Estimating Prevalence and Infection Intensity of Soil-Transmitted Helminths Using Quantitative Polymerase Chain Reaction and Kato-Katz in School-Age Children in Angola.

Quantitative polymerase chain reaction (qPCR) is gaining recognition in soil-transmitted helminth (STH) diagnostics, especially for Strongyloides stercoralis and differentiating hookworm species. However, sample preservation and DNA extraction may influence qPCR performance. We estimated STH prevalence and infection intensity by using qPCR in schoolchildren from Huambo, Uige, and Zaire, Angola, and compared its performance with that of the Kato-Katz technique (here termed Kato-Katz). Stool samples from 3,063 children (219 schools) were preserved in 96% ethanol and analyzed by qPCR, of which 2,974 children (215 schools) had corresponding Kato-Katz results. Cluster-adjusted prevalence and infection intensity estimates were calculated by qPCR and Kato-Katz, with cycle threshold values converted to eggs per gram for qPCR. Cohen's kappa statistic evaluated agreement between qPCR and Kato-Katz. DNA extraction and qPCR were repeated on 191 (of 278) samples that were initially qPCR negative but Kato-Katz positive, of which 112 (58.6%) became positive. Similar prevalence for Ascaris lumbricoides (37.5% versus 34.6%) and Trichuris trichiura (6.5% versus 6.1%) were found by qPCR and Kato-Katz, respectively, while qPCR detected a higher hookworm prevalence (11.9% versus 2.9%). The prevalence of moderate- or high-intensity infections was higher by Kato-Katz than by qPCR. Agreement between qPCR and Kato-Katz was very good for A. lumbricoides, moderate for T. trichiura, and fair for hookworm. Strongyloides stercoralis prevalence was 4.7% (municipality range, 0-14.3%), and no Ancylostoma ceylanicum was detected by qPCR. Despite suboptimal performance, presumably due to fixative choice, qPCR was fundamental in detecting S. stercoralis and excluding zoonotic A. ceylanicum. Further evaluations on sample fixatives and DNA extraction methods are needed to optimize and standardize the performance of qPCR.

Invasive fungal disease in children with solid tumors: An Australian multicenter 10-year review.

Invasive fungal disease (IFD) occurs less frequently during treatment for solid compared to hematological malignancies in children, and risk groups are poorly defined. Retrospective national multicenter cohort data (2004-2013) were analyzed to document prevalence, clinical characteristics, and microbiology of IFD. Amongst 2067 children treated for solid malignancy, IFD prevalence was 1.9% overall and 1.4% for proven/probable IFD. Of all IFD episodes, 42.5% occurred in patients with neuroblastoma (prevalence 7.0%). Candida species comprised 54.8% of implicated pathogens in proven/probable IFD. In children with solid tumors, IFD is rare, and predominantly caused by yeasts.Routine prophylaxis may not be warranted.

Are serious games seriously good at preparing students for clinical practice?: A randomized controlled trial.

PURPOSE: Serious games (SGs) have great potential for pediatric medical education. This study evaluated the efficacy of a SG in improving learner satisfaction, knowledge, and behavior. MATERIALS AND METHODS: This was an investigator-blinded randomized controlled trial (RCT) comparing a SG against two controls: (i) adaptive tutorial (AT), and (ii) low-stimulus control (LSC). SG is a highly immersive role-playing game in a virtual hospital. AT delivers interactive web-based lessons. LSC is paper-based clinical practice guidelines. Metropolitan senior medical students at UNSW were eligible. A total of 154 enrolled and were block randomized to one intervention. Participants had access to one intervention for 8 weeks which taught pediatric acute asthma and seizure assessment and management. Satisfaction was assessed with Likert-scale responses to 5 statements and 2 free-text comments. Knowledge was assessed with 10 multiple-choice questions (MCQs). Clinical behavior was assessed during a 30-point simulated clinical management scenario (CMS). Primary analysis was performed on a modified intention-to-treat basis and compared: (1) SG vs. AT; and (2) SG vs. LSC. RESULTS: A total of 118 participants were included in the primary analysis (modified intention-to-treat model). No significant differences in MCQ results between the SG and control groups. SG group outperformed the LSC group in the CMS, with a moderate effect (score out of 30: 20.8 (3.2) vs. 18.7 (3.2), respectively, d = 0.65 (0.2-1.1), p = 0.005). No statistically significant difference between SG and AT groups in the CMS (score: 20.8 (3.2) vs. 19.8 (3.1), respectively, d = 0.31 (-0.1 to 0.8), p = 0.18). A sensitivity analysis (per-protocol model) was performed with similar outcomes. CONCLUSIONS: This is the first investigator-blinded RCT assessing the efficacy of a highly immersive SG on learner attitudes, knowledge acquisition, and performance in simulated pediatric clinical scenarios. The SG demonstrated improved translation of knowledge to a simulated clinical environment, particularly compared to LSC. SGs show promise in pediatric medical education.

Risk Factors and Clinical Prognosis Associated With RSV-ALRI Intensive Care Unit Admission in Children <2 Years of Age: A Multicenter Study.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRIs) in children aged <2 years. Currently, there are limited data on risk factors for very severe RSV-ALRI requiring intensive care unit (ICU) admission. METHODS: We conducted a case-control study of children aged <2 years admitted with RSV-ALRI to the Sydney Children's Hospital Network, comprising 2 large tertiary pediatric hospitals. Cases were children with laboratory-confirmed RSV-ALRI admitted to ICU, and controls were (1:2, matched on date of admission) children hospitalized with RSV-ALRI but not requiring ICU transfer. Data on risk factors were retrieved from the electronic medical record system. Adjusted odds ratios (aORs) with 95% confidence intervals (95% CI) associated with risk factors for ICU admission and the association with clinical and treatment factors were determined from logistic regression models. RESULTS: A total of 44 (44%) of 100 cases and 90 (48.1%) of 187 controls were male. Age <6 months and preterm births were associated with a 2.10-fold (95% CI: 1.14-3.79) and 2.35-fold (95% CI: 1.26-4.41) increased risk in ICU admissions, respectively. The presence of any chronic health condition was a significant risk factor for ICU admission. The clinical presentations on admission more commonly seen in cases were apnea (aOR: 5.01, 95% CI: 1.50-17.13) and respiratory distress (aOR: 15.91, 95% CI: 4.52-55.97). Cases were more likely to be hospitalized for longer duration and require respiratory support. CONCLUSIONS: Our results can be translated into a clinical risk algorithm to identify children at risk of very severe RSV disease.

Protocol for spatial prediction of soil transmitted helminth prevalence in the Western Pacific region using a meta-analytical approach.

BACKGROUND: Soil transmitted helminth (STH) infections are estimated to impact 24% of the world's population and are responsible for chronic and debilitating morbidity. Disadvantaged communities are among the worst affected and are further marginalized as infection prevalence fuels the poverty cycle. Ambitious targets have been set to eliminate STH infections, but accurate epidemiological data will be required to inform appropriate interventions. This paper details the protocol for an analysis that aims to produce spatial prediction mapping of STH prevalence in the Western Pacific Region (WPR). METHODS: The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P) guidelines. The study design will combine the principles of systematic review, meta-analysis, and geospatial analysis. Systematic searches will be undertaken in PubMed, Scopus, ProQuest, Embase, and Web of Science for studies undertaken post 2000, to identify surveys that enable the prevalence of human STH infection within the WPR to be calculated. Covariate data for multivariable analysis will be obtained from publicly accessible sources. Survey data will be geolocated, and STH prevalence and covariates will be linked to produce a spatially referenced dataset for analysis. Bayesian model-based geostatistics will be used to generate spatially continuous estimates of STH prevalence mapped to a resolution of 1 km2. A separate geospatial model will be constructed for each STH species. Predictions of prevalence will be made for unsampled locations and maps will be overlaid for each STH species to obtain co-endemicity maps. DISCUSSION: This protocol facilitates study replication and may be applied to other infectious diseases or alternate geographies. Results of the subsequent analysis will identify geographies with high STH prevalence's and can be used to inform resource allocation in combating this neglected tropical disease. TRIAL REGISTRATION: Open Science Framework: osf.io/qmxcj.

Clinical, Genomic, and Immunological Characterization of RSV Surge in Sydney, Australia, 2022.

OBJECTIVES: The 2022 seasonal respiratory syncytial virus (RSV) epidemic in Sydney, Australia saw an unprecedented number of RSV detections. We aimed to characterize genomic and immunologic factors associated with the surge in RSV cases. METHODS: Whole genome sequences of RSV were generated from 264 RSV-infected infants and linked to case-matched clinical data from the 2022 southern hemisphere RSV season. We then performed an immunologic analysis of baseline RSV-specific humoral immunity in women of childbearing age before and throughout the coronavirus disease 2019 pandemic. RESULTS: Clinical analysis revealed a high burden of disease across patients of all health backgrounds. More than one-half of RSV-related health care visits by infants resulted in hospitalization, and one-quarter required high-flow respiratory support or a higher level of care. Viral phylogenetic analyses revealed that 2022 Sydney RSV sequences were closely related to viruses that had been circulating globally since 2017, including those detected in recent US outbreaks. Nonsynonymous mutations within the palivizumab and nirsevimab binding sites were detected at low frequencies. There was no difference in baseline RSV-neutralizing antibody titers between 2020 and 2022. CONCLUSIONS: Collectively, these findings suggest that neither the emergence of a novel RSV genotype nor hypothesized immune debt was associated with the surge of RSV cases and hospitalizations in 2022. Continued genomic and immunologic surveillance is required to further understand the factors driving outbreaks of RSV globally, and to inform guidelines for the rollout and ongoing use of recently developed immunotherapeutics and vaccines.

Knowledge, attitudes, practices and acceptability of a school preventive chemotherapy programme for schistosomiasis and soil-transmitted helminths control in Angola.

Schistosomiasis and soil-transmitted helminth (STH) control programs require target population engagement, assessed through knowledge, attitudes and practices (KAP) surveys. We report the results of a KAP survey of Angolan schoolchildren supported by a school preventive chemotherapy (PC) programme, without or with a school water, sanitation and hygiene (WASH) programme (PC+/WASH- and PC+/WASH+, respectively); and schoolchildren without a school PC or WASH program (PC-/WASH-). Schoolchildren from PC+/WASH- (N = 218), PC+/WASH+ (N = 250) and PC-/WASH- (N = 254) schools were interviewed. Descriptive statistics were used to report demographics and survey responses. Chi-square or Fisher's exact test was used to compare PC+/WASH- schoolchildren with (i) PC+/WASH+ and (ii) PC-/WASH- schoolchildren. A lower proportion of PC+/WASH- schoolchildren used latrines and a higher proportion practised open defecation at school compared with PC+/WASH+ schoolchildren. A lower proportion of PC+/WASH- schoolchildren always washed their hands after toileting and before meals at school compared with PC+/WASH+ schoolchildren. However, the PC+/WASH- schoolchildren reported better toileting and handwashing practices at school compared to PC-/WASH- schoolchildren. Over 90% of PC+ schoolchildren agreed with schistosomiasis and STH control and accepted schoolteacher PC delivery. Expanding the integration of both school PC and WASH programs will improve health behaviours relevant to reduce the risk of schistosomiasis and STHs in schoolchildren. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

A unique cytotoxic CD4+ T cell-signature defines critical COVID-19.

Objectives: SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T-cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T-cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. Methods: Immunophenotyping of T-cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID-19 clinical presentation. Computational and manual analyses were used to identify T-cell populations associated with distinct disease states. Results: Critical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+ lymphocytes (CTL). These CD4+ CTLs were largely absent in asymptomatic to severe disease states. In contrast, non-critical COVID-19 was associated with high frequencies of naïve T cells and lack of activation marker expression. Conclusion: Highly activated and cytotoxic CD4+ T-cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Induction of these potentially detrimental T-cell responses should be considered when developing and implementing effective COVID-19 control strategies.

School-based preventive chemotherapy program for schistosomiasis and soil-transmitted helminth control in Angola: 6-year impact assessment.

BACKGROUND: A school preventive chemotherapy (PC) program for soil-transmitted helminths (STHs) and schistosomiasis has operated in Huambo, Uige and Zaire provinces, Angola, since 2013 and 2014, respectively; complemented by a school water, sanitation and hygiene (WASH) program in a subset of schools from 2016. Conducted in 2021, this is the first impact assessment of the school program for the control of schistosomiasis and STHs. METHODOLOGY/PRINCIPAL FINDINGS: A two-stage cluster design was used to select schools and schoolchildren for parasitological and WASH surveys. The rapid diagnostic tests (RDTs), point of care circulating cathodic antigen (POC-CCA) and Hemastix, were used to estimate Schistosoma mansoni and Schistosoma haematobium prevalence, respectively. Kato Katz was used to detect STHs, and quantify STH and S. mansoni infections. Urine filtration was used to quantify S. haematobium infections. Prevalence, infection intensity, relative prevalence reduction and egg reduction rates were calculated for schistosomiasis and STHs. Cohen's Kappa co-efficient was used to assess agreement between RDTs and microscopy. Chi-square or Fisher's exact test was used to compare WASH indicators in WASH-supported and WASH-unsupported schools. Overall, 17,880 schoolchildren (599 schools) and 6,461 schoolchildren (214 schools) participated in the schistosomiasis and STH surveys, respectively. Prevalence of any schistosomiasis in Huambo was 29.6%, Uige 35.4%, and Zaire 28.2%. Relative reduction in schistosomiasis prevalence from 2014 for Huambo was 18.8% (95% confidence interval (CI) 8.6, 29.0), Uige -92.3% (95%CI -162.2, -58.3), and Zaire -14.0% (95%CI -48.6, 20.6). Prevalence of any STH in Huambo was 16.3%, Uige 65.1%, and Zaire 28.2%. Relative reduction in STH prevalence for Huambo was -28.4% (95%CI -92.1, 35.2), Uige -10.7% (95%CI -30.2, 8.8), and Zaire -20.9% (95%CI -79.5, 37.8). A higher proportion of WASH-supported schools had improved water sources, and toilet and handwashing facilities compared to WASH-unsupported schools. CONCLUSIONS/SIGNIFICANCE: The limited impact this school program has had in controlling schistosomiasis and STHs identifies the need for a comprehensive understanding of individual, community, and environmental factors associated with transmission, and consideration for a community-wide control program.

Detection of dengue virus infection in children presenting with fever in Hawassa, southern Ethiopia.

Dengue fever is a mosquito-borne viral infection, with rising incidence globally. Eastern Ethiopia has had dengue fever outbreaks in recent years. However, the extent to which the infection contributes to hospital presentation among children with fever in southern Ethiopia is unknown. We examined 407 stored plasma samples collected to investigate the aetiology of fever in children aged at least 2 months and under 13 years presenting to the outpatient of the largest tertiary hospital in southern Ethiopia. We analyzed samples for dengue virus non-structural 1 antigen using enzyme-linked immunosorbent assay. The median (interquartile range) age of the 407 children examined was 20 (10-48) months, and 166 (40.8%) of the children were females. Of 407 samples analyzed, 9 (2.2%) were positive for dengue virus non-structural 1 antigen, of whom 2 were initially treated with antimalarial drugs despite having negative malaria microscopy, and 1 of the 8 patients had a persistent fever at the seventh day of follow-up time. The presence of active dengue virus infection in the study area highlights the need for studies at the community level as well as the integration of dengue diagnostics into fever-management strategies. Further research to characterize circulating strains is warranted.

High activation levels maintained in receptor-binding domain-specific memory B cells in people with severe coronavirus disease 2019.

The long-term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are still being understood. The molecular and phenotypic properties of SARS-CoV-2 antigen-specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen-specific memory B-cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID-19). Here, we performed single-cell molecular analysis of the SARS-CoV-2 receptor-binding domain (RBD)-specific MBC population in three patients after severe COVID-19 and four patients after mild/moderate COVID-19. We analyzed the transcriptomic and B-cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor-alpha (TNF-α) signaling via nuclear factor-kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hi TNFAIP3hi and CD11chi CD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long-term RBD-specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID-19 severity.

Days alive and out of hospital after laparoscopic cholecystectomy.

BACKGROUND: Days alive and out of hospital (DAOH) is a metric that incorporates several outcomes into a single, standardized measure. This study aimed to explore the utility of DAOH in assessing the outcomes of a retrospective cohort of patients undergoing laparoscopic cholecystectomy (LC). METHODS: Patients undergoing LC at Auckland City Hospital between 1 January 2010 and 31 August 2015 were included. DAOH values were calculated for the 90 days from the date of surgery (DAOH90 ) and described using median and interquartile ranges (IQR). DAOH90 distributions were compared using a two-tailed (non-parametric) Wilcoxon-Mann-Whitney test. RESULTS: 1652 patients undergoing LC were studied. Patients experiencing complications (n = 70, 4.2%) had fewer DAOH90 (median 83, IQR 79, 86) than patients who underwent uncomplicated LC (median 88, IQR 86, 88), P < 0.001. Patients who were converted to open cholecystectomy (n = 70, 4.2%) also had fewer DAOH90 (median 82.5, IQR 79, 84) than patients who underwent uncomplicated LC, P < 0.001. Post-operative complications and conversion had a statistically significant effect on DAOH90 at each of the tested quantiles, except for conversion at the 0.1 quantile. CONCLUSION: DAOH90 is readily calculable from existing New Zealand administrative data sources and is sensitive to the occurrence of complications after LC.

Transarterial Radioembolization for Hepatic Metastases of Pancreatic Adenocarcinoma: A Systematic Review.

PURPOSE: To assess the safety and effectiveness of transarterial radioembolization (TARE) in the treatment of hepatic metastases from pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: A systematic search of the Embase and MEDLINE databases was conducted using keywords and Medical Subject Headings terms related to TARE and hepatic metastases from PDAC. Observational studies and clinical trials reporting overall survival (OS), hepatic progression-free survival (hPFS), or tumor response after TARE were included. RESULTS: Eight studies, comprising 145 patients with metastatic PDAC, met the inclusion criteria. No randomized controlled trials were identified, and 4 studies were prospective. Forty-four (30.3%) patients underwent previous pancreatic resection, and 66 (45.5%) had extrahepatic metastases at the time of TARE. Most studies (n = 6) used resin microspheres for TARE. The pooled disease control rate was 69.4% at a median of 3 months. The median OS from the time of TARE ranged from 3.7 to 9 months. The median hPFS ranged from 2.4 to 5.2 months. There were 31 Grade 3-4 biochemical toxicities and 4 treatment-related deaths. CONCLUSIONS: The role of TARE in patients with hepatic metastases from PDAC remains unclear owing to low patient numbers, limited prospective data, and heterogeneity in the study design. Further prospective studies are required to evaluate the role of TARE in carefully selected patients with liver-only metastatic disease.

Portal vein embolization with absolute ethanol to induce hypertrophy of the future liver remnant.

BACKGROUND: Preoperative portal vein embolization (PVE) is widely used prior to major liver resection to reduce the risk of post-hepatectomy liver failure (PHLF). We evaluated the efficacy and safety of PVE using absolute ethanol. METHODS: Consecutive patients undergoing preoperative PVE between February 2003 and February 2020 at a high-volume tertiary institution were retrospectively reviewed. Hypertrophy of the future liver remnant (FLR) was determined by comparing volumetric data using semi-automated software on computed tomography or magnetic resonance imaging before and after PVE. Efficacy of absolute ethanol was evaluated by the percentage increase in the FLR volume and the ratio of the FLR to the total liver volume (TLV). Technical success and complications following PVE were evaluated. Feasibility of hepatectomy following PVE and the incidence of PHLF were determined. RESULTS: Sixty-two patients underwent preoperative PVE using absolute ethanol. The technical success rate was 95.2%. Median time interval between PVE and follow-up imaging was 34 days (range 6-144 days). The mean increase in FLR volume and ratio of the FLR to TLV were 43.6 ± 34.4% and 12.3 ± 7.7% respectively. Major adverse events occurred in 3 cases (4.8%) and did not preclude consideration of surgery. Forty-two patients (67.8%) proceeded to surgery for intended hepatectomy of which 36 patients (58.1%) underwent liver resection. Major post-operative complications occurred in 4 patients (11.1%) and there were no cases of PHLF. CONCLUSION: Preoperative PVE with absolute ethanol is effective and safe in inducing hypertrophy of the FLR before partial hepatectomy to prevent PHLF.

Burden and factors associated with schistosomiasis and soil-transmitted helminth infections among school-age children in Huambo, Uige and Zaire provinces, Angola.

BACKGROUND: Schistosomiasis and soil-transmitted helminths (STHs) contribute high disease burdens amongst the neglected tropical diseases (NTDs) and are public health problems in Angola. This study reports the prevalence, intensity and risk factors for schistosomiasis and STH infection in Huambo, Uige and Zaire provinces, Angola, to inform a school-based preventive chemotherapy program. METHODS: A two-stage cluster design was used to select schools and schoolchildren to participate in parasitological and water, sanitation and hygiene (WASH) surveys across Huambo, Uige, and Zaire provinces. Point-of-care circulating cathodic antigen and urinalysis rapid diagnostic tests (RDTs) were used to determine the prevalence of Schistosoma mansoni and S. haematobium, respectively. Kato-Katz was used to identify and quantify STH species and quantify and compare with RDTs for S. mansoni. Urine filtration was used to quantify and compare with RDTs for S. haematobium. Descriptive statistics were used for prevalence and infection intensity of schistosomiasis and STH infection. Performance of RDTs was assessed through specificity and Cohen's Kappa agreement with microscopy. A multivariate regression analysis was used to determine demographic and WASH factors associated with schistosomiasis and STH infection. RESULTS: A total 575 schools and 17,093 schoolchildren participated in the schistosomiasis survey, of which 121 schools and 3649 schoolchildren participated in the STH survey. Overall prevalence of S. mansoni was 21.2% (municipality range 0.9-74.8%) and S. haematobium 13.6% (range 0-31.2%), with an overall prevalence of schistosomiasis of 31.4% (range 5.9-77.3%). Overall prevalence of Ascaris lumbricoides was 25.1% (range 0-89.7%), hookworm 5.2% (range 0-42.6%), and Trichuris trichiura 3.6% (range 0-24.2%), with an overall prevalence of STH infection of 29.5% (range 0.8-89.7%). Ecological zone and ethnicity were factors associated with schistosomiasis and STH infection, with older age and female sex additional risk factors for S. haematobium. CONCLUSIONS: Most municipalities met World Health Organization defined prevalence thresholds for a schistosomiasis preventive chemotherapy program. A STH preventive chemotherapy program is indicated for nearly all municipalities in Uige and select municipalities in Huambo and Zaire. The association between ecological zone and ethnicity with schistosomiasis and STH infection necessitates further evaluation of home and school environmental, sociodemographic and behavioural factors to inform targeted control strategies to complement preventive chemotherapy programs.

Clinical management and outcomes of acute febrile illness in children attending a tertiary hospital in southern Ethiopia.

BACKGROUND: The management of febrile illnesses is challenging in settings where diagnostic laboratory facilities are limited, and there are few published longitudinal data on children presenting with fever in such settings. We have previously conducted the first comprehensive study of infectious aetiologies of febrile children presenting to a tertiary care facility in Ethiopia. We now report on clinicians' prescribing adherence with guidelines and outcomes of management in this cohort. METHODS: We consecutively enrolled febrile children aged 2 months and under 13 years, who were then managed by clinicians based on presentation and available laboratory and radiologic findings on day of enrolment. We prospectively collected outcome data on days 7 and 14, and retrospectively evaluated prescribing adherence with national clinical management guidelines. RESULTS: Of 433 children enrolled, the most common presenting syndromes were pneumonia and acute diarrhoea, diagnosed in 177 (40.9%) and 82 (18.9%), respectively. Antibacterial agents were prescribed to 360 (84.7%) of 425 children, including 36 (34.0%) of 106 children without an initial indication for antibacterials according to guidelines. Antimalarial drugs were prescribed to 47 (11.1%) of 425 children, including 30 (7.3%) of 411 children with negative malaria microscopy. Fever had resolved in 357 (89.7%) of 398 children assessed at day 7, and in-hospital death within 7 days occurred in 9 (5.9%) of 153 admitted patients. Among children with pneumonia, independent predictors of persisting fever or death by 7 days were young age and underweight for age. Antibacterial prescribing in the absence of a guideline-specified indication (overprescribing) was more likely among infants and those without tachypnea, while overprescribing antimalarials was associated with older age, anaemia, absence of cough, and higher fevers. CONCLUSION: Our study underscores the need for improving diagnostic support to properly guide management decisions and enhance adherence by clinicians to treatment guidelines.

Totally extraperitoneal laparoscopic inguinal hernia repair post-radical prostatectomy.

BACKGROUND: Previous radical prostatectomy (RP) is considered a relative contraindication to the laparoscopic approach for inguinal hernia repair (LIHR). This study aimed to compare feasibility, safety and outcomes for patients undergoing totally extraperitoneal (TEP) LIHR who have previously undergone RP. METHODS: This single surgeon, case-control study was performed using a prospective database of all patients undergoing TEP LIHR between 1995 and 2020. Patients who underwent previous RP were identified and compared to matched controls. Pre-operative, operative and post-operative data were analysed. The type of RP, open, laparoscopic or robotic, was identified and operative outcomes compared between the three groups. RESULTS: 6532 LIHR cases were identified. 165 had previously undergone RP and 6367 had undergone primary LIHR without prior RP. The groups were matched for age, demographics and co-morbidities. All operations were commenced laparoscopically, three converted to open in the LIHR + RP group and none in the LIHR group. Median operative time in patients with previous RP was longer, for unilateral (40 min vs. 21 min, p < 0.0001) and bilateral (71 vs. 30 min, p < 0.0001) LIHR. The majority of cases were performed as day stay procedures. There was no difference in immediate recovery parameters including time to discharge, complication rates, return to normal function, return to driving or post-operative analgesia. At 3 months of follow-up there was no difference in hernia recurrence for unilateral (2/128 vs 6/2234, p = 0.0658) or bilateral (0/24 vs 3/1490, p ≥ 0.999) LIHR, nor chronic pain as measured by patient awareness or restriction of activity. No differences in operative and post-operative outcomes were identified between the three types of RP, other than difference in operative time (p = 0.0336). CONCLUSIONS: Previous RP should not be an absolute contraindication for TEP LIHR. Although previous RP adds complexity, in experienced hands TEP LIHR can be done safely, with outcomes equivalent to patients who have not previously undergone RP.

Severe COVID-19 represents an undiagnosed primary immunodeficiency in a high proportion of infected individuals.

Since the emergence of the COVID-19 pandemic in early 2020, a key challenge has been to define risk factors, other than age and pre-existing comorbidities, that predispose some people to severe disease, while many other SARS-CoV-2-infected individuals experience mild, if any, consequences. One explanation for intra-individual differences in susceptibility to severe COVID-19 may be that a growing percentage of otherwise healthy people have a pre-existing asymptomatic primary immunodeficiency (PID) that is unmasked by SARS-CoV-2 infection. Germline genetic defects have been identified in individuals with life-threatening COVID-19 that compromise local type I interferon (IFN)-mediated innate immune responses to SARS-CoV-2. Remarkably, these variants - which impact responses initiated through TLR3 and TLR7, as well as the response to type I IFN cytokines - may account for between 3% and 5% of severe COVID-19 in people under 70 years of age. Similarly, autoantibodies against type I IFN cytokines (IFN-α, IFN-ω) have been detected in patients' serum prior to infection with SARS-CoV-2 and were found to cause c. 20% of severe COVID-19 in the above 70s and 20% of total COVID-19 deaths. These autoantibodies, which are more common in the elderly, neutralise type I IFNs, thereby impeding innate antiviral immunity and phenocopying an inborn error of immunity. The discovery of PIDs underlying a significant percentage of severe COVID-19 may go some way to explain disease susceptibility, may allow for the application of targeted therapies such as plasma exchange, IFN-α or IFN-ß, and may facilitate better management of social distancing, vaccination and early post-exposure prophylaxis.