Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer’s disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APPΔNL/ΔNLx PS1P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small strokes. Cortical Aβ deposition was not significantly increased in the diabetic mice, though overall expression of presenilin was elevated. Surprisingly, Aβ was not deposited in the vasculature or removed to the plasma, and there was no stimulation of activity or expression of major Aβ-clearing enzymes (neprilysin, insulin degrading enzyme, or endothelin-converting enzyme). The db/AD mice displayed marked cognitive impairment in the Morris Water Maze, compared to either db/db or APPΔNLx PS1P264L mice. We conclude that the diabetes and/or obesity in these mice leads to a destabilization of the vasculature, leading to strokes and that this, in turn, leads to a profound cognitive impairment and that this is unlikely to be directly dependent on Aβ deposition. This model of mixed or vascular dementia provides an exciting new avenue of research into the mechanisms underlying the obesity-related risk for age-related dementia, and will provide a useful tool for the future development of therapeutics.

Background: Sphingolipids play an important role in glucose homeostasis. Results: High glucose induces SphK activity, leading to increases in S1P levels and stimulation of insulin secretion. Conclusion: SphK activity and S1P levels are critical for glucose-stimulated insulin secretion. Significance: The presented data uncover a new role for SphK and S1P in regulation of insulin secretion by glucose.

Objectives: To determine if children with laryngeal penetration on videofluoroscopic swallow study (VFSS) who received feeding interventions (thickened liquids, change in liquid flow rate and/or method of liquid delivery) had improved symptoms and decreased hospitalizations compared to those without intervention. Methods: We performed a retrospective cohort study of children under 2 years with laryngeal penetration on VFSS at our institution in 2015 to determine initial and follow-up VFSS findings, symptom improvement at follow-up, and hospitalization risk before and after VFSS. Proportions were compared with Fisher's exact test and hospitalizations with paired t-tests. Results: We evaluated 137 subjects with age 8.93±0.59 months who had laryngeal penetration without aspiration on VFSS. 55% had change in management, with 40% receiving thickening and 15% a change in flow rate. There was significant improvement in symptoms for children that had feeding intervention and this improvement was greatest with thickening (OR 41.8, 95% CI 12.34-141.69, p<0.001). On repeat VFSS, 26% had evidence of aspiration that was not captured on initial VFSS. Subjects had decreased total and pulmonary hospitalizations with feeding intervention and decreased pulmonary nights with thickening (p<0.05). Conclusions: Laryngeal penetration appears to be clinically significant in children with oropharyngeal dysphagia and interventions to decrease its occurrence are associated with improved outcomes including decreased symptoms of concern and hospitalization nights. Thickening or other feeding intervention should be considered for all symptomatic children with laryngeal penetration on swallow study.

Presenting symptoms are varied in patients with aspiration and cannot be relied upon to determine which patients have aspiration on VFSS. The CFE does not have the sensitivity to consistently diagnose aspiration so a VFSS should be performed in persistently symptomatic patients.

Children with cancer and their families experience shifts in spiritual wellness from diagnosis through treatment and survivorship or bereavement. An interdisciplinary team conducted a systematic review of quantitative and qualitative research on spiritual assessments, interventions, and outcomes in childhood cancer following PRISMA guidelines using a PROSPERO registered protocol. Thirty‐nine well‐designed studies were included in the final analysis. The findings from this systematic review indicate the need for early spiritual assessment with offering of continued support for the spiritual functioning of children with cancer and their families as a standard of care.

Objective To compare the frequency of hospitalization rates between aspirating patients treated with gastrostomy versus those fed oral thickened liquids. Study design A retrospective review was performed of patients with an abnormal videofluoroscopic swallow study between February 2006 and August 2013. 114 patients at Boston Children's Hospital were included. Frequency, length, and type of hospitalizations within one year of abnormal swallow study or gastrostomy tube placement were analyzed using a negative binomial regression model. Results Gastrostomy tube fed patients had a median of 2 (IQR: 1, 3) admissions per year as compared with orally fed patients who had a 1 (IQR: 0, 1) admissions per year, p<0.0001. Patients fed by gastrostomy were hospitalized for more days (median 24 (IQR: 6, 53) days) versus orally fed patients (median: 2 (IQR: 1, 4) days, (P<0.001)). Despite the potential risk of feeding patients orally, no differences in total pulmonary admissions (IRR: 1.65 (95%CI [0.70, 3.84])) between the two groups were found, except gastrostomy tube patients had 2.58 times (95%CI [1.02, 6.49]) more urgent pulmonary admissions. Conclusion Patients who underwent gastrostomy tube placement for the treatment of aspiration had two times as many admissions as compared with aspirating patients fed orally. We recommend a trial of oral feeding in all children cleared to take nectar or honey thickened liquids prior to gastrostomy tube placement.

PURPOSE We conducted this systematic review to evaluate the clinical outcomes associated with molecular tumor board (MTB) review in patients with cancer. METHODS A systematic search of PubMed was performed to identify studies reporting clinical outcomes in patients with cancer who were reviewed by an MTB. To be included, studies had to report clinical outcomes, including clinical benefit, response, progression-free survival, or overall survival. Two reviewers independently selected studies and assessed quality with the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group or the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies depending on the type of study being reviewed. RESULTS Fourteen studies were included with a total of 3,328 patients with cancer. All studies included patients without standard-of-care treatment options and usually with multiple prior lines of therapy. In studies reporting response rates, patients receiving MTB-recommended therapy had overall response rates ranging from 0% to 67%. In the only trial powered on clinical outcome and including a control group, the group receiving MTB-recommended therapy had significantly improved rate of progression-free survival compared with those receiving conventional therapy. CONCLUSION Although data quality is limited by a lack of prospective randomized controlled trials, MTBs appear to improve clinical outcomes for patients with cancer. Future research should concentrate on prospective trials and standardization of approach and outcomes.

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