Search

Intensive care units (ICU) for various reasons, including the increasing age of admitted patients, comorbidities, and increasingly complex surgical procedures (e.g., transplants), have become "the epicenter" of nosocomial infections, these are characterized by the presence of multidrug-resistant organisms (MDROs) as the cause of infection. Therefore, the perfect match of fragile patients and MDROs, as the cause of infection, makes ICU mortality very high. Furthermore, carbapenems were considered for years as last-resort antibiotics for the treatment of infections caused by MDROs; unfortunately, nowadays carbapenem resistance, mainly among Gram-negative pathogens, is a matter of the highest concern for worldwide public health. This comprehensive review aims to outline the problem from the intensivist's perspective, focusing on the new definition and epidemiology of the most common carbapenem-resistant MDROs (Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales) to emphasize the importance of the problem that must be permeating clinicians dealing with these diseases.

Using data from the 2013–14 Saudi Arabia epidemic, we use a counterfactual analysis on inferred transmission trees (who-infected-whom analysis) to assess the potential impact of vaccination campaigns targeting health-care workers, as quantified by the proportion of cases or deaths averted. We investigate the conditions under which proactive campaigns (ie vaccinating in anticipation of the next outbreak) would outperform reactive campaigns (ie vaccinating in response to an unfolding outbreak), considering vaccine efficacy, duration of vaccine protection, effectiveness of animal reservoir control measures, wait (time between vaccination and next outbreak, for proactive campaigns), reaction time (for reactive campaigns), and spatial level (hospital, regional, or national, for reactive campaigns). We also examine the relative efficiency (cases averted per thousand doses) of different strategies.FindingsThe spatial scale of reactive campaigns is crucial. Proactive campaigns outperform campaigns that vaccinate health-care workers in response to outbreaks at their hospital, unless vaccine efficacy has waned significantly. However, reactive campaigns at the regional or national levels consistently outperform proactive campaigns, regardless of vaccine efficacy. When considering the number of cases averted per vaccine dose administered, the rank order is reversed: hospital-level reactive campaigns are most efficient, followed by regional-level reactive campaigns, with national-level and proactive campaigns being least efficient. If the number of cases required to trigger reactive vaccination increases, the performance of hospital-level campaigns is greatly reduced; the impact of regional-level campaigns is variable, but that of national-level campaigns is preserved unless triggers have high thresholds.InterpretationSubstantial reduction of MERS-CoV morbidity and mortality is possible when vaccinating only health-care workers, underlining the need for countries at risk of outbreaks to stockpile vaccines when available. Background Several vaccine candidates are in development against MERS-CoV, which remains a major public health concern. In anticipation of available MERS-CoV vaccines, we examine strategies for their optimal deployment among health-care workers.Methods Using data from the 2013-14 Saudi Arabia epidemic, we use a counterfactual analysis on inferred transmission trees (who-infected-whom analysis) to assess the potential impact of vaccination campaigns targeting health-care workers, as quantified by the proportion of cases or deaths averted. We investigate the conditions under which proactive campaigns (ie vaccinating in anticipation of the next outbreak) would outperform reactive campaigns (ie vaccinating in response to an unfolding outbreak), considering vaccine efficacy, duration of vaccine protection, effectiveness of animal reservoir control measures, wait (time between vaccination and next outbreak, for proactive campaigns), reaction time (for reactive campaigns), and spatial level (hospital, regional, or national, for reactive campaigns). We also examine the relative efficiency (cases averted per thousand doses) of different strategies.Findings The spatial scale of reactive campaigns is crucial. Proactive campaigns outperform campaigns that vaccinate health-care workers in response to outbreaks at their hospital, unless vaccine efficacy has waned significantly. However, reactive campaigns at the regional or national levels consistently outperform proactive campaigns, regardless of vaccine efficacy. When considering the number of cases averted per vaccine dose administered, the rank order is reversed: hospital-level reactive campaigns are most efficient, followed by regional -level reactive campaigns, with national-level and proactive campaigns being least efficient. If the number of cases required to trigger reactive vaccination increases, the performance of hospital-level campaigns is greatly reduced; the impact of regional-level campaigns is variable, but that of national-level campaigns is preserved unless triggers have high thresholds.Interpretation Substantial reduction of MERS-CoV morbidity and mortality is possible when vaccinating only health-care workers, underlining the need for countries at risk of outbreaks to stockpile vaccines when available.

Background: Endoscopic vein harvesting is an alternative to open vein harvesting during coronary artery bypass grafting. Although endoscopic vein harvesting includes significant clinical benefits, few long-term cost-effectiveness studies have been performed, limiting its use in the United Kingdom. In this study, we assessed the cost-effectiveness of endoscopic vein harvesting compared with open vein harvesting from the United Kingdom's National Health Service perspective. Methods: A Markov model was developed to estimate the cost-effectiveness of endoscopic vein harvesting vs open vein harvesting by investigating the incremental lifetime costs per quality-adjusted life-year gained. A scoping literature review was conducted to inform the development of the model. One-way and probabilistic sensitivity analyses examined the robustness of the results. Results: Compared with open vein harvesting, endoscopic vein harvesting leads to cost savings of £68.46 and quality-adjusted life-year gains of 0.206 per patient over a lifetime perspective. Thus, endoscopic vein harvesting is a dominant treatment option over open vein harvesting (net monetary benefit: £6248.46). In the scenario analysis, which accounted for a high-risk population with respect to leg wound infections, the net monetary benefit was £7341.47. The probabilistic sensitivity analysis showed that endoscopic vein harvesting has a 62.3% probability of being cost-effective at a threshold of £30,000 per quality-adjusted life-year, highlighting uncertainties resulting from follow-up event rates. Conclusions: Endoscopic vein harvesting is a cost-effective method of harvesting a saphenous vein graft. Further clinical data beyond 5 years of follow-up are required to confirm the long-term cost-effectiveness.

Respiratory viruses including the respiratory syncytial virus (RSV) aggravate the global burden of virus-inflictedmorbidity and mortality. Entry inhibitors are a promising class of antiviral drugs for combating these viruses, asthey can prevent infection at the site of viral entry, i.e., the respiratory tract. Here we used a broad-spectrumentry inhibitor, composed of a β-cyclodextrin backbone, functionalized with 11-mercapto-1-undecanesulfonate(CD-MUS) that is capable of neutralizing a variety of viruses that employ heparan sulfate proteoglycans(HSPG) to infect host cells. CD-MUS inactivates viral particles irreversibly by binding to viral attachment proteinsthrough a multivalent binding mechanism. In the present study, we show that CD-MUS is well tolerated whenadministered to the respiratory tract of mice. Based on this, we developed an inhalable spray-dried powderformulation that fits the size requirements for lung deposition and disperses well upon use with the Cyclops drypowder inhaler (DPI). Using an in vitro dose-response assay, we show that the compound retained its activityagainst RSV after the spray drying process. Our study sets the stage for further in vivo studies, exploring theefficacy of pulmonary administered CD-MUS in animal models of RSV infection.

The coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is caused when Spike-protein (S-protein) present on the surface of SARS-CoV-2 interacts with human cell surface receptor, Angiotensin-converting enzyme 2 (ACE2). This binding facilitates SARS-CoV-2 genome entry into the human cells, which in turn causes infection. Since the beginning of the pandemic, many different therapies have been developed to combat COVID-19, including treatment and prevention. This review is focused on the currently adapted and certain other potential therapies for COVID-19 treatment, which include drug repurposing, vaccines and drug-free therapies. The efficacy of various treatment options is constantly being tested through clinical trials and in vivo studies before they are made medically available to the public.

ObjectiveThe objective of this formative study was to gather women's perspectives in the design and communication modalities of a health kiosk set within a Planned Parenthood setting to promote patient education about the Human papillomavirus (HPV) and to motivate uptake of the HPV vaccine.MethodsTwenty-four women aged 18-35 participated in in-depth one-on-one interviews at a Planned Parenthood health center, which were analyzed in code-associated categories using NVivo11 Pro.ResultsMost women showed receptivity to using an on-site health kiosk, as well as QR codes linked to text messages, to receive HPV-related health information outside of the clinic setting and reminders. Participants provided suggestions for kiosk design and communication modalities.ConclusionsAmong low-income women we interviewed at Planned Parenthood, increasing HPV vaccination rates necessitates engaging digital health tools which incorporate both the preferences and needs of vulnerable populations.InnovationDesigning a point-of-service health kiosk that 1) draws on user preferences early in the design phase, 2) integrates multiple communication technologies, and 3) disseminates culturally grounded HPV vaccination decisions narratives that are tailored to vaccination awareness level is a promising approach in reducing barriers to HPV vaccine education and vaccine uptake among low-income women at safety-net clinics.

BackgroundBacterial urinary tract infections have been associated with comorbidities and increased antimicrobial resistance over time.ObjectiveTo identify bacterial species, antimicrobial susceptibility patterns and risk factors associated with antimicrobial resistance.AnimalsThree hundred sixty-three positive urine cultures from 308 cats.MethodsBacterial species and antimicrobial susceptibility data from positive aerobic bacterial urine cultures from cats with growth of ≥103 colony forming units per milliliter (cfu/ml) were included. Medical records were reviewed, and bacteriuria was classified as sporadic bacterial cystitis, recurrent bacterial cystitis or subclinical bacteriuria (SBU). Multivariable logistic regression analysis was used to evaluate antimicrobial resistance risk factors.ResultsA total of 444 bacterial isolates from 363 bacteriuric episodes were identified. Escherichia coli (52%) and SBU (59%) were the most common organism and classification, respectively. When compared to other classifications of bacteriuria, Enterococcus spp. were more likely to be isolated from SBU episodes (P 90% susceptible designation to all bacteria isolated highlighting the importance of performing urine culture and susceptibility testing, particularly for cats with recurrent bacterial cystitis.

Haemophilus influenzae (Hi) can cause meningitis and other serious invasive disease. Encapsulated Hi is classified into six serotypes (a-f) based on chemical composition of the polysaccharide capsule; unencapsulated strains are termed nontypeable Hi (NTHi). Hi serotype b (Hib) was the most common cause of bacterial meningitis in children in the pre-Hib vaccine era, and secondary transmission of Hi among children (e.g., to household contacts and in child care facilities) (1,2) led to the Advisory Committee on Immunization Practices (ACIP) recommendation for antibiotic chemoprophylaxis to prevent Hib disease in certain circumstances.* High Hib vaccination coverage since the 1990s has substantially reduced Hib disease, and other serotypes now account for most Hi-associated invasive disease in the United States (3). Nevertheless, CDC does not currently recommend chemoprophylaxis for contacts of persons with invasive disease caused by serotypes other than Hib and by NTHi (non-b Hi). Given this changing epidemiology, U.S. surveillance data were reviewed to investigate secondary cases of invasive disease caused by Hi. The estimated prevalence of secondary transmission was 0.32% among persons with encapsulated Hi disease (≤60 days of one another) and 0.12% among persons with NTHi disease (≤14 days of one another). Isolates from all Hi case pairs were genetically closely related, and all patients with potential secondary infection had underlying medical conditions. These results strongly suggest that secondary transmission of non-b Hi occurs. Expansion of Hi chemoprophylaxis recommendations might be warranted to control invasive Hi disease in certain populations in the United States, but further analysis is needed to evaluate the potential benefits against the risks, such as increased antibiotic use.

BACKGROUND: Acute respiratory infections make up a sizable percentage of emergency department (ED) visits and many result in antibiotics being prescribed. Procalcitonin has been found to reduce antibiotic use in both outpatient and critical care settings, yet remains underused in the ED. OBJECTIVE: To evaluate whether point of care molecular influenza and Respiratory Syncytial Virus (RSV) testing, procalcitonin, and a pharmacist driven educational intervention in aggregate optimizes antibiotic and antiviral prescribing in the ED setting. METHODS: A randomized trial of the Cobas Liat Flu/RSV Assay, procalcitonin, and the use of pharmacist-led education in patients 0–50 years of age being seen in the ED for Influenza Like Illness (ILI) or acute respiratory illness. The study enrolled 200 ED patients between March 2018 and April 2022 at the University of California Davis Medical Results: There was little difference in antibiotic or antiviral prescribing between the intervention and control groups in this study (39% - 32% = 7.0%, 95% CI: −6.2, 20.2, P=0.30). However, a post-hoc analysis of the use of PCT showed PCT results were used as indicated in the ED (P=0.001). CONCLUSION: Procalcitonin can be used in both adult and pediatric populations to help guide the decision of whether to treat with antibiotics in the ED setting. Pharmacist guided education may not be a driving factor.

Beyond Xylella, Integrated Management Strategies for Mitigating Xylella fastidiosa Impact in Europe (BeXyl) (Grant Agreement 101060593). Partner/Coordinador principal: Blanca B. Landa del Castillo, Investigadora Científica del Instituto de Agricultura Sostenible (IAS-CSIC)., While there are documented host shifts in many bacterial plant pathogens, the genetic foundation of host shifts is largely unknown. Xylella fastidiosa is a bacterial pathogen found in over 600 host plant species. Two parallel host shifts occurred-in Brazil and Italy-in which X. fastidiosa adapted to infect olive trees, whereas related strains infected coffee. Using 10 novel whole-genome sequences from an olive-infecting population in Brazil, we investigated whether these olive-infecting strains diverged from closely related coffee-infecting strains. Several single-nucleotide polymorphisms, many derived from recombination events, and gene gain and loss events separated olive-infecting strains from coffee-infecting strains in this clade. The olive-specific variation suggests that this event was a host jump with genetic isolation between coffee- and olive-infecting X. fastidiosa populations. Next, we investigated the hypothesis of genetic convergence in the host shift from coffee to olive in both populations (Brazil and Italy). Each clade had multiple mutations and gene gain and loss events unique to olive, yet no overlap between clades. Using a genome-wide association study technique, we did not find any plausible candidates for convergence. Overall, this work suggests that the two populations adapted to infect olive trees through independent genetic solutions., This work was partially funded by the California Department of Food and Agriculture Pierce's Disease Control Program. Additional funding was from Horizon 2020 (XF Actors project number 727987), BeXyl Project (HORIZON, id: 101060593), and FAPESP (São Paulo Research Foundation 2016/02176-7). H.D.C.F. received CNPq research fellowships (proc. no. 313676/2017-8).

Free-living amoebae are rare causes of morbidity and mortality in humans and animals around the globe. Because the route of exposure and clinical progression of disease caused by different species of amoebae may vary in people and animals, determining the species of amoeba present is important. We describe here a fatal infection by the free-living amoeba Balamuthia mandrillaris in a Siberian tiger ( Panthera tigris altaica). The 17-y-old patient had a rapid clinical decline after a peracute onset of severe lethargy, dull mentation, and anorexia. Autopsy did not identify a cause of death. Histology revealed inflammation associated with amoebic trophozoites in the brain, lungs, and iris of one eye. These amoebae were confirmed to be B. mandrillaris based on a PCR assay and sequencing. Although there are subtle morphologic differences between cyst stages of Acanthamoeba spp., B. mandrillaris, and Naegleria fowleri when present and identified on routine staining, other modalities, including PCR, immunofluorescence, electron microscopy, and immunohistochemistry, are typically utilized to confirm the pathogen involved in these cases. We review the reports of balamuthosis in animals.

ObjectivesTo identify factors associated with adverse maternal outcomes during the coronavirus disease 2019 (COVID-19) pandemic.MethodsThis was a single-centre prospective cohort study at a maternity department in a public general hospital in Rio de Janeiro. All pregnant women evaluated for emergency care, labour and delivery, respiratory symptoms, obstetric reasons or medical reasons between May 2020 and March 2022 at the study institution were invited to enrol in this study. The endpoint was maternal mortality or intensive care unit (ICU) admission.ResultsIn total, 1609 pregnant women were enrolled in this study. Of these, 25.5% (n=410) were infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) based on reverse transcription polymerase chain reaction or an antigen test. There were 21 deaths and 67 ICU admissions in 4% of the cohort. The incidence of severe maternal morbidity and mortality was higher during the Gamma wave than during the Delta wave (P=0.003). Vaccination conferred protection against the endpoint [relative risk (RR) 0.4, 95% confidence interval (CI) 0.1-0.9; P=0.0169]. Factors associated with severe morbidity and mortality included caesarean section (RR 3.7, 95% CI 1.7-7.9; P=0.0008), SARS-CoV-2 infection in the third trimester (RR 2.4, 95% CI 1.1-5.6; P=0.0006) and comorbidities (RR 3, 95% CI 1.8-5.2; P

Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.

Since emerging in Brazil in 1985, wheat blast has spread throughout South America and recently appeared in Bangladesh and Zambia. Here we show that two wheat resistance genes, Rwt3 and Rwt4, acting as host-specificity barriers against non-Triticum blast pathotypes encode a nucleotide-binding leucine-rich repeat immune receptor and a tandem kinase, respectively. Molecular isolation of these genes will enable study of the molecular interaction between pathogen effector and host resistance genes.

The APOBEC3 (A3) proteins are host antiviral cellular proteins that hypermutate the viral genome of diverse viral families. In retroviruses, this process requires A3 packaging into viral particles1–4. The lentiviruses encode a protein, Vif, that antagonizes A3 family members by targeting them for degradation. Diversification of A3 allows host escape from Vif whereas adaptations in Vif enable cross-species transmission of primate lentiviruses. How this ‘molecular arms race’ plays out at the structural level is unknown. Here, we report the cryogenic electron microscopy structure of human APOBEC3G (A3G) bound to HIV-1 Vif, and the hijacked cellular proteins that promote ubiquitin-mediated proteolysis. A small surface explains the molecular arms race, including a cross-species transmission event that led to the birth of HIV-1. Unexpectedly, we find that RNA is a molecular glue for the Vif–A3G interaction, enabling Vif to repress A3G by ubiquitin-dependent and -independent mechanisms. Our results suggest a model in which Vif antagonizes A3G by intercepting it in its most dangerous form for the virus—when bound to RNA and on the pathway to packaging—to prevent viral restriction. By engaging essential surfaces required for restriction, Vif exploits a vulnerability in A3G, suggesting a general mechanism by which RNA binding helps to position key residues necessary for viral antagonism of a host antiviral gene.

The purpose of this document is to highlight practical recommendations to assist acute-care hospitals in prioritization and implementation of strategies to prevent healthcare-associated infections through hand hygiene. This document updates the Strategies to Prevent Healthcare-Associated Infections in Acute Care Hospitals through Hand Hygiene, published in 2014. This expert guidance document is sponsored by the Society for Healthcare Epidemiology (SHEA). It is the product of a collaborative effort led by SHEA, the Infectious Diseases Society of America, the Association for Professionals in Infection Control and Epidemiology, the American Hospital Association, and The Joint Commission, with major contributions from representatives of a number of organizations and societies with content expertise.

Vascular graft or endograft infection (VGEI) is a complex disease that complicates vascular-surgery and endovascular-surgery procedures and determines high morbidity and mortality. This review article provides the most updated general evidence on the pathogenesis, prevention, diagnosis, and treatment of VGEI. Several microorganisms are involved in VGEI development, but the most frequent one, responsible for over 75% of infections, is Staphylococcus aureus. Specific clinical, surgical, radiologic, and laboratory criteria are pivotal for the diagnosis of VGEI. Surgery and antimicrobial therapy are cornerstones in treatment for most patients with VGEI. For patients unfit for surgery, alternative treatment is available to improve the clinical course of VGEI.

Sepsis is a severe affection, that requires an urgent and specific treatment sequence. Physiological changes occurring during pregnancy make the diagnosis of sepsis more challenging in this setting, with possible delay in treatment initiation, that in turn is responsible for poorer maternal and fetal outcome. This review aims to summarize current knowledge on the diagnosis and treatment of maternal sepsis, as well as persistent knowledge gaps in the field.

The risk of vertical transmission from breastfeeding with HIV (BFHIV) has been found to be very low in optimal scenarios with sustained maternal viral suppression during pregnancy and postpartum. Medical providers must account for the risk of this serious adverse event alongside parental autonomy, breastfeeding benefits, and patient values. To assess provider practices, comfort, and challenges with BFHIV, an online mixed-method survey was sent to breastfeeding and HIV provider listservs from June to July 2021. The target population was US medical professionals from diverse practice settings with experience in clinical issues associated with BFHIV, including physicians, advanced practice providers, nurses, and lactation consultants. Data analysis utilized nonparametric hypothesis testing, ordinal regression, and reflexive thematic analysis. Most providers reported counseling pregnant people with HIV on infant feeding choices, but fewer specifically endorsed counseling about breastfeeding. Of 84 unique institutions identified by 100 included respondents, 10% had an institutional protocol supporting BFHIV. Institutional protocols were associated with higher degrees of provider comfort with BFHIV in optimal scenario clinical vignettes. Providers perceived that White patients faced fewer BFHIV barriers than patients with other racial identities. Discomfort balancing the goals to protect infants from infection risk and support the parent's role in infant feeding decisions was a key theme in free text responses; this manifested in a spectrum of management styles ranging from patient's informed choice to paternalism. This study highlights the tension providers navigate regarding BFHIV discussions, calling for patient care guidelines and protocols grounded in risk reduction and respect of patient autonomy.

HIV cure research requires interrogating latent HIV reservoirs in deep tissues, which necessitates autopsies to avoid risks to participants. An HIV autopsy biobank would facilitate this research, but such research raises ethical issues and requires participant engagement. This study explores the willingness to participate in HIV cure research at the end of life. Participants include Canadians with HIV [people with HIV (PWHIV)] aged 55 years or older. Following a mixed-method study design, all participants completed a phone or online survey, and a subset of participants participated in in-depth phone or videoconference interviews. We produced descriptive statistics of quantitative data and a thematic analysis of qualitative data. Barriers and facilitators were categorized under domains of the Theoretical Domains Framework. From April 2020 to August 2021, 37 participants completed the survey (mean age = 69.9 years old; mean duration of HIV infection = 28.5 years), including 15 interviewed participants. About three quarters of participants indicated being willing to participate in hypothetical medical studies toward the end of life (n = 30; 81.1%), in HIV biobanking (n = 30; 81.1%), and in a research autopsy (n = 28; 75.7%) to advance HIV cure research, mainly for altruistic benefits. The main perceived risks had to do with physical pain and confidentiality. Barriers and facilitators were distributed across five domains: social/professional role and identity, environmental context and resources, social influences, beliefs about consequences, and capabilities. Participants wanted more information about study objectives and procedures, possible accommodations with their last will, and rationale for studies or financial interests funding studies. Our results indicate that older PWHIV would be willing to participate in HIV cure research toward the end of life, HIV biobanking, and research autopsy. However, a dialogue should be initiated to inform participants thoroughly about HIV cure studies, address concerns, and accommodate their needs and preferences. Additional work is required, likely through increased community engagement, to address educational needs.

Major climatic changes in conjunction with animal movement may be associated with the spread of parasites and their vectors into new populations, with potentially important consequences for population persistence. Parasites can evolve to adapt to unsuitable ecological conditions and take up refuge within new host species, with consequences for the population growth of the new host species. One parasite species that has likely been increasing its geographic range, and potentially infecting new hosts, is the recently described air sac nematode Serratospiculoides amaculata, in great tits (Parus major) in Slovakia. In this study, we screened wild birds for potential air sac nematode infection in a woodland area of southern Germany. We identified four additional host species: Eurasian nuthatch, great spotted woodpecker, greenfinch and robin. As infection by this group of nematodes can be highly pathogenic, we recommend further investigation into its potential risk to these populations., International Journal for Parasitology. Parasites and Wildlife, 21, ISSN:2213-2244

Funder: Infectious Diseases Institute, Makerere University, Funder: John Hopkins University, INTRODUCTION: The evaluation of the patterns of liver injury, derived from liver chemistry panels, often may narrow on probable causes of the liver insult especially when coupled with clinical history, examination, and other diagnostic tests. METHODS: Among people living with and without HIV and attending care, we used the R ratio to evaluate for liver injury patterns. Liver injury patterns were defined as cholestatic (R < 2), mixed (R = 2-5), and hepatocellular (R > 5). RESULTS: Overall, the proportions of participants with cholestatic liver injury, mixed liver injury, and hepatocellular liver injury were 55%, 34%, and 4%, respectively, with similar distribution when stratified by HIV status. Alcohol use among participants without HIV was associated with all patterns of liver injury (cholestatic liver injury (OR = 4.9 CI (1.0-24.2); p = 0.054), mixed liver injury (OR = 5.3 CI (1.1-27.3); p = 0.043), and hepatocellular liver injury (OR = 13.2 CI (1.0-167.3); p = 0.046)). Increasing age was associated with cholestatic liver injury among participants with HIV (OR = 2.3 CI (1.0-5.3); p = 0.038). Despite a high hepatitis B prevalence among participants with HIV, there was no association with liver injury. CONCLUSIONS: Liver injury is prevalent among both people living with and without HIV in care, and cholestatic liver injury is the most common pattern. Alcohol is associated with all patterns of liver injury and increasing age associated with cholestatic liver injury among people living without HIV and people living with HIV, respectively.

Food insecurity (FI) impacts people with HIV (PWH) and those who use substances (i.e. drugs and alcohol). We evaluated the longitudinal association between FI and HIV transmission risks (unprotected sexual contacts and shared needles/syringes). Among 351 PWH who use substances in Russia, 51.6% reported FI and 37.0% past month injection drug use. The mean number of unprotected sexual contacts in the past 90days was 13.4 (SD 30.1); 9.7% reported sharing needles/syringes in the past month. We did not find a significant association between mild/moderate FI (adjusted IRR = 0.87, 95% CI 0.47, 1.61) or severe FI (aIRR = 0.84, 95% CI 0.46, 1.54; global p = 0.85) and unprotected sexual contacts. We observed a significant association between severe FI and sharing needles/syringes in the past month (adjusted OR = 3.27, 95% CI 1.45, 7.39; p = 0.004), but not between mild/moderate FI and sharing needles/syringes in the past month (aOR = 1.40,95% CI 0.58, 3.38; p = 0.45). These findings suggest that severe FI could be a potential target for interventions to lower HIV transmission.

OBJECTIVES: People experiencing homelessness (PEH) have been especially impacted by the COVID-19 pandemic, likely due to increased vulnerabilities stemming from chronic diseases, substance use, and mental health conditions. DESIGN: A case-control study to assess the presence of antibodies against SARS-CoV-2 among PEH and associations with key variables. SAMPLE: A convenience sample of 97 PEH in Skid Row, Los Angeles. MEASUREMENTS: A structured questionnaire assessing socio-demographic, mental health, drug and alcohol use, health care access, pandemic stress, and other COVID-19-specific questions. RESULTS: We found high anti-receptor binding domain (RBD) IgG titers among 5 of 15 PEH who reported no prior COVID-19 diagnosis or being vaccinated, suggesting undiagnosed and/or asymptomatic COVID-19. While anti-RBD IgG titers across vaccination categories were not statistically significant (P = 0.069), participants vaccinated with Janssen had the lowest mean anti-RBD IgG titers. In multivariable analysis, we found negative associations between level of SARS-CoV-2 antibody titers with the Janssen vaccine and depression; thus a need for integrated care for PEH with depression and COVID-19. CONCLUSIONS: Further research is warranted to confirm the immune response, initial and over time, to SARS-CoV-2 infection and to COVID-19 vaccinations, particularly among PEH whose immune systems may be impacted by multiple health conditions.

In recent decades, several new diseases have emerged in different geographical areas, with pathogens including Ebola virus, Zika virus, Nipah virus, and last year it was Covid-19. Covid-10 has not only lowered demographic figures but also created economic problems. The rapid spread of infection made it necessary to limit the rights of individuals in order to protect the public from infections with Covid-19. One of the duties imposed on the public is the performance of a Covid-19test where the person is suspected to be infected by Covid-19.

BackgroundThe Centers for Disease Control and Prevention recommends that men who have sex with men (MSM) get tested annually for urethral and rectal chlamydia (CT) and gonorrhea (NG), and pharyngeal NG. There are no national recommendations to screen women and heterosexual men at extragenital sites. We assessed extragenital CT/NG screening among men and women at Louisiana's Parish Health Units (PHU).MethodsThe Louisiana STD/HIV/Hepatitis Program piloted extragenital screening at 4 PHUs in February 2016 and expanded to 11 PHUs in 2017. Sexual histories were used to identify gender of sex partners and exposed sites. Because of billing restrictions, up to 2 anatomical sites were tested for CT/NG.ResultsFrom February 2016 to June 2019, 70,895 urogenital and extragenital specimens (56,086 urogenital, 13,797 pharyngeal, and 1,012 rectal) were collected from 56,086 patients. Pharyngeal CT positivity was 160 of 7,868 (2.0%) among women, 54 of 4,838 (1.1%) among men who have sex with women (MSW) and 33 of 1,091 (3.0%) among MSM. Rectal CT positivity was 51 of 439 (11.6%) among women and 95 of 573 (16.6%) among MSM. Pharyngeal NG positivity was 299 of 7,868 (3.8%) among women, 222 of 4,838 (4.6%) among MSW, and 97 of 1,091 (8.9%) among MSM. Rectal NG positivity was 20 of 439 (4.6%) among women and 134 of 573 (23.4%) among MSM.Urogenital-only screening would have missed: among women, 173 of 3,923 (4.4%) CT and 227 of 1,480 (15.3%) NG infections; among MSW, 26 of 2,667 (1%) CT and 149 of 1,709 (8.7%) NG infections; and among MSM, 116 of 336 (34.5%) CT and 127 of 413 (42.1%) NG infections.ConclusionsMany CT/NG infections would have been missed with urogenital-only screening. Men who have sex with men had much higher extragenital infection rates than women and MSW.

The vast majority of seasonal influenza vaccines administered each year are derived from virus propagated in eggs using technology that has changed little since the 1930s. The immunogenicity, durability, and breadth of response would likely benefit from a recombinant nanoparticle-based approach. Although the E2 protein nanoparticle (NP) platform has been previously shown to promote effective cell-mediated responses to peptide epitopes, it has not yet been reported to deliver whole protein antigens. In this study, we synthesized a novel maleimido tris-nitrilotriacetic acid (NTA) linker to couple protein hemagglutinin (HA) from H1N1 influenza virus to the E2 NP, and we evaluated the HA-specific antibody responses using protein microarrays. We found that recombinant H1 protein alone is immunogenic in mice but requires two boosts for IgG to be detected and is strongly IgG1 (Th2) polarized. When conjugated to E2 NPs, IgG2c is produced leading to a more balanced Th1/Th2 response. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) significantly enhances the immunogenicity of H1-E2 NPs while retaining the Th1/Th2 balance. Interestingly, broader homo- and heterosubtypic cross-reactivity is also observed for conjugated H1-E2 with MPLA, compared to unconjugated H1 with or without MPLA. These results highlight the potential of an NP-based delivery of HA for tuning the immunogenicity, breadth, and Th1/Th2 balance generated by recombinant HA-based vaccination. Furthermore, the modularity of this protein-protein conjugation strategy may have utility for future vaccine development against other human pathogens.

The coronavirus SARS-CoV-2 causes the severe disease COVID-19. SARS-CoV-2 infection is initiated by interaction of the viral spike protein and host receptor angiotensin-converting enzyme 2 (ACE2). We report an improved bright and reversible fluorogenic reporter, named SURF (split UnaG-based reversible and fluorogenic protein-protein interaction reporter), that we apply to monitor real-time interactions between spike and ACE2 in living cells. SURF has a large dynamic range with a dark-to-bright fluorescence signal that requires no exogenous cofactors. Utilizing this reporter, we carried out a high-throughput screening of small-molecule libraries. We identified three natural compounds that block replication of SARS-CoV-2 in both Vero cells and human primary nasal and bronchial epithelial cells. Cell biological and biochemical experiments validated all three compounds and showed that they block the early stages of viral infection. Two of the inhibitors, bruceine A and gamabufotalin, were also found to block replication of the Delta and Omicron variants of SARS-CoV-2. Both bruceine A and gamabufotalin exhibited potent antiviral activity in K18-hACE2 and wild-type C57BL6/J mice, as evidenced by reduced viral titres in the lung and brain, and protection from alveolar and peribronchial inflammation in the lung, thereby limiting disease progression. We propose that our fluorescent assay can be applied to identify antiviral compounds with potential as therapeutic treatment for COVID-19 and other respiratory diseases.

IntroductionBelatacept has shown potential for prevention of rejection after kidney transplantation, given its demonstration of reduced nephrotoxicity in combination with absence of significant incidence of rejection. However, concerns have been raised regarding increased risk of viral infection.MethodsWe set out to explore the impact of the switch to belatacept on alloimmune and antiviral immunity through the study of patients switched from calcineurin inhibitor (CNI) to belatacept within 3months of kidney transplantation compared with a matched cohort of control patients on a CNI-based regimen.ResultsAfter the switch to belatacept, immune phenotyping demonstrated a decrease in naive and an increase in terminally differentiated effector memory (TMRA) T cells, with no significant difference compared with control patients. Donor-specific immune response, measured by intracellular cytokine staining (ICS), did not change significantly either by single or double cytokine secretion, but it was associated with the appearance of donor-specific antibody (DSA) in the control but not the belatacept cohort (P= 0.039 for naive and P= 0.002 for TMRA subtypes). Increased incidence of de novo DSA development was observed in the control group (P= 0.035). Virus-specific immune response, as measured by ICS in response to cytomegalovirus (CMV) or Epstein-Barr virus (EBV), was similar in both groups and stable over time.ConclusionWe found that belatacept use was associated with an absence of alloreactivity without impact on immune phenotype, while preserving the antiviral immune response, for patients switched from a CNI-based regimen. In parallel, the antiviral immune response against CMV and EBV was preserved after the belatacept switch (clinicaltrials.gov: NCT01953120).

A patient in California, USA, with rare and usually fatal Balamuthia mandrillaris granulomatous amebic encephalitis survived after receiving treatment with a regimen that included the repurposed drug nitroxoline. Nitroxoline, which is a quinolone typically used to treat urinary tract infections, was identified in a screen for drugs with amebicidal activity against Balamuthia.

BACKGROUND: Previous studies have indicated an increased risk of periprosthetic joint infection (PJI) in patients treated with reverse shoulder arthroplasty (RSA) compared with patients treated with anatomic total shoulder arthroplasty. The reason for this is unclear but may be related to a high prevalence of previous rotator cuff repair in patients who are treated with RSA. The purpose of this study was to determine previous non-arthroplasty surgery as a risk factor for revision owing to PJI after RSA for cuff tear arthropathy, massive irreparable rotator cuff tears, or osteoarthritis.METHODS: Data were retrieved from the Danish Shoulder Arthroplasty Registry and medical records. We included 2217 patients who underwent RSA for cuff tear arthropathy, massive irreparable rotator cuff tears, or osteoarthritis between 2006 and 2019. PJI was defined as ≥3 of 5 tissue samples positive for the same bacteria or as definite or probable PJI evaluated based on criteria from the International Consensus Meeting. The Kaplan-Meier method was used to illustrate the unadjusted 14-year cumulative rates of revision. A Cox regression model was used to report hazard for revision owing to PJI. Results were adjusted for previous non-arthroplasty surgery, sex, diagnosis, and age.RESULTS: Revision was performed in 88 shoulders (4.0%), of which 40 (1.8%) underwent revision owing to PJI. There were 272 patients (12.3%) who underwent previous rotator cuff repair, of whom 11 (4.0%) underwent revision owing to PJI. The 14-year cumulative rate of revision owing to PJI was 14.1% for patients with previous rotator cuff repair and 2.7% for patients without previous surgery. The adjusted hazard ratio for revision owing to PJI for patients with previous rotator cuff repair was 2.2 (95% confidence interval, 1.04-4.60) compared with patients without previous surgery.CONCLUSION: There is an increased risk of revision owing to PJI after RSA for patients with previous rotator cuff repair. We recommend that patients with previous rotator cuff repair be regarded as high-risk patients when considering RSA.

Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort (n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4⁺ T cells including CXCR3⁺ circulating follicular helper T cells and the TH1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific TH1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8⁺ T cell responses. Thus, an inefficient CD4⁺ T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4⁺ T cell response following the first dose is key to improving vaccine efficacy in older adults., 高齢者のT細胞応答は立ち上がりが遅く収束は早い --新型コロナワクチン接種機会を活用した免疫応答の個人差・年齢差の解明--. 京都大学プレスリリース. 2023-01-13., T-Cell Responses in the Elderly Rise Slowly and Contract Quickly --Learning About Individual and Age Differences in Immune Response From COVID-19 Vaccinations--. 京都大学プレスリリース. 2023-01-13.

Background: The aim of this study is to compare the effects of %4 articaine and %2 lidocaine on inferior alveolar nerve block (IANB) for implant surgery in the posterior mandible.Material and Methods: The patients who have inserted implants in the posterior mandible were divided into 2 groups for IANB: lidocaine and articaine. VAS = visual analog scale, pain during surgery and injection, lip numb-ness time, mandibular canal-implant apex distance, age, gender, bone density, implant number, release incision, adjacent teeth, and duration of surgery were analyzed using t-test, Mann-Whitney U test, Spearman's coefficient, and, Pearson's chi-squared test. This trial followed the recommendations of the Consort Statement for reporting randomized controlled trials. Results: 577 patients were included and 1185 dental implants were analyzed. There was no significant difference between the two groups in terms of injection and surgery VAS values (p>0.05). The lip numbness time of lido-caine was 3.06 +/- 3.22min while articaine was found to be 2.96 +/- 3.09min (p>0.05). Mandibular canal-implant apex distance was found to be 2.28 +/- 0.75mm in the articaine and 2.45 +/- 0.86mm in the lidocaine group (p

PurposeWe hypothesized that an intervention designed to create girl-friendly drug shops would increase access to sexual and reproductive health products and services among adolescent girls and young women (AGYW) (ages 15-24 years) in Tanzania.MethodsWe conducted a four-month randomized trial at 20 drug shops in Shinyanga, Tanzania from August-December 2019 to determine if the Malkia Klabu ("Queen Club") intervention increased AGYW patronage and the provision of HIV self-testing (HIVST), contraception, and health facility referrals to AGYW (primary outcomes). Drug shops were randomized 1:1 to the intervention or comparison arm. All shops were provided with OraQuick HIVST kits to give to AGYW for free. Intervention shops implemented Malkia Klabu, a loyalty program for AGYW created using human-centered design through which AGYW could also access free contraception. We compared outcomes in intention-to-treat analyses using shop observations and shopkeeper records.ResultsBy endline, shops implementing Malkia Klabu had higher AGYW patronage than comparison shops (rate ratio: 4.4; 95% confidence interval: 2.0, 9.8). Intervention shops distributed more HIVST kits (median per shop: 130.5 vs. 58.5, P= .02) and contraceptives (325.5 vs. 7.0, P < .01) to AGYW and provided more referrals for HIV, family planning, or pregnancy services combined (3.5 vs. 0.5, P= .02) than comparison shops.DiscussionThe Malkia Klabu intervention increased AGYW patronage and the provision of HIVST kits, contraception, and referrals to AGYW at drug shops, despite HIVST kits being freely available at all participating shops. Enhancing drug shops with girl-friendly services may be an effective strategy to reach AGYW with sexual and reproductive health services.

BackgroundIn response to the COVID-19 pandemic, San Francisco County (SFC) had to shift many nonemergency health care resources to COVID-19, reducing HIV control resources. We sought to quantify COVID-19 effects on HIV burden among men who have sex with men (MSM) as SFC returns to pre-COVID service levels and progresses toward the Ending the HIV Epidemic (EHE) goals.SettingMicrosimulation model of MSM in SFC tracking HIV progression and treatment.MethodsScenario analysis where services affected by COVID-19 [testing, care engagement, pre-exposure prophylaxis (PrEP) uptake, and retention] return to pre-COVID levels by the end of 2022 or 2025, compared against a counterfactual where COVID-19 changes never occurred. We also examined scenarios where resources are prioritized to reach new patients or retain of existing patients from 2023 to 2025 before all services return to pre-COVID levels.ResultsThe annual number of MSM prescribed PrEP, newly acquired HIV, newly diagnosed, and achieving viral load suppression (VLS) rebound quickly after HIV care returns to pre-COVID levels. However, COVID-19 service disruptions result in measurable reductions in cumulative PrEP use, VLS person-years, incidence, and an increase in deaths over the 2020-2035 period. The burden is statistically significantly larger if these effects end in 2025 instead of 2022. Prioritizing HIV care/prevention initiation over retention results in more person-years of PrEP but less VLS person-years and more deaths, influencing EHE PrEP outcomes.ConclusionsEarlier HIV care return to pre-COVID levels results in lower cumulative HIV burdens. Resource prioritization decisions may differentially affect different EHE goals.

The worldwide coronavirus disease 2019 pandemic was sparked by the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) that first surfaced in December 2019 (COVID-19). The effects of COVID-19 differ substantially not just between patients individually but also between populations with different ancestries. In humans, the human leukocyte antigen (HLA) system coordinates immune regulation. Since HLA molecules are a major component of antigen-presenting pathway, they play an important role in determining susceptibility to infectious disease. It is likely that differential susceptibility to SARS-CoV-2 infection and/or disease course in COVID-19 in different individuals could be influenced by the variations in the HLA genes which are associated with various immune responses to SARS-CoV-2. A growing number of studies have identified a connection between HLA variation and diverse COVID-19 outcomes. Here, we review research investigating the impact of HLA on individual responses to SARS-CoV-2 infection and/or progression, also discussing the significance of MHC-related immunological patterns and its use in vaccine design.

Objectives The aim of this study is to evaluate the effectiveness of a CRISPR-based human and bacterial ribosomal RNA (rRNA) depletion kit (JUMPCODE Genomics) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shotgun metagenomic sequencing in weakly positive respiratory samples. Methods Shotgun metagenomics was performed on 40 respiratory specimens collected from solid organ transplant patients and deceased intensive care unit patients at UCLA Medical Center in late 2020 to early 2021. Human and bacterial rRNA depletion was performed on remnant library pools prior to sequencing by Illumina MiSeq. Data quality was analyzed using Geneious Prime, whereas the identification of SARS-CoV-2 variants and lineages was determined by Pangolin. Results The average genome coverage of the rRNA-depleted respiratory specimens increased from 72.55% to 93.71% in overall samples and from 29.3% to 83.3% in 15 samples that failed to achieve sufficient genome coverage using the standard method. Moreover, rRNA depletion enhanced genome coverage to over 85% in 11 (73.3%) of 15 low viral load samples with cycle threshold values up to 35, resulting in the identification of genotypes. Conclusion The CRISPR-based human and bacterial rRNA depletion enhanced the sensitivity of SARS-CoV-2 shotgun metagenomic sequencing, especially in low viral load samples.

Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn2+ active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PAN using a FRET-based enzymatic assay, and their mode of binding in PAN was determined using X-ray crystallography.

Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza.One-Sentence SummaryIn situ dynamics of influenza glycoproteins expose antigenically relevant states and a new site of vulnerability in neuraminidase.

BackgroundMycoplasma genitalium (MG) is associated with urethritis in men and weakly associated with pelvic inflammatory disease in women. Mycoplasma genitalium coinfections with Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) are commonly reported; however, little is known about their interaction. One study suggested that MG/NG coinfections might increase the bacterial load of NG, which has been shown to have a higher transmission potential. As even less is known about the impact of a simultaneous MG/CT infection, we assessed whether patients with urogenital MG/CT coinfections have a higher bacterial load than patients with a single infection.MethodsThere were 1673 urogenital samples from patients from a population-based chlamydia study, and our sexually transmitted infection clinic tested for both CT and MG. When positive, the load was quantified. Nonparametric tests compared the CT and MG load, and linear regression analyses tested the association of the CT and MG load within a patient.ResultsIn 60 MG-positive patients, MG load ranged from 1.7 to 6.0 log10 copies/ml, similar to the CT load distribution. Only 6 patients were MG-positive and CT-negative, but the MG load distribution was similar to that of CT-positive patients (n.s.). The MG and CT load was unrelated in coinfected persons (n.s.).ConclusionsWe found no correlation between the CT and MG load in urogenital samples, and the MG load distribution was similar in CT-positive and CT-negative patients. These results could have implications for the transmission risk of these infections.

The absence of microbial exposure early in life leaves individuals vulnerable to immune overreaction later in life, manifesting as immunopathology, autoimmunity, or allergies. A key factor is thought to be a “critical window” during which the host's immune system can “learn” tolerance, and beyond which learning is no longer possible. Animal models indicate that many mechanisms have evolved to enable critical windows, and that their time limits are distinct and consistent. Such a variety of mechanisms, and precision in their manifestation suggest the outcome of strong evolutionary selection. To strengthen our understanding of critical windows, we explore their underlying evolutionary ecology using models encompassing demographic and epidemiological transitions, identifying the length of the critical window that would maximize fitness in different environments. We characterize how direct effects of microbes on host mortality, but also indirect effects via microbial ecology, will drive the optimal length of the critical window. We find that indirect effects such as magnitude of transmission, duration of infection, rates of reinfection, vertical transmission, host demography, and seasonality in transmission all have the effect of redistributing the timing and/or likelihood of encounters with microbial taxa across age, and thus increasing or decreasing the optimal length of the critical window. Declining microbial population abundance and diversity are predicted to result in increases in immune dysfunction later in life. We also make predictions for the length of the critical window across different taxa and environments. Overall, our modeling efforts demonstrate how critical windows will be impacted over evolution as a function of both host-microbiome/pathogen interactions and dispersal, raising central questions about potential mismatches between these evolved systems and the current loss of microbial diversity and/or increases in infectious disease.

International audience; The presence of CD8+ T cells with a memory phenotype in nonimmunized mice has been noted for decades, but it was not until about 2 decades ago that they began to be studied in greater depth. Currently called virtual memory CD8+ T cells, they consist of a heterogeneous group of cells with memory characteristics, without any previous contact with their specific antigens. These cells were identified in mice, but a few years ago, a cell type with characteristics equivalent to the murine ones was described in healthy humans. In this review, we address the different aspects of its biology mainly developed in murine models and what is currently known about its cellular equivalent in humans.

Background: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. Objective: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. Design: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). Setting: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. Participants: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. Intervention: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. Measurements: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. Results: In the intention-to-treat analysis, RT-PCR–confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR–confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. Limitation: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. Conclusion: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR–confirmed COVID-19 for medical masks when compared with HRs of RT-PCR–confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. Primary Funding Source: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

Sialidases or neuraminidases are sialic-acid-cleaving enzymes that are expressed by a broad spectrum of organisms, including pathogens. In nature, sialic acids are monosaccharides with diverse structural variations, but the lack of novel probes has made it difficult to determine how sialic acid modifications impact the recognition by sialidases. Here, we used a chemoenzymatic synthon strategy to generate a set of α2-3- and α2-6-linked sialoside probes that contain 7-N-acetyl or 7,9-di-N-acetyl sialic acid as structure mimics for those containing the less stable naturally occurring 7-O-acetyl- or 7,9-di-O-acetyl modifications. These probes were used to compare the substrate specificity of several sialidases from different origins. Our results show that 7-N-acetyl sialic acid was readily cleaved by neuraminidases from H1N1 and H3N2 influenza A viruses, but not by sialidases of human or bacterial origin, thereby indicating that the influenza enzymes possess a distinctive and more promiscuous substrate binding pocket.

Objectives: The aim of this study was to establish an international, interorganisational consensus on wound infection terminology. Methods: This project consisted of definition scoping and a Delphi process to produce a consensus glossary for 18 wound infection terms. Recent guidelines/consensus documents were reviewed to identify 2–4 definitions for each term. An online consensus process was undertaken using the RAND Appropriateness Method, a consensus method for panels to reach agreement. International wound organisations nominated experts to participate, from whom 21 participants were selected to represent different organisations, geographic regions and disciplines. In the first consensus round, each term was presented alongside 2–3 definitions and participants nominated their preferred definition, with the majority vote used to select a baseline definition. The consensus process then proceeded, with participants using a 9-point Likert scale to score their level of agreement or disagreement with the definition for each term. Participants also provided a justification outlining the reason behind their rating. At the end of each round, an index was calculated to provide a quantitative evaluation indicating whether agreement or disagreement had been reached. Results: Reasoning statements were summarised and the definitions were adjusted to incorporate concepts identified by participants. The adjusted definition was presented in the next consensus round, together with the reasoning statements. Terms for which a final definition was not achieved in three consensus rounds were finalised with preferential voting using 2–3 definitions that had reached consensus. Project progress and significance: The project generated a glossary of wound infection terms, endorsed through participation of 15 international organisations, for dissemination of guidelines and clinical decision-making/teaching tools.

Tigerfish (Hydrocynus vittatus Castelnau, 1861) is of considerable importance in both the commercial and recreational fishery activities of Lake Kariba. In our previous paper (Mabika et al. 2019) we provided information on the seasonal occurrence of metazoan parasites of H. vittatus. This communication provides endohelminth infection statistics of male and female H. vittatus across two seasons not previously included. A total of 80 H. vittatus individuals consisting of 56 females and 24 males were examined for endohelminth parasites during the period October 2014–July 2015 in the Sanyati basin, Lake Kariba. Parasites were recovered from the abdominal cavity, mesentery and intestines. Most of the parasites were harboured in the abdominal cavity in both sexes. Parasite infection was more prevalent during the dry season in comparison to the rainy season for both sexes. Contracaecum larval infection was significantly higher in female (84%) than in male tigerfish (24%), whereas larval cestode infections were significantly higher in male tigerfish (59%) than female fish (16%). The mean condition factor of the male tigerfish (1.68) was not significantly higher than that of the female (1.64). The results of the study indicate that female tigerfish were more suitable hosts to Contracaecum larval infection than the male fish. Further parasitological and histopathological research on tigerfish is recommended to contribute to knowledge on endohelminth diversity and conservation.

Alcohol use is especially problematic for people living with HIV (PLWH) and was likely to be impacted by the coronavirus disease (COVID-19) pandemic and its restrictions. In a study of PLWH with latent tuberculosis infection, we measured unhealthy alcohol use with the Alcohol Use Disorders Identification Test (AUDIT-C), phosphatidylethanol (PEth) and bar attendance. We analyzed data collected before and after COVID-19 restrictions, and used Generalized Estimating Equations (GEE) logistic regression models to evaluate changes in unhealthy alcohol use. While bar attendance declined from 57.0% before to 38.3% after the restrictions started, multivariable analysis controlling for bar use showed a significant increase in unhealthy alcohol use; the adjusted odds ratio for unhealthy drinking before versus after the restrictions started was 1.37 (95% CI: 0.89–2.12) which increased to 1.64 (95% CI: 1.08–2.50) when bar attendance was added to the model. Decline in bar attendance did not decrease unhealthy alcohol use.

Legionella pneumophila (L.p.) is a bacterial pathogen which is a common causative agent of pneumonia. In humans, it infects alveolar macrophages and transfers hundreds of virulence factors that interfere with cellular signalling pathways and the transcriptomic landscape to sustain its own replication. By this interaction, it has acquired eukaryote-like protein motifs by gene transfer events that partake in the pathogenicity of Legionella. In a computational screening approach for eukaryotic motifs in the transcriptome of Legionella, we identified the L.p. strain Corby protein ABQ55614 as putative histone-deacetylase and named it "suppressing modifier of histones 1" (Smh1). During infection, Smh1 is translocated from the Legionella vacuole into the host cytosol. When expressed in human macrophage THP-1 cells, Smh1 was localized predominantly in the nucleus, leading to broad histone H3 and H4 deacetylation, blunted expression of a large number of genes (e.g. IL-1β and IL-8), and fostered intracellular bacterial replication. L.p. with a Smh1 knockdown grew normally in media but showed a slight growth defect inside the host cell. Furthermore, Smh1 showed a very potent histone deacetylation activity in vitro, e.g. at H3K14, that could be inhibited by targeted mutation of the putative catalytic center inferred by analogy with eukaryotic HDAC8, and with the deacetylase inhibitor trichostatin A. In summary, Smh1 displays functional homology with class I/II type HDACs. We identified Smh1 as a new Legionella virulence factor with a eukaryote-like histone-deacetylase activity that moderates host gene expression and might pave the way for further histone modifications.IMPORTANCELegionella pneumophila (L.p.) is a prominent bacterial pathogen, which is a common causative agent of pneumonia. In order to survive inside the host cell, the human macrophage, it profoundly interacts with host cell processes to advance its own replication. In this study, we identify a bacterial factor, Smh1, with yet unknown function as a host histone deacetylase. The activity of this factor in the host cell leads to attenuated gene expression and increased intracellular bacterial replication.