ASST Fatebenefratelli Sacco

Importance: In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) emerged in China and has spread globally, creating a pandemic. Information about the clinical characteristics of infected patients who require intensive care is limited. Objective: To characterize patients with coronavirus disease 2019 (COVID-19) requiring treatment in an intensive care unit (ICU) in the Lombardy region of Italy. Design, Setting, and Participants: Retrospective case series of 1591 consecutive patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinator center (Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network and treated at one of the ICUs of the 72 hospitals in this network between February 20 and March 18, 2020. Date of final follow-up was March 25, 2020. Exposures: SARS-CoV-2 infection confirmed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assay of nasal and pharyngeal swabs. Main Outcomes and Measures: Demographic and clinical data were collected, including data on clinical management, respiratory failure, and patient mortality. Data were recorded by the coordinator center on an electronic worksheet during telephone calls by the staff of the COVID-19 Lombardy ICU Network. Results: Of the 1591 patients included in the study, the median (IQR) age was 63 (56-70) years and 1304 (82%) were male. Of the 1043 patients with available data, 709 (68%) had at least 1 comorbidity and 509 (49%) had hypertension. Among 1300 patients with available respiratory support data, 1287 (99% [95% CI, 98%-99%]) needed respiratory support, including 1150 (88% [95% CI, 87%-90%]) who received mechanical ventilation and 137 (11% [95% CI, 9%-12%]) who received noninvasive ventilation. The median positive end-expiratory pressure (PEEP) was 14 (IQR, 12-16) cm H2O, and Fio2 was greater than 50% in 89% of patients. The median Pao2/Fio2 was 160 (IQR, 114-220). The median PEEP level was not different between younger patients (n = 503 aged ≤63 years) and older patients (n = 514 aged ≥64 years) (14 [IQR, 12-15] vs 14 [IQR, 12-16] cm H2O, respectively; median difference, 0 [95% CI, 0-0]; P = .94). Median Fio2 was lower in younger patients: 60% (IQR, 50%-80%) vs 70% (IQR, 50%-80%) (median difference, -10% [95% CI, -14% to 6%]; P = .006), and median Pao2/Fio2 was higher in younger patients: 163.5 (IQR, 120-230) vs 156 (IQR, 110-205) (median difference, 7 [95% CI, -8 to 22]; P = .02). Patients with hypertension (n = 509) were older than those without hypertension (n = 526) (median [IQR] age, 66 years [60-72] vs 62 years [54-68]; P < .001) and had lower Pao2/Fio2 (median [IQR], 146 [105-214] vs 173 [120-222]; median difference, -27 [95% CI, -42 to -12]; P = .005). Among the 1581 patients with ICU disposition data available as of March 25, 2020, 920 patients (58% [95% CI, 56%-61%]) were still in the ICU, 256 (16% [95% CI, 14%-18%]) were discharged from the ICU, and 405 (26% [95% CI, 23%-28%]) had died in the ICU. Older patients (n = 786; age ≥64 years) had higher mortality than younger patients (n = 795; age ≤63 years) (36% vs 15%; difference, 21% [95% CI, 17%-26%]; P < .001). Conclusions and Relevance: In this case series of critically ill patients with laboratory-confirmed COVID-19 admitted to ICUs in Lombardy, Italy, the majority were older men, a large proportion required mechanical ventilation and high levels of PEEP, and ICU mortality was 26%.

BACKGROUND: Before April 2022, monkeypox virus infection in humans was seldom reported outside African regions where it is endemic. Currently, cases are occurring worldwide. Transmission, risk factors, clinical presentation, and outcomes of infection are poorly defined. METHODS: We formed an international collaborative group of clinicians who contributed to an international case series to describe the presentation, clinical course, and outcomes of polymerase-chain-reaction-confirmed monkeypox virus infections. RESULTS: We report 528 infections diagnosed between April 27 and June 24, 2022, at 43 sites in 16 countries. Overall, 98% of the persons with infection were gay or bisexual men, 75% were White, and 41% had human immunodeficiency virus infection; the median age was 38 years. Transmission was suspected to have occurred through sexual activity in 95% of the persons with infection. In this case series, 95% of the persons presented with a rash (with 64% having ≤10 lesions), 73% had anogenital lesions, and 41% had mucosal lesions (with 54 having a single genital lesion). Common systemic features preceding the rash included fever (62%), lethargy (41%), myalgia (31%), and headache (27%); lymphadenopathy was also common (reported in 56%). Concomitant sexually transmitted infections were reported in 109 of 377 persons (29%) who were tested. Among the 23 persons with a clear exposure history, the median incubation period was 7 days (range, 3 to 20). Monkeypox virus DNA was detected in 29 of the 32 persons in whom seminal fluid was analyzed. Antiviral treatment was given to 5% of the persons overall, and 70 (13%) were hospitalized; the reasons for hospitalization were pain management, mostly for severe anorectal pain (21 persons); soft-tissue superinfection (18); pharyngitis limiting oral intake (5); eye lesions (2); acute kidney injury (2); myocarditis (2); and infection-control purposes (13). No deaths were reported. CONCLUSIONS: In this case series, monkeypox manifested with a variety of dermatologic and systemic clinical findings. The simultaneous identification of cases outside areas where monkeypox has traditionally been endemic highlights the need for rapid identification and diagnosis of cases to contain further community spread.

This is the third European Crohn’s and Colitis Organisation [ECCO] consensus guideline that addresses ulcerative colitis [UC]. It has been drafted by 28 ECCO members from 14 European countries. It is derived from and updates the previous ECCO consensus advice on UC.1–3 All the authors recognise and are grateful to previous ECCO members who contributed to creating the previous consensus guidelines1–6 on which some of the text is based. Attention is also drawn to other ECCO consensus guidelines which have contributed to this endeavour, on extra-intestinal manifestations [EIMs],7 malignancy,8 imaging,9 small bowel endoscopy,10 opportunistic infections [OIs],11 surgery,12 endoscopy,13 pathology,14 anaemia,15 reproduction and pregnancy,16 and paediatric UC.17 The guideline has been condensed into two papers, the first detailing definitions, classification, diagnosis, imaging, pathology, and management of special situations [EIMs, pregnancy, cancer surveillance, surgery, and ileo-anal pouch disorders of UC]; and the second describing current therapeutic management [treatment of active disease and maintenance of medically induced remission]. The strategy to define consensus was similar to that previously described in other ECCO consensus guidelines [available at www.ecco-ibd.eu]. Briefly, an open call for participants was made, with participants selected by the Guidelines’ Committee of ECCO [known as GuiCom] on the basis of their publication record and a personal statement. Working parties were established to review the consensus statements published in 2012,1–3 after which a recommendation was issued on whether they required revision based upon advances in the published literature. There was agreement that extensive review of histopathology, endoscopy, OI, anaemia, EIMs, surgery, and pregnancy was not required, as these subjects are reviewed in other recent ECCO guidelines7,11–16; rather, abbreviated text and selected statements from these guidelines specific to UC are provided. Paediatric UC is dealt with in a separate ECCO initiative17 which is currently being updated. Provisional ECCO statements and supporting text were written following a comprehensive literature review, then refined following two voting rounds which included national representative participation by ECCO’s 35 member countries. The level of evidence was graded according to the Oxford Centre for Evidence-Based Medicine [www.cebm.net]. The ECCO statements were finalised by the authors at a meeting in Barcelona in October 2015 and represent consensus with agreement of at least 80% of participants. Consensus statements are intended to be read in context with their qualifying comments and not in isolation. The supporting text was then finalised under the direction of each working group leader [FM, FC, AD, PG, FR], including an updated literature search to October 2016 of the most relevant [eight] journals, before being integrated by a consensus leader [MH]. This consensus guideline is pictorially represented within the freely available ECCO e-Guide [http://www.e-guide.ecco-ibd.eu/]. UC is a lifelong disease arising from an interaction between genetic and environmental factors, observed predominantly in developed countries. Its precise aetiology is unknown, and therefore curative medical therapy is not yet available. Within Europe there is an east-west and north-south gradient, but the incidence appears to have increased in southern and eastern countries during recent years.18–20 Patients may live with a considerable symptom burden and high risk of disability21 despite medical treatment.22 Clinicians must advise and treat patients on the basis of currently available information. Despite robust evidence from rigorously conducted randomised trials, the strict and somewhat necessarily restrictive inclusion and exclusion criteria in trial design may limit translation of such evidence to ‘real-world’ patients. Ulcerative colitis [UC] is a chronic inflammatory condition that causes continuous mucosal inflammation of the colon, usually without granulomas on biopsy. It affects the rectum and to a variable extent the colon in a continuous fashion, and is characterised by a relapsing and remitting course.23 Inflammatory bowel disease unclassified [IBDU] is the term best suited for a minority of cases in which a definitive distinction between UC, Crohn’s disease, or other causes of colitis cannot be made after taking into account the history, endoscopic appearance, histopathology of multiple mucosal biopsies, and appropriate radiology.23,24 Indeterminate colitis is a term reserved for pathologists to describe a colectomy specimen with overlapping features of UC and Crohn’s disease.24,25 Detailed information on definitions can be found in Supplementary material, available as Supplementary data at ECCO-JCC online.1,23,24,26–39 Distribution of UC [adapted from Silverberg et al.23]. Disease activity in UC [adapted from Truelove & Witts32]. Montréal classification of disease activity in UC [adapted from Silverberg et and et Disease extent whether therapy and and of It is by the extent at as and extensive colitis of inflammation the management and the of for a therapy in the of or is usually the for and therapy with is appropriate for extensive of colitis the risk of of or cancer and the and the of Patients with extensive colitis have the risk of with have a risk similar to the Patients with colitis an their risk that of patients with extensive colitis as disease patients with and extensive colitis are to have patients with not such It be that the extent at may the extent of disease as with and are to the extent of information and risk for of or colitis may in of patients with Disease and of of disease have not been imaging, and endoscopic including histopathology, on management is as and at of a inflammatory of disease It be to the of active colitis by and before which may causes of that active disease such as mucosal Crohn’s disease, or bowel and patients with active disease including to Patients with an appropriate also have to a from of patients are in at during a a of a relapsing after of Disease activity in the first after to an increased of of active a an was between the to first and the of a the the was patients a for the maintenance of in patients with at patients from to at and from to at in the of described the in patients in the first following of UC between and the most recent the of patients an during the first after was a or within the first but and an activity at least during the first is also UC, a chronic inflammatory was in and were in of patients with an inflammatory after of with who without such an were in with and mucosal The of bowel inflammation is also a risk for in patients with extensive Detailed information on the of can be found in Supplementary material, available as Supplementary data at ECCO-JCC and and are of have been with of The is not as in UC as is in Crohn’s disease for the of disease in colitis have been established for and patients a to following for colitis with to a is for and have been but has been to be to The most are and other such as and have also at has for and of disease a with endoscopic and to can be as a for in patients with inflammatory bowel disease of was with an increased risk of It must be that of these is specific for UC, they represent active with disease there is of The consensus group that the best to define is a of with and mucosal at classification of ulcerative colitis according to at is of as disease has a according to the of is as the for and of patients with UC to have disease and and with All current available for UC have an in with The risk of in patients with UC the of is an in patients with UC, as the risk for The of genetic or is not for the classification of ulcerative colitis Detailed information on can be found in Supplementary material, available as Supplementary data at ECCO-JCC of ulcerative colitis are upon extent and of disease and and and are bowel and colitis UC in and the may be made at small in incidence has been in some after the of UC appears to The inflammation in the rectum and in a and to a variable extent of the colon, or mucosal The extent of inflammation may or but after disease the of inflammation to the extent of previous in the of The that UC continuous inflammation been by of a in and of patients with active UC the of mucosal disease, and may according to disease in for extensive UC from most cases of Patients with active disease also of and patients with usually with and may in UC, or the of Crohn’s The of UC is usually are for or before medical advice is with a in with including and EIMs, in or and may the in of cases and can in of of ulcerative colitis or Crohn’s disease the risk for ulcerative colitis for before and the risk and of UC may to ulcerative colitis of patients with UC have an increased risk of the The risk of UC is in but is also in and of UC as as in of patients with Crohn’s disease in a and the of but may not the of the have a risk of the disease, which is extensive and to with who have or but the data are and during or are to a risk of UC in The of is to that of but not to the of is after the of UC, the on the of disease is and is to may the evidence from and a trial that with is medical the of and and extra-intestinal with and of inflammatory bowel disease or and previous be The of UC is in the context of or of colitis be and be and and for and and may be may be in patients with or disease on on the extent and of of patients with or activity is usually from on Patients with a may and bowel for of ulcerative colitis not It is established by imaging, and endoscopic including be with review after an may be The of UC is characterised by of and of continuous in of the as a by The that of patients a in The of of is usually during the first and may be characterised as continuous UC without or the recent the of patients with UC in from at the of to after of It is to the diagnosis, and of disease, as these and disease It is to the to to a diagnosis, but mucosal active UC as the of of the may to Crohn’s disease or be during the first and and The be including be and be diagnosis, have a inflammatory and and a for is an of of chronic inflammation may be in or The may as a of the chronic inflammatory or chronic active disease, and which the of an UC, and with the of with patients with an is with an and have been as to the for colectomy in after a of extensive colitis an increased risk of is specific to UC from or other causes of be to and for may be according to the medical history, for the of for or other or with are required at and may be required to disease is in patients with colitis This for and is a and has been with and ECCO guidelines with disease be in the of or of can in UC, not in patients with may not disease can or It be in patients who The for relevant in patients with colitis has not been but most of in the inclusion with on histopathology not necessarily but multiple are usually including information on can be reviewed in the ECCO Consensus on and in a recent The most are and are in to of patients with UC and in of patients with Crohn’s the current of these their for the of UC and for therapeutic is not such as and have been as of inflammation in appears to be the most the of in patients for in the of disease with endoscopic and in the of and to with the to between of a in the of UC a to inflammation and to be a to a of patients by and has been described in with a or inflammation in the rectum is to to inflammation in the is to as a and may be observed in patients with the of and or a in of the small bowel in to an is The of patients with inflammation to be similar to with of the as a is in to of patients with inflammation has been with a and a risk of after pouch a recent a similar in patients with an of inflammation with with a in of disease and of or inflammation from the into is and is observed in to of patients with extensive may in patients without which the that that from a of into the Patients with to be to a of which may an increased risk of colon in not to be with pouch of the small bowel be in cases of to UC from Crohn’s bowel by or or endoscopy, as reviewed in the ECCO consensus on in Crohn’s and small bowel in is not is the of an to Crohn’s disease in to an is for endoscopic disease activity in ulcerative colitis are available. The of a endoscopic is to of ulcerative colitis patients and to a for inflammatory bowel disease to is for patients criteria for to which may to increased and The classification of UC was by Truelove and in This classification is to be the for of in of to and the of patients with colitis have inflammatory or and with a for and of be to and to the extent of disease and for features that to The extent of disease with the of in a of the extent of disease was in and in The of mucosal by or two of small bowel is with a to the of colitis and may be required is as a on with high in which histopathology be with a within before is in patients with colitis is not in in patients on criteria for colitis with mucosal on the of these and of which can be by is of is appropriate at for or ulcerative colitis or colectomy Despite the of disease in risk of and of the of after has been a mucosal after of was with a risk of in of the patients with mucosal with of without of patients who endoscopic as a of inflammation at and on during of in to of patients that to endoscopic in patients with UC, who were the disease and endoscopic after and and then at the third were to patients with or between and in the of and colectomy were of mucosal was the with and a disease patients with UC with and in that with endoscopic as with to after patients in The most endoscopic of ulcerative colitis is with of inflammation and ulcerative colitis is by mucosal and at the and in a and The between and is usually and may within in in the endoscopic of disease activity is and have been to the of endoscopic and are within the for UC, which is for trial The Ulcerative Colitis of the and the of and each with or of This is the first endoscopic of in The is the of in the of the colon at the of the a of to the of a a was made to the of the a to a of that the of the from to for ulcerative for The endoscopic features of inflammation are and at least of the active colitis is characterised by a of to the of the and with a and mucosal to colitis is characterised by and in et to Crohn’s disease, in UC are in The of is a disease, mucosal can in of and The of in UC has therefore been the of information on colon can be found in Supplementary material, available as Supplementary data at ECCO-JCC Detailed information on can be found in Supplementary material, available as Supplementary data at ECCO-JCC in ulcerative multiple endoscopic be to by be are not or the is not UC, a an increased risk for and the be by a second is the most in the of and then management in a is to a the mucosal to the and extra-intestinal is for diagnosis, of disease and of and The following and updates of the ECCO guideline on UC is a chronic inflammatory to the of features have been and they can be into mucosal and information on on the can be found in Supplementary material, available as Supplementary data at ECCO-JCC a of ulcerative a of two from at least the colon the and the be be by including endoscopic of disease and current be by in or an before the features found in UC are observed in of patients within of the first of The distinction from colitis which is characterised by and is therefore a is the with the for the of ulcerative colitis and the of a inflammatory not ulcerative colitis at an after an may to and a definitive by features or has been as the with the for UC It can be in of patients within after this the of is but may into a the disease mucosal or mucosal and an or mucosal during the of disease least after The of ulcerative colitis is based upon the of and mucosal and a inflammatory with with active inflammation and The of features for UC has not been of UC is in of cases two or of the following features an and in the of of inflammation from to a of ulcerative colitis may the of of these is in the of from patients to an UC a of continuous inflammation that in the rectum and with a in The between the and the is can disease, the extent of during the of the disease or after may such as from continuous to inflammation of the of these features is to in the of to Crohn’s disease, the may features to and as as of and increased inflammation is usually not observed disease is characterised by the of active mucosal features to chronic mucosal such as and as as may mucosal is characterised by the of and inflammatory the can some features of such as with and of usually the of is from endoscopic mucosal inflammation may in cases with disease and has been with of mucosal inflammation following has been can be to between and active disease, as as to the of disease have been for this in therapeutic of or mucosal a definitions of from inflammation with to of the as in with of an increased with of or a high of been with a risk of The of histopathology to and to the level of inflammation may have in therapeutic mucosal is from endoscopic mucosal have a for diagnosis, with the at and endoscopic activity in and disease, but for The of histopathology as the or to disease activity is in to and may be in and with There and updates of the ECCO guideline on and is in UC, found in of for of et criteria for on the level of patients without or evidence of active disease, is an appropriate the of a to may be with the of or evidence of the criteria for of chronic disease are and the level is between and a of and of chronic disease is The most of in UC are of chronic disease, and a of or anaemia, and are but also be is by the as a in to a of in and in All UC patients be for anaemia, and this a and be with and is with and The level of with and is by the of and in et is in ulcerative colitis patients is Detailed information on and can be found in Supplementary material, available as Supplementary data at ECCO-JCC is the second most in UC, in of can be as and of with ulcerative colitis is based on of inflammation and exclusion of other specific of classification for has been but not is and affects in an This is and and is with disease is a and which affects small is of UC and can for to of is on the basis of features of inflammatory with or features of and The of is made according to the is the current as can inflammation before and The of management is the of of and of trial in patients is of the UC usually within Patients may from and Patients with usually or for symptom for be with a and are to be in with patients with active to or of are The and of and in are The of not as the to the risk of the with not is based on which be in patients with active UC, to or with disease and are the statements to in et Patients on therapy and or with a of be or other as these can statements & in et of is made on a be is usually based on that of the ulcerative are required in cases and can be with or usually affects the of the the and has a It is to disease and is based on that of the are usually or or may be can be with or and or are by a as most on the and to The of with disease activity is are to be the first of has been and has to in therefore be a to is not or are an but advice is to on and inflammation can be found in Supplementary material, available as Supplementary data at ECCO-JCC UC It can be and usually to and of the not to an and may has to UC, is has an and is The of to of to an usually of or or and have each been to be of in cases statements & in et the most condition UC chronic and are also in these patients. of the to treat UC have the to is a risk for and colon is as a in patients with for is and small is a be statements to in et was to the of and to the risk of in but therapy has been to to or the was with a disease and therefore be the of to disease with is the statements to in et or after of in UC patients is in et and in et on and disease can be found in Supplementary material, available as Supplementary data at ECCO-JCC Ulcerative colitis patients at risk of opportunistic infections are with in and with and a of infections be is an risk for opportunistic infections to are according to the for Disease and is as a by a that has under for can be or UC patients are not but may have as a of their medical in et is an risk for and in the risk of in a of for All for the of OI, and the of at a may an increased risk of This risk is of the and of but may be by the of OI, have not been to the risk of All ulcerative colitis patients be for at patients with also be is in patients with ulcerative colitis of is in inflammatory bowel disease, by the disease and by the be after of the may be required to of be in patients at risk and for at least after has patients who are with high to of the of in to of with therapy in ulcerative colitis be but therapy is not is the increased risk of UC patients be to is not a for in et UC patients also be for the be by not a with or is but they can the of in on or can be found in Supplementary material, available as Supplementary data at ECCO-JCC information on and can be found in Supplementary material, available as Supplementary data at ECCO-JCC of in patients with is increased and is in 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pregnancy in et to their during pregnancy, with and be as the a is an in specific situations be in a with for UC during pregnancy can to during the first and to in the third but is to represent a risk for the in et information on endoscopy, and can be found in Supplementary material, available as Supplementary data at ECCO-JCC is that UC is with an increased risk of the risk between et described a including and that after of disease the risk was that the incidence of in UC patients was the risk of may have been has a incidence of at at and at This may the increased of the of that inflammation or the to maintenance therapy or The risk of cancer in ulcerative colitis is increased with the is with disease extent and or inflammatory activity has been that is disease a of may by this in patients who are at colitis or in patients with Patients with extensive colitis the risk of colitis patients an risk is not increased in patients with UC to the without may be an for and a of cancer an risk for cancer The most risk for are an increased risk of to and disease may be of previous inflammatory and have also been found to be a risk of is with an increased the risk

Importance: Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). Objective: To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. Design, Setting, and Participants: This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. Exposures: Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. Main Outcomes and Measures: Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. Results: Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (Fio2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low Pao2:Fio2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). Conclusions and Relevance: In this retrospective cohort study of critically ill patients admitted to ICUs in Lombardy, Italy, with laboratory-confirmed COVID-19, most patients required IMV. The mortality rate and absolute mortality were high.

To the Editor—We read with interest the article by Wang et al [1] describing the clinical features of 69 patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Wuhan, China. The authors provide a detailed description of major signs and symptoms of overt disease [2, 3], but fail to give an account of minor symptoms that may be present at earlier stages of the infection. After some patients admitted for coronavirus disease 2019 (COVID-19) at the Infectious Disease Department of L. Sacco Hospital in Milan, Italy, complained of olfactory and taste disorders (OTDs), we performed a cross-sectional survey of the prevalence of these alterations in the context of SARS-CoV-2 infection. On 19 March 2020, a simple questionnaire including questions about the presence or absence of OTDs, their type and time of onset respective to hospitalization were submitted through verbal interview to all SARS-CoV-2–positive hospitalized patients who were able to give informed consent. Of 88 hospitalized patients, 59 were able to be interviewed (29 were nonrespondents, of whom 4 had dementia, 2 had a linguistic barrier, and 23 were on noninvasive ventilation) (Table 1). Of these, 20 (33.9%) reported at least 1 taste or olfactory disorder and 11 (18.6%) both. Twelve patients (20.3%) presented the symptoms before the hospital admission, whereas 8 (13.5%) experienced the symptoms during the hospital stay. Taste alterations were more frequently (91%) before hospitalization, whereas after hospitalization taste and olfactory alteration appeared with equal frequency. Females reported OTDs more frequently than males (10/19 [52.6%] vs 10/40 [25%]; P = .036). Moreover, patients with at least 1 OTD were younger than those without (median, 56 years [interquartile range {IQR}, 47–60] vs 66 [IQR, 52–77]; P = .035). All patients reported the persistence of OTDs at the time of the interview. Characteristics of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection Assessed for Taste and Olfactory Disorders (N = 59) Data are presented as no. (%) unless otherwise indicated. Abbreviations: IQR, interquartile range; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Characteristics of Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Infection Assessed for Taste and Olfactory Disorders (N = 59) Data are presented as no. (%) unless otherwise indicated. Abbreviations: IQR, interquartile range; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. Olfactory and taste disorders are well known to be related with a wide range of viral infections [4, 5]. SARS-CoV has demonstrated in a mice model a transneural penetration through the olfactory bulb [6]. Moreover, angiotensin-converting enzyme 2 receptor, which is used by SARS-CoV-2 to bind and penetrate into the cell, is widely expressed on the epithelial cells of the mucosa of the oral cavity [7]. These findings could explain the underlying pathogenetic mechanism of taste and olfactory disorders in SARS-CoV-2 infection. Due to limitations related to the diffusivity of the disease and emergency contingencies, it was impossible to perform a more structured questionnaire associated with validated tests (ie, Pennsylvania smell identification test) [8]. However, our survey shows that OTDs are fairly frequent in patients with SARS-CoV-2 infection and may precede the onset of full-blown clinical disease. In a pandemic context, further investigations on nonhospitalized infected patients are required to ascertain if these symptoms, albeit unspecific, may represent a clinical screening tool to orientate testing of pauci-symptomatic individuals. Acknowledgments. The authors thank all patients enrolled in the cohort and all medical staff (paramedics, nurses, and physicians) who began this fight on one side of the wall and eventually fell ill during the battle. The authors also thank Tiziana Formenti and Bianca Ghisi for their excellent and indefatigable technical help. Potential conflicts of interest. A. G. has received consultancy fees from Mylan and nonfinancial support from Gilead. S. R. and C. G. have received grants and fees for speaker’s bureaus, advisory boards, and continuing medical education (CME) activities from Bristol-Myers Squibb (BMS), ViiV, Merck Sharp & Dohme (MSD), AbbVie, Gilead, and Janssen. M. G. and G. R. have received grants and fees for speaker’s bureaus, advisory boards, and CME activities from BMS, ViiV, MSD, AbbVie, Gilead, Janssen, and Roche. S. A. has received support for research activities from Pfizer and MSD. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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.

This paper is the second in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease [CD] and concerns the surgical management of CD as well as special situations including management of perianal CD and extraintestinal manifestations. Diagnostic approaches and medical management of CD of this ECCO Consensus are covered in the first paper [Gomollon et al JCC 2016].

SARS-CoV-2 can mutate and evade immunity, with consequences for efficacy of emerging vaccines and antibody therapeutics. Here, we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is a highly variable region of S and provide epidemiological, clinical, and molecular characterization of a prevalent, sentinel RBM mutation, N439K. We demonstrate N439K S protein has enhanced binding affinity to the hACE2 receptor, and N439K viruses have similar in vitro replication fitness and cause infections with similar clinical outcomes as compared to wild type. We show the N439K mutation confers resistance against several neutralizing monoclonal antibodies, including one authorized for emergency use by the US Food and Drug Administration (FDA), and reduces the activity of some polyclonal sera from persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics.

BACKGROUND: Simplified regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection may increase patient satisfaction and facilitate adherence. METHODS: In this phase 3, open-label, multicenter, noninferiority trial involving patients who had had plasma HIV-1 RNA levels of less than 50 copies per milliliter for at least 6 months while taking standard oral antiretroviral therapy, we randomly assigned participants (1:1) to either continue their oral therapy or switch to monthly intramuscular injections of long-acting cabotegravir, an HIV-1 integrase strand-transfer inhibitor, and long-acting rilpivirine, a nonnucleoside reverse-transcriptase inhibitor. The primary end point was the percentage of participants with an HIV-1 RNA level of 50 copies per milliliter or higher at week 48, determined with the use of the Food and Drug Administration snapshot algorithm. RESULTS: Treatment was initiated in 308 participants per group. At week 48, HIV-1 RNA levels of 50 copies per milliliter or higher were found in 5 participants (1.6%) receiving long-acting therapy and in 3 (1.0%) receiving oral therapy (adjusted difference, 0.6 percentage points; 95% confidence interval [CI], -1.2 to 2.5), a result that met the criterion for noninferiority for the primary end point (noninferiority margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 92.5% of participants receiving long-acting therapy and in 95.5% of those receiving oral therapy (adjusted difference, -3.0 percentage points; 95% CI, -6.7 to 0.7), a result that met the criterion for noninferiority for this end point (noninferiority margin, -10 percentage points). Virologic failure was confirmed in 3 participants who received long-acting therapy and 4 participants who received oral therapy. Adverse events were more common in the long-acting-therapy group and included injection-site pain, which occurred in 231 recipients (75%) of long-acting therapy and was mild or moderate in most cases; 1% withdrew because of this event. Serious adverse events were reported in no more than 5% of participants in each group. CONCLUSIONS: Monthly injections of long-acting cabotegravir and rilpivirine were noninferior to standard oral therapy for maintaining HIV-1 suppression. Injection-related adverse events were common but only infrequently led to medication withdrawal. (Funded by ViiV Healthcare and Janssen; ATLAS ClinicalTrials.gov number, NCT02951052.).

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients.

Morosini P‐L, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM‐IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social funtioning. Acta Psychiatr Scand 2000: 101:323–329. © Munksgaard 2000. Objective: Development of a scale to assess patients' social functioning, the Personal and Social Performance scale (PSP). Method: PSP has been developed through focus groups and reliability studies on the basis of the social functioning component of the DSM‐TV Social and Occupational Functioning Assessment Scale (SOFAS). The last reliability study was carried out by 39 workers with different professional roles on a sample of 61 psychiatric patients admitted to the rehabilitation unit. Each patient was rated independently on the scale by the two workers who knew them best. Results: The PSP is a 100–point single‐item rating scale, subdivided into 10 equal intervals. The ratings are based mainly on the assessment of patient's functioning in four main areas: 1) socially useful activities; 2) personal and social relationships; 3) self‐care; and 4) disturbing and aggressive behaviours. Operational criteria to rate the levels of disabilities have been defined for the above‐mentioned areas. Excellent inter‐rater reliability was also obtained in less educated workers. Conclusion: Compared to SOFAS, PSP has better face validity and psychometric properties. It was found to be an acceptable, quick and valid measure of patients' personal and social functioning.

A severe outbreak of coronavirus disease 2019 (COVID-19) emerged in China in December 2019, and spread so rapidly that more than 200,000 cases have so far been reported worldwide; on January 30, 2020, the WHO declared it the sixth public health emergency of international concern. The two previously reported coronavirus epidemics (severe acute respiratory syndrome [SARS] and Middle East respiratory syndrome [MERS]) share similar pathogenetic, epidemiological and clinical features as COVID-19. As little is currently known about SARS-CoV-2, it is likely that lessons learned from these major epidemics can be applied to the new pandemic, including the use of novel immunosuppressive drugs.

The spillovers of betacoronaviruses in humans and the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants highlight the need for broad coronavirus countermeasures. We describe five monoclonal antibodies (mAbs) cross-reacting with the stem helix of multiple betacoronavirus spike glycoproteins isolated from COVID-19 convalescent individuals. Using structural and functional studies, we show that the mAb with the greatest breadth (S2P6) neutralizes pseudotyped viruses from three different subgenera through the inhibition of membrane fusion, and we delineate the molecular basis for its cross-reactivity. S2P6 reduces viral burden in hamsters challenged with SARS-CoV-2 through viral neutralization and Fc-mediated effector functions. Stem helix antibodies are rare, oftentimes of narrow specificity, and can acquire neutralization breadth through somatic mutations. These data provide a framework for structure-guided design of pan-betacoronavirus vaccines eliciting broad protection.

Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

The goal of this consensus initiated by the European Crohn’s and Colitis Organisation [ECCO] and European Society of Colo-Proctology [ESCP] was to establish European consensus guidelines for the surgical treatment of Crohn’s disease [CD]. The strategy to reach the consensus involved several steps and follows the standard operating procedures for consensus guidelines of ECCO. An open call for chairs and participants for this consensus was made among members of the ESCP, surgeons of ECCO, and ECCO members. Participants were selected by the Guidelines’ Committee of ECCO [GuiCom] and the guideline committee of the ESCP on the basis of their publication record and personal statement. Five working groups [WGs] were formed: WG 1, perioperative management; WG 2, upper gastrointestinal tract and small bowel; WG 3, large bowel; WG 4, perianal CD; and WG 5, special conditions. Participants were asked to answer relevant questions on current practice and areas of controversy related to the surgical treatment of CD based on their experience as well as evidence from the literature [Delphi procedure].1 In parallel, the WG members performed a systematic literature search of their topic with the appropriate key words using Medline/PubMed/ISI/Scopus, and the Cochrane database, as well as their own files. Provisional guideline statements [with supporting text] were then written by the WG chairs based on answers to the questionnaire and were subsequently circulated among the WG members, prompting discussion and exchange of available evidence. The proposed statements and the supporting text were submitted to an online platform for discussion and two online voting rounds were conducted. The first round involved all participants of the consensus development process and, for the second voting round, all national representatives of ECCO and ESCP were invited to participate. The consensus participants finally met in Dublin on September 22, 2015 for face-to-face discussion and voting for consensus on the statements. This was done by projecting the statements and revising them on screen until consensus was reached. Consensus was defined as agreement by more than 80% of participants; the consensus statements were numbered for convenience in the document. The level of evidence was graded according that published by the Oxford Centre for Evidence-based Medicine 2011 [http://www.cebm.net/mod_product/design/files/CEBM-Levels-of-Evidence-2.1.pdf]. The final manuscript was written by the WG chairs [OZ, GS, JW, WB, ZS] in conjunction with the WG members and revised for consistency by WB and AD. Officially, WB is representing the ECCO and AD the ESCP. It was agreed to publish the consensus guideline in JCC and to post links to the original publication in JCC on the websites of ECCO and the ESCP. The surgical treatment of CD was covered in the Third European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016. Part 1: Diagnosis and Medical Management, and Part 2: Surgical Management and Special Situations.2 The following guidelines add to the surgical aspects of the multidisciplinary management of Crohn’s disease. The present document is to be seen as complementary to the surgical section published in the 2016 consensus. Some consensus statements are modified or expanded and others are entirely new. In order to have a complete overview,2 the surgical statements of the existing Third European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management, and Part 2: Surgical Management and Special Situations3 are added, without supporting text. A number of statements account for the general management of CD, and are listed in this section. If a patient has a relapse, escalation of the maintenance treatment can be considered to prevent disease progression [EL2]. Steroids should not be used to maintain remission [EL1]. Surgery should always be considered as an option in localised disease [EL4]. Whether there is a higher rate of postoperative complications from abdominal surgery during or after anti-tumour necrosis factor [TNF] therapy remains controversial [EL3]. Prednisolone 20 mg daily or equivalent for more than 6 weeks is a risk factor for surgical complications [EL2]. Therefore, corticosteroids should be weaned if possible [EL5]. Laparoscopy, when feasible, should be the preferred approach in surgery for CD. It results in reduced morbidity, shorter hospital stay, reduction in adhesions and hernia formation, and improved cosmesis [EL1] Anti-TNF therapy is associated with higher postoperative septic complications after abdominal surgery for CD. The safest period for omission of anti-TNF therapy is unknown [EL2] The impact of preoperative medical therapy on postoperative surgical complications has been widely studied. Prednisolone 20 mg daily or equivalent for more than 6 weeks before surgery is a significant risk factor for surgical complications. Therefore, steroids should be weaned if possible. Conversely, thiopurines can safely be continued in the perioperative period. In the past, the association of anti-TNF therapy before surgery with postoperative complications was controversial, but recent studies and meta-analysis have shown an increased risk of postoperative sepsis, intra-abdominal abscesses, anastomotic leak, wound infections, and readmission in CD patients. The of steroids and anti-TNF the risk for complications. are available to the safest period of before surgery in order to the risk related to anti-TNF with and to are for surgery in CD CD can present with complications surgery in of with and of with should of the with or without is the of in is a of of gastrointestinal tract should be using and If are or surgery is with CD surgery should and to before of be in of should be used for or treatment of surgery are risk for and have been shown to after and are for should with CD present with should be daily and by a and in without [EL5]. or to medical treatment should for an surgery in CD a from of should be for and and by a multidisciplinary a and Medical treatment for should be and and should be daily to of or of should of for surgical treatment are to the management of in by an or should be with surgery is in of complete or if is In of to medical surgery can be after the patient is is by a and of or and to and steroids should be considered in If there are of or surgery be and a of the should be In the of the patient present with several of by there is to medical is to disease and and the and be before Surgery is the preferred option in with localised CD with but significant evidence of in a patient for surgery is a for if there is significant evidence of The of is and on the of small to surgery treatment with or for shorter than with should be first by medical In of of surgery is with and of disease are first with as in the ECCO guidelines for medical treatment of If are not by medical treatment or are surgery should be The to medical is to as there are medical that have not been The of should be the surgical risk should this to The medical and surgical treatment in of a can be and are discussion for and to the are An surgery and medical treatment in with disease and in treatment in the In with surgery should be considered an In CD, surgery should be considered an In with significant to and there is a higher risk of to medical This should be the risk of surgery following medical In with intra-abdominal have several with a an or disease are more to An from the treatment in in the The of an in an patient should not be considered an for surgery or Surgery should be considered in with CD in or if for is reduced a period of in of an medical and therapy In with CD, is a for surgery as the of be It is to that treatment with as an are before the of surgery is surgery is not and the disease after or increased of maintenance as or be considered as for should be with surgery is if to treatment or is not a in CD and septic complications. should be with for CD, medical therapy is not with and is surgery be if not to treatment Surgery for septic complications a significant risk of anastomotic leak, abscesses, and A of the of and a in the first and in the second should be considered in is a significant risk factor for postoperative complications. should be before surgery or If surgery is in a a is have or more of their in a period are considered and from preoperative by or is a significant risk factor for postoperative anastomotic leak, as wound and level is not a of as level be by or should be used in to the is and for preoperative in should be considered for In surgery a of the with of a by of is can safely be continued in the perioperative period and [EL2] available literature association the of and an increased risk of surgical of thiopurines before surgery is not abdominal surgery for CD, is to have a recent of the disease and and from the and are procedures in the of a recent should be by the multidisciplinary has in recent and present is widely used for the of CD and and and have and for the of and as the of for CD as can disease and disease and complications as abscesses, and The and It patient and a of for of the In with is the of and preferred as should be in patients. In localised is an but significant and have been shown to in abdominal surgery with recent of should perioperative therapy of steroids have been considered the perioperative standard of the for on This practice is based on two from the of postoperative of surgery with steroids before surgery have a is evidence to this practice of the preoperative several and a Cochrane not of preoperative This widely used practice should be and a should be to the evidence. has a be an for with CD surgery are a higher risk for and should be considered [EL2] with CD surgery are a higher risk for and the of and should be considered for is for patients. In the risk of is to risk an and an this are published for the and of related to CD surgery in Therefore, the and to be considered of the of after surgery is for CD, and in postoperative studies have the of after with a shorter hospital and this the of after surgery should be possible to the surgical management of CD patients. has the of after surgery in surgery of CD. 20 for CD with with with perioperative stay, to first and first were shorter in the of preoperative preoperative of and to and to 6 before of of and with and is for in with CD the upper tract more in than in but for surgery not to be increased [EL2] gastrointestinal Crohn’s disease is a of of CD. This has been in an of of with the European In this of the as and of the upper and upper was in of and of upper disease or with the of In with CD without upper in the upper tract were in to of the the of the upper in with CD, there are on the of surgery for this disease Therefore, that more upper CD not more surgical in CD have an of with a large number of with or without or and are all The is the be in the of gastrointestinal disease. with of CD to be present a have upper and perianal and surgeons working in an multidisciplinary to be with The for surgical treatment of is The or should be during multidisciplinary with an CD is a and in the of CD is more in disease with The of of CD from to in and in The of and from to but the of remains is in the of all and to a of CD, and to CD and It is if there is a to upper in Medical and surgical treatment of is as or small the of therapy is used for medical but disease a surgical A of and have been and and with as the are with the the level of the the level of the or to the Some have been The of has been without The of covered has been in with an a risk of and can be are are by In to be CD of the the and If surgery is and is in Crohn’s In CD of the and and are considered surgical of the second and are when with or have to be considered as is the or the is of should be with the possible [EL4]. CD disease of the and is an and the and are to the of the basis of and the of is to in of patients. In or is in and of The are upper abdominal and and are with and and anti-TNF have been to be The for surgery in CD is for complications. The of the The are in the and in of in the second and in in the and in of have in in the and are by a with An to is a are when feasible, with as there is of a or anastomotic The of CD in a is the and the have been as of from a of the or In is to relevant the is in of and Surgery be as as with and of and has been in recent surgical is for but all have the of CD is to the small number of in the medical after surgery is not It is to have and the and and of all the of the small before on In with not all the present with the level of or the of and or The and for CD are and should be used in the surgical impact on the postoperative treatment and the and are all for of small CD with but their and are to be and It is not to more than there were in the preoperative a can be used to the and with the to a is for is a to in CD, with and is when the of the is in disease with the small be [EL3]. Diagnosis during and are risk for risk of surgery and surgical for small CD [EL2] with complications were to have more with an risk of and surgical evidence for this in the and with disease are as the level of disease This be for and Crohn’s but with and a have a surgical Surgical as as and and are in have of and and of the the and the of the small of CD, the treatment should be on the basis of the of [EL2] The first of surgical for CD be a complete of the A complete and is to or all the CD have been a approach can be The of as localised and the of a are for in a that CD surgical is by the of from and involved were first in CD by and in and then by and several have been for of and of the small and and are to for are disease of a large of small of more than without an associated or anastomotic a from and in can be used as a treatment In with the surgical is based on a of small and disease of the with is not a to in In with of the are for and the for to the the and the of of the is are the and the to as the of the for of the and of the of are surgery is in and localised CD of the small should be with or [EL2] The preferred treatment of of the small when feasible, are [EL2] the treatment of to the of is the [EL2]. as is the preferred for the treatment of or and [EL2]. 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The impact of SARS-CoV-2 infection during gestation remains unclear. Here, we analyse the viral genome on maternal and newborns nasopharyngeal swabs, vaginal swabs, maternal and umbilical cord plasma, placenta and umbilical cord biopsies, amniotic fluids and milk from 31 mothers with SARS-CoV-2 infection. In addition, we also test specific anti-SARS-CoV-2 antibodies and expression of genes involved in inflammatory responses in placentas, and in maternal and umbilical cord plasma. We detect SARS-CoV-2 genome in one umbilical cord blood and in two at-term placentas, in one vaginal mucosa and in one milk specimen. Furthermore, we report the presence of specific anti-SARS-CoV-2 IgM and IgG antibodies in one umbilical cord blood and in one milk specimen. Finally, in the three documented cases of vertical transmission, SARS-CoV-2 infection was accompanied by a strong inflammatory response. Together, these data support the hypothesis that in utero SARS-CoV-2 vertical transmission, while low, is possible. These results might help defining proper obstetric management of COVID-19 pregnant women, or putative indications for mode and timing of delivery.

Background: Ceftazidime-avibactam (CAZ-AVI) has been approved in Europe for the treatment of complicated intra-abdominal and urinary tract infections, as well as hospital-acquired pneumonia, and for gram-negative infections with limited treatment options. CAZ-AVI displays in vitro activity against Klebsiella pneumoniae carbapenemase (KPC) enzyme producers, but clinical trial data on its efficacy in this setting are lacking. Methods: We retrospectively reviewed 138 cases of infections caused by KPC-producing K. pneumoniae (KPC-Kp) in adults who received CAZ-AVI in compassionate-use programs in Italy. Case features and outcomes were analyzed, and survival was then specifically explored in the large subcohort whose infections were bacteremic. Results: The 138 patients started CAZ-AVI salvage therapy after a first-line treatment (median, 7 days) with other antimicrobials. CAZ-AVI was administered with at least 1 other active antibiotic in 109 (78.9%) cases. Thirty days after infection onset, 47 (34.1%) of the 138 patients had died. Thirty-day mortality among the 104 patients with bacteremic KPC-Kp infections was significantly lower than that of a matched cohort whose KPC-Kp bacteremia had been treated with drugs other than CAZ-AVI (36.5% vs 55.8%, P = .005). Multivariate analysis of the 208 cases of KPC-Kp bacteremia identified septic shock, neutropenia, Charlson comorbidity index ≥3, and recent mechanical ventilation as independent predictors of mortality, whereas receipt of CAZ-AVI was the sole independent predictor of survival. Conclusions: CAZ-AVI appears to be a promising drug for treatment of severe KPC-Kp infections, especially those involving bacteremia.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

OBJECTIVE: To report mode of delivery and immediate neonatal outcome in women infected with COVID-19. DESIGN: Retrospective study. SETTING: Twelve hospitals in northern Italy. PARTICIPANTS: Pregnant women with COVID-19-confirmed infection who delivered. EXPOSURE: COVID 19 infection in pregnancy. METHODS: SARS-CoV-2-infected women who were admitted and delivered from 1 to 20 March 2020 were eligible. Data were collected from the clinical records using a standardised questionnaire on maternal general characteristics, any medical or obstetric co-morbidity, course of pregnancy, clinical signs and symptoms, treatment of COVID 19 infection, mode of delivery, neonatal data and breastfeeding. MAIN OUTCOME AND MEASURES: Data on mode of delivery and neonatal outcome. RESULTS: In all, 42 women with COVID-19 delivered at the participating centres; 24 (57.1%, 95% CI 41.0-72.3) delivered vaginally. An elective caesarean section was performed in 18/42 (42.9%, 95% CI 27.7-59.0) cases: in eight cases the indication was unrelated to COVID-19 infection. Pneumonia was diagnosed in 19/42 (45.2%, 95% CI 29.8-61.3) cases: of these, 7/19 (36.8%, 95% CI 16.3-61.6) required oxygen support and 4/19 (21.1%, 95% CI 6.1-45.6) were admitted to a critical care unit. Two women with COVID-19 breastfed without a mask because infection was diagnosed in the postpartum period: their newborns tested positive for SARS-Cov-2 infection. In one case, a newborn had a positive test after a vaginal operative delivery. CONCLUSIONS: Although postpartum infection cannot be excluded with 100% certainty, these findings suggest that vaginal delivery is associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn. TWEETABLE ABSTRACT: This study suggests that vaginal delivery may be associated with a low risk of intrapartum SARS-Cov-2 transmission to the newborn.

OBJECTIVES: COVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear. DESIGN: This Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death). RESULTS: Between 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death. CONCLUSIONS: Active IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.