Objective To test for effects of a problem-solving intervention for stroke caregivers on stroke survivor activities of daily living. Design Two-arm parallel randomized clinical trial with repeated measures at 11 weeks and 19 weeks. Setting Medical centers for US military Veterans. Subjects Caregivers of stroke survivors. Intervention A registered nurse guided caregivers in using problem-solving strategies emphasizing creative thinking, optimism, planning, and expert information to address challenges associated with caregiving. Caregivers in the intervention completed one telephone orientation session followed by eight online, asynchronous messaging center sessions. The messaging center sessions involved (a) education on the Resources and Education for Stroke Caregivers’ Understanding and Empowerment website ( https://www.stroke.cindrr.research.va.gov/en/ ), (b) supportive communication between the nurse and caregiver, (c) nurse and caregiver interactions to improve problem-solving, and (d) maintain adherence to discharge planning instructions. Main Outcome The Barthel Index was used to measure activities of daily living. Results 174 participants (standard care n = 88, intervention n = 86) were enrolled at baseline. There were no significant differences between groups at baseline. Change scores in activities of daily living between baseline and 11 weeks were significantly higher in the intervention group than the standard care group (group difference = 6.43, 95% confidence interval: 1.28, 11.58). Group differences in change scores between baseline and 19 weeks were not statistically significant (group difference = 3.89, 95% confidence interval: −3.58, 11.36). Conclusions This web-based caregiver intervention improved stroke survivor activities of daily living by 11 weeks, but intervention effects were undetectable after 19 weeks.

Tapeworms grow at rates rivaling the fastest-growing metazoan tissues. To propagate they shed large parts of their body; to replace these lost tissues they regenerate proglottids (segments) as part of normal homeostasis. Their remarkable growth and regeneration are fueled by adult somatic stem cells that have yet to be characterized molecularly. Using the rat intestinal tapeworm, Hymenolepis diminuta, we find that regenerative potential is regionally limited to the neck, where head-dependent extrinsic signals create a permissive microenvironment for stem cell-driven regeneration. Using transcriptomic analyses and RNA interference, we characterize and functionally validate regulators of tapeworm growth and regeneration. We find no evidence that stem cells are restricted to the regeneration-competent neck. Instead, lethally irradiated tapeworms can be rescued when cells from either regeneration-competent or regeneration-incompetent regions are transplanted into the neck. Together, the head and neck tissues provide extrinsic cues that regulate stem cells, enabling region-specific regeneration in this parasite.

Prenatal maternal stress has a negative impact on child health but the mechanisms through which maternal stress affects child health are unclear. Epigenetic variation, such as DNA methylation, is a likely mechanistic candidate as DNA methylation is sensitive to environmental insults and can regulate long-term changes in gene expression. We recruited 155 mother-newborn dyads in the Democratic Republic of Congo to investigate the effects of maternal stress on DNA methylation in mothers and newborns. We used four measures of maternal stress to capture a range of stressful experiences: general trauma, sexual trauma, war trauma, and chronic stress. We identified differentially methylated positions (DMPs) associated with general trauma, sexual trauma, and war trauma in both mothers and newborns. No DMPs were associated with chronic stress. Sexual trauma was positively associated with epigenetic age acceleration across several epigenetic clocks in mothers. General trauma and war trauma were positively associated with newborn epigenetic age acceleration using the extrinsic epigenetic age clock. We tested the top DMPs for enrichment of DNase I hypersensitive sites (DHS) and found no enrichment in mothers. In newborns, top DMPs associated with war trauma were enriched for DHS in embryonic and foetal cell types. Finally, one of the top DMPs associated with war trauma in newborns also predicted birthweight, completing the cycle from maternal stress to DNA methylation to newborn health outcome. Our results indicate that maternal stress is associated with site-specific changes in DNAm and epigenetic age acceleration in both mothers and newborns.

The developing infant gut microbiome is highly sensitive to environmental exposures, enabling its evolution into an organ that supports the immune system, confers protection from infection, and facilitates optimal gut and central nervous system function. In this study, we focus on the impact of maternal psychosocial stress on the infant gut microbiome. Forty-seven mother–infant dyads were recruited at the HEAL Africa Hospital in Goma, Democratic Republic of Congo. Extensive medical, demographic, and psychosocial stress data were collected at birth, and infant stool samples were collected at six weeks, three months, and six months. A composite maternal psychosocial stress score was created, based on eight questionnaires to capture a diverse range of stress exposures. Full-length 16S rRNA gene sequences were generated. Infants of mothers with high composite stress scores showed lower levels of gut microbiome beta diversity at six weeks and three months, as well as higher levels of alpha diversity at six months compared to infants of low stress mothers. Longitudinal analyses showed that infants of high stress mothers had lower levels of health-promoting Lactobacillus gasseri and Bifidobacterium pseudocatenulatum at six weeks compared to infants of low stress mothers, but the differences largely disappeared by three to six months. Previous research has shown that L. gasseri can be used as a probiotic to reduce inflammation, stress, and fatigue, as well as to improve mental state, while B. pseudocatenulatum is important in modulating the gut–brain axis in early development and in preventing mood disorders. Our finding of reduced levels of these health-promoting bacteria in infants of high stress mothers suggests that the infant gut microbiome may help mediate the effect of maternal stress on infant health and development.

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Background and objectives The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that early life adversity is associated with poor adult health outcomes. Epidemiological evidence has supported this framework by linking low birthweight with adult health and mortality, but the mechanisms remain unclear. Accelerated epigenetic aging may be a pathway to connect early life experiences with adult health outcomes, based on associations of accelerated epigenetic aging with increased morbidity and mortality. Methodology Sixty-seven mother-infant dyads were recruited in the eastern Democratic Republic of Congo. Birthweight data were collected at birth, and blood samples were collected at birth and follow-up visits up to age three. DNA methylation data were generated with the Illumina MethylationEPIC array and used to estimate epigenetic age. A multilevel model was used to test for associations between birthweight and epigenetic age acceleration. Results Chronological age was highly correlated with epigenetic age from birth to age three (r = 0.95, p < 2.2 x 10 -16). Variation in epigenetic age acceleration increased over time. Birthweight, dichotomized around 2500 grams, predicted epigenetic age acceleration over the first three years of life (b = -0.39, p = 0.005). Conclusions and implications Our longitudinal analysis provides the first evidence for accelerated epigenetic aging that emerges between birth and age three and associates with low birthweight. These results suggest that early life experiences, such as low birthweight, may shape the trajectory of epigenetic aging in early childhood. Furthermore, accelerated epigenetic aging may be a pathway that links low birthweight and poor adult health outcomes.

15Tapeworms grow at rates rivaling the fastest-growing metazoan tissues. To propagate 16 they shed large parts of their body; to replace these lost tissues they regenerate proglottids 17 (segments) as part of normal homeostasis. Their remarkable growth and regeneration are fueled 18 by adult somatic stem cells that have yet to be characterized molecularly. Using the rat intestinal 19 tapeworm, Hymenolepis diminuta, we find that regenerative potential is regionally limited to the 20 neck, where head-dependent extrinsic signals create a permissive microenvironment for stem 21 cell-driven regeneration. Using transcriptomic analyses and RNA interference, we characterize 22 and functionally validate regulators of tapeworm growth and regeneration. We find no evidence 23 that stem cells are restricted to the regeneration-competent neck. Instead, lethally irradiated 24 tapeworms can be rescued when cells from either regeneration-competent or regeneration-25 incompetent regions are transplanted into the neck. Together, the head and neck tissues provide 26 extrinsic cues that regulate stem cells, enabling region-specific regeneration in this parasite. 27 7 Previous in vivo studies have shown that H. diminuta can regenerate after serial rounds of 103 amputation and transplantation for over a decade 5 and perhaps indefinitely. Using in vitro culture, 104we confirmed that anterior fragments of H. diminuta can regenerate after at least four rounds of 105 serial amputation ( Fig. 1f-g). Decapitated (-head) fragments regenerated proglottids after the first 106 amputation; however, re-amputation abrogated regeneration (Fig. 1f-g). After decapitation, a 107 definitive neck could not be maintained and eventually, the whole tissue was comprised of 108 proglottids ( Fig. 1-figure supplement 2). Without the head, proglottid regeneration from the neck 109 is finite. Thus, while the neck is necessary and sufficient for proglottid regeneration, the head is 110 required to maintain an unsegmented neck and for persistent regeneration. 111If signals from the head regulate regeneration, is regenerative potential asymmetric across 112 the anterior-posterior (A-P) axis of the neck? We subdivided the neck into three 1 mm fragments 113 and found that the most-anterior neck fragments regenerated more proglottids than the middle or 114 posterior neck fragments ( Fig. 1h-i). Thus, regeneration potential is asymmetric across the neck 115

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