Promotion as contrastive increase in expected fit

Abstract

What is required for an action to promote the satisfaction of a desire? We reject extant answers and propose an alternative. Our account differs from competing answers in two ways: first, it is contrastive, in that actions promote the satisfaction of desires only as contrasted with other possible actions. Second, it employs a notion of expected fit between desire and world, defined as the weighted sum of the fit between the desire and the world in all possible outcomes, where each weight is given by the probability of the agent's obtaining the relevant outcome. According to our proposal, then, an action promotes a desire when the expected fit for the desire given that the agent performs the action is greater than the expected fit of the desire given that the agent performs the contrasting action. We highlight this account's attractive features and explain how it improves on its competitors.

Reply to Lewin

Method for identifying outliers of soil heavy metal data

Abstract

Artificial errors in the experimental process may lead to some outliers, which reduce data quality and cause erroneous judgment in soil pollution assessment. Based on this, a method for detecting outliers of soil heavy metal data was proposed in this study. The As, Cd, and Pb concentrations of the soil in Beijing, China, were taken as samples to verify the validity of the method. Results showed that there were 8, 34, and 38 outliers for the As, Cd, and Pb concentrations in the Beijing soil, respectively. The result of re-analyzed revealed that 75.0, 76.5, and 92.1% of the As, Cd, and Pb outliers, respectively, were caused by artificial errors. After correcting, the interpolation accuracy for data was improved significantly. The mean relative error (MRE) of the As, Cd, and Pb outliers decreased by 48.0, 44.6, and 54.7%, while the mean square error of these outliers decreased by 34.2, 33.3, and 46.4%, respectively. The MRE values of the nearest neighboring points which were influenced by the outliers decreased by 5.2, 20.6, and 27.6%, while the mean square error of these points decreased by 5.3, 17.3, and 33.2%, respectively. To our knowledge, this is the first study on detecting outliers of soil heavy metal data. The method considers both spatial and numerical outliers, which avoids the limitation of single method, and can effectively improve the data quality of soil heavy metal concentrations with a finite sample size and analysis time.

Cutaneous tuberculosis in China: A multicenter retrospective study of cases diagnosed between 1957 and 2013

Abstract

Background

China has one of the largest populations with tuberculosis worldwide. Cutaneous tuberculosis (CTB) is a rare manifestation of mycobacterial infection. Although CTB is well described, it is important to periodically revisit the prevailing clinical and epidemiological features in most populated countries such as China, India, and Indonesia, where tuberculosis is still a major health problem.

Objective

This retrospective study aimed to reevaluate the CTB cases in China in the past 50 years to btain a comprehensive insight into this multiplex entity.

Methods

Cases of diagnosed CTB with confirmed histology from four large medical centers in central China between 1957 and 2013 were collected and analyzed, including demographic data, clinical manifestations and pathological findings.

Results

Of the 1194 cases enrolled, there were 666 (55.78%) and 528 cases (44.22%) of true CTB and tuberculids, respectively. Erythema induratum of Bazin (EIB) was the most common CTB (35.8%), followed by lupus vulgaris (LV, 32.7%), tuberculosis verrucosa cutis (18.9%), papulonecrotic tuberculid (8.0%), scrofuloderma (2.8%), tuberculosis cutis ulcerosa (1.3%), penile tuberculids (0.4%), and lichen scrofulosorum (0.1%). EIB was the predominant tuberculid (80.87%), while LV the predominant true CTB (58.7%). The number of diagnosed CTB showed a decreasing trend in the 1960s and 1970s, then increased again, and peaked in the 1990s.

Conclusions

CTB is still a common problem in China. Chronologic changes of CTB cases reported in China over the past 50 years may reflect the prevalence transition of overall tuberculosis. CTB has diverse clinical presentations, and each subtype is characterized by specific gender predilection, duration, age, clinic, and pathological findings.

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Fast sonochemically-assisted synthesis of pure and doped zinc sulfide quantum dots and their applicability in organic dye removal from aqueous media

Publication date: Available online 22 February 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Hamid Reza Rajabi, Fatemeh Karimi, Hossein Kazemdehdashti, Leila Kavoshi
In this research, a sono-assisted chemical precipitation method was developed for a quick and efficient water-based synthesis of zinc sulfide (ZnS) quantum dots (QDs), in room temperature. ZnS QDs as pure and doped with some transition metal ions (such as Cu²⁺, Mn²⁺, Ag⁺) were prepared in the presence of l-cysteine, as capping agent. In comparison with the previous conventional methods, applying the ultrasonic irradiation provides a significant decrease in the reaction time. In comparison with previous reported conventional chemical QD synthesis methods, the required time for a complete synthesis in the presence of ultrasonic irradiations was significantly reduced to a period as short as 15 min, in a temperature of 40 °C. The sono-synthesized QDs were characterized with various techniques such as colorimetry, UV–Vis absorption spectroscopy, X-ray diffraction (XRD) and transmission electron microscopy (TEM). A broad absorption band between 270 and 290 nm was observed for colloidal ZnS QDs with the optical band gap larger than 3.68 eV. From the XRD and TEM results, the average particle size below 5 nm was estimated for the prepared QDs. After characterization, the samples were employed as nanophotocatalysts during a UV-derivate photocatalytic process for the degradation of Victoria blue R (VBR), as a pollutant dye. To obtain the optimal operating conditions, the influence of the affecting parameters such as the initial pH of the dye solution, irradiation time, initial dye concentration, type, electrolyte salt concentration and dosage of the nanophotocatalyst samples on the degradation efficiency (DE % was comprehensively studied, all in batch mode. Taking the optimum conditions into account, the maximum removal of VBR dye (>95%) can be obtained by spectrophotometric measurements at alkaline pH of 10.5, in the presence of low amounts of QDs (3 mg) and after 30 min of being exposed to UV irradiations. The results demonstrate that despite the removal of VBR, the QDs prepared by sonochemically method can be reused for at least six more times; without a significant decrease in their photocatalytic properties.

Graphical abstract

Migration and Cooperative Infrastructures

Abstract

A proper understanding of the moral and political significance of migration requires a focus on global inequalities. More specifically, it requires a focus on those global inequalities that affect people's ability to participate in the production of economic goods and non-economic goods (e.g., relationships of intimacy and care, opportunities for self-expression, well-functioning institutions, etc.). We call cooperative infrastructures the complex material and immaterial technologies that allow human beings to cooperate in order to generate human goods. By enabling migrants to access high-quality cooperative infrastructures, migration contributes to the diffusion of technical and socio-political innovations. In this way, it positively affects the ability of individuals from poorer countries to participate in the production of human goods, to benefit from such production, and to contribute to human development. Migration can also damage the material and immateri al components of the cooperative infrastructures accessible in both the host and sending countries; these potential downsides of migration should not be ignored, although arguably they can often be neutralized, alleviated, or compensated.

Enhancement of nitrogen and phosphorus removal in landscape water using polymeric ferric sulfate as well as the synergistic effect of four kinds of natural rocks as promoter

Abstract

Eutrophication in lakes and rivers caused by the nitrogen (N) and phosphorus (P) is urgent since the accumulation of N and P can possibly cause the algal blooms and devastation to the water ecological system. The removal of N and P in the landscape water would be an efficient way to reduce the enrichment of nutrition before they reach the large water system. The N and P removal efficiency of PFS as well as the synergistic effect of natural rocks (four types of purple parent rock (J₃p, J₂s, T₁f, and J₃s)) as promoter was examined under laboratory conditions. The results indicated that TN and TP removal efficiency of the composite coagulant was significantly better than that of PFS or purple parent rock alone and J₃p + PFS (combination of PFS and J₃p purple parent rock) showed the best TN and TP removal efficiency. TN and TP removal efficiency of 53.53 and 86.48%, respectively, were achieved with coagulant dosage of 6 g L⁻¹ J₃p and 30 mg L⁻¹ PFS, water temperature of 30 °C, and wastewater initial pH of 9. In addition, Fourier transformed infrared (FTIR) spectrophotometer, X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive analysis (EDX), and the water quality index analysis revealed that the treatment of TN and TP by using J₃p + PFS was taking advantage of the flocculation function of PFS and the adsorption function of PFS and J₃p. In which, the flocculation mechanism was mainly charge neutralization; adsorption mechanism was mainly physical and chemical adsorption.

Ecotoxicity tests with Allium cepa to determine the efficiency of rice husk ash in the treatment of groundwater contaminated with benzene, toluene, ethylbenzene, and xylene

Abstract

The validation of adsorption treatment based on toxicity assays aims to assess the actual environmental impact caused by effluents after treatment. This study describes the use of rice husk ash as adsorbent and evaluates the efficiency of adsorption treatment to remediate groundwater contaminated with benzene, toluene, ethylbenzene, and xylene (BTEX). The synthetic effluent was prepared with standard benzene, toluene, ethylbenzene, and xylene solutions. Adsorption was assessed at treatment times 0, 60, 120, and 240 min. Compounds were quantified by gas chromatography with flame ionization detector. The treatment was validated based on ecotoxicity assays using Allium cepa as indicator organism. For the treatment times stipulated, samples containing 25, 50, and 100% of BTEX were used. The dilutions were carried out with drinking water according to Fiskesjö (1985). The relative growth index (RGI), root inhibition index (Ii), and germination index (GI) confirmed the efficiency of the treatment approach tested. The best adsorption time for an initial BTEX concentration of 3.378 mg/L was 60 min. Critical level (EC50) and critical concentration that induced phytotoxic effect on A. cepa germination was observed only for the undiluted effluent.

Wound irrigation and the lack of evidence-based-practice

Dear Editor,

The potent pro-oxidant activity of rhododendrol-eumelanin is enhanced by ultraviolet A radiation

Summary

RS-4-(4-hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, is known to induce leukoderma in some consumers. To explore the mechanism underlying this effect, we previously showed that the oxidation of RD with mushroom or human tyrosinase produces cytotoxic quinone oxidation products and RD-eumelanin exerts a potent pro-oxidant activity. Cellular antioxidants were oxidized by RD-eumelanin with a concomitant production of H₂O₂. In this study, we examined whether this pro-oxidant activity of RD-eumelanin is enhanced by ultraviolet A (UVA) radiation because most RD-induced leukoderma lesions are found in sun-exposed areas. Exposure to a physiological level of UVA (3.5 mW/cm²) induced a two to four-fold increase in the rates of oxidation of GSH, cysteine, ascorbic acid and NADH. This oxidation was oxygen-dependent and was accompanied by the production of H₂O₂. These results suggest that RD-eumelanin is cytotoxic to melanocytes through its potent pro-oxidant activity that is enhanced by UVA radiation.

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Melanoma cases demonstrate increased carrier frequency of Phenylketonuria/hyperphenylalanemia mutations

Summary

Identifying novel melanoma genetic risk factors informs screening and prevention efforts. Mutations in the phenylalanine hydroxylase gene (the causative gene in phenylketonuria) lead to reduced pigmentation in untreated phenylketonuria patients, and reduced pigmentation is associated with greater melanoma risk. Therefore, we sought to characterize the relationship between phenylketonuria carrier status and melanoma risk. Using National Newborn Screening Reports, we determined the United States phenylketonuria/hyperphenylalanemia carrier frequency in Caucasians to be 1.76%. We examined three publically available melanoma datasets for germline mutations in the phenylalanine hydroxylase gene associated with classic phenylketonuria and/or hyperphenylalanemia. Mutations were identified in 29/814 melanoma patients, with a carrier frequency of 3.56%. There was a two-fold enrichment (p-value=3.4 x 10^-5) compared to the Caucasian frequency of hyperphenylalanemia/phenylketonuria carriers. These data demonstrate a novel association between phenylalanine hydroxylase carrier status and melanoma risk. Further functional investigation is warranted to determine the link between phenylalanine hydroxlase mutations and melanomagenesis.

This article is protected by copyright. All rights reserved.

Should Metaphysics Care About Linguistics?

Abstract

Naturalized metaphysics is based on the idea that philosophy should be guided by the sciences. The paradigmatic science that is relevant for metaphysics is physics because physics tells us what fundamental reality is ultimately like. There are other sciences, however, that de facto play a role in philosophical inquiries about what there is, one of them being the science of language, i.e. linguistics. In this paper I will be concerned with the question what role linguistics should and does play for the metametaphysical question of how our views about fundamental reality can be reconciled with the everyday truisms about what there is. I will present several examples of two kinds of approaches to this question, linguistics-based accounts and purely philosophical accounts, and will discuss their respective methodological merits and shortcomings. In the end I will argue that even proponents of a purely philosophical answer to the metametaphysical question should take the results of linguistics seriously.

Geert Keil, Lara Keuck, and Rico Hauswald (eds): Vagueness in Psychiatry

Assessing a portable, real-time display handheld meter with UV-A and UV-B sensors for potential application in personal sun exposure studies

Abstract

Background

Observing accurate real-time measurements of solar ultraviolet radiation (UVR) levels is important since personal excess sun exposure is associated with skin cancers. Handheld measurement devices may be helpful but their accuracy is unknown. We compare a portable, science-grade solar UVR monitoring device against two fixed, science-grade solar UVR instruments.

Methods

Instruments were (1) a fixed Solar Light 501 UV-B biometer to measure UV-B; (2) a fixed Kipp and Zonen radiometer used to measure UV-A and UV-B; and (3) Goldilux ultraviolet probes which are commercially available portable devices. Two different probes were used, one measured UV-A and the other UV-B radiation. The Goldilux probes were levelled and secured next to the UV-B biometer. Between 10:00 and 14:40 UTC+2, the UV-B biometer was set to record at 10-minute intervals and measurements by the Goldilux probes were manually taken simultaneously. Results were compared for all data and by solar zenith angle (SZA) ranges.

Results

The Goldilux UV-B probe measured UV-B relatively well in its diurnal pattern, however, its readings were ~77% higher than those made by the UV-B biometer. While UV-A measurements from the Goldilux UV-A probe and those from the radiometer were in relatively good agreement in pattern, the radiometer read ~47% higher than the Goldilux UV-A probe. UV-B data from Goldilux UV-B probe had a moderately strong correlation with UV-B biometer data for small SZAs; conversely, for UV-A, the Goldilux UV-A probe had a strong correlation with the UV-A radiometer data for large SZAs.

Conclusion

Handheld devices may be useful to provide real-time readings of solar UVR patterns, however, to achieve synchronicity in the magnitude of readings to those made by science-grade fixed instruments, devices may need to be used during certain times of the day and in clear-sky conditions which may not be practical in personal exposure studies.

A novel approach in red mud neutralization using cow dung

Abstract

In this study, cow dung was identified as a neutralizing agent for red mud (RM). Present research estimated a significant reduction in pH value of red mud (10 g) from 10.28 to 8.15 and reduction in alkalinity of ~148 mg/L from ~488 mg/L by adding 80 g of cow dung in 40 days of anaerobic condition. XRD results exhibit a high intensity of quartz and found new compound, the calcium carbide. The acid neutralizing capacity (ANC) of NRM reduces to ~0.87 from ~1.506 mol H⁺/kg. Based on the resultant research, present study proposes cow dung as an efficient neutralizing agent for reducing the pH and alkalinity in the red mud.

Effect of platelets-rich plasma on scalp hair diameter

Summary

Objectives

To measure the effects of platelet-rich plasma (PRP) on hair diameter in Pakistani population.

Materials and methods

The study was conducted in a private setup in the adult patients undergoing PRP treatment. Baseline platelets count was noted for each patient. PRP was prepared using a commercial kit. Three PRP injections were administered in the scalp at 0, 1, and 3 months of interval. The hair caliber was measured in the mid-scalp area using a separate stencil for each patient. The diameter of 10 hair (1 cm sq) was measured randomly using the caliper (2 hair on each side of the square and 4 in the center). After 6 months of 3rd injection, the hair caliber was measured and the results were analyzed statistically using Mann-Whitney's test.

Results

Seven men and 3 women were included in the study. The mean age of the patients was 24.2 years (26.3 years in males and 19.3 in females). The average platelets count was found to be 283,580/μL. The mean hair caliber was 37.3 μm (39.1 μm in men and 33.0 μm in women). At the end of the study, the mean hair caliber was found to be 52.3 μm (P < .01). The mean hair caliber was 53.9 μm in men and 48.7 μm in women (P < .01). The increase in the hair caliber was noted to be 27.5% more in men and 31.3% more in women (P < .01).

Conclusion

The PRP injections can increase the hair diameter.

Skin Notations for Low-Molecular-Weight Amines: Development of a Testing Protocol with Isopropylamine as an Example

Abstract

Owing to their volatility, the most important occupational exposure route for low-molecular-weight amines is considered to be inhalation. However, dermal exposure is also possible in many workplace situations. There are limited data available on the dermal uptake of these amines through human skin, and existing exposure standard skin notations are typically based on acute toxicity animal studies or by chemical analogy. This gap in knowledge is in part due to a lack of standardized approach for assessing dermal uptake. We describe a relatively simple protocol for the determination of permeation of low-molecular-weight amines through human skin in vitro. Using isopropylamine as a test amine, it was found that isopropylamine vapour has limited capacity to absorb into, or penetrate through, the epidermal layer of human skin, even at lethal atmospheric concentrations. This protocol can be adapted for a range of exposure scenarios, including clothing effects, and may be used to determine whether skin notations are warranted.

Arbuscular mycorrhizal fungi in two vertical-flow wetlands constructed for heavy metal-contaminated wastewater bioremediation

Abstract

Over the last three decades, the presence of arbuscular mycorrhizal fungi (AMF) in wetland habitats had been proven, and their roles played in wetland ecosystems and potential functions in wastewater bioremediation technical installations are interesting issues. To increase knowledge on the functions of AMF in the plant-based bioremediation of wastewater, we constructed two vertical-flow wetlands planting with Phragmites australis and investigated AMF distribution in plant roots and their roles played in purification of wastewater polluted by heavy metals (HMs), utilizing the Illumina sequencing technique. A total of 17 operational taxonomic units (OTUs) from 33,031 AMF sequences were obtained, with Glomus being the most dominant. P. australis living in the two vertical-flow constructed wetlands (CWs) harbored diverse AMF comparable with the AM fungal communities in upland habitats. The AMF composition profiles of CW1 (vegetated with non-inoculated plants) and CW2 (vegetated with mycorrhizal plants inoculated with Rhizophagus intraradices) were significantly different. CW1 (15 OTUs) harbored more diverse AMF than CW2 (7 OTUs); however, CW2 harbored much more OTU13 than CW1. In addition, a zipf species abundance distribution (SAD), which might due to the heavy overdominance of OTU13, was observed across AM fugal taxa in P. australis roots of the two CWs. CW1 and CW2 showed high (> 70%) removal capacity of HMs. CW2 exhibited significant higher Cd and Zn removal efficiencies than CW1 (CK) (p = 0.005 and p = 0.008, respectively). It was considered that AMF might play a role in HM removal in CWs.

In vivo toxicity evaluation of pristine graphene in developing zebrafish ( Danio rerio ) embryos

Abstract

Graphene has been used in several fields covering from electronics to biomedicine, especially exhibiting a widespread variety of promising biological and biomedical applications. In the past decade, the biomedical applications of graphene have attracted much interest. However, the effect of pristine graphene (pG) toxicity in aquatic vertebrates has not been fully studied. Thus, in this study, the toxicity of pG was experimentally evaluated using developing zebrafish embryos as in vivo model system. To determine this, 4-hpf embryos were exposed to different concentrations of pG (1, 5, 10, 15, 20, 25, 30, 35, 40, 45, and 50 μg/L) and different early life-stage parameters were observed at 24, 48, 72, and 96 hpf. Through embryogenesis, pG was observed to induce significant embryonic mortality, delayed hatching, heartbeat, several morphological defects, pericardial toxicity, and bradycardia. Yolk sac edema and pericardial edema were induced by pG in developing embryos. These outcomes would provide new insights into the adverse effects of pG on the developing embryonic cardiac defects in vertebrates and highlight the probable natural environment and health hazards of pG flakes.

Nivolumab combined with Ruxolitinib: Antagonism or synergy?

Time is up for PD-L1 testing standardization in lung cancer

Treatment effects measured by restricted mean survival time in trials of immune checkpoint inhibitors for cancer

Abstract

BACKGROUND

The hazard ratio (HR) is used routinely to quantify the treatment effect for time-to-event endpoints in oncology trials, but its use requires that there be proportional hazards in the treatment arms. Non-proportional hazards are observed frequently in cancer immunotherapy trials due to the long-term survival and delayed clinical effect. Although values of HR are quoted in such trials they are not valid measures of outcome.

METHODS

Reports of parallel group randomized controlled trials (RCTs) evaluating immune checkpoint inhibitors with overall survival data were eligible. For each trial the ratio of restricted mean survival time (RMST) between the arms were based on reconstructed individual patient data for overall survival.

RESULTS

25 RCTs totaling 12,870 patients were included in this study. Overall survival was used as primary or co-primary endpoint in 18 trials (72%). In all trials, there was agreement between the ratio of RMST or RMTL and the reported HR about the direction of treatment effect. Estimates of HR provided larger estimates of treatment effect than the ratio of RMST or RMTL in all these trials. The estimated HR and RMST-based measures were in agreement regarding the statistical significance of the effect in all but two trials.

CONCLUSIONS

Ratio of RMST is a complementary technique that provides alternative method of summarizing treatment effects. Proportional hazards of the treatment effect should not be assumed in RCTs evaluating immune checkpoint inhibitors, and RMST analysis should be reported in such trials.

What is the optimal systemic treatment for men with metastatic, hormone- naive prostate cancer? A STOPCAP systematic review and network meta-analysis

Abstract

Background

Our prior STOPCAP systematic reviews showed improved survival for men with metastatic hormone-naive prostate cancer (mHNPC) when abiraterone acetate plus prednisolone/prednisone (AAP) or docetaxel (Doc), but not zoledronic acid (ZA), were added to androgen deprivation therapy (ADT). Trial evidence also suggests a benefit of combining celecoxib (Cel) with ZA and ADT. To establish the optimal treatments, a network meta-analysis (NMA) was performed based on aggregate data (AD) from all available studies.

Methods

Overall survival (OS) and failure-free survival (FFS) data from completed STOPCAP reviews of Doc, ZA and AAP and from recent trials of ZA and Cel contributed to this comprehensive AD-NMA. The primary outcome was overall survival (OS). Correlations between treatment comparisons within one multi-arm multi-stage (MAMS) trial were estimated from control-arm event counts. Network consistency and a common heterogeneity variance were assumed.

Results

We identified 10 completed trials which had closed to recruitment, and one trial in which recruitment was ongoing, as eligible for inclusion. Results are based on six trials including 6204 men (97% of men randomised in all completed trials). Network estimates of effects on OS were consistent with reported comparisons with ADT alone for: AAP (HR = 0.61, 95% CI 0.53-0.71); Doc (HR = 0.77, 95% CI 0.68-0.87); ZA + Cel (HR = 0.78, 95%CI 0.62-0.97) and ZA + Doc (HR = 0.79 95% CI 0.66-0.94); Cel (HR = 0.94 95% CI 0.75-1.17) and ZA (HR = 0.90 95% CI 0.79-1.03). The effect of ZA + Cel is consistent with the additive effects of the individual treatments. Results suggest that AAP has the highest probability of being the most effective treatment both for OS (94% probability) and FFS (100% probability). Doc was the second-best treatment for overall survival (35% probability).

Conclusions

Uniquely, we have included all available results and appropriately accounted for inclusion of MAMS trials in this AD-NMA. Our results support the use of AAP or Doc with ADT in men with mHNPC. AAP appears to be the most effective treatment, but it is not clear to what extent and whether this is due to a true increased benefit with AAP or the variable features of the individual trials. To fully account for patient variability across trials, changes in prognosis or treatment effects over time, and the potential impact of treatment on progression, a network meta-analysis based on individual participant data is in development.

Letter to the Editor: Should de-escalation of bone-targeting agents be standard of care for patients with bone metastases from breast cancer? A systematic review and meta-analysis

breast cancerbone metastasesbone modifying agentsdrug delivery frequencymeta-analysis

Physical activity in relation to risk of prostate cancer: a systematic review and meta-analysis

Abstract

Background

Prostate cancer (PCa) is one of the most common cancers among men, yet little is known about its modifiable risk and protective factors. This paper aims to quantitatively summarize observational studies relating physical activity (PA) to PCa incidence and mortality.

Materials and methods

Published articles pertaining to PA and PCa incidence and mortality were retrieved in July, 2017 using the MEDLINE and EMBASE databases. The literature review yielded 48 cohort studies and 24 case-control studies with a total of 151 748 PCa cases. The mean age of the study participants at baseline was 61 years.

Results

In random effects models, comparing the highest versus the lowest level of overall PA showed a summary relative risk (RR) estimate for total PCa incidence close to the null (RR = 0.99, 95% CI = 0.94-1.04). The corresponding RRs for advanced and non-advanced PCa were 0.92 (95% CI = 0.80-1.06) and 0.95 (95% CI = 0.85-1.07), respectively. We noted a statistically significant inverse association between long-term occupational activity and total PCa (RR = 0.83, 95% CI = 0.71-0.98, n studies=13), although that finding became statistically non-significant when individual studies were removed from the analysis. When evaluated by cancer subtype, an inverse association with long-term occupational activity was noted for non-advanced/non-aggressive PCa (RR = 0.51, 95% CI = 0.37-0.71, n studies=2) and recreational activity was inversely related to advanced/aggressive PCa (RR = 0.75, 95% CI = 0.60-0.95, n studies=2), although these observations are based on a low number of studies.Moreover, PA after diagnosis was related to reduced risk of PCa mortality among survivors of PCa (summary RR based on 4 studies=0.69, 95% CI = 0.55-0.85).

Conclusions

Whether PA protects against PCa remains elusive. Further investigation taking into account the complex clinical and pathologic nature of PCa is needed to clarify the PA and PCa incidence relation. Moreover, future studies are needed to confirm whether PA after diagnosis reduces risk of PCa mortality.

Phase I Study of the Checkpoint Kinase 1 Inhibitor GDC-0575 in Combination with Gemcitabine in Patients with Refractory Solid Tumors

Abstract

Background

Checkpoint kinase 1 (Chk1) inhibition following chemotherapy-elicited DNA damage overrides cell cycle arrest and induces mitotic catastrophe and cell death. GDC-0575 is a highly-selective oral small-molecule Chk1 inhibitor that results in tumor shrinkage and growth delay in xenograft models. We evaluated the safety, tolerability, and pharmacokinetic (PK) properties of GDC-0575 alone and in combination with gemcitabine. Anti-tumor activity and Chk1 pathway modulation were assessed.

Patients and methods

In this Phase I open-label study, in the dose escalation stage, patients were enrolled in a GDC-0575 monotherapy Arm (1) or GDC-0575 combination with gemcitabine Arm (2) to determine the maximum tolerated dose (MTD). Patients in Arm 2 received either IV gemcitabine 1000 mg/m² (Arm 2a) or 500 mg/m² (Arm 2b), followed by GDC-0575 (45 or 80 mg, respectively as RP2D). Stage II enrolled disease-specific cohorts.

Results

Of 102 patients treated, 70% were female, the median age was 59 years (range 27-85), and 47% were ECOG PS 0. The most common tumor type was breast (37%). The most frequent adverse events (all grades) related to GDC-0575 and/or gemcitabine were neutropenia (68%), anemia (48%), nausea (43%), fatigue (42%), and thrombocytopenia (35%). Maximum concentrations of GDC-0575 were achieved within 2 hours of dosing, and half-life was ∼23 hours. No PK drug-drug interaction was observed between GDC-0575 and gemcitabine. Among patients treated with GDC-0575 and gemcitabine, there were 4 confirmed partial responses, 3 occurring in patients with tumors harboring TP53 mutation. Pharmacodynamic data were consistent with GDC-0575 inhibition of gemcitabine-induced expression of pCDK1/2.

Conclusion

GDC-0575 can be safely administered as a monotherapy and in combination with gemcitabine, however, overall tolerability with gemcitabine was modest. Hematological toxicities were frequent but manageable. Preliminary anti-tumor activity was observed, but limited to a small number of patients with a variety of refractory solid tumors treated with GDC-0575 and gemcitabine.

Clinical trial number

NCT01564251

Combined pathologic-genomic algorithm for early stage breast cancer improves cost-effective use of the 21-gene recurrence score assay.

Abstract

Background

The 21-gene recurrence score (RS) [Oncotype DX®] partitions hormone receptor positive, node negative breast cancers into 3 risk groups for recurrence. The AAMC Model has previously been shown to accurately predict RS risk categories using standard pathology data. A Pathologic-Genomic (P-G) Algorithm then is presented using the AAMC model, and reserving the RS assay only for AAMC intermediate risk patients.

Patients and Methods

A survival analysis was done using a prospectively collected institutional database of newly diagnosed invasive breast cancers that underwent RS assay testing from February 2005 to May 2015. Patients were assigned to risk categories based on the AAMC Model. Using Kaplan-Meier methods, five-year distant recurrence rates (DRR) were evaluated within each risk group, and compared between AAMC and RS-defined risk groups. Five-year DRR were calculated for the P-G Algorithm and compared to DRR for RS risk groups and the AAMC Model's risk groups.

Results

A total of 1,268 cases were included. Five-year DRR were similar between the AAMC low-risk group (2.7%, n = 322) and the RS < 18 low-risk group (3.4%, n = 703), as well as between the AAMC high-risk group (22.8%, n = 230) and the RS > 30 high-risk group (23.0%, n = 141). Using the P-G Algorithm, more patients were categorized as either low- or high-risk, and the distant metastasis rate was 3.3% for the low-risk group (n = 739) and 24.2% for the high-risk group (n = 272). Using the P-G Algorithm, 44% (552/1268) of patients would have avoided RS testing.

Conclusions

AAMC Model is capable of predicting five-year recurrences in high- and low-risk groups similar to RS. Further, using the P-G Algorithm, reserving RS for AAMC intermediate cases, results in larger low- and high-risk groups with similar prognostic accuracy. Thus the P-G Algorithm reliably identifies a significant portion of patients unlikely to benefit from RS assay and with improved ability to categorize risk.

Response to commentary by Drs. Rositch and Krakow, “Moving from evidence to impact for HPV vaccination: the critical role of translation and communication in epidemiology”

Assessment of Quadrivalent Human Papillomavirus Vaccine Safety Using the Self-Controlled Tree-Temporal Scan Statistic Signal-Detection Method in the Sentinel System

Abstract

The self-controlled tree-temporal scan statistic—a new signal-detection method—can evaluate whether any of a wide variety of health outcomes are temporally associated with receipt of a specific vaccine, while adjusting for multiple testing. Neither health outcomes nor post-vaccination potential periods of increased risk need be pre-specified. Using US medical claims data in the Sentinel System, the method was used to evaluate adverse events after quadrivalent human papillomavirus vaccine (4vHPV). Incident outcomes occurring in emergency department or inpatient settings within 56 days after first doses of 4vHPV received by 9-through-26-year-olds in 2006–2014 were identified using International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes and analyzed by pairing the new method with a standard hierarchical classification of diagnoses. On scanning diagnoses of 1.9 million 4vHPV recipients, two statistically significant categories of adverse event were found: cellulitis on Days 2–3 after vaccination and "other complications of surgical and medical procedures" on Days 1–3. Cellulitis is a known adverse event. Clinically-informed investigation of electronic claims records of the patients with "other complications" did not suggest any previously unknown vaccine safety problem. Considering that thousands of potential short-term adverse events and hundreds of potential risk intervals were evaluated, these findings add significantly to the growing safety record of 4vHPV.

Moving From Evidence to Impact for HPV Vaccination: the critical role of translation and communication in epidemiology

Abstract

In response to Yih and Maro, et al., we highlight the importance of moving beyond epidemiologic research on HPV vaccine safety to focus on translation of this strong evidence-base into successful vaccine safety communication strategies to bolster vaccine uptake. The potential of the HPV vaccine to reduce cancer is substantial and yet actual vaccination rates in the United States are disappointingly low in comparison to other routine childhood vaccines with similar safety profiles. This is no doubt, in part, due to persistent parental safety concerns. In 2016, safety remained the second most common reason for lack of vaccination intent by parents of unvaccinated adolescents. While the strong study by Yih and Maro, et al., makes use of a novel statistical method and a large medical claims database to confirm the low occurrence of adverse events following HPV vaccination observed globally, their study also highlights a key challenge for epidemiologists—translating our research findings to other public health domains, so that evidence-informed communication strategies can be used to disseminate the information in a way that is understandable and useful to the public. Moving forward, multidisciplinary research teams will be essential to ensure our epidemiologic findings have a broad public health impact.