Search

As a lower middle-income country, Pakistan faces multiple issues that influence the course of healthy ageing. Although there is some understanding of these issues and the objective health outcomes of people in Pakistan, there is less knowledge on the perceptions, experiences, and priorities of the ageing population and their caretakers (hereafter, "stakeholders"). The aim of the study was to identify the needs and priorities of older adults and stakeholders across both urban and rural locations. We sought to explore the views of two groups of people, older adults and stakeholders on topics including the definition of ageing as well as areas of importance, services available, and barriers to older people living well. Two-day workshops were conducted in one rural city, Thatta and one urban city, Karachi. The workshops were designed using the Nominal Group Technique, which included plenary and roundtable discussions. The responses were ranked through rounds of voting and a consensus priority list was obtained for each topic and group. Responses were categorized using the socio-ecological framework. Responses were compared between stakeholders and older people and between different geographical areas. 24 urban and 26 rural individuals aged over 60 years and 24 urban and 26 rural stakeholders attended the workshops. There were few areas of agreement with respect to both geographical region and participant group. Comparing older adults' definition of ageing, there was no overlap between the top five ranked responses across urban and rural locations. With respect to areas of importance, there was agreement on free health care as well as financial support. In terms of barriers to healthy ageing, only nation-wide inflation was ranked highly by both groups. In addition, there were relatively few areas of congruence between stakeholder and older adult responses, irrespective of location, although engagement with family, adequate nutrition and monetary benefits were responses ranked by both groups as important for healthy ageing. Both groups ranked issues with the pension system and financial difficulties as barriers. When categorized using the socio-ecological model, across all questions, societal factors were prioritized most frequently (32 responses), followed by individual (27), relationship (15), and environment (14). Overcoming barriers to facilitate healthy ageing will require a multi-faceted approach and must incorporate the priorities of older individuals. Our results may serve as a guide for researchers and policymakers for future engagement and to plan interventions for improving the health of the ageing population in Pakistan.

This qualitative study explores agriculture research faculty's challenges with participating in Science Communication. To explore the challenges shared by faculty, we utilized the proposed Faculty Science Communication Engagement Framework, which identifies three dimensions that may cause challenges for faculty Science Communication work: personal, professional, and institutional. During interviews with 11 research faculty, we identified Science Communication challenges within these dimensions. Participant challenges within the personal dimension include allocation of time, the learning curve, audience familiarity, and mass-media concern. Professional dimension challenges were "it's not my job" and disciplinary norms, while challenges within the institutional dimension included a lack of support and resources. Across these dimensions, faculty challenges revolved around the time required to invest in Science Communication activities, the needed resources (personnel, technology, and financial), the value placed on efforts by their academic institution, and the lack of knowledge regarding Science Communication techniques and audience. These findings are described through rich data, and practical recommendations are provided for fostering future Science Communication engagement and interest among faculty. These include Science Communication training focused on specific content areas, hands-on training and support with Science Communication technologies, including Extension and non-Extension faculty in training sessions, creating structured and strategically implemented shared Science Communication resources at the institutional level, including Science Communication efforts in university strategic planning, and awarding and recognizing faculty who utilize Science Communication successfully.

BackgroundThere are few data reporting the needs and priorities of older adults in Brazil. This hampers the development and/or implementation of policies aimed at older adults to help them age well. The aim of this study was to understand areas of importance, priorities, enablers and obstacles to healthy ageing as identified by older adults and key stakeholders in both urban and rural environments.MethodsTwo locations were selected, one urban and one rural in the municipality of Santo André, in the metropolitan region of São Paulo (SP). Workshops for older adults (>60 y) and stakeholders were conducted separately in each location. The workshops incorporated an iterative process of discussion, prioritisation and ranking of responses, in roundtable groups and in plenary. Areas of commonality and differences between older adult and stakeholder responses were identified by comparing responses between groups as well as mapping obstacles and enablers to healthy ageing identified by older adults, to the priorities identified by stakeholder groups. The socio-ecologic model was used to categorise responses.ResultsThere were few shared responses between stakeholders and older adults and little overlap between the top ranked responses of urban and rural groups. With respect to areas of importance, both stakeholder groups ranked policies for older people within their top five reponses. Both older adult groups ranked keeping physically and mentally active, and nurturing spirituality. There was a marked lack of congruence between older adults' obstacles and enablers to healthy ageing and stakeholder priorities, in both urban and rural settings. Most responses were located within the Society domain of the socio-ecologic model, although older adults also responded within the Individual/ Relationships domains, particularly in ranking areas of most importance for healthy ageing.ConclusionsOur results highlight substantial differences between older adults and stakeholders with respect to areas of importance, priorities, enablers and obstacles to healthy ageing, and point to the need for more engagement between those in advocacy and policymaking roles and the older people whose needs they serve.

[This corrects the article DOI: 10.1371/journal.pone.0227773.].

IntroductionPeriprosthetic joint infection (PJI) represents a devastating complication of total joint arthroplasty associated with significant morbidity and mortality. Literature suggests a possible higher incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA). There is, however, no consensus on this purported risk nor a well-defined mechanism. This study investigates how collagen-induced arthritis (CIA), a validated animal model of RA, impacts infectious burden in a well-established model of PJI.MethodsControl mice were compared against CIA mice. Whole blood samples were collected to quantify systemic IgG levels via ELISA. Ex vivo respiratory burst function was measured via dihydrorhodamine assay. Ex vivo Staphylococcus aureus Xen36 burden was measured directly via colony forming unit (CFU) counts and crystal violet assay to assess biofilm formation. In vivo, surgical placement of a titanium implant through the knee joint and inoculation with S. aureus Xen36 was performed. Bacterial burden was then quantified by longitudinal bioluminescent imaging.ResultsMice with CIA demonstrated significantly higher levels of systemic IgG compared with control mice (p = 0.003). Ex vivo, there was no significant difference in respiratory burst function (p = 0.89) or S. aureus bacterial burden as measured by CFU counts (p = 0.91) and crystal violet assay (p = 0.96). In vivo, no significant difference in bacterial bioluminescence between groups was found at all postoperative time points. CFU counts of both the implant and the peri-implant tissue were not significantly different between groups (p = 0.82 and 0.80, respectively).ConclusionThis study demonstrated no significant difference in S. aureus infectious burden between mice with CIA and control mice. These results suggest that untreated, active RA may not represent a significant intrinsic risk factor for PJI, however further mechanistic translational and clinical studies are warranted.

An ecologically valid, reliable and sensitive method of quantifying punch force variables would be useful for coaches and practitioners monitoring combat-specific performance. The present study utilised a vertically mounted force plate to quantify the peak punch force and rate of force development (RFD) of amateur boxers. Ten male senior elite amateur boxers performed maximal jab, cross, and hook punches across two separate days. The force plate showed excellent within-day and good-to-excellent between-day reliability for peak punch impact force and RFD (ICC 0.89-0.99). The CV% for all punch force variables were similar on day 1 (3-9%) and day 2 (4-10%). Standard error of measurement (SEM) and smallest worthwhile changes (SWC) revealed the force plate can detect small-to-moderate changes in punch performance. The greatest impact forces and RFD were found in the rear hook (2624 ± 581 N, 296448 ± 101823 N.s-1), followed by the lead hook (2524 ± 532 N, 256813 ± 81735 N.s-1), cross 2425 ± 545 N, 193004 ± 62671 N.s-1) and jab (1645 ± 537 N, 116675 ± 41577 N.s-1). The vertically mounted force plate is a reliable and sensitive test of punch performance, thus may be useful in determining the efficacy of training interventions.

Healthcare workers (HCWs) are at risk of contracting TB, particularly when in high tuberculosis (TB) burden settings. Routine surveillance data and evidence are limited on the burden of TB amongst HCWs in Indonesia. We aimed to measure the prevalence of TB infection (TBI) and disease among HCWs in four healthcare facilities in Yogyakarta province in Indonesia, and explore risk factors for TBI. A cross-sectional TB screening study targeted all HCWs from four pre-selected facilities (1 hospital, 3 primary care) in Yogyakarta, Indonesia. Voluntary screening included symptom assessment, Chest X-ray (CXR), Xpert MTB/RIF (if indicated) and tuberculin skin test (TST). Analyses were descriptive and included multivariable logistic regression. Of 792 HCWs, 681 consented (86%) to the screening; 59% (n = 401) were female, 62% were medical staff (n = 421), 77% worked in the one participating hospital (n = 524), and the median time working in the health sector was 13 years (IQR: 6-25 years). Nearly half had provided services for people with TB (46%, n = 316) and 9% reported ever having TB (n = 60). Among participants with presumptive TB (15%, n = 99/662), none were diagnosed microbiologically or clinically with active TB disease. TBI was detected in 25% (95% CI: 22-30; n = 112/441) of eligible HCWs with a TST result. A significant association was found between TB infection and being male (adjusted Odds Ratio (aOR) 2.02 (95%CI: 1.29-3.17)), currently working in the participating hospital compared to primary care (aOR 3.15 (95%CI: 1.75-5.66)), and older age (1.05 OR increase per year of life between 19-73 years (95%CI: 1.02-1.06)). This study supports prioritisation of HCWs as a high-risk group for TB infection and disease, and the need for comprehensive prevention and control programs in Indonesia. Further, it identifies characteristics of HCWs in Yogyakarta at higher risk of TBI, who could be prioritised in screening programs if universal coverage of prevention and control measures cannot be achieved.

This study investigated whether heat acclimation (HA) could improve rowing performance in temperate conditions in national-level rowers. Using a parallel-group design, eleven rowers (3 female, 8 male, age: 21±3 years, height: 182.3±6.8cm, mass: 79.2±9.0kg, [Formula: see text]: 61.4±5.1ml·kg·min-1) completed either a HA intervention (HEAT, n = 5) or acted as controls (CON, n = 6). The intervention replaced usual cross-training sessions and consisted of an hour of submaximal cycling or rowing ergometry in either 34±0°C for HEAT or 14±1°C for CON daily over two five-day blocks (10 sessions total), separated by 72h. Participants performed the '10+4' test that consists of 10-min submaximal rowing and a 4-min time-trial (TT) in temperate conditions (20±0°C) before and after the intervention. Heat acclimation following the 10-session intervention was evidenced by large significant (p0.05) decreases were seen in average tympanic temperature (d = -3.08) and average heart rate (d = -1.53) in HEAT from session 2 to session 10 of the intervention. Furthermore, a large significant increase was seen in plasma volume (d = 3.74), with large significant decreases in haemoglobin concentration (d = -1.78) and hematocrit (d = -12.9). Following the intervention, large non-significant increases in respiratory exchange ratio (d = 0.87) and blood lactate (d = 1.40) as well as a large non-significant decrease in RPE (d = -1.23) were seen in HEAT during the 10-min submaximal rowing. A large significant decrease in peak heart rate (d = -2.27), as well as a large non-significant decrease in relative [Formula: see text] (d = -0.90) and large non-significant increases in respiratory exchange ratio (d = 1.18), blood lactate concentration (d = 1.25) and power output (d = 0.96) were seen in HEAT during the 4-min TT. This study suggests that a 10-session HA intervention may elicit HA in national-level rowers, with potential to improve 4-min TT performance in temperate conditions.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

During the 2014-16 Ebola virus disease (EVD) outbreak, the Magburaka Ebola Management Centre (EMC) operated by Médecins Sans Frontières (MSF) in Tonkolili District, Sierra Leone, identified that available district maps lacked up-to-date village information to facilitate timely implementation of EVD control strategies. In January 2015, we undertook a survey in chiefdoms within the MSF EMC catchment area to collect mapping and village data. We explore the feasibility and cost to mobilise a local community for this survey, describe validation against existing mapping sources and use of the data to prioritise areas for interventions, and lessons learned.We recruited local people with self-owned Android smartphones installed with open-source survey software (OpenDataKit (ODK)) and open-source navigation software (OpenStreetMap Automated Navigation Directions (OsmAnd)). Surveyors were paired with local motorbike drivers to travel to eligible villages. The collected mapping data were validated by checking for duplication and comparing the village names against a pre-existing village name and location list using a geographic distance and text string-matching algorithm.The survey teams gained sufficient familiarity with the ODK and OsmAnd software within 1-2 hours. Nine chiefdoms in Tonkolili District and three in Bombali District were surveyed within two weeks. Following de-duplication, the surveyors collected data from 891 villages with an estimated 127,021 households. The overall survey cost was €3,395; €3.80 per village surveyed. The MSF GIS team (MSF-OCG) created improved maps for the MSF Magburaka EMC team which were used to support surveillance, investigation of suspect EVD cases, hygiene-kit distribution and EVD survivor support. We shared the mapping data with OpenStreetMap, the local Ministry of Health and Sanitation and Sierra Leone District and National Ebola Response Centres.Involving local community and using accessible technology allowed rapid implementation, at moderate cost, of a survey to collect geographic and essential village information, and creation of updated maps. These methods could be used for future emergencies to facilitate response.

Lyme disease (LD), caused by bacteria of the Borrelia burgdorferi sensu lato species complex, is the most common vector-borne disease in North America and Europe. A systematic review (SR) was conducted to summarize the global literature on adverse birth outcomes associated with gestational LD in humans. The SR followed an a priori protocol of pretested screening, risk of bias, and data extraction forms. Data were summarized descriptively and random effects meta-analysis (MA) was used where appropriate. The SR identified 45 relevant studies, 29 describing 59 cases reported as gestational LD in the United States, Europe, and Asia (1969-2017). Adverse birth outcomes included spontaneous miscarriage or fetal death (n = 12), newborn death (n = 8), and newborns with an abnormal outcome (e.g. hyperbilirubinemia, respiratory distress and syndactyly) at birth (n = 16). Only one report provided a full case description (clinical manifestations in the mother, negative outcome for the child, and laboratory detection of B. burgdorferi in the child) that provides some evidence for vertical transmission of B. burgdorferi that has negative consequences for the fetus. The results of 17 epidemiological studies are included in this SR. Prevalence of adverse birth outcomes in an exposed population (defined by the authors as: gestational LD, history of LD, tick bites or residence in an endemic area) was compared to that in an unexposed population in eight studies and no difference was reported. A meta-analysis of nine studies showed significantly fewer adverse birth outcomes in women reported to have been treated for gestational LD (11%, 95%CI 7-16) compared to those who were not treated during pregnancy (50%, 95%CI 30-70) providing indirect evidence of an association between gestational LD and adverse birth outcomes. Other risk factors investigated; trimester of exposure, length of LD during pregnancy, acute vs. disseminated LD at diagnosis, and symptomatic LD vs. seropositive women with no LD symptoms during pregnancy were not significantly associated with adverse birth outcomes. This SR summarizes evidence from case studies that provide some limited evidence for transplacental transmission of B. burgdorferi. There was inconsistent evidence for adverse birth outcomes of gestational LD in the epidemiological research, and uncommon adverse outcomes for the fetus may occur as a consequence of gestational LD. The global evidence does not fully characterize the potential impact of gestational LD, and future research that addresses the knowledge gaps may change the findings in this SR. Given the current evidence; prompt diagnosis and treatment of LD during pregnancy is recommended.

Despite their wide-spread use, only limited information is available on the comparative test-retest reliability of task-based functional and resting state magnetic resonance imaging measures of blood oxygen level dependence (tb-fMRI and rs-fMRI) and cerebral blood flow (CBF) using arterial spin labeling. This information is critical to designing properly powered longitudinal studies. Here we comprehensively quantified and compared the test-retest reliability and reproducibility performance of 8 commonly applied fMRI tasks, 6 rs-fMRI metrics and CBF in 30 healthy volunteers. We find large variability in test-retest reliability performance across the different tb-fMRI paradigms and rs-fMRI metrics, ranging from poor to excellent. A larger extent of activation in tb-fMRI is linked to higher between-subject reliability of the respective task suggesting that differences in the amount of activation may be used as a first reliability estimate of novel tb-fMRI paradigms. For rs-fMRI, a good reliability of local activity estimates is paralleled by poor performance of global connectivity metrics. Evaluated CBF measures provide in general a good to excellent test-reliability matching or surpassing the best performing tb-fMRI and rs-fMRI metrics. This comprehensive effort allows for direct comparisons of test-retest reliability between the evaluated MRI domains and measures to aid the design of future tb-fMRI, rs-fMRI and CBF studies.

Between August-December 2014, Ebola Virus Disease (EVD) patients from Tonkolili District were referred for care to two Médecins Sans Frontières (MSF) Ebola Management Centres (EMCs) outside the district (distant EMCs). In December 2014, MSF opened an EMC in Tonkolili District (district EMC). We examined the effect of opening a district-based EMC on time to admission and number of suspect cases dead on arrival (DOA), and identified factors associated with fatality in EVD patients, residents in Tonkolili District. Residents of Tonkolili district who presented between 12 September 2014 and 23 February 2015 to the district EMC and the two distant EMCs were identified from EMC line-lists. EVD cases were confirmed by a positive Ebola PCR test. We calculated time to admission since the onset of symptoms, case-fatality and adjusted Risk Ratios (aRR) using Binomial regression. Of 249 confirmed Ebola cases, 206 (83%) were admitted to the distant EMCs and 43 (17%) to the district EMC. Of them 110 (45%) have died. Confirmed cases dead on arrival (n = 10) were observed only in the distant EMCs. The median time from symptom onset to admission was 6 days (IQR 4,8) in distant EMCs and 3 days (IQR 2,7) in the district EMC (p3 days after symptom onset) in the distant compared with the district EMC, but were less likely (aRR = 0.8; 95%CI 0.6-1.0) to have a high viral load (cycle threshold ≤22). A fatal outcome was associated with a high viral load (aRR 2.6; 95%CI 1.8-3.6) and vomiting at first presentation (aRR 1.4; 95%CI 1.0-2.0). The opening of a district EMC was associated with earlier admission of cases to appropriate care facilities, an essential component of reducing EVD transmission. High viral load and vomiting at admission predicted fatality. Healthcare providers should consider the location of EMCs to ensure equitable access during Ebola outbreaks.

INTRODUCTION:Patients who develop intensive care unit (ICU) acquired delirium stay longer in the ICU, and hospital, and are at risk of long-term mental and physical health problems. Despite guidelines for patient assessment, risk limitation, and treatment in the ICU population, delirium and associated delusions remain a relatively common occurrence on the ICU. There is considerable information in the literature describing the incidence, suspected causes of, and discussion of the benefits and side-effects of the various treatments for delirium in the ICU. But peer-reviewed patient-focused research is almost non-existent. There is therefore a very limited understanding of the reality of delusions in the intensive care unit from the patient's point of view. METHOD:A secondary analysis of the original interviews conducted by the University of Oxford Health Experiences Research Group was undertaken to explore themes relating specifically to sleep and delirium. RESULTS:Patients describe a liminal existence on the ICU. On the threshold of consciousness their reality is uncertain and their sense of self is exposed. Lack of autonomy in an unfamiliar environment prompts patients to develop explanations and understandings for themselves with no foothold in fact. CONCLUSION:Patients on the ICU are perhaps more disoriented than they appear and early psychological intervention in the form of repeated orientation whilst in the ICU might improve the patient experience and defend against development of side-effects.

The global primary literature on Zika virus (ZIKV) (n = 233 studies and reports, up to March 1, 2016) has been compiled using a scoping review methodology to systematically identify and characterise the literature underpinning this broad topic using methods that are documented, updateable and reproducible. Our results indicate that more than half the primary literature on ZIKV has been published since 2011. The articles mainly covered three topic categories: epidemiology of ZIKV (surveillance and outbreak investigations) 56.6% (132/233), pathogenesis of ZIKV (case symptoms/ outcomes and diagnosis) 38.2% (89/233) and ZIKV studies (molecular characterisation and in vitro evaluation of the virus) 18.5% (43/233). There has been little reported in the primary literature on ZIKV vectors (12/233), surveillance for ZIKV (13/233), diagnostic tests (12/233) and transmission (10/233). Three papers reported on ZIKV prevention/control strategies, one investigated knowledge and attitudes of health professionals and two vector mapping studies were reported. The majority of studies used observational study designs, 89.7% (209/233), of which 62/233 were case studies or case series, while fewer (24/233) used experimental study designs. Several knowledge gaps were identified by this review with respect to ZIKV epidemiology, the importance of potential non-human primates and other hosts in the transmission cycle, the burden of disease in humans, and complications related to human infection with ZIKV. Historically there has been little research on ZIKV; however, given its current spread through Australasia and the Americas, research resources are now being allocated to close many of the knowledge gaps identified in this scoping review. Future updates of this project will probably demonstrate enhanced evidence and understanding of ZIKV and its impact on public health.

Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the 'Blalock Alzheimer's Disease Up' pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound's ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI.

Head motion (HM) is a well known confound in analyses of functional MRI (fMRI) data. Neuroimaging researchers therefore typically treat HM as a nuisance covariate in their analyses. Even so, it is possible that HM shares a common genetic influence with the trait of interest. Here we investigate the extent to which this relationship is due to shared genetic factors, using HM extracted from resting-state fMRI and maternal and self report measures of Inattention and Hyperactivity-Impulsivity from the Strengths and Weaknesses of ADHD Symptoms and Normal Behaviour (SWAN) scales. Our sample consisted of healthy young adult twins (N = 627 (63% females) including 95 MZ and 144 DZ twin pairs, mean age 22, who had mother-reported SWAN; N = 725 (58% females) including 101 MZ and 156 DZ pairs, mean age 25, with self reported SWAN). This design enabled us to distinguish genetic from environmental factors in the association between head movement and ADHD scales. HM was moderately correlated with maternal reports of Inattention (r = 0.17, p-value = 7.4E-5) and Hyperactivity-Impulsivity (r = 0.16, p-value = 2.9E-4), and these associations were mainly due to pleiotropic genetic factors with genetic correlations [95% CIs] of rg = 0.24 [0.02, 0.43] and rg = 0.23 [0.07, 0.39]. Correlations between self-reports and HM were not significant, due largely to increased measurement error. These results indicate that treating HM as a nuisance covariate in neuroimaging studies of ADHD will likely reduce power to detect between-group effects, as the implicit assumption of independence between HM and Inattention or Hyperactivity-Impulsivity is not warranted. The implications of this finding are problematic for fMRI studies of ADHD, as failing to apply HM correction is known to increase the likelihood of false positives. We discuss two ways to circumvent this problem: censoring the motion contaminated frames of the RS-fMRI scan or explicitly modeling the relationship between HM and Inattention or Hyperactivity-Impulsivity.

[This corrects the article DOI: 10.1371/journal.pone.0153775.].

Ultrasound studies of carotid intima media thickness (cIMT) and plaques are limited in South Asians, a group at elevated cardiovascular disease (CVD) risk. We determined whether South Asians have a difference in these ultrasound markers compared to Europeans living in the United Kingdom and whether measured risk factor(s) could account for any such differences.One hundred South Asian men, aged 40 to 70 years and 100 European men of similar age and BMI, without diagnosed CVD or diabetes, underwent carotid ultrasound for measurement of cIMT and carotid plaque presence. Physical activity, cardiorespiratory fitness, anthropometry and blood pressure were assessed, fasted blood taken for measurement of cardiometabolic risk factors and demographic and lifestyle factors recorded.Age-adjusted mean (SD) cIMT was similar in South Asians and Europeans (0.64 (0.16) mm v 0.65 (0.12) mm, p = 0.64). Plaque was present in 48 South Asians and 37 Europeans and overall, there was no age-adjusted difference between South Asian and Europeans for plaque score(odds ratio 1.49, 95% CI, 0.86-2.80, p = 0.16), however, South Asians appeared to have more plaques at a younger age than Europeans; at age 40-50 years the odds of South Asians having plaques was 2.63 (95% CI, 1.16-5.93) times that for Europeans.cIMT is similar between healthy South Asian and European men. Whilst there was no overall difference in plaque presence in South Asians, there is an indication of greater plaque prevalence at younger ages--an observation requiring further investigation. Prospective studies linking plaques to CVD outcomes in South Asians are needed to investigate whether these measures help improve CVD risk prediction.

Dogs accompanied people in their migrations across the Pacific Ocean and ultimately reached New Zealand, which is the southern-most point of their oceanic distribution, around the beginning of the fourteenth century AD. Previous ancient DNA analyses of mitochondrial control region sequences indicated the New Zealand dog population included two lineages. We sequenced complete mitochondrial genomes of fourteen dogs from the colonisation era archaeological site of Wairau Bar and found five closely-related haplotypes. The limited number of mitochondrial lineages present at Wairau Bar suggests that the founding population may have comprised only a few dogs; or that the arriving dogs were closely related. For populations such as that at Wairau Bar, which stemmed from relatively recent migration events, control region sequences have insufficient power to address questions about population structure and founding events. Sequencing mitogenomes provided the opportunity to observe sufficient diversity to discriminate between individuals that would otherwise be assigned the same haplotype and to clarify their relationships with each other. Our results also support the proposition that at least one dispersal of dogs into the Pacific was via a south-western route through Indonesia.

Intramuscular (IM) administration of adeno-associated viral (AAV) vectors has entered the early stages of clinical development with some success, including the first approved gene therapy product in the West called Glybera. In preparation for broader clinical development of IM AAV vector gene therapy, we conducted detailed pre-clinical studies in mice and macaques evaluating aspects of delivery that could affect performance. We found that following IM administration of AAV8 vectors in mice, a portion of the vector reached the liver and hepatic gene expression contributed significantly to total expression of secreted transgenes. The contribution from liver could be controlled by altering injection volume and by the use of traditional (promoter) and non-traditional (tissue-specific microRNA target sites) expression control elements. Hepatic distribution of vector following IM injection was also noted in rhesus macaques. These pre-clinical data on AAV delivery should inform safe and efficient development of future AAV products.

Organophosphorus (OP) nerve agents are deadly chemical weapons that pose an alarming threat to military and civilian populations. The irreversible inhibition of the critical cholinergic degradative enzyme acetylcholinesterase (AChE) by OP nerve agents leads to cholinergic crisis. Resulting excessive synaptic acetylcholine levels leads to status epilepticus that, in turn, results in brain damage. Current countermeasures are only modestly effective in protecting against OP-induced brain damage, supporting interest for evaluation of new ones. (-)-Phenserine is a reversible AChE inhibitor possessing neuroprotective and amyloid precursor protein lowering actions that reached Phase III clinical trials for Alzheimer's Disease where it exhibited a wide safety margin. This compound preferentially enters the CNS and has potential to impede soman binding to the active site of AChE to, thereby, serve in a protective capacity. Herein, we demonstrate that (-)-phenserine protects neurons against soman-induced neuronal cell death in rats when administered either as a pretreatment or post-treatment paradigm, improves motoric movement in soman-exposed animals and reduces mortality when given as a pretreatment. Gene expression analysis, undertaken to elucidate mechanism, showed that (-)-phenserine pretreatment increased select neuroprotective genes and reversed a Homer1 expression elevation induced by soman exposure. These studies suggest that (-)-phenserine warrants further evaluation as an OP nerve agent protective strategy.

BACE1 (β-secretase) and α-secretase cleave the Alzheimer's amyloid β protein (Aβ) precursor (APP) to C-terminal fragments of 99 aa (CTFβ) and 83 aa (CTFα), respectively, which are further cleaved by γ-secretase to eventually secrete Aβ and Aα (a.k.a. P3) that terminate predominantly at residues 40 and 42. A number of γ-secretase inhibitors (GSIs), such as N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), have been developed with the goal of reducing Aβ to treat Alzheimer's disease (AD). Although most studies show that DAPT inhibits Aβ in a dose-dependent manner several studies have also detected a biphasic effect with an unexpected increase at low doses of DAPT in cell cultures, animal models and clinical trials. In this article, we confirm the increase in Aβ40 and Aβ42 in SH-SY5Y human neuroblastoma cells treated with low doses of DAPT and identify one of the mechanisms for this paradox. We studied the pathway by first demonstrating that stimulation of Aβ, a product of γ-secretase, was accompanied by a parallel increase of its substrate CTFβ, thereby demonstrating that the inhibitor was not anomalously stimulating enzyme activity at low levels. Secondly, we have demonstrated that inhibition of an Aβ degrading activity, endothelin converting enzyme (ECE), yielded more Aβ, but abolished the DAPT-induced stimulation. Finally, we have demonstrated that Aα, which is generated in the secretory pathway before endocytosis, is not subject to the DAPT-mediated stimulation. We therefore conclude that impairment of γ-secretase can paradoxically increase Aβ by transiently skirting Aβ degradation in the endosome. This study adds to the growing body of literature suggesting that preserving γ-secretase activity, rather than inhibiting it, is important for prevention of neurodegeneration.

BACKGROUND: In 2010, Médecins Sans Frontières (MSF) investigated reports of high mortality in young children in Zamfara State, Nigeria, leading to confirmation of villages with widespread acute severe lead poisoning. In a retrospective analysis, we aimed to determine venous blood lead level (VBLL) thresholds and risk factors for encephalopathy using MSF programmatic data from the first year of the outbreak response. METHODS AND FINDINGS: We included children aged ≤5 years with VBLL ≥45 µg/dL before any chelation and recorded neurological status. Odds ratios (OR) for neurological features were estimated; the final model was adjusted for age and baseline VBLL, using random effects for village of residence. 972 children met inclusion criteria: 885 (91%) had no neurological features; 34 (4%) had severe features; 47 (5%) had reported recent seizures; and six (1%) had other neurological abnormalities. The geometric mean VBLLs for all groups with neurological features were >100 µg/dL vs 65.9 µg/dL for those without neurological features. The adjusted OR for neurological features increased with increasing VBLL: from 2.75, 95%CI 1.27-5.98 (80-99.9 µg/dL) to 22.95, 95%CI 10.54-49.96 (≥120 µg/dL). Neurological features were associated with younger age (OR 4.77 [95% CI 2.50-9.11] for 1-

Neurodegenerative diseases comprise both hereditary and sporadic conditions characterized by an identifying progressive nervous system dysfunction and distinctive neuopathophysiology. The majority are of non-familial etiology and hence environmental factors and lifestyle play key roles in their pathogenesis. The extensive use of and ever increasing worldwide demand for electricity has stimulated societal and scientific interest on the environmental exposure to low frequency electromagnetic fields (EMFs) on human health. Epidemiological studies suggest a positive association between 50/60-Hz power transmission fields and leukemia or lymphoma development. Consequent to the association between EMFs and induction of oxidative stress, concerns relating to development of neurodegenerative diseases, such as Alzheimer disease (AD), have been voiced as the brain consumes the greatest fraction of oxygen and is particularly vulnerable to oxidative stress. Exposure to extremely low frequency (ELF)-EMFs are reported to alter animal behavior and modulate biological variables, including gene expression, regulation of cell survival, promotion of cellular differentiation, and changes in cerebral blood flow in aged AD transgenic mice. Alterations in inflammatory responses have also been reported, but how these actions impact human health remains unknown. We hence evaluated the effects of an electromagnetic wave (magnetic field intensity 1 mT; frequency, 50-Hz) on a well-characterized immortalized neuronal cell model, human SH-SY5Y cells. ELF-EMF exposure elevated the expession of NOS and O2(-), which were countered by compensatory changes in antioxidant catylase (CAT) activity and enzymatic kinetic parameters related to CYP-450 and CAT activity. Actions of ELF-EMFs on cytokine gene expression were additionally evaluated and found rapidly modified. Confronted with co-exposure to H2O2-induced oxidative stress, ELF-EMF proved not as well counteracted and resulted in a decline in CAT activity and a rise in O2(-) levels. Together these studies support the further evaluation of ELF-EMF exposure in cellular and in vivo preclinical models to define mechanisms potentially impacted in humans.

This study explored inter-relationships between vertebral fracture, thoracic kyphosis and trunk muscle control in elderly people with osteoporosis. Osteoporotic vertebral fractures are associated with increased risk of further vertebral fractures; but underlying mechanisms remain unclear. Several factors may explain this association, including changes in postural alignment (thoracic kyphosis) and altered trunk muscle contraction patterns. Both factors may increase risk of further fracture because of increased vertebral loading and impaired balance, which may increase falls risk. This study compared postural adjustments in 24 individuals with osteoporosis with and without vertebral fracture and with varying degrees of thoracic kyphosis. Trunk muscle electromyographic activity (EMG) associated with voluntary arm movements was recorded and compared between individuals with and without vertebral fracture, and between those with low and high thoracic kyphosis. Overall, elderly participants in the study demonstrated co-contraction of the trunk flexor and extensor muscles during forwards arm movements, but those with vertebral fractures demonstrated a more pronounced co-contraction than those without fracture. Individuals with high thoracic kyphosis demonstrated more pronounced alternating flexor and extensor EMG bursts than those with less kyphosis. Co-contraction of trunk flexor and extensor muscles in older individuals contrasts the alternating bursts of antagonist muscle activity in previous studies of young individuals. This may have several consequences, including altered balance efficacy and the potential for increased compressive loads through the spine. Both of these outcomes may have consequences in a population with fragile vertebrae who are susceptible to fracture.

OBJECTIVES: To identify associations between specific WHO stage 3 and 4 conditions diagnosed after ART initiation and all cause mortality for patients in resource-limited settings (RLS). DESIGN, SETTING: Analysis of routine program data collected prospectively from 25 programs in eight countries between 2002 and 2010. SUBJECTS, PARTICIPANTS: 36,664 study participants with median ART follow-up of 1.26 years (IQR 0.55-2.27). OUTCOME MEASURES: Using a proportional hazards model we identified factors associated with mortality, including the occurrence of specific WHO clinical stage 3 and 4 conditions during the 6-months following ART initiation. RESULTS: There were 2922 deaths during follow-up (8.0%). The crude mortality rate was 5.41 deaths per 100 person-years (95% CI: 5.21-5.61). The diagnosis of any WHO stage 3 or 4 condition during the first 6 months of ART was associated with increased mortality (HR: 2.21; 95% CI: 1.97-2.47). After adjustment for age, sex, region and pre-ART CD4 count, a diagnosis of extrapulmonary cryptococcosis (aHR: 3.54; 95% CI: 2.74-4.56), HIV wasting syndrome (aHR: 2.92; 95%CI: 2.21 -3.85), non-tuberculous mycobacterial infection (aHR: 2.43; 95% CI: 1.80-3.28) and Pneumocystis pneumonia (aHR: 2.17; 95% CI 1.80-3.28) were associated with the greatest increased mortality. Cerebral toxoplasmosis, pulmonary and extra-pulmonary tuberculosis, Kaposi's sarcoma and oral and oesophageal candidiasis were associated with increased mortality, though at lower rates. CONCLUSIONS: A diagnosis of certain WHO stage 3 and 4 conditions is associated with an increased risk of mortality in those initiating ART in RLS. This information will assist initiatives to reduce excess mortality, including prioritization of resources for diagnostics, therapeutic interventions and research.

The objective of this study was to investigate the effects of modulating brain amyloid-β (Aβ) levels at different stages of amyloid pathology on synaptic function, inflammatory cell changes and hippocampal neurogenesis, i.e. processes perturbed in Alzheimer's disease (AD). Young (4- to 6-month-old) and older (15- to 18-month-old) APP(SWE) transgenic (Tg2576) mice were treated with the AD candidate drug (+)-phenserine for 16 consecutive days. We found significant reductions in insoluble Aβ1-42 levels in the cortices of both young and older transgenic mice, while significant reductions in soluble Aβ1-42 levels and insoluble Aβ1-40 levels were only found in animals aged 15-18 months. Autoradiography binding with the amyloid ligand Pittsburgh Compound B ((3)H-PIB) revealed a trend for reduced fibrillar Aβ deposition in the brains of older phenserine-treated Tg2576 mice. Phenserine treatment increased cortical synaptophysin levels in younger mice, while decreased interleukin-1β and increased monocyte chemoattractant protein-1 and tumor necrosis factor-alpha levels were detected in the cortices of older mice. The reduction in Aβ1-42 levels was associated with an increased number of bromodeoxyuridine-positive proliferating cells in the hippocampi of both young and older Tg2576 mice. To determine whether the increased cell proliferation was accompanied by increased neuronal production, the endogenous early neuronal marker doublecortin (DCX) was examined in the dentate gyrus (DG) using immunohistochemical detection. Although no changes in the total number of DCX(+)-expressing neurons were detected in the DG in Tg2576 mice at either age following (+)-phenserine treatment, dendritic arborization was increased in differentiating neurons in young Tg2576 mice. Collectively, these findings indicate that reducing Aβ1-42 levels in Tg2576 mice at an early pathological stage affects synaptic function by modulating the maturation and plasticity of newborn neurons in the brain. In contrast, lowering Aβ levels in Tg2576 mice when Aβ plaque pathology is prominent mainly alters the levels of proinflammatory cytokines and chemokines.

Neuronal dysfunction and demise together with a reduction in neurogenesis are cardinal features of Alzheimer's disease (AD) induced by a combination of oxidative stress, toxic amyloid-β peptide (Aβ) and a loss of trophic factor support. Amelioration of these was assessed with the Aβ lowering AD experimental drugs (+)-phenserine and (-)-phenserine in neuronal cultures, and actions in mice were evaluated with (+)-phenserine. Both experimental drugs together with the metabolite N1-norphenserine induced neurotrophic actions in human SH-SY5Y cells that were mediated by the protein kinase C (PKC) and extracellular signal-regulated kinases (ERK) pathways, were evident in cells expressing amyloid precursor protein Swedish mutation (APP(SWE)), and retained in the presence of Aβ and oxidative stress challenge. (+)-Phenserine, together with its (-) enantiomer as well as its N1- and N8-norphenserine and N1,N8-bisnorphenserine metabolites, likewise provided neuroprotective activity against oxidative stress and glutamate toxicity via the PKC and ERK pathways. These neurotrophic and neuroprotective actions were evident in primary cultures of subventricular zone (SVZ) neural progenitor cells, whose neurosphere size and survival were augmented by (+)-phenserine. Translation of these effects in vivo was assessed in wild type and AD APPswe transgenic (Tg2576) mice by doublecortin (DCX) immunohistochemical analysis of neurogenesis in the SVZ, which was significantly elevated by 16 day systemic (+)-phenserine treatment, in the presence of a (+)-phenserine-induced elevation in brain- derived neurotrophic factor (BDNF).

Traumatic brain injury represents a major public health issue that affects 1.7 million Americans each year and is a primary contributing factor (30.5%) of all injury-related deaths in the United States. The occurrence of traumatic brain injury is likely underestimated and thus has been termed "a silent epidemic". Exendin-4 is a long-acting glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes mellitus that not only effectively induces glucose-dependent insulin secretion to regulate blood glucose levels but also reduces apoptotic cell death of pancreatic β-cells. Accumulating evidence also supports a neurotrophic and neuroprotective role of glucagon-like peptide-1 in an array of cellular and animal neurodegeneration models. In this study, we evaluated the neuroprotective effects of Exendin-4 using a glutamate toxicity model in vitro and fluid percussion injury in vivo. We found neuroprotective effects of Exendin-4 both in vitro, using markers of cell death, and in vivo, using markers of cognitive function, as assessed by Morris Water Maze. In combination with the reported benefits of ex-4 in other TBI models, these data support repositioning of Exendin-4 as a potential treatment for traumatic brain injury.

BACKGROUND: The Médecins Sans Frontières project of Uzbekistan has provided multidrug-resistant tuberculosis treatment in the Karakalpakstan region since 2003. Rates of default from treatment have been high, despite psychosocial support, increasing particularly since programme scale-up in 2007. We aimed to determine factors associated with default in multi- and extensively drug-resistant tuberculosis patients who started treatment between 2003 and 2008 and thus had finished approximately 2 years of treatment by the end of 2010. METHODS: A retrospective cohort analysis of multi- and extensively drug-resistant tuberculosis patients enrolled in treatment between 2003 and 2008 compared baseline demographic characteristics and possible risk factors for default. Default was defined as missing ≥60 consecutive days of treatment (all drugs). Data were routinely collected during treatment and entered in a database. Potential risk factors for default were assessed in univariate analysis using chi-square test and in multivariate analysis with logistic regression. RESULTS: 20% (142/710) of patients defaulted after a median of 6 months treatment (IQR 2.6-9.9). Factors associated with default included severity of resistance patterns (pre-extensively drug-resistant/extensively drug-resistant tuberculosis adjusted odds ratio 0.52, 95%CI: 0.31-0.86), previous default (2.38, 1.09-5.24) and age >45 years (1.77, 1.10-2.87). The default rate was 14% (42/294) for patients enrolled 2003-2006 and 24% (100/416) for 2007-2008 enrolments (p = 0.001). CONCLUSIONS: Default from treatment was high and increased with programme scale-up. It is essential to ensure scale-up of treatment is accompanied with scale-up of staff and patient support. A successful first course of tuberculosis treatment is important; patients who had previously defaulted were at increased risk of default and death. The protective effect of severe resistance profiles suggests that understanding disease severity or fear may motivate against default. Targeted health education and support for at-risk patients after 5 months of treatment when many begin to feel better may decrease default.

With parallels to concussive mild traumatic brain injury (mTBI) occurring in humans, anesthetized mice subjected to a single 30 g weight drop mTBI event to the right parietal cortex exhibited significant diffuse neuronal degeneration that was accompanied by delayed impairments in recognition and spatial memory. To elucidate the involvement of reversible p53-dependent apoptosis in this neuronal loss and associated cognitive deficits, mice were subjected to experimental mTBI followed by the systemic administration of the tetrahydrobenzothiazole p53 inactivator, PFT-α, or vehicle. Neuronal loss was quantified immunohistochemically at 72 hr. post-injury by the use of fluoro-Jade B and NeuN within the dentate gyrus on both sides of the brain, and recognition and spatial memory were assessed by novel object recognition and Y-maze paradigms at 7 and 30 days post injury. Systemic administration of a single dose of PFT-α 1 hr. post-injury significantly ameliorated both neuronal cell death and cognitive impairments, which were no different from sham control animals. Cellular studies on human SH-SY5Y cells and rat primary neurons challenged with glutamate excitotoxicity and H2O2 induced oxidative stress, confirmed the ability of PFT-α and a close analog to protect against these TBI associated mechanisms mediating neuronal loss. These studies suggest that p53-dependent apoptotic mechanisms underpin the neuronal and cognitive losses accompanying mTBI, and that these are potentially reversible by p53 inactivation.

BACKGROUND:Sarcopenia, the loss of muscle mass and function with age, is associated with increased morbidity and mortality. Current understanding of the underlying mechanisms is limited. Glucocorticoids (GC) in excess cause muscle weakness and atrophy. We hypothesized that GC may contribute to sarcopenia through elevated circulating levels or increased glucocorticoid receptor (GR) signaling by increased expression of either GR or the GC-amplifying enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11βHSD1) in muscle. METHODS:There were 82 participants; group 1 comprised 33 older men (mean age 70.2 years, SD 4.4) and 19 younger men (22.2 years, 1.7) and group 2 comprised 16 older men (79.1 years, 3.4) and 14 older women (80.1 years, 3.7). We measured muscle strength, mid-thigh cross-sectional area, fasting morning plasma cortisol, quadriceps muscle GR and 11βHSD1 mRNA, and urinary glucocorticoid metabolites. Data were analysed using multiple linear regression adjusting for age, gender and body size. RESULTS:Muscle strength and size were not associated with plasma cortisol, total urinary glucocorticoids or the ratio of urinary 5β-tetrahydrocortisol +5α-tetrahydrocortisol to tetrahydrocortisone (an index of systemic 11βHSD activity). Muscle strength was associated with 11βHSD1 mRNA levels (β -0.35, p = 0.04), but GR mRNA levels were not significantly associated with muscle strength or size. CONCLUSION:Although circulating levels of GC are not associated with muscle strength or size in either gender, increased cortisol generation within muscle by 11βHSD1 may contribute to loss of muscle strength with age, a key component of sarcopenia. Inhibition of 11βHSD1 may have therapeutic potential in sarcopenia.

OBJECTIVES: In Lagos, Nigeria, Médecins Sans Frontières (MSF) and the Ministry of Health (MoH) commenced free antiretroviral treatment (ART) in a hospital-based clinic. We performed a cross-sectional study to compare factors associated with raised viral load between patients with ("experienced") and without ("naïve") prior antiretroviral (ARV) exposure at commencement of ART at the clinic. We also examined factors influencing ARV adherence in experienced patients prior to clinic entry. METHODS: We included adult patients receiving ART from MSF who answered a questionnaire about previous antiretroviral use. Multivariate logistic regression was used to estimate odds ratios (OR) for raised viral load (≥1000 copies/mL). RESULTS: 1246 (96%) patients answered: 1075 (86%) reported no, and 171 (14%) some, prior ARV exposure. ARV-naïve patients were more immunosuppressed at baseline: 65% vs 37% (p

The HIV epidemic has increased the proportion of patients with smear-negative and extrapulmonary tuberculosis (TB) diagnoses, with related higher rates of poor TB treatment outcomes. Unlike in smear-positive pulmonary TB, no interim markers of TB treatment progress are systematically used to identify individuals most at risk of mortality. The objective of this study was to assess the association of body mass index (BMI) change at 1 month (±15 days) from TB treatment start with mortality among HIV-positive individuals with smear-negative and extrapulmonary TB.A retrospective cohort study of adult HIV-positive new TB patients in Médecins Sans Frontières (MSF) treatment programmes in Myanmar and Zimbabwe was conducted using Cox proportional hazards regression to estimate the association between BMI category change and mortality. A cohort of 1090 TB patients (605 smear-negative and 485 extrapulmonary) was followed during TB treatment with mortality rate of 28.9 per 100 person-years. In multivariable analyses, remaining severely underweight or moving to a lower BMI category increased mortality (adjusted hazard ratio 4.05, 95% confidence interval 2.77-5.91, p

OBJECTIVES: To determine the incidence of WHO clinical stage 3 and 4 conditions during early anti-retroviral therapy (ART) in resource limited settings (RLS). DESIGN/SETTING: A descriptive analysis of routine program data collected prospectively from 25 Médecins Sans Frontières supported HIV treatment programs in eight countries between 2002 and 2010. SUBJECTS/PARTICIPANTS: 35,349 study participants with median follow-up on ART of 1.33 years (IQR 0.51-2.41). OUTCOME MEASURES: Incidence in 100 person-years of WHO stage 3 or 4 conditions during 5 periods after ART initiation. Diagnoses of conditions were made according to WHO criteria and relied upon clinical assessments supported by basic laboratory investigations. RESULTS: The incidence of any WHO clinical stage 3 or 4 condition over 3 years was 40.02 per 100 person-years (31.77 for stage 3 and 8.25 for stage 4). The incidence of stage 3 and 4 conditions fell by over 97% between months 0-3 and months 25-36 (77.81 to 2.40 for stage 3 and 28.70 to 0.64 for stage 4). During months 0-3 pulmonary tuberculosis was the most common condition diagnosed in adults (incidence 22.24 per 100 person-years) and children aged 5-14 years (25.76) and oral candidiasis was the most common in children

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.

Overproduction of amyloid-β (Aβ) protein in the brain has been hypothesized as the primary toxic insult that, via numerous mechanisms, produces cognitive deficits in Alzheimer's disease (AD). Cholinesterase inhibition is a primary strategy for treatment of AD, and specific compounds of this class have previously been demonstrated to influence Aβ precursor protein (APP) processing and Aβ production. However, little information is available on the effects of rivastigmine, a dual acetylcholinesterase and butyrylcholinesterase inhibitor, on APP processing. As this drug is currently used to treat AD, characterization of its various activities is important to optimize its clinical utility. We have previously shown that rivastigmine can preserve or enhance neuronal and synaptic terminal markers in degenerating primary embryonic cerebrocortical cultures. Given previous reports on the effects of APP and Aβ on synapses, regulation of APP processing represents a plausible mechanism for the synaptic effects of rivastigmine. To test this hypothesis, we treated degenerating primary cultures with rivastigmine and measured secreted APP (sAPP) and Aβ. Rivastigmine treatment increased metabolic activity in these cultured cells, and elevated APP secretion. Analysis of the two major forms of APP secreted by these cultures, attributed to neurons or glia based on molecular weight showed that rivastigmine treatment significantly increased neuronal relative to glial secreted APP. Furthermore, rivastigmine treatment increased α-secretase cleaved sAPPα and decreased Aβ secretion, suggesting a therapeutic mechanism wherein rivastigmine alters the relative activities of the secretase pathways. Assessment of sAPP levels in rodent CSF following once daily rivastigmine administration for 21 days confirmed that elevated levels of APP in cell culture translated in vivo. Taken together, rivastigmine treatment enhances neuronal sAPP and shifts APP processing toward the α-secretase pathway in degenerating neuronal cultures, which mirrors the trend of synaptic proteins, and metabolic activity.

Wound healing is a complex process involving intrinsic dermal and epidermal cells, and infiltrating macrophages and leukocytes. Excessive oxidative stress and associated inflammatory processes can impair wound healing, and antioxidants have been reported to improve wound healing in animal models and human subjects. Uric acid (UA) is an efficient free radical scavenger, but has a very low solubility and poor tissue penetrability. We recently developed novel UA analogs with increased solubility and excellent free radical-scavenging properties and demonstrated their ability to protect neural cells against oxidative damage. Here we show that the uric acid analog (6, 8 dithio-UA, but not equimolar concentrations of UA or 1, 7 dimethyl-UA) modified the behaviors of cultured vascular endothelial cells, keratinocytes and fibroblasts in ways consistent with enhancement of the wound healing functions of all three cell types. We further show that 6, 8 dithio-UA significantly accelerates the wound healing process when applied topically (once daily) to full-thickness wounds in mice. Levels of Cu/Zn superoxide dismutase were increased in wound tissue from mice treated with 6, 8 dithio-UA compared to vehicle-treated mice, suggesting that the UA analog enhances endogenous cellular antioxidant defenses. These results support an adverse role for oxidative stress in wound healing and tissue repair, and provide a rationale for the development of UA analogs in the treatment of wounds and for modulation of angiogenesis in other pathological conditions.

The salmon-eating Southern Resident killer whale (SRKW) (Orcinus orca) population currently comprises only 73 individuals, and is listed as 'endangered' under the Species at Risk Act in Canada. Recent evidence suggests that the growth of this population may be limited by food resources, especially Chinook salmon (Oncorhynchus tshawytscha). We present spatio-temporal bioenergetics model for SRKW in the Salish Sea and the West Coast of Vancouver Island from 1979-2020 with the objective of evaluating how changes in the abundance, age-structure, and length-at-age of Chinook salmon populations has influenced the daily food consumption of the SRKW population. Our model showed that the SRKW population has been in energetic deficit for six of the last 40 years. Our results also suggested that the abundance of age-4 and age-5 Chinook salmon are significant predictors of energy intake for SRKW. We estimated that the annual consumption (April-October) of Chinook salmon by the whales between 1979 and 2020 ranged from 166,000 216,300. Over the past 40 years, the model estimated that the contribution in the predicted SRKW diet of Chinook salmon originating from the Columbia River has increased by about 34%, and decreased by about 15% for Chinook salmon stocks originating from Puget Sound. Overall, our study provides an overview of the requirements and availability of prey for SRKW over the last 40 years, while supporting the hypothesis that SRKW were limited by prey abundance in the study period.

Detailed, well-dated palaeoclimate and archaeological records are critical for understanding the impact of environmental change on human evolution. Ga-Mohana Hill, in the southern Kalahari, South Africa, preserves a Pleistocene archaeological sequence. Relict tufas at the site are evidence of past flowing streams, waterfalls, and shallow pools. Here, we use laser ablation screening to target material suitable for uranium-thorium dating. We obtained 33 ages covering the last 110 thousand years (ka) and identify five tufa formation episodes at 114-100 ka, 73-48 ka, 44-32 ka, 15-6 ka, and ~3 ka. Three tufa episodes are coincident with the archaeological units at Ga-Mohana Hill dating to ~105 ka, ~31 ka, and ~15 ka. Based on our data and the coincidence of dated layers from other local records, we argue that in the southern Kalahari, from ~240 ka to ~71 ka wet phases and human occupation are coupled, but by ~20 ka during the Last Glacial Maximum (LGM), they are decoupled.

Higher acuity levels in COVID-19 patients and increased infection prevention and control routines have increased the work demands on nurses. To understand and quantify these changes, discrete event simulation (DES) was used to quantify the effects of varying the number of COVID-19 patient assignments on nurse workload and quality of care. Model testing was based on the usual nurse-patient ratio of 1:5 while varying the number of COVID-19 positive patients from 0 to 5. The model was validated by comparing outcomes to a step counter field study test with eight nurses. The DES model showed that nurse workload increased, and the quality of care deteriorated as nurses were assigned more COVID-19 positive patients. With five COVID-19 positive patients, the most demanding condition, the simulant-nurse donned and doffed personal protective equipment (PPE) 106 times a shift, totaling 6.1 hours. Direct care time was reduced to 3.4 hours (-64% change from baseline pre-pandemic case). In addition, nurses walked 10.5km (+46% increase from base pre-pandemic conditions) per shift while 75 care tasks (+242%), on average, were in the task queue. This contributed to 143 missed care tasks (+353% increase from base pre-pandemic conditions), equivalent to 9.6 hours (+311%) of missed care time and care task waiting time increased to 1.2 hours (+70%), in comparison to baseline (pre-pandemic) conditions. This process simulation approach may be used as potential decision support tools in the design and management of hospitals in-patient care settings, including pandemic planning scenarios.

This study investigated whether hot water immersion (HWI) could heat acclimate athletes and improve intermittent running performance and perception of in-game running ability, during a competitive Australian Rules Football (ARF) season. Fifteen male semi-professional ARF athletes (Mean (SD); age: 22 (3) years, height: 182.3 (6.5) cm, mass: 80.5 (5.1) kg) completed either HWI (HEAT, N = 8, 13 (2) sessions, 322 (69) min exposure, 39.5 (0.3) °C) or acted as a control (CON, N = 7, no water immersion) over 6-weeks. Athletes completed a 30-15 Intermittent Fitness Test pre and post-intervention to assess intermittent running performance (VIFT), with perception of in-game running ability measured. Heat acclimation was determined via change in resting plasma volume, as well as physiological and perceptual responses during HWI. HEAT elicited large PV expansion (mean ± 90% CI: d = 1.03 ± 0.73), large decreases in heart rate (d = -0.89 ± 0.70), thermal sensation (d = -2.30 ± 1.15) and tympanic temperature (d = -1.18 ± 0.77). Large improvements in VIFT were seen in HEAT (d = 1.67 ± 0.93), with HEAT showing a greater improvement in VIFT when compared to CON (d = 0.81 ± 0.88). HEAT also showed greater belief that in-game running ability improved post-intervention (d = 2.15 ± 1.09) compared to CON. A 6-week HWI intervention can elicit heat acclimation, improve perception of in-game running ability, and potentially improve VIFT in semi-professional ARF athletes.

Physical training, testing, and monitoring are three key constitutes of athlete physical performance; however, there is a currently a lack of information on the prevalence of such methods in amateur boxing. This study aimed to explore the physical preparation practices of senior elite (SEB) and senior development (SDB) amateur boxers, and to determine whether these practices were discriminated by competitor level. One hundred and one amateur boxers (SEB n = 59, SDB n = 42) were surveyed on their understanding, perceptions and application of physical training, monitoring, and testing practices. SEB were associated with strength/power training (SEB 78%, SDB 50%, P = 0.005), monitor of training intensities (SEB 68%, SDB 40%, P = 0.006), and performing regular fitness testing (SEB 76%, SDB 50%, P = 0.006), compared to SDB. Likewise, SEB were twice as likely (56%) to have their physical preparation managed by a strength and conditioning (S&C) coach or sport scientist, compared to SDB (26%; P = 0.005). For the first time, these data demonstrate the extent to which competitor level is associated with preparatory practices in amateur boxing. Cost was identified as the main barrier in implementing several forms of scientific support in SDB. These data serve as a framework to enhance preparatory practices across different competitor levels in amateur boxing. This might include boxer and coach education on the benefits to a more scientific approach, and the use of cost-effective methods to develop, monitor and assess amateur boxers physical performance. This may be of particular importance where boxers are not funded, such as the SDB in the current study. However, this work may also be used to emphasise the importance of strength/power training, physical fitness testing and monitoring at the elite level of amateur boxing.

IntroductionPeriprosthetic joint infection (PJI) represents a devastating complication of total joint arthroplasty associated with significant morbidity and mortality. Literature suggests a possible higher incidence of periprosthetic joint infection (PJI) in patients with rheumatoid arthritis (RA). There is, however, no consensus on this purported risk nor a well-defined mechanism. This study investigates how collagen-induced arthritis (CIA), a validated animal model of RA, impacts infectious burden in a well-established model of PJI.MethodsControl mice were compared against CIA mice. Whole blood samples were collected to quantify systemic IgG levels via ELISA. Ex vivo respiratory burst function was measured via dihydrorhodamine assay. Ex vivo Staphylococcus aureus Xen36 burden was measured directly via colony forming unit (CFU) counts and crystal violet assay to assess biofilm formation. In vivo, surgical placement of a titanium implant through the knee joint and inoculation with S. aureus Xen36 was performed. Bacterial burden was then quantified by longitudinal bioluminescent imaging.ResultsMice with CIA demonstrated significantly higher levels of systemic IgG compared with control mice (p = 0.003). Ex vivo, there was no significant difference in respiratory burst function (p = 0.89) or S. aureus bacterial burden as measured by CFU counts (p = 0.91) and crystal violet assay (p = 0.96). In vivo, no significant difference in bacterial bioluminescence between groups was found at all postoperative time points. CFU counts of both the implant and the peri-implant tissue were not significantly different between groups (p = 0.82 and 0.80, respectively).ConclusionThis study demonstrated no significant difference in S. aureus infectious burden between mice with CIA and control mice. These results suggest that untreated, active RA may not represent a significant intrinsic risk factor for PJI, however further mechanistic translational and clinical studies are warranted.

INTRODUCTION:High quality diagnostic imaging can provide increased diagnostic accuracy and help guide medical decision-making and management, however challenges for radiology in resource-limited settings are numerous. Diagnostic imaging and teleradiology have financial and logistical implications, so evidence of impact is crucial. We sought to test the hypothesis that the implementation of computed radiography with teleradiology consultation support will significantly change diagnoses and treatment plans in a resource limited setting. METHOD:Paired before-after study to determine the therapeutic impact of an add-on diagnostic test. 'Preliminary Plan' and 'Final Plan' forms allowed direct comparison of diagnosis and treatment plans at initial consultation and following radiography and teleradiology. Consecutive consenting patients were included until the sample size (600) was reached. Changes in both diagnosis and treatment plan were analysed in the whole cohort, with sub-analyses of children aged