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Pandemic-related lapses in infection control practices may have caused an outbreak of multidrug-resistant Candida auris yeast infections in a Florida hospital’s coronavirus disease 2019 (COVID-19) unit, investigators from the CDC and the Florida Department of Health reported.

Coronavirus disease 2019 (COVID-19) incidence increased by 56% in counties where colleges held in-person classes after the start of last fall’s school year, the CDC reported.

In this narrative medicine essay, a medical school professor expresses gratitude for the caring and empathy expressed by the team caring for her mother hospitalized with COVID-19 and emphasizes the importance of humanity and compassion over facts and statistics for families physically separated from their critically ill loved ones.

This randomized trial compares the effect of vitamin C, thiamine, and hydrocortisone vs matching placebo on 30-day ventilator- and vasopressor-free days among patients with sepsis-induced respiratory and/or cardiovascular dysfunction.

Informational videos starring physicians modestly improved coronavirus disease 2019 (COVID-19) knowledge among US Black and Latino adults regardless of the clinician’s race, according to a trial published in the Annals of Internal Medicine.

In Reply Dr Xu and colleagues raise several interesting questions about our study. First, they correctly point out that neuroimaging is the gold standard for the diagnosis of spinal hematoma and suggest that we may have missed some asymptomatic cases. However, neuroimaging data were unavailable for the registry-based part of the study, and we focused on clinically meaningful end points of neurological deficits requiring hospitalization. Reassuringly, in a medical record review of all lumbar punctures performed in patients with coagulopathy in the North Denmark Region during a 20-year period, we confirmed the very low absolute risk observed in the registry-based study, suggesting that any potential misclassification likely resulted in an overestimation of risk. Second, the anatomical location of spinal hematoma was unknown in the registry-based part of the study since we relied on diagnosis codes for their detection. Third, we are unaware of an official definition of traumatic spinal tap, and the red blood cell count thresholds in cerebrospinal fluid have ranged from more than 10 × 106/L to more than 1000 × 106/L in previous studies. In spite of the relatively low red blood cell count cutoff used in our study, the 28% with traumatic spinal tap was comparable with some studies but was higher than one study using a more refined definition. As described in the Methods section, we excluded patients with a diagnosis code of subarachnoid hemorrhage within 14 days of lumbar puncture without any changes in the results. Fourth, data on the number of attempts for successful lumbar puncture were restricted to medical record review; as mentioned in the Supplement, only 1 case of spinal hematoma was diagnosed in a patient with severe thrombocytopenia after multiple lumbar puncture attempts. Fifth, cross-tabulation of platelet levels and international normalized ratio are available in eTable 5 in the Supplement.

by Tobias Flieder, Tanja Vollmer, Benjamin Müller, Jens Dreier, Bastian Fischer, Cornelius Knabbe, Ingvild Birschmann Background The novel coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread across the world. The aim of our study was to characterize mild courses and to determine the antibody status for these patients. Methods We initiated an appeal for convalescent plasma donations. 615 people contacted us, and we ultimately included 426 in our analyses, in whom it was possible to assume COVID-19 based on detection of specific SARS-CoV-2 antibodies or virus detection during the disease using RT-PCR. Results The median duration of the disease was 12 days and the most common symptoms were fatigue, cough and olfactory and gustatory dysfunction. Anti-SARS-CoV-2 IgG was detected in 82.4% of the persons and IgA antibodies were found in 73.9%. In 10.8%, no antibodies were detectable despite a positive RT-PCR result during the disease. Nevertheless, of 24 persons with asymptomatic courses of COVID-19, antibodies against SARS-CoV-2 could be detected in 23 (96%). Furthermore, there was a correlation between the duration of the disease and the detection of IgG antibodies. In addition, a correlation between the determined IgG antibodies and neutralizing antibodies was shown. Conclusion In this study, we were able to describe mild COVID-19 courses and determine antibody statuses for them. It could be shown that, despite SARS-CoV-2 detection during the disease, not all individuals developed antibodies or their level of antibodies had dropped below the detection limit shortly after the end of the disease. The extent to which immunity to re-infection is given in persons with undetectable antibodies (IgG, IgA) needs to be investigated in future studies.

by Cristina Mussini, Alessandro Cozzi-Lepri, Marianna Menozzi, Marianna Meschiari, Erica Franceschini, Jovana Milic, Lucio Brugioni, Antonello Pietrangelo, Massimo Girardis, Andrea Cossarizza, Roberto Tonelli, Enrico Clini, Marco Massari, Michele Bartoletti, Anna Ferrari, Anna Maria Cattelan, Paola Zuccalà, Miriam Lichtner, Roberto Rossotti, Enrico Girardi, Emanuele Nicastri, Massimo Puoti, Andrea Antinori, Pierluigi Viale, Giovanni Guaraldi Background The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients’ profile. Methods Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day 6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort. Results 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively. Conclusions Our score could assist clinicians in identifying, early after tocilizumab administration, patients who are likely to progress to mechanical ventilation or death, so that they could be selected for eventual rescue therapies.

by Akinniyi Paul Akinduti, Joshua Adekunle Osiyemi, Temitope Temitayo Banjo, Oluwaseun Ejilude, Maged El-Ashker, Adewale Gideon Adeyemi, Yemisi Dorcas Obafemi, Patrick Omoregie Isibor Spread of genetically diverse Staphylococcus aureus characterized with multi-antibiotic resistance and regulated by high level agr functionalities in several communities in southwest Nigeria was investigated and evaluated for infection control. Staphylococcus aureus pathotypes recovered from 256 cases including purulent pus from skin infections, soft tissue aspirates, wounds, otorrhea, eye, throat and endocervical infections were assayed for biofilm and antibiogram. Further genotyped with micro-array, mapped for geospatial distribution and evaluated for clonal diversity and functional accessory gene regulators (agr). Significant Staphylococci infection among the ages (OR:0.021, CI:0.545–1.914) and female gender with prevalence rate of MSSA (53.0%) and MRSA (1.5%) (OR:1.021, CI:0.374–1.785) were observed. More than 52.5% resistance rates to tetracycline and amoxicillin with significant median resistance were observed in all the infection cases (p = 0.001). Resistance rate of 78.8% at MIC50 32μg/ml and MIC90 128μg/ml to amoxicillin-clavulanate, and more than 40% resistance to ceftazidime, ciprofloxacin and tetracycline of MIC90 and MIC50 at 32 μg/ml were observed. Strains with multi-antibiotic resistance index above 0.83, high beta-lactamase and strong biofilm clustered into separate phylo-group. Heterogeneous t442 (wound and pus), t657 (wound), t091 (ear) and t657 (ear and wound) revealed high phylogenetic diversity. Only 4.6% pvl+ MSSA-CC1 agrI, pvl+ MSSA-CC5 (13.6%) and pvl+ MRSA-CC7 agrII (4.6%), expressed enterotoxin, leukocidins, proteases and resistance gene determinants. Livestock clonal types clustered with identified community-associated strains. Clonal dissemination of resistant pvl+ MSSA-CC1 and MRSA-CC5 encoding agr were predominant in several peri-urban communities where adequate geno-surveillance, population-target antimicrobial stewardship, extensive community structured infection control programs are needed to prevent further focal dissemination.

by Qing Sun, Jonathan Li, Hui Ren, Larry Pastor, Yulia Loginova, Roberta Madej, Kristopher Taylor, Joseph K. Wong, Zhao Zhang, Aiguo Zhang, Chuanyi M. Lu, Michael Y. Sha Background Sensitive and high throughput molecular detection assays are essential during the coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vast majority of the SARS-CoV-2 molecular assays use nasopharyngeal swab (NPS) or oropharyngeal swab (OPS) specimens collected from suspected individuals. However, using NPS or OPS as specimens has apparent drawbacks, e.g. the collection procedures for NPS or OPS specimens can be uncomfortable to some people and may cause sneezing and coughing which in turn generate droplets and/or aerosol particles that are of risk to healthcare workers, requiring heavy use of personal protective equipment. There have been recent studies indicating that self-collected saliva specimens can be used for molecular detection of SARS-CoV-2 and provides more comfort and ease of use for the patients. Here we report the performance of QuantiVirus™ SARS-CoV-2 test using saliva as the testing specimens with or without pooling. Methods Development and validation studies were conducted following FDA-EUA and molecular assay validation guidelines. Using SeraCare Accuplex SARS-CoV-2 reference panel, the limit of detection (LOD) and clinical performance studies were performed with the QuantiVirus™ SARS-CoV-2 test. For clinical evaluation, 85 known positive and 90 known negative clinical NPS samples were tested. Additionally, twenty paired NPS and saliva samples collected from recovering COVID-19 patients were tested and the results were further compared to that of the Abbott m2000 SARS-CoV-2 PCR assay. Results of community collected 389 saliva samples for COVID-19 screening by QuantiVirus™ SARS-CoV-2 test were also obtained and analyzed. Additionally, testing of pooled saliva samples was evaluated. Results The LOD for the QuantiVirus™ SARS-CoV-2 test was confirmed to be 100–200 copies/mL. The clinical performance studies using contrived saliva samples indicated that the positive percentage agreement (PPA) of the QuantiVirus™ SARS-CoV-2 test is 100% at 1xLOD, 1.5xLOD and 2.5xLOD. No cross-reactivity was observed for the QuantiVirus™ SARS-CoV-2 test with common respiratory pathogens. Testing of clinical samples showed a positive percentage agreement (PPA) of 100% (95% CI: 94.6% to 100%) and a negative percentage agreement (NPA) of 98.9% (95% CI: 93.1% to 99.9%). QuantiVirus™ SARS CoV-2 test had 80% concordance rate and no significant difference (p = 0.13) between paired saliva and NPS specimens by Wilcoxon matched pairs signed rank test. Positive test rate was 1.79% for 389 saliva specimens collected from local communities for COVID-19 screening. Preliminary data showed that saliva sample pooling up to 6 samples (1:6 pooling) for SARS-CoV-2 detection is feasible (sensitivity 94.8% and specificity 100%). Conclusion The studies demonstrated that the QuantiVirus™ SARS-CoV-2 test has a LOD of 200 copies/mL in contrived saliva samples. The clinical performance of saliva-based testing is comparable to that of NPS-based testing. Pooling of saliva specimens for SARS-CoV-2 detection is feasible. Saliva based and high-throughput QuantiVirus™ SARS-CoV-2 test offers a highly desirable testing platform during the ongoing COVID-19 pandemic.

Abstract Background In Mozambique, infection by intestinal parasites is reported all over the country. However, infection in children with diarrhoea is mostly focused in the southern region of Mozambique. This work aims to determine the frequency and potential risk factors for infection by Cryptosporidium spp., Giardia lamblia, and Entamoeba histolytica in children under-five years hospitalized with diarrhoea in Hospital Central de Nampula, northern Mozambique. Methods A cross-sectional hospital-based surveillance was conducted between March 2015 and January 2018 in children admitted with diarrhoea in Hospital Central de Nampula. Sociodemographic information was obtained through semi-structured interviews applied to the children’s caregivers. A single stool sample was collected from each child to detect antigens from Cryptosporidium spp., G. lamblia, and E. histolytica using an immune-enzymatic technique. Crude and adjusted odds ratios (with 95% Confidence Intervals) were obtained by logistic regression models to identify factors associated with infection by Cryptosporidium spp. and G. lamblia. Results The median age and interquartile intervals of our sample population was 12 months (8–20). Intestinal protozoa were detected in 21.4% (59/276). Cryptosporidium spp. was the most common protozoa (13.9% - 38/274), followed by G. lamblia (9.1% - 25/274) and E. histolytica (0.4% - 1/275). Children with illiterate caregiver’s (p-value = 0.042) and undernourished (p-value = 0.011) were more likely to be infected by Cryptosporidium spp. G. lamblia was more common in children living in households with more than four members (p-value = 0.039). E. histolytica was detected in an eleven month’s child, co-infected with Cryptosporidium spp. and undernourished. Conclusion Cryptosporidium spp. and Giardia lamblia were the most common pathogenic intestinal protozoa detected in children with diarrhoea hospitalized in the Hospital Central de Nampula. Our findings obtained highlight the importance of exploring the caregiver’s education level, children’s nutritional status for infections with Cryptosporidium spp., and living conditions, namely crowded households for infections with G. lamblia in children younger than five years.

Abstract Background Quality of life (QOL) is one of the major factors to assessing the health and wellbeing of People living with HIV (PLWH). Likewise, improved QOL is among the prominent goals of patient treatment. This study was conducted to investigate the QOL of PLWH in Kermanshah, Iran. Methods This cross-sectional study was conducted on 364 PLWH of Kermanshah between 2016 and 2017. Outpatients were selected as the sample through the convenience sampling method from HIV Positive Clients of Kermanshah Behavioral Diseases Counseling Center. The reasons for the selection of outpatients include: (a) some patients were substance users, homeless or did not have a fixed address to follow-up; (b) addresses and personal details that were registered on the first admission were incorrect or incomplete; (c) due to financial issues, some were forced to relocate frequently and were difficult to track; (d) some patients were convicts or prisoners, making it hard to find them after their release; (e) some of them were from other provinces, where managing access was not easy/possible. Data was collected using WHOQOL-HIV BREF questionnaire (Persian Version). Data also analyzed with STATA 14, and SPSS 23 using T-test and multiple regression. Results This study showed that mean (SD) age of PLWH was 40.21 (10.45) years. Females had better QOL than males except for spirituality, religion and personal beliefs. The gender differences disappeared in multivariate results. A significant association was observed between education and the independence, environment, and spirituality domains of QOL. In addition, being married was correlated with overall QOL, psychological and social relationships domains of QOL of PLWH. Drug use was a behavioral factor with negative influence on the QOL. Conclusion This study found that marital status and drug use were the main predictors of various domains of QOL. Drug use was a behavioral factor with a negative influence on the QOL. Hence, it is recommended that health professionals, planners, and policymakers take effective measures to improve the status quo.

Abstract Background Melioidosis is an infectious disease caused by Burkholderia pseudomallei. In Mexico, the disease is rarely diagnosed in humans and there is no evidence of simultaneous environmental isolation of the pathogen. Here, we describe clinical profiles of fatal cases of melioidosis in two children, in a region without history of that disease. Case presentation About 48 h before onset of symptoms, patients swam in a natural body of water, and thereafter they rapidly developed fatal septicemic illness. Upon necropsy, samples from liver, spleen, lung, cerebrospinal fluid, and bronchial aspirate tissues contained Burkholderia pseudomallei. Environmental samples collected from the locations where the children swam also contained B. pseudomallei. All the clinical and environmental strains showed the same BOX-PCR pattern, suggesting that infection originated from the area where the patients were swimming. Conclusions The identification of B. pseudomallei confirmed that melioidosis disease exists in Sonora, Mexico. The presence of B. pseudomallei in the environment may suggest endemicity of the pathogen in the region. This study highlights the importance of strengthening laboratory capacity to prevent and control future melioidosis cases.

Abstract Background Persistence of cholera outbreaks in developing countries calls for concern and more targeted intervention measures for long-term control. This research undertook spatial analysis of cholera incidence in Nigeria over a seventeen-year period to determine the existence of regional hotspots and predictors. Methods A cross-sectional study design was used for the research. Cholera data for each of the thirty-six states and the federal capital territory (FCT) were obtained from the Nigeria Centre for Disease Control (NCDC) of the Federal Ministry of Health, Nigeria. Socioeconomic data including proportion of households using solid waste disposal (unapproved dumpsite, refuse burying, refuse burning, public dumpsite, and refuse collectors), water sources (pipe borne water, well, borehole, rain water, surface waters and water vendors), sewage disposal (water closet, pit latrines, bucket/pan, public toilet and nearby bush/stream), living in a single room and earning less than minimum wage (18,000 naira) were obtained from National Population Commission. On the other hand, proportion of illiterate adults (15 years and above) and poor people; and population density were obtained from National Bureau of Statistics. Each socioeconomic data was obtained at state level. Cholera patterns were analysed at state level using Global Moran’s I while specific locations of cholera clusters were determined using Local Moran’s I. Stepwise multiple regression was used to determine socioeconomic predictors of cholera incidence. Results Local Moran’s I revealed significant cluster patterns in 1999, 2001, 2002, 2009 and 2010 in Adamawa, Gombe, Katsina, Bauchi, Borno, Yobe, and Kano states. Households using surface water was the significant predictor (23%) of the observed spatial variations in cholera incidence. Conclusions Persistence of cholera outbreaks in some north east and north western states calls for more targeted, long-term and effective intervention measures especially on provision of safe sources of water supply by government and other stakeholders.

Abstract Background Rapid diagnostic tests (RDTs) targeting histidine rich protein 2(HRP2) are widely used for diagnosis of Plasmodium falciparum infections. Besides PfHRP2, the PfHRP3 antigen contributes to the detection of P. falciparum infections in PfHRP2 RDTs. However, the performance HRP2-based RDT is affected by pfhrp2/3 gene deletions resulting in false-negative test results. The objective of this study was to determine the presence and prevalence of pfhrp2/3 gene deletions including the respective flanking regions among symptomatic patients in Assosa zone, Northwest Ethiopia. Methods A health-facility based cross-sectional study was conducted in febrile patients seeking a malaria diagnosis in 2018. Blood samples were collected by finger-prick for microscopic examination of blood smears, malaria RDT, and molecular analysis using dried blood spots (DBS) prepared on Whatman filter paper. A total of 218 P. falciparum positive samples confirmed by quantitative PCR were included for molecular assay of pfhrp2/3 target gene. Results Of 218 P. falciparum positive samples, exon 2 deletions were observed in 17.9% of pfhrp2 gene and in 9.2% of pfhrp3 gene. A high proportion of deletions in short segments of pfhrp2 exon1-2 (50%) was also detected while the deletions of the pfhrp3 exon1-2 gene were 4.1%. The deletions were extended to the downstream and upstream of the flanking regions in pfhrp2/3 gene (above 30%). Of eighty-six PfHRP2 RDT negative samples, thirty-six lacked pfhrp2 exon 2. Five PfHRP2 RDT negative samples had double deletions in pfhrp2 exon 2 and pfhrp3 exon2. Of these double deletions, only two of the samples with a parasite density above 2000 parasite/µl were positive by the microscopy. Three samples with intact pfhrp3 exon2 in the pfhrp2 exon2 deleted parasite isolates were found to be positive by PfHRP2 RDT and microscopy with a parasite density above 10,000/µl. Conclusion This study confirms the presence of deletions of pfhrp2/3 gene including the flanking regions. Pfhrp2/3 gene deletions results in false-negative results undoubtedly affect the current malaria control and elimination effort in the country. However, further countrywide investigations are required to determine the magnitude of pfhrp2/3 gene deletions and its consequences on routine malaria diagnosis.

In some parts of the tropics, melioidosis is an important public health problem and diagnostic laboratories frequently encounter Burkholderia pseudomallei. Most of these laboratories use disc diffusion for antimicrobial susceptibility testing but have had difficulty with B. pseudomallei because of a lack of internationally accepted criteria to interpret the results. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has recently published guidelines for interpretation of disc diffusion testing for B.

We read with interest the recent publication by Kahn et al who derived and validated the POSITIVE scoring system to predict the likelihood of infective endocarditis (IE) in patients with Staphylococcus aureus bacteremia (SAB)[1]. They also calculated sensitivity and specificity of time to blood culture positivity as a predictor of IE and found that in patients with no prior antimicrobial use, time-to-positivity (TTP) of ≤13 hours had 100% sensitivity in predicting IE…

Artesunate is the recommended initial treatment for severe malaria, followed by 3 days of arteminisin-based combination (ACT) therapy (World Health Organization, 2015).. Artesunate monotherapy may lead to recrudescence of the parasitemia in 4050% of the cases within 28 days (Wellems et al., 2020). This recrudescence is related to the parasite persistence due to induced dormancy and should be distinguished from drug resistance.

Introduction Facial hygiene promotion and environmental improvements are central components of the global trachoma elimination strategy despite a lack of experimental evidence supporting the effectiveness of water, sanitation and hygiene (WASH) measures for reducing trachoma transmission. The objective of the WUHA (WASH Upgrades for Health in Amhara) trial is to evaluate if a comprehensive water improvement and hygiene education programme reduces the prevalence of ocular chlamydia infection in rural Africa. Methods and analysis Forty study clusters, each of which had received at least annual mass azithromycin distributions for the 7 years prior to the start of the study, are randomised in a 1:1 ratio to the WASH intervention arm or a delayed WASH arm. The WASH package includes a community water point, community-based hygiene promotion workers, household wash stations, household WASH education books, household soap distribution and a primary school hygiene curriculum. Educational activities emphasise face-washing and latrine use. Mass antibiotic distributions are not provided during the first 3 years but are provided annually over the final 4 years of the trial. Annual monitoring visits are conducted in each community. The primary outcome is PCR evidence of ocular chlamydia infection among children aged 0–5 years, measured in a separate random sample of children annually over 7 years. A secondary outcome is improvement of the clinical signs of trachoma between the baseline and final study visits as assessed by conjunctival photography. Laboratory workers and photo-graders are masked to treatment allocation. Ethics and dissemination Study protocols have been approved by human subjects review boards at the University of California, San Francisco, Emory University, the Ethiopian Food and Drug Authority, and the Ethiopian Ministry of Innovation and Technology. A data safety and monitoring committee oversees the trial. Results will be disseminated through peer-reviewed publications and presentations. Trial registration number (http://www.clinicaltrials.gov): NCT02754583; Pre-results.

Objective To examine mortality and morbidity patterns before and after premalignancy diagnosis in individuals with monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL) and compare their secondary healthcare activity to that of the general population. Design Population-based patient cohort, within which each patient is matched at diagnosis to 10 age-matched and sex-matched individuals from the general population. Both cohorts are linked to nationwide information on deaths, cancer registrations and Hospital Episode Statistics. Setting The UK’s Haematological Malignancy Research Network, which has a catchment population of around 4 million served by 14 hospitals and a central diagnostic laboratory. Participants All patients newly diagnosed during 2009–2015 with MGUS (n=2193) or MBL (n=561) and their age and sex-matched comparators (n=27 538). Main outcome measures Mortality and hospital inpatient and outpatient activity in the 5 years before and 3 years after diagnosis. Results Individuals with MGUS experienced excess morbidity in the 5 years before diagnosis and excess mortality and morbidity in the 3 years after diagnosis. Increased rate ratios (RRs) were evident for nearly all clinical specialties, the largest, both before and after diagnosis, being for nephrology (before RR=4.29, 95% CI 3.90 to 4.71; after RR=13.8, 95% CI 12.8 to 15.0) and rheumatology (before RR=3.40, 95% CI 3.18 to 3.63; after RR=5.44, 95% CI 5.08 to 5.83). Strong effects were also evident for endocrinology, neurology, dermatology and respiratory medicine. Conversely, only marginal increases in mortality and morbidity were evident for MBL. Conclusions MGUS and MBL are generally considered to be relatively benign, since most individuals with monoclonal immunoglobulins never develop a B-cell malignancy or any other monoclonal protein-related organ/tissue-related disorder. Nonetheless, our findings offer strong support for the view that in some individuals, monoclonal gammopathy has the potential to cause systemic disease resulting in wide-ranging organ/tissue damage and excess mortality.

Objectives Although the National Early Warning Score (NEWS) and its latest version NEWS2 are recommended for monitoring deterioration in patients admitted to hospital, little is known about their performance in COVID-19 patients. We aimed to compare the performance of the NEWS and NEWS2 in patients with COVID-19 versus those without during the first phase of the pandemic. Design A retrospective cross-sectional study. Setting Two acute hospitals (Scarborough and York) are combined into a single dataset and analysed collectively. Participants Adult (≥18 years) non-elective admissions discharged between 11 March 2020 and 13 June 2020 with an index or on-admission NEWS2 electronically recorded within ±24 hours of admission to predict mortality at four time points (in-hospital, 24 hours, 48 hours and 72 hours) in COVID-19 versus non-COVID-19 admissions. Results Out of 6480 non-elective admissions, 620 (9.6%) had a diagnosis of COVID-19. They were older (73.3 vs 67.7 years), more often male (54.7% vs 50.1%), had higher index NEWS (4 vs 2.5) and NEWS2 (4.6 vs 2.8) scores and higher in-hospital mortality (32.1% vs 5.8%). The c-statistics for predicting in-hospital mortality in COVID-19 admissions was significantly lower using NEWS (0.64 vs 0.74) or NEWS2 (0.64 vs 0.74), however, these differences reduced at 72hours (NEWS: 0.75 vs 0.81; NEWS2: 0.71 vs 0.81), 48 hours (NEWS: 0.78 vs 0.81; NEWS2: 0.76 vs 0.82) and 24hours (NEWS: 0.84 vs 0.84; NEWS2: 0.86 vs 0.84). Increasing NEWS2 values reflected increased mortality, but for any given value the absolute risk was on average 24% higher (eg, NEWS2=5: 36% vs 9%). Conclusions The index or on-admission NEWS and NEWS2 offers lower discrimination for COVID-19 admissions versus non-COVID-19 admissions. The index NEWS2 was not proven to be better than the index NEWS. For each value of the index NEWS/NEWS2, COVID-19 admissions had a substantially higher risk of mortality than non-COVID-19 admissions which reflects the increased baseline mortality risk of COVID-19.

Objectives Healthcare personnel (HCP) are at an increased risk of acquiring COVID-19 infection especially in resource-restricted healthcare settings, and return to homes unfit for self-isolation, making them apprehensive about COVID-19 duty and transmission risk to their families. We aimed at implementing a novel multidimensional HCP-centric evidence-based, dynamic policy with the objectives to reduce risk of HCP infection, ensure welfare and safety of the HCP and to improve willingness to accept and return to duty. Setting Our tertiary care university hospital, with 12 600 HCP, was divided into high-risk, medium-risk and low-risk zones. In the high-risk and medium-risk zones, we organised training, logistic support, postduty HCP welfare and collected feedback, and sent them home after they tested negative for COVID-19. We supervised use of appropriate personal protective equipment (PPE) and kept communication paperless. Participants We recruited willing low-risk HCP, aged <50 years, with no comorbidities to work in COVID-19 zones. Social distancing, hand hygiene and universal masking were advocated in the low-risk zone. Results Between 31 March and 20 July 2020, we clinically screened 5553 outpatients, of whom 3012 (54.2%) were COVID-19 suspects managed in the medium-risk zone. Among them, 346 (11.4%) tested COVID-19 positive (57.2% male) and were managed in the high-risk zone with 19 (5.4%) deaths. One (0.08%) of the 1224 HCP in high-risk zone, 6 (0.62%) of 960 HCP in medium-risk zone and 23 (0.18%) of the 12 600 HCP in the low-risk zone tested positive at the end of shift. All the 30 COVID-19-positive HCP have since recovered. This HCP-centric policy resulted in low transmission rates (<1%), ensured satisfaction with training (92%), PPE (90.8%), medical and psychosocial support (79%) and improved acceptance of COVID-19 duty with 54.7% volunteering for re-deployment. Conclusion A multidimensional HCP-centric policy was effective in ensuring safety, satisfaction and welfare of HCP in a resource-poor setting and resulted in a willing workforce to fight the pandemic.

Objectives Recent reports suggest a high prevalence of hypertension and diabetes in COVID-19 patients, but the role of cardiovascular disease (CVD) risk factors in the clinical course of COVID-19 is unknown. We evaluated the time-to-event relationship between hypertension, dyslipidaemia, diabetes and COVID-19 outcomes. Design We analysed data from the prospective Dutch CovidPredict cohort, an ongoing prospective study of patients admitted for COVID-19 infection. Setting Patients from eight participating hospitals, including two university hospitals from the CovidPredict cohort were included. Participants Admitted, adult patients with a positive COVID-19 PCR or high suspicion based on CT-imaging of the thorax. Patients were followed for major outcomes during the hospitalisation. CVD risk factors were established via home medication lists and divided in antihypertensives, lipid-lowering therapy and antidiabetics. Primary and secondary outcomes measures The primary outcome was mortality during the first 21 days following admission, secondary outcomes consisted of intensive care unit (ICU) admission and ICU mortality. Kaplan-Meier and Cox regression analyses were used to determine the association with CVD risk factors. Results We included 1604 patients with a mean age of 66±15 of whom 60.5% were men. Antihypertensives, lipid-lowering therapy and antidiabetics were used by 45%, 34.7% and 22.1% of patients. After 21-days of follow-up; 19.2% of the patients had died or were discharged for palliative care. Cox regression analysis after adjustment for age and sex showed that the presence of ≥2 risk factors was associated with increased mortality risk (HR 1.52, 95% CI 1.15 to 2.02), but not with ICU admission. Moreover, the use of ≥2 antidiabetics and ≥2 antihypertensives was associated with mortality independent of age and sex with HRs of, respectively, 2.09 (95% CI 1.55 to 2.80) and 1.46 (95% CI 1.11 to 1.91). Conclusions The accumulation of hypertension, dyslipidaemia and diabetes leads to a stepwise increased risk for short-term mortality in hospitalised COVID-19 patients independent of age and sex. Further studies investigating how these risk factors disproportionately affect COVID-19 patients are warranted.

Objectives To determine the feasibility of conducting a randomised trial of the effectiveness of cranberry extract in reducing antibiotic use by women with symptoms of acute, uncomplicated urinary tract infection (UTI). Design Open-label feasibility randomised parallel group trial. Setting Four general practices in Oxfordshire. Participants Women aged 18 years and above presenting to general practice with symptoms of acute, uncomplicated UTI. Interventions Women were randomly assigned using Research Electronic Data Capture in a 1:1:1 ratio to: (1) immediate antibiotics alone (n=15); (2) immediate antibiotics and immediate cranberry capsules for up to 7 days (n=15); or (3) immediate cranberry capsules and delayed antibiotics for self-initiation in case of non-improvement or worsening of symptoms (n=16). Primary and secondary outcome measures The primary outcome measures were: rate of recruitment of participants; numbers lost to follow-up; proportion of electronic diaries completed by participants; and acceptability of the intervention and study procedures to participants and recruiters. Secondary outcomes included an exploration of differences in symptom burden and antibiotic use between groups. Results Four general practitioner practices (100%) were opened and recruited participants between 1 July and 2 December 2019, with nine study participants recruited per month on average. 68.7% (46/67) of eligible participants were randomised (target 45) with a mean age of 48.4 years (SD 19.9, range 18–81). 89.1% (41/46) of diaries contained some participant entered data and 69.6% (32/46) were fully complete. Three participants (6.5%) were lost to follow-up and two (4.4%) withdrew. Of women randomly assigned to take antibiotics alone (controls), one-third of respondents reported consuming cranberry products (33.3%, 4/12). There were no serious adverse events. Conclusions It appears feasible to conduct a randomised trial of the use of cranberry extract in the treatment of acute, uncomplicated UTI in general practice. Trial registration number ISRCTN Registry (ID: 10399299).

Objectives To assess the seroprevalence of anti-SARS-CoV-2 IgG among health careworkers (HCWs) in our university hospital and verify the risk of acquiring the infection according to work area. Design Cross-sectional study. Setting Monocentric, Italian, third-level university hospital. Participants All the employees of the hospital on a voluntary base, for a total of 4055 participants among 4572 HCWs (88.7%). Primary and secondary outcome measures Number of anti-SARS-CoV-2 positive serology according to working area. Association of anti-SARS-CoV-2 positive serology to selected variables (age, gender, country of origin, body mass index, smoking, symptoms and contact with confirmed cases). Results From 27 April 2020 to 12 June 2020, 4055 HCWs were tested and 309 (7.6%) had a serological positive test. No relevant difference was found between men and women (8.3% vs 7.3%, p=0.3), whereas a higher prevalence was observed among foreign-born workers (27/186, 14.5%, p<0.001), employees younger than 30 (64/668, 9.6%, p=0.02) or older than 60 years (38/383, 9.9%, p=0.02) and among healthcare assistants (40/320, 12.5%, p=0.06). Working as frontline HCWs was not associated with an increased frequency of positive serology (p=0.42). A positive association was found with presence and number of symptoms (p<0.001). The symptoms most frequently associated with a positive serology were taste and smell alterations (OR 4.62, 95% CI: 2.99 to 7.15) and fever (OR 4.37, 95% CI: 3.11 to 6.13). No symptoms were reported in 84/309 (27.2%) HCWs with positive IgG levels. Declared exposure to a suspected/confirmed case was more frequently associated (p<0.001) with positive serology when the contact was a family member (19/94, 20.2%) than a patient or colleague (78/888, 8.8%). Conclusions SARS-CoV-2 infection occurred undetected in a large fraction of HCWs and it was not associated with working in COVID-19 frontline areas. Beyond the hospital setting, exposure within the community represents an additional source of infection for HCWs.

Inorganic polyphosphate (polyP) is produced by both bacteria and their eukaryotic hosts, and it appears to play multiple important roles in the interactions between those organisms. However, the detailed mechanisms of how polyP synthesis is regulated in bacteria, and how it influences both bacterial and host biology, remain largely unexplored. In this review, we examine recent developments in the understanding of how bacteria regulate the synthesis of polyP, what roles polyP plays in controlling virulence in pathogenic bacteria, and the effects of polyP on the mammalian immune system, as well as progress on developing drugs that may be able to target bacterial polyP synthesis as novel means of treating infectious disease.

The ability of HIV to integrate into the host genome and establish latent reservoirs is the main hurdle preventing an HIV cure. LEDGINs are small-molecule integrase inhibitors that target the binding pocket of LEDGF/p75, a cellular cofactor that substantially contributes to HIV integration site selection. They are potent antivirals that inhibit HIV integration and maturation. In addition, they retarget residual integrants away from transcription units and towards a more repressive chromatin environment. As a result, treatment with the LEDGIN CX14442 yielded residual provirus that proved more latent and more refractory to reactivation, supporting the use of LEDGINs as research tools to study HIV latency and a functional cure strategy. In this study we compared GS-9822, a potent, pre-clinical lead compound, with CX14442 with respect to antiviral potency, integration site selection, latency and reactivation. GS-9822 was more potent than CX14442 in most assays. For the first time, the combined effects on viral replication, integrase-LEDGF/p75 interaction, integration sites, epigenetic landscape, immediate latency and latency reversal was demonstrated at nanomolar concentrations achievable in the clinic. GS-9822 profiles as a preclinical candidate for future functional cure research.

Recent outbreaks of cardiac surgery-associated Mycobacterium chimaera infections have highlighted the importance of species differentiation within the Mycobacterium avium complex and pointed to a lack of antibiotic susceptibility data for M. chimaera. Using the MGIT 960/EpiCenter TB eXiST platform, we have determined antibiotic susceptibility patterns of 48 clinical M. chimaera isolates and 139 other non-tuberculous mycobacteria including 119 members of the M. avium complex and 20 Mycobacterium kansasii towards clofazimine and other drugs used to treat infections with slowly growing nontuberculous mycobacteria (NTM). MIC50, MIC90 and tentative epidemiological cutoff (ECOFF) values for clofazimine were 0.5 mg/L, 1 mg/L and 2 mg/L for M. chimaera. Comparable values were observed for other M. avium complex members, lower MIC50 (≤0.25 mg/L), MIC90 (0.5 mg/L) and ECOFF (1 mg/L) values were found for M. kansasii. Susceptibility to clarithromycin, ethambutol, rifampin, rifabutin, amikacin, moxifloxacin and linezolid was in general similar for M. chimaera and other members of the M. avium complex but increased for M. kansasii. The herein determined MIC distributions, MIC90 and ECOFF values of clofazimine for M. chimaera and other NTM provide the basis for the definition of clinical breakpoints. Further studies are needed to establish correlation of in vitro susceptibility and clinical outcome.

Background: Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to MDR pathogens. Objective: The aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16g/daily by intermittent (II) or continuous infusion (CI), and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections. Methods: Patients underwent blood sampling on day 5 of therapy (2-3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T>MIC, and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20g/day administered by II, extended-infusion (EI) or CI. Results: Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CLCR) was included as covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs (≥90%) may be achieved in three different classes of renal function by administering a daily dosage of: 2g q6h by II against S. aureus, E. coli, ESBL-producing E. Coli and MRSA; 8g by CI against CoNS, K. pneumoniae and ESBL-producing K. pneumoniae; 12g by CI against P. aeruginosa, and 16g by CI against KPC-producing K. pneumoniae. Conclusion: Our study provides a strong rationale for considering fosfomycin dosages of 8-16 g daily by CI in several clinical scenarios for OI patients. Feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.

Isavuconazole (ISA) is an azole antifungal used in the treatment of invasive aspergillosis and mucormycosis. Patients with mild and moderate hepatic impairment have lower clearance (CL) as compared to the healthy population. Currently, there is no data on ISA in patients with severe hepatic impairment (Child-Pugh Class C). The purpose of this study was to build a physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics (PK) of intravenous ISA, and to predict changes in ISA disposition in different patient populations and in patients with hepatic impairment to guide personalized dosing. By incorporating the systemic and drug specific parameters of ISA, the model was initially developed in healthy population and validated with 10 independent PK profiles obtained from healthy subjects and from patients with normal liver function. The results showed a satisfactory predictive capacity, with most of the relative predictive errors being between ±30% for area under the curve (AUC) and Cmax. The observed plasma concentration-time profiles of ISA were well described by the model predicted profiles. The model adequately predicted the reduced CL of ISA in patients with mild and moderate hepatic impairment. Furthermore, the model predicted a decrease in CL of about 60% in patients with severe hepatic impairment. Therefore, we recommend reducing the dose by 50% in patients with severe hepatic impairment. The model also predicted differences in the PK of ISA between Caucasian and Asian population, with the CL ratio of 0.67 in Chinese vs Caucasian population. The developed PBPK model of ISA provides a reasonable approach for optimizing the dosage regimen in different ethnic populations and in patients with severe hepatic impairment.

Malassezia are emerging fungal pathogens causing opportunistic skin and severe systemic infection. Nosocomial outbreaks are associated with azole resistance and understanding of the underlying mechanisms are limited to knowledge from other fungal species. Herein, we identified distinct antifungal susceptibility patterns in 26 Malassezia furfur isolates derived from healthy and diseased individuals. A Y67F CYP51 mutation was identified in five isolates of M. furfur. However, this mutation alone was insufficient to induce reduce azole susceptibility in the wild type strain. RNA-seq and differential gene analysis of healthy and disease derived strains exposed to clotrimazole in vitro identified several key metabolic pathways and transporter proteins which are involved in reduce azole susceptibility. The pleiotropic drug transporter PDR10 was the single most highly upregulated transporter gene in multiple strains of M. furfur after azole treatment and increased expression of PDR10 is associated with reduced azole susceptibility in some systemic disease isolates of M. furfur. Deletion of PDR10 in a pathogenic M. furfur strain with reduced susceptibility reduced MIC values to the level of that in susceptible isolates. The current dearth of antifungal technologies, globally emerging multi-azole resistance, and broad agriculture and consumer care use of azoles means improved understanding of the mechanisms underlying intrinsic and acquired azole resistance in Malassezia is crucial for development of antibiotic stewardship and antifungal treatment strategies.

N-acetylcysteine (NAC) is most commonly used for the treatment of acetaminophen overdose and acetaminophen-induced liver injury. In patients infected with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), NAC is given to treat hepatotoxicity induced by TB drugs. We had previously shown that cysteine, a derivative of NAC, potentiated the activity of isoniazid, a first-line TB drug, by preventing the emergence of INH resistance and persistence in M. tuberculosis in vitro. Herein, we demonstrate that in vitro, NAC has the same boosting activity with various combinations of first- and second-line TB drugs against drug-susceptible and multidrug-resistant M. tuberculosis strains. Similar to cysteine, NAC increased M. tuberculosis respiration. However, in M. tuberculosis-infected mice, the addition of NAC did not augment the activity of first- or second-line TB drugs. A comparison of the activity of NAC combined with TB drugs in murine and human macrophage cell lines revealed that studies in mice might not be recapitulated during host infection in vivo.