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Background and purposeThe aim of our study was to determine the utility of longitudinal magnetic resonance imaging (MRI) measurements as potential biomarkers in the main genetic variants of frontotemporal dementia (FTD), including microtubule‐associated protein tau (MAPT) and progranulin (GRN) mutations and C9ORF72 repeat expansions, as well as sporadic FTD.MethodsIn this longitudinal study, 58 subjects were identified who had at least two MRI and MAPT mutations (n = 21), GRN mutations (n = 11), C9ORF72 repeat expansions (n = 11) or sporadic FTD (n = 15). A total of 198 serial MRI measurements were analyzed. Rates of whole brain atrophy were calculated using the boundary shift integral. Regional rates of atrophy were calculated using tensor‐based morphometry. Sample size estimates were calculated.ResultsProgressive brain atrophy was observed in all groups, with fastest rates of whole brain atrophy in GRN, followed by sporadic FTD, C9ORF72 and MAPT. All variants showed greatest rates in the frontal and temporal lobes, with parietal lobes also strikingly affected in GRN. Regional rates of atrophy across all lobes were greater in GRN compared to the other groups. C9ORF72 showed greater rates of atrophy in the left cerebellum and right occipital lobe than MAPT, and sporadic FTD showed greater rates in the anterior cingulate than C9ORF72 and MAPT. Sample size estimates were lowest using temporal lobe rates in GRN, ventricular rates in MAPT and C9ORF72, and whole brain rates in sporadic FTD.ConclusionThese data support the utility of using rates of atrophy as outcome measures in future drug trials in FTD and show that different imaging biomarkers may offer advantages in the different variants of FTD.

We have previously shown that voluntary wheel running (VWR) attenuates, whereas forced treadmill running (FTR) exacerbates, intestinal inflammation and clinical outcomes in a mouse model of colitis. As the gut microbiome is implicated in colitis, we hypothesized that VWR and FTR would differentially affect the gut microbiome. Mice (9-10/treatment) were randomly assigned to VWR, FTR, or sedentary home cage control (SED) for 6 wk. VWR were given running wheel access, whereas FTR ran on a treadmill for 40 min/day at 8–12 m/min, 5% grade. Forty-eight hours after the last exercise session, DNA was isolated from the fecal pellets and cecal contents, and the conserved bacterial 16S rRNA gene was amplified and sequenced using the Illumina Miseq platform. Permutational multivariate analysis of variance based on weighted UniFrac distance matrix revealed different bacterial clusters between feces and cecal contents in all groups ( P < 0.01). Interestingly, the community structures of the three treatment groups clustered separately from each other in both gut regions ( P < 0.05). Contrary to our hypothesis, the α-diversity metric, Chao1, indicated that VWR led to reduced bacterial richness compared with FTR or SED ( P < 0.05). Taxonomic evaluation revealed that both VWR and FTR altered many individual bacterial taxa. Of particular interest, Turicibacter spp., which has been strongly associated with immune function and bowel disease, was significantly lower in VWR vs. SED/FTR. These data indicate that VWR and FTR differentially alter the intestinal microbiome of mice. These effects were observed in both the feces and cecum despite vastly different community structures between each intestinal region.

Purpose The optimal timing of postoperative radiotherapy (RT) after radical prostatectomy (RP) is unclear. We hypothesized that a genomic classifier (GC) would provide prognostic and predictive insight into the development of clinical metastases in men receiving post-RP RT and inform decision making. Patients and Methods GC scores were calculated from 188 patients with pT3 or margin-positive prostate cancer, who received post-RP RT at Thomas Jefferson University and Mayo Clinic between 1990 and 2009. The primary end point was clinical metastasis. Prognostic accuracy of the models was tested using the concordance index for censored data and decision curve analysis. Cox regression analysis tested the relationship between GC and metastasis. Results The cumulative incidence of metastasis at 5 years after RT was 0%, 9%, and 29% for low, average, and high GC scores, respectively (P = .002). In multivariable analysis, GC and pre-RP prostate-specific antigen were independent predictors of metastasis (both P < .01). Within the low GC score (< 0.4), there were no differences in the cumulative incidence of metastasis comparing patients who received adjuvant or salvage RT (P = .79). However, for patients with higher GC scores (≥ 0.4), cumulative incidence of metastasis at 5 years was 6% for patients treated with adjuvant RT compared with 23% for patients treated with salvage RT (P < .01). Conclusion In patients treated with post-RP RT, GC is prognostic for the development of clinical metastasis beyond routine clinical and pathologic features. Although preliminary, patients with low GC scores are best treated with salvage RT, whereas those with high GC scores benefit from adjuvant therapy. These findings provide the first rational selection of timing for post-RP RT.

Abstract Background. nab-Paclitaxel in combination with gemcitabine has emerged as a new treatment option for patients with metastatic pancreatic cancer (MPC), based on superiority over gemcitabine demonstrated in the phase III MPACT trial. Previously, Karnofsky performance status (KPS) score and the presence of liver metastases were shown to be predictive of survival with nab-paclitaxel plus gemcitabine treatment. This analysis sought to further explore the relationship between clinical characteristics and survival in the MPACT trial and to identify potential predictors of overall survival and progression-free survival in patients with MPC. Materials and Methods. Cox regression models adjusted for stratification factors and a stepwise multivariate analysis of prespecified baseline prognostic factors were performed. Results. Treatment effect was significantly associated with survival, with a similar magnitude of reduction in risk of death compared with the previously reported primary analysis. Treatment effect consistently favored nab-paclitaxel plus gemcitabine across the majority of the prespecified factors. In addition to KPS score and presence of liver metastases, age and number of metastatic sites were independent prognostic factors of overall and progression-free survival. Baseline carbohydrate antigen 19-9 was not found to be an independent prognostic factor of survival in this analysis. Conclusion. The results of this analysis confirm broad utility of nab-paclitaxel plus gemcitabine for the treatment of MPC. In addition, these findings suggest that KPS score, presence of liver metastases, age, and number of metastatic sites are important predictors of survival that may be useful when making treatment decisions and designing future clinical trials.

AbstractIntroductionAnalyzing hospital naloxone use may assist in identification of areas for quality and safety improvement. Our primary objective is to quantitate the incidence of hospital naloxone use and to assess certain patient populations at risk.MethodsDuring the years 2008 to 2011, each clinical scenario where naloxone was administered on an in‐patient care ward was reviewed. The events were assessed to separate situations where naloxone rescue was effective in reversing opioid‐induced intoxication vs. others. Further analysis was conducted to stratify patient populations at greatest risk.ResultsNaloxone was administered for well‐defined opioid‐induced respiratory depression and oversedation 61% of the time, the remainder used for patient deterioration of other etiology. Surgical populations are at risk with an incidence of 3.8/1,000 hospitalized patients, and this is the greatest within 24 hours of surgery. General surgical patients represent the highest surgical patient risk at 5.5/1,000. Medical patients represent lower risk at 2.0/1,000. Patients with patient‐controlled analgesia and epidural opioid infusion are high risk at 12.1 and 13.1/1,000 patients, respectively. Many quality and safety interventions were gradually implemented in response to this data and are summarized. These include nursing and provider education, electronic medical record modification, and more stringent patient monitoring practices.ConclusionExamination of naloxone use can assist in the identification and stratification of patients at risk for opioid‐induced respiratory depression and oversedation and can serve as a driver for improvements in hospital patient safety. This information can also guide other institutions interested in similar improvements.

Objective: Several techniques are described in the literature for nasal septal perforation repair. Most of these involve interposition grafts in conjunction with local pedicled mucosal flaps. The following article describes our experience using acellular dermis as a bioscaffold to support the regrowth of nasal septal mucosa by secondary intention. Methods: Retrospective chart review of all patients who underwent repair of nasal septal perforations by the senior author using acellular dermis placed between the 2 sides of the perforation and covered with silastic splints to allow for mucosalization. Results: Thirteen patients underwent nasal septal perforation repair using this technique. All perforations repaired were under 2 cm in greatest dimension. Two-thirds of patients had complete closure of the perforation upon initial use of bioscaffolding technique. The remaining third achieved near-total closure with bioscaffolding technique and were able to be completely closed with a single additional procedure. Conclusions: Acellular dermis offers an alternative to most currently described complex flaps. The method can be used in patients with defects less than 2 cm, but initial data suggest caution when using in those with wound healing impediments. This technique is also an excellent choice for patients with multiple small septal perforations.