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Background: Impaired recovery of blood pressure (BP) in response to standing up is a prevalent condition in older individuals. We evaluated the relationship between the early recovery of hemodynamic responses to standing and brain health in adults over 50. Methods: Participants from The Irish Longitudinal Study on Ageing (TILDA) (n=411; age 67.6 ± 7.3 years; 53.4 % women) performed an active stand challenge while blood pressure and heart rate were continuously monitored. The recovery of these parameters was determined as the slope of the BP and HR response, following the initial drop/rise after standing. We have previously reported a novel and validated measure of brain ageing using MRI data, which measures the difference between biological brain age and chronological age, providing a brain-predicted age difference (brainPAD) score. Results: Slower recovery of systolic and diastolic BP was found to be significantly associated with higher brainPAD scores (i.e., biologically older brains), where a one-year increase in brainPAD was associated with a decrease of 0.02 mmHg/s and 0.01 mmHg/s in systolic and diastolic BP recovery, respectively, after standing. Heart rate (HR) recovery was not significantly associated with brainPAD score. Conclusion: These results demonstrate that slower systolic and diastolic BP recovery in the early phase after standing is associated with accelerated brain ageing in older individuals. This suggests that the BP response to standing, measured using beat-to-beat monitoring, has the potential to be used as a marker of accelerated brain ageing, relying on a simple procedure and devices that are easily accessible.

We examined the relationship between hippocampal subfield volumes and cognitive decline over a 4-year period in a healthy older adult population with the goal of identifying subjects at risk of progressive cognitive impairment which could potentially guide therapeutic interventions and monitoring. 482 subjects (68.1 years +/− 7.4; 52.9% female) from the Irish Longitudinal Study on Ageing underwent magnetic resonance brain imaging and a series of cognitive tests. Using K-means longitudinal clustering, subjects were first grouped into three separate global and domain-specific cognitive function trajectories; High-Stable, Mid-Stable and Low-Declining. Linear mixed effects models were then used to establish associations between hippocampal subfield volumes and cognitive groups. Decline in multiple hippocampal subfields was associated with global cognitive decline, specifically the presubiculum (estimate −0.20; 95% confidence interval (CI) -0.78 – −0.02; p = 0.03), subiculum (−0.44; −0.82 – −0.06; p = 0.02), CA1 (−0.34; −0.78 – −0.02; p = 0.04), CA4 (−0.55; −0.93 – −0.17; p = 0.005), molecular layer (−0.49; −0.87 – −0.11; p = 0.01), dentate gyrus (−0.57; −0.94 – −0.19; p = 0.003), hippocampal tail (−0.53; −0.91 – −0.15; p = 0.006) and HATA (−0.41; −0.79 – −0.03; p = 0.04), with smaller volumes for the Low-Declining cognition group compared to the High-Stable cognition group. In contrast to global cognitive decline, when specifically assessing the memory domain, cornu ammonis 1 subfield was not found to be associated with low declining cognition (−0.14; −0.37 – 0.10; p = 0.26). Previously published data shows that atrophy of specific hippocampal subfields is associated with cognitive decline but our study confirms the same effect in subjects asymptomatic at time of enrolment. This strengthens the predictive value of hippocampal subfield atrophy in risk of cognitive decline and may provide a biomarker for monitoring treatment efficacy.

Background: In this observational study, we compared continuous physiological signals during an active standing test in adults aged 50 years and over, characterised as frail by three different criteria, using data from The Irish Longitudinal Study on Ageing (TILDA). Methods: This study utilised data from TILDA, an ongoing landmark prospective cohort study of community-dwelling adults aged 50 years or older in Ireland. The initial sampling strategy in TILDA was based on random geodirectory sampling. Four independent groups were identified: those characterised as frail only by one of the frailty tools used (the physical Frailty Phenotype (FP), the 32-item Frailty Index (FI), or the Clinical Frailty Scale (CFS) classification tree), and a fourth group where participants were not characterised as frail by any of these tools. Continuous non-invasive physiological signals were collected during an active standing test, including systolic (sBP) and diastolic (dBP) blood pressure, as well as heart rate (HR), using digital artery photoplethysmography. Additionally, the frontal lobe cerebral oxygenation (Oxy), deoxygenation (Deoxy), and tissue saturation index (TSI) were also non-invasively measured using near-infrared spectroscopy (NIRS). The signals were visualised across frailty groups and statistically compared using one-dimensional statistical parametric mapping (SPM). Results: A total of 1124 participants (mean age of 63.5 years; 50.2% women) were included: 23 were characterised as frail only by the FP, 97 by the FI, 38 by the CFS, and 966 by none of these criteria. The SPM analyses revealed that only the group characterised as frail by the FI had significantly different signals (p < 0.001) compared to the non-frail group. Specifically, they exhibited an attenuated gain in HR between 10 and 15 s post-stand and larger deficits in sBP and dBP between 15 and 20 s post-stand. Conclusions: The FI proved to be more adept at capturing distinct physiological responses to standing, likely due to its direct inclusion of cardiovascular morbidities in its definition. Significant differences were observed in the dynamics of cardiovascular signals among the frail populations identified by different frailty criteria, suggesting that caution should be taken when employing frailty identification tools on physiological signals, particularly the neurocardiovascular signals in an active standing test.

Poverty is the outcome of the unequal distribution of resources reinforced by a legal, political, economic, and cultural model and is the central expression of social injustice. The impact of economic inequality on humanity’s quality of life can be better explained from the perspective of basic needs and their ties with rights, the unequal opportunities and their connection with the degree of autonomy that situated individuals effectively enjoy, and the effectiveness of public policy and the responsibilities and duties of the governments. This article discusses the close (and not visible) ties between justice, law, and poverty, emphasizing that the current legal framework -even the human rights system- legitimizes an unequal status quo that prevents real access to and enjoyment of rights and freedoms for people living in poverty conditions. Moreover, it also endangers democratic stability.

Introduction: Lutein and zeaxanthin are diet-derived carotenoids that are proposed to help mitigate frailty risk and age-related declines in musculoskeletal health via their anti-oxidant and anti-inflammatory properties. Therefore, this study aimed to investigate the association between lutein and zeaxanthin status and indices of musculoskeletal health and incident frailty among community-dwelling adults aged ≥50 years in the Irish Longitudinal Study on Ageing (TILDA). Methods: Cross-sectional analyses (n = 4513) of plasma lutein and zeaxanthin concentrations and grip strength, usual gait speed, timed up-and-go (TUG), probable sarcopenia (defined as grip strength 0.05). Plasma lutein concentration was positively associated with bone stiffness index (0.54 [0.15, 0.93], p 0.05). Conclusion: Higher plasma lutein and zeaxanthin concentrations at baseline were associated with a reduced likelihood of incident frailty after ~8 years of follow up. Baseline plasma lutein and zeaxanthin concentrations were also positively associated with several indices of musculoskeletal health cross-sectionally but were not predictive of longitudinal changes in these outcomes over 4–8 years.

BackgroundFrailty in older adults has been associated with reduced brain health. However, structural brain signatures of frailty remain understudied. Our aims were: (1) Explore associations between a frailty index (FI) and brain structure on magnetic resonance imaging (MRI). (2) Identify the most important FI features driving the associations.MethodsWe designed a cross-sectional observational study from a population-based study (The Irish Longitudinal Study on Aging: TILDA). Participants aged ≥50 years who underwent the wave 3 MRI sub-study were included. We measured cortex, basal ganglia, and each of the Desikan-Killiany regional volumes. Age-and sex-adjusted correlations were performed with a 32-item self-reported FI that included conditions commonly tested for frailty in research and clinical settings. A graph theory analysis of the network composed by each FI item and cortex volume was performed. White matter fiber integrity was quantified using diffusion tensor imaging (DTI).ResultsIn 523 participants (mean age 69, 49% men), lower cortex and thalamic volumes were independently associated with higher FI. Sensory and functional difficulties, diabetes, polypharmacy, knee pain, and self-reported health were the main FI associations with cortex volume. In the network analysis, cortex volume had a modest influence within the frailty network. Regionally, higher FI was significantly associated with lower volumes in both orbitofrontal and temporal cortices. DTI analyses revealed inverse associations between the FI and the integrity of some association bundles.ConclusionThe FI used had a recognizable but subtle structural brain signature in this sample. Only some FI deficits were directly associated with cortex volume, suggesting scope for developing FIs that include metrics more specifically related with brain health in future aging neuroscience studies.

This study was carried out using a large cohort (N = 4265; 416 deceased) of older, community-dwelling adults from The Irish Longitudinal Study on Ageing (TILDA). The study compared the performance of a new 3-item health index (HI) with two existing measures, the 32-item frailty index (FI) and the frailty phenotype (FP), in predicting mortality risk. The HI was based on the objective measurement of resting-state systolic blood pressure sample entropy, sustained attention reaction time performance, and usual gait speed. Mortality data from a 12-year follow up period were analyzed using Cox proportional regression. All data processing was performed using MATLAB and statistical analysis using STATA 15.1. The HI showed good discriminatory power (AUC = 0.68) for all-cause mortality, similar to FI (AUC = 0.68) and superior to FP (AUC = 0.60). The HI classified participants into Low-Risk (84%), Medium-Risk (15%), and High-Risk (1%) groups, with the High-Risk group showing a significant hazard ratio (HR) of 5.91 in the unadjusted model and 2.06 in the fully adjusted model. The HI also exhibited superior predictive performance for cardiovascular and respiratory deaths (AUC = 0.74), compared with FI (AUC = 0.70) and FP (AUC = 0.64). The HI High-Risk group had the highest HR (15.10 in the unadjusted and 5.61 in the fully adjusted models) for cardiovascular and respiratory mortality. The HI remained a significant predictor of mortality even after comprehensively adjusting for confounding variables. These findings demonstrate the effectiveness of the 3-item HI in predicting 12-year mortality risk across different causes of death. The HI performed similarly to FI and FP for all-cause mortality but outperformed them in predicting cardiovascular and respiratory deaths. Its ability to classify individuals into risk groups offers a practical approach for clinicians and researchers. Additionally, the development of a user-friendly MATLAB App facilitates its implementation in clinical settings. Subject to external validation in clinical research settings, the HI can be more useful than existing frailty measures in the prediction of cardio-respiratory risk.

Summary: Background: Severe COVID-19 is associated with a high circulating level of calprotectin, the S100A8/S100A9 alarmin heterodimer. Baseline calprotectin amount measured in peripheral blood at diagnosis correlates with disease severity. The optimal use of this biomarker along COVID-19 course remains to be delineated. Methods: We focused on patients with a WHO-defined moderate COVID-19 requiring hospitalization in a medical ward. We collected plasma and serum from three independent cohorts (N = 626 patients) and measured calprotectin amount at admission. We performed longitudinal measures of calprotectin in 457 of these patients (1461 samples) and used a joint latent class mixture model in which classes were defined by age, body mass index and comorbidities to identify calprotectin trajectories predicting the risk of transfer into an intensive care unit or death. Findings: After adjustment for age, sex, body mass index and comorbidities, the predictive value of baseline calprotectin in patients with moderate COVID19 could be refined by serial monitoring of the biomarker. We discriminated three calprotectin trajectories associated with low, moderate, and high risk of poor outcome, and we designed an algorithm available as online software (https://calpla.gustaveroussy.fr:8443/) to monitor the probability of a poor outcome in individual patients with moderate COVID-19. Interpretation: These results emphasize the clinical interest of serial monitoring of calprotectin amount in the peripheral blood to anticipate the risk of poor outcomes in patients with moderate COVID-19 hospitalized in a standard care unit. Funding: The study received support (research grants) from ThermoFisher immunodiagnostics (France) and Gustave Roussy Foundation.

Abstract Head and neck squamous cell carcinomas (HNSCC) induced by human papillomavirus (HPV) have increased recently in the US. However, the distinct alterations of molecules involved in the death pathways and drug effects targeting inhibitor of apoptosis proteins (IAPs) have not been extensively characterized in HPV(+) HNSCC cells. In this study, we observed the distinct genomic and expression alterations of nine genes involved in cell death in 55% HNSCC tissues, which were associated with HPV status, tumor staging, and anatomic locations. Expression of four genes was statistically correlated with copy number variation. A panel of HPV(+) HNSCC lines showed abundant TRAILR2 and IAP1 protein expression, but were not sensitive to IAP inhibitor birinapant alone, while combinatory treatment with TNFα or especially TRAIL enhanced this drug sensitivity. The death agonistic TRAILR2 antibody alone showed no cell inhibitory effects, whereas its combination with birinapant and/or TRAIL protein demonstrated additive or synergistic effects. We observed predominantly late apoptosis mode of cell death after combinatorial treatments, and pan-caspase (ZVAD) and caspase-8 (ZIETD) inhibitors attenuated treatment-induced cell death. Our genomic and expression data-driven study provides a framework for identifying relevant combinatorial therapies targeting death pathways in HPV(+) HNSCC and other squamous cancer types.

Recent research has indicated that the relationship between age‐related cognitive decline and falling may be mediated by the individual's capacity to quickly cancel or inhibit a motor response. This longitudinal investigation demonstrates that higher white matter fibre density in the motor inhibition network paired with low physical activity was associated with falling in elderly participants. We measured the density of white matter fibre tracts connecting key nodes in the inhibitory control network in a large sample (n = 414) of older adults. We modelled their self‐reported frequency of falling over a 4‐year period with white matter fibre density in pathways corresponding to the direct and hyperdirect cortical–subcortical loops implicated in the inhibitory control network. Only connectivity between right inferior frontal gyrus and right subthalamic nucleus was associated with falling as measured cross‐sectionally. The connectivity was not, however, predictive of future falling when measured 2 and 4 years later. Higher white matter fibre density was associated with falling, but only in combination with low levels of physical activity. No such relationship existed for selected control brain regions that are not implicated in the inhibitory control network. Albeit statistically robust, the direction of this effect was counterintuitive (more dense connectivity associated with falling) and warrants further longitudinal investigation into whether white matter fibre density changes over time in a manner correlated with falling, and mediated by physical activity. [ABSTRACT FROM AUTHOR]

Background Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT.Methods Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens.Results In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so.Conclusions These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients.

Abstract In bacterial system, direct conversion of xylose to xylonic acid is mediated through NAD-dependent xylose dehydrogenase (xylB) and xylonolactonase (xylC) genes. Heterologous expression of these genes from Caulobacter crescentus into recombinant Corynebacterium glutamicum ATCC 13032 and C. glutamicum ATCC 31831 (with an innate pentose transporter, araE) resulted in an efficient bioconversion process to produce xylonic acid from xylose. Process parameters including the design of production medium was optimized using a statistical tool, Response Surface Methodology (RSM). Maximum xylonic acid of 56.32 g/L from 60 g/L xylose, i.e. about 76.67% of the maximum theoretical yield was obtained after 120 h fermentation from pure xylose with recombinant C. glutamicum ATCC 31831 containing the plasmid pVWEx1 xylB. Under the same condition, the production with recombinant C. glutamicum ATCC 13032 (with pVWEx1 xylB) was 50.66 g/L, i.e. 69% of the theoretical yield. There was no significant improvement in production with the simultaneous expression of xylB and xylC genes together indicating xylose dehydrogenase activity as one of the rate limiting factor in the bioconversion. Finally, proof of concept experiment in utilizing biomass derived pentose sugar, xylose, for xylonic acid production was also carried out and obtained 42.94 g/L xylonic acid from 60 g/L xylose. These results promise a significant value addition for the future bio refinery programs.

Abstract Background Over the last 25 years, the prominent forest certification system established by the Forest Stewardship Council (FSC) has used by many companies worldwide for claiming responsible forest management. The objectives of the Russian National FSC standard to decrease the size of clearcuts and the retention of forest elements such as residual seed trees need on-site validation to proof the effectiveness of FSC. To assess the ecological impacts of harvesting practices and benefits of FSC certification, we geospatially compared logging activities with and without FSC certification. Within a sample area covering approximately 3,000 km2 in the east of the Russian Arkhangelsk Region, we used available data on tree cover loss and satellite images to assess secondary impacts of clearcuttings on adjacent remnant forests and to quantify the logging intensity. Additionally, the size and structure as well as the density of skidding trails of ten specific clearcuttings located within the sample area were surveyed using satellite images and in the field observation to delineate the boundaries of clearcuts and forested remnants within the clearcuts. Results We found a significant increase of small-scale tree cover loss in the proximity of the clearcuts. Patchy dieback is possibly linked to the scale and intensity of logging in the surroundings. On the investigated clearcuts, FSC failed to reduce the size, to increase the retention of forest remnants including seed trees on logged areas, and to maintain larger tracts of undisturbed ground and soil compared to clearcuts that were logged before they received FSC-certification. Conclusions Trees and forest remnants remaining inside an increasingly stressed forest ecosystem matrix may not resist further harvesting-related and climate change-induced stresses and disturbances. Large-scale clearcuttings seem to have negative impacts even in adjacent forests and undermine the ecological effectiveness of FSC certification in the study area. The Russian FSC standard is not clearly setting effective guidelines that induce a change in clearcutting practices in order to reduce ecological risks.

Background. Stillbirth adversely affects pregnancy outcomes in low- and middle-income countries (LMICs). Viral infections have been implicated as one of the causes of stillbirths. Despite high rates of stillbirths and high viral prevalence in LMICs, there is limited information regarding their association. This study investigated the magnitude of herpes simplex 2 virus (HSV-2) and human cytomegalovirus (HCMV) among women with macerated stillbirth. Methods. A cross-sectional hospital-based study was conducted involving 279 women with macerated stillbirth between July and August 2018 at different health facilities in Mwanza, Tanzania. Detection of HSV-2 was done by immunochromatographic test while that of HCMV was done using enzyme-linked immunosorbent assay (ELISA). Descriptive data analysis was done using STATA version 13. Results. A total of 28 (10.04%, 95% CI: 6.8-13.9) tested positive for HSV-2 IgG antibodies with only 4 (1.43%, 95% CL: 0.3-2.8) testing positive for HSV-2 IgM antibodies. HCMV IgG antibodies were detected in 131 (77.98%, 95% CI: 71-84) of 168 women tested. By multivariate logistic regulation analysis, advanced age (OR: 0.93, 95% CI: 0.87-0.99, p=0.025) was significantly associated with negative HSV-2 IgG antibodies. By log multinomial regression analysis, only urban residence (RRR.4.43: 95% CI 1.53-12.80, p=0.006) independently predicted HCMV IgG seropositivity among women with stillbirth. Twenty-one (30.9%) of women with positive HCMV IgG antibodies had low avidity index (