The role of the central nervous system as a sanctuary site for HIV due to limited penetration of antiretroviral drugs

Introduction. HIV-associated neurocognitive disorders appear to remain common despite access to antiretroviral therapy (ART). Penetration of ART into the central nervous system (CNS) is highly variable between drugs and between individuals. Cerebrospinal fluid (CSF) concentrations of many antiretroviral medications fall below the minimum inhibitory concentration for wild type virus. HIV-1 RNA can be detected in the CSF at greater levels than in plasma (CSF/plasma discordance), however the clinical significance of this is unclear, and the degree of difference considered pathological varies. Whether the CNS can act as a sanctuary site leading to persistent HIV detection in plasma is not known. Methods. The PARTITION study recruited HIV positive adults from 13 UK clinical sites. Paired CSF and plasma was collected from patients undergoing LP for clinical indication (group A) and subjects with unexplained viraemia despite ART (group B). The study aimed to determine a) the prevalence of CSF/plasma discordance and factors associated with this occurrence, and b) the prevalence of HIV-1 RNA detection in CSF in those with HIV-1 RNA persistence in plasma. A sensitive assay detected HIV-1 RNA below 50 copies/ml in a subgroup and a cytometric bead array determined CSF biomarkers. A matrix of clinical features and CSF/plasma biomarkers was related to cognitive decline in subjects from the CHARTER study. Drug concentrations in CSF and plasma were measured by mass spectrometry assays and related to host genetic factors in subjects in the PARTITION study and a Vietnamese cohort with tuberculous meningitis. Results. CSF/plasma HIV discordance occurred in 13% of this cohort and was associated with nadir, but not current, CD4 cell count. CSF/plasma discordance occurred in 7 of 40 (18%) of subjects with ongoing viral detection in plasma vs. 0 of 39 of those without. Residual HIV-1 RNA detection below 50 copies/ml was also associated with CSF HIV-1 RNA detection. Resistance associated HIV mutations were detected in CSF of subjects with CSF/plasma discordance. CSF/plasma discordance above 0.5log10 was associated with raised profiles of inflammatory CSF proteomic biomarkers compared to those without discordance. In the CHARTER cohort, cognitive decline over 18 months was associated with lower concentrations of CSF TNFa and plasma IGF1/2. CSF concentrations of efavirenz were associated with the CYP2B6 c.516G>T single nucleotide polymorphism. Efavirenz metabolites were mainly glucuronidated in CSF, were present at neurotoxic levels, and were related to degree of blood brain barrier permeability. Host genetic factors were did not relate to CSF DRV concentrations. Conclusions. CSF/plasma discordance is a frequent occurrence, likely related to processes established during advanced immunosuppression not fully reversed by ART. It is associated with CSF HIV resistance and raised CSF biomarkers, even at levels 0.5-1log10 which have been considered non-significant in some studies. Potentially neurotoxic CSF concentrations of efavirenz relate to host genetic factors

Interrogating the technical, economic and cultural challenges of delivering the PassivHaus standard in the UK.

A peer-reviewed eBook, which is based on a collaborative research project coordinated by Dr. Henrik Schoenefeldt at the Centre for Architecture and Sustainable Environment at the University of Kent between May 2013 and June 2014. This project investigated how architectural practice and the building industry are adapting in order to successfully deliver Passivhaus standard buildings in the UK. Through detailed case studies the project explored the learning process underlying the delivery of fourteen buildings, certified between 2009 and 2013. Largely founded on the study of the original project correspondence and semi-structured interviews with clients, architects, town planners, contractors and manufacturers, these case studies have illuminated the more immediate technical as well as the broader cultural challenges. The peer-reviewers of this book stressed that the findings included in the book are valuable to students, practitioners and academic researchers in the field of low-energy design. It was launched during the PassivHaus Project Conference, held at the Bulb Innovation Centre on the 27th June 2014

Exercise and aerobic capacity in individuals with spinal cord injury:A systematic review with meta-analysis and meta-regression

BACKGROUND: A low level of cardiorespiratory fitness [CRF; defined as peak oxygen uptake (V̇O2peak) or peak power output (PPO)] is a widely reported consequence of spinal cord injury (SCI) and a major risk factor associated with chronic disease. However, CRF can be modified by exercise. This systematic review with meta-analysis and meta-regression aimed to assess whether certain SCI characteristics and/or specific exercise considerations are moderators of changes in CRF.METHODS AND FINDINGS: Databases (MEDLINE, EMBASE, CENTRAL, and Web of Science) were searched from inception to March 2023. A primary meta-analysis was conducted including randomised controlled trials (RCTs; exercise interventions lasting &gt;2 weeks relative to control groups). A secondary meta-analysis pooled independent exercise interventions &gt;2 weeks from longitudinal pre-post and RCT studies to explore whether subgroup differences in injury characteristics and/or exercise intervention parameters explained CRF changes. Further analyses included cohort, cross-sectional, and observational study designs. Outcome measures of interest were absolute (AV̇O2peak) or relative V̇O2peak (RV̇O2peak), and/or PPO. Bias/quality was assessed via The Cochrane Risk of Bias 2 and the National Institute of Health Quality Assessment Tools. Certainty of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Random effects models were used in all meta-analyses and meta-regressions. Of 21,020 identified records, 120 studies comprising 29 RCTs, 67 pre-post studies, 11 cohort, 7 cross-sectional, and 6 observational studies were included. The primary meta-analysis revealed significant improvements in AV̇O2peak [0.16 (0.07, 0.25) L/min], RV̇O2peak [2.9 (1.8, 3.9) mL/kg/min], and PPO [9 (5, 14) W] with exercise, relative to controls (p &lt; 0.001). Ninety-six studies (117 independent exercise interventions comprising 1,331 adults with SCI) were included in the secondary, pooled meta-analysis which demonstrated significant increases in AV̇O2peak [0.22 (0.17, 0.26) L/min], RV̇O2peak [2.8 (2.2, 3.3) mL/kg/min], and PPO [11 (9, 13) W] (p &lt; 0.001) following exercise interventions. There were subgroup differences for RV̇O2peak based on exercise modality (p = 0.002) and intervention length (p = 0.01), but there were no differences for AV̇O2peak. There were subgroup differences (p ≤ 0.018) for PPO based on time since injury, neurological level of injury, exercise modality, and frequency. The meta-regression found that studies with a higher mean age of participants were associated with smaller changes in AV̇O2peak and RV̇O2peak (p &lt; 0.10). GRADE indicated a moderate level of certainty in the estimated effect for RV̇O2peak, but low levels for AV̇O2peak and PPO. This review may be limited by the small number of RCTs, which prevented a subgroup analysis within this specific study design.CONCLUSIONS: Our primary meta-analysis confirms that performing exercise &gt;2 weeks results in significant improvements to AV̇O2peak, RV̇O2peak, and PPO in individuals with SCI. The pooled meta-analysis subgroup comparisons identified that exercise interventions lasting up to 12 weeks yield the greatest change in RV̇O2peak. Upper-body aerobic exercise and resistance training also appear the most effective at improving RV̇O2peak and PPO. Furthermore, acutely injured, individuals with paraplegia, exercising for ≥3 sessions/week will likely experience the greatest change in PPO. Ageing seemingly diminishes the adaptive CRF responses to exercise training in individuals with SCI.REGISTRATION: PROSPERO: CRD42018104342.</p

Estimating number of cases and spread of coronavirus disease (COVID-19) using critical care admissions, United Kingdom, February to March 2020.

An exponential growth model was fitted to critical care admissions from two surveillance databases to determine likely coronavirus disease (COVID-19) case numbers, critical care admissions and epidemic growth in the United Kingdom before the national lockdown. We estimate, on 23 March, a median of 114,000 (95% credible interval (CrI): 78,000-173,000) new cases and 258 (95% CrI: 220-319) new critical care reports, with 527,000 (95% CrI: 362,000-797,000) cumulative cases since 16 February

Clinical and prognostic features among children with acute encephalitis syndrome in Nepal; a retrospective study

<p>Abstract</p> <p>Background</p> <p>Acute encephalitis syndrome (AES) is commonly seen among hospitalized Nepali children. Japanese Encephalitis (JE) accounts for approximately one-quarter of cases. Although poor prognostic features for JE have been identified, and guide management, relatively little is reported on the remaining three-quarters of AES cases.</p> <p>Methods</p> <p>Children with AES (n = 225) were identified through admission records from two hospitals in Kathmandu between 2006 and 2008. Patients without available lumbar puncture results (n = 40) or with bacterial or plasmodium infection (n = 40) were analysed separately. The remaining AES patients with suspected viral aetiology were classified, based on positive IgM antibody in serum or cerebral spinal fluid, as JE (n = 42) or AES of unknown viral aetiology (n = 103); this latter group was sub-classified into Non-JE (n = 44) or JE status unknown (n = 59). Bad outcome was defined as death or neurological sequelae at discharge.</p> <p>Results</p> <p>AES patients of suspected viral aetiology more frequently had a bad outcome than those with bacterial or plasmodium infection (31% versus 13%; P = 0.039). JE patients more frequently had a bad outcome than those with AES of unknown viral aetiology (48% versus 24%; P = 0.01). Bad outcome was independently associated in both JE and suspected viral aetiology groups with a longer duration of fever pre-admission (P = 0.007; P = 0.002 respectively) and greater impairment of consciousness (P = 0.02; P < 0.001). A higher proportion of JE patients presented with a focal neurological deficit compared to patients of unknown viral aetiology (13/40 versus 11/103; P = 0.005). JE patients weighed less (P = 0.03) and exhibited a higher respiratory rate (P = 0.003) compared to Non-JE patients.</p> <p>Conclusions</p> <p>Nepali children with AES of suspected viral aetiology or with JE frequently suffered a bad outcome. Despite no specific treatment, patients who experienced a shorter duration of fever before hospital admission more frequently recovered completely. Prompt referral may allow AES patients to receive potentially life-saving supportive management. Previous studies have indicated supportive management, such as fluid provision, is associated with better outcome in JE. The lower weight and higher respiratory rate among JE patients may reflect multiple clinical complications, including dehydration. The findings suggest a more systematic investigation of the influence of supportive management on outcome in AES is warranted.</p

Bumps and Babies Longitudinal Study (BABBLES): An independent evaluation of the Baby Buddy app

Introduction: Developments in information and communication technologies have enabled and supported the development and expansion of electronic health in the last decade. This has increased the possibility of self-management and care of health issues.Objectives: To assess the effectiveness of on maternal self-efficacy and mental wellbeing three months post-birth in a sample of mothers recruited during the antenatal period. In addition, to explore when, why and how mothers use the app and consider any benefits the app may offer them in relation to their parenting, health, relationships or communication with their child, friends, family members or health professionals.Design: A mixed methods approach, including a longitudinal cohort study, a qualitative study and detailed analysis and synthesis of data from the Baby Buddy app about the way in which mothers accessed and used the app content.Setting: The study was conducted in five geographically separate sites in England: Coventry, Lewisham, Bradford, Blackpool and Leicester. These areas were chosen as they were geographically, ethnically and socio-economically diverse and where the Baby Buddy app was reported to be well-embedded, both formally and informally, into the maternity and child health pathways by the relevant healthcare staff.Participants: Pregnant women who were aged 16 years and over, had no previous live child, were between 12-16 weeks and six days gestation and booked with the maternity services in each of the five study sites were invited to take part.Interventions: Self-reported use of the Baby Buddy app at one of the three data collection time-points: 12-16+6 weeks gestation, 35 weeks gestation and three months post-birth.Outcome measures: The primary outcome measure was parental self-efficacy at three months post-birth using the Tool to measure Parenting Self-Efficacy (TOPSE). The main secondary outcome was maternal mental well-being at three months post-birth using the Warwick and Edinburgh Mental Wellbeing Scale (WEMWBS).Results: Recruitment took place between September 2016 and February 2017. A total of 488 participants provided valid data at baseline (12-16 weeks gestation), 296 participants also provided valid data at 3 months post-birth, 114 (38.5%) of whom reported that they had used the Baby Buddy app at one or more of the data collection time-points (‘app user’). Seventeen first-time mothers participated in the qualitative arm via telephone interviews (n=9) and a focus group (n=8). Twenty healthcare professionals participated in interviews (n=5) and two focus groups (n=15). Consent was gained from 98 participants who gave permission for their in-app4data to be made accessible but just 61 participants could be identified from the database provided, of whom 51 were included in the analyses.At recruitment there were no differences between Baby Buddy app users and non-app users in respect to: age, IMD, ethnicity, highest education, employment, relationship status. Baby Buddy app users were more likely to use pregnancy or parenting apps (80.7% vs 69.6%, p=.035), more likely to have been introduced to the app by a healthcare professional (p=.005) and have a lower median score for perceived social support (81 vs 83, p=.034) than non-app users. The Baby Buddy app did not illicit a statistically significant change in TOPSE scores from baseline to 3 months post-birth (adjusted OR 1.12, 95%CI 0.59 to 2.13, p=.730). Finding out about the Baby Buddy app from a healthcare professional appeared to grant no additional benefit to app users compared to all other participants in terms of self-efficacy at three months post-birth (adjusted OR 1.16, 95%CI 0.60 to 2.23, p=.666).Apps were popular; Baby Buddy app users were more likely to use other pregnancy-related apps than non-Baby Buddy users and the most frequent source from which Baby Buddy app users found out about the app was a midwife. A post-hoc analysis found that Baby Buddy app users were more likely to breastfeed than non-Baby Buddy app users. This was a consistent pattern for both exclusive breastfeeding and any breast feeding: there was a 9% increase in exclusive breastfeeding at any time up to 3 months post-birth in Baby Buddy app users and a 12% increase in any breastfeeding up to three months post-birth, compared to non-app users. Whilst this is an important finding, this needs to be used with care due to the post-hoc element of the analysis.First-time mothers who participated in the qualitative arm of the study found that the Baby Buddy app worked well due to its accessibility and that the information was concise and easy to find. They liked that it followed the progress of pregnancy with appropriately-timed information and that different aspects could be accessed as and when needed. The app was designed to be an adjunct to service delivery not a replacement for healthcare. The importance of this was demonstrated by many first-time mothers reporting that they preferred in-practice support from a healthcare professional.The qualitative data indicated that the four preconditions of normalisation process theory: implementation, adoption, translation and stabilisation were met in regard to healthcare professionals’ use of the Baby Buddy app. This suggests that the healthcare professionals were actively integrating the Baby Buddy app into clinical practice with other professionals and first-time mothers, therefore embedding the Baby Buddy app into their service delivery.The in-app data from the sub-sample of participants (n=51) suggest that there was a difference in the amount of time participants spent accessing elements of the app; the median time spent using the app per session was 8.3 minutes (SD 5.8 minutes). The most popular features that5were used were ‘Today’s Information’, videos, ‘Bump/Baby Booth’, ‘Ask Me’ and ‘What does that mean?’. Participants used the app most often between 9-10am with another peak in the evening around 8-9pm. There were also a broad range of topics and issues that the participants searched for, of which the most searched words included: ‘labour’, ‘form’, ‘birth’, ‘pregnant’ and ‘developing’. In the sub-sample for whom we had in-app data, there was a large range for the number of times the app was used, from 0-593 times. The median number of times the app was opened was 146.5 but the data were positively skewed (LQ 52.5 – UQ 329). This indicates that the data are bunched towards the smaller number of times opened. Within this sub-sample, 21.6% of the engaged type of user used the app up to 25 times and 47% of this type of user used the app more than 100 times. This contrasts with the highly engaged type of user where 43% used the app 25 or less times and just 9.8% of this proactive type of user used it more than 100 times.We found no statistically significant difference in the TOPSE or the WEMWBS scores between the type of user who was engaged with the app and non-app users (adjusted OR 0.69, 95%CI 0.22 to 2.16, p=.519 and adjusted OR 1.54, 95%CI 0.57 to 4.16, p=.329, respectively). Similarly, we found no statistically significant difference between the type of users who were highly engaged users and non-app users (TOPSE: adjusted OR 0.48, 95%CI 0.14t o 1.68, p=.251; WEMWBS: adjusted OR 1.40, 95%CI 0.52 to 3.76, p=.509).Strengths and limitations: The primary objective was to explore the impact of the Baby Buddy app on parental self-efficacy and the Tool for Parenting Self-Efficacy (TOPSE website, Kendall, Bloomfield and Nash 2009), a validated measure, was selected to measure the primary outcome. The retention rate of 60.7% from baseline to three months post-birth demonstrates the difficulty of engaging new mothers during this demanding period of their lives. Nevertheless, in the initial and final samples, app users and non-users remained generally comparable and relevant confounders were adjusted for. Mothers were invited to take part in interviews and/or focus groups, the latter of which were held in a baby-friendly, welcoming environment for women and babies. Telephone interviews were offered for greater convenience for the women. Analysing the in-app data, we were able to compare outcomes for both the high versus low or non-user app groups and for those mothers who were the type of highly engaged users versus those who were a less engaged type. This was for a relatively small number of mothers but was a new method of analysing the in-app data.The Baby Buddy app was publicly available, meaning randomisation was not possible and therefore participants were only asked about their specific use of the app after the 35 weeks gestation data collection point to avoid directed app use. The participants were a self-selected group, especially those for whom we had in-app data and this is reflected in the higher than the national average for women who were degree holders (58.6% in final sample versus 42% nationally). The overall TOPSE scores were high at baseline which meant there was little room6for improvement. Nevertheless, there was no difference between the Baby Buddy app users and those participants who did not use the app.Conclusions: First-time mothers in the study found the app accessible and the information concise. The quantitative results, including those from the in-app data, found no evidence of impact from the Baby Buddy app on the primary outcome of parental self-efficacy or mental well-being (secondary outcome) at three months post-birth. The participant mothers had lower social support scale scores, which might suggest that the app attracted mothers who had a smaller social support network. Both mothers and healthcare professionals valued the fact that the Baby Buddy app was professionally endorsed which encouraged the women to trust the contents and the healthcare professionals to use it in their everyday practice. The most frequent source from which Baby Buddy app users found out about the app was a midwife, which suggests that the embedding of the app into service delivery by Best Beginnings was beneficial. A post-hoc finding was that women who used the Baby Buddy app were significantly more likely to exclusively breastfeed, or ever breastfeed, than those not using the app. The Baby Buddy app has gone some way to help to ‘Make Every Contact Count’ for both first-time mothers and healthcare professionals

Analysis of temporal trends in potential COVID-19 cases reported through NHS Pathways England.

The National Health Service (NHS) Pathways triage system collates data on enquiries to 111 and 999 services in England. Since the 18th of March 2020, these data have been made publically available for potential COVID-19 symptoms self-reported by members of the public. Trends in such reports over time are likely to reflect behaviour of the ongoing epidemic within the wider community, potentially capturing valuable information across a broader severity profile of cases than hospital admission data. We present a fully reproducible analysis of temporal trends in NHS Pathways reports until 14th May 2020, nationally and regionally, and demonstrate that rates of growth/decline and effective reproduction number estimated from these data may be useful in monitoring transmission. This is a particularly pressing issue as lockdown restrictions begin to be lifted and evidence of disease resurgence must be constantly reassessed. We further assess the correlation between NHS Pathways reports and a publicly available NHS dataset of COVID-19-associated deaths in England, finding that enquiries to 111/999 were strongly associated with daily deaths reported 16 days later. Our results highlight the potential of NHS Pathways as the basis of an early warning system. However, this dataset relies on self-reported symptoms, which are at risk of being severely biased. Further detailed work is therefore necessary to investigate potential behavioural issues which might otherwise explain our conclusions

The local burden of disease during the first wave of the COVID-19 epidemic in England: estimation using different data sources from changing surveillance practices.

BACKGROUND: The COVID-19 epidemic has differentially impacted communities across England, with regional variation in rates of confirmed cases, hospitalisations and deaths. Measurement of this burden changed substantially over the first months, as surveillance was expanded to accommodate the escalating epidemic. Laboratory confirmation was initially restricted to clinical need ("pillar 1") before expanding to community-wide symptomatics ("pillar 2"). This study aimed to ascertain whether inconsistent measurement of case data resulting from varying testing coverage could be reconciled by drawing inference from COVID-19-related deaths. METHODS: We fit a Bayesian spatio-temporal model to weekly COVID-19-related deaths per local authority (LTLA) throughout the first wave (1 January 2020-30 June 2020), adjusting for the local epidemic timing and the age, deprivation and ethnic composition of its population. We combined predictions from this model with case data under community-wide, symptomatic testing and infection prevalence estimates from the ONS infection survey, to infer the likely trajectory of infections implied by the deaths in each LTLA. RESULTS: A model including temporally- and spatially-correlated random effects was found to best accommodate the observed variation in COVID-19-related deaths, after accounting for local population characteristics. Predicted case counts under community-wide symptomatic testing suggest a total of 275,000-420,000 cases over the first wave - a median of over 100,000 additional to the total confirmed in practice under varying testing coverage. This translates to a peak incidence of around 200,000 total infections per week across England. The extent to which estimated total infections are reflected in confirmed case counts was found to vary substantially across LTLAs, ranging from 7% in Leicester to 96% in Gloucester with a median of 23%. CONCLUSIONS: Limitations in testing capacity biased the observed trajectory of COVID-19 infections throughout the first wave. Basing inference on COVID-19-related mortality and higher-coverage testing later in the time period, we could explore the extent of this bias more explicitly. Evidence points towards substantial under-representation of initial growth and peak magnitude of infections nationally, to which different parts of the country contribute unequally