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Rationale: The elderly experience profound systemic responses after stroke, which contribute to higher mortality and more severe long-term disability. Recent studies have revealed that stroke outcomes can be influenced by the composition of gut microbiome. However, the potential benefits of manipulating the gut microbiome after injury is unknown. Objective: To determine if restoring youthful gut microbiota after stroke aids in recovery in aged subjects, we altered the gut microbiome through young fecal transplant gavage (young FTG) in aged mice after experimental stroke. Further, the effect of direct enrichment of selective bacteria producing short-chain fatty acids (SCFAs) was tested as a more targeted and refined microbiome therapy. Methods and Results: Aged male mice (18-20 months) were subjected to ischemic stroke by middle cerebral artery occlusion (MCAO). We performed FTG three days after MCAO using young donor biome (2-3 months) or aged biome (18-20 months). At day 14 after stroke, aged stroke mice receiving young FTG had less behavioral impairment, and reduced brain and gut inflammation. Based on data from microbial sequencing and metabolomics analysis demonstrating that young fecal transplants contained much higher SCFA levels and related bacterial strains, we selected four SCFA-producers (Bifidobacterium longum, Clostridium symbiosum, Faecalibacterium prausnitzii and Lactobacillus fermentum) for transplantation. These SCFA-producers alleviated post-stroke neurological deficits and inflammation, and elevated gut, brain and plasma SCFA concentrations in aged stroke mice. Conclusions: This is the first study suggesting that the poor stroke recovery in aged mice can be reversed via "post-stroke bacteriotherapy" following the replenishment of youthful gut microbiome via modulation of immunologic, microbial and metabolomic profiles in the host.

Background:This study investigated longitudinal patterns of psychological distress in adult survivors of childhood cancer.Methods:Participants included 4569 adult survivors in the Childhood Cancer Survivor Study Cohort (CCSS) who completed the Brief Symptom Inventory-18 on three occasions between 1994 and 2010. Longitudinal latent class analysis was used to identify discrete classes of psychological distress. Predictors of class membership were examined through logistic regression modelling with odds ratios (ORs) and 95% confidence intervals (CIs) reported.Results:Survivors were a median of 39 years of age and 30 years from diagnosis at the most recent follow-up. Most survivors reported few or no symptoms of distress over time, although subsets of survivors reported persistently elevated (depression: 8.9% anxiety: 4.8% somatisation: 7.2%) or significant increases in distress symptoms over the follow-up period (depression: 10.2% anxiety: 11.8% somatisation: 13.0%). Increasing distress symptoms were predicted by survivor perception of worsening physical health over time (depression: OR=3.3; 95% CI=2.4–4.5; anxiety: OR=3.0; 95% CI=2.2–4.0; somatisation: OR=5.3; 95% CI=3.9–7.4). Persistent distress symptoms were also predicted by survivor perception of worsening physical health over time, as well as by worsening pain and ending analgesic use.Conclusion:Subgroups of adult survivors are at-risk for chronic distress or significant increases in distress decades following their original cancer diagnosis. Routine screening of psychological distress in adult survivors of childhood cancer is warranted, especially for survivors who experience physical health morbidities.

A B S T R A C T PurposeLong-term survivors of childhood Hodgkin lymphoma (HL) are at risk for cardiopulmonary complications and CNS stroke, although neurocognitive function has not been previously examined. The aim of this study was to examine neurocognitive and brain imaging outcomes in adult survivors of childhood HL. Patients and MethodsIn all, 62 adult survivors (mean age, 42.2 years; standard deviation [SD], 4.77; mean age at diagnosis, 15.1 years; SD, 3.30) were identified by stratified random selection from a large cohort treated with either high-dose (Ն 30 Gy) thoracic radiation (n ϭ 38) or lower-dose (Ͻ 30 Gy) thoracic radiation combined with anthracycline (n ϭ 24). Patients underwent neurocognitive evaluations, brain magnetic resonance imaging (MRI), echocardiograms, pulmonary function tests, and physical examinations. ResultsCompared with national age-adjusted norms, HL survivors demonstrated lower performance on sustained attention (P ϭ .004), short-term memory (P ϭ .001), long-term memory (P ϭ .006), working memory (P Ͻ .001), naming speed (P Ͻ .001), and cognitive fluency (P ϭ .007). MRI revealed leukoencephalopathy in 53% of survivors, and 37% had evidence of cerebrovascular injury. Higher thoracic radiation dose was associated with impaired cardiac diastolic function (E/EЈ; ratio of peak mitral flow velocity of early rapid filling [E] to early diastolic velocity of the mitral annulus [EЈ]; P ϭ .003), impaired pulmonary function (diffusing capacity of lungs for carbon monoxide [DL co corr ; P ϭ .04), and leukoencephalopathy (P ϭ .02). Survivors with leukoencephalopathy demonstrated reduced cognitive fluency (P ϭ .001). Working memory impairment was associated with E/EЈ, although impaired sustained attention and naming speed were associated with DL co corr . Neurocognitive performance was associated with academic and vocational functioning. ConclusionThese results suggest that adult long-term survivors of childhood HL are at risk for neurocognitive impairment, which is associated with radiologic indices suggestive of reduced brain integrity and which occurs in the presence of symptoms of cardiopulmonary dysfunction.

This study describes skeletal, neuromuscular and fitness impairments among 109 children (median age 10 (range 4–18) years, 65.1% male, 63.3% white) with acute lymphoblastic leukemia (ALL), enrolled on a physical activity trial from 2009 to 2013. Outcomes were measured 7-10 days after diagnosis and compared to age- and sex-specific expected values. Associations between function and HRQL were evaluated with logistic regression. Children low values for BMD z-scores/height (mean±standard error: −0.53±0.16 vs. 0.00±0.14, p <0.01), body mass index percentile (57.6±3.15 vs. 50.0±3.27%, p=0.02), quadriceps strength (201.9±8.3 vs. 236.1±5.4 Newtons, p<0.01), six minute walk distance (385.0±13.1 vs. 628.2±7.1 meters, p < 0.001), and Bruininks-Oseretsky Test of Motor Proficiency (23±2.5 vs. 50±3.4%, p < 0.001). Quadriceps weakness was associated with a 20.9-fold (95% CI 2.5–173.3) increase in poor physical HRQL. Children with newly diagnosed ALL have weakness and poor endurance and may benefit from early rehabilitation that includes strengthening and aerobic conditioning.

The intervention delivered during treatment was not successful in modifying BMD, physical function, or HRQL. Physical activity, at the level and intensity required to modify these factors, may not be feasible during early treatment owing to the child's responses to the disease and treatment. Future studies will consider intervention implementation during late maintenance therapy, extending into survivorship.

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A B S T R A C T PurposeMany Childhood Cancer Survivor Study (CCSS) participants are at increased risk for obesity. The etiology of their obesity is likely multifactorial but not well understood. Patients and MethodsWe evaluated the potential contribution of demographic, lifestyle, treatment, and intrapersonal factors and self-reported pharmaceutical use to obesity (body mass index Ն 30 kg/m 2 ) among 9,284 adult (Ͼ 18 years of age) CCSS participants. Independent predictors were identified using multivariable regression models. Interrelationships were determined using structural equation modeling (SEM). ResultsIndependent risk factors for obesity included cancer diagnosed at 5 to 9 years of age (relative risk [RR], 1.12; 95% CI, 1.01 to 1.24; P ϭ .03), abnormal Short Form-36 physical function (RR, 1.19; 95% CI, 1.06 to 1.33; P Ͻ .001), hypothalamic/pituitary radiation doses of 20 to 30 Gy (RR, 1.17; 95% CI, 1.05 to 1.30; P ϭ .01), and paroxetine use (RR, 1.29; 95% CI, 1.08 to 1.54; P ϭ .01). Meeting US Centers for Disease Control and Prevention guidelines for vigorous physical activity (RR, 0.90; 95% CI, 0.82 to 0.97; P ϭ .01) and a medium amount of anxiety (RR, 0.86; 95% CI, 0.75 to 0.99; P ϭ .04) reduced the risk of obesity. Results of SEM (N ϭ 8,244; comparative fit index ϭ 0.999; Tucker Lewis index ϭ 0.999; root mean square error of approximation ϭ 0.014; weighted root mean square residual ϭ 0.749) described the hierarchical impact of the direct predictors, moderators, and mediators of obesity. ConclusionTreatment, lifestyle, and intrapersonal factors, as well as the use of specific antidepressants, may contribute to obesity among survivors. A multifaceted intervention, including alternative drug and other therapies for depression and anxiety, may be required to reduce risk.