We sought to determine the prevalence of phosphodiesterase type 5 inhibitor (PDE-5) mediated drug-drug interactions (DDIs) in males with HIV infection receiving antiretroviral therapy (ART) and ...identify factors associated with PDE-5-mediated DDIs.
Male US Military HIV Natural History Study participants diagnosed with erectile dysfunction (ED) and having a PDE-5 inhibitor and potentially-interacting ART co-dispensed within 30 days were included. DDIs were defined according to criteria found in published guidelines and drug information resources. The primary outcome of interest was overall PDE-5 inhibitor-mediated DDI prevalence and episode duration. A secondary logistic regression analysis was performed on those with and without DDIs to identify factors associated with initial DDI episode.
A total of 235 male participants with ED met inclusion criteria. The majority were White (50.6%) or African American (40.4%). Median age at medication co-dispensing (45 years), duration of HIV infection (14 years), and duration of ED (1 year) did not differ between the two groups (p>0.05 for all). PDE-5 inhibitors included sildenafil (n = 124), vardenafil (n = 99), and tadalafil (n = 14). ART regimens included RTV-boosted protease inhibitors (PIs) atazanavir (n = 83) or darunavir (n = 34), and COBI-boosted elvitegravir (n = 43). Potential DDIs occurred in 181 (77.0%) participants, of whom 122 (67.4%) had multiple DDI episodes. The median DDI duration was 8 (IQR 1-12) months. In multivariate analyses, non-statistically significant higher odds of DDIs were observed with RTV-boosted PIs or PI-based ART (OR 2.13, 95% CI 0.85-5.37) and in those with a diagnosis of major depressive disorder (OR 1.74, 95% CI 0.83-3.64).
PDE-5-mediated DDIs were observed in the majority of males with HIV infection on RTV- or COBI-boosted ART in our cohort. This study highlights the importance of assessing for DDIs among individuals on ART, especially those on boosted regimens.
Background
Dermatofibrosarcoma protuberans (DFSP) is a rare, low‐grade mesenchymal skin tumour, characterized by slow infiltrative growth and common local recurrence, with infrequent distant ...metastases.
Objective
The aim of this study is to better clarify clinicopathological characteristics of this tumour and to evaluate the cure rates of Mohs Tübingen technique (MTT) and wide local excision (WLE). Eventually, we perform a literature review to compare our experience with published data.
Methods
A retrospective review was conducted on 135 patients diagnosed, treated and followed up between 1997 and 2014 at two different institutions. Sixty‐two patients underwent to WLE and 73 to MTT. The primary end‐points were the following: percentage of recurrences, time to progression and recurrence annual risk rate. Then, the PubMed database was searched for DFSP case series treated with standard surgical resection (SSR), WLE, Mohs’ micrographic surgery (MMS) and MTT. The annual risk rate of recurrence calculated and reported for the four separate procedures was pooled to compare them.
Results
Five of the 62 patients with WLE (8.1%) experienced recurrences after a mean follow‐up of 4.7 years; the percentage of recurred patients 9 years after MTT was 5.5%, and the annual recurrence risk rate of 0.6%. Pooling these data with those from literature, the recurrence rate varies from 26% to 60% for SSR, from 0% and 41% for WLE, from 0% and 8.3% for MMS and from 0% to 5.5% for MTT. The lowest annual recurrence risk rate was found for MTT.
Conclusion
Significantly lower recurrence rates were recorded in patients treated with classic or Tübingen Mohs’ technique. To the best of our knowledge, our case series is the widest treated with MTT ever described in the literature; these data may be useful to guide clinicians in the choice of the gold standard treatment for Dermatofibrosarcoma protuberans.
We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors.
...We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan–Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients.
LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001, which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors.
The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy.
•In a study of 17 322 early BC patients, LVI had a significant independent negative prognostic impact on survival.•LVI negatively impacted survival in almost every patient category and cancer subtype, with and without AC.•LVI did not have a negative survival impact in patients with ER+ grade 3 or with luminal A-like tumors with chemotherapy.•Results suggest a possible benefit of AC in LVI-positive luminal A-like patients.
PurposeThis paper evaluates the effects of tax incentives on business innovation in Brazil that were established by Law 11,196/05 (the “Fiscal Incentives Law”) to test whether they have had a ...positive impact on beneficiary firms' innovation input and output and on their performance.Design/methodology/approachThe policy impacts are estimated using microdata on 13,706 firms available in the 2008 and 2011 editions of the Brazilian Innovation Survey (PINTEC) and by applying propensity score matching with difference-in-differences.FindingsThe results suggest a positive and statistically significant impact of the policy on research and development (R&D) expenditures (average of approximately US$ 264,000 in 2011), the number of research staff (average of five researchers) and total employment (approximately 5% of the beneficiary firms' mean size). However, no impact was found on the overall spending on innovative activities, the percentage of sales and exports from new products, net revenue or net revenue per employee.Practical implicationsThe findings provide empirical support in favor of tax incentives as a policy tool to boost business innovation in the country. However, the absence of significant effects on innovative activities expenditures and on most indicators of innovation output and firms' performance reveals shortcomings of the policy that need to be addressed.Originality/valueThe study complements and advances the findings of previous studies by assessing policy impact on total innovative activities expenditures and on innovation output and firm performance.
•Synbiotic supplementation is the combination of probiotics and prebiotics.•This supplement was added to feedlot diets in conjunction or to replace antibiotics.•Feed efficiency was reduced when the ...synbiotic supplement replaced antibiotics.•The synbiotic feed did not alter general performance but improved carcass traits.•Synbiotic + antimicrobials can improve efficiency and carcass quality in cattle.
Feedlot diets are often enriched with additives to mitigate health disorders and promote cattle performance, including the feed-grade antimicrobials monensin and tylosin. However, alternative feeding strategies are warranted given the increasing regulations regarding the use of antimicrobials in feedlot diets. This study evaluated the performance, physiological, and health responses of feedlot cattle offered a synbiotic supplement (yeast-derived prebiotic + Bacillus subtilis probiotic), which replaced or was fed in conjunction with monensin and tylosin. Angus-influenced steers (n = 192) from four different cowherds were weaned on day −1 and transported (800 km) to the feedlot. Steers were allocated to 1 of 24 pens (eight steers/pen) upon arrival on day 0. Pens were assigned to receive (n = 8/treatment) a total-mixed ration (TMR) containing: (1) monensin and tylosin (RT; 360 mg/steer daily from Rumensin and 90 mg/steer daily from Tylan; Elanco Animal Health, Greenfield, IN, USA), (2) yeast-derived ingredient and B. subtilis probiotic (CC; 18 g/steer daily of Celmanax and 28 g/steer daily of Certillus; Church and Dwight Co., Inc., Princeton, NJ, USA), or (3) a combination of RT and CC (RTCC). Steers were slaughtered according to BW in four groups balanced by treatment and pens and received treatments for 252 ± 4 days. No treatment effects were detected (P ≥ 0.17) for steer BW gain and morbidity responses. Mean TMR intake was greater and gain:feed ratio was less (P ≤ 0.01) in CC compared with RT and RTCC steers. Mean plasma leptin concentration was greater (P ≤ 0.05) in CC compared with RT and RTCC steers. Steers receiving CC had greater (P ≤ 0.04) concentrations of plasma cortisol, haptoglobin, glucose, and beta-hydroxybutyrate, and less (P ≤ 0.05) concentration of non-esterified fatty acids compared with RT and RTCC steers on day 14 of the experiment. Carcass marbling was greater (P = 0.01) in CC compared with RT steers and tended to be greater (P = 0.07) in RTCC compared with RT steers. Proportion of carcasses that graded Choice or better and Longissimus muscle area were greater (P ≤ 0.05) in CC and RTCC compared with RT steers. Incidence of liver abscesses was less (P = 0.01) in RTCC compared with CC steers and tended to be less (P = 0.09) in RT compared with CC steers. Results from this experiment indicate that the synbiotic supplement may replace monensin and tylosin without reducing steer BW gain, with potential improvements to carcass quality traits.
Abstract Aims The standard treatment for advanced ovarian cancer consists of cytoreductive surgery associated with a platinum/paclitaxel-based chemotherapy. Nevertheless, there is still the question ...as to the extent and timing of the surgical debulking. The aim of this study was to evaluate the place of surgery in the therapeutic sequence. Patients and methods We reviewed data from all consecutive patients with stage IIIC and IV epithelial ovarian cancer, operated on at our institution between 1990 and 2005. Patients were divided into 2 groups, according to the position of surgery in the therapeutic sequence. Patients in group 1 received initial debulking surgery. Group 2 consisted of patients having received their first debulking after initial chemotherapy. Results Two hundred and three patients were identified and frequently underwent aggressive surgery, in particular, digestive surgery with bowel resections. Perioperative mortality and morbidity rates were low (2% and 14%, respectively) and there was no difference between the groups. Overall survival in group 1 for patients with complete cytoreduction (residual disease (RD) = 0), optimal surgery (RD < 1 cm) or sub-optimal surgery (RD > 1 cm) was 50%, 30% and 14%, respectively. In group 2, overall survival following complete surgery was 30%, and no long-term survival was observed when surgery was not complete at the time of interval surgery. Survival was worse for patients who had received more than 4 cycles of neoadjuvant chemotherapy. Conclusion This study confirms the importance of surgery in the prognosis of advanced ovarian cancer. Only the patient subgroup that underwent complete initial or interval surgery was associated with a prolonged remission. Optimal surgery with a controlled morbidity can be achieved in many cases, even if bowel resection is needed, at the time of primary debulking. In the interval cytoreductive surgery subgroup, the response to initial chemotherapy and surgery was found to be essential for prognosis.
This study presents a formal generative model that integrates perception and reading, and uses English intervocalic consonants borrowed into Italian as either singletons or geminates to illustrate ...how the model works. Consisting of words borrowed in the 20th century, our data show that the quantity of the intervocalic consonant in an Italian loanword depends on its written representation in English, the source language. Thus only English intervocalic consonants that are written with two identical letters (for example, as in splatter) are borrowed as geminates. We provide a formalization of these orthographic adaptations with grapheme-to-phoneme mappings in the shape of Optimality-theoretic constraints that model the native reading process, and show how the output of these mappings is restricted by native phonotactic constraints. Furthermore, we illustrate that the native reading grammar proposed here complements the perceptual adaptation model by Boersma and Hamann (2009). This combined model is shown to be able to account for simultaneous orthographic and perceptual borrowings in Italian, as well as to hold for reading and perception outside the realm of loanword adaptation.
This study compared vaginal temperature, physiologic, and productive parameters in lactating dairy cows supplemented or not with Omnigen-AF (Phibro Animal Health, Teaneck, NJ) during the summer ...months in a tropical environment. Thirty-two lactating, primiparous (n = 16) and multiparous (n = 16) pregnant Holstein × Gir cows were ranked by parity, days in milk, body weight, and body condition score (BCS), and assigned to receive (SUPP; n = 16) or not (CON; n = 16) Omnigen-AF (Phibro Animal Health, Teaneck, NJ) at 56 g/cow daily (as-fed basis). During the experimental period (d −6 to 56), cows were maintained in a single drylot pen with ad libitum access to water and a total mixed ration, and milked twice daily. Cows received Omnigen-AF mixed with 200 g of corn (as-fed basis) after the daily morning milking through self-locking head gates, whereas CON cows concurrently received 56 g of kaolin mixed with 200 g of corn. For feed intake evaluation, cows from both treatments were randomly divided in 4 groups of 8 cows each, and allocated to 8 individual feeding stations for 3 d. Intake was evaluated 4 times per group from d 1 to 56. From d −6 to 0, d 15 to 28, and d 43 to 56, cow vaginal temperature was recorded hourly. Environmental temperature-humidity index (THI) was also recorded hourly from d 15 to 28 and d 43 to 56. Cows were evaluated for body weight and BCS on d −6 and 56, individual milk production was recorded daily from d −6 to 56, and milk samples were collected on d −6, 0, 7, 14, 21, 28, 35, 42, 49, and 56 for analyses of somatic cell count and milk components. Blood samples were collected on d −6, −3, 0, 9, 15, 18, 21, 24, 27, 36, 45, 48, 51, 54, and 56. Results from samples or observations collected from d −6 to 0 were included as an independent covariate in each respective analysis. Environmental THI was 74.2 ± 0.5 and cows were exposed to THI >68 for 633 h within a total of 672 h of evaluation. Cows assigned to CON had greater vaginal temperature on d 28, 43, 45, and from d 48 to 55 (by 0.38 to 0.52%), as well as greater mean somatic cell count (by 97%) and serum haptoglobin concentrations (by 89%) compared with SUPP cows. Cows assigned to SUPP had greater mean dry matter intake (by 7%), BCS on d 56 (by 11%), and mean serum insulin concentrations (by 35%) compared with CON cows. Hence, SUPP ameliorated hyperthermia, improved nutritional status, and modulated systemic and mammary gland immune parameters in lactating dairy cows exposed to heat stress conditions.
Summary
Endogenous retroviruses (HERV) are believed to be pathogenic in several autoimmune diseases. Among them, HERV‐K viruses have been reported recently to be involved in the pathogenesis of ...rheumatoid arthritis (RA). In this study we have explored the role of humoral immune response against HERV‐K as a potential pathogenetic mechanism in RA. Four different peptides from the extracellular portion of the env protein of HERV‐K (env‐su19–37, env‐su109–126, env‐su164–186, env‐su209–226) were selected by bioinformatic analysis on the basis of their putative immunogenicity. Indirect enzyme‐linked immunosorbent assay (ELISA) was then carried out to quantify antibodies against those peptides on blood samples of 70 consecutive RA patients and 71 healthy controls (HC). Differences between the two groups were analysed using the Mann–Whitney test. Potential correlations between RA laboratory, clinical descriptors and immunoglobulin (Ig)G levels were explored by bivariate regression analysis. Serum autoantibodies against one of four tested peptides of HERV‐K (env‐su19–37) were significantly higher in RA than in HC (19 versus 3%, P = 0·0025). Subgroup analysis showed no association between anti‐HERV‐K peptide humoral response and clinical, serological and clinimetric RA disease descriptors. Serum from RA patients in our series reacted significantly against HERV‐K env‐su19–37 peptide in comparison to the general population suggesting a role for the HERV‐K‐ related, secondary antigenic‐driven immune response in the pathogenesis of RA. Further studies are needed to confirm these results and to explore the role of this HERV‐K surface peptide as a potential therapeutic target.
We report the novel observation related to the presence of antibodies recognizing a specific epitope of HERV‐K in serum of Rheumatoid Arthritis (RA) patients in comparison to healthy controls.
The peptide may be used as a biomarker of disease progression if confirmed in a larger setting of patients.
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