Safety profile of avelumab in patients with advanced solid tumors: A pooled analysis of data from the phase 1 JAVELIN solid tumor and phase 2 JAVELIN Merkel 200 clinical trials.

BACKGROUND: Antibodies targeting the programmed death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) checkpoint may cause adverse events (AEs) that are linked to the mechanism of action of this therapeutic class and unique from those observed with conventional chemotherapy. METHODS: Patients with advanced solid tumors who were enrolled in the phase 1 JAVELIN Solid Tumor (1650 patients) and phase 2 JAVELIN Merkel 200 (88 patients) trials received avelumab, a human anti-PD-L1 IgG1 antibody at a dose of 10 mg/kg every 2 weeks. Treatment-related AEs (TRAEs) were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0). In post hoc analyses, immune-related AEs (irAEs) were identified via an expanded AE list and medical review, and infusion-related reactions (IRRs) occurring ≤2 days after infusion and symptoms occurring ≤1 day after infusion and resolving ≤2 days after onset were identified based on prespecified Medical Dictionary for Regulatory Activities (MedDRA) terms. RESULTS: Of the 1738 patients analyzed, grade ≥3 TRAEs occurred in 177 (10.2%); the most common were fatigue (17 patients; 1.0%) and IRR (10 patients; 0.6%). TRAEs led to discontinuation in 107 patients (6.2%) and death in 4 patients (0.2%). Grade ≥3 irAEs occurred in 39 patients (2.2%) and led to discontinuation in 34 patients (2.0%). IRRs or related symptoms occurred in 439 patients (25.3%; grade 3 in 0.5% [9 patients] and grade 4 in 0.2% [3 patients]). An IRR occurred at the time of first infusion in 79.5% of 439 patients who had an IRR, within the first 4 doses in 98.6% of 439 patients who had an IRR, and led to discontinuation in 35 patients (2.0%). CONCLUSIONS: Avelumab generally was found to be well tolerated and to have a manageable safety profile. A minority of patients experienced grade ≥3 TRAEs or irAEs, and discontinuation was uncommon. IRRs occurred mainly at the time of first infusion, and repeated events were infrequent. Cancer 2018;124:2010-7. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Testosterone for low libido in postmenopausal women not taking estrogen.

BACKGROUND: The efficacy and safety of testosterone treatment for hypoactive sexual desire disorder in postmenopausal women not receiving estrogen therapy are unknown. METHODS: We conducted a double-blind, placebo-controlled, 52-week trial in which 814 women with hypoactive sexual desire disorder were randomly assigned to receive a patch delivering 150 or 300 microg of testosterone per day or placebo. Efficacy was measured to week 24; safety was evaluated over a period of 52 weeks, with a subgroup of participants followed for an additional year. The primary end point was the change from baseline to week 24 in the 4-week frequency of satisfying sexual episodes. RESULTS: At 24 weeks, the increase in the 4-week frequency of satisfying sexual episodes was significantly greater in the group receiving 300 microg of testosterone per day than in the placebo group (an increase of 2.1 episodes vs. 0.7, P<0.001) but not in the group receiving 150 microg per day (1.2 episodes, P=0.11). As compared with placebo, both doses of testosterone were associated with significant increases in desire (300 microg per day, P<0.001; 150 microg per day, P=0.04) and decreases in distress (300 microg per day, P<0.001; 150 microg per day, P=0.04). The rate of androgenic adverse events - primarily unwanted hair growth - was higher in the group receiving 300 microg of testosterone per day than in the placebo group (30.0% vs. 23.1%). Breast cancer was diagnosed in four women who received testosterone (as compared with none who received placebo); one of the four received the diagnosis in the first 4 months of the study period, and one, in retrospect, had symptoms before undergoing randomization. CONCLUSIONS: In postmenopausal women not receiving estrogen therapy, treatment with a patch delivering 300 microg of testosterone per day resulted in a modest but meaningful improvement in sexual function. The long-term effects of testosterone, including effects on the breast, remain uncertain. (ClinicalTrials.gov number, NCT00131495.)

Accessibility for persons with mobility impairments within an informal trading site: A case study on the markets of Warwick, South Africa.

BACKGROUND: There are a number of informal trading sites across cities in sub-Saharan Africa, of which the markets of Warwick is one example. Since the informal economy is an important contributor to a city's economy as well as a source of employment, it is important for these sites to be accessible for all persons. Whilst the South African government has put structures in place to identify and remove environmental barriers in order to meet the individual needs of persons with mobility impairments and improve their quality of life, persons with mobility impairments still face barriers and restricting environments that prevent them from participating in society and its social and economic activities. OBJECTIVES: This case study aimed at exploring accessibility within the markets of Warwick for persons with mobility impairments by an ergonomic assessment, augmented by voices of participants within the market. METHOD: A qualitative, instrumental, single case study design was utilised with purposive sampling of the markets of Warwick as the study setting. Multiple sources of data were gathered, such as semi-structured interviews, direct observations of an environmental survey supported by photographs, and the authors' review of relevant documents. Transcriptions were analysed using NVivo 10 software programme with inductive coding. RESULTS: Whilst policies have been in place since 1996 to adjust infrastructure, the markets of Warwick still remain inaccessible to persons with mobility impairments and do not meet the standardised infrastructural design. CONCLUSION: The findings of this study may offer a significant understanding of the complexity of accessibility within an informal trading site and create an awareness of the limitations this has for persons with mobility impairments. Additionally, these findings may assist in effecting a positive change in terms of the infrastructure of the Markets and in continuous advocating for the rights of persons with all disabilities.

High-throughput single-nucleotide polymorphism genotyping by fluorescent competitive allele-specific polymerase chain reaction (SNiPTag).

Single nucleotide polymorphisms (SNPs) are becoming widely recognized as the new currency for gene mapping as increasing numbers are discovered. Here we outline a method for their rapid analysis based on an allele-specific polymerase chain reaction (PCR) which employs a competitive approach, whereby both allele-specific primers are present in the same reaction and carry different fluorescent labels. This procedure is simple and amenable to high-throughput genotyping using conventional automated sequencing equipment, and no post-PCR modifications are required. Verification of the procedure was carried out by comparison of results derived by this method with those from restriction enzyme digestion of the ALDH2 exon 12 functional polymorphism (Glu-487-Lys) in 109 individuals. Additionally, we have examined all combinations of nucleotide substitutions and shown them to be differentiated by this method. As proof of concept, several assays were combined and loaded on a single gel lane/capillary to substantially improve throughput. This was made possible by designing the PCR products to be of different lengths and no interference was observed between products differing in size by only six nucleotides. We outline a number of test assays for well-characterized SNPs in human candidate genes for behavioral disorders.

Accessibility for persons with mobility impairments within an informal trading site: a case study on the markets of Warwick, South Africa

Background: There are a number of informal trading sites across cities in sub-Saharan Africa, of which the markets of Warwick is one example. Since the informal economy is an important contributor to a city's economy as well as a source of employment, it is important for these sites to be accessible for all persons. Whilst the South African government has put structures in place to identify and remove environmental barriers in order to meet the individual needs of persons with mobility impairments and improve their quality of life, persons with mobility impairments still face barriers and restricting environments that prevent them from participating in society and its social and economic activities. Objectives: This case study aimed at exploring accessibility within the markets of Warwick for persons with mobility impairments by an ergonomic assessment, augmented by voices of participants within the market. Method: A qualitative, instrumental, single case study design was utilised with purposive sampling of the markets of Warwick as the study setting. Multiple sources of data were gathered, such as semi-structured interviews, direct observations of an environmental survey supported by photographs, and the authors' review of relevant documents. Transcriptions were analysed using NVivo 10 software programme with inductive coding. Results: Whilst policies have been in place since 1996 to adjust infrastructure; the markets of Warwick still remain inaccessible to persons with mobility impairments and do not meet the standardised infrastructural design. Conclusion: The findings of this study may offer a significant understanding of the complexity of accessibility within an informal trading site and create an awareness of the limitations this has for persons with mobility impairments. Additionally, these findings may assist in effecting a positive change in terms of the infrastructure of the Markets and in continuous advocating for the rights of persons with all disabilities