EPR Studies of Aß42 Oligomers Indicate a Parallel In-Register ß-Sheet Structure.

Aß aggregation leads to the formation of both insoluble amyloid fibrils and soluble oligomers. Understanding the structures of Aß oligomers is important for delineating the mechanism of Aß aggregation and developing effective therapeutics. Here, we use site-directed spin labeling and electron paramagnetic resonance (EPR) spectroscopy to study Aß42 oligomers prepared by using the protocol of Aß-derived diffusible ligands. We obtained the EPR spectra of 37 Aß42 oligomer samples, each spin-labeled at a unique residue position of the Aß42 sequence. Analysis of the disordered EPR components shows that the N-terminal region has a lower local structural stability. Spin label mobility analysis reveals three structured segments at residues 9-11, 15-22, and 30-40. Intermolecular spin-spin interactions indicate a parallel in-register ß-sheet structure, with residues 34-38 forming the structural core. Residues 16-21 also adopt the parallel in-register ß-structure, albeit with weaker intermolecular packing. Our results suggest that there is a structural class of Aß oligomers that adopt fibril-like conformations.

Endoscopic Management of Gastric Band Erosion: a Systematic Review and Meta-Analysis.

BACKGROUND: Gastric band erosion may be seen in up to 3% of patients. Endoscopic intervention has become increasingly utilized due to its minimally invasive nature. The purpose of this study was to perform a systematic review and meta-analysis to examine the role of endoscopic removal for eroded gastric bands. METHODS: Individualized search strategies were developed for PubMed, EMBASE, Web of Science, and Cochrane Library databases in accordance with PRISMA and MOOSE guidelines. Outcomes included technical success, clinical success, procedure duration, adverse events, and surgical conversion. Pooled proportions were analyzed using random effects models. Heterogeneity and publication bias was assessed with I2 statistics and funnel plot asymmetry using Egger and Begg tests. Meta-regression was also performed comparing outcomes by endoscopic tools. RESULTS: Ten studies (n=282 patients) were included in this meta-analysis. Mean age was 40.68±7.25 years with average duration of band placement of 38.49±19.88 months. Pre-operative BMI was 42.76±1.06 kg/m2 with BMI of 33.06±3.81 kg/m2 at time of band erosion treatment. Endoscopic removal was attempted in 240/282 (85.11%) of cases. Pooled technical and clinical success of the endoscopic therapy was 86.08% (95% CI: 79.42-90.83; I2=28.62%) and 85.34% (95% CI: 88.70-90.62; I2=38.56%), respectively. Mean procedure time for endoscopic removal was 46.47±11.52 min with an intra-operative adverse event rate of 4.15% (95% CI: 1.98-8.51; I2=0.00%). Post-procedure-associated adverse events occurred in 7.24% (CI: 4.46-11.55; I2=0.00%) of patients. Conversion to laparotomy/laparoscopy occurred in 10.54% (95% CI: 6.12-17.54) of cases. CONCLUSION: Endoscopic intervention is a highly effective and safe modality for the treatment of gastric band erosion.

Immediate versus delayed urinary catheter removal following non-hysterectomy benign gynaecological laparoscopy: a randomised trial.

OBJECTIVE: To compare rates of urinary retention and postoperative urinary tract infection between women with immediate versus women with delayed removal of indwelling catheter following benign non-hysterectomy gynaecological laparoscopic surgery. DESIGN: This randomised clinical trial was conducted between February 2012 and December 2019, with follow-up to 6 weeks. SETTING: Two university-affiliated teaching hospitals in Sydney, Australia. POPULATION: Study participants were 693 women aged 18 years or over, undergoing non-hysterectomy laparoscopy for benign gynaecological conditions, excluding pelvic floor or concomitant bowel surgery. METHODS: Three hundred and fifty-five participants were randomised to immediate removal of urinary catheter and 338 participants were randomised to delayed removal of urinary catheter. MAIN OUTCOME MEASURES: The co-primary outcomes were urinary retention and urinary tract infection. Secondary outcomes included hospital readmission, analgesia requirements, duration of hospitalisation and validated bladder function questionnaires. RESULTS: Urinary retention was higher after immediate compared with delayed removal of the urinary catheter (8.2% vs 4.2%, RR 1.8, 95% CI 1.0-3.0, p = 0.04). Although urinary tract infection was 7.2% following delayed removal of the urinary catheter and 4.7% following immediate removal of the urinary catheter, the difference was not statistically significant (RR 0.7, 95% CI 0.3-1.2, p = 0.2). CONCLUSIONS: There is an increased risk of urinary retention with the immediate compared with the delayed removal of the urinary catheter following benign non-hysterectomy gynaecological laparoscopic surgery. The difference in urinary tract infection was not significant. There is 1/12 risk of re-catheterisation after immediate urinary catheter removal. It is important to ensure that patients report normal voiding and emptying prior to discharge, to reduce the need for readmission for the management of urinary retention.

Use of the Nintendo Wii Balance Board for Studying Standing Static Balance Control: Technical Considerations, Force-Plate Congruency, and the Effect of Battery Life.

The Nintendo Wii Balance Board (WBB) has become popular as a low-cost alternative to research-grade force plates. The purposes of this study were to characterize a series of technical specifications for the WBB, to compare balance control metrics derived from time-varying center of pressure (COP) signals collected simultaneously from a WBB and a research-grade force plate, and to investigate the effects of battery life. Drift, linearity, hysteresis, mass accuracy, uniformity of response, and COP accuracy were assessed from a WBB. In addition, 6 participants completed an eyes-closed quiet standing task on the WBB (at 3 battery life levels) mounted on a force plate while sway was simultaneously measured by both systems. Characterization results were all associated with less than 1% error. R2 values reflecting WBB sensor linearity were > .99. Known and measured COP differences were lowest at the center of the WBB and greatest at the corners. Between-device differences in quiet stance COP summary metrics were of limited clinical significance. Lastly, battery life did not affect WBB COP accuracy, but did influence 2 of 8 quiet stance WBB parameters. This study provides general support for the WBB as a low-cost alternative to research-grade force plates for quantifying COP movement during standing.

Response rates and durability of chemotherapy among 62 patients with metastatic Merkel cell carcinoma.

Cytotoxic chemotherapy is commonly used to treat advanced Merkel cell carcinoma (MCC). However, its efficacy in distant metastatic MCC patients is unclear, in part because most prior reports aggregated these patients with those receiving adjuvant chemotherapy and combined chemoradiation for whom prognosis and outcomes may differ. In this retrospective study, we analyzed detailed records from 62 patients with distant metastatic MCC treated with cytotoxic chemotherapy. Efficacy outcomes including response rate (RR), durability of response (DOR), progression-free survival (PFS), and overall survival (OS) were evaluated. In this cohort, platinum plus etoposide was the most commonly used first-line regimen (69%). RR to first-line chemotherapy was 55% (34/62) with complete responses (CR) in 13% (8/62) and partial responses (PR) in 42% (26/62) while 6% (4/62) had stable disease and 39% (24/62) had progressive disease. Median PFS was 94 days and median OS was 9.5 months from start of chemotherapy. Among responding patients (n = 34), median PFS was 168 days and median DOR was 85 days. Among 30 of the 62 patients who received second-line chemotherapy, RR was 23% (7/30; 1 CR, 6 PR), median PFS was 61 days, and median DOR was 101 days. In summary, first-line chemotherapy is associated with a high RR in metastatic MCC, but responses are typically not durable, and the median PFS is only 3 months. These results suggest rapid emergence of chemoresistance in MCC tumors, and may serve as a useful comparator for immunotherapies currently being explored for metastatic MCC.

Redesigning Health Care Practices to Address Childhood Poverty.

Child poverty in the United States is widespread and has serious negative effects on the health and well-being of children throughout their life course. Child health providers are considering ways to redesign their practices in order to mitigate the negative effects of poverty on children and support the efforts of families to lift themselves out of poverty. To do so, practices need to adopt effective methods to identify poverty-related social determinants of health and provide effective interventions to address them. Identification of needs can be accomplished with a variety of established screening tools. Interventions may include resource directories, best maintained in collaboration with local/regional public health, community, and/or professional organizations; programs embedded in the practice (eg, Reach Out and Read, Healthy Steps for Young Children, Medical-Legal Partnership, Health Leads); and collaboration with home visiting programs. Changes to health care financing are needed to support the delivery of these enhanced services, and active advocacy by child health providers continues to be important in effecting change. We highlight the ongoing work of the Health Care Delivery Subcommittee of the Academic Pediatric Association Task Force on Child Poverty in defining the ways in which child health care practice can be adapted to improve the approach to addressing child poverty.

Determinants of Health and Pediatric Primary Care Practices.

More than 20% of children nationally live in poverty. Pediatric primary care practices are critical points-of-contact for these patients and their families. Practices must consider risks that are rooted in poverty as they determine how to best deliver family-centered care and move toward action on the social determinants of health. The Practice-Level Care Delivery Subgroup of the Academic Pediatric Association's Task Force on Poverty has developed a roadmap for pediatric providers and practices to use as they adopt clinical practice redesign strategies aimed at mitigating poverty's negative impact on child health and well-being. The present article describes how care structures and processes can be altered in ways that align with the needs of families living in poverty. Attention is paid to both facilitators of and barriers to successful redesign strategies. We also illustrate how such a roadmap can be adapted by practices depending on the degree of patient need and the availability of practice resources devoted to intervening on the social determinants of health. In addition, ways in which practices can advocate for families in their communities and nationally are identified. Finally, given the relative dearth of evidence for many poverty-focused interventions in primary care, areas that would benefit from more in-depth study are considered. Such a focus is especially relevant as practices consider how they can best help families mitigate the impact of poverty-related risks in ways that promote long-term health and well-being for children.

Topical platelet-derived growth factor vs placebo therapy of diabetic foot ulcers offloaded with windowed casts: a randomized, controlled trial.

OBJECTIVE: This study sought to compare the efficacy of topical platelet derived growth factor (Regranex, Smith and Nephew, London, UK) (test group) to placebo (control group) in treating diabetic foot ulcers. All subjects had a short leg walking cast with a window fashioned in the cast over the site of the ulcer. METHODS: Forty-six subjects were randomized (double-blind) 1:1 to the test or control group and treated for up to 4 months. Subjects had Wagner grade I ulcers with wound area of 1 cm2 to 16 cm2 without severe peripheral arterial disease, osteomyelitis, or any infection requiring antibiotics. Study medication was applied daily and casts changed approximately every 14 days. RESULTS: Of the 46 subjects randomized, 38 either healed or completed 16 weeks of therapy without healing. Eight subjects dropped out prior to 16 weeks. Based on intention-to-treat, 12 of 23 (52%) test group subjects healed before 16 weeks compared to 13 of 23 (57%) control group subjects (not significant). Regression analysis demonstrated that slower healing was associated with larger initial wound size (hazard radio [HR] = 0.997, 95% confidence interval [CI]: 0.995-1.00, P = 0.028) and excessive wound drainage (HR = 0.346, 95% CI: 0.126-0.948, P = 0.039). Excluding the patients who dropped out, 25 of 38 (66%) subjects healed by 4 months. Three additional subjects healed with casts that were worn longer than 4 months, for an overall rate of 74% at 9 months. Five subjects developed cast burns, and 3 patients required amputation. CONCLUSION: Topical platelet derived growth factor does not appear to significantly improve healing of Wagner grade I diabetic foot ulcers that are treated by offloading with a short leg walking cast. Excellent healing rates may be achieved with casting alone.

Cytokine responses in a severe case of glandular fever treated successfully with foscarnet combined with prednisolone and intravenous immunoglobulin.

Viral loads and cytokine responses Epstein-Barr virus (EBV) were measured in an 18-year-old boy with severe glandular fever complicated by a mild anaemia, severe thrombocytopaenia and neutropaenia. Hepatosplenomegaly was detected by abdominal ultrasound in the presence of significant hepatitis. Cytokine testing demonstrated elevated cell-mediated Th1 (IFN-gamma, IL-12, sTNFR1, CXCL10, CXCL9 and CCL3) and humoral Th2 (IL-4) immune responses. Serum antibodies to EBV virus capsid antigen (VCA) IgM and IgG antibodies were detected, together with a raised EBV DNA level (up to about 70,000 DNA copies/mL) in the acute phase of the illness. This EBV DNA load decreased rapidly in response to treatment with a combination of foscarnet, intravenous immunoglobulin and prednisolone, and the boy's symptoms settled eventually after approximately 50 days of illness, following this combined antiviral and immune-modulating therapy. Detailed immunological, virological, haematological and biochemical laboratory parameters are presented to document this patient's severe EBV disease and eventual recovery.

Associations between housing instability and food insecurity with health care access in low-income children.

OBJECTIVE: Homelessness and hunger are associated with poor health care access among children. Housing instability and food insecurity represent milder and more prevalent forms of homelessness and hunger. The aim of this study was to determine the association between housing instability and food insecurity with children's health care access and acute health care utilization. METHODS: We conducted a cross-sectional analysis of 12,746 children from low-income households included in the 2002 National Survey of America's Families (NSAF). In multivariate models controlling for important covariates, we measured the association between housing instability and food insecurity with 3 health care access measures: 1) no usual source of care, 2) postponed medical care, and 3) postponed medications. We also measured 3 health care utilization measures: 1) not receiving the recommended number of well-child care visits, 2) increased emergency department visits, and 3) hospitalizations. RESULTS: Our analysis showed that 29.5% of low-income children lived in households with housing instability and 39.0% with food insecurity. In multivariate logistic regression models, housing instability was independently associated with postponed medical care, postponed medications, and increased emergency department visits. Food insecurity was independently associated with no usual source of care, postponed medical care, postponed medications, and not receiving the recommended well-child care visits. CONCLUSION: Families that experience housing instability and food insecurity, without necessarily experiencing homelessness or hunger, have compromised ability to receive adequate health care for their children. Policy makers should consider improving programs that decrease housing instability and food insecurity, and clinicians should consider screening for housing instability and food insecurity so as to provide comprehensive care.

Evening continuity clinic: preserving primary care education in the face of duty hour limitations?

OBJECTIVE: Residency programs with postcall afternoon continuity clinics violate the new Accreditation Council for Graduate Medical Education (ACGME) limitations on resident duty hours. We evaluated housestaff experience with a pilot intervention that replaced postcall continuity clinics with evening continuity clinics. METHODS: We began this pilot program at one continuity clinic site for pediatric residents. Instead of postcall clinics, residents had evening continuity clinic added to a regular clinic day when they were neither postcall nor on call. At 5 and 11 months, we surveyed housestaff satisfaction and experience with the evening clinics, particularly in comparison to postcall clinics. RESULTS: Nineteen of 23 pediatric residents participated in the pilot program. Twenty-two and 17 residents completed the 5- and 11-month follow-up surveys, respectively. A significantly greater proportion of residents rated their overall satisfaction with evening clinic as good/outstanding (16/18, 89%) compared with postcall clinic (2/19, 11%) at the 5-month survey (P<.01). Resident preference for evening clinic over postcall clinic persisted but was not statistically significant at 11 months (P =.05), and overall satisfaction with evening clinic was unchanged from the 5- and 11-month surveys (P =.64). All areas of patient care, medical education, and clinic infrastructure were better or equal in evening clinic in comparison to postcall clinic except for continuity of preceptors and access to medical services. CONCLUSION: Housestaff had greater satisfaction and a better clinic experience with evening clinic versus postcall clinic. Evening continuity clinic is a viable solution to meeting the ACGME work hour limitations while preserving housestaff primary care education.