Longitudinal analysis within one hospital in sub-Saharan Africa over 20 years reveals repeated replacements of dominant clones of Klebsiella pneumoniae and stresses the importance to include temporal patterns for vaccine design considerations.

BACKGROUND: Infections caused by multidrug-resistant gram-negative bacteria present a severe threat to global public health. The WHO defines drug-resistant Klebsiella pneumoniae as a priority pathogen for which alternative treatments are needed given the limited treatment options and the rapid acquisition of novel resistance mechanisms by this species. Longitudinal descriptions of genomic epidemiology of Klebsiella pneumoniae can inform management strategies but data from sub-Saharan Africa are lacking. METHODS: We present a longitudinal analysis of all invasive K. pneumoniae isolates from a single hospital in Blantyre, Malawi, southern Africa, from 1998 to 2020, combining clinical data with genome sequence analysis of the isolates. RESULTS: We show that after a dramatic increase in the number of infections from 2016 K. pneumoniae becomes hyperendemic, driven by an increase in neonatal infections. Genomic data show repeated waves of clonal expansion of different, often ward-restricted, lineages, suggestive of hospital-associated transmission. We describe temporal trends in resistance and surface antigens, of relevance for vaccine development. CONCLUSIONS: Our data highlight a clear need for new interventions to prevent rather than treat K. pneumoniae infections in our setting. Whilst one option may be a vaccine, the majority of cases could be avoided by an increased focus on and investment in infection prevention and control measures, which would reduce all healthcare-associated infections and not just one.

Exploring equity in global health collaborations: a qualitative study of donor and recipient power dynamics in Liberia.

IntroductionGlobal health collaborations between individuals from high-resource and low-resource settings are complex and often built on hierarchical structures and power differentials that are difficult to change. There have been many calls and frameworks developed to facilitate more equity within these collaborations, yet little is known about the lived experiences of global health donors and recipients working within such collaborations and how those experiences can facilitate more equitable collaboration. Liberia, a postconflict, post-Ebola country, provides an ideal setting to study lived experiences of global health collaborations.MethodsOur qualitative analysis used key informant interviews representing the perspectives of those working on behalf of the Liberian government, Liberian academics, foreign donors and non-governmental organisations and implementing partners. Thematic analysis guided this analysis to explore topics such as financial control, accountability and decision making.ResultsThe first phase of the analysis mapped the existing patterns of priority setting. Priority-setting power was most strongly held by those with financial control (donors), and implementation plans tended to be built on metrics that aim to meet donor expectations. The second phase of the analysis explored the interplay between underlying factors that we identified in our data associated with driving collaborative inequity: history of prior of engagement, level of transparency and patterns of accountability.ConclusionsOur findings highlight that global health collaborations in Liberia are structured to hinder equitable partnerships. The power structure tied to financial ownership offers little space for recipients to have an equitable role in collaborations, which maintains dependence on external aid and ensures that weak systems remain weak. While our study is limited to Liberia, we anticipate that these dynamics are common elsewhere and reinforce the importance of intentional efforts to ensure equitable decision making and power structures in similar settings worldwide.

Four antenatal care visits by four months of pregnancy and four vital tests for pregnant mothers: impact of a community-facility health systems strengthening intervention in Migori County, Kenya.

BACKGROUND: Early attendance at antenatal care (ANC), coupled with good-quality care, is essential for improving maternal and child health outcomes. However, achieving these outcomes in sub-Saharan Africa remains a challenge. This study examines the effects of a community-facility health system strengthening model (known as 4byFour) on early ANC attendance, testing for four conditions by four months of pregnancy, and four ANC clinic visits in Migori county, western Kenya. METHODS: We conducted a mixed methods quasi-experimental study with a before-after interventional design to assess the impact of the 4byFour model on ANC attendance. Data were collected between August 2019 and December 2020 from two ANC hospitals. Using quantitative data obtained from facility ANC registers, we analysed 707 baseline and 894 endline unique ANC numbers (attendances) based on negative binomial regression. Logistic regression models were used to determine the impact of patient factors on outcomes with Akaike Information Criterion (AIC) and likelihood ratio testing used to compare models. Regular facility stock checks were undertaken at the study sites to assess the availability of ANC profile tests. Analysis of the quantitative data was conducted in R v4.1.1 software. Additionally, qualitative in-depth interviews were conducted with 37 purposively sampled participants, including pregnant mothers, community health volunteers, facility staff, and senior county health officials to explore outcomes of the intervention. The interview data were audio-recorded, transcribed, and coded; and thematic analysis was conducted in NVivo. RESULTS: There was a significant 26% increase in overall ANC uptake in both facilities following the intervention. Early ANC attendance improved for all age groups, including adolescents, from 22% (baseline) to 33% (endline, p = 0.002). Logistic regression models predicting early booking were a better fit to data when patient factors were included (age, parity, and distance to clinic, p = 0.004 on likelihood ratio testing), suggesting that patient factors were associated with early booking.The proportion of women receiving all four tests by four months increased to 3% (27/894), with haemoglobin and malaria testing rates rising to 8% and 4%, respectively. Despite statistical significance (p < 0.001), the rates of testing remained low. Testing uptake in ANC was hampered by frequent shortage of profile commodities not covered by buffer stock and low ANC attendance during the first trimester. Qualitative data highlighted how community health volunteer-enhanced health education improved understanding and motivated early ANC-seeking. Community pregnancy testing facilitated early detection and referral, particularly for adolescent mothers. Challenges to optimal ANC attendance included insufficient knowledge about the ideal timing for ANC initiation, financial constraints, and long distances to facilities. CONCLUSION: The 4byFour model of community-facility health system strengthening has the potential to improve early uptake of ANC and testing in pregnancy. Sustained improvement in ANC attendance requires concerted efforts to improve care quality, consistent availability of ANC commodities, understand motivating factors, and addressing barriers to ANC. Research involving randomised control trials is needed to strengthen the evidence on the model's effectiveness and inform potential scale up.

A Bayesian approach to identifying the role of hospital structure and staff interactions in nosocomial transmission of SARS-CoV-2.

Nosocomial infections threaten patient safety, and were widely reported during the COVID-19 pandemic. Effective hospital infection control requires a detailed understanding of the role of different transmission pathways, yet these are poorly quantified. Using patient and staff data from a large UK hospital, we demonstrate a method to infer unobserved epidemiological event times efficiently and disentangle the infectious pressure dynamics by ward. A stochastic individual-level, continuous-time state-transition model was constructed to model transmission of SARS-CoV-2, incorporating a dynamic staff-patient contact network as time-varying parameters. A Metropolis-Hastings Markov chain Monte Carlo (MCMC) algorithm was used to estimate transmission rate parameters associated with each possible source of infection, and the unobserved infection and recovery times. We found that the total infectious pressure exerted on an individual in a ward varied over time, as did the primary source of transmission. There was marked heterogeneity between wards; each ward experienced unique infectious pressure over time. Hospital infection control should consider the role of between-ward movement of staff as a key infectious source of nosocomial infection for SARS-CoV-2. With further development, this method could be implemented routinely for real-time monitoring of nosocomial transmission and to evaluate interventions.

Prep-Tok: a queer critical discourse analysis of TikToks regarding HIV-related pre-exposure prophylaxis.

Human immunodeficiency virus (HIV) continues to present a public health problem, and pre-exposure prophylaxis (PrEP) offers a promising preventative intervention; however, its uptake remains low, so investigating determinants of use is essential. This article applies queer critical discourse analysis to a corpus of 121 TikToks sampled via the TikTok algorithm, coded and refined into three overarching content categories: 'what makes a PrEP user?', 'what is PrEP as a drug?', and 'sexual health and HIV'. Examples from within these categories reveal four underlying discursive themes: (1) stigmatisation of HIV as a 'gay disease' with a poor prognosis; (2) stigmatisation of gay men as unsafe, high-risk and untrustworthy; (3) stigmatisation of PrEP as increasing 'unsafe' sexual practices; (4) poor healthcare and education gay men and other beneficiaries of PrEP. These themes are influenced by a broad spectrum of homophobic and heteronormative discourses available with specific examples reflecting parts of this spectrum from predominantly perpetuating to occasionally challenging. The findings report complementary evidence obtained from other media platforms yet offer a unique take while suggesting useful avenues for future public health messaging relating to PrEP which may be used to inform the next steps against HIV.

Preferences and Perspectives of Black Male Barbershop Patrons on Receiving Health Care in Nontraditional Settings.

Introduction: Non-Hispanic Black men experience a disproportionate rate of morbidity and mortality from hypertension, cardiovascular disease, and other chronic conditions in the United States. Studies have demonstrated the efficacy of community-based health outreach in settings not traditionally utilized for health care. Understanding how potential future participants view health care services in nontraditional settings is a necessary step to ascertain the success of these interventions in the real world. Our study objective was to explore the preferences of Black male barbershop patrons regarding health care-provided services in these nontraditional settings. Methods: We recruited patrons of a Black-owned barbershop in the San Francisco Bay Area. Study participants were asked to complete a survey assessing individual attitudes and preferences toward the idea of receiving health care services in traditional and nontraditional settings. Results: Among non-Hispanic Black males (n=17), 81% agreed or strongly agreed that they would prefer to receive health care in traditional clinics. Receiving care at the pharmacy (56% agreed or strongly agreed) and the patient's own home (53% agreed or strongly agreed) were the next most preferred locations. A minority of participants agreed or strongly agreed that they preferred to receive health care in nontraditional settings: 47% for barbershops, 19% for churches, and 6% for grocery stores. Discussion: Participants expressed preference for traditional over nontraditional settings, despite listing barriers that may be addressed, in part, by nontraditional settings. One potential reason for this is simply a lack of familiarity. Establishing and normalizing nontraditional clinical settings may allow for enhanced acceptance within Black communities, ultimately increasing health care access.

Investigating One Health risks for human colonisation with extended spectrum ß-lactamase-producing Escherichia coli and Klebsiella pneumoniae in Malawian households: a longitudinal cohort study.

BACKGROUND: Low-income countries have high morbidity and mortality from drug-resistant infections, especially from enteric bacteria such as Escherichia coli. In these settings, sanitation infrastructure is of variable and often inadequate quality, creating risks of extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales transmission. We aimed to describe the prevalence, distribution, and risks of ESBL-producing Enterobacterales colonisation in sub-Saharan Africa using a One Health approach. METHODS: Between April 29, 2019, and Dec 3, 2020, we recruited 300 households in Malawi for this longitudinal cohort study: 100 each in urban, peri-urban, and rural settings. All households underwent a baseline visit and 195 were selected for longitudinal follow-up, comprising up to three additional visits over a 6 month period. Data on human health, antibiotic usage, health-seeking behaviours, structural and behavioural environmental health practices, and animal husbandry were captured alongside human, animal, and environmental samples. Microbiological processing determined the presence of ESBL-producing E coli and Klebsiella pneumoniae, and hierarchical logistic regression was performed to evaluate the risks of human ESBL-producing Enterobacterales colonisation. FINDINGS: A paucity of environmental health infrastructure and materials for safe sanitation was identified across all sites. A total of 11 975 samples were cultured, and ESBL-producing Enterobacterales were isolated from 1190 (41·8%) of 2845 samples of human stool, 290 (29·8%) of 973 samples of animal stool, 339 (66·2%) of 512 samples of river water, and 138 (46·0%) of 300 samples of drain water. Multivariable models illustrated that human ESBL-producing E coli colonisation was associated with the wet season (adjusted odds ratio 1·66, 95% credible interval 1·38-2·00), living in urban areas (2·01, 1·26-3·24), advanced age (1·14, 1·05-1·25), and living in households where animals were observed interacting with food (1·62, 1·17-2·28) or kept inside (1·58, 1·00-2·43). Human ESBL-producing K pneumoniae colonisation was associated with the wet season (2·12, 1·63-2·76). INTERPRETATION: There are extremely high levels of ESBL-producing Enterobacterales colonisation in humans and animals and extensive contamination of the wider environment in southern Malawi. Urbanisation and seasonality are key risks for ESBL-producing Enterobacterales colonisation, probably reflecting environmental drivers. Without adequate efforts to improve environmental health, ESBL-producing Enterobacterales transmission is likely to persist in this setting. FUNDING: Medical Research Council, National Institute for Health and Care Research, and Wellcome Trust. TRANSLATION: For the Chichewa translation of the abstract see Supplementary Materials section.

A systematic review of economic evaluations of whole-genome sequencing for the surveillance of bacterial pathogens.

Whole-genome sequencing (WGS) has unparalleled ability to distinguish between bacteria, with many public health applications. The generation and analysis of WGS data require significant financial investment. We describe a systematic review summarizing economic analyses of genomic surveillance of bacterial pathogens, reviewing the evidence for economic viability. The protocol was registered on PROSPERO (CRD42021289030). Six databases were searched on 8 November 2021 using terms related to 'WGS', 'population surveillance' and 'economic analysis'. Quality was assessed with the Drummond-Jefferson checklist. Following data extraction, a narrative synthesis approach was taken. Six hundred and eighty-one articles were identified, of which 49 proceeded to full-text screening, with 9 selected for inclusion. All had been published since 2019. Heterogeneity was high. Five studies assessed WGS for hospital surveillance and four analysed foodborne pathogens. Four were cost-benefit analyses, one was a cost-utility analysis, one was a cost-effectiveness analysis, one was a combined cost-effectiveness and cost-utility analysis, one combined cost-effectiveness and cost-benefit analyses and one was a partial analysis. All studies supported the use of WGS as a surveillance tool on economic grounds. The available evidence supports the use of WGS for pathogen surveillance but is limited by marked heterogeneity. Further work should include analysis relevant to low- and middle-income countries and should use real-world effectiveness data.

Colonization dynamics of extended-spectrum beta-lactamase-producing Enterobacterales in the gut of Malawian adults.

Drug-resistant bacteria of the order Enterobacterales which produce extended-spectrum beta-lactamase enzymes (ESBL-Enterobacterales, ESBL-E) are global priority pathogens. Antimicrobial stewardship interventions proposed to curb their spread include shorter courses of antimicrobials to reduce selection pressure but individual-level acquisition and selection dynamics are poorly understood. We sampled stool of 425 adults (aged 16-76 years) in Blantyre, Malawi, over 6 months and used multistate modelling and whole-genome sequencing to understand colonization dynamics of ESBL-E. Models suggest a prolonged effect of antimicrobials such that truncating an antimicrobial course at 2 days has a limited effect in reducing colonization. Genomic analysis shows largely indistinguishable diversity of healthcare-associated and community-acquired isolates, hence some apparent acquisition of ESBL-E during hospitalization may instead represent selection from a patient's microbiota by antimicrobial exposure. Our approach could help guide stewardship protocols; interventions that aim to review and truncate courses of unneeded antimicrobials may be of limited use in preventing ESBL-E colonization.

Differential Neutralization of Unfractionated Heparin and Enoxaparin by Andexanet Alfa.

INTRODUCTION: Andexanet alfa (andexanet) is an approved antidote used to reverse the bleeding effects of Direct Oral Anticoagulant (Direct-Xa agents) agents because it reverses anti-Xa activity. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) exhibit anti-Xa activity. The purpose is to investigate the neutralization of UFH and LMWH by andexanet in activated clotting time (ACT), thrombelastography (TEG), and anti-Xa due to the protamine sulfate shortage. METHODS: UFH and LMWH were studied with andexanet, PS, or saline as potential reversal agents/controls at varying concentrations in ACT, TEG, and anti-Xa and compared to each other. RESULTS: Andexanet partially neutralized both drugs several TEG parameters at high andexanet concentrations, but it was not as effective as protamine sulfate in any of the assays used. Most TEG parameters were correlated with andexanet concentration. In ACT, significant neutralization was demonstrated at many andexanet concentrations for UFH, but not LMWH. UFH was completely neutralized by PS in ACT, while LMWH was partially neutralized by PS in ACT. Andexanet alfa was a less effective neutralization agent than the protamine sulfate as it only partially neutralized UFH in ACT and was ineffective at neutralizing LMWH when tested at the same concentration as PS (10 ug/mL). CONCLUSION: Andexanet partially neutralized UFH and LMWH with variability between assays, necessitating investigation into assay-dependent differences.

The Relevance of Anti-PF4 Antibody Isotypes and Endogenous Glycosaminoglycans and their Relationship with Inflammatory Biomarkers in Pulmonary Embolism Patients.

INTRODUCTION: Previous studies have shown that inflammation may contribute to the interplay of endogenous glycosaminoglycans (GAGs) and anti-PF4 antibodies. In this study, we quantified the levels of anti-PF4 antibody isotypes and endogenous GAGs together with inflammatory biomarkers in pulmonary embolism (PE) patients to determine whether there is a relationship in between. Identification of this relationship may provide insight to the complex pathophysiology of PE and HIT and may also be useful for development of potential prognostic, diagnostic and therapeutic interventions. MATERIALS AND METHODS: Plasma samples from PE patients (n: 210) were analyzed for anti-PF4 antibody isotypes and various thrombo-inflammatory cytokines utilizing commercially available biochip array and ELISA methods. The endogenous GAG levels in PE patients' plasma were quantified using a fluorescence quenching method. The collected data analyzed to demonstrate the relationship between various parameters. RESULTS: The endogenous GAG levels were increased in the PE group (P < .05). The levels of anti-PF4 antibody isotypes were higher in varying levels in comparison to the normal group (P < .05). Inflammatory cytokines have shown varying levels of increase with IL-6, IL-8 and IL-10 showing the most pronounced values. Mortality outcome was related to increased GAGs and some of the cytokines. CONCLUSION: In this study, we demonstrated increased levels of anti-PF4 antibody isotypes, endogenous GAGs, and inflammatory biomarkers in a large patient cohort in PE. The levels of the endogenous GAGs and inflammatory biomarkers were associated with PE severity and mortality. More studies are needed to understand this complex pathophysiology.

Genomic and antigenic diversity of colonizing Klebsiella pneumoniae isolates mirrors that of invasive isolates in Blantyre, Malawi.

Members of the Klebsiella pneumoniae species complex, particularly K. pneumoniae subsp. pneumoniae are antimicrobial resistance (AMR) associated pathogens of global importance, and polyvalent vaccines targeting Klebsiella O-antigens are in development. Whole-genome sequencing has provided insight into O-antigen distribution in the K. pneumoniae species complex, as well as population structure and virulence determinants, but genomes from sub-Saharan Africa are underrepresented in global sequencing efforts. We therefore carried out a genomic analysis of extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae species complex isolates colonizing adults in Blantyre, Malawi. We placed these isolates in a global genomic context, and compared colonizing to invasive isolates from the main public hospital in Blantyre. In total, 203 isolates from stool and rectal swabs from adults were whole-genome sequenced and compared to a publicly available multicounty collection and previously sequenced Malawian and Kenyan isolates from blood or sterile sites. We inferred phylogenetic relationships and analysed the diversity of genetic loci linked to AMR, virulence, capsule and LPS O-antigen (O-types). We find that the diversity of Malawian K. pneumoniae subsp. pneumoniae isolates represents the species' population structure, but shows distinct local signatures concerning clonal expansions. Siderophore and hypermucoidy genes were more frequent in invasive versus colonizing isolates (present in 13 % vs 1 %) but still generally lacking in most invasive isolates. O-antigen population structure and distribution was similar in invasive and colonizing isolates, with O4 more common (14%) than in previously published studies (2-5 %). We conclude that host factors, pathogen opportunity or alternate virulence loci not linked to invasive disease elsewhere are likely to be the major determinants of invasive disease in Malawi. Distinct ST and O-type distributions in Malawi highlight the need to sample locations where the burden of invasive Klebsiella disease is greatest to robustly define secular trends in Klebsiella diversity to assist in the development of a useful vaccine. Colonizing and invasive isolates in Blantyre are similar, hence O-typing of colonizing Klebsiella isolates may be a rapid and cost-effective approach to describe global diversity and guide vaccine development.

Surgical interventions for treating extracapsular hip fractures in older adults: a network meta-analysis.

BACKGROUND: Hip fractures are a major healthcare problem, presenting a challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising. The majority of extracapsular hip fractures are treated surgically. OBJECTIVES: To assess the relative effects (benefits and harms) of all surgical treatments used in the management of extracapsular hip fractures in older adults, using a network meta-analysis of randomised trials, and to generate a hierarchy of interventions according to their outcomes. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Web of Science and five other databases in July 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing different treatments for fragility extracapsular hip fractures in older adults. We included internal and external fixation, arthroplasties and non-operative treatment. We excluded studies of hip fractures with specific pathologies other than osteoporosis or resulting from high-energy trauma. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. One review author completed data extraction which was checked by a second review author. We collected data for three outcomes at different time points: mortality and health-related quality of life (HRQoL) - both reported within 4 months, at 12 months and after 24 months of surgery, and unplanned return to theatre (at end of study follow-up). We performed a network meta-analysis (NMA) with Stata software, using frequentist methods, and calculated the differences between treatments using risk ratios (RRs) and standardised mean differences (SMDs) and their corresponding 95% confidence intervals (CIs). We also performed direct comparisons using the same codes. MAIN RESULTS: We included 184 studies (160 RCTs and 24 quasi-RCTs) with 26,073 participants with 26,086 extracapsular hip fractures in the review. The mean age in most studies ranged from 60 to 93 years, and 69% were women. After discussion with clinical experts, we selected nine nodes that represented the best balance between clinical plausibility and efficiency of the networks: fixed angle plate (dynamic and static), cephalomedullary nail (short and long), condylocephalic nail, external fixation, hemiarthroplasty, total hip arthroplasty (THA) and non-operative treatment. Seventy-three studies (with 11,126 participants) with data for at least two of these treatments contributed to the NMA. We selected the dynamic fixed angle plate as a reference treatment against which other treatments were compared. This was a common treatment in the networks, providing a clinically appropriate comparison.  We downgraded the certainty of the evidence for serious and very serious risks of bias, and because some of the estimates included the possibility of transitivity owing to the proportion of stable and unstable fractures between treatment comparisons. We also downgraded if we noted evidence of inconsistency in direct or indirect estimates from which the network estimate was derived. Most estimates included the possibility of benefits and harms, and we downgraded the evidence for these treatments for imprecision.  Overall, 20.2% of participants who received the reference treatment had died by 12 months after surgery. We noted no evidence of any differences in mortality at this time point between the treatments compared. Effect estimates of all treatments included plausible benefits as well as harms. Short cephalomedullary nails had the narrowest confidence interval (CI), with 7 fewer deaths (26 fewer to 15 more) per 1000 participants, compared to the reference treatment (risk ratio (RR) 0.97, 95% CI 0.87 to 1.07). THA had the widest CI, with 62 fewer deaths (177 fewer to 610 more) per 1000 participants, compared to the reference treatment (RR 0.69, 95% CI 0.12 to 4.03). The certainty of the evidence for all treatments was low to very low. Although we ranked the treatments, this ranking should be interpreted cautiously because of the imprecision in all the network estimates for these treatments. Overall, 4.3% of participants who received the reference treatment had unplanned return to theatre. Compared to this treatment, we found very low-certainty evidence that 58 more participants (14 to 137 more) per 1000 participants returned to theatre if they were treated with a static fixed angle plate (RR 2.48, 95% CI 1.36 to 4.50), and 91 more participants (37 to 182 more) per 1000 participants returned to theatre if treated with a condylocephalic nail (RR 3.33, 95% CI 1.95 to 5.68). We also found that these treatments were ranked as having the highest probability of unplanned return to theatre. In the remaining treatments, we noted no evidence of any differences in unplanned return to theatre, with effect estimates including benefits as well as harms. The certainty of the evidence for these other treatments ranged from low to very low. We did not use GRADE to assess the certainty of the evidence for early mortality, but our findings were similar to those for 12-month mortality, with no evidence of any differences in treatments when compared to dynamic fixed angle plate. Very few studies reported HRQoL and we were unable to build networks from these studies and perform network meta-analysis.  AUTHORS' CONCLUSIONS: Across the networks, we found that there was considerable variability in the ranking of each treatment such that there was no one outstanding, or subset of outstanding, superior treatments. However, static implants such as condylocephalic nails and static fixed angle plates did yield a higher risk of unplanned return to theatre. We had insufficient evidence to determine the effects of any treatments on HRQoL, and this review includes data for only two outcomes. More detailed pairwise comparisons of some of the included treatments are reported in other Cochrane Reviews in this series. Short cephalomedullary nails versus dynamic fixed angle plates contributed the most evidence to each network, and our findings indicate that there may be no difference between these treatments. These data included people with both stable and unstable extracapsular fractures. At this time, there are too few studies to draw any conclusions regarding the benefits or harms of arthroplasty or external fixation for extracapsular fracture in older adults. Future research could focus on the benefits and harms of arthroplasty interventions compared with internal fixation using a dynamic implant.

An Update on the Status of Vaccine Development for SARS-CoV-2 Including Variants. Practical Considerations for COVID-19 Special Populations.

The progress in the development of various vaccine platforms against SARS-CoV-2 have been rather remarkable owing to advancement in molecular and biologic sciences. Most of the current vaccines and those in development focus on targeting the viral spike proteins by generating antibodies of varying spectrum. These vaccines represent a variety of platforms including whole virus vaccines, viral vector vaccines, nucleic acid vaccines representing RNA, DNA, and their hybrid forms.The therapeutic efficacy of these vaccines varies owing to their pharmacodynamic individualities. COVID-19 variants are capable of inducing different pathologic responses and some of which may be resistant to antibodies generated by current vaccines. The current clinical use of these vaccines has been through emergency use authorization until recently. Moreover, the efficacy and safety of these vaccines have been tested in substantial numbers of individuals but studies in special populations that better reflect the global population are pending results. These specialized populations include young children, immunocompromised patients, pregnant individuals, and other specialized groups. Combination approaches, molecularly modified vaccination approaches, and vaccines conferring longer periods of immunity are being currently being investigated, as well as pharmacovigilance studies.The continual transformation of SARS-CoV-2 and its variants are of concern along with the breakthrough infections. These considerations pose new challenges for the development of vaccination platforms. For this purpose, booster doses, combination vaccine approaches, and other modalities are being discussed. This review provides an updated account of currently available vaccines and those in advanced development with reference to their composition and mechanisms of action.A discussion on the use of vaccines in special populations including immunocompromised patients, pregnant women and other specialized populations are also included.

A Longitudinal, Observational Study of Etiology and Long-Term Outcomes of Sepsis in Malawi Revealing the Key Role of Disseminated Tuberculosis.

BACKGROUND: Sepsis protocols in sub-Saharan Africa are typically extrapolated from high-income settings, yet sepsis in sub-Saharan Africa is likely caused by distinct pathogens and may require novel treatment strategies. Data to guide such strategies are lacking. We aimed to define causes and modifiable factors associated with sepsis outcomes in Blantyre, Malawi, in order to inform the design of treatment strategies tailored to sub-Saharan Africa. METHODS: We recruited 225 adults who met a sepsis case definition defined by fever and organ dysfunction in an observational cohort study at a single tertiary center. Etiology was defined using culture, antigen detection, serology, and polymerase chain reaction. The effect of treatment on 28-day outcomes was assessed using Bayesian logistic regression. RESULTS: There were 143 of 213 (67%) participants living with human immunodeficiency virus (HIV). We identified a diagnosis in 145 of 225 (64%) participants, most commonly tuberculosis (TB; 34%) followed by invasive bacterial infections (17%), arboviral infections (13%), and malaria (9%). TB was associated with HIV infection, whereas malaria and arboviruses with the absence of HIV infection. Antituberculous chemotherapy was associated with survival (adjusted odds ratio for 28-day death, 0.17; 95% credible interval, 0.05-0.49 for receipt of antituberculous therapy). Of those with confirmed etiology, 83% received the broad-spectrum antibacterial ceftriaxone, but it would be expected to be active in only 24%. CONCLUSIONS: Sepsis in Blantyre, Malawi, is caused by a range of pathogens; the majority are not susceptible to the broad-spectrum antibacterials that most patients receive. HIV status is a key determinant of etiology. Novel antimicrobial strategies for sepsis tailored to sub-Saharan Africa, including consideration of empiric antituberculous therapy in individuals living with HIV, should be developed and trialed.

Public Perceptions of Current COVID-19 Vaccinations. Results of a Pilot Survey.

INTRODUCTION: We conducted a cross-sectional survey as a part of an educational program in collaboration with the Global Thrombosis Forum (GTF), an affiliate of North American Thrombosis Forum (NATF), and Loyola University about public perceptions of COVID-19 and COVID-19 vaccinations in the US. In this study, we are reporting the results of this survey. MATERIALS AND METHODS: The survey, in the form of a questionnaire, has been developed by GTF and faculty members. A prepared questionnaire was sent to the members of the Georgia and Illinois communities. RESULTS: In our current study, the COVID-19 vaccine willingness rate was 94.5% and vaccination rate was 90.9%. In multivariate analysis believing to have enough information about the safety and efficacy of COVID-19 vaccines (OR: 3.730, 95% CI: 1.199-11.603, p: 0.023) and gender (OR: 0.123, 95% CI: 0.016-0.967, p: 0.046) were significant predictors for vaccine willingness. Previous COVID-19 infection (OR: 0.215, 95% CI: 0.061-0.758, p: 0.017), moderate and severe effects of COVID-19 pandemic on participant's life (OR: 4.631, 95% CI 1.681-12.760, p: 0.003) and believing to have enough information about the safety and efficacy of COVID-19 vaccines (OR: 4.119, 95% CI: 1.508-11.253, p: 0.006) were significant predictors for final vaccination status. CONCLUSION: In conclusion, currently vaccination remains one of the most effective tools in the fight against the COVID-19 pandemic. The vaccine hesitancy is a complex phenomenon that is driven by individuals' perceptions of safety, and efficiency of the vaccines. We must continue to educate the public and communities that vaccines are safe, that they are effective and that they are still required even after a COVID-19 infection.

CPAP delivered outside critical care during the second wave of COVID-19: outcomes from a UK respiratory surge unit.

BACKGROUND: NHS England recommends non-invasive continuous positive airway pressure (CPAP) as a possible treatment for type 1 respiratory failure associated with COVID-19 pneumonitis, either to avoid intubation or as a ceiling of care. However, data assessing this strategy are sparse, especially for the use of CPAP as a ceiling of care, and particularly when delivered outside of a traditional critical care environment. We describe a cohort of patients from Liverpool, UK, who received CPAP on a dedicated respiratory surge unit at the start of the second wave of the COVID-19 pandemic in UK. METHODS: Retrospective cohort analysis of consecutive patients receiving CPAP for the treatment of respiratory failure secondary to COVID-19 on the respiratory surge unit at the Royal Liverpool Hospital, Liverpool, UK from 21 September until 30 November 2020. RESULTS: 88 patients were included in the analysis. 56/88 (64%) were deemed suitable for escalation to invasive mechanical ventilation (IMV) and received CPAP as a trial; 32/88 (36%) received CPAP as a ceiling of care. Median age was 63 years (IQR: 56-74) and 58/88 (66%) were men. Median SpO2/FiO2 immediately prior to CPAP initiation was 95 (92-152). Among patients for escalation to IMV, the median time on CPAP was 6 days (IQR 4-7) and survival at day 30 was 84% (47/56) with 14/56 (25%) escalated to IMV. Of those patients for whom CPAP was ceiling of care, the median duration of CPAP was 9 days (IQR 7-11) and 18/32 (56%) survived to day 30. Pulmonary barotrauma occurred in 9% of the cohort. There were no associations found on multivariant analysis that were associated with all-cause 30-day mortality. CONCLUSIONS: With adequate planning and resource redistribution, CPAP may be delivered effectively outside of a traditional critical care setting for the treatment of respiratory failure due to COVID-19. Clinicians delivering CPAP to patients with COVID-19 pneumonitis should be alert to the dangers of pulmonary barotrauma. Among patients who are for escalation of care, the use of CPAP may avoid the need for IMV in some patients. Our data support the NHS England recommendation to consider CPAP as a ceiling of care.

The COVID-19 Pandemic and the Need for an Integrated and Equitable Approach: An International Expert Consensus Paper.

BACKGROUND: One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. MANAGEMENT: Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. CURRENT ISSUES: The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. PERSPECTIVES: There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). CONCLUSION: The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

An Update on the Pathogenesis of COVID-19 and the Reportedly Rare Thrombotic Events Following Vaccination.

Today the coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global health problem. After more than a year with the pandemic, although our knowledge has progressed on COVID-19, there are still many unknowns in virological, pathophysiological and immunological aspects. It is obvious that the most efficient solution to end this pandemic are safe and efficient vaccines. This manuscript summarizes the pathophysiological and thrombotic features of COVID-19 and the safety and efficacy of currently approved COVID-19 vaccines with an aim to clarify the recent concerns of thromboembolic events after COVID-19 vaccination. The influx of newer information is rapid, requiring periodic updates and objective assessment of the data on the pathogenesis of COVID-19 variants and the safety and efficacy of currently available vaccines.