Construction of a Secondary Enclosure for UVB Irradiation of Mice.

UV irradiation is commonly used in murine models of skin cancers. Despite the popularity of using UVB rays to model photocarcinogenesis in animals, there is a lack of standardization in the secondary enclosures used to administer radiation. An appraisal of the literature also shows a general lack of details regarding the materials and procedures utilized in the fabrication of such enclosures. We present in this study a detailed overview of the construction of a UVB exposure chamber that successfully induces lesions in hairless mice. A standardized protocol for producing a UVB enclosure may reduce methodological variation in future studies seeking to investigate photocarcinogenesis in animals.

Failure and Complication Rates in Common Sports and Arthroscopic Procedures: Reality Check.

Expectations following sports medicine and arthroscopic procedures have been elevated because of captivating modern-day media coverage of high-profile athletic injuries, surgery, and rapid return to sports. Unfortunately, this general perception may be misleading, and orthopedic sports medicine physicians must be aware of the harsh reality of the trials and tribulations associated with the subspecialty. The purpose of this review article is to provide an updated brief overview of the complications and failure rates associated with common arthroscopic procedures including rotator cuff repair, biceps tenodesis, Bankart procedure, Latarjet procedure, anterior cruciate ligament reconstruction, anterior cruciate ligament repair, meniscal repair, tibial tubercle osteotomy, and medial patellofemoral ligament reconstruction. Highlighting the complications is the first step toward early recognition, enhancing preventative measures, and successful management.

Rural breast cancer survivors are able to maintain diet quality improvements during a weight loss maintenance intervention.

PURPOSE: Obesity and poor diet quality (DQ) are associated with increased risk of morbidity/mortality among breast cancer survivors. This study explored DQ changes during a weight loss maintenance intervention in a cohort of rural female breast cancer survivors (n = 131) who lost ≥ 5% body weight in a weight loss intervention. Previous analyses demonstrated significant DQ improvements during weight loss. METHODS: DQ was calculated using the alternate Healthy Eating Index (aHEI)-2010. Differences in scores across time for the cohort and between those that maintained weight loss within 5% (low regainers) and those that regained > 5% (high regainers) were analyzed by linear mixed models. RESULTS: Significant improvements in aHEI total score were observed from baseline (M = 52.3 ± 11) to 6 months (M = 60.7 ± 8; p < 0.001); these improvements were sustained from 6 to 18 months (M = 58.4 ± 11; p = 0.16). Total aHEI-2010 score at 18 months was higher in low regainers, compared with high regainers (60.7 vs. 56.0, p = 0.03), with healthier component scores for red meat (p = 0.01) and fruit (p = 0.04), and a trend for a healthier score for sugar-sweetened beverages (p = 0.08). CONCLUSIONS: Overall DQ improvements made during a weight loss intervention for rural breast cancer survivors were sustained during a weight loss maintenance intervention; this intervention was effective in helping low regainers maintain healthier scores in fruit, red meat, and sugar-sweetened beverage components. IMPLICATIONS FOR CANCER SURVIVORS: Maintaining higher DQ may help breast cancer survivors maintain weight loss, thereby reducing risk of breast cancer recurrence and premature death from comorbidities.

Arthroscopic Rotator Cuff Repair With Allograft Augmentation: Making It Simple.

Rotator cuff tears are increasing in frequency in the aging population and are a common issue seen by orthopaedic surgeons. In patients with large, multi-tendon rotator cuff tears or retears, treatment can be challenging. Failure rates of up to 90% have been reported for rotator cuff repair (RCR) of large, multi-tendon tears. Biological augmentation has been an area of interest because of the distinctly different biology of the repaired tendon compared with the native tendon. These biological differences affect the ultimate tensile properties of the repair and may contribute to gap formation and the high failure rate of repairs. RCR with allograft augmentation is a technique that shows potential benefit to healing and preventing retears. Arthroscopic augmentation of RCRs can be challenging. The technique described in this Technical Note illustrates a simple and easily reproducible method for augmenting RCRs with human acellular dermal allograft.

Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial.

BACKGROUND: The approval of anti-programmed death ligand 1 (PD-L1) and anti-programmed death 1 agents has expanded treatment options for patients with locally advanced or metastatic urothelial carcinoma. Avelumab, a human monoclonal anti-PD-L1 antibody, has shown promising antitumour activity and safety in this disease. We aimed to assess the safety profile in patients (both post-platinum therapy and cisplatin-naive) treated with avelumab and to assess antitumour activity of this drug in post-platinum patients. METHODS: In this pooled analysis of two cohorts from the phase 1 dose-expansion JAVELIN Solid Tumor study, patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic urothelial carcinoma that had progressed after at least one previous platinum-based chemotherapy were enrolled from 80 cancer treatment centres or hospitals in the USA, Europe, and Asia. Eligible patients had adequate end-organ function, an Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, and at least one measurable lesion. Cisplatin-ineligible patients who might have been previously treated in the perioperative setting, including platinum-naive patients, were also eligible. Patients unselected for PD-L1 expression received avelumab (10 mg/kg, 1 h intravenous infusion) every 2 weeks until confirmed disease progression, unacceptable toxicity, or other criterion for withdrawal. The primary endpoint for this efficacy expansion cohort was confirmed best overall response (according to RECIST version 1.1), adjudicated by independent review. Safety analysis was done in all patients who received at least one dose of avelumab. Antitumour activity was assessed in post-platinum patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort of patients with metastatic urothelial carcinoma is closed and the trial is ongoing. FINDINGS: Between Sept 3, 2014, and March 15, 2016, 329 patients with advanced metastatic urothelial carcinoma were screened for enrolment into this study; 249 patients were eligible and received treatment with avelumab for a median of 12 weeks (IQR 6·0-19·7) and followed up for a median of 9·9 months (4·3-12·1). Safety and antitumour activity were evaluated at data cutoff on June 9, 2016. In 161 post-platinum patients with at least 6 months of follow-up, a best overall response of complete or partial response was recorded in 27 patients (17%; 95% CI 11-24), including nine (6%) complete responses and 18 (11%) partial responses. The most frequent treatment-related adverse events (any grade in ≥10% patients) were infusion-related reaction (73 [29%]; all grade 1-2) and fatigue (40 [16%]). Grade 3 or worse treatment-related adverse events occurred in 21 (8%) of 249 patients, the most common of which were fatigue (four [2%]), and asthenia, elevated lipase, hypophosphataemia, and pneumonitis in two (1%) patients each. 19 (8%) of 249 patients had a serious adverse event related to treatment with avelumab, and one treatment-related death occurred (pneumonitis). INTERPRETATION: Avelumab showed antitumour activity in the treatment of patients with platinum-refractory metastatic urothelial carcinoma; a manageable safety profile was reported in all avelumab-treated patients. These data provide the rationale for therapeutic use of avelumab in metastatic urothelial carcinoma and it has received accelerated US FDA approval in this setting on this basis. FUNDING: Merck KGaA, and Pfizer Inc.

Molecular interactions of the γ-clade homeodomain-leucine zipper class I transcription factors during the wheat response to water deficit.

The γ-clade of class I homeodomain-leucine zipper (HD-Zip I) transcription factors (TFs) constitute members which play a role in adapting plant growth to conditions of water deficit. Given the importance of wheat (Triticum aestivum L.) as a global food crop and the impact of water deficit upon grain yield, we focused on functional aspects of wheat drought responsive HD-Zip I TFs. While the wheat γ-clade HD-Zip I TFs share significant sequence similarities with homologous genes from other plants, the clade-specific features in transcriptional response to abiotic stress were detected. We demonstrate that wheat TaHDZipI-3, TaHDZipI-4, and TaHDZipI-5 genes respond differentially to a variety of abiotic stresses, and that proteins encoded by these genes exhibit pronounced differences in oligomerisation, strength of DNA binding, and trans-activation of an artificial promoter. Three-dimensional molecular modelling of the protein-DNA interface was conducted to address the ambiguity at the central nucleotide in the pseudo-palindromic cis-element CAATNATTG that is recognised by all three HD-Zip I proteins. The co-expression of these genes in the same plant tissues together with the ability of HD-Zip I TFs of the γ-clade to hetero-dimerise suggests a role in the regulatory mechanisms of HD-Zip I dependent transcription. Our findings highlight the complexity of TF networks involved in plant responses to water deficit. A better understanding of the molecular complexity at the protein level during crop responses to drought will enable adoption of efficient strategies for production of cereal plants with enhanced drought tolerance.

Efavirenz Capsule Sprinkle and Liquid Formulations With Didanosine and Emtricitabine in HIV-1-infected Infants and Children 3 Months to 6 Years of Age: Study AI266-922.

BACKGROUND: AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years). METHODS: Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle. RESULTS: Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 µM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 µM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance. CONCLUSIONS: Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported.

Race, common genetic variation, and therapeutic response disparities in heart failure.

Because of its comparatively recent evolution, Homo sapiens exhibit relatively little within-species genomic diversity. However, because of genome size, a proportionately small amount of variation creates ample opportunities for both rare mutations that may cause disease as well as more common genetic variations that may be important in disease modification or pharmacogenetics. Primarily because of the East African origin of modern humans, individuals of African ancestry (AA) exhibit greater degrees of genetic diversity than more recently established populations, such as those of European ancestry (EA) or Asian ancestry. Those population effects extend to differences in frequency of common gene variants that may be important in heart failure natural history or therapy. For cell-signaling mechanisms important in heart failure, we review and present new data for genetic variation between AA and EA populations. Data indicate that: 1) neurohormonal signaling mechanisms frequently (16 of the 19 investigated polymorphisms) exhibit racial differences in the allele frequencies of variants comprising key constituents; 2) some of these differences in allele frequency may differentially affect the natural history of heart failure in AA compared with EA individuals; and 3) in many cases, these differences likely play a role in observed racial differences in drug or device response.

Decreased levels of BAG3 in a family with a rare variant and in idiopathic dilated cardiomyopathy.

The most common cause of dilated cardiomyopathy and heart failure (HF) is ischemic heart disease; however, in a third of all patients the cause remains undefined and patients are diagnosed as having idiopathic dilated cardiomyopathy (IDC). Recent studies suggest that many patients with IDC have a family history of HF and rare genetic variants in over 35 genes have been shown to be causative of disease. We employed whole-exome sequencing to identify the causative variant in a large family with autosomal dominant transmission of dilated cardiomyopathy. Sequencing and subsequent informatics revealed a novel 10-nucleotide deletion in the BCL2-associated athanogene 3 (BAG3) gene (Ch10:del 121436332_12143641: del. 1266_1275 [NM 004281]) that segregated with all affected individuals. The deletion predicted a shift in the reading frame with the resultant deletion of 135 amino acids from the C-terminal end of the protein. Consistent with genetic variants in genes encoding other sarcomeric proteins there was a considerable amount of genetic heterogeneity in the affected family members. Interestingly, we also found that the levels of BAG3 protein were significantly reduced in the hearts from unrelated patients with end-stage HF undergoing cardiac transplantation when compared with non-failing controls. Diminished levels of BAG3 protein may be associated with both familial and non-familial forms of dilated cardiomyopathy.

Cost Comparison Model: Blended eLearning versus traditional training of community health workers.

OBJECTIVES: Another one million community healthcare workers are needed to address the growing global population and increasing demand of health care services. This paper describes a cost comparison between two training approaches to better understand costs implications of training community health workers (CHWs) in Sub-Saharan Africa. METHODS: Our team created a prospective model to forecast and compare the costs of two training methods as described in the Dalburge Report - (1) a traditional didactic training approach ("baseline") and (2) a blended eLearning training approach ("blended"). After running the model for training 100,000 CHWs, we compared the results and scaled up those results to one million CHWs. RESULTS: A substantial difference exists in total costs between the baseline and blended training programs. RESULTS indicate that using a blended eLearning approach for training community health care workers could provide a total cost savings of 42%. Scaling the model to one million CHWs, the blended eLearning training approach reduces total costs by 25%. DISCUSSION: The blended eLearning savings are a result of decreased classroom time, thereby reducing the costs associated with travel, trainers and classroom costs; and using a tablet with WiFi plus a feature phone rather than a smartphone with data plan. CONCLUSION: The results of this cost analysis indicate significant savings through using a blended eLearning approach in comparison to a traditional didactic method for CHW training by as much as 67%. These results correspond to the Dalberg publication which indicates that using a blended eLearning approach is an opportunity for closing the gap in training community health care workers.

Ipsilateral motor cortical responses to TMS during lengthening and shortening of the contralateral wrist flexors.

Unilateral lengthening contractions provide a greater stimulus for neuromuscular adaptation than shortening contractions in the active and non-active contralateral homologous muscle, although little is known of the potential mechanism. Here we examined the possibility that corticospinal and spinal excitability vary in a contraction-specific manner in the relaxed right flexor carpi radialis (FCR) when humans perform unilateral lengthening and shortening contractions of the left wrist flexors at the same absolute force. Corticospinal excitability in the relaxed right FCR increased more during lengthening than shortening at 80% and 100% of maximum voluntary contraction (MVC). Short-interval intracortical inhibition diminished during shortening contractions, and it became nearly abolished during lengthening. Intracortical facilitation lessened during shortening but increased during lengthening. Interhemispheric inhibition to the 'non-active' motor cortex diminished during shortening, and became nearly abolished during lengthening at 90% MVC. The amplitude of the Hoffman reflex in the relaxed right FCR decreased during and remained depressed for 20 s after lengthening and shortening of the left wrist flexors. We discuss the possibility that instead of the increased afferent input, differences in the descending motor command and activation of brain areas that link function of the motor cortices during muscle lengthening vs. shortening may cause the contraction-specific modulation of ipsilateral motor cortical output. In conclusion, ipsilateral motor cortex responses to transcranial magnetic stimulation are contraction-specific; unilateral lengthening and shortening contractions reduced contralateral spinal excitability, but uniquely modulated ipsilateral corticospinal excitability and the networks involved in intracortical and interhemispheric connections, which may have clinical implications.

Neighbourhood food environment and area deprivation: spatial accessibility to grocery stores selling fresh fruit and vegetables in urban and rural settings.

BACKGROUND: The 'deprivation amplification' hypothesis suggests that residents of deprived neighbourhoods have universally poorer access to high-quality food environments, which in turn contributes to the development of spatial inequalities in diet and diet-related chronic disease. This paper presents results from a study that quantified access to grocery stores selling fresh fruit and vegetables in four environmental settings in Scotland, UK. METHODS: Spatial accessibility, as measured by network travel times, to 457 grocery stores located in 205 neighbourhoods in four environmental settings (island, rural, small town and urban) in Scotland was calculated using Geographical Information Systems. The distribution of accessibility by neighbourhood deprivation in each of these four settings was investigated. RESULTS: Overall, the most deprived neighbourhoods had the best access to grocery stores and grocery stores selling fresh produce. Stratified analysis by environmental setting suggests that the least deprived compared with the most deprived urban neighbourhoods have greater accessibility to grocery stores than their counterparts in island, rural and small town locations. Access to fresh produce is better in more deprived compared with less deprived urban and small town neighbourhoods, but poorest in the most affluent island communities with mixed results for rural settings. CONCLUSIONS: The results presented here suggest that the assumption of a universal 'deprivation amplification' hypothesis in studies of the neighbourhood food environment may be misguided. Associations between neighbourhood deprivation and grocery store accessibility vary by environmental setting. Theories and policies aimed at understanding and rectifying spatial inequalities in the distribution of neighbourhood exposures for poor diet need to be context specific.

Variations in fresh fruit and vegetable quality by store type, urban-rural setting and neighbourhood deprivation in Scotland.

OBJECTIVE: Neighbourhood differences in access to fresh fruit and vegetables may explain social inequalities in diet. Investigations have focused on variations in cost and availability as barriers to the purchase and consumption of fresh produce; investigations of quality have been neglected. Here we investigate whether produce quality systematically varies by food store type, rural-urban location and neighbourhood deprivation in a selection of communities across Scotland. DESIGN: Cross-sectional survey of twelve fresh fruit and vegetable items in 288 food stores in ten communities across Scotland. Communities were selected to reflect a range of urban-rural settings and a food retail census was conducted in each location. The quality of twelve fruit and vegetable items within each food store was evaluated. Data from the Scottish Executive were used to characterise each small area by deprivation and urban-rural classification. SETTING: Scotland. RESULTS: Quality of fruit and vegetables within the surveyed stores was high. Medium-sized stores, stores in small town and rural areas, and stores in more affluent areas tended to have the highest-quality fresh fruit and vegetables. Stores where food is secondary, stores in urban settings and stores in more deprived areas tended have the lowest-quality fresh produce. Although differences in quality were not always statistically significant, patterns were consistent for the majority of fruit and vegetable items. CONCLUSIONS: The study provides evidence that variations in food quality may plausibly be a micro-environmental mediating variable in food purchase and consumption and help partially explain neighbourhood differences in food consumption patterns.

Identification of a novel class of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents with protein tyrosine phosphatase inhibitory activity.

A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.