The frail-LESS (LEss sitting and sarcopenia in frail older adults) remote intervention to improve sarcopenia and maintain independent living via reductions in sedentary behaviour: findings from a randomised controlled feasibility trial

The datasets supporting the conclusions of this article are available in Figshare, https://doi.org/10.17633/rd.brunel.26028892.v1. The raw qualitative data (transcripts) are not publicly available due to privacy restrictions. Further detail on the qualitative data and analysis that supports the findings of this study are available upon request to the corresponding author.Electronic supplementary material is available online at: https://bmcgeriatr.biomedcentral.com/articles/10.1186/s12877-024-05310-9#Sec40 .Background: Sarcopenia leads to functional disability, dependence in activities of daily living (ADL), and is a key contributor to frailty. Reducing and breaking up sedentary time is associated with improved sarcopenia and frailty-related outcomes. The aim of this study was to determine the feasibility of delivering and evaluating a remote sedentary behaviour intervention to improve sarcopenia and independent living in older adults with frailty. Methods: A two-arm randomised controlled feasibility trial was conducted with a target of 60 older adults (mean age 74 ± 6 years) with very mild or mild frailty. Participants were randomised to the Frail-LESS (LEss Sitting and Sarcopenia in Frail older adults) intervention or usual care control group for six months. The intervention included tailored feedback on sitting, standing and stepping; an education workbook that included goal setting and action planning; one-to-one health coaching; peer support; and a wearable device to self-monitor sedentary behaviour. Participant recruitment (percentage of eligible individuals recruited), retention and data completion rates were used to assess trial feasibility. Acceptability of the trial was explored through interviews and safety was evaluated via unplanned healthcare utilisation and number of falls. Sitting, standing, stepping and sarcopenia were measured to evaluate potential intervention effects. Results: Sixty participants were recruited. Recruitment and retention rates were 72% and 83%, respectively. Completion rates for outcome measures ranged from 70 to 100%. The trial was safe (< 1 fall per participant on average at each timepoint) and trial procedures were acceptable. Descriptive analysis (mean ± SD) showed that daily sitting was 25.1 ± 82.1 min/day lower in the intervention group, and 6.4 ± 60.5 min/day higher in the control group, at 6 months compared with baseline. Hand grip strength and sit-to-stand score were improved by 1.3 ± 2.4 kg and 0.7 ± 1.0, respectively, in the intervention group. Conclusions: This study demonstrates the feasibility and safety of delivering and evaluating a remote intervention to reduce and break up sitting in older adults with frailty. The intervention showed evidence towards reducing daily sitting and improving sarcopenia, supporting its evaluation in a definitive randomised controlled trial. Trial registration: ISRCTN registry (registration number: ISRCTN17158017). Registered 6th August 2021.Abbeyfield Research Foundatio

Integrating climate adaptation and biodiversity conservation in the global ocean

The impacts of climate change and the socioecological challenges they present are ubiquitous and increasingly severe. Practical efforts to operationalize climate-responsive design and management in the global network of marine protected areas (MPAs) are required to ensure long-term effectiveness for safeguarding marine biodiversity and ecosystem services. Here, we review progress in integrating climate change adaptation into MPA design and management and provide eight recommendations to expedite this process. Climate-smart management objectives should become the default for all protected areas, and made into an explicit international policy target. Furthermore, incentives to use more dynamic management tools would increase the climate change responsiveness of the MPA network as a whole. Given ongoing negotiations on international conservation targets, now is the ideal time to proactively reform management of the global seascape for the dynamic climate-biodiversity reality

Increased methylation of glucocorticoid receptor gene (NR3C1) in adults with a history of childhood maltreatment: a link with the severity and type of trauma

Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology

HIV Infection and Gut Mucosal Immune Function: Updates on Pathogenesis with Implications for Management and Intervention

HIV is primarily a sexually transmitted infection. However, given that the gastrointestinal tract (GIT) houses most of the body’s lymphocytes, including activated memory CD4+ T cells that are preferential targets for HIV, recent research has focused on the role of the GIT in transmission and pathogenesis. In health, the GIT maintains a balance between immune tolerance and rapid responsiveness. A complex network of innate and adaptive responses maintains this balance, which is severely perturbed in HIV infection. Recent studies have focused on mechanisms of GIT CD4+ T-cell depletion and epithelial disruption in HIV infection, the role of inflammation in accelerating viral dissemination, the kinetics of the adaptive response following transmission, and the extent of T-cell reconstitution following antiretroviral therapy. This review summarizes the results of recent investigations that may have important implications for the development of vaccines, microbicides, and therapeutic interventions for HIV and other mucosal pathogens

Large Proteins Have a Great Tendency to Aggregate but a Low Propensity to Form Amyloid Fibrils

The assembly of soluble proteins into ordered fibrillar aggregates with cross-β structure is an essential event of many human diseases. The polypeptides undergoing aggregation are generally small in size. To explore if the small size is a primary determinant for the formation of amyloids under pathological conditions we have created two databases of proteins, forming amyloid-related and non-amyloid deposits in human diseases, respectively. The size distributions of the two protein populations are well separated, with the systems forming non-amyloid deposits appearing significantly larger. We have then investigated the propensity of the 486-residue hexokinase-B from Saccharomyces cerevisiae (YHKB) to form amyloid-like fibrils in vitro. This size is intermediate between the size distributions of amyloid and non-amyloid forming proteins. Aggregation was induced under conditions known to be most effective for amyloid formation by normally globular proteins: (i) low pH with salts, (ii) pH 5.5 with trifluoroethanol. In both situations YHKB aggregated very rapidly into species with significant β-sheet structure, as detected using circular dichroism and X-ray diffraction, but a weak Thioflavin T and Congo red binding. Moreover, atomic force microscopy indicated a morphology distinct from typical amyloid fibrils. Both types of aggregates were cytotoxic to human neuroblastoma cells, as indicated by the MTT assay. This analysis indicates that large proteins have a high tendency to form toxic aggregates, but low propensity to form regular amyloid in vivo and that such a behavior is intrinsically determined by the size of the protein, as suggested by the in vitro analysis of our sample protein

Eggs in the Freezer: Energetic Consequences of Nest Site and Nest Design in Arctic Breeding Shorebirds

Birds construct nests for several reasons. For species that breed in the Arctic, the insulative properties of nests are very important. Incubation is costly there and due to an increasing surface to volume ratio, more so in smaller species. Small species are therefore more likely to place their nests in thermally favourable microhabitats and/or to invest more in nest insulation than large species. To test this hypothesis, we examined characteristics of nests of six Arctic breeding shorebird species. All species chose thermally favourable nesting sites in a higher proportion than expected on the basis of habitat availability. Site choice did not differ between species. Depth to frozen ground, measured near the nests, decreased in the course of the season at similar non-species-specific speeds, but this depth increased with species size. Nest cup depth and nest scrape depth (nest cup without the lining) were unrelated to body mass (we applied an exponent of 0.73, to account for metabolic activity of the differently sized species). Cup depth divided by diameter2 was used as a measure of nest cup shape. Small species had narrow and deep nests, while large species had wide shallow nests. The thickness of nest lining varied between 0.1 cm and 7.6 cm, and decreased significantly with body mass. We reconstruct the combined effect of different nest properties on the egg cooling coefficient using previously published quantitative relationships. The predicted effect of nest cup depth and lining depth on heat loss to the frozen ground did not correlate with body mass, but the sheltering effect of nest cup diameter against wind and the effects of lining material on the cooling coefficient increased with body mass. Our results suggest that small arctic shorebirds invest more in the insulation of their nests than large species

Is drinking water a risk factor for endemic cryptosporidiosis? A case-control study in the immunocompetent general population of the San Francisco Bay Area

BACKGROUND: Cryptosporidiosis, caused by Cryptosporidium, is an enteric illness that has received much attention as an infection of immunocompromised persons as well as in community outbreaks (frequently waterborne). There are, however, no studies of the risk factors for sporadic community-acquired cryptosporidiosis in the immunocompetent US population. We undertook a case-control study in the San Francisco Bay Area as part of a national study sponsored by the Centers for Disease Control and Prevention to ascertain the major routes of transmission for endemic cryptosporidiosis, with an emphasis on evaluating risk from drinking water. METHODS: Cases were recruited from a population-based, active surveillance system and age-matched controls were recruited using sequential random-digit dialing. Cases (n = 26) and controls (n = 62) were interviewed by telephone using a standardized questionnaire that included information about the following exposures: drinking water, recreational water, food items, travel, animal contact, and person-to-person fecal contact, and (for adults) sexual practices. RESULTS: In multivariate conditional logistic regression analyses no significant association with drinking water was detected. The major risk factor for cryptosporidiosis in the San Francisco Bay Area was travel to another country (matched odds ratio [95% confidence interval]: 24.1 [2.6, 220]). CONCLUSION: The results of this study do not support the hypothesis that drinking water is an independent risk factor for cryptosporidiosis among the immunocompetent population. These findings should be used to design larger studies of endemic cryptosporidiosis to elucidate the precise mechanisms of transmission, whether waterborne or other

Genome-wide DNA methylation levels and altered cortisol stress reactivity following childhood trauma in humans

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 � 10?6). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability

Immunomodulation Targeting Abnormal Protein Conformation Reduces Pathology in a Mouse Model of Alzheimer's Disease

Many neurodegenerative diseases are characterized by the conformational change of normal self-proteins into amyloidogenic, pathological conformers, which share structural properties such as high β-sheet content and resistance to degradation. The most common is Alzheimer's disease (AD) where the normal soluble amyloid β (sAβ) peptide is converted into highly toxic oligomeric Aβ and fibrillar Aβ that deposits as neuritic plaques and congophilic angiopathy. Currently, there is no highly effective treatment for AD, but immunotherapy is emerging as a potential disease modifying intervention. A major problem with most active and passive immunization approaches for AD is that both the normal sAβ and pathogenic forms are equally targeted with the potential of autoimmune inflammation. In order to avoid this pitfall, we have developed a novel immunomodulatory method that specifically targets the pathological conformations, by immunizing with polymerized British amyloidosis (pABri) related peptide which has no sequence homology to Aβ or other human proteins. We show that the pABri peptide through conformational mimicry induces a humoral immune response not only to the toxic Aβ in APP/PS1 AD transgenic mice but also to paired helical filaments as shown on AD human tissue samples. Treated APP/PS1 mice had a cognitive benefit compared to controls (p<0.0001), associated with a reduction in the amyloid burden (p = 0.0001) and Aβ40/42 levels, as well as reduced Aβ oligomer levels. This type of immunomodulation has the potential to be a universal β-sheet disrupter, which could be useful for the prevention or treatment of a wide range of neurodegenerative diseases