Neuraminidase inhibitors: who, when, where?

Although the neuraminidase inhibitors (NIs), oseltamivir and zanamivir were first licensed in 1999, their clinical effectiveness is still hotly debated. Two rigorous systematic reviews and meta-analyses of the data from clinical trials conducted in community settings against relatively benign influenza, both suggest that reductions in symptom duration are extremely modest, under one day. Whilst one of these reviews could find no evidence of reductions in complications, the most recent review reported clinically meaningful and statistically significant reductions in the likelihood of requiring antibiotics (44%) and hospitalizations (63%) in adult patients with confirmed influenza, treated with oseltamivir. A further meta-analysis of observational data from the 2009 influenza A(H1N1) pandemic suggested that, in hospitalised patients, NIs significantly reduced mortality in adults by 25% overall, and by 62% if started within 48 hours of symptom onset, compared with no treatment. But, the effectiveness of NIs in children is far less clear. Taken together, these data suggest that NIs should be reserved for patients with influenza who are at high-risk of complications, or when clinically assessed found to be markedly unwell, or rapidly deteriorating. In such patients, treatment should be initiated empirically, as soon as possible, preferably with follow-on virological confirmation

Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis

Introduction: The objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA). Methods: We conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined. Results: 2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P < 0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P < 0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013). Conclusion: TGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA

Motor development in infancy and spine shape in early old age: findings from a British birth cohort study

Spine shape changes dramatically in early life, influenced by attainment of developmental milestones such as independent walking. Whether these associations persist across life is unknown. Therefore, we investigated associations between developmental milestones and spine shape, as determined using statistical shape models (SSMs) of lumbar spine from DXA scans in 1327 individuals (688 female) at 60‐64y in the MRC National Survey of Health and Development. Lumbar lordosis angle (L4 inferior endplate to T12 superior endplate) was measured using the two‐line Cobb method. In analyses adjusted for sex, height, lean and fat mass, socioeconomic position and birthweight, later walking age was associated with greater lordosis described by SSM1 (regression coefficient 0.023, 95%CI 0.000‐0.047, p=0.05) and direct angle measurement. Modest associations between walking age and less variation in anterior‐posterior vertebral size caudally (SSM6) were also observed (0.021, 95%CI ‐0.002‐0.044, p=0.07). Sex interactions showed that later walking was associated with larger relative vertebral anterior‐posterior dimensions in men (SSM3; ‐0.043, 95%CI ‐0.075‐0.01, p=0.01) but not women (0.018, 95%CI ‐0.0007‐0.043, p=0.17). Similar associations were observed between age at independent standing and SSMs but there was little evidence of association between sitting age and spine shape. Unadjusted associations between walking age and SSMs 1 and 6 remained similar after adjustment for potential confounders and mediators. This suggests that these associations may be explained by altered mechanical loading of the spine during childhood growth, although other factors could contribute. Early life motor development, particularly walking, may have a lasting effect on features of spine morphology with clinical significance

Age at onset of walking in infancy is associated with hip shape in early old age

Bones’ shapes and structures adapt to the muscle and reaction forces they experience during everyday movements. Onset of independent walking, at approximately 12 months, represents the first postnatal exposure of the lower limbs to the large forces associated with bipedal movements, and, accordingly, earlier walking is associated with greater bone strength. However, associations between early life loading and joint shape have not been explored. We therefore examined associations between walking age and hip shape at age 60-64y in 1423 individuals (740 women) from the MRC National Survey of Health and Development, a nationally-representative British birth cohort. Walking age in months was obtained from maternal interview at age 2y. Ten modes of variation in hip shape (HM1-HM10), described by statistical shape models, were ascertained from dual-energy X-ray absorptiometry (DXA) images. In sex-adjusted analyses, earlier walking age was associated with higher HM1 and HM7 scores; these associations were maintained after further adjustment for height, body composition and socioeconomic position. Earlier walking was also associated with lower HM2 scores in women only, and lower HM4 scores in men only. Taken together, this suggests that earlier walkers have proportionately larger (HM4) and flatter (HM1,4) femoral heads, wider (HM1,4,7) and flatter (HM1, 7) femoral necks, smaller neck-shaft angle (HM1,4), anteversion (HM2,7) and development of osteophytes (HM1). These results suggest that age at onset of walking in infancy is associated with variations in hip shape in older age. Early walkers have a larger femoral head and neck and smaller neck-shaft angle; these features are associated with reduced hip fracture risk, but also represent an osteoarthritic-like phenotype. Unlike results of previous studies of walking age and bone mass, associations in this study were not affected by adjustment for lean mass suggesting that associations may relate directly to skeletal loading in early life when joint shape changes rapidly. This article is protected by copyright. All rights reserve

Associations between body mass index across adult life and hip shapes at age 60 to 64:Evidence from the 1946 British birth cohort

Funding: The NSHD is funded by the UK Medical Research Council. SGM, RC, RJH and DK are supported by the UK Medical Research Council (Programme codes: MC_UU_12019/1, MC_UU_12019/2 and MC_UU_12019/4). This project was funded by the UK Medical Research Council (Grant MR/L010399/1) which supported SGM, AVP and FRS. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of this manuscript. Acknowledgements: We thank Dr. Michael Machin for his valuable assistance obtaining the images and the University of Aberdeen Data Management Team for programming support for ‘Shape’. The authors are grateful to NSHD study members who took part in the clinic data collection for their continuing support. We thank members of the NSHD scientific and data collection teams at the following centres: MRC Unit for Lifelong Health and Ageing; Wellcome Trust (WT) Clinical Research Facility (CRF) Manchester; WTCRF and Medical Physics at the Western General Hospital in Edinburgh; WTCRF and Department of Nuclear Medicine at University Hospital Birmingham; WTCRF and the Department of Nuclear Medicine at University College London Hospital; CRF and the Department of Medical Physics at the University Hospital of Wales; CRF and Twin Research Unit at St Thomas' Hospital London. Data used in this publication are available to bona fide researchers upon request to the NSHD Data Sharing Committee via a standard application procedure. Further details can be found at: http://www.nshd.mrc.ac.uk/data; doi: http://dx.doi.org/10.5522/NSHD/Q102; doi: http://dx.doi.org/10.5522/NSHD/Q102A.Peer reviewedPublisher PD

Impact of outpatient neuraminidase inhibitor treatment in patients infected with influenza A(H1N1)pdm09 at high risk of hospitalization: an Individual Participant Data (IPD) meta-analysis

Background: While evidence exists to support the effectiveness of neuraminidase inhibitors (NAIs) in reducing mortality when given to hospitalized patients with A(H1N1)pdm09 virus infection, the impact of outpatient treatment on hospitalization has not been clearly established. We investigated the impact of outpatient NAI treatment on subsequent hospitalization in patients with A(H1N1)pdm09 virus infection. Methods: We assembled general community and outpatient data from 9 clinical centers in different countries collected between January 2009 and December 2010. We standardized data from each study center to create a pooled dataset and then used mixed-effects logistic regression modeling to determine the effect of NAI treatment on hospitalization. We adjusted for NAI treatment propensity and preadmission antibiotic use, including “study center” as a random intercept to account for differences in baseline hospitalization rate between centers. Results: We included 3376 patients with influenza A(H1N1)pdm09, of whom 3085 (91.4%) had laboratory-confirmed infection. Eight hundred seventy-three patients (25.8%) received outpatient or community-based NAI treatment, 928 of 2395 (38.8%) with available data had dyspnea or respiratory distress, and hospitalizations occurred in 1705 (50.5%). After adjustment for preadmission antibiotics and NAI treatment propensity, preadmission NAI treatment was associated with decreased odds of hospital admission compared to no NAI treatment (adjusted odds ratio, 0.24; 95% confidence interval, 0.20–0.30). Conclusions: In a population with confirmed or suspected A(H1N1)pdm09 and at high risk of hospitalization, outpatient or community-based NAI treatment significantly reduced the likelihood of requiring hospital admission. These data suggest that community patients with severe influenza should receive NAI treatment

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09‐related pneumonia: an individual participant data meta‐analysis

BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on influenza‐related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. METHODS: A worldwide meta‐analysis of individual participant data from 20 634 hospitalised patients with laboratory‐confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) ‘pandemic influenza’. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Of 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64–1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44–1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71–1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55–0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54–0·85; P = 0·001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support

Physical Activity Across Adulthood and Bone Health in Later Life: The 1946 British Birth Cohort

© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. Leisure-time physical activity (LTPA) is widely recommended for the prevention of osteoporosis and fractures in older populations. However, whether the beneficial effects of LTPA on bone accumulate across life and are maintained even after reduction or cessation of regular PA in later life is unknown. We examined whether LTPA across adulthood was cumulatively associated with volumetric and areal bone mineral density (vBMD, aBMD) at ages 60 to 64 and whether associations were mediated by lean mass. Up to 1498 participants from the Medical Research Council National Survey of Health and Development were included in analyses. LTPA was self-reported at ages 36, 43, 53, and 60 to 64, and responses summed to generate a cumulative score (range 0 = inactive at all four ages to 8 = most active at all four ages). Total and trabecular vBMD were measured at the distal radius using pQCT and aBMD at the total hip and lumbar spine (L1 to L4) using DXA. Linear regression was used to test associations of the cumulative LTPA score with each bone outcome. After adjustment for height and weight, a 1-unit increase in LTPA score (95% CI) in men was associated with differences of 1.55% (0.78% to 2.31%) in radial trabecular vBMD, 0.83% (0.41% to 1.25%) in total hip aBMD, and 0.97% (0.44% to 1.49%) in spine aBMD. Among women, positive associations were seen for radial trabecular vBMD and total hip aBMD, but only among those of greater weight (LTPA × weight interaction p ≤ 0.01). In men, there was evidence to suggest that lean mass index may partly mediate these associations. These findings suggest that there are cumulative benefits of LTPA across adulthood on BMD in early old age, especially among men. The finding of weaker associations among women suggests that promotion of specifıc types of LTPA may be needed to benefit bone health in women. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc