COVID-19 Induces Neuroinflammation and Suppresses Peroxisomes in the Brain.

OBJECTIVE: Peroxisome injury occurs in the central nervous system (CNS) during multiple virus infections that result in neurological disabilities. We investigated host neuroimmune responses and peroxisome biogenesis factors during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using a multiplatform strategy. METHODS: Brain tissues from coronavirus disease 2019 (COVID-19) (n = 12) and other disease control (ODC) (n = 12) patients, as well as primary human neural cells and Syrian hamsters, infected with a clinical variant of SARS-CoV-2, were investigated by droplet digital polymerase chain reaction (ddPCR), quantitative reverse transcriptase PCR (RT-qPCR), and immunodetection methods. RESULTS: SARS-CoV-2 RNA was detected in the CNS of 4 patients with COVID-19 with viral protein (NSP3 and spike) immunodetection in the brainstem. Olfactory bulb, brainstem, and cerebrum from patients with COVID-19 showed induction of pro-inflammatory transcripts (IL8, IL18, CXCL10, NOD2) and cytokines (GM-CSF and IL-18) compared to CNS tissues from ODC patients (p < 0.05). Peroxisome biogenesis factor transcripts (PEX3, PEX5L, PEX11ß, and PEX14) and proteins (PEX3, PEX14, PMP70) were suppressed in the CNS of COVID-19 compared to ODC patients (p < 0.05). SARS-CoV-2 infection of hamsters revealed viral RNA detection in the olfactory bulb at days 4 and 7 post-infection while inflammatory gene expression was upregulated in the cerebrum of infected animals by day 14 post-infection (p < 0.05). Pex3 transcript levels together with catalase and PMP70 immunoreactivity were suppressed in the cerebrum of SARS-CoV-2 infected animals (p < 0.05). INTERPRETATION: COVID-19 induced sustained neuroinflammatory responses with peroxisome biogenesis factor suppression despite limited brainstem SARS-CoV-2 neurotropism in humans. These observations offer insights into developing biomarkers and therapies, while also implicating persistent peroxisome dysfunction as a contributor to the neurological post-acute sequelae of COVID-19. ANN NEUROL 2023;94:531-546.

Evolving etiologies, comorbidities, survival, and costs of care in adult encephalitis.

Encephalitis is a central nervous system disorder, often caused by infectious agents or aberrant immune responses. We investigated causes, comorbidities, costs, and outcomes of encephalitis in a population-based cohort. ICD-10 codes corresponding to encephalitis were used to identify health services records for all adults from 2004 to 2019. Data were cross-validated for identified diagnoses based on laboratory confirmation using univariate and multivariate statistical analyses. We identified persons with a diagnosis of encephalitis and abnormal cerebrospinal fluid (CSF) results (n = 581) in whom viral genome was detected (n = 315) in a population of 3.2 million adults from 2004 to 2019. Viral genome-positive CSF samples included HSV-1 (n = 133), VZV (n = 116), HSV-2 (n = 34), enterovirus (n = 4), EBV (n = 5), and CMV (n = 3) with the remaining viruses included JCV (n = 12) and HHV-6 (n = 1). The mean Charlson Comorbidity Index (2.0) and mortality rate (37.6%) were significantly higher in the CSF viral genome-negative encephalitis group although the mean costs of care were significantly higher for the CSF viral genome-positive group. Cumulative incidence rates showed increased CSF VZV detection in persons with encephalitis, which predominated in persons over 65 years with a higher mean Charlson index. We detected HSV-2 and VZV more frequently in CSF from encephalitis cases with greater material-social deprivation. The mean costs of care were significantly greater for HSV-1 encephalitis group. Encephalitis remains an important cause of neurological disability and death with a viral etiology in 54.2% of affected adults accompanied by substantial costs of care and mortality. Virus-associated encephalitis is evolving with increased VZV detection, especially in older persons.

Infection of Glia by Human Pegivirus Suppresses Peroxisomal and Antiviral Signaling Pathways.

Human pegivirus (HPgV) infects peripheral leukocytes but was recently shown to be a neurotropic virus associated with leukoencephalitis in humans. In the present study, we investigated the neural cell tropism of HPgV as well as its effects on host immune responses. HPgV wild type (WT) and a mutant virus with a deletion in the HPgV NS2 gene (ΔNS2) were able to productively infect human astrocytes and microglia but not neurons or an oligodendrocyte-derived cell line. Of note, the ΔNS2 virus replicated better than WT pegivirus in astrocytes, with both viruses being able to subsequently infect and spread in fresh human astrocyte cultures. Infection of human glia by HPgV WT and ΔNS2 viruses resulted in suppression of peroxisome-associated genes, including PEX11B, ABCD1, PEX7, ABCD3, PEX3, and PEX5L, during peak viral production, which was accompanied by reduced expression of IFNB, IRF3, IRF1, and MAVS, particularly in ΔNS2-infected cells. These data were consistent with analyses of brain tissue from patients infected with HPgV in which we observed suppression of peroxisome and type I interferon gene transcripts, including PEX11B, ABCD3, IRF1, and IRF3, with concurrent loss of PMP70 immunoreactivity in glia. Our data indicate that human astrocytes and microglia are permissive to HPgV infection, resulting in peroxisome injury and suppressed antiviral signaling that is influenced by viral diversity. IMPORTANCE Human pegiviruses are detected in 1 to 5% of the general population, principally infecting leukocytes, although their effects on human health remain uncertain. Here, we show that human pegivirus infects specific neural cell types in culture and human brain and, like other neurotropic flaviviruses, causes suppression of peroxisome and antiviral signaling pathways, which could favor ongoing viral infection and perhaps confer susceptibility to the development of neurological disease.

The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer.

BACKGROUND: Pre-treatment tumour-associated lymphocytes (TILs) and stromal lymphocytes (SLs) are independent predictive markers of future pathological complete response (pCR) in HER2-positive breast cancer. Whilst studies have correlated baseline lymphocyte levels with subsequent pCR, few have studied the impact of neoadjuvant therapy on the immune environment. METHODS: We performed TIL analysis and T-cell analysis by IHC on the pretreatment and 'On-treatment' samples from patients recruited on the Phase-II TCHL (NCT01485926) clinical trial. Data were analysed using the Wilcoxon signed-rank test and the Spearman rank correlation. RESULTS: In our sample cohort (n = 66), patients who achieved a pCR at surgery, post-chemotherapy, had significantly higher counts of TILs (p = 0.05) but not SLs (p = 0.08) in their pre-treatment tumour samples. Patients who achieved a subsequent pCR after completing neo-adjuvant chemotherapy had significantly higher SLs (p = 9.09 × 10-3) but not TILs (p = 0.1) in their 'On-treatment' tumour biopsies. In a small cohort of samples (n = 16), infiltrating lymphocyte counts increased after 1 cycle of neo-adjuvant chemotherapy only in those tumours of patients who did not achieve a subsequent pCR. Finally, reduced CD3 + (p = 0.04, rho = 0.60) and CD4 + (p = 0.01, rho = 0.72) T-cell counts in 'On-treatment' biopsies were associated with decreased residual tumour content post-1 cycle of treatment; the latter being significantly associated with increased likelihood of subsequent pCR (p < 0.01). CONCLUSIONS: The immune system may be 'primed' prior to neoadjuvant treatment in those patients who subsequently achieve a pCR. In those patients who achieve a pCR, their immune response may return to baseline after only 1 cycle of treatment. However, in those who did not achieve a pCR, neo-adjuvant treatment may stimulate lymphocyte influx into the tumour.

Increased targeted HIV testing and reduced undiagnosed HIV infections among gay and bisexual men.

OBJECTIVES: To evaluate the impact of government HIV strategies that aimed to increase HIV testing uptake and frequency among gay and bisexual men (GBM) in New South Wales (NSW), Australia. DESIGN: We analysed HIV testing data from existing passive and sentinel surveillance systems between 2010 and 2018. METHODS: Six indicators were measured: (1) state-wide total HIV laboratory tests; (2) number of GBM attending publicly-funded clinics; (3) 12-monthly testing uptake; (4) annual testing frequency; (5) HIV testing with a STI diagnosis; and (6) HIV positivity. Mathematical modelling was used to estimate (7) the proportion of men with undiagnosed HIV. Indicators were stratified by Australian vs. overseas-born. RESULTS: Overall, 43,560 GBM attended participating clinics (22,662 Australian-born, 20,834 overseas-born) from 2010-2018. Attendees increased from 5,186 in 2010 to 16,507 in 2018. There were increasing trends (p<0.001 for all) in testing uptake (83.9% to 95.1%); testing with a STI diagnosis (68.7% to 94.0%); annual HIV testing frequency (1.4 to 2.7); and a decreasing trend (p<0.01) in HIV positivity (1.7% to 0.9%).Increases in testing were similar in Australian-born and overseas-born GBM. However, there were decreasing trends in the estimated undiagnosed HIV proportion overall (9.5% to 7.7%) and in Australian-born GBM (7.1% to 2.8%), but an increasing trend in overseas-born GBM (15.3% to 16.9%) (p<0.001 for all).

Progressive multifocal leukoencephalopathy and Creutzfeldt-Jakob disease: population-wide incidences, comorbidities, costs of care, and outcomes.

Neurological disorders associated with chronic infections are often progressive as well as challenging to diagnose and manage. Among 4.4 million persons from 2004 to 2019 receiving universal health, progressive multifocal leukoencephalopathy (PML, n = 58) and Creutzfeldt-Jakob disease (CJD, n = 93) cases were identified, revealing stable yearly incidence rates with divergent comorbidities: HIV/AIDS affected 37.8% of PML cases while cerebrovascular disease affected 26.9% of CJD cases. Most CJD cases died within 1 year (73%) although PML cases lived beyond 5 years (34.1%) despite higher initial costs of care. PML and CJD represent important neurological disorders with evolving risk variables and impact on health care.

Differential disease phenotypes and progression in relapsing-remitting multiple sclerosis: comparative analyses of single Canadian and Saudi Arabian clinics.

OBJECTIVE: Relapsing-remitting multiple sclerosis (RR-MS) phenotypes differ widely although the variables contributing to this heterogeneity remain uncertain. To assess geographic and ethnic effects on RR-MS phenotypes, we investigated RR-MS patients in Canada and Saudi Arabia. METHODS: A retrospective analysis of patients followed in two MS Clinics was performed in Medina, Saudi Arabia and Edmonton, Canada. Demographic and clinical data were collected for each patient and analyzed using univariable and multivariable statistics. Univariable and multivariable linear regression were used to distinguish the significant clinical and demographic features and neurological systems associated with the change in expanded disability status scale (EDSS) between clinical assessments. RESULTS: Patients with treated RR-MS were recruited (n = 51, Saudi; n = 47, Canada) although the disease duration was longer in the Canadian cohort (5.6 ± 2.2 yr.) compared to the Saudi cohort (4.4 ± 1.4 yr.) (P < 0.05), annual relapse rate and EDSS change were higher in the Saudi cohort (P < 0.05). Infratentorial lesion-associated presentation differed (Canada, n = 23; Saudi, n = 13) among groups (P < 0.05). Spinal cord lesions on MRI were more frequently detected in Canadian (n = 23) compared to Saudi (n = 1) patients (P < 0.05). Patients within the Saudi cohort displayed a significantly greater change in Expanded Disability Status Scale (EDSS) between first and second assessments. CONCLUSIONS: Despite differences in geographic location, ethnicity, and predominance of infratentorial lesions in the Canadian group, the RR-MS phenotypes were similar although the Saudi cohort displayed a more severe disease course.

Disability progression in multiple sclerosis is associated with plasma neuroactive steroid profile.

BACKGROUND: Neuroactive steroids (NASs) exert multiple biological effects on development and inflammation. The effects of NASs on disease progression in multiple sclerosis (MS) are uncertain, prompting analyses of NAS profiles during the transition from clinically isolated syndrome (CIS) to relapsing-remitting (RR) MS. METHODS: Subjects with CIS or RRMS and healthy controls (HCs) were recruited; demographic and clinical data as well as disability scores measured by the Expanded Disability Status Scale (EDSS) were recorded. Matched plasma NAS and amino acid (AA) concentrations were measured. RESULTS: HC (n = 17), CIS (n = 31), and RRMS (n = 33) groups showed similar ages and sex distribution although disability scores were higher in the RRMS group. The conversion rate of CIS to RRMS group was 51.6% (n = 16) during a mean follow-up period of 1.85 years. The RRMS group showed significantly higher mean allopregnanolone, aspartate, and taurine concentrations with lower epiallopregnanolone concentrations than CIS patients, and higher L-serine-O-phosphate and lower alanine, arginine, and glutamine concentrations than the HC group. Among CIS and RRMS groups, multivariate hierarchical regressions revealed that higher concentrations of plasma tetrahydrodeoxycorticosterone (THDOC) may predict disability worsening. CONCLUSIONS: RRMS and CIS patients exhibited differing concentrations of both NASs and AAs in plasma while both THDOC and pregnanolone might serve as biomarkers of disability worsening.

One-year parasitological screening of stray dogs and cats in County Dublin, Ireland.

To date, there are no recent studies identifying the prevalence of parasites of human and veterinary importance in dogs and cats in Ireland. The interaction between pets and wildlife species in the environment is an important source of parasite exposure to canids and felines, and one likely to be heightened in the stray animal population. This study aimed to establish the prevalence of endoparasites in unowned dogs and cats in County Dublin, Ireland. Feces from stray dogs (n = 627) and cats (n = 289) entering a rehoming centre were collected immediately after defecation. The main parasitic agents detected were ascarids (15.52 and 30.26%), Cystoisospora (3.27 and 3.69%), Giardia spp. (6.02 and 1.84%) and lungworms (0.64 and 2.08%), in dogs and cats respectively. Animals younger than 3 months of age were more likely to be infected with ascarids (P < 0.001) and Cystoisospora spp. (P = 0.008 and P = 0.014) than older animals. All lungworms were morphologically identified and dogs were infected with Angiostrongylus vasorum (0.48%) and Crenosoma vulpis (0.16%) whereas cats were only infected with Aelurostrongylus abstrusus (2.08%). This represents the first prevalence study of stray animals in Ireland. Data collected will inform the treatment and in addition, the future monitoring and control studies of parasite populations.

A hypothesis for the existence of two types of tuberculosis, reflecting two distinct types of immune failure to control the pathogen, based upon prevalence of mycobacterium-specific IgG subclasses.

Most people infected by Mycobacterium tuberculosis, about 90%, contain the pathogen and are healthy. Most investigators have concluded that pathogen-specific Th1 cells contribute to protection. Pulmonary tuberculosis, the most prevalent form of disease, is associated with destructive granulomas, the formation of which also appears to involve Th1 cells. In what sense then do the two Th1 components of the response, in healthy infected individuals and patients, differ? An insight into this question might provide clues for attaining effective vaccination and better treatment. We approached this question by examining the relative prevalence of different IgG isotypes among anti-mycobacterium-specific antibodies in patients and healthy infected individuals as a surrogate marker for the Th1/Th2 phenotype of the response. Our observations lead us to agree that healthy infected individuals generate a predominant Th1 response. Our observations also lead us to propose that many patients make a similar kind of response as healthy infected individuals, but that this response is too weak to contain the infection. We refer to such individuals as having type I tuberculosis. Other patients appear to have a greater and detrimental Th2 component to their immune response than that of healthy infected individuals. We refer to these individuals as having type II tuberculosis. This proposal that there are two types of tuberculosis, reflecting two distinct types of failure by the immune system, will, if correct, be pertinent to vaccine design, treatment of tuberculosis and in making further progress in our understanding the genetics of susceptibility to M. tuberculosis.

Are early-life antecedents of suicide mortality associated with psychiatric disorders and suicidal ideation in midlife?

OBJECTIVE: To establish whether previously identified early-life antecedents of suicide mortality (i.e. low birthweight, younger maternal age, higher birth order, externalizing problems and adversities) are associated with proximal psychiatric disorders and suicidal ideation, which are themselves associated with an increased risk of suicide. METHODS: Participants were from the 1958 British birth-cohort (N = 8905) with information on prenatal/childhood experiences and the Clinical Interview Schedule-Revised at age 45 years. Outcomes were as follows: any internalizing disorder (anxiety disorder/depressive episode), depressive episode, alcohol use disorder and suicidal ideation. RESULTS: After adjustment, higher birth order (Ptrend = 0.043), younger maternal age (Ptrend = 0.017) and increased number of childhood adversities (Ptrend = 0.026) were associated with an increased risk of internalizing disorders. For example, the OR (95% CI) in fourth- or later-born children was 1.48 (1.06-2.07) and for young maternal age (<19 years) was 1.31 (0.89-1.91). Effect sizes were similar in magnitude for depressive episode and suicidal ideation, although associations did not reach conventional significance levels. No associations were found for low birthweight and externalizing problems (in males) and investigated outcomes. CONCLUSION: Associations for younger maternal age, higher birth order and adversities with adult internalizing disorders suggest that psychiatric disorders may be on the pathway linking some early-life factors and suicide.

Childhood adversity and midlife suicidal ideation.

BACKGROUND: Childhood adversity predicts adolescent suicidal ideation but there are few studies examining whether the risk of childhood adversity extends to suicidal ideation in midlife. We hypothesized that childhood adversity predicts midlife suicidal ideation and this is partially mediated by adolescent internalizing disorders, externalizing disorders and adult exposure to life events and interpersonal difficulties. METHOD: At 45 years, 9377 women and men from the UK 1958 British Birth Cohort Study participated in a clinical survey. Childhood adversity was prospectively assessed at the ages of 7, 11 and 16 years. Suicidal ideation at midlife was assessed by the depressive ideas subscale of the Revised Clinical Interview Schedule. Internalizing and externalizing disorders were measured by the Rutter scales at 16 years. Life events, periods of unemployment, partnership separations and alcohol dependence were measured through adulthood. RESULTS: Illness in the household, paternal absence, institutional care, parental divorce and retrospective reports of parental physical and sexual abuse predicted suicidal ideation at 45 years. Three or more childhood adversities were associated with suicidal ideation at 45 years [odds ratio (OR) 4.31, 95% confidence interval (CI) 2.67-6.94]. Psychological distress at 16 years partially mediated the associations of physical abuse (OR 3.41, 95% CI 2.29-5.75), sexual abuse (OR 4.99, 95% CI 2.90-11.16) with suicidal ideation. Adult life events partially mediated the association of parental divorce (OR 6.34, 95% CI -7.16 to 36.75) and physical (OR 9.59, 95% CI 4.97-27.88) and sexual abuse (OR 6.59, 95% CI 2.40-38.36) with suicidal ideation at 45 years. CONCLUSIONS: Adversity in childhood predicts suicidal ideation in midlife, partially mediated by adolescent internalizing and externalizing disorders, adult life events and interpersonal difficulties. Understanding the pathways from adversity to suicidal ideation can inform suicide prevention and the targeting of preventive interventions.

Prenatal and childhood antecedents of suicide: 50-year follow-up of the 1958 British Birth Cohort study.

BACKGROUND: We aimed to elucidate early antecedents of suicide including possible mediation by early child development. METHOD: Using the 1958 birth cohort, based on British births in March 1958, individuals were followed up to adulthood. We used data collected at birth and at age 7 years from various informants. Suicides occurring up to 31 May 2009 were identified from linked national death certificates. Multivariable Cox proportional hazard models were used to investigate risk factors. RESULTS: Altogether 12399 participants (n = 44 suicides) had complete data. The strongest prenatal risk factors for suicide were: birth order, with risk increasing in later-born children [p trend = 0.063, adjusted hazard ratio (HR)], e.g. for fourth- or later-born children [HR = 2.27, 95% confidence interval (CI) 0.90-5.75]; young maternal age (HR = 1.18, 95% CI 0.34-4.13 for ⩽19 years and HR = 0.41, 95% CI 0.19-0.91 for >29 years, p trend = 0.034); and low (<2.5 kg) birth weight (HR = 2.48, 95% CI 1.03-5.95). The strongest risk factors at 7 years were externalizing problems in males (HR = 2.96, 95% CI 1.03-8.47, p trend = 0.050) and number of emotional adversities (i.e. parental death, neglected appearance, domestic tension, institutional care, contact with social services, parental divorce/separation and bullying) for which there was a graded association with risk of suicide (p trend = 0.033); the highest (HR = 3.12, 95% CI 1.01-9.62) was for persons with three or more adversities. CONCLUSIONS: Risk factors recorded at birth and at 7 years may influence an individual's long-term risk of suicide, suggesting that trajectories leading to suicide have roots in early life. Some factors are amenable to intervention, but for others a better understanding of causal mechanisms may provide new insights for intervention to reduce suicide risk.

Depressive symptoms and body mass index: co-morbidity and direction of association in a British birth cohort followed over 50 years.

BACKGROUND: An unhealthy body mass index (BMI) has been associated with depression but the direction of association is uncertain. Our aim was to estimate the co-morbidity and direction of association between BMI and depressive symptoms at several ages, from childhood to mid-adulthood. METHOD: The data were from 18,558 individuals born in 1 week in March 1958, in England, Scotland and Wales, with follow-up at ages 7, 11, 16, 23, 33, 42, 45 and 50 years. Depression (scores>or=90th percentile) was identified from child/adolescent (teacher questionnaires) and adult (self-complete questionnaires and clinical interview) measures. BMI (kg/m2) measured in child/adolescence and adulthood was classified as underweight, normal, overweight or obese. RESULTS: In cross-sectional analyses, obesity and underweight (not overweight) from 11 to 45 years were associated respectively with 1.3-2.1 and 1.5-2.3 times the risk of depression compared with normal weight. Using the time-lagged generalized estimating equation (GEE) approach, we tested (a) whether underweight or obesity at prior ages (7 to 45 years) predicted subsequent risk of depression (11 to 50 years), adjusting for baseline depression; and (b) whether depression at prior ages (7 to 42 years) predicted subsequent risk of underweight or obesity (11 to 45 years), adjusting for baseline BMI. In longitudinal analyses, underweight predicted subsequent depression in both sexes [odds ratio (OR) 1.25, 95% confidence interval (CI) 1.11-1.40] and depression predicted subsequent underweight in males only (OR 1.84, 95% CI 1.52-2.23). Obesity predicted subsequent depressive symptoms in females only (OR 1.34, 95% CI 1.14-1.56), but depression did not predict obesity. CONCLUSIONS: Clinicians should consider screening routinely for depression patients with unhealthy BMI, namely underweight and obesity, and vice versa.

Metabolomic profiling in multiple sclerosis: insights into biomarkers and pathogenesis.

Metabolomics enables the provision of sensitive bio-markers of disease. We performed 800 MHz (1)H-nuclear magnetic resonance (NMR) spectroscopic analyses of cerebrospinal fluid (CSF) specimens to identify biomarkers of multiple sclerosis (MS), yielding reproducible detection of 15 metabolites from MS (n=15) and non-MS (n=17) patients. Mean levels of choline, myo-inositol and threonate were increased, whereas 3-hydroxybutyrate, citrate, phenylalanine, 2-hydroxyisovalerate and mannose were decreased in MS-derived CSF (p<0.05), suggesting alterations to energy and phospholipid metabolism. Multivariate hierarchal cluster analysis indicated a high correlation within the metabolite profiles, significantly clustering samples into the two clinical groups, which was corroborated using principal components analysis. CSF metabolomics have the capacity to yield quantitative biomarkers and insights into the pathogenesis of MS.

Efficacy of neuromuscular exercises to promote movement quality and reduce musculoskeletal injury during initial military training in Royal Navy recruits.

INTRODUCTION: Musculoskeletal injuries (MSKIs) are a significant problem in the Royal Navy, contributing to 48% of all medical discharges from service between 2019 and 2020. The objective of the study was to assess efficacy of implementing a neuromuscular training intervention to improve movement quality and reduce MSKIs in Royal Navy recruits undertaking initial military training. METHODS: Neuromuscular training (pre-activation exercises, focusing on hip control) was integrated into the warm-up exercise regimen preceding physical training during the 10-week initial naval training (recruits) programme (January-March 2020) at HMS Raleigh (intervention group; n=162). A control group comprised (n=90) of recruits entering training from January 2019, who completed the standard warm-up programme prior to physical training. Movement control of the intervention group (intervention) was assessed before and after the 10-week programme using the Hip and Lower-Limb Movement Screen (HLLMS). Injury incidence proportion for both groups was determined retrospectively by review of medical notes. RESULTS: The control group's MSKI incidence proportion was 31%, which was higher (p<0.05) than the 8% reported in the intervention group. The majority of MSKIs were of the lower limb, and were reported in weeks 1, 2 and 5 of the 10-week training programme. Movement control, as assessed by the HLLMS score, improved (pretraining (week 1) and post-training (week 10) HLLMS score (mean (SD) pre: 11.2 (5.6); post: 8.4 (3.9); t=5.829, p<0.001) following the neuromuscular training in the intervention group but was not assessed in the control group. CONCLUSION: A neuromuscular control intervention was successfully implemented during the initial military training in the Royal Navy. The cohort undertaking the intervention demonstrated lower injury incidence compared with an equivalent cohort of recruits who undertook standard training. Movement control improved following the intervention, indicating better movement quality. Continued use of the programme may reduce military training attrition in the Royal Navy.

Parental obesity and risk factors for cardiovascular disease among their offspring in mid-life: findings from the 1958 British Birth Cohort Study.

BACKGROUND: Few studies have investigated whether parental adiposity is associated with offspring cardiovascular health or the underlying pathways. Studying these associations may help to illuminate the paradox of increasing prevalence of obesity and declining trends in cardiovascular disease (CVD) mortality, which may be partially explained by beneficial adaptations to an obesogenic environment among people exposed to such environments from younger ages. OBJECTIVE: To investigate associations between parental body mass index (BMI) and risk factors for CVD among their offspring in mid-life and to test whether associations of offspring BMI with CVD risk factors were modified by parental BMI. METHODS: Data from parents and offspring in the 1958 British birth cohort were used (N=9328). Parental BMI was assessed when offspring were aged 11 years; offspring BMI, waist circumference and CVD risk factors (lipid levels, blood pressure, glycosylated haemoglobin (HbA1c) and inflammatory and haemostatic markers) were measured at 44-45 years. RESULTS: Higher parental BMI was associated with less favourable levels of offspring risk factors for CVD. Most associations were maintained after adjustment for offspring lifestyle and socioeconomic factors but were largely abolished or reversed after adjustment for offspring adiposity. For some CVD risk factors, there was evidence of effect modification; the association between higher BMI and an adverse lipid profile among offspring was weaker if maternal BMI had been higher. Conversely, offspring BMI was more strongly associated with HbA1c if parental BMI had been higher. CONCLUSIONS: Intergenerational influences may be important in conferring the effect of high BMI on CVD risk among offspring.

Genetic association analysis of vitamin D pathway with obesity traits.

OBJECTIVE: Observational studies have examined the link between vitamin D deficiency and obesity traits. Some studies have reported associations between vitamin D pathway genes such as VDR, GC and CYP27B1 with body mass index (BMI) and waist circumference (WC); however, the findings have been inconsistent. Therefore, we investigated the involvement of vitamin D metabolic pathway genes in obesity-related traits in a large population-based study. METHODS: We undertook a comprehensive analysis between 100 tagging single nucleotide polymorphisms (tagSNPs) in genes encoding for DHCR7, CYP2R1, VDBP, CYP27B1, CYP27A1, CYP24A1, VDR and RXRG, and obesity traits in 5224 participants (aged 45 years) in the 1958 British birth cohort (1958BC). We further extended our analyses to investigate the associations between SNPs and obesity traits using the summary statistics from the GIANT (Genetic Investigation of Anthropometric Traits) consortium (n=123 865). RESULTS: In the 1958BC (n=5224), after Bonferroni correction, none of the tagSNPs were associated with obesity traits except for one tagSNP from CYP24A1 that was associated with waist-hip ratio (WHR) (rs2296239, P=0.001). However, the CYP24A1 SNP was not associated with BMI-adjusted WHR (WHRadj) in the 1958BC (rs2296239, P=1.00) and GIANT results (n=123 865, P=0.18). There was also no evidence for an interaction between the tagSNPs and obesity on BMI, WC, WHR and WHRadj in the 1958BC. In the GIANT consortium, none of the tagSNPs were associated with obesity traits. CONCLUSIONS: Despite a very large study, our findings suggest that the vitamin D pathway genes are unlikely to have a major role in obesity-related traits in the general population.

Predictors of symptomatic HIV-associated neurocognitive disorders in universal health care.

OBJECTIVES: The aim of the study was to determine the risk factors predictive of symptomatic HIV-associated neurocognitive disorders (sHAND) among HIV-infected patients receiving active medical care. METHODS: Baseline demographic and clinical characteristics were analysed in patients with sHAND (HIV-associated dementia and minor neurocognitive disorder) in a population-based longitudinal cohort of HIV-infected patients with access to universal health care, including combination antiretroviral therapy (cART) from 1999 to 2008. Variables evaluated for their association with sHAND included age and ethnicity, survival duration with HIV-1 infection, vascular disease risk factors, and laboratory indices such as blood CD4 T-cell count at its nadir and at cART initiation, using both univariable and multivariable logistic regression models. RESULTS: A total of 1320 patients were investigated, including the patients diagnosed with sHAND (n = 90) during the study period. In univariable analyses, increased age, increased length of survival with HIV, low nadir CD4 and CD8 T-cell counts, high baseline viral load (> 1,000,000 HIV-1 RNA copies/mL), and African origin were predictive of a diagnosis of sHAND (P < 0.05). In multivariable analysis, increased age, increased length of survival, low nadir CD4 T-cell counts, and high baseline viral load remained predictive of sHAND (P < 0.05). Remarkably, CD4 T-cell counts at cART initiation, hepatitis C virus coinfection, and vascular disease risk factors failed to predict sHAND in both analyses. CONCLUSIONS: Increased age and survival duration, lower nadir CD4 T-cell counts, and higher baseline viral load were consistent predictors of the development of sHAND among persons with HIV/AIDS in universal health care, underscoring the importance of attention to these variables in clinical care.