Daily surveillance of falls is feasible and reveals a high incidence of falls among older adults

OBJECTIVE: To ensure accurate data capture for a fall study through a system of daily contact with participants. METHODS: Fifty‐eight adults older than 60 years of age and living independently in the community in Canberra, Australia, were recruited for a prospective fall study. We adopted a system of daily contact with study participants for at least 12 months, either by email or by text, asking whether they had suffered a fall in the previous 24 h. At the final testing session, we asked participants whether they had experienced a fall during the previous twelve months. RESULTS: We found no evidence that the daily reporting regime led to excess participant attrition. Only three participants withdrew over the course of the study, and the burden of responding was not cited as a factor in any of these cases. Of the 55 participants who completed the full twelve‐month study period, 38 (69%) experienced at least one fall. We also identified inconsistencies between recall of falls occurring during the last twelve months of the study and the contemporaneously recorded data. CONCLUSIONS: Previous studies have found that increasing the reporting demands on fall study participants will lead to higher attrition. This study demonstrates that it is possible to maintain participant engagement and minimise attrition with appropriate design of reporting procedures. We confirm existing evidence regarding the unreliability of retrospective recall of falls. The study highlights the importance of comprehensive and accurate data capture and points to the possibility of under‐reporting of fall incidence

The Complete Star Formation History of the Universe

The determination of the star-formation history of the Universe is a key goal of modern cosmology, as it is crucial to our understanding of how structure in the Universe forms and evolves. A picture has built up over recent years, piece-by-piece, by observing young stars in distant galaxies at different times in the past. These studies indicated that the stellar birthrate peaked some 8 billion years ago, and then declined by a factor of around ten to its present value. Here we report on a new study which obtains the complete star formation history by analysing the fossil record of the stellar populations of 96545 nearby galaxies. Broadly, our results support those derived from high-redshift galaxies elsewhere in the Universe. We find, however, that the peak of star formation was more recent - around 5 billion years ago. Our study also shows that the bigger the stellar mass of the galaxy, the earlier the stars were formed. This striking result indicates a very different formation history for high- and low-mass formation.Comment: Accepted by Nature. Press embargo until publishe

Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a

Background Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. Methods and Findings We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. Conclusions Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge

Specific star-formation and the relation to stellar mass from 0<z<2 as seen in the far-infrared at 70 and 160mu

We use the Spitzer Wide-area InfraRed Extragalactic Legacy Survey (SWIRE) to explore the specific star-formation activity of galaxies and their evolution near the peak of the cosmic far-infrared (FIR) background at 70 and 160um. We use a stacking analysis to determine the mean FIR properties of well defined subsets of galaxies at flux levels well below the FIR catalogue detection limits of SWIRE and other Spitzer surveys. We tabulate the contribution of different subsets of galaxies to the FIR background at 70um and 160um. These long wavelengths provide a good constraint on the bolometric, obscured emission. The large area provides good constraints at low z and in finer redshift bins than previous work. At all redshifts we find that the specific FIR Luminosity (sLFIR) decreases with increasing mass, following a trend L_FIR/M* propto M_* ^beta with beta =-0.38\pm0.14. This is a more continuous change than expected from the {Delucia2007} semi-analytic model suggesting modifications to the feedback prescriptions. We see an increase in the sLFIR by about a factor of ~100 from 0<z<2 and find that the sLFIR evolves as (1+z)^alpha with alpha=4.4\pm0.3 for galaxies with 10.5 < log M*/Msun < 12. This is considerably steeper than the {Delucia2007} semi-analytic model (alpha \sim 2.5). When separating galaxies into early and late types on the basis of the optical/IR spectral energy distributions we find that the decrease in sLFIR with stellar mass is stronger in early type galaxies (beta ~ -0.46), while late type galaxies exhibit a flatter trend (beta \sim -0.15). The evolution is strong for both classes but stronger for the early type galaxies. The early types show a trend of decreasing strength of evolution as we move from lower to higher masses while the evolution of the late type galaxies has little dependence on stellar mass. We suggest that in late-type galaxies we are seeing a consistently declining sSFR..Comment: v2 Update doesn't change the content of the paper, but now includes data files for the plots Fig 5-13 (all.plotdat, spi.plotdat and ell.plotdat on arXiv package

Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever

Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever

Proprioceptive performance of bilateral upper and lower limb joints: side-general and site-specific effects

Superiority of the left upper limb in proprioception tasks performed by right-handed individuals has been attributed to better utilization of proprioceptive information by a non-preferred arm/hemisphere system. However, it is undetermined whether this holds for multiple upper and lower limb joints. Accordingly, the present study tested active movement proprioception at four pairs of upper and lower limb joints, after selecting twelve participants with both strong right arm and right leg preference. A battery of versions of the active movement extent discrimination apparatus were employed to generate the stimuli for movements of different extents at the ankle, knee, shoulder and fingers on the right and left sides of the body, and discrimination scores were derived from participants’ responses. Proprioceptive performance on the non-preferred left side was significantly better than the preferred right side at all four joints tested (overall F(1, 11) = 36.36, p < 0.001, partial η(2) = 0.77). In the 8 × 8 matrix formed by all joints, only correlations between the proprioceptive accuracy scores for the right and left sides at the same joint were significant (ankles 0.93, knees 0.89, shoulders 0.87, fingers 0.91, p ≤ 0.001; all others r ≤ 0.40, p ≥ 0.20). The results point to both a side-general effect and a site-specific effect in the integration of proprioceptive information during active movement tasks, whereby the non-preferred limb/hemisphere system is specialized in the utilization of the best proprioceptive sources available at each specific joint, but the combination of sources employed differs between body sites

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans

An immune dysfunction score for stratification of patients with acute infection based on whole-blood gene expression.

Dysregulated host responses to infection can lead to organ dysfunction and sepsis, causing millions of global deaths each year. To alleviate this burden, improved prognostication and biomarkers of response are urgently needed. We investigated the use of whole-blood transcriptomics for stratification of patients with severe infection by integrating data from 3149 samples from patients with sepsis due to community-acquired pneumonia or fecal peritonitis admitted to intensive care and healthy individuals into a gene expression reference map. We used this map to derive a quantitative sepsis response signature (SRSq) score reflective of immune dysfunction and predictive of clinical outcomes, which can be estimated using a 7- or 12-gene signature. Last, we built a machine learning framework, SepstratifieR, to deploy SRSq in adult and pediatric bacterial and viral sepsis, H1N1 influenza, and COVID-19, demonstrating clinically relevant stratification across diseases and revealing some of the physiological alterations linking immune dysregulation to mortality. Our method enables early identification of individuals with dysfunctional immune profiles, bringing us closer to precision medicine in infection

'Physical activity at home (PAAH)', evaluation of a group versus home based physical activity program in community dwelling middle aged adults: rationale and study design

<p>Abstract</p> <p>Background</p> <p>It is well recognised that the adoption and longer term adherence to physical activity by adults to reduce the risk of chronic disease is a challenge. Interventions, such as group and home based physical activity programs, have been widely reported upon. However few studies have directly compared these interventions over the longer term to determine their adherence and effectiveness. Participant preference for home based or group interventions is important. Some evidence suggests that home based physical activity programs are preferred by middle aged adults and provide better long term physical activity adherence. Physiotherapists may also be useful in increasing physical activity adherence, with limited research on their impact.</p> <p>Methods</p> <p>'Physical Activity at Home' is a 2 year pragmatic randomised control trial, with a non-randomised comparison to group exercise. Middle-aged adults not interested in, or unable to attend, a group exercise program will be targeted. Sedentary community dwelling 50-65 year olds with no serious medical conditions or functional impairments will be recruited via two mail outs using the Australian federal electoral roll. The first mail out will invite participants to a 6 month community group exercise program. The second mail out will be sent to those not interested in the group exercise program inviting them to take part in a home based intervention. Eligible home based participants will be randomised into a 6 month physiotherapy-led home based physical activity program or usual care. Outcome measures will be taken at baseline, 6, 12, 18 and 24 months. The primary outcome is physical activity adherence via exercise diaries. Secondary outcomes include the Active Australia Survey, accelerometry, aerobic capacity (step test), quality of life (SF-12v2), blood pressure, waist circumference, waist-to-hip ratio and body mass index. Costs will be recorded prospectively and qualitative data will be collected.</p> <p>Discussion</p> <p>The planned 18 month follow-up post intervention will provide an indication of the effectiveness of the group and home based interventions in terms of adherence to physical activity, health benefits and cost. If the physiotherapy-led home based physical activity program is successful it could provide an alternative option for physical activity program delivery across a number of settings.</p> <p>Trial registration</p> <p>Australia and New Zealand Clinical Trials Register (ANZCTR): <a href="http://www.anzctr.org.au/ACTRN12611000890932.aspx">ACTRN12611000890932</a></p