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AbstractBackgroundWhile widely used in clinical practice, the reproducibility of high‐definition anorectal manometry (HD‐ARM) remains unclear. We evaluated the intra‐individual reproducibility of HD‐ARM and compared pressures measured with HD‐ARM and high‐resolution anorectal manometry (HR‐ARM).MethodsThirty‐six women with fecal incontinence had an initial HD‐ARM (HD‐ARM1); on the same day, after randomization, 21 had a second (HD‐ARM2). Sixteen women had a third (HD‐ARM3) 4 weeks later. Twenty‐five had also been evaluated by HR‐ARM previously. Rectoanal pressures were assessed at rest, during squeeze and simulated evacuation. Concordance among pressures was assessed with Lin's concordance correlation coefficient (CCC).Key ResultsAnal resting and squeeze pressures measured with HD‐ARM were reproducible on the same and different days; for average resting pressures of HD‐ARM1 vs HD‐ARM2, CCC = 0.73 (95% confidence interval [CI]: 0.53–0.94), and for HD‐ARM1 vs HD‐ARM3, CCC = 0.60 (95% CI: 0.28–0.93). For maximum squeeze pressures of HD‐ARM1 vs HD‐ARM2, CCC = 0.86 (95% CI: 0.75–0.97), and for HD‐ARM1 vs HD‐ARM3, CCC = 0.56 (95% CI: 0.21–0.91). The rectoanal gradient during evacuation was significantly concordant between HD‐ARM1 and HD‐ARM2 but not HD‐ARM1 and HD‐ARM3. Resting (CCC = 0.38 [95% CI: 0.14–0.62]) and squeeze pressures (CCC = 0.73 [95% CI: 0.57–0.89]) measured with HD‐ARM1 and HR‐ARM were also concordant.Conclusions & InferencesAmong women with fecal incontinence, measurements with HD‐ARM were reproducible on the same (anal resting and squeeze pressures and rectoanal gradient during evacuation) and different days (anal resting and squeeze pressures) and correlated with HR‐ARM measurements. These findings support use of HD‐ARM and HR‐ARM for longitudinal assessments of anal resting and squeeze pressures.

Objective: Successful repair of segmental peripheral nerve defects remains a clinical challenge. The current clinical gold standard for such injuries is to use an autologous nerve graft, but this creates donor site morbidity with loss of sensation and potential scarring. Processed nerve allografts have been used to bridge segmental nerve gaps experimentally and clinically. However, in large nerve defects, functional outcomes are not comparable with autograft reconstruction yet; the longer the nerve gap, the poorer the outcome. Nerve architecture and the extracellular matrix (ECM) are preserved after processing; however, all cellular material including Schwann cells and axons are removed. The addition of supporting cells has been proposed to improve the decellularized allograft. Adipose-Derived Mesenchymal Stem Cells (AMSC) can potentially provide the necessary support for nerve regeneration due to local production of essential growth factors. While the mechanisms underlying the neurotrophic potential of AMSC remains unknown, it is postulated that the remaining ECM still has biological activity that influences the AMSC and their differentiation. Therefore, the purpose of this study was to quantitate the changes in gene expression profiles of the cells and quantify the actual produced growth factors after seeding the allograft with AMSC in vitro. Method: A total of 35 human nerve allografts were decellularized and seeded with human AMSC. At each time point (1, 3, 14, 21, and 28 days), total RNA was extracted, reverse transcribed into complementary DNA (cDNA), and quantitative reverse transcription–polymerase chain reaction (qRT-PCR) was performed in combination with gene specific assays for genes essential for nerve regeneration including nerve growth factor (NGF), Brain-derived neurotrophic factor (BDNF), pleiotrophin vascular endothelial growth factor (PTN VEGF), and growth associated protein 43 (GAP43).Additional genes were analyzed to map AMSC characteristics including proliferation, apoptosis, myelinization, and ECM molecules. Production of growth factors was evaluated and quantified using enzyme-linked immunosorbent assay (ELISA). All samples were analyzed in triplicates and data were compared with AMSC cultured in media only. Results: Semiquantitative RT-PCR analysis showed that the interaction of the processed allograft and AMSC enhanced the expression of the neurotrophic factors NGF, BDNF, and GAP43. The expression of the angiogenic molecules, vascular endothelial growth factor A (VEGF-A) was also increased and remained significantly elevated at 28 days post seeding. Analysis of ECM-related gene expression showed that laminin subunit beta-2 (LAMB2), collagen type I alpha 1 (COL1A1), collagen type III alpha 1 (COL3A1), fibulin 1 (FBLN1), were significantly elevated until 21 days post seeding while after 28 days, these levels were normalized. Angiogenic factor cluster of differentiation 31 (CD31) and neurotrophic factor PTN expression were down regulated in the seeded cells. Quantitative results of the ELISA analysis are pending. We anticipate differences in growth factor levels released by the seeded allograft compared with the control expression levels. Conclusion: This study demonstrates that the remaining ECM of the decellularized nerve allograft has a stimulating effect on AMSC. Upon the seeding, secretion of neurotrophic and angiogenic factors were triggered; the cells cultured on the allograft showed enhanced levels of neurotrophic genes. This is hypothesized to be a consequence of specific cell-ECM interactions within the allograft. The combination of patient’s own easily accessible, abundant supply of stem cells harvested from adipose tissue and the readily available processed nerve allograft is potentially a promising method for individualized peripheral nerve repair.

OBJECTIVETo examine temporal trends in utilization of glucose-lowering medications, glycemic control, and rate of severe hypoglycemia among patients with type 2 diabetes (T2DM).RESEARCH DESIGN AND METHODSUsing claims data from 1.66 million privately insured and Medicare Advantage patients with T2DM from 2006 to 2013, we estimated the annual 1) age- and sex-standardized proportion of patients who filled each class of agents; 2) age-, sex-, race-, and region-standardized proportion with hemoglobin A1c (HbA1c) <6%, 6 to <7%, 7 to <8%, 8 to <9%, ≥9%; and 3) age- and sex-standardized rate of severe hypoglycemia among those using medications. Proportions were calculated overall and stratified by age-group (18–44, 45–64, 65–74, and ≥75 years) and number of chronic comorbidities (zero, one, and two or more).RESULTSFrom 2006 to 2013, use increased for metformin (from 47.6 to 53.5%), dipeptidyl peptidase 4 inhibitors (0.5 to 14.9%), and insulin (17.1 to 23.0%) but declined for sulfonylureas (38.8 to 30.8%) and thiazolidinediones (28.5 to 5.6%; all P < 0.001). The proportion of patients with HbA1c <7% declined (from 56.4 to 54.2%; P < 0.001) and with HbA1c ≥9% increased (9.9 to 12.2%; P < 0.001). Glycemic control varied by age and was poor among 23.3% of the youngest and 6.3% of the oldest patients in 2013. The overall rate of severe hypoglycemia remained the same (1.3 per 100 person-years; P = 0.72), declined modestly among the oldest patients (from 2.9 to 2.3; P < 0.001), and remained high among those with two or more comorbidities (3.2 to 3.5; P = 0.36).CONCLUSIONSDuring the recent 8-year period, the use of glucose-lowering drugs has changed dramatically among patients with T2DM. Overall glycemic control has not improved and remains poor among nearly a quarter of the youngest patients. The overall rate of severe hypoglycemia remains largely unchanged.

Abstract Nontuberculous mycobacteria (NTM) cause an increasingly important chronic and debilitating lung disease in older adults. Diagnosis is often delayed, although awareness among clinicians and patients is increasing. When necessary, treatment often lasts 18–24 months and consists of three or four antibiotics that can have serious side effects. Relapses are common and commonly require resumption of prolonged therapy. Given the need for improved diagnostic techniques and clinical trials to identify new therapies or to improve existing therapies, a group of North American clinicians and researchers formed the NTM Research Consortium (NTMRC) in 2014. The NTMRC recognized the importance of including the patient voice in determining research priorities for NTM. In November 2015, patients, caregivers, patient advocates, clinical experts, and researchers gathered for a 1-day meeting in Portland, Oregon funded by the Patient-Centered Outcomes Research Institute. The meeting goal was to define patient-centered research priorities for NTM lung infections. Patients expressed frustration with the number of people who have endured years of missed diagnoses or inadequate treatment of NTM. Participants identified as top research priorities the prevention of NTM infection; approval of more effective treatments with fewer side effects and easier administration; understanding the best chest physiotherapy methods; validating and using tools to measure quality of life; and developing a disease-specific activity and severity assessment tool. Workshop participants agreed that two complementary objectives are critical to ensure the best achievable outcomes for patients: (1) additional clinician education to improve screening and diagnosis of NTM infections; and (2) development of a geographically distributed network of experts in NTM disease to offer consultation or direct therapy after a diagnosis is made.

Chemically crosslinking GOa and CNTpega followed by in situ reduction fabricated a conductive rGOa–CNTpega–OPF hydrogel that strongly stimulated neurite growth.

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

Purpose We aimed to update a previously published, multi-institutional nomogram of outcomes for salvage radiotherapy (SRT) following radical prostatectomy (RP) for prostate cancer, including patients treated in the contemporary era. Methods Individual data from node-negative patients with a detectable post-RP prostate-specific antigen (PSA) treated with SRT with or without concurrent androgen-deprivation therapy (ADT) were obtained from 10 academic institutions. Freedom from biochemical failure (FFBF) and distant metastases (DM) rates were estimated, and predictive nomograms were generated. Results Overall, 2,460 patients with a median follow-up of 5 years were included; 599 patients (24%) had a Gleason score (GS) ≤ 6, 1,387 (56%) had a GS of 7, 244 (10%) had a GS of 8, and 230 (9%) had a GS of 9 to 10. There were 1,370 patients (56%) with extraprostatic extension (EPE), 452 (18%) with seminal vesicle invasion (SVI), 1,434 (58%) with positive surgical margins, and 390 (16%) who received ADT (median, 6 months). The median pre-SRT PSA was 0.5 ng/mL (interquartile range, 0.3 to 1.1). The 5-yr FFBF rate was 56% overall, 71% for those with a pre-SRT PSA level of 0.01 to 0.2 ng/mL (n = 441), 63% for those with a PSA of 0.21 to 0.50 ng/mL (n = 822), 54% for those with a PSA of 0.51 to 1.0 ng/mL (n = 533), 43% for those with a PSA of 1.01 to 2.0 ng/mL (n = 341), and 37% for those with a PSA > 2.0 ng/mL (n = 323); P < .001. On multivariable analysis, pre-SRT PSA, GS, EPE, SVI, surgical margins, ADT use, and SRT dose were associated with FFBF. Pre-SRT PSA, GS, SVI, surgical margins, and ADT use were associated with DM, whereas EPE and SRT dose were not. The nomogram concordance indices were 0.68 (FFBF) and 0.74 (DM). Conclusion Early SRT at low PSA levels after RP is associated with improved FFBF and DM rates. Contemporary nomograms can estimate individual patient outcomes after SRT in the modern era.

AbstractScaffolds with porous structures are highly applicable for tissue engineering and regenerative medicine. In the present study, 3‐dimensional poly(propylene fumarate‐co‐caprolactone) [P(PF‐co‐CL)] scaffolds were fabricated from a P(PF‐co‐CL)–dioxane‐water ternary system through thermally induced phase separation (TIPS). Cloud points of P(PF‐co‐CL) in dioxane‐water solutions increased with increased solute concentration, but increased dioxane composition decreased cloud point. Among 3 polymer concentrations (4, 8, and 12 wt%), 8 wt% P(PF‐co‐CL) scaffolds exhibited the best pore interconnectivity, with large, regular sized pores. Scaffolds were formed in 3 solutions with different dioxane‐water ratios (74/26, 78/22, and 82/18 wt/wt); the 78/22 wt/wt scaffold had finger‐shaped patterns with better interconnectivity than scaffolds from the other two ratios. Higher dioxane‐water ratios resulted in a larger contact angle and thus less wettability for the fabricated scaffold, while scaffolds fabricated from higher concentrations of P(PF‐co‐CL) or high dioxane‐water ratios had better biomineralization after soaking in simulated body fluid. In vitro cell viability testing showed the scaffolds had good biocompatibility with both bone and nerve cells. The results indicate that the polymer concentration and solvents ratio significantly affect the formation of porous structures, and optimum processing parameters were found to be 8% polymer concentration and 22% to 24% water content. These porous P(PF‐co‐CL) scaffolds fabricated via TIPS may be useful in various tissue engineering applications © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 226–235, 2017.