Immunization with HIV AIDSVAX gp120 vaccines in the phase III VAX003 and VAX004 trials did not confer protection. To understand the shortcomings in antibody (Ab) responses induced by these vaccines, ...we evaluated the kinetics of Ab responses to the V1V2 and V3 regions of gp120 and the induction of Ab-mediated antiviral functions during the course of 7 vaccinations over a 30.5-month period. Plasma samples from VAX003 and VAX004 vaccinees and placebo recipients were measured for ELISA-binding Abs and for virus neutralization, Ab-dependent cellular phagocytosis (ADCP), and Ab-dependent cellular cytotoxicity (ADCC). Ab responses to V1V2 and V3 peaked after 3 to 4 immunizations and declined after 5 to 7 immunizations. The deteriorating responses were most evident against epitopes in the underside of the V1V2 β-barrel and in the V3 crown. Correspondingly, vaccinees demonstrated higher neutralization against SF162 pseudovirus sensitive to anti-V1V2 and anti-V3 Abs after 3 or 4 immunizations than after 7 immunizations. Higher levels of ADCP and ADCC were also observed at early or mid-time points as compared with the final time point. Hence, VAX003 and VAX004 vaccinees generated V1V2- and V3-binding Abs and functional Abs after 3 to 4 immunizations, but subsequent boosts did not maintain these responses.
Disrupting data sharing for a healthier ocean Pendleton, Linwood H; Beyer, Hawthorne; Estradivari ...
ICES journal of marine science,
12/2019, Letnik:
76, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Abstract
Ocean ecosystems are in decline, yet we also have more ocean data, and more data portals, than ever before. To make effective decisions regarding ocean management, especially in the face of ...global environmental change, we need to make the best use possible of these data. Yet many data are not shared, are hard to find, and cannot be effectively accessed. We identify three classes of challenges to data sharing and use: uploading, aggregating, and navigating. While tremendous advances have occurred to improve ocean data operability and transparency, the effect has been largely incremental. We propose a suite of both technical and cultural solutions to overcome these challenges including the use of natural language processing, automatic data translation, ledger-based data identifiers, digital community currencies, data impact factors, and social networks as ways of breaking through these barriers. One way to harness these solutions could be a combinatorial machine that embodies both technological and social networking solutions to aggregate ocean data and to allow researchers to discover, navigate, and download data as well as to connect researchers and data users while providing an open-sourced backend for new data tools.
Pleomorphic lobular carcinoma in situ (PLCIS) is a variant of LCIS with high grade morphologic features. However, the number of case series are limited, and the natural history and optimal clinical ...management are not well-defined. We report the largest breast core biopsy series of PLCIS which included 37 patients with PLCIS diagnosed on core biopsy. Upgrade rate to invasive carcinoma on excision was 60%, which was multifocal in 46%. Over one-half of our cohort had a family history of breast cancer.
Pleomorphic lobular carcinoma in situ (PLCIS) is a variant of LCIS with high-grade morphologic features. The number of case series studying PLCIS is limited, and clinical management of patients with PLCIS is controversial. We report a breast core biopsy (BCBx) series of PLCIS.
We reviewed 37 cases of PLCIS with or without microinvasion diagnosed by BCBx. PLCIS was defined as dyscohesive cells showing acinar expansion and loss of immunohistochemical membranous expression of e-cadherin or beta-catenin with nuclear pleomorphism with at least 2- to 3-fold variation in nuclear size, membrane irregularities, and variably prominent nucleoli. Clinical information and findings on excision were evaluated.
Thirty-one (84%) patients presented with mammographic calcifications, 4 (11%) presented with ultrasound findings, 1 (3%) presented with magnetic resonance imaging enhancement, and 1 (3%) with combined imaging abnormality. The mean patient age was 62.3 years. Nineteen patients (51%) had a family history of breast cancer. Microinvasion was present on BCBx in 9 (24%) of the 37 patients. Excision, available in 34 patients, demonstrated invasive carcinoma in 24 (65%), which was multifocal in 11 (46%). Twenty-three patients with PLCIS without microinvasion on BCBx, and without known history of ipsilateral invasive cancer, underwent excision; 14 of these patients demonstrated invasive carcinoma, representing an upgrade to invasive carcinoma of 60%.
We report the largest BCBx series of PLCIS and confirm its aggressive biology and frequent association with multifocal invasive lobular carcinoma, as well as frequent presentation in patients with a family history of breast cancer. Our results support excision to negative margins.
Abstract Objective Although storage alters red blood cells, several recent, randomized trials found no differences in clinical outcomes between patients transfused with red blood cells stored for ...shorter versus longer periods of time. The objective of this study was to see whether storage impairs the in vivo ability of erythrocytes to traverse the microcirculation and deliver oxygen at the tissue level. Methods A subset of subjects from a clinical trial of cardiac surgery patients randomized to receive transfusions of red blood cells stored ≤10 days or ≥21 days were assessed for thenar eminence and cerebral tissue hemoglobin oxygen saturation (St O2 ) via the use of near-infrared spectroscopy and sublingual microvascular blood flow via side-stream darkfield videomicroscopy. Results Among 55 subjects, there was little change in the primary endpoint (thenar eminence St O2 from before to after transfusion of one unit) and the change was similar in the 2 groups: +1.7% (95% confidence interval, −0.3, 3.8) for shorter-storage and +0.8% (95% confidence interval, −1.1, 2.9) for longer-storage; P = .61). Similarly, no significant differences were observed for cerebral St O2 or sublingual microvascular blood flow. These parameters also were not different from preoperatively to 1 day postoperatively, reflecting the absence of a cumulative effect of all red blood cell units transfused during this period. Conclusions There were no differences in thenar eminence or cerebral St O2 , or sublingual microcirculatory blood flow, in cardiac surgery patients transfused with red blood cells stored ≤10 days or ≥21 days. These results are consistent with the clinical outcomes in the parent study, which also did not differ, indicating that storage may not impair oxygen delivery by red blood cells in this setting.
Evidence is growing that sleep problems in adolescents are significant impediments to learning and negatively affect behaviour, attainment of social competence and quality of life. The objectives of ...the study were to determine the level of sleepiness among students in high school, to identify factors to explain it, and to determine the association between sleepiness and performance in both academic and extracurricular activities
A cross-sectional survey of 2201 high school students in the Hamilton Wentworth District School Board and the Near North District School Board in Ontario was conducted in 1998/9. A similar survey was done three years later involving 1034 students in the Grand Erie District School Board in the same Province. The Epworth Sleepiness Scale (ESS) was used to measure sleepiness and we also assessed the reliability of this tool for this population. Descriptive analysis of the cohort and information on various measures of performance and demographic data were included. Regression analysis, using the generalised estimating equation (GEE), was utilized to investigate factors associated with risk of sleepiness (ESS>10).
Seventy per cent of the students had less than 8.5 hours weeknight sleep. Bedtime habits such as a consistent bedtime routine, staying up late or drinking caffeinated beverages before bed were statistically significantly associated with ESS, as were weeknight sleep quantity and gender. As ESS increased there was an increase in the proportion of students who felt their grades had dropped because of sleepiness, were late for school, were often extremely sleepy at school, and were involved in fewer extracurricular activities. These performance measures were statistically significantly associated with ESS. Twenty-three percent of the students felt their grades had dropped because of sleepiness. Most students (58-68%) reported that they were "really sleepy" between 8 and 10 A.M.
Sleep deprivation and excessive daytime sleepiness were common in two samples of Ontario high school students and were associated with a decrease in academic achievement and extracurricular activity. There is a need to increase awareness of this problem in the education and health communities and to translate knowledge already available to strategies to address it.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Disinhibited eating behavior (DEB), or the propensity toward overeating when presented with palatable food, has been documented extensively in youth with obesity. However, the role of ...satiety responsiveness in observed differences in DEB in youth with obesity (OB) and youth with healthy weight (HW) has not been previously studied. Methods: In the current study, we assessed DEB concurrently with satiety ratings in a group of 27 adolescents (13-18 years old; 15 females) with OB (n=12, body mass index BMI>99th percentile) and with HW (n=15, BMI<85th percentile). DEB was estimated via eating in the absence of hunger (EAH) using an established laboratory-based protocol consisting of a lunch meal of typical lunch food items and a test meal of highly palatable snacks. All food items and snacks were measured pre/post serving, and kcals consumed during the test meal used to indicate DEB (EAH kcals). Participants rated their fullness on a visual analog scale (VAS) pre/post lunch meal and test meal. K-means clustering was used to identify groupings of satiety responsiveness using the fullness VAS ratings timeseries. Results: Three clusters were identified (A: n=8 HW, n=7 OB; B: n=3 HW, n=4 OB; C: n=4 HW, n=1 OB). Clusters A and B were satiety responders (SR), participants whose fullness ratings were low/moderate pre-lunch, high post-lunch, and remained high pre/post-test meal. Cluster C were satiety non-responders (SnR), participants whose fullness ratings were low pre-lunch, moderate postlunch, and decreased pre/post-test meal. Mean EAH kcals differed among clusters (F=3.40, p=0.09), such that Cluster A (mean EAH kcals SD, 410 305) was further classified as SR with DEB, Cluster B as SR without DEB (110 113), and Cluster C as SnR with DEB (362 348). Within clusters, mean EAH kcals did not differ between adolescents with HW vs. OB. Conclusions: These preliminary results suggest that DEB can occur with or without satiety responsiveness and independent of weight status in adolescents.
Background
Combination BRAF and MEK inhibitor therapy is an active regimen in patients who have BRAF V600E‐mutated tumors; however, the clinical efficacy of this therapy is limited by resistance. ...Preclinically, the addition of heat shock protein 90 (HSP90) inhibition improves the efficacy of BRAF inhibitor therapy in both BRAF inhibitor–sensitive and BRAF inhibitor–resistant mutant cell lines.
Methods
Cancer Therapy Evaluation Program study 9557 (ClinicalTrials.gov identifier NCT02097225) is a phase 1 study that was designed to assess the safety and efficacy of the small‐molecule HSP90 inhibitor, AT13387, in combination with dabrafenib and trametinib in BRAF V600E/K–mutant solid tumors. Correlative analyses evaluated the expression of HSP90 client proteins and chaperones.
Results
Twenty‐two patients with metastatic, BRAF V600E–mutant solid tumors were enrolled using a 3 + 3 design at four dose levels, and 21 patients were evaluable for efficacy assessment. The most common tumor type was colorectal cancer (N = 12). Dose‐limiting toxicities occurred in one patient at dose level 3 and in one patient at dose level 4; specifically, myelosuppression and fatigue, respectively. The maximum tolerated dose was oral dabafenib 150 mg twice daily, oral trametinib 2 mg once daily, and intravenous AT13387 260 mg/m2 on days 1, 8, and 15. The best response was a partial response in two patients and stable disease in eight patients, with an overall response rate of 9.5% (90% exact confidence interval CI, 2%–27%), a disease control rate of 47.6% (90% CI, 29%–67%), and a median overall survival of 5.1 months (90% CI, 3.4–7.6 months). There were no consistent proteomic changes associated with response or resistance, although responders did have reductions in BRAF expression, and epidermal growth factor receptor downregulation using HSP90 inhibition was observed in one patient who had colorectal cancer.
Conclusions
HSP90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of modest disease control in a heavily pretreated population. Additional translational work may identify tumor types and resistance mechanisms that are most sensitive to this approach.
Heat shock protein 90 inhibition combined with BRAF/MEK inhibition was safe and produced evidence of disease control in a heavily pretreated population of patients with BRAF V600E–mutant solid tumors. Translational work is needed to identify the tumor types and mechanisms of resistance most sensitive to this targeted approach.
Background
Over 90,000 rescue and recovery responders to the September 2001 World Trade Center (WTC) attacks were exposed to toxic materials that can impair cardiac function and increase ...cardiovascular disease (CVD) risk. We examined WTC‐related exposures association with annual and cumulative CVD incidence and risk over 17 years in the WTC Health Program (HP) General Responder Cohort (GRC).
Methods
Post 9/11 first occurrence of CVD was assessed in 37,725 responders from self‐reported physician diagnosis of, or current treatment for, coronary artery disease, myocardial infarction, stroke and/or congestive heart failure from WTCHP GRC monitoring visits. Kaplan–Meier estimates of CVD incidence used the generalized Wilcoxon test statistic to account for censored data. Cox proportional hazards regression analyses estimated the CVD hazard ratio associated with 9/11/2001 arrival in responders with and without dust cloud exposure, compared with arrival on or after 9/12/2001. Additional analyses adjusted for comorbidities.
Results
To date, 6.3% reported new CVD. In covariate‐adjusted analyses, men's CVD 9/11/2001 arrival risks were 1.40 (95% confidence interval CI = 1.26, 1.56) and 1.43 (95% CI = 1.29, 1.58) and women's were 2.16 (95% CI = 1.49, 3.11) and 1.59 (95% CI = 1.11, 2.27) with and without dust cloud exposure, respectively. Protective service employment on 9/11 had higher CVD risk.
Conclusions
WTCHP GRC members with 9/11/2001 exposures had substantially higher CVD risk than those initiating work afterward, consistent with observations among WTC‐exposed New York City firefighters. Women's risk was greater than that of men's. GRC‐elevated CVD risk may also be occurring at a younger age than in the general population.
Adherence to the medical regimen after pediatric organ transplantation is important for maximizing good clinical outcomes. However, the literature provides inconsistent evidence regarding prevalence ...and risk factors for nonadherence posttransplant.
A total of 61 studies (30 kidney, 18 liver, 8 heart, 2 lung/heart-lung, and 3 with mixed recipient samples) were included in a meta-analysis. Average rates of nonadherence to six areas of the regimen, and correlations of potential risk factors with nonadherence, were calculated.
Across all types of transplantation, nonadherence to clinic appointments and tests was most prevalent, at 12.9 cases per 100 patients per year (PPY). The immunosuppression nonadherence rate was six cases per 100 PPY. Nonadherence to substance use restrictions, diet, exercise, and other healthcare requirements ranged from 0.6 to 8 cases per 100 PPY. Only the rate of nonadherence to clinic appointments and tests varied by transplant type: heart recipients had the lowest rate (4.6 cases per 100 PPY vs. 12.7-18.8 cases per 100 PPY in other recipients). Older age of the child, family functioning (greater parental distress and lower family cohesion), and the child's psychological status (poorer behavioral functioning and greater distress) were among the psychosocial characteristics significantly correlated with poorer adherence. These correlations were small to modest in size (r=0.12-0.18).
These nonadherence rates provide benchmarks for clinicians to use to estimate patient risk. The identified psychosocial correlates of nonadherence are potential targets for intervention. Future studies should focus on improving the prediction of nonadherence risk and on testing interventions to reduce risk.
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