ICU admission and discharge, adaptation of criteria as demand changes, equality across health conditions and healthcare systems, decision-making processes, communication of decisions, and guideline development processes. We have synthesised the current guidelines and identified the different approaches taken globally to manage the triage of intensive care resources during the COVID-19 pandemic. There is limited consensus on how to allocate the finite resource of ICU beds and ventilators, and a lack of high-quality evidence and guidelines on resource allocation during the pandemic. We have developed a set of factors to consider when developing guidelines for managing intensive care admissions, and outlined implications for clinical leads and local implementation.

The introduction of vaccines has inspired hope in the battle against SARS-CoV-2. However, the emergence of viral variants, in the absence of potent antivirals, has left the world struggling with the uncertain nature of this disease. Antibodies currently represent the strongest correlate of immunity against SARS-CoV-2, thus we profiled the earliest humoral signatures in a large cohort of acutely ill (survivors and nonsurvivors) and mild or asymptomatic individuals with COVID-19. Although a SARS-CoV-2–specific immune response evolved rapidly in survivors of COVID-19, nonsurvivors exhibited blunted and delayed humoral immune evolution, particularly with respect to S2-specific antibodies. Given the conservation of S2 across β-coronaviruses, we found that the early development of SARS-CoV-2–specific immunity occurred in tandem with preexisting common β-coronavirus OC43 humoral immunity in survivors, which was also selectively expanded in individuals that develop a paucisymptomatic infection. These data point to the importance of cross-coronavirus immunity as a correlate of protection against COVID-19.

Therapeutic blockade of co-inhibitory immune receptors PD-1 and CTLA-4 has revolutionized oncology, but treatments are limited by immune-related adverse events (IRAEs). IRAE Colitis (irColitis) is the most common, severe IRAE affecting up to 25% of patients on dual PD-1 and CTLA-4 inhibition. Here, we present a systems biology approach to define the cell populations and transcriptional programs driving irColitis. We collected paired colon mucosal biopsy and blood specimens from 13 patients with irColitis, 8 healthy individuals, and 8 controls on immune checkpoint inhibitors (ICIs), and analyzed them with single-cell/nuclei RNA sequencing with paired TCR and BCR sequencing, multispectral fluorescence microscopy, and secreted factor analysis (Luminex). We profiled 299,407 cells from tissue and blood and identified 105 cell subsets that revealed significant tissue remodeling in active disease. Colon mucosal immune populations were dominated by tissue-resident memory (TRM) ITGAE-expressing CD8 T cells representing a phenotypic spectrum defined by gene programs associated with T cell activation, cytotoxicity, cycling, and exhaustion. CD8 TRM and effector CD4 T cells upregulated type 17 immune programs (IL17A, IL26) and Tfh-like programs (CXCL13, PDCD1). We also identified for the first time an increased abundance of two KLRG1 and ITGB2-expressing CD8 T cell populations with circulatory cell markers, including a GZMK TRM-like population and a CX3CR1 population that is predicted to be intravascular. These two populations were more abundant in irColitis patients treated with dual PD-1/CTLA-4 inhibition than those receiving anti-PD-1 monotherapy. They also had significant TCR sharing with PBMCs, suggesting a circulatory origin. In irColitis we observed significant epithelial turnover marked by fewer LGR5-expressing stem cells, more transit amplifying cells, and upregulation of apoptotic and DNA-sensing programs such as the cGAS-STING pathway. Mature epithelial cells with top crypt genes upregulated interferon-stimulated pathways, CD274 (PD-L1), anti-microbial genes, and MHC-class II genes, and downregulated aquaporin and solute-carrier gene families, likely contributing to epithelial cell damage and absorptive dysfunction. Mesenchymal remodeling was defined by increased endothelial cells, both in irColitis patients and specifically in patients on dual PD-1/CTLA-4 blockade. Cell-cell communication analysis identified putative receptor-ligand pairs that recruit CD8 T cells from blood to inflamed endothelium and positive feedback loops such as the CXCR3 chemokine system that retain cells in tissue. This study highlights the cellular and molecular drivers underlying irColitis and provides new insights into the role of CTLA-4 and PD-1 signaling in maintaining CD8 TRM homeostasis, regulating CD8 T recruitment from blood, and promoting epithelial-immune crosstalk critical to gastrointestinal immune tolerance and intestinal barrier function.

Mechanisms underlying severe coronavirus disease 2019 (COVID-19) disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNA-seq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune-cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell-type-specific intracellular death signatures, cellular angiotensin-converting enzyme 2 (ACE2) expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease., Graphical abstract, Filbin et al. use plasma proteomics in 306 coronavirus disease 2019 (COVID-19) patients and 78 symptomatic controls over time to better understand the role of circulating immune cells and tissue cells in inflammation, disease severity, and survival. They propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage.

Background: Previous research has mainly focused on the impacts of epidemics on those people who are directly affected by the epidemic infection, or of healthcare workers caring for them. Less is known about the impact on mental health of their relatives, and potential interventions to support them. Methods: Systematic review and narrative synthesis. Outcomes: 28 studies were identified, sixteen quantitative and twelve qualitative. One involved health workers' relatives, and the rest covered relatives of directly affected individuals. We found considerable burden of mental ill-health in both groups. Among relatives of healthcare workers, 29.4% reported symptoms consistent with probable anxiety disorder and 33.7% with probable depression. Prevalence rates for probable anxiety disorder ranged from 24 to 42% and probable depression 17–51% for the relatives of affected people. One study found a 2% prevalence of PTSD and another found odds of PTSS were significantly higher among relatives of affected individuals compared with the general population. Only two intervention studies were identified and both were descriptive in nature. Interpretation: Available evidence suggests relatives of people affected by infective outbreaks report mental ill-health. Having a relative who died particularly increased risk. Good outcomes for relatives of affected individuals were promoted by practical and social support, public health guidance that recognises the caring role of relatives, and being supported to see the positives as well as negatives in their situation. Good outcomes for relatives of health workers were promoted by perceived effectiveness of protective equipment. High quality evidence on potential interventions to support relatives is lacking. Funding: No external funding sought.

BACKGROUND: SARS-CoV-2 plasma viremia has been associated with severe disease and death in COVID-19 in small-scale cohort studies. The mechanisms behind this association remain elusive. METHODS: We evaluated the relationship between SARS-CoV-2 viremia, disease outcome, and inflammatory and proteomic profiles in a cohort of COVID-19 emergency department participants. SARS-CoV-2 viral load was measured using a quantitative reverse transcription PCR–based platform. Proteomic data were generated with Proximity Extension Assay using the Olink platform. RESULTS: This study included 300 participants with nucleic acid test–confirmed COVID-19. Plasma SARS-CoV-2 viremia levels at the time of presentation predicted adverse disease outcomes, with an adjusted OR of 10.6 (95% CI 4.4–25.5, P < 0.001) for severe disease (mechanical ventilation and/or 28-day mortality) and 3.9 (95% CI 1.5–10.1, P = 0.006) for 28-day mortality. Proteomic analyses revealed prominent proteomic pathways associated with SARS-CoV-2 viremia, including upregulation of SARS-CoV-2 entry factors (ACE2, CTSL, FURIN), heightened markers of tissue damage to the lungs, gastrointestinal tract, and endothelium/vasculature, and alterations in coagulation pathways. CONCLUSION: These results highlight the cascade of vascular and tissue damage associated with SARS-CoV-2 plasma viremia that underlies its ability to predict COVID-19 disease outcomes. FUNDING: Mark and Lisa Schwartz; the National Institutes of Health (U19AI082630); the American Lung Association; the Executive Committee on Research at Massachusetts General Hospital; the Chan Zuckerberg Initiative; Arthur, Sandra, and Sarah Irving for the David P. Ryan, MD, Endowed Chair in Cancer Research; an EMBO Long-Term Fellowship (ALTF 486-2018); a Cancer Research Institute/Bristol Myers Squibb Fellowship (CRI2993); the Harvard Catalyst/Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, NIH awards UL1TR001102 and UL1TR002541-01); and by the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases, 5P30AI060354).

Immunotherapy for cancer holds great promise, but immune dysregulation of checkpoint blockade has resulted in new autoimmune adverse events. Hepatic toxicity occurs in 1%–17% of patients on immune checkpoint inhibitors. Hepatitis is usually a low‐grade toxicity, but grade 3 and 4 hepatotoxicity does occur. This article answers frequently asked questions about immune‐related hepatitis to assist in the recognition and management of this important condition., Many human tumors are recognized by the adaptive immune system, but these spontaneous antitumor responses are typically inadequate to mediate regression. Blockade of immune regulatory “checkpoint” receptors such as cytotoxic T‐lymphocyte‐associated antigen 4 and programmed cell death 1 can unleash antitumor immunity, resulting in tumor responses that can be durable. Alongside the enormous promise of immunotherapy for cancer, the immune dysregulation of checkpoint blockade has led to a plethora of new autoimmune adverse events. Hepatic toxicity occurs in 1%–17% of patients on immune checkpoint inhibitors, with the precise incidence dependent on both the drug used and the underlying malignancy. Hepatitis is most commonly a low‐grade toxicity, but grade 3 and 4 hepatotoxicity does occur. Here we will answer frequently asked questions regarding immune‐related hepatitis to assist in the recognition and management of this important condition. Key Points. Immune related hepatitis is a potentially serious complication of checkpoint blockade.The differential for elevated liver function tests in patients on checkpoint blockade is broad.Diagnostic testing such as viral serologies, liver ultrasound, cross sectional imaging, and liver biopsy may help in the diagnosis of immune related hepatitis in select patients.Patients with underlying cirrhosis are an at risk population for whom current grading criteria may underestimate the severity of liver inflammation.Severe immune related hepatitis is best managed by a multi‐disciplinary team that includes a hepatologist.Most patients with immune related hepatitis respond to corticosteroids, but a substantial fraction require treatment with a secondary immunosuppressive agent.

BackgroundIn 2017, Massachusetts General Hospital implemented the Severe Immunotherapy Complications (SIC) Service, a multidisciplinary care team for patients hospitalized with immune-related adverse events (irAEs), a unique spectrum of toxicities associated with immune checkpoint inhibitors (ICIs). This study’s objectives were to evaluate the intervention’s (1) effect on patient outcomes and healthcare utilization, and (2) ability to collect biological samples via a central infrastructure, in order to study the mechanisms responsible for irAEs.MethodsA hospital database was used to identify patients who received ICIs for a malignancy and were hospitalized with severe irAEs, before (April 2, 2016–October 3, 2017) and after (October 3, 2017–October 24, 2018) SIC Service initiation. The primary outcome was readmission rate after index hospitalization. Secondary outcomes included length of stay (LOS) for admissions, corticosteroid and non-steroidal second-line immunosuppression use, ICI discontinuation, and inpatient mortality.ResultsIn the pre-SIC period, 127 of 1169 patients treated with ICIs were hospitalized for irAEs; in the post-SIC period, 122 of 1159. After SIC service initiation, reductions were observed in irAE readmission rate (14.8% post-SIC vs 25.9% pre-SIC; OR 0.46; 95% CI 0.22 to 0.95; p=0.036) and readmission LOS (median 6 days post-SIC vs 7 days pre-SIC; 95% CI −16.03 to –0.14; p=0.046). No significant pre-initiation and post-initiation differences were detected in corticosteroid use, second-line immunosuppression, ICI discontinuation, or inpatient mortality rates. The SIC Service collected 789 blood and tissue samples from 234 patients with suspected irAEs.ConclusionsThis is the first study to report that establishing a highly subspecialized care team focused on irAEs is associated with improved patient outcomes and reduced healthcare utilization. Furthermore, the SIC Service successfully integrated blood and tissue collection safety into routine care.

Self-organized strontium ion crosslinked alginate/carboxymethyl cellulose composite materials with gold nanoparticles (Au-NPs) and graphene oxide (GO) were effectively fabricated using dissipative convective procedures followed by the freeze-drying method. Composite gels were characterized by using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy with Energy dispersive X-ray analysis (SEM-EDAX) and transmission electron microscopy (TEM) analysis. Moreover, thermal, mechanical and rheological properties were also performed to identify their strength and stability. The results revealed that Sr/Alg/CMC/Au and Sr/Alg/CMC/GO/Au composites showed remarkably porous structures with ordered capillaries; rheologically gel-like structures with high mechanical strength. Moreover, composites were tested for the reduction of o-nitroaniline and Suzuki-Miyaura cross-coupling reaction. The Sr/Alg/CMC/GO/Au composite competently reduced the o-nitroaniline within 2min (k=4.86×10-2s-1) with recyclability up to 7 consecutive cycles and also displayed 98% isolated yield (TOF value is 4900h-1) for Suzuki-Miyaura cross-coupling reaction with 6cycles recyclability. This approach of using nanoparticles incorporated composite systems as reusable catalysts opens a door of new materials for various catalytic applications.

Novel nanocomposites of Sr2+ ion crosslinked alginate/carboxymethyl cellulose (Alg/CMC) with TiO2 nanoparticles (TiO2-NPs) and graphene oxide (GO) incorporation was synthesized using simple dissipative convective route followed by freeze drying processes. As-synthesized nanocomposites were characterized using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), UV- visible-diffuse reflectance spectroscopy (UV-vis-DRS), surface area study, Raman spectroscopy, scanning electron microscopy with energy dispersive X-ray analysis (SEM-EDAX) and transmission electron microscopy (TEM) analysis, respectively. The results revealed that GO and TiO2-NPs were successfully incorporated into alginate/CMC matrix and visible light response of TiO2 was significantly improved. Photocatalytic performance of nanocomposites was evaluated by degradation of congo red (CR) dye under direct sunlight irradiation. The degradation results disclosed that GO and TiO2-NPs incorporated Sr/alginate/CMC nanocomposites (Sr/Alg/CMC/GO/TiO2) can competently degrade the tested CR dye molecules and showed greater degradation efficiency (98%) than the Sr/Alg/CMC/TiO2 (70%), Sr/Alg/CMC (60%) and bare TiO2 (62%) photocatalyst, respectively. Moreover, recyclability study of Sr/Alg/CMC/GO/TiO2 nanocomposite demonstrated that it was highly stable under reaction condition and retained its degradation efficiency up to seven consecutive cycles of degradation reaction. Our results suggested that Sr/Alg/CMC/GO/TiO2 is an efficient visible light responsive photocatalyst for degradation of dye molecules in the presence of direct sunlight irradiation using present reaction conditions.

2654 Background: The exponential increase in FDA-approved indications for immune checkpoint inhibitors (ICI) in cancer care has resulted in therapeutic success but also in the occurrence of immune-related adverse effects (irAEs) that can represent a significant clinical challenge. On October 3 2017, the Massachusetts General Hospital (MGH) implemented the Severe Immunotherapy Complications (SIC) Service, a multi-disciplinary care team for patients hospitalized with irAEs. The objectives of this study were to evaluate the impact of SIC Service on 1) healthcare utilization and 2) patients outcomes. Methods: Using pharmacy and hospital admission databases, a list of patients was identified that both received ICI for a malignancy and were hospitalized with severe irAEs in the period prior to initiation of the SIC service and after SIC initiation. The pre-SIC period was defined as an admission between 4/2/2016 through 10/3/2017, and the post-SIC period as an admission from 10/3/2017 through 10/24/2018. The rate of readmission after the index hospitalization was the primary outcome. Secondary outcomes included lengths of stay (LOS) for both initial irAE admissions and readmissions, use of corticosteroids and non-steroidal second-line immunosuppression, ICI discontinuation, and inpatient mortality in the pre- and post-SIC periods. Results: Among 1169 patients treated in the pre-SIC service intervention period; 127 were hospitalized for irAE. Among 1159 patients treated in the post-SIC intervention 122 were hospitalized for irAE. SIC Service implementation was associated with a significant reduction in irAE readmission rates (post-SIC 14.8% vs. pre-SIC 25.9%; odds ratio [OR], 0.46; 95% CI, 0.22-0.95; p=0.036). The length of stay, rates of corticosteroid use, second-line immunosuppression, and ICI discontinuation for irAE, as well as inpatient mortality rates were not significantly different before and after SIC Service implementation. Conclusions: This is the first study to report that establishing a highly subspecialized care team focused on irAEs can be associated with improved clinical outcomes for patients receiving ICI therapy. Such care teams may play an essential part in optimizing irAE care.

Nanocomposite hydrogels of barium ion crosslinked alginate/carboxymethyl cellulose (CMC) with encapulation of TiO 2 -NPs were synthesized sucessfully using dissipative convective method followed by freeze-drying procedure. As-prepared composite hydrogels were charecterized by different techniques such as Fourier Transform Infrared spectroscopy (FT-IR), Powder X-ray diffraction (PXRD), UV- Diffuse reflectance spectroscopy (UV-DRS), BET-Surface area study, Scanning Electron Microscopy with Energy Dispersive X-ray analysis (SEM-EDAX), Transmission Electron Microscopy (TEM) and mechanical strength study. Ba/Alg/CMC/TiO2 composite hydrogels exhibited excellent photocatalytic activity towards CR under direct solar light irradiation with pseudo-first order kinetics. The recycling ability of Ba/Alg/CMC/TiO2 composite hydrogels confirms that photocatalyst is highly photostable.

Composite gels of Ba/alginate(Alg)/carboxymethyl cellulose (CMC) were prepared by a dissipative convective process. Graphene oxide (GO) and Au nanoparticle (Au-NPs) were successfully encapsulated into the polysaccharide matrix. The resulting composite gels were characterized by Fourier transform infrared (FTIR) spectrometry, Raman spectroscopy, powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The rheological and mechanical behaviors of the composite gels were also investigated. The composite gels were tested for the reduction of o-nitroaniline (o-NA), to 1,2-benzenediamine in the presence of NaBH4. Ba/Alg/CMC/GO/Au composite gels reduce o-NA within 3 min with a rate constant of 0.45 s−1 and the composite can be recycled for up to 4 successive cycles.

3060Background: Immune checkpoint inhibitors such as anti-CTLA4 and anti-PD1 antibodies represent a paradigm shift in the treatment of many advanced malignancies. However, immune related adverse ef...

Muscle spasm and hypertonia limit mobility in children with spastic cerebral palsy. This double-blind, placebo-controlled, randomized controlled clinical trial studies the clinical efficacy of a low dose of diazepam in enhancing movement in children with spastic cerebral palsy. One hundred and eighty children fulfilled the criteria and were randomly allocated to receive one of two doses of diazepam or placebo at bedtime; 173 completed the study. There was a significant reduction of hypertonia, improvement in the range of passive movement, and an increase in spontaneous movement in the children who received diazepam. There was no report of daytime drowsiness. In developing countries, where cost factors often determine choice of drug, diazepam is a cheap and effective way of relieving spasm and stiffness, optimizing physical therapy and facilitating movement in children with spasticity.

127 Background: Disruption of the immune system with immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude of irAE’s in the real-world, particularly inpatient is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE needing admission to an academic hospital (Feb 2011 to June 2017). Each case was reviewed comprehensively by minimum of two reviewers, including one sub-specialist. In addition, oncologists at our institution were surveyed regarding their confidence about managing patients with irAEs. Results: Over a span of 6 years, there were 343 hospitalizations for suspected irAEs and the majority (65%; N = 223) were confirmed irAEs that required treatment with immunosuppression or therapy stopped as result. The mean length of stay was 6.3 days (range 1 to 31 days), readmission rate for another irAE event 25%, total readmission rate 61.7%, and inpatient mortality 8%. The most common irAEs were enterocolitis (43.9%), pulmonary (16%), hepatic (15%), neurological (8.9%), endocrinopathies (7.1%), rheumatological (4%), dermatological (3%), cardiovascular (3%), renal (1.8%), and allergy (1.3%). Over the past 5 years, there was a significant increase in admissions due to irAEs (admissions in 2016 vs 2011, odds ratio = 3.07; p < 0.01). The Cancer Center survey (N = 26) revealed majority of oncologists do not feel very comfortable managing irAEs, and 48% felt that irAE complications should be managed on a different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, high rate of readmissions, and mortality. The number of patients admitted due to irAEs has significantly increased by more than three-fold in the recent years, but majority of oncologists do not feel very comfortable managing irAEs. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research program for early detection and intervention.

A study was undertaken to evaluate the effect of aqueous and methanolic plant extracts of Acorus calamus rhizome, Pongamia glabra leaves, Aegle marmelos unripe fruit and Strychnos nux-vomica root bark for their antidiarrhoeal potential against castor-oil induced diarrhoea in mice. The methanolic plant extracts were more effective than aqueous plant extracts against castor-oil induced diarrhoea. The methanolic plant extracts significantly reduced induction time of diarrhoea and total weight of the faeces. The result obtained establish the efficacy of these plant extracts as antidiarrhoeal agents.

Rational drug use workshops were conducted in various centres in India. The effects of these workshops on some of the indicators for rational drug use are discussed. An evaluation based on responses to questionnaires does not permit the measurement of the effects on practice changes, and only perceived changes by the respondents are indicated. Within the short period of evaluation, drug use skills and awareness about various aspects of rational drug use are perceived to have improved. There is a need to re-emphasize through personal interaction and workshops the concept of rational drug use.

A study of adverse drug reactions to anti tuberculosis therapy in the medical outpatients showed that the overall incidence of adverse reactions was 26 per cent. Side-effects to isoniazid and rifampicin were mainly hepatitis, nausea, vomiting. Ethambutol caused reversible optic neuritis in 7.9 per cent cases. Most adverse drug reactions occurred during the first 3 months of treatment.

The awareness of the inherent risks attached to medication use during pregnancy is increasing. There is, however, a paucity of available following childbirth. We have conducted a prospective study in women who gave birth in hospital with the objective of analysing the use of medication in this lying in period. The results show that, in addition to the vitamins and minerals routinely prescribed for every young mother and the antipyretics administered as required, the following medicaments were most often used: analgesics (by approx. 9%), antiinflammatory agents (49%) and antibiotics (38%). The antibiotics were either used prophylactically or, in cases of proven infection, administered therapeutically. The use of antibiotics appears more intensive compared to western countries, presumably due to the greater risk of infection in this group in India. On the other hand, the use of sleep inducing medication and tranquillizers during the lying in period appears, in comparison to other studies, almost negligable. The majority of the women were unaware of the potential side-effects of medication during breastfeeding.

Background A number of dermatological conditions present with features of systemic inflammatory response syndrome (SIRS). This study evaluated the incidence and outcome of SIRS in patients with dermatological diseases. Study design Prospective cohort study. Results Patients admitted to a university hospital with a skin disease and fulfilling at least two SIRS criteria were included. The primary outcome measure was mortality. Secondary outcomes included incidence of multiple organ dysfunction syndrome (MODS), sepsis, severe sepsis and shock. Over 14 months, 2765 inpatients with skin related problems were examined. These included 721 patients admitted directly to the dermatology ward and 2044 patients referred from other departments within the hospital, with cutaneous manifestations. The incidence of SIRS in this cohort was 2.4% (n=67). The mean (SD) age was 32.6 (19.7) years with a male:female ratio of 1.2:1. Cutaneous adverse drug reaction (CADR) was the most common cause of SIRS (35.8%). During hospitalisation, 37 patients (55.2%) developed sepsis, 23 (34.4%) MODS, 15 (22.4%) severe sepsis and 6 (9%) shock. Methicillin sensitive Staphylococcus aureus was the most common skin isolate (41.4%) and Enterococcus the most common blood isolate. Overall mortality was 15% (10/67). Older age, low albumin, MODS, severe sepsis and shock were associated with an increased risk of death (p Conclusion The incidence of SIRS was low in dermatological diseases. In this cohort, CADR was the most common cause of SIRS. Patients who developed sepsis or MODS had a poor outcome.

Whereas it is now clear that human bone marrow stromal cells (BMSCs) can be immunosuppressive and escape cytotoxic lymphocytes (CTLs) in vitro and in vivo, the mechanisms of this phenomenon remain controversial. Here, we test the hypothesis that BMSCs suppress immune responses by Fas-mediated apoptosis of activated lymphocytes and find both Fas and FasL expression by primary BMSCs. Jurkat cells or activated lymphocytes were each killed by BMSCs after 72 h of co-incubation. In comparison, the cytotoxic effect of BMSCs on non-activated lymphocytes and on caspase-8(−/−) Jurkat cells was extremely low. Fas/Fc fusion protein strongly inhibited BMSC-induced lymphocyte apoptosis. Although we detected a high level of Fas expression in BMSCs, stimulation of Fas with anti-Fas antibody did not result in the expected BMSC apoptosis, regardless of concentration, suggesting a disruption of the Fas activation pathway. Thus BMSCs may have an endogenous mechanism to evade Fas-mediated apoptosis. Cumulatively, these data provide a parallel between adult stem/progenitor cells and cancer cells, consistent with the idea that stem/progenitor cells can use FasL to prevent lymphocyte attack by inducing lymphocyte apoptosis during the regeneration of injured tissues.

Prophylactic and curative use of antibiotics was studied prospectively in 87 consecutive medical and surgical cases of a tertiary care hospital and in 98 cases of a primary care hospital. Based on Kunins' criteria, antibiotic prophylaxis was found to be more inappropriate in the primary care hospital (49%) than in the tertiary care hospital (34%). Antibiotic therapy, however, was more appropriate at the primary level; 67% as opposed to 60% at the tertiary level. This resulted in a similar overall level of inappropriate antibiotic use in the two hospitals. Surgical prophylaxis was started postoperatively in 68% of the primary care hospital cases. Though prophylaxis was always perioperative in the tertiary care hospital, the postoperative duration was more than 7 days in one third of the cases. The nosocomial infection rate in those given prolonged prophylaxis was higher than those who received antibiotics for less than 72 hours. Antibiotics were started empirically in 78% of tertiary hospital care cases and 100% of cases in the primary hospital. Though culture sensitivity was done in 80% of the tertiary care cases, more than half the specimens were sent after multiple doses of antibiotics were started. The choice of antibiotic did not always correlate with the sensitivity report. Though cost-effective drugs were chosen in 50% of cases, in more than 20% of cases expensive drugs were started. The study highlights the need for an antibiotic audit and suggests the necessity of having an ongoing peer audit.

Epidermolytic acanthoma (EA) is a rare benign tumor that shows epidermolytic hyperkeratosis (EH) on histopathology. It can occur in a solitary or disseminated form. This condition needs to be distinguished from other hereditary or acquired conditions that may show EH. We diagnosed an unusual case of EA of the vulva presenting in a linear pattern in a 50-year-old lady based on the clinical features and typical histopathological findings and stress the importance of considering epidermolytic acanthoma in the differential diagnosis of verrucous lesions of the genitalia.

One of the neglected areas in medical education is undoubtedly organized continuing medical education (CME) for the general practitioners. A programme on CME for general practitioners working under difficult and varied conditions is reported. The aim of the programme was to improve knowledge, skills and attitude of the practitioners, and its measurable effects are improvement of knowledge and skills. Attitude changes and final effect on patient care are difficult to evaluate and methods need be developed for this.

The efficacy of jasmine flowers (Jasminum Sambac) applied to the breasts to suppress puerperal lactation was compared that of Bromocriptine. Effectiveness of both regimens was monitored by serum prolactin levels, clinical evaluation of the degree of breast engorgement and milk production and the analgesic intake. While both bromocriptine and jasmine flowers brought about a significant reduction in serum prolactin, the decrease was significantly greater with bromocriptine. However, clinical parameters such as breast engorgement, milk production and analgesic intake showed the 2 modes of therapy to be equally effective. The failure rates of the 2 regimens to suppress lactation were similar; however, rebound lactation occurred in a small proportion of women treated with bromocriptine. Jasmine flowers seem to be an effective and inexpensive method of suppressing puerperal lactation and can be used as an alternative in situations where cost and nonavailability restrict the use of bromocriptine.

A double blind study to evaluate in allergic rhinitis the efficacy of Astemizole with a classical antihistaminic—Chlorpheneramine is described. The results indicate that there is a significantly better clinical improvement with Astemizole compared with Chlorpheneramine. Except of weight gain, adverse Cholinergic and sedative effects were also minimal with Astemizole.

Ni l'histamine, ni la cimetidine aux concentrations entre 1 et 10 mM n'ont produit de modification significative de la motilite des spermatozoides. Les deux antihistaminiques classiques: promethazine et allorpheniramine, ont provoque tous deux une reduction en rapport avec la dose de la motilite des spermatozoides, la promethazine etant le plus puissant. L'histamine s'est opposee a l'inhibiteur de la motilite induite par la promethazine

Rats maintained on cholesterol-free diet and fed neutral detergent fiber (NDF) from blackgram showed lower concentrations of cholesterol in the serum, liver and aorta, when compared to those fed isocaloric, fiber-free diet. Incorporation of labeled precursors, [1,2(-14)C]acetate and [U-14C]glucose, into cholesterol of liver was higher in these rats. The activity of hepatic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase was also increased. Concentration of cholic acid and chenodeoxycholic acid in the liver was also more in rats fed blackgram NDF. The decreased concentration of cholesterol in the tissues may be due to its higher rate of hepatic degradation to bile acids.

The levels of pseudocholinesterase and its nature were studied in 390 leprosy patients and 343 control subjects. The levels of the enzyme in both leprosy patients and normal controls were comparable. The study of the nature of the enzyme by determining its dibucaine number showed that a statistically significant number of lepromatous patients had the atypical variety of the enzyme compared with normal controls or tuberculoid patients. Since the presence of the atypical variety of the enzyme is genetically determined it is suggested that genetic factors play an important part in deciding susceptibility to lepromatous leprosy.