Nyt fra tidsskrifterne

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.

Drug combination therapy is an interesting approach to increase the success of drug repurposing for neglected diseases. Thus, the objective of this work was to evaluate binary and ternary therapies composed of itraconazole, ezetimibe and miltefosine for the treatment of visceral leishmaniasis. Intracellular Leishmania infantum amastigotes were incubated with the drugs alone or in combination for 72 h. For in vivo experiments, we tested a long-course (21 days, once per day) and a short-course treatment (5 days, twice per day) for the binary combination with itraconazole and ezetimibe. For the ternary therapy including miltefosine, we adopted the short-course treatment and varied the vehicle. None of the combinations were toxic to macrophages. Binary combination of itraconazole plus ezetimibe and ternary combination of itraconazole, ezetimibe and miltefosine had synergistic effects in intracellular amastigotes, in some of the proportions evaluated. Although the in vivo long-course therapy had been more effective than the short-course protocol, it showed hepatic toxicity signs. Ezetimibe has proven to be able to reduce the parasite burden alone or in combination. Both suspensions of the ternary combination were active, but when the drugs were suspended in the commercial ORA-Plus formulation instead of purified water, the parasite burden was reduced by 98% in the liver and spleen. Altogether, the results demonstrate for the first time the activity of ezetimibe in a viscerotropic species of Leishmania and indicate that ternary treatment composed of miltefosine, itraconazole, and ezetimibe at low doses is a promising therapeutic alternative for the treatment of visceral leishmaniasis.

Candida auris is a novel Candida species that has spread in all continents causing nosocomial outbreaks of invasive candidiasis. C. auris has the ability to develop resistance to all antifungal drug classes. Notably, many C. auris isolates are resistant to the azole drug fluconazole, a standard therapy of invasive candidiasis. Azole resistance in C. auris can result from mutations in the azole target gene ERG11 and/or overexpression of the efflux pump Cdr1. TAC1 is a transcription factor controlling CDR1 expression in C. albicans. The role of TAC1 homologs in C. auris (TAC1a and TAC1b) remains to be better defined. In this study, we compared sequences of ERG11, TAC1a and TAC1b between a fluconazole-susceptible and five fluconazole-resistant C. auris isolates of clade IV. Among four of the resistant isolates, we identified a similar genotype with concomitant mutations in ERG11 (F444L) and TAC1b (S611P). The simultaneous deletion of tandemly arranged TAC1a/TAC1b resulted in a decrease of minimal inhibitory concentration (MIC) for fluconazole. Introduction of the ERG11 and TAC1b mutations separately and/or combined in the wild-type azole susceptible isolate resulted in a significant increase of azole resistance with a cumulative effect of the two combined mutations. Interestingly, CDR1 expression was not significantly affected by TAC1a/TAC1b deletion or by the presence of the TAC1b S611P mutation, suggesting the existence of Tac1-dependent and Cdr1-independent azole resistance mechanisms. We demonstrated the role of two previously unreported mutations responsible for azole resistance in C. auris, which were a common signature among four azole-resistant isolates of clade IV.

Tuberculosis (TB) is a leading global cause of mortality owing to an infectious agent, accounting for almost one-third of antimicrobial resistance (AMR) deaths annually. We aimed to identify synergistic anti-TB drug combinations with the capacity to restore therapeutic efficacy against drug-resistant mutants of the causative agent, Mycobacterium tuberculosis. We investigated combinations containing the known translational inhibitors, spectinomycin (SPT) and fusidic acid (FA), or the phenothiazine, chlorpromazine (CPZ), which disrupts mycobacterial energy metabolism. Potentiation of whole-cell drug efficacy was observed in SPT-CPZ combinations. This effect was lost against an M. tuberculosis mutant lacking the major facilitator superfamily (MFS) efflux pump, Rv1258c. Notably, the SPT-CPZ combination partially restored SPT efficacy against an SPT-resistant mutant carrying a g1379t point mutation in rrs, encoding the mycobacterial 16S ribosomal RNA. Combinations of SPT with FA, which targets the mycobacterial elongation factor G, exhibited potentiating activity against wild-type M. tuberculosis. Moreover, this combination produced a modest potentiating effect against both FA-monoresistant and SPT-monoresistant mutants. Finally, combining SPT with the frontline anti-TB agents, rifampicin (RIF) and isoniazid, resulted in enhanced activity in vitro and ex vivo against both drug-susceptible M. tuberculosis and a RIF-monoresistant rpoB S531L mutant.These results support the utility of novel potentiating drug combinations in restoring antibiotic susceptibility of M. tuberculosis strains carrying genetic resistance to any one of the partner compounds.

Tuberculosis, caused by Mycobacterium tuberculosis, is an urgent global health problem requiring new drugs, new drug targets and an increased understanding of antibiotic resistance. We have determined the mode of resistance to a series of arylamide compounds in M. tuberculosis. We isolated M. tuberculosis resistant mutants to two arylamide compounds which are inhibitory to growth under host-relevant conditions (butyrate as a sole carbon source). Thirteen mutants were characterized, and all had mutations in Rv2571c; mutations included a premature stop codon and frameshifts as well as non-synonymous polymorphisms. We isolated a further ten strains with mutations in Rv2571c with resistance. Complementation with a wild-type copy of Rv2571c restored arylamide sensitivity. Over-expression of Rv2571c was toxic in both wild-type and mutant backgrounds. We constructed M. tuberculosis strains with an unmarked deletion of the entire Rv2571c gene by homologous recombination and confirmed that these were resistant to the arylamide series. Rv2571c is a member of the aromatic amino acid transport family and has a fusaric acid resistance domain which is associated with compound transport. Since loss or inactivation of Rv2571c leads to resistance, we propose that Rv2571c is involved in the import of arylamide compounds.

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.

Nature Medicine, Published online: 22 February 2021; doi:10.1038/s41591-021-01256-2 First-in-human test of topical application of a commensal bacterium on skin of individuals with atopic dermatitis reduces colonization by proinflammatory Staphylococcus aureus.

Nature Medicine, Published online: 22 February 2021; doi:10.1038/s41591-021-01238-4 A genetic link suggests that interventions that halve the risk of malaria episodes could reduce the prevalence of iron deficiency in African children by nearly 50%.

by Joseph Y. T. Mugisha, Joseph Ssebuliba, Juliet N. Nakakawa, Cliff R. Kikawa, Amos Ssematimba Background Uganda has a unique set up comprised of resource-constrained economy, social-economic challenges, politically diverse regional neighborhood and home to long-standing refuge crisis that comes from long and protracted conflicts of the great lakes. The devastation of the on-going global pandemic outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is likely to be escalated by these circumstances with expectations of the impact of the disease being severe. Materials and methods In this study, we formulate a mathematical model that incorporates the currently known disease characteristics and tracks various intervention measures that the government of Uganda has implemented since the reporting of the first case in March 2020. We then evaluate these measures to understand levels of responsiveness and adherence to standard operating procedures and quantify their impact on the disease burden. Novel in this model was the unique aspect of modeling the trace-and-isolate protocol in which some of the latently infected individuals tested positive while in strict isolation centers thereby reducing their infectious period. Results The study findings show that even with elimination of all imported cases at any given time it would take up to nine months to rid Uganda of the disease. The findings also show that the optimal timing of easing of lockdowns while mitigating the possibility of re-emergence of a second epidemic wave requires avoiding the scenario of releasing too-many-too-soon. It is even more worrying that enhancing contact tracing would only affect the magnitude and timing of the second wave but cannot prevent it altogether. Conclusion We conclude that, given the prevailing circumstances, a phased-out lifting of lockdown measures, minimization of COVID-19 transmissibility within hospital settings, elimination of recruitment of infected individuals as well as enhanced contact tracing would be key to preventing overwhelming of the healthcare system that would come with dire consequences.

by Alinane Linda Nyondo-Mipando, Leticia Suwedi Kapesa, Sangwani Salimu, Thokozani Kazuma, Victor Mwapasa Background Gender disparities exist in the scale-up and uptake of HIV services with men being disproportionately under-represented in the services. In Eastern and Southern Africa, of the people living with HIV infection, more adult women than men were on treatment highlighting the disparities in HIV services. Delayed initiation of antiretroviral treatment creates a missed opportunity to prevent transmission of HIV while increasing HIV and AIDS-associated morbidity and mortality. The main objective of this study was to assess the strategies that men prefer for Antiretroviral Therapy (ART) initiation in Blantyre, Malawi. Methods This was a qualitative study conducted in 7 Health facilities in Blantyre from January to July 2017. We selected participants following purposive sampling. We conducted 20 in-depth interviews (IDIs) with men of different HIV statuses, 17 interviews with health care workers (HCWs), and 14 focus group discussions (FGDs) among men of varying HIV statuses. We digitally recorded all the data, transcribed verbatim, managed using NVivo, and analysed it thematically. Results Restructuring the delivery of antiretroviral (ARVs) treatment and conduct of ART clinics is key to optimizing early initiation of treatment among heterosexual men in Blantyre. The areas requiring restructuring included: Clinic days by offering ARVs daily; Clinic hours to accommodate schedules of men; Clinic layout and flow that preserves privacy and establishment of male-specific clinics; ARV dispensing procedures where clients receive more pills to last them longer than 3 months. Additionally there is need to improve the packaging of ARVs, invent ARVs with less dosing frequency, and dispense ARVs from the main pharmacy. It was further suggested that the test-and-treat strategy be implemented with fidelity and revising the content in counseling sessions with an emphasis on the benefits of ARVs. Conclusion The success in ART initiation among men will require a restructuring of the current ART services to make them accessible and available for men to initiate treatment. The inclusion of people-centered approaches will ensure that individual preferences are incorporated into the initiation of ARVs. The type, frequency, distribution, and packaging of ARVs should be aligned with other medicines readily available within a health facility to minimize stigma.

by Chen Yuan, Hongling Wang, Kefeng Li, An Tang, Yaxin Dai, Bing Wu, Hui Zhang, Jiabei Chen, Jienan Liu, Wenjie Wu, Songye Gu, Hai Wang, Haodi Xu, Mingyu Wu, Menglu Yu, Yuchao Wang, Xinwei Yu, Jialu He, Shelan Liu, Yongli Zhang, Zhendong Tong, Jianbo Yan This study aimed to identify the specimen type that has high positivity and its proper sampling time for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing to promote diagnostic efficiency. All SARS-CoV-2-infected patients with a laboratory-confirmed diagnosis in Zhoushan City were followed up for viral shedding in respiratory tract specimens and faecal samples. Positivity was analysed both qualitatively and quantitatively by proper statistical approaches with strong testing power. Viral shedding in respiratory tract and faecal specimens was prolonged to 45 and 40 days after the last exposure, respectively. The overall positive rate in respiratory tract specimens was low and relatively unstable, being higher in the early-to-mid stage than in the mid-to-late stage of the disease course. Compared with respiratory tract specimens, faecal samples had a higher viral load, higher overall positive rate, and more stable positivity in different disease courses and varied symptomatic status. Faecal specimens have the potential ability to surpass respiratory tract specimens in virus detection. Testing of faecal specimens in diagnosis, especially for identifying asymptomatic carriers, is recommended. Simultaneously, testing respiratory tract specimens at the early-to-mid stage is better than testing at the mid-to-late stage of the disease course. A relatively small sample size was noted, and statistical approaches were used to address it. Information was missing for both specimen types at different stages of the disease course due to censored data. Our research extends the observed viral shedding in both specimen types and highlights the importance of faecal specimen testing in SARS-CoV-2 diagnosis. Healthcare workers, patients, and the general public may all benefit from our study findings. Disposal of sewage from hospitals and residential areas should be performed cautiously because the virus sheds in faeces and can last for a long time.

by Zachary D. Miller, Wayne Freimund, Douglas Dalenberg, Madison Vega Introduction Visitation to parks and protected areas is a common COVID-19 coping strategy promoted by state and national public health officials and political leadership. Crowding and congestions in parks has been a perennial problem and the ability to socially distance within them is an unproven assumption. Is it possible to socially distance in a busy national park that has been designed to concentrate use? Methodology/Principal findings An observational study was conducted in July 2020 at the outside foyer of the Visitor Center of Arches National Park. Motion sensor cameras were placed to record one-minute videos when a person entered the field of view. Number of groups, group size, facial coverings and encounters within 6 feet (1.83 meters) of other groups were recorded. Groups were smaller on average than recorded in previous studies. Approximately 61% of the visitors wore masks. Most groups (69%) were able to experience the visitor center with no intergroup encounters. We model the probability of intergroup encounters and find as group size and number of groups increases, the probability of encounters rises. With four groups present, the probability of one or more encounters ranges from 19% to 40% for common group sizes, while if eight groups are present, the probability of one or more encounters increases from 34% to 64% for common group sizes. Conclusions/Significance Under conditions in which park visitors have the physical space to avoid close encounters with other groups they are taking advantage of the opportunity. Visitors are minimizing group size, wearing masks, and remaining socially distant. However, encounters increase as the number or the size of the groups increases. In other areas of the parks this ability to avoid encounters may not be as possible. We recommend that park managers continue to appeal for compliance with CDC guidelines, especially the wearing of masks and encouraging visitors to split up into small groups when visiting.

by Jamyang Namgyal, Tenzin Tenzin, Sylvia Checkley, Tim J. Lysyk, Sangay Rinchen, Ratna B. Gurung, Sithar Dorjee, Isabelle Couloigner, Susan C. Cork Livestock farming plays an important role in supporting the livelihood of resource-poor subsistence farmers in Bhutan. However, ticks and tick-borne diseases (TBDs) are one of the major constraints to livestock farming due to their negative effect on health and production. To date, no study has been conducted in Bhutan to assess farmers’ knowledge, attitude, and practices (KAP) about ticks and TBDs in cattle, although such information is essential in ensuring the development and adoption of effective prevention and control measures. Therefore, a KAP survey was conducted among 246 cattle owners in the Samkhar sub-district of eastern Bhutan in June 2019, using a structured questionnaire. Based on our scoring criteria, 52% [95%CI: 45.5–58.4] had adequate knowledge about ticks as potential vectors of diseases. Logistic regression analysis showed that the individuals who practiced a stall-feeding system of cattle rearing were 2.8 times [OR = 2.8 (95%CI: 1.66–4.78)] more likely to have adequate knowledge than others. Sixty-eight percent [95%CI: 62.5–74.4] had a favorable attitude toward tick prevention and control programs. Men were 1.95 times [OR = 1.95 (95%CI: 1.09–3.55)] more likely to have a favorable attitude than women, and the individuals who practiced a stall-feeding system were 2.59 times [OR = 2.59 95%CI: 1.45–4.78)] more likely to have a favorable attitude than others, after adjusting for the effect of other variables in the model. Overall, only 38% [95%CI 32.5–45] of the respondents reported tick infestation as one of the most important animal health problems, but 100% reported using acaricides to control ticks in cattle. Despite a high level of acaricide usage, the level of knowledge was low among the farmers interviewed. Findings from this study underline the importance of considering identified knowledge gaps and initiating education efforts to improve the adoption of effective tick prevention and control measures among farmers.

by David Forgacs, Rodrigo B. Abreu, Giuseppe A. Sautto, Greg A. Kirchenbaum, Elliott Drabek, Kevin S. Williamson, Dongkyoon Kim, Daniel E. Emerling, Ted M. Ross Recent advances in high-throughput single cell sequencing have opened up new avenues into the investigation of B cell receptor (BCR) repertoires. In this study, PBMCs were collected from 17 human participants vaccinated with the split-inactivated influenza virus vaccine during the 2016–2017 influenza season. A combination of Immune Repertoire Capture (IRCTM) technology and IgG sequencing was performed on ~7,800 plasmablast (PB) cells and preferential IgG heavy-light chain pairings were investigated. In some participants, a single expanded clonotype accounted for ~22% of their PB BCR repertoire. Approximately 60% (10/17) of participants experienced convergent evolution, possessing public PBs that were elicited independently in multiple participants. Binding profiles of one private and three public PBs confirmed they were all subtype-specific, cross-reactive hemagglutinin (HA) head-directed antibodies. Collectively, this high-resolution antibody repertoire analysis demonstrated the impact evolution can have on BCRs in response to influenza virus vaccination, which can guide future universal influenza prophylactic approaches.

by Lillian Musila, Cecilia Kyany’a, Rosslyn Maybank, Jason Stam, Valerie Oundo, Willie Sang Carbapenem-resistant gram-negative bacteria are an increasingly significant clinical threat globally. This risk may be underestimated in Kenya as only four carbapenemase genes in three bacterial species have been described. The study aimed to understand the antibiotic resistance profiles, genes, sequence types, and distribution of carbapenem-resistant gram-negative bacteria from patients in six hospitals across five Kenyan counties by bacterial culture, antibiotic susceptibility testing, and whole-genome sequence analysis. Forty-eight, non-duplicate, carbapenem non-susceptible, clinical isolates were identified across the five counties (predominantly in Nairobi and Kisii): twenty-seven Acinetobacter baumannii, fourteen Pseudomonas aeruginosa, three Escherichia coli, two Enterobacter cloacae, and two Klebsiella pneumoniae. All isolates were non-susceptible to β-lactam drugs with variable susceptibility to tigecycline (66%), minocycline (52.9%), tetracycline (29.4%), and levofloxacin (22.9%). Thirteen P. aeruginosa isolates were resistant to all antibiotics tested. Eleven carbapenemase genes were identified: blaNDM-1, blaOXA-23, -58, -66, -69, and -91 in A. baumannii (STs 1, 2, 164 and a novel ST1475), blaNDM-1 in E. cloacae (STs 25,182), blaNDM-1, blaVIM-1and -6, blaOXA-50 in P. aeruginosa (STs 316, 357, 654, and1203), blaOXA-181, blaNDM-1 in K. pneumoniae (STs 147 and 219), and blaNDM-5 in E. coli (ST164). Five A. baumannii isolates had two carbapenemases, blaNDM-1, and either blaOXA-23 (4) or blaOXA-58 (1). AmpC genes were detected in A. baumannii (blaADC-25), E. cloacae (blaDHA-1 and blaACT-6, 16), and K. pneumoniae (blaCMY). Significant multiple-drug resistant genes were the pan-aminoglycoside resistance16srRNA methyltransferase armA, rmtB, rmtC, and rmtF genes. This study is the first to report blaOXA-420, -58, -181, VIM-6, and blaNDM-5 in Kenyan isolates. High-risk STs of A. baumannii (ST1475, ST2), E. cloacae ST182, K. pneumoniae ST147, P. aeruginosa (ST357, 654), and E. coli ST167, ST648 were identified which present considerable therapeutic danger. The study recommends urgent carbapenem use regulation and containment of high-risk carbapenem-resistant bacteria.

by Byungwon Kim, Seonghong Kim, Woncheol Jang, Sungkyu Jung, Johan Lim This work is motivated by the recent worldwide pandemic of the novel coronavirus disease (COVID-19). When an epidemiological disease is prevalent, estimating the case fatality rate, the proportion of deaths out of the total cases, accurately and quickly is important as the case fatality rate is one of the crucial indicators of the risk of a disease. In this work, we propose an alternative estimator of the case fatality rate that provides more accurate estimate during an outbreak by reducing the downward bias (underestimation) of the naive CFR, the proportion of deaths out of confirmed cases at each time point, which is the most commonly used estimator due to the simplicity. The proposed estimator is designed to achieve the availability of real-time update by using the commonly reported quantities, the numbers of confirmed, cured, deceased cases, in the computation. To enhance the accuracy, the proposed estimator adapts a stratification, which allows the estimator to use information from heterogeneous strata separately. By the COVID-19 cases of China, South Korea and the United States, we numerically show the proposed stratification-based estimator plays a role of providing an early warning about the severity of a epidemiological disease that estimates the final case fatality rate accurately and shows faster convergence to the final case fatality rate.

by Asmaa M. Zahran, Omnia El-Badawy, Wageeh A. Ali, Zainab Gaber Mahran, Essam Eldeen M. O. Mahran, Amal Rayan Background and aim The study aimed to determine whether the MPs levels and platelet activation are affected by the COVID-19 infection in both malignant and non-malignant patients compared to healthy individuals and define their contribution to the COVID-19 associated coagulopathy and the relation of these MPs to other hematologic parameters. Patients and methods We recruited 23 malignant patients with reverse transcription polymerase chain reaction (RT-PCR) positive COVID-19, also, 19 COVID-19 non-malignant patients, and 20 healthy volunteers were also enrolled for comparison. Blood samples were collected from patients and healthy donors into 5 mL vacutainer tube containing 3.5% buffered sodium citrate solution for measurement of total microparticles (TMPs), platelet microparticles (PMPs), endothelial microparticles (EMPs), CD62 activated platelets, and CD41 platelet marker. Results COVID-19 malignant patients had significantly lower hemoglobin and platelets compared to COVID non-malignant ones, while they had significantly higher C-reactive protein, LDH, AST, Albunim, creatinine, and prognostic index (PI) compared to COVID-19 non-malignant patients. significant accumulations of TMPs, PMPs, EMPs, and activated platelets in COVID-19 affected patients compared to healthy controls. TMPs, and EMPs were significantly accumulated in COVID-19 malignant compared to COVID-19 non-malignant patients with no significant difference in PMPs between both. Conclusion Circulating MPs and activated platelets may be promising novel prognostic biomarkers capable of identifying potentially severe COVID-19 patients who require immediate care especially in cancer patients.

by Ya-Wei Chen, Lin-Yang Chi, Oscar Kuang-Sheng Lee Most of complications after impacted mandibular third molar (iLM3) extraction surgeries are transient and resolved spontaneously within one or two weeks, but some of them are more complicated and required further treatments to alleviate the symptoms. The aim of study is to revisit incidence and predictors of complications after iLM3 surgery by reviewing previous literature and investigating a population-based data. From Taiwan National Health Insurance Research Database, records of 16,609 patients who had received iLM3 extraction under ambulatory settings were retrieved for analysis. Outcomes of interest included dry socket (DS), prolonged temporomandibular joint symptoms (TMD), and surgical site infection (SSI), which necessitated additional appointments to manage. Odds ratios of having those complications between different variables were analyzed. The incidence rates of DS, TMD, and SSI were 3.6%, 0.41%, 0.17%, respectively; while they ranged from 0.33–19.14% (DS), 0–4.17% (TMD), and 0.2–5.17% (SSI) in previous studies. Logistic regression revealed DS significantly correlated with complexity of odontectomy (2.5-fold of risk) and history of gingivitis or pericoronitis (1.3-fold of risk). More TMD was found in female than male patients (0.5% versus 0.3%). However, no factors associated with SSI was found; neither did we find aging as a risk in association with any of above complications. Compared to previous studies, our data supports that surgical intervention should be considered in iLM3 with risk of gingivitis or pericoronitis to reduce the occurrence of DS. The original information in this article, which provides a “real-world” evidence, along with the organizing data we summarized from previous article, can serve as a reference for clinicians in assessing the complication risks before treatment of iLM3.