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Background The hospital environment is characterised by a dense network of interactions between healthcare workers (HCWs) and patients. As highlighted by the coronavirus pandemic, this represents a risk for disease transmission and a challenge for contact tracing. We aimed to develop and pilot an automated system to address this challenge and describe contacts between HCWs and patients. Methods We developed a bespoke Bluetooth Low Energy (BLE) system for the hospital environment with anonymous tags worn by HCWs and fixed receivers at patient room doors. Proximity between wearable tags inferred contact between HCWs. Tag-receiver interactions inferred patient room entry and exit by HCWs. We performed a pilot study in four negative pressure isolation rooms from 13 April to 18 April 2021. Nursing and medical staff who consented to participate were able to collect one of ten wearable BLE tags during their shift. Results Over the four days, when divided by shift times, 27 nursing tags and 3 medical tags were monitored. We recorded 332 nurse–nurse interactions, for a median duration of 58 s [interquartile range (IQR): 39–101]. We recorded 45 nursing patient room entries, for a median 7 min [IQR: 3–21] of patient close contact. Patient close contact was shorter in rooms on airborne precautions, compared to those not o transmission-based precautions. Conclusion This pilot study supported the functionality of this approach to quantify HCW proximity networks and patient close contact. With further refinements, the system could be scaled-up to support contact tracing in high-risk environments.

Many studies have found that borderline personality disorder (BPD) is associated with romantic relationship instability, with relationship dissolution being a recurring theme. Scant research, however, has examined the dissolution strategies and post-breakup outcomes for individuals with elevated levels of borderline traits. Findings from two studies revealed that there was an association between BPD criteria and tendency to employ less adaptive dissolution strategies when terminating a relationship. Furthermore, elevated levels of BPD traits were associated with less self-concept clarity and more unwanted pursuit of ex-partners. These findings both provide insight into how individuals with BPD traits experience relationship dissolution and suggest possible factors underlying the unstable relationship processes typically associated with borderline traits.

Introduction Annually more than 100,000 Japanese encephalitis (JE) cases and 25,000 deaths worldwide are caused by JE virus infection. More than 15 JE vaccines are currently in use worldwide. It is unknown whether any of the vaccines is superior to the others in terms of immunogenicity and safety. Methods Four databases were systematically searched for randomised controlled trials that compared two or more types of JE vaccines. Vaccines were classified into four classes: inactivated mouse brain-derived (oldest class), inactivated Vero cell, live chimeric, and live attenuated. Network meta-analysis was used to generate mixed effect estimates against inactivated mouse brain-derived vaccines for seroconversion, and against placebo for adverse event (AE) and severe adverse event (SAE). Results 23 studies (38,496 participants) were included. All newer vaccine classes had better immunogenicity, the difference was statistically significant for inactivated Vero cell (OR = 2.98; 95 %CI: 1.02–8.65) and live chimeric (OR = 5.93; 95 %CI: 1.73–20.32) vaccines. Inactivated mouse-derived vaccines had the highest odds for AEs (OR = 2.27; 95 %CI: 1.59–3.23), the odds of AE of newer vaccines was not different to placebo. There was no difference in SAEs across vaccine classes. Conclusions All newer JE vaccines have comparable safety profiles, live chimeric and inactivated Vero cell vaccines are the most immunogenic among the newer vaccine classes.

Common lung diseases are first diagnosed using chest X-rays. Here, we show that a fully automated deep-learning pipeline for the standardization of chest X-ray images, for the visualization of lesions and for disease diagnosis can identify viral pneumonia caused by coronavirus disease 2019 (COVID-19) and assess its severity, and can also discriminate between viral pneumonia caused by COVID-19 and other types of pneumonia. The deep-learning system was developed using a heterogeneous multicentre dataset of 145,202 images, and tested retrospectively and prospectively with thousands of additional images across four patient cohorts and multiple countries. The system generalized across settings, discriminating between viral pneumonia, other types of pneumonia and the absence of disease with areas under the receiver operating characteristic curve (AUCs) of 0.94-0.98; between severe and non-severe COVID-19 with an AUC of 0.87; and between COVID-19 pneumonia and other viral or non-viral pneumonia with AUCs of 0.87-0.97. In an independent set of 440 chest X-rays, the system performed comparably to senior radiologists and improved the performance of junior radiologists. Automated deep-learning systems for the assessment of pneumonia could facilitate early intervention and provide support for clinical decision-making.

Zika virus (ZIKV) has caused large, brief outbreaks in isolated populations, however ZIKV can also persist at low levels over multiple years. The reasons for these diverse transmission dynamics remain poorly understood. In Fiji, which has experienced multiple large single-season dengue epidemics, there was evidence of multi-year transmission of ZIKV between 2013 and 2017. To identify factors that could explain these differences in dynamics between closely related mosquito-borne flaviviruses, we jointly fit a transmission dynamic model to surveillance, serological and molecular data. We estimate that the observed dynamics of ZIKV were the result of two key factors: strong seasonal effects, which created an ecologically optimal time of year for outbreaks; and introduction of ZIKV after this optimal time, which allowed ZIKV transmission to persist over multiple seasons. The ability to jointly fit to multiple data sources could help identify a similar range of possible outbreak dynamics in other settings., Dengue and Zika virus are closely related flaviviruses but can have contrasting transmission dynamics in the same populations. Here, the authors use a model combining serological, surveillance and viral sequence data to explain differences in transmission dynamics in Fiji.

Over 892 million people in 48 countries are at risk of infection by nematodes that cause lymphatic filariasis. As part of the Global Programme to Eliminate Lymphatic Filariasis, mass drug administration is distributed to communities until surveillance indicates infection rates are below target prevalence thresholds. In some countries, including American Samoa, lymphatic filariasis transmission persists despite years of mass drug administration and/or has resurged after cessation. Nothing is known about the population genetics of Wuchereria bancrofti worms in Polynesia, or whether local transmission is persisting and/or increasing due to inadequate mass drug administration coverage, expansion from residual hotspots, reintroduction from elsewhere, or a combination. We extracted DNA from microfilariae on blood slides collected during prevalence surveys in 2014 and 2016, comprising 31 pools of five microfilariae from 22 persons living in eight villages. We sequenced 1104 bp across three mitochondrial markers (ND4, COI, CYTB). We quantified parasite genetic differentiation using variant calls and estimated haplotypes using principal components analysis, F-statistics, and haplotype networks. Of the variants called, all but eight were shared across the main island of Tutuila, and three of those were from a previously described hotspot village, Fagali’i. Genotypic data did not support population genetic structure among regions or villages in 2016, although differences were observed between worms collected in Fagali’i in 2014 and those from 2016. Because estimated haplotype frequency varied between villages, these statistics suggested genetic differentiation, but were not consistent among villages. Finally, haplotype networks demonstrated American Samoan sequence clusters were related to previously published sequences from Papua New Guinea. These are, to our knowledge, the first reports of W. bancrofti genetic variation in Polynesia. The resurgent parasites circulating on the main island of American Samoa represent a single population. This study is the first step towards investigating how parasite population structure might inform strategies to manage resurgence and elimination of lymphatic filariasis.

Background Management of primary cutaneous malignant melanoma is with initial excision biopsy followed by a wide local excision to achieve locoregional control. For low-risk thin melanomas, the added survival benefit from the wide local excision is minimal. In this study, we investigated the morbidities of wide local excision and evaluated the current clinical practice in managing stage IA malignant melanoma. Methods Patients with confirmed stage IA malignant melanoma who had undergone a wide local excision in the 2013/14 period were identified using a specialist cancer multidisciplinary team-held database. Primary pathology, surgical data and follow-up documentation were analysed. Results A total of 231 cases were identified; 95% of patients (n = 220) had malignant melanoma excised completely at first excision biopsy, mean margin 2.8mm (range 0.5–8.0mm). Postoperative morbidities occurred in 25% of patients (n = 57), including 6.6% wound problems, 10.9% scarring problems, 10.0% psychological stress and 0.4% cosmetic concern. Wide local excision reconstructions were performed with primary closure in 82% of patients, split skin grafts in 4%, full-thickness skin grafts in 3% and flaps in 10%. Of the total, 44% of patients (n = 101) had further excisions and 17 received new low-risk melanoma diagnoses. Conclusions We demonstrated that 1cm wide local excision is associated with significant morbidity, which can affect patients’ physical, psychological and social wellbeing. Since wide local excision does not give a survival advantage, and its margin is already frequently reduced in cosmetically sensitive areas, the need for a second full 1cm wide local excision procedure for thin melanoma should be re-evaluated, especially when 95% of our study cohort had their malignant melanoma completely excised by the initial biopsy alone.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

The 2019 novel coronavirus disease (COVID‐19) pandemic has been spreading worldwide at an alarming rate. Health‐care workers have been confronted with the challenge of not only treating patients with the virus, but also managing the disruption of health‐care services caused by COVID‐19. In anticipation of outbreak, clinic sessions and operation theater lists have been actively cut back since February 2020 to reduce hospital admissions and clinic attendances. This has severely disrupted health‐care services, leading to accumulating clinic caseload and substantial delays for operations. The head and neck cancer service has been faced with the difficult task of managing the balance between infection risk to health‐care providers and the risk of disease progression from prolonged waiting times. We share our experience in Hong Kong on the mitigation of head and neck cancer service disruption through telehealth and multi‐institution collaboration.

Onchocerciasis and lymphatic filariasis are targeted for elimination, primarily using mass drug administration at the country and community levels. Elimination of transmission is the onchocerciasis target and global elimination as a public health problem is the end point for lymphatic filariasis. Where program duration, treatment coverage, and compliance are sufficiently high, elimination is achievable for both parasites within defined geographic areas. However, transmission has re-emerged after apparent elimination in some areas, and in others has continued despite years of mass drug treatment. A critical question is whether this re-emergence and/or persistence of transmission is due to persistence of local parasites—i.e., the result of insufficient duration or drug coverage, poor parasite response to the drugs, or inadequate methods of assessment and/or criteria for determining when to stop treatment—or due to re-introduction of parasites via human or vector movement from another endemic area. We review recent genetics-based research exploring these questions in Onchocerca volvulus, the filarial nematode that causes onchocerciasis, and Wuchereria bancrofti, the major pathogen for lymphatic filariasis. We focus in particular on the combination of genomic epidemiology and genome-wide associations to delineate transmission zones and distinguish between local and introduced parasites as the source of resurgence or continuing transmission, and to identify genetic markers associated with parasite response to chemotherapy. Our ultimate goal is to assist elimination efforts by developing easy-to-use tools that incorporate genetic information about transmission and drug response for more effective mass drug distribution, surveillance strategies, and decisions on when to stop interventions to improve sustainability of elimination.

ObjectiveTo evaluate the dynamics of the oral microbiome and associated patient outcomes following treatment of head and neck squamous cell carcinoma (HNSCC).Materials and MethodsThis was a prospective cohort study at a tertiary academic center in Hong Kong SAR of patients with head and neck squamous cell carcinoma evaluating the oral microbiome in pre- and postsurgery oral rinses (at 1, 3, and 6 months) with 16S rRNA gene V3–V4 amplicon sequencing.ResultsIn total, 76 HNSCC patients were evaluated. There was a significantly depressed alpha diversities of oral microbial communities observed in HNSCC oral rinse samples within the first 6 months post-surgery when compared to presurgery or healthy controls. Distant clustering between pre- and postsurgery was also observed (p < 0.022). Following treatment, eight oral bacterial genera showed a trend towards the restoration in the relative abundances that approximate healthy persons. In evaluating patient outcomes, the decreased relative abundance of three periodontal bacteria (Capnocytophaga, Prevotella 7, and Leptotrichia) and the increased relative abundance of two commensal bacteria (Streptococcus and Rothia) at 6 months postsurgery compared to presurgery showed a better 3-year disease-specific survival (a cutoff of Kaplan–Meier survival curve test p < 0.3 at 36 months). In particular, the postsurgery restoration of Prevotella 7 was statistically significant in the surveyed patients (survival rate of 84% vs. 56% at 36 months, p = 0.0065).ConclusionsOral microbiome dysbiosis associated with HNSCC is dynamic. These dynamics of the oral microbiome postsurgery are also associated with patient treatment and outcomes and may serve as potential biomarkers for patient management in HNSCC.

Lymph node metastasis is the most reliable indicator of a poor prognosis for patients with oral tongue cancers. Currently, there are no biomarkers to predict whether a cancer will spread in the future if it has not already spread at the time of diagnosis. The aim of this study was to quantitatively profile the proteomes of extracellular vesicles (EVs) isolated from blood samples taken from patients with oral tongue squamous cell carcinoma with and without lymph node involvement and non-cancer controls. EVs were enriched using size exclusion chromatography (SEC) from pooled plasma samples of patients with non-nodal and nodal oral tongue squamous cell carcinoma (OTSCC) and non-cancer controls. Protein cargo was quantitatively profiled using isobaric labelling (iTRAQ) and two-dimensional high-performance liquid chromatography followed by tandem mass spectrometry. We identified 208 EV associated proteins and, after filtering, generated a short list of 136 proteins. Over 85% of the EV-associated proteins were associated with the GO cellular compartment term “extracellular exosome”. Comparisons between non-cancer controls and oral tongue squamous cell carcinoma with and without lymph node involvement revealed 43 unique candidate EV-associated proteins with deregulated expression patterns. The shortlisted EV associated proteins described here may be useful discriminatory biomarkers for differentiating OTSCC with and without nodal disease or non-cancer controls.

Background Ross River virus (RRV) is a zoonotic alphavirus transmitted by several mosquito species. Until recently, endemic transmission was only considered possible in the presence of marsupial reservoirs. Methods RRV seroprevalence was investigated in placental mammals (including horses, cows, goats, pigs, dogs, rats, and mice) in Fiji, where there are no marsupials. A total of 302 vertebrate serum samples were collected from 86 households from 10 communities in Western Fiji. Results Neutralizing antibodies against RRV were detected in 28% to 100% of sera depending on the species, and neutralization was strong even at high dilutions. Conclusions These results are unlikely to be due to cross-reactions. Chikungunya is the only other alphavirus known to be present in the Pacific Islands, but it rarely spills over into non-humans, even during epidemics. The study findings, together with a recent report of high RRV seroprevalence in humans, strongly suggest that RRV is circulating in Fiji in the absence of marsupial reservoirs. Considering that all non-human vertebrates present in Fiji are pan-global in distribution, RRV has the potential to further expand its geographic range. Further surveillance of RRV and access to RRV diagnostics will be critical for the early detection of emergence and outbreaks.

In this study, a spatially-explicit agent-based modelling framework GEOFIL was developed to predict lymphatic filariasis (LF) transmission dynamics in American Samoa. GEOFIL included individual-level information on age, gender, disease status, household location, household members, workplace/school location and colleagues/schoolmates at each time step during the simulation. In American Samoa, annual mass drug administration from 2000 to 2006 successfully reduced LF prevalence dramatically. However, GEOFIL predicted continual increase in microfilaraemia prevalence in the absence of further intervention. Evidence from seroprevalence and transmission assessment surveys conducted from 2010 to 2016 indicated a resurgence of LF in American Samoa, corroborating GEOFIL’s predictions. The microfilaraemia and antigenaemia prevalence in 6-7-yo children were much lower than in the overall population. Mosquito biting rates were found to be a critical determinant of infection risk. Transmission hotspots are likely to disappear with lower biting rates. GEOFIL highlights current knowledge gaps, such as data on mosquito abundance, biting rates and within-host parasite dynamics, which are important for improving the accuracy of model predictions. Keywords: Lymphatic filariasis, Agent-based modelling, Commuting networks, Spatial heterogeneity, Disease dynamics, Vector-borne diseases

Significance Huntington’s disease (HD) is a devastating neurodegenerative disorder caused by expansion of a polyglutamine repeat within the huntingtin (HTT) protein. A normal function of HTT is that of a scaffold for selective autophagy, a mechanism of protein and organelle degradation by the lysosome required for neuronal health. Here, we show that the inflammatory IκB kinase (IKK) kinase subunit IKKβ may function in vivo to regulate autophagy through direct phosphorylation of HTT at serine 13 and through the activation of autophagy gene expression. IKKβ is required to slow HD behavioral progression and to suppress neurodegeneration and microglial activation in HD transgenic mice. Our work suggests that the early activation of IKK may be protective to activate autophagy, thereby slowing HD progression., Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

International audience; A unique outbreak of Ross River virus (RRV) infection was reported in Fiji in 1979. In 2013, RRV seroprevalence among residents was 46.5% (362/778). Of the residents who were seronegative in 2013 and retested in 2015, 10.9% (21/192) had seroconverted to RRV, suggesting ongoing endemic circulation of RRV in Fiji.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of patients with HD and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex. Of these targets, SG components were enriched, including the SG-nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of the brains of patients with HD. Intriguingly, we also observed that the SG-associated TAR DNA-binding protein 43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1 granule-positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.

Background Chemoprophylaxis with weekly doses of tafenoquine (200 mg/day for 3 days before departure [loading dose], 200 mg/week during travel and 1-week post-travel [maintenance doses]) is effective in preventing malaria. Effectiveness of malaria chemoprophylaxis drugs in travellers is often compromised by poor compliance. Shorter schedules that can be completed before travel, allowing ‘drug-free holidays’, could increase compliance and thus reduce travel-related malaria. In this meta-analysis, we examined if a loading dose of tafenoquine alone is effective in preventing malaria in short-term travellers. Methods Four databases were searched in November 2020 for randomized controlled trials (RCTs) that assessed efficacy and/or safety of tafenoquine for chemoprophylaxis. Network meta-analysis using the generalized pair-wise modelling framework was utilized to estimate the odds ratio (OR) of malaria infection in long-term (>28 days) and short-term (≤28 days) travellers, as well as adverse events (AEs) associated with receiving loading dose of tafenoquine alone, loading dose of tafenoquine followed by maintenance doses, loading dose of mefloquine followed by maintenance doses, or placebo. Results Nine RCTs (1714 participants) were included. In long-term travellers, compared to mefloquine, tafenoquine with maintenance doses (OR = 1.05; 95% confidence interval [CI]: 0.44–2.46) was equally effective in preventing malaria, while there was an increased risk of infection with the loading dose of tafenoquine alone (OR = 2.89; 95% CI: 0.78–10.68) and placebo (OR = 62.91; 95% CI: 8.53–463.88). In short-term travellers, loading dose of tafenoquine alone (OR = 0.98; 95% CI: 0.04–22.42) and tafenoquine with maintenance doses (OR = 1.00; 95% CI: 0.06–16.10) were as effective as mefloquine. The risk of AEs with tafenoquine with maintenance doses (OR = 1.03; 95% CI: 0.67–1.60) was similar to mefloquine, while loading dose of tafenoquine alone (OR = 0.58; 95% CI: 0.20–1.66) was associated with lower risk of AEs, although the difference was not statistically significant. Conclusions For short-term travellers, loading dose of tafenoquine alone was equally effective, had possibly lower rate of AEs, and likely better compliance than standard tafenoquine or mefloquine chemoprophylaxis schedules with maintenance doses. Studies are needed to confirm if short-term travellers remain free of infection after long-term follow-up. Registration The meta-analysis was registered in PROSPERO (CRD42021223756). Highlight Tafenoquine is the latest approved drug for malaria chemoprophylaxis. A loading dose of tafenoquine (200 mg/day for 3 days before departure) is as effective in preventing malaria in short-term (≤28 days) travellers as chemoprophylaxis schedules of tafenoquine or mefloquine with maintenance doses, allowing travellers to have a ‘drug-free holiday’.

Following the first triple-drug MDA for lymphatic filariasis in Samoa in 2018, unexpected persistence of Mf-positivity in 18 (15%) of 121 antigen-positive persons was observed in a nationwide household survey 1-2 months later, raising concerns about MDA efficacy. In 2019, a monitored treatment study was done before and 7 days after directly observed weight-based treatment. Mf presence and density were evaluated using 1 mL membrane filtered venous blood, and 60uL thick blood films on slides prepared from venous or fingerprick blood. All 14 participants were still Mf positive on filters from venous blood pre-treatment samples, but two were negative by slide made from the same samples. Mf were cleared completely by day 7 in 12 of 13 participants followed up, and by day 30 in the remaining participant. Filtered blood using EDTA samples (to reduce clumping of Mf) is preferred over slides alone for improving the likelihood of detecting Mf and estimating their density. The triple-drug MDA strategy was effective at clearing Mf by day 30 when given and taken at the correct dose.

Background Current guidelines for rabies pre-exposure prophylaxis (PrEP) recommend multiple vaccine doses. Travellers sometimes present for pre-travel consultation with insufficient time to complete standard PrEP schedules. We investigated the efficacy of one-dose intramuscular (IM) vaccine in priming the immune system (as PrEP) by measuring antibody response to simulated post-exposure prophylaxis (PEP). Methods A quasi-experimental pre–post intervention clinical trial was conducted at a specialist travel clinic in Australia. Adults (≥18 years) without a history of rabies vaccination were included. At Visit 1, seronegative status was confirmed and one dose of 0.5 ml IM rabies vaccine (Verorab®) administered. At Visit 2 (≥60 days after Visit 1), serology was repeated and a simulated PEP dose (0.5 ml IM) given on this day and again 3 days later (Visit 3). Serology was repeated at Visit 4 (7 days after Visit 2). Results A total of 94 antibody-negative participants were included (4 EU/ml, respectively. Conclusions One-dose IM vaccine was effective as PrEP for priming the immune system in both age groups, resulting in rapid development of antibodies 7 days after commencing simulated PEP. If there is insufficient time to complete a standard PrEP schedule, one-dose IM could be considered as an alternative schedule for short trips, rather than not offering travellers any doses at all. Clinical trials registration: ACTRN12619000946112.

Following the first triple-drug mass drug administration (MDA) for lymphatic filariasis in Samoa in 2018, unexpected persistence of microfilaria (Mf) positivity in 18 (15%) of 121 antigen-positive persons was observed in a nationwide household survey 1–2 months later. Of the 18 Mf positive persons, 14 reported taking the MDA, raising concerns about MDA efficacy. In 2019, 5–6 months after the 2018 survey, a monitored treatment study was done to evaluate directly observed weight-based treatment in these Mf positive individuals. Mf presence and density were assessed before and 7 days after treatment, using 1 mL membrane filtered venous blood, and 60 uL thick blood films on slides prepared from venous or fingerprick blood. All 14 participants were still Mf positive on filters from venous blood pre-treatment samples, but two were negative by slide made from the same samples. Mf were cleared completely by day 7 in 12 of 13 participants followed up, and by day 30 in the remaining participant. Filtered blood using EDTA samples (to reduce clumping of Mf) is preferred over slides alone for improving the likelihood of detecting Mf and estimating their density. The triple-drug MDA strategy was effective at clearing Mf when given and taken at the correct dose.

Lung ischemia-reperfusion injury (LIRI) and primary graft dysfunction are leading causes of morbidity and mortality among lung transplant recipients. Although extensive research endeavors have been undertaken, few preventative and therapeutic treatments have emerged for clinical use. Novel strategies are still needed to improve outcomes after lung transplantation. In this review, we discuss the underlying mechanisms of transplanted LIRI, potential modifiable targets, current practices, and areas of ongoing investigation to reduce LIRI and primary graft dysfunction in lung transplant recipients.

BACKGROUND Management of patients with infective endocarditis (IE) is complex and associated with a high mortality and morbidity. Both European and American Societies of Cardiology recommend implementation of an infective endocarditis team (IET) involving multiple specialities including cardiology, infectious diseases, cardiac surgery, neurology, and addiction medicine. The objective of this study was to evaluate the clinical outcomes before and after implementation of such a team at our institution. METHODS AND RESULTS An observational before-and-after study was conducted on 89 consecutive patients with definite IE treated at one tertiary care center between July 2019 and April 2021. The study was divided into two periods: before (n=54) and after (n=39) implementation of the IET on July 1, 2020. The IET consisted of cardiologists with expertise in echocardiography, infectious diseases specialists, cardiac surgeons, and included involvement by a neurologist, radiologist, microbiologist, addiction medicine specialist, and/or intensivist as necessary. The patients’ attending physicians were also invited to participate in discussion. Weekly meetings were conducted, and recommendations were provided to the treating team regarding further investigation or medical and/or surgical therapy. The IET was able to meet every week as well as when needed to discuss ad-hoc cases. Importantly, it also enabled the discussion of cases from referring community hospitals. Baseline demographic, echo, and microbiologic characteristics were similar between the before and after groups (Table) except a trend towards a lower proportion of patients with systemic embolization after implementation of the IET (36% vs. 52%, p=0.10). The IET led to involvement of a cardiac surgeon in all cases, compared to only in 76% previously. The proportion who were ultimately considered for surgery overall (54% vs. 76%, p CONCLUSION Implementation of a multidisciplinary IET is feasible within a Canadian hospital setting and facilitates routine and timely consultation with cardiovascular and infectious diseases experts. The IET led to a borderline significant reduction in the time from consultation to surgery in patients whom urgent surgery was indicated. These results are preliminary and ongoing study is required to characterize the longer-term outcomes of the IET.

BACKGROUND Centres that perform percutaneous coronary intervention (PCI) have resources specialized in the care of ST-elevation myocardial infarction (STEMI) patients both during and after PCI. Due to limited hospital resources, many centres that perform PCI have adopted protocols where STEMI patients are transferred to a non-PCI capable centre following successful PCI. However, the safety of this practice is not well established. The study objective is to evaluate the clinical outcomes of the current practice of transferring patients to non-PCI capable centres following successful PCI in a single, tertiary care regional PCI centre. METHODS AND RESULTS A retrospective analysis was performed of all consecutive STEMI patients presenting to a single, regional cardiac care centre between January 2013 and December 2014. STEMI patients with high-risk features including cardiac arrest, cardiogenic shock, medical complication nof STEMI, requiring transvenous pacing, mechanical ventiliation, mechanical circulatory support or not reperfused by PCI were excluded. Patients who were unable to be linked to the Provincial Population Registry were also excluded. Patients were analyzed based on whether they were transferred to a non-PCI capable centre following PCI for ongoing post-STEMI care. Clinical presentation, comorbidities, angiographic findings, revascularization, and repatriation status data were collected from the electronic medical record and cath lab database. Study data was linked to the Research Repository at the Manitoba Centre for Health Policy for long-term clinical outcomes. Of the 1092 consecutive STEMI patients screened, 337 patients (31%) were excluded (Figure). The final study cohort (n=697) included 397 repatriated patients and 300 non-repatriated patients. The median age of the study cohort was 60 (53-70) years. Baseline characteristics are summarized in the Table. The median length of stay at the PCI-capable hospital was 139 minutes (IQR 97-235 minutes) with 84% of patients transferred within 6 hours. Inverse probability of treatment weighting (IPTW) was used to adjust for unbalanced characteristics between the two study groups. All-cause mortality (12.9% admitted vs 10.4% repatriated patients, adjusted HR 0.90, 95% CI 0.64-1.26, p=0.535) and repeat MI (11.0% admitted vs 5.4% repatriated, adjusted HR 0.71, 95% CI 0.49-1.02, p=0.06) at 5 years were not statistically significant after IPTW adjustment, respectively. CONCLUSION This analysis demonstrated that there is no increased risk of mortality or repeat MI at five years in STEMI patients who are transferred to a non-PCI capable centre following successful PCI. This suggests that early repatriation is safe and effective for low-risk STEMI patients.

Lymphatic filariasis (LF) is a major public health problem globally and in the Pacific Region. The Global Programme to Eliminate LF has made great progress but LF is persistent and resurgent in some Pacific countries and territories. Samoa remains endemic for LF despite elimination efforts through multiple two-drug mass drug administrations (MDA) since 1965, including renewed elimination efforts started in 1999 under the Pacific Programme for Elimination of LF (PacELF). Despite eight rounds of national and two rounds of subnational MDA under PacELF, Samoa failed transmission assessment surveys (TAS) in all three evaluation units in 2017. In 2018, Samoa was the first to distribute countrywide triple-drug MDA using ivermectin, diethylcarbamazine (DEC), and albendazole. This paper provides a review of MDAs and historical survey results from 1998 to 2017 in Samoa and highlights lessons learnt from LF elimination efforts, including challenges and potential ways to overcome them to successfully achieve elimination.

[No abstract available] Scopus

Background: Neonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries (LMICs). We therefore completed a systematic review and meta-analysis of available data from all LMICs since 2010, with a focus on regional differences in Gram-negative infections and AMR. Methods: All studies published from 2010 with microbiologically confirmed bloodstream infections or meningitis in neonates and AMR from LMICs were assessed for eligibility. Small case series or number of Gram-negative isolates (

Background Considerable progress towards controlling malaria has been made in Papua New Guinea through the national malaria control programme’s free distribution of long-lasting insecticidal nets, improved diagnosis with rapid diagnostic tests and improved access to artemisinin combination therapy. Predictive prevalence maps can help to inform targeted interventions and monitor changes in malaria epidemiology over time as control efforts continue. This study aims to compare the predictive performance of prevalence maps generated using Bayesian decision network (BDN) models and multilevel logistic regression models (a type of generalized linear model, GLM) in terms of malaria spatial risk prediction accuracy. Methods Multilevel logistic regression models and BDN models were developed using 2010/2011 malaria prevalence survey data collected from 77 randomly selected villages to determine associations of Plasmodium falciparum and Plasmodium vivax prevalence with precipitation, temperature, elevation, slope (terrain aspect), enhanced vegetation index and distance to the coast. Predictive performance of multilevel logistic regression and BDN models were compared by cross-validation methods. Results Prevalence of P. falciparum, based on results obtained from GLMs was significantly associated with precipitation during the 3 driest months of the year, June to August (β = 0.015; 95% CI = 0.01–0.03), whereas P. vivax infection was associated with elevation (β = − 0.26; 95% CI = − 0.38 to − 3.04), precipitation during the 3 driest months of the year (β = 0.01; 95% CI = − 0.01–0.02) and slope (β = 0.12; 95% CI = 0.05–0.19). Compared with GLM model performance, BDNs showed improved accuracy in prediction of the prevalence of P. falciparum (AUC = 0.49 versus 0.75, respectively) and P. vivax (AUC = 0.56 versus 0.74, respectively) on cross-validation. Conclusions BDNs provide a more flexible modelling framework than GLMs and may have a better predictive performance when developing malaria prevalence maps due to the multiple interacting factors that drive malaria prevalence in different geographical areas. When developing malaria prevalence maps, BDNs may be particularly useful in predicting prevalence where spatial variation in climate and environmental drivers of malaria transmission exists, as is the case in Papua New Guinea.

Background: Public health surveillance is crucial for supporting a rapid and effective response to public health emergencies. In response to the coronavirus disease (COVID-19) pandemic, an enhanced surveillance system of hospitalised COVID-19 patients was established by the Victorian Department of Health and Human Services (DHHS) and the Victorian Healthcare Associated Infection Surveillance System Coordinating Centre. The system aimed to reduce workforce capacity constraints and increase situational awareness on the status of hospitalised patients. Methods: The system was evaluated, using guidelines from the United States Centers for Disease Control and Prevention, against eight attributes: acceptability; data quality; flexibility; representativeness; simplicity; stability; timeliness; and usefulness. Evidence was generated from stakeholder consultation, participant observation, document review, systems review, issues log review and audits. Data were collected and analysed over a period of up to three months, covering pre- and post-implementation from March to June 2020. Results: This system was rapidly established by leveraging established relationships and infrastructure. Stakeholders agreed that the system was important but was limited by a reliance on daily manual labour (including weekends), which impeded scalability. The ability of the system to perform well in each attribute was expected to shift with the severity of the pandemic; however, at the time of this evaluation, when there were an average 23 new cases per day (0.3 cases per 100,000 population per day), the system performed well. Conclusion: This enhanced surveillance system was useful and achieved its key DHHS objectives during the COVID-19 public health emergency in Victoria. Recommendations for improvement were made to the current and future systems, including the need to plan alternatives to improve the system’s scalability and to maintain stakeholder acceptability.

Less than a third of Australian travellers who attended a travel medicine specialist prior to a trip to a Japanese encephalitis (JE) risk area opted to be vaccinated. Perception of low risk of the disease and vaccine cost were possible drivers for the low uptake. Cheaper vaccination alternatives for travellers at risk of JE may increase the uptake.

The Global Programme to Eliminate Lymphatic Filariasis has made considerable progress but is experiencing challenges in meeting targets in some countries. Recent World Health Organization guidelines have recommended two rounds of triple-drug therapy with ivermectin, diethylcarbamazine (DEC), and albendazole (IDA), in areas where mass drug administration (MDA) results with two drugs (DEC and albendazole) have been suboptimal, as is the case in Samoa. In August 2018, Samoa was the first country in the world to implement countrywide triple-drug MDA. This paper aims to describe Samoa’s experience with program coverage and adverse events (AEs) in the first round of triple-drug MDA. We conducted a large cross-sectional community survey to assess MDA awareness, reach, compliance, coverage and AEs in September/October 2018, 7–11 weeks after the first round of triple-drug MDA. In our sample of 4420 people aged ≥2 years (2.2% of the population), age-adjusted estimates indicated that 89.0% of the eligible population were offered MDA, 83.9% of the eligible population took MDA (program coverage), and 80.2% of the total population took MDA (epidemiological coverage). Overall, 83.8% (2986/3563) reported that they did not feel unwell at all after taking MDA. Mild AEs (feeling unwell but able to do normal everyday things) were reported by 13.3% (476/3563) and moderate or severe AEs (feeling unwell and being unable to do normal everyday activities such as going to work or school) by 2.9% (103/3563) of participants. This study following the 2018 triple-drug MDA in Samoa demonstrated a high reported program awareness and reach of 90.8% and 89.0%, respectively. Age-adjusted program coverage of 83.9% of the total population showed that MDA was well accepted and well tolerated by the community., Author summary Lymphatic filariasis is a disease caused by worms and transmitted between humans by mosquitoes. A global program underway aims to eliminate lymphatic filariasis as a public health problem by distributing two deworming drugs to the whole population once a year for at least five years. In some countries, including Samoa, this strategy has not been sufficient to eliminate transmission. A new drug has been added, and in 2018, Samoa was the first country in the world to distribute country-wide triple-drug mass drug administration (MDA) using ivermectin, diethylcarbamazine, and albendazole. This study reports on the coverage achieved (percentage of people who reported taking the drugs) and adverse events after taking the drugs. The study was a large community survey of over 4000 people, done 7–11 weeks after the distribution of the first round of triple-drug MDA. We found that the program reached and offered MDA to approximately 90% of the whole population, and approximately 80% of the whole population swallowed the drugs. We also collected data on whether people felt unwell after taking the pills, and found that 84% of people taking the pills did not feel unwell at all, while 13% reported feeling unwell afterwards but were able to do normal everyday activities, and 3% reported that they had felt unwell and that it stopped them doing normal everyday activities, such as going to school or work.

The global elimination of lymphatic filariasis (LF) is a major focus of the World Health Organization. One key challenge is locating residual infections that can perpetuate the transmission cycle. We show how a targeted sampling strategy using predictions from a geospatial model, combining random forests and geostatistics, can improve the sampling efficiency for identifying locations with high infection prevalence. Predictions were made based on the household locations of infected persons identified from previous surveys, and environmental variables relevant to mosquito density. Results show that targeting sampling using model predictions would have allowed 52% of infections to be identified by sampling just 17.7% of households. The odds ratio for identifying an infected individual in a household at a predicted high risk compared to a predicted low risk location was 10.2 (95% CI 4.2–22.8). This study provides evidence that a ‘one size fits all’ approach is unlikely to yield optimal results when making programmatic decisions based on model predictions. Instead, model assumptions and definitions should be tailored to each situation based on the objective of the surveillance program. When predictions are used in the context of the program objectives, they can result in a dramatic improvement in the efficiency of locating infected individuals.

Highlight Uptake of Japanese encephalitis (JE) vaccine remains low among travellers, with cost of vaccines likely being one of the main hurdles. We found that smaller doses of JE vaccine administered via intradermal (ID) had similar effect on seroconversion than standard doses administered via subcutaneous. ID is a cheaper yet effective route of JE vaccine administration, and could potentially increase vaccination uptake among travellers.

There are a myriad of vaccine schedules for rabies pre- (PrEP) and post-exposure prophylaxis (PEP) that differ in the number and timedoses, number of visits, length of schedule, and route of administration. The objective of this study was to systematically review the evidence and investigate how thedifferences in schedules influence titres over time. Four databaseswere searched from inception to January 2020 for rabies PrEP and PEP studies. Adose-response meta-analysis was utilised to pool geometric mean titres (GMT) over time. Subgroup analyses by route of administration, age group, and schedule were conducted. 80 studies met the inclusion criteria and contributed with 191 datasets and 12,413 participants. Both intradermal (ID) and intramuscular (IM) PrEP/PEP produce adequate GMTs. Significantly lower GMT levels were achieved in older (>50yrs) compared to younger (

Background Samoa conducted eight nationwide rounds of mass drug administration (MDA) for lymphatic filariasis (LF) between 1999 and 2011, and two targeted rounds in 2015 and 2017 in North West Upolu (NWU), one of three evaluation units (EUs). Transmission Assessment Surveys (TAS) were conducted in 2013 (failed in NWU) and 2017 (all three EUs failed). In 2018, Samoa was the first in the world to distribute nationwide triple-drug MDA using ivermectin, diethylcarbamazine, and albendazole. Surveillance and Monitoring to Eliminate LF and Scabies from Samoa (SaMELFS Samoa) is an operational research program designed to evaluate the effectiveness of triple-drug MDA on LF transmission and scabies prevalence in Samoa, and to compare the usefulness of different indicators of LF transmission. This paper reports results from the 2018 baseline survey and aims to i) investigate antigen (Ag) prevalence and spatial epidemiology, including geographic clustering; ii) compare Ag prevalence between two different age groups (5–9 years versus ≥10 years) as indicators of areas of ongoing transmission; and iii) assess the prevalence of limb lymphedema in those aged ≥15 years. Methods A community-based cluster survey was conducted in 30 randomly selected and five purposively selected clusters (primary sampling units, PSUs), each comprising one or two villages. Participants were recruited through household surveys (age ≥5 years) and convenience surveys (age 5–9 years). Alere Filariasis Test Strips (FTS) were used to detect Ag, and prevalence was adjusted for survey design and standardized for age and gender. Adjusted Ag prevalence was estimated for each age group (5–9, ≥10, and all ages ≥5 years) for random and purposive PSUs, and by region. Intraclass correlation (ICC) was used to quantify clustering at regions, PSUs, and households. Results A total of 3940 persons were included (1942 children aged 5–9 years, 1998 persons aged ≥10 years). Adjusted Ag prevalence in all ages ≥5 years in randomly and purposively selected PSUs were 4.0% (95% CI 2.8–5.6%) and 10.0% (95% CI 7.4–13.4%), respectively. In random PSUs, Ag prevalence was lower in those aged 5–9 years (1.3%, 95% CI 0.8–2.1%) than ≥10 years (4.7%, 95% CI 3.1–7.0%), and poorly correlated at the PSU level (R-square = 0.1459). Adjusted Ag prevalence in PSUs ranged from 0% to 10.3% (95% CI 5.9–17.6%) in randomly selected and 3.8% (95% CI 1.3–10.8%) to 20.0% (95% CI 15.3–25.8%) in purposively selected PSUs. ICC for Ag-positive individuals was higher at households (0.46) compared to PSUs (0.18) and regions (0.01). Conclusions Our study confirmed ongoing transmission of LF in Samoa, in accordance with the 2017 TAS results. Ag prevalence varied significantly between PSUs, and there was poor correlation between prevalence in 5–9 year-olds and older ages, who had threefold higher prevalence. Sampling older age groups would provide more accurate estimates of overall prevalence, and be more sensitive for identifying residual hotspots. Higher prevalence in purposively selected PSUs shows local knowledge can help identify at least some hotspots., Author summary Lymphatic filariasis (LF), a disease caused by infection with worms transmitted by mosquitoes, has long been present in Samoa. Since the 1960s, Samoa has attempted to control the disease through many rounds of annual administration of two deworming drugs to the whole population. However, Samoa recently observed that LF transmission was still occurring, prompting mass drug administration (MDA) with three drugs in 2018. Here, we report the baseline survey of an operational research program to evaluate the triple-drug MDA. The survey assessed prevalence and geographical distribution of LF in the population, compared prevalence by age groups, and investigated the burden of elephantiasis (swollen limbs caused by long-term LF infection). The study confirmed ongoing transmission, with 4% of those aged ≥5 years showing antigen in their blood as evidence of infection. Antigen prevalence was more than three times higher in those aged ≥10 years (4.7%) than in 5–9 year-old children (1.3%). Infection was highly clustered within households and villages, with up to 20% of residents infected in known hotspot villages. Future surveillance strategies should consider that i) testing older age groups would provide more accurate indication of LF transmission, and ii) local knowledge can help identify transmission hotspots.

International audience; Zika and chikungunya viruses were first detected in Fiji in 2015. Examining surveillance and phylogenetic and serologic data, we found evidence of low-level transmission of Zika and chikungunya viruses during 2013-2017, in contrast to the major outbreaks caused by closely related virus strains in other Pacific Island countries.

BackgroundUnder the Global Programme to Eliminate Lymphatic Filariasis (LF), American Samoa conducted mass drug administration (MDA) from 2000-2006. Despite passing Transmission Assessment Surveys (TAS) in 2011/2012 and 2015, American Samoa failed TAS-3 in 2016, with antigen (Ag) prevalence of 0.7% (95%CI 0.3-1.8%) in 6-7 year-olds. A 2016 community survey (Ag prevalence 6.2% (95%CI 4.4-8.5%) in age ≥8 years) confirmed resurgence. Here, we explore the potential of targeted strategies to strengthen post-MDA surveillance.Methodology/Principal FindingsUsing Ag data plus new antibody data (Wb123, Bm14, Bm33) from the 2016 surveys, we identified risk factors for seropositivity using multivariable logistic regression. We compared TAS with strategies that targeted high-risk subpopulations (older ages, householders of Ag-positive TAS children [index children]) and/or known hotspots, and used NNTestav (average number needed to test to identify one positive) to compare sampling efficiency.Antibody prevalence in TAS-3 (n=1143) were 1.6% for Bm14 (95%CI 0.9-2.9%), 7.9% for Wb123 (95%CI 6.4-9.6%), and 20.2% for Bm33 (95%CI 16.7-24.3%); and in the community survey (n=2507), 13.9% for Bm14 (95%CI 11.2-17.2%), 27.9% for Wb123 (95%CI 24.6-31.4%), and 47.3% for Bm33 (95%CI 42.1-52.6%). Ag prevalence was 20.7% (95%CI 9.7-53.5%) in households of index children. Higher Ag prevalence was found in males (adjusted odds ratio [aOR] 3.01), age ≥18 years (aOR 2.18), residents of Fagali’i (aOR 15.81), and outdoor workers (aOR 2.61). Using Ag, NNTestav ranged from 142.5 for TAS, to av was lower in older ages, and highest for Ag, followed by Bm14, Wb123 and Bm33 antibodies.Conclusions/SignificanceWe propose a multi-stage surveillance strategy, starting with population-representative sampling (e.g. TAS), followed by targeted strategies in subgroups and locations with low NNTestav. This approach could potentially improve the efficiency of identifying remaining infected persons and residual hotspots. The utility of antibodies in surveillance should also be explored.AUTHOR SUMMARYLymphatic filariasis (LF) is a parasitic infection transmitted by mosquito bites. Globally, tens of millions are infected, with many disfigured and disabled by severe damage to their lymphatic systems, such as severe swelling of the legs (elephantiasis) or scrotum (hydrocele). The Global Programme to Eliminate LF (GPELF) aims to interrupt disease transmission through mass drug administration (MDA), and to control illness and suffering in affected persons. The World Health Organization recommends conducting Transmission Assessment Surveys (TAS) in school children aged 6 to 7 years, to determine if infection rates have dropped to levels where disease transmission is no longer sustainable. From 2000-2006, American Samoa conducted MDA and made significant progress towards eliminating LF. However, despite passing TAS in 2011/2012 and 2015, surveys in 2016 showed evidence of resurgence. Our study explored alternative surveillance strategies and compared their efficiency with TAS. Based on our findings, we recommended that in addition to TAS, strategies that target high-risk populations and hotspots would strengthen surveillance and help countries achieve their goals of LF elimination.

Background Prevalence of lymphatic filariasis (LF) antigen in American Samoa was 16.5% in 1999. Seven rounds of mass drug administration (MDA) programmes between 2000 and 2006 reduced antigen prevalence to 2.3%. The most efficient methods of surveillance after MDA are not clear, but testing specific at-risk groups such as adults may provide earlier warning of resurgence. The role of migration from LF endemic countries in maintaining transmission also needs investigation. Few studies have investigated knowledge about LF and how that relates to infection risk. This study aims to investigate associations between socio-demographics, population mobility, disease knowledge and LF infection risk. Methods In 2014, we surveyed 670 adults aged 16–68 years (62% female) at two worksites in American Samoa. Sera were tested for LF antigen and antibodies (Bm14 and Wb123) by rapid test and/or ELISA. Multivariate logistic regression was used to assess association between seromarkers and demographic factors, household socioeconomic status (SES), residence, travel history, and knowledge of LF. Results Overall, 1.8% of participants were positive for antigen, 11.8% for Bm14, 11.3% for Wb123 and 17.3% for at least one antibody. Recent travel outside American Samoa was not associated with positivity for any seromarker. Men had higher seroprevalence than women for all outcomes (any antibody: adjusted odds ratio (aOR) = 3.49 (95% CI: 2.21–5.49). Those aged over 35 years (compared to 15–24 years) had higher prevalence of Bm14 antibody (aOR = 3.75, 3.76 and 4.17 for ages 35–44, 45–54 and ≥ 55 years, respectively, P Conclusions Opportunistic sampling of adults at worksites provided an efficient and representative way to assess prevalence and risk factors for LF in American Samoa and in hindsight, foreshadowed the resurgence of transmission. Risk of LF infection, detected by one or more serological markers, was not related to recent travel history, but was strongly associated with male gender, older age, lower SES, and lack of knowledge about mosquito transmission. These results could guide future efforts to increase MDA participation.

Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase 1 (SOD1) is partly non-cell autonomous, involving cellular dysfunction of astrocytes. Whether non-cell autonomous effects occur in other forms of ALS, such as TAR DNA binding protein 43 (TDP-43)-related disease, remains unclear. Here, we characterised the impact of mutant TDP-43 expression on primary astrocytes derived from transgenic TDP-43A315T mice. Mutant TDP-43 astrocytes revealed evidence for TDP-43 pathology, shown by cytoplasmic TDP-43 inclusions and accumulation in insoluble cell fractions which was exacerbated by proteasomal inhibition. L-glutamate uptake, measured using an [3H]D-aspartate assay, was impaired in mutant TDP-43 astrocytes, while ATP accumulation was abnormal, suggesting mutant TDP-43 induced astrocytic dysfunction. Astrocyte activation coupled with spinal and cortical motor neuron loss in transgenic TDP-43A315T mice could imply non-cell autonomous effects of astrocytes in vivo. These data demonstrate mutant TDP-43-mediated cell autonomous effects on astrocytes that may contribute to motor neuron pathology in ALS.

Aim The prevalence of chronic pain among nursing home residents with dementia is high. This present study aimed to explore the effectiveness of a play activities program among nursing home residents with dementia. Methods Each nursing home was randomly assigned to an experimental group or control group. A 1-h play activities program was offered weekly for 8 weeks to the experimental group, whereas participants in the control group read books and magazines for 15 min weekly for the 8 weeks. Outcome measures were assessed at baseline, post-intervention (at week 8) and 4 weeks after the intervention. Results A total of 53 nursing home residents from four nursing homes were recruited. There were significant treatment effects on pain, depression and happiness level when comparing the experimental group and control group. However, there were no treatment effects on activities of daily living, social engagement, behavioral symptoms and mobility between the two groups. Conclusion The play activities program was useful in reducing pain and improving the psychological health of nursing home residents with dementia. Geriatr Gerontol Int 2018; 18: 1485-1490.

BACKGROUND: Canadian guidelines recommend against population-based screening for prostate cancer because of the risk of overdiagnosis and overtreatment. We sought to assess whether a higher proportion of patients receiving surgery had clinically significant cancer over time. METHODS: All hospitals in Eastern Ontario that perform prostatectomy participate in a Prostate Cancer Community of Practice, which prospectively maintains a database for the region. Using these data, we conducted a retrospective cohort study that included all patients who underwent prostatectomy from 2009 to 2015 in the region. We examined trends in biopsy findings, clinical stage, prostate-specific antigen level and Gleason score. We then determined whether the proportion of patients with clinically significant cancer (Gleason score ≥ 7 or stage pT3) increased over time. RESULTS: During the study period, 1897 patients underwent prostatectomy in Eastern Ontario (mean 271 surgeries/yr). The proportion of patients who were determined to have National Comprehensive Cancer Network intermediate or high-risk disease increased from 46.7% in 2009 to 90.2% in 2015. The proportion of men with clinically significant cancer on prostatectomy increased from 59.7% in 2009 to 93.1% in 2015. Adjusted analyses suggested that the proportion of patients with clinically significant cancer increased by 5% per year during the study period. INTERPRETATION: There has been a change in the tumour characteristics of patients who undergo prostatectomy in Eastern Ontario. In recent years, almost all patients have had clinically significant cancer, which suggests that overtreatment of prostate cancer has decreased.

Ross River virus (RRV) is endemic to Australia and Papua New Guinea, with marsupials (especially macropods) as the primary reservoir hosts. Its geographic range was thought to be limited by the distribution of reservoir hosts, but recent evidence suggests that the virus can circulate endemically in the Pacific Islands, where marsupials are absent. RRV therefore has the potential for wider emergence because mammalian diversity in the Pacific Islands is limited and the possible species that have been sustaining endemic transmission are panglobal in distribution. Furthermore, RRV is a vector generalist and can be transmitted by numerous mosquito species, including Culex and the globally invasive Aedes aegypti and Ae. albopictus. We review the evidence for RRV expanding its host and geographic range from prehistoric times to the present and for it to potentially pose a threat as another emerging arbovirus with significant implications for human health far beyond its currently known endemic range.

As the population worldwide ages, the epidemic of kidney disease will also increase. Anti-neutrophil cytoplasmic antibodies (ANCA) positive rapidly progressive positive glomerulonephritis (RPGN) is the most common etiology for biopsied patients among the very elderly. Its pathological features and clinical course are well described, though there is still debate about the mechanism of injury involved in individual patients. From very ancient times, the cornerstone of treatment historically has been high-dose cyclophosphamide and a lengthy course of high-dose corticosteroids. Although this regimen has diminished the immediate mortality rate of RPGN, its intermediate and long-term adverse effects are not insignificant. Attempts to minimize toxicity and improve efficacy have been made through the years to allow physicians some options for therapy. Lower cumulative cyclophosphamide regimens, shorter corticosteroid courses, and the introduction of rituximab have modified the armamentarium for treatment of ANCA positive RPGN. As progress is made in understanding the molecular pathogenesis of this disease, new targets will be found for potential therapeutic attack. The complement system is an area of active interest for all glomerular diseases at this time. Indeed, animal studies and preliminary human studies suggest that targeting the complement system can ameliorate the course of ANCA-positive RPGN. Hopefully, as the population ages, we will see more and safer therapeutic options to treat this once rapidly fatal disease.

Background Neonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms, which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR. Methods and findings All studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (, Sophie Wen and co-workers report a meta-analysis on bacterial isolates and antimicrobial resistance in neonatal sepsis in low- and lower-middle-income countries., Author summary Why was this study done? Neonatal sepsis is a significant cause of childhood mortality with marked disparities across world regions and countries. Gram-negative bacteria are becoming increasingly predominant in neonatal sepsis, particularly in low- and middle-income countries, along with growing concerns of multidrug resistance. It is likely that the World Health Organization (WHO) empirical neonatal sepsis antibiotic recommendations are no longer adequate. We analysed data on neonatal sepsis from low- and lower-middle-income countries (LLMICs) to assess the burden of Gram-negative infections and associated antimicrobial resistance (AMR). What did the researchers do and find? We pooled data from 88 published studies from 19 LLMICs on neonatal sepsis (with a total of 10,458 Gram-negative isolates) and summarised the proportions of Gram-negative sepsis caused by E. coli, Klebsiella, Enterobacter, Pseudomonas, and Acinetobacter. We also examined the rates of AMR against key empirical antibiotics used in neonatal sepsis. Gram-negative bacteria accounted for 60% of neonatal sepsis in LLMICs. Regional variations in types of Gram-negative bacteria were observed, along with high rates of resistance against the WHO-recommended empirical antibiotics for neonatal sepsis. What do these findings mean? The WHO empirical antibiotic recommendations for neonatal sepsis are likely inadequate in many LLMICs. Robust AMR surveillance and reporting in LLMICs is necessary to develop region-specific empirical antibiotic recommendations for neonatal sepsis.

Purpose Recent research suggests an emergence of eating disorders [ED] in non-western settings for unknown reasons. This research investigates the presence of ED in Khartoum State [Sudan], and explores relevant factors amongst women at risk of ED and stakeholders involved with mental health care and policy-making.Methods Women from four summer schools were approached and screened for risk of ED using a validated and adapted form of the Eating Attitudes Test-26. Focus groups were performed within the schools, selected participants at high risk were interviewed, and interviews with stakeholders were performed.Results Around a third (32.6%) of participants scored as having high risk of ED. Interviews showed recurring themes determining eating attitudes including: intention, knowledge, environment and habit. Stakeholders' opinions depended on whether they work directly with those affected by ED or in policy-making. The former advocated increased attention on ED, the latter did not. Overall, services for ED were lacking.Conclusions A high presence of negative eating attitudes was found amongst screened participants with high risk of ED. Individual intention overrides all other determinants for abnormal eating. Moreover, evidence suggests that westernization may attribute to ED, supporting the view that ED are culturally bound. The differing stakeholders' views, together with other data found in this study, allow a number of recommendations for increasing awareness and identification of ED in Sudan.

Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo, rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.

Regression models are the standard approaches used in infectious disease epidemiology, but have limited ability to represent causality or complexity. We explore Bayesian networks (BNs) as an alternative approach for modelling infectious disease transmission, using leptospirosis as an example. Data were obtained from a leptospirosis study in Fiji in 2013. We compared the performance of naive versus expert-structured BNs for modelling the relative importance of animal species in disease transmission in different ethnic groups and residential settings. For BNs of animal exposures at the individual/household level, R-2 for predicted versus observed infection rates were 0.59 for naive and 0.75-0.93 for structured models of ethnic groups; and 0.54 for naive and 0.93-1.00 for structured models of residential settings. BNs provide a promising approach for modelling infectious disease transmission under complex scenarios. The relative importance of animal species varied between subgroups, with important implications for more targeted public health control strategies. (C) 2017 Elsevier Ltd. All rights reserved.

Objective The current supply of acceptable donor lungs is not sufficient for the number of patients awaiting transplantation. We hypothesized that ex vivo lung perfusion (EVLP) with targeted drug therapy would allow successful rehabilitation and transplantation of donation after circulatory death lungs exposed to 2 hours of warm ischemia. Methods Donor porcine lungs were procured after 2 hours of warm ischemia postcardiac arrest and subjected to 4 hours of cold preservation or EVLP. ATL802, an adenosine A 2B receptor antagonist, was administered to select groups. Four groups (n = 4/group) were randomized: cold preservation (Cold), cold preservation with ATL802 during reperfusion (Cold + ATL802), EVLP (EVLP), and EVLP with ATL802 during ex vivo perfusion (EVLP + ATL802). Lungs subsequently were transplanted, reperfused, and assessed by measuring dynamic lung compliance and oxygenation capacity. Results EVLP + ATL802 significantly improved dynamic lung compliance compared with EVLP (25.0 ± 1.8 vs 17.0 ± 2.4 mL/cmH 2 O, P = .04), and compared with cold preservation (Cold: 12.2 ± 1.3, P = .004; Cold + ATL802: 10.6 ± 2.0 mL/cmH 2 O, P = .002). Oxygenation capacity was highest in EVLP (440.4 ± 37.0 vs Cold: 174.0 ± 61.3 mm Hg, P = .037). No differences in oxygenation or pulmonary edema were observed between EVLP and EVLP + ATL802. A significant decrease in interleukin-12 expression in tissue and bronchoalveolar lavage was identified between groups EVLP and EVLP + ATL802, along with less neutrophil infiltration. Conclusions Severely injured donation after circulatory death lungs subjected to 2 hours of warm ischemia are transplanted successfully after enhanced EVLP with targeted drug therapy. Increased use of lungs after uncontrolled donor cardiac death and prolonged warm ischemia may be possible and may improve transplant wait list times and mortality.