Switchgrass extractives to mitigate Escherichia coli O157:H7 and Salmonella enterica serovar Typhimurium contamination of romaine lettuce at pre- and postharvest.

The antimicrobial potential of switchgrass extractives (SE) was evaluated on cut lettuce leaves and romaine lettuce in planta, using rifampicin-resistant Escherichia coli O157:H7 and Salmonella Typhimurium strain LT2 as model pathogens. Cut lettuce leaves were swabbed with E. coli O157:H7 or S. Typhimurium followed by surface treatment with 0.8% SE, 0.6% sodium hypochlorite, or water for 1 to 45 min. For in planta studies, SE was swabbed on demarcated leaf surfaces either prior to or after inoculation of greenhouse-grown lettuce with E. coli O157:H7 or S. Typhimurium; the leaf samples were collected after 0, 24, and 48 h of treatment. Bacteria from inoculated leaves were enumerated on tryptic soy agar plates (and also on MacConkey's and XLT4 agar plates), and the recovered counts were statistically analyzed. Cut lettuce leaves showed E. coli O157:H7 reduction between 3.25 and 6.17 log CFU/leaf, whereas S. Typhimurium reductions were between 2.94 log CFU/leaf and 5.47 log CFU/leaf depending on the SE treatment durations, from initial levels of ∼7 log CFU/leaf. SE treatment of lettuce in planta, before bacterial inoculation, reduced E. coli O157:H7 and S. Typhimurium populations by 1.88 and 2.49 log CFU after 24 h and 3 h, respectively. However, SE treatment after bacterial inoculation of lettuce plants decreased E. coli O157:H7 populations by 3.04 log CFU (after 0 h) with negligible reduction of S. Typhimurium populations. Our findings demonstrate the potential of SE as a plant-based method for decontaminating E. coli O157:H7 on lettuce during pre- and postharvest stages in hurdle approaches.

Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Interleukin-31 promotes pathogenic mechanisms underlying skin and lung fibrosis in scleroderma.

OBJECTIVES: Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis. METHODS: IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFß, and the fibrotic reaction measured by histology and ELISA of plasma. RESULTS: IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFß, which supressed IL-31RA. CONCLUSION: IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients.

Current Approaches to the Treatment of Advanced or Metastatic Renal Cell Carcinoma.

The optimal management approach to advanced or metastatic renal cell cancer of the clear cell type continues to rapidly evolve. Risk stratification of patients into favorable-, intermediate-, and poor-risk categories is now routinely performed. In selected individuals with low-volume indolent disease, active surveillance may be an appropriate option. Cytoreductive nephrectomy and/or surgical metastasectomy may be also be considered for selected patients after evaluation by a multidisciplinary tumor board. Systemic frontline therapy options now include immune checkpoint inhibitor-based combination (IBC) therapies such as pembrolizumab/axitinib, nivolumab/ipilimumab, and avelumab/axitinib. With unusual exceptions, monotherapy with vascular growth factor receptor tyrosine kinase inhibitors or mTOR inhibitors are no longer appropriate options in the frontline setting. Despite the established efficacy of frontline IBC, most patients will ultimately require additional lines of therapy, and oncologists must think carefully when switching to another therapy, particularly in situations of drug intolerance or apparent disease progression. Systemic therapy options after IBC are generally tyrosine kinase inhibitor-based, and ongoing clinical trials will help optimize the treatment algorithm further. Despite many recent drug approvals for renal cell cancer (RCC), there remains a pressing must identify new therapeutic targets. Finally, other systemic therapy or supportive care approaches must be considered for special patient populations such as those with poor performance status, end-organ dysfunction, brain metastases, or who have undergone metastasectomy.

Stereotactic Radiosurgery for Multiple Brain Metastases From Renal-Cell Carcinoma.

BACKGROUND: Brain metastases (BM) pose a significant problem in patients with metastatic renal-cell carcinoma (mRCC). Local and systemic therapies including stereotactic radiosurgery (SRS) are rapidly evolving, necessitating reassessments of outcomes for modern patient management. PATIENTS AND METHODS: The mRCC patients with BM treated with SRS were reviewed. Patient demographics, clinical history, and SRS treatment parameters were identified. RESULTS: Among 268 patients with mRCC treated between 2006 and 2015, 38 patients were identified with BM. A total of 243 BM were treated with SRS with 1 to 26 BMs treated per SRS session (median, 2 BMs). The median (range) BM size was 0.6 (0.2-3.1) cm and median (range) SRS treatment dose was 18 (12-24) Gy. Treated BM local control rates at 1 and 2 years were 91.8% (95% confidence interval, 85.7-95.4) and 86.1% (95% confidence interval, 77.1-91.7), respectively. BM control declined for larger tumors. Survival after 1-year was 57.5% (95% CI 40.2-71.4) for all patients. Survival was not statistically different between patients with < 5 BM versus ≥ 5 BM. Survival was prognostic based on International Metastatic Renal Cell Carcinoma Database (IMDC) risk groups in patients with < 5 BM. Two patients experienced grade 3 radiation necrosis requiring surgical intervention. CONCLUSION: SRS is effective in controlling BM in patients with mRCC. Over half of treated patients survive past a year, and no differences in survival were noted in patients with > 5 metastases. Prognostic risk categories based on systemic disease (IMDC) are predictive of survival in this BM population, with limited rates of symptomatic radiation necrosis.

Misalignment of sexual and reproductive health priorities among older Latino adolescents and their mothers.

OBJECTIVE: The study describes maternal and adolescent perspectives on sexual decision making and the role of mothers in shaping use of contraception for the prevention of unplanned pregnancies and sexually transmitted infections (STIs) among older Latino adolescents. STUDY DESIGN: Researchers used a semistructured interview guide to conduct focus group discussions with 21 mother-adolescent Latino dyads (n=42). Latino adolescents ages 17-19 were eligible for the study. We recruited families from the South Bronx, New York City, using area sampling methodology. For analysis of qualitative data, we used the framework method involving open coding, identification of dominant themes, refining of codebooks and indexing. RESULTS: Overwhelmingly, results suggest asymmetric priorities and preferences regarding maternal involvement in older adolescent sexual and contraceptive decision making. Mothers primarily employed practices designed to prevent adolescent sexual activity. Most teens reported already having experienced sexual debut and were currently sexually active. Adolescents expressed a strong interest in practical support for sexual decision making, including maternal guidance regarding effective access to and use of contraception. Mothers offered limited guidance or support with such matters. Maternal views focused entirely on the health and social consequences of sex in lieu of specific guidance on contraception for older sexually active adolescents. The findings highlight a missed opportunity for Latino mothers to support their older adolescent children to prevent unplanned pregnancies, STIs and HIV. CONCLUSION: Mothers have the potential to positively shape adolescent contraceptive decision making and behavior. Misalignment of priorities between mothers and adolescents diminishes the potential of reducing adolescent sexual and reproductive health (SRH) disparities. IMPLICATIONS: Mothers are influential in reducing adolescent SRH risk. However, asymmetric priorities among Latino adolescents and their mothers regarding support for SRH reduce likelihood of reducing adolescent negative SRH outcomes and supporting adolescent health. Programs supporting better alignment of maternal guidance and adolescent SRH needs are warranted.

Addressing a Critical Gap in U.S. National Teen Pregnancy Prevention Programs: The Acceptability and Feasibility of Father-Based Sexual and Reproductive Health Interventions for Latino Adolescent Males.

PURPOSE: The purpose of the research was to examine the feasibility and acceptability of a father-based sexual and reproductive health intervention designed to reduce sexual and reproductive (SRH) disparities and increase correct and consistent condom use among Latino adolescent males. METHODS: The current study conducted in-depth semi-structured interviews with Latino father-son dyads (N=30) designed to elicit perspectives on communication regarding sex and condom use. In addition, the interview protocol included father-son preferences regarding paternal involvement in condom instruction and perceived obstacles and advantages of father direct involvement in education efforts designed to increase correct and consistent condom use among their adolescent sons. Three independent coders conducted both vertical and horizontal analyses of the data to identify emergent themes and reach theoretical saturation. RESULTS: The main findings from this study suggest that Latino fathers can be impactful in shaping Latino adolescent male sexual decision-making and correct and consistent condom use. However, our data highlight that while both feasible and acceptable, Latino fathers identify needing additional support in how best to communicate and seek opportunities to master their own knowledge and skills regarding condom use and effective communication with their adolescent sons about sex. CONCLUSIONS: Latino father-based interventions represent an acceptable and feasible option for building upon the recent success of U.S. national efforts to reduce teen pregnancy rates and STI disparities among Latino youth. However, there exists a need for father-based programs that will support Latino fathers in best educating their sons about condom use and better addressing their SRH. Ongoing national efforts to reduce Latino teen SRH disparities warrant the consideration of father-son interventions for Latino adolescent males in the United States.

Strengthening the HIV Care Continuum in the Dominican Republic: Application of a Triadic Implementation Framework to Meet the UNAIDS 90-90-90 Treatment Goal.

Innovative empirical frameworks to evaluate progress in efforts addressing HIV treatment and prevention barriers in resource-limited areas are sorely needed to achieve the UNAIDS 90-90-90 goal (90% diagnosed, 90% on treatment, and 90% virally suppressed). A triadic implementation framework (TIF) is a comprehensive conceptual tool for (1) monitoring attrition, (2) evaluating operational programs, and (3) measuring the impact of specific implementation goals within the care continuum. TIF will assess the effects of enhanced programs on adherence and virologic suppression within the HIV care continuum at a regional clinic in the Dominican Republic (Clínica de Familia La Romana [CFLR]) and its program serving high-risk, migratory batey (sugarcane cultivation) communities. A retrospective cohort study completed during 2015 collected deidentified data from a CFLR chart review of adult HIV patients diagnosed in 2013. The results were quantitatively analyzed and compared to 2011 cohort data. In 2013, 310 patients were diagnosed HIV positive. The results demonstrated 73% enrolling in care, 28% adhering to care, and 16% achieving viral load suppression. Engagement increased across all steps of the care continuum compared to a 2011 cohort, culminating in a significant increase in undetectable viral load from 4% to 16% (p < 0.001). The batey program showed significant increases in patient enrollment compared to the 2011 cohort (p < 0.001). Meeting the UNAIDS 90-90-90 goal requires enhanced services in high-burden, resource-limited regions. CFLR employs TIF to assess progress and programmatic areas in need of strengthening. Data suggest enhanced CFLR services improve outcomes. Given improvements, maintenance and expansion of similar programs are warranted to achieve the 90-90-90 goal.

Optimizing current and emerging therapies in multiple myeloma: a guide for the hematologist.

Multiple myeloma (MM) is the second most common hematologic malignancy. The diagnosis of MM requires ⩾10% clonal plasma cells in the bone marrow or biopsy-proven plasmacytoma, plus evidence of end-organ damage (hypercalcemia, renal failure, anemia, and lytic bone lesions). The definition of MM has recently been expanded to include a ⩾60% clonal plasma cell burden in the bone marrow, serum involved/uninvolved light chain ratio of ⩾100, or more than one focal lesion on magnetic resonance imaging ⩾5 mm in the absence of end-organ damage. MM is an incurable malignancy previously associated with poor survival rates. However, over the past two decades, the introduction of novel treatment options has resulted in a dramatic improvement in response rates and overall survival (OS). The combination of a proteasome inhibitor and an immunomodulator (IMiD) is the preferred induction treatment for newly diagnosed transplant-eligible MM patients. After induction, high-dose therapy with autologous stem cell transplant (ASCT) is still the standard of care for these patients. In patients who are transplant ineligible, dose adjusted IMiDs or proteasome inhibitor-based combinations are the preferred treatment option. With the recent approval of novel drugs like carfilzomib, ixazomib, pomalidomide, panobinostat, and monoclonal antibodies (elotuzumab and daratumumab), as well as improved understanding of risk stratification, management of comorbidities and treatment side effects, clinicians can optimize anti-MM therapy, particularly in relapse/refractory MM patients. In this review, we outline the current therapeutic approach to the management of MM.

Evaluation of patient care cascade for HIV-positive patients diagnosed in La Romana, Dominican Republic in 2011: a retrospective cohort study.

The Caribbean has the highest adult HIV prevalence in the world after sub-Saharan Africa (2011). One sub-population in the Dominican Republic is the migratory Batey community primarily comprised of Haitian immigrants with limited access to healthcare and HIV prevalence rates of between 3.0% and 9.0%, compared to 0.7% nationally. This retrospective cohort study describes the cumulative retention from diagnosis to virological suppression for newly-diagnosed HIV-infected adults presenting to the Clínica de Familia and its Batey programme in La Romana, during 2011. Of the patients diagnosed with HIV, 65% entered into care, 59% completed immunologic testing, 53% were eligible for antiretroviral therapy (ART) initiation, 36% initiated ART within three months of eligibility and 27% were retained in care. Seventeen per cent of those retained on ART with a 12-month viral load measure had undetectable viral load. Attrition primarily occurred before ART initiation. The Batey programme had a first step lost-to-follow-up of 88% compared to 20% at the clinic (p < 0.001). This retrospective study details the continuum of care and indicates where structural changes must occur to increase continuity between steps. The manuscript results are important to help implement programmes to enhance engagement and retention in HIV primary care.

Metabotropic glutamate receptor-5 and protein kinase C-epsilon increase in dorsal root ganglion neurons and spinal glial activation in an adolescent rat model of painful neck injury.

There is growing evidence that neck pain is common in adolescence and is a risk factor for the development of chronic neck pain in adulthood. The cervical facet joint and its capsular ligament is a common source of pain in the neck in adults, but its role in adolescent pain remains unknown. The aim of this study was to define the biomechanics, behavioral sensitivity, and indicators of neuronal and glial activation in an adolescent model of mechanical facet joint injury. A bilateral C6-C7 facet joint distraction was imposed in an adolescent rat and biomechanical metrics were measured during injury. Following injury, forepaw mechanical hyperalgesia was measured, and protein kinase C-epsilon (PKCɛ) and metabotropic glutamate receptor-5 (mGluR5) expression in the dorsal root ganglion and markers of spinal glial activation were assessed. Joint distraction induced significant mechanical hyperalgesia during the 7 days post-injury (p < 0.001). Painful injury significantly increased PKCɛ expression in small- and medium-diameter neurons compared to sham (p < 0.05) and naïve tissue (p < 0.001). Similarly, mGluR5 expression was significantly elevated in small-diameter neurons after injury (p < 0.05). Spinal astrocytic activation after injury was also elevated over sham (p < 0.035) and naïve (p < 0.0001) levels; microglial activation was only greater than naïve levels (p < 0.006). Mean strains in the facet capsule during injury were 32.8 ± 12.9%, which were consistent with the strains associated with comparable degrees of hypersensitivity in the adult rat. These results suggest that adolescents may have a lower tissue tolerance to induce pain and associated nociceptive response than do adults.

Quantitative PCR detection of t(14;18) bcl-2/JH fusion sequences in follicular lymphoma patients: comparison of peripheral blood and bone marrow aspirate samples.

In patients with follicular lymphoma (FL), it is unresolved whether peripheral blood (PB) can replace bone marrow (BM) aspirate samples for detection of bcl-2/JH fusion sequences that result from the t(14;18)(q32;q21). We compare here the results of quantitative polymerase chain reaction (q-PCR) analysis for bcl-2/JH involving the major breakpoint cluster region (mbr) on paired PB and BM aspirate samples from 60 consecutive FL patients. There was a significant correlation between the level of bcl-2/JH fusion sequence obtained from PB and BM aspirate samples (r = 0.886), with 82% of samples showing less than one log of difference. Patients who had histological evidence of FL involving concurrent BM biopsy specimens had moderate to high levels of bcl-2/JH in both PB and BM aspirate samples, allowing unequivocal determination of translocation status (median bcl-2/JH to cyclophilin level was 8.014%). In contrast, patients with no detectable FL in their BM biopsy specimens often showed low levels of bcl-2/JH in both PB and BM aspirate samples (bcl-2/JH to cyclophilin median level = 0.006%), in a range similar to background levels that could be detected in patients without FL (n = 15, median bcl-2 mbr/JH to cyclophilin level = 0.002%). We conclude that PB can be used in place of BM aspirate samples to test for the presence of bcl-2 mbr/JH fusion sequence in FL patients and that either PB or BM aspirate testing yields a rough approximation of the degree of BM involvement by FL. However, in patients with minimal levels of bcl-2/JH in PB or BM aspirate samples, confirmation of this result by testing the primary tumor is recommended to confirm the presence of an identical bcl-2/JH fusion sequence and exclude false-positive results.