Tyrosine kinase inhibitors significantly improved survival outcomes in patients with metastatic gastrointestinal stromal tumour: a multi-institutional cohort study.

Background: The real-world impact of tyrosine kinase inhibitors (tkis) in clinical practice for gastrointestinal stromal tumour (gist) has not been extensively reported. We sought to assess how outcomes have changed over the eras and to evaluate the effect of access to imatinib and sunitinib on survival in patients with unresectable or metastatic gist in British Columbia. Methods: Patients with metastatic or unresectable gist were allocated to one of three eras: pre-2002, 2002-2007, and post-2007 based on treatment availability (pre-imatinib, post-imatinib, and post-sunitinib). Overall survival (os) and progression-free survival (pfs) were compared between eras. Univariate and multivariate analyses were performed to determine the effects of tumour, patient, and treatment characteristics on survival outcomes. Results: Of 657 patients diagnosed with gist throughout British Columbia during 1996-2016, 196 had metastatic disease: 23 in the pre-imatinib era, 67 in the post-imatinib era, and 106 in the post-sunitinib era. A significant increase in os, by 53.6 months (p = 0.0007), and pfs, by 29.1 months (p = 0.044), was observed after the introduction of imatinib. The introduction of sunitinib did not significantly affect os or pfs. Conclusions: Implementation of tkis has drastically improved survival outcomes for patients with metastatic gist by up to 4.55 years in the real-world setting. Our study demonstrates that implementation of tkis in clinical practice has outperformed their benefit predicted in clinical trials.

Stereotactic Body Radiotherapy for Large Unresectable Hepatocellular Carcinomas - A Single Institution Phase II Study.

AIMS: To evaluate the safety and efficacy of liver stereotactic body radiotherapy (SBRT) in the treatment of unresectable hepatocellular carcinomas (HCC) measuring >5 cm. MATERIALS AND METHODS: Between November 2013 and February 2016, 13 patients with unresectable HCC (>5 cm), ineligible for other local treatments, with a Child-Pugh score (CPS) ≤ B7, were enrolled into a single-institution phase II study. SBRT was delivered by volumetric-modulated arc radiotherapy. Radiological response was reported using modified Response Evaluation Criteria in Solid Tumours criteria and toxicities graded by Common Terminology Criteria for Adverse Events v4 criteria. RESULTS: Sixteen hepatomas (median size 7.5 cm, range 5.1-9.7 cm) were treated in 13 patients. The baseline CPS was A5/6 in nine patients (69%) and B7 in four patients (31%). Five patients (38%) received previous liver-directed treatment. The median prescribed dose was 45 Gy (range 40-45 Gy) in five fractions. The median follow-up was 17.7 months. The 1-year local control rate was 92%. The median overall survival was 17.7 months and the 1-year overall survival was 62%. The median time to local progression was not reached. Five patients (39%) had an increase in CPS by two or more points at 3 months. Overall, there were 10 grade 3 acute toxicities occurring in seven patients, of which six were haematological. Quality of life remained clinically stable or improved at 3 months in 61.5% and 53.8% of patients based on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 Global Health Score and Functional Assessment of Cancer Therapy - Hepatobiliary version 4 score, respectively. CONCLUSIONS: In our cohort, SBRT to unresectable large HCC tumours provided excellent local control with acceptable toxicities. Regional recurrence remained the major cause of failure. Further studies are warranted to examine the role for SBRT in combination with other modalities to maximise disease control in the liver.

How did the Good School Toolkit reduce the risk of past week physical violence from teachers to students? Qualitative findings on pathways of change in schools in Luwero, Uganda.

Violence against children is a serious violation of children's rights with significant impacts on current and future health and well-being. The Good School Toolkit (GST) is designed to prevent violence against children in primary schools through changing schools' operational cultures. Conducted in the Luwero District in Uganda between 2012 and 2014, findings from previous research indicate that the Toolkit reduced the odds of past week physical violence from school staff (OR = 0.40, 95%CI 0.26-0.64, p < 0.001), corresponding to a 42% reduction in risk of past week physical violence. This nested qualitative study involved 133 interviews with students, teachers, school administration, and parents, and two focus group discussion with teachers. Interviews were conducted using semi-structured tools and analysed using thematic analysis complemented by constant comparison and deviant case analysis techniques. Within a context of normative acceptance of corporal punishment this qualitative paper reports suggestive pathways related to teacher-student relationships through which reductions in violence operated. First, improved student-teacher relationships resulted in improved student voice and less fear of teachers. Second, the intervention helped schools to clarify and encourage desired behaviour amongst students through rewards and praise. Third, many teachers valued positive discipline and alternative discipline methods, including peer-to-peer discipline, as important pathways to reduced use of violence. These shifts were reflected in changes in the views, use, and context of beating. Although the GST is effective for reducing physical violence from teachers to students, violence persisted, though at significantly reduced levels, in all schools with reductions varying across schools and individuals. Much of the success of the Toolkit derives from the support it provides for fostering better student-teacher relationships and alternative discipline options. Such innovation could usefully be incorporated in teacher training syllabi to equip teachers with knowledge and skills to maintain discipline without the use of fear or physical punishment.

Occurrence and impact of domestic violence and abuse in gay and bisexual men: A cross sectional survey.

This cross-sectional survey measured adult experience and perpetration of negative and potentially abusive behaviours with partners and its associations with mental and sexual health problems, drug and alcohol abuse in gay and bisexual men attending a UK sexual health service. Of 532 men, 33.9% (95% CI: 29.4-37.9) experienced and 16.3% (95% CI: 13.0-19.8) reported carrying out negative behaviour. Ever being frightened of a partner (aOR 2.5; 95% CI: 2.0-3.1) and having to ask a partner's permission (aOR 2.7; 95% CI: 1.6-4.7) were associated with increased odds of being anxious. There were increased odds of cannabis use in the last 12 months amongst men who reported ever being physically hurt (aOR 2.4; 95% CI: 1.7-3.6). Being frightened (aOR 2.2; 95% CI: 1.5-3.2), being physically hurt (aOR 2.3; 95% CI: 1.4-3.8), being forced to have sex (aOR 2.5; 95% CI: 1.3-4.9) and experiencing negative behaviour in the last 12 months (aOR 1.7; 95% CI: 1.2-2.5) were associated with increased odds of using a Class A drugs in the last 12 months. Sexual health practitioners should be trained with regards to the risk indicators associated with domestic violence and abuse, how to ask about domestic violence and abuse and refer to support.

Global differences between women and men in the prevalence of obesity: is there an association with gender inequality?

BACKGROUND/OBJECTIVES: In most populations the prevalence of obesity is greater in women than in men; however, the magnitude of the difference between the sexes varies significantly by country. We considered the role of gender inequality in explaining these disparities. SUBJECTS/METHODS: We undertook an ecological analysis of internationally comparable obesity prevalence data to examine the association between indicators of gender inequality and the differences between men and women in obesity prevalence. Gender inequality was assessed using three measures: the Gender Inequality Index, the Global Gender Gap Index and the Social Institutions and Gender Index. We fitted multiple regression models to examine the association. RESULTS: We found that the prevalence of obesity across countries shows gendered patterning with greater prevalence and greater heterogeneity in women than in men (P<0.001). We also found that two of three measures of gender inequality were significantly associated with the sex differences in obesity prevalence across countries. CONCLUSIONS: The patterning of obesity across countries is gendered. However, the association between global measures of gender inequality and the sex gap in obesity is dependent on the measure used. Further research is needed to investigate the mechanisms that underpin the gendered nature of obesity prevalence.

Surface control and cryogenic durability of transparent CNT coatings on dip-coated glass substrates.

Transparent carbon nanotube (CNT) coatings were deposited on boro-silicate glass substrates by dip-coating. Ultraviolet-visible (UV) spectra, surface resistance measurement, and the wettability tests were used to investigate the optical transmittance and electrical properties of these CNT coatings. The changes in electrical and optical properties of these coatings were observed to be functions of the number of dip-coating cycles. The surface resistance of the CNT coated substrates decreased dramatically as the number of dip-coatings was increased, whereas the increases in the CNT layer thickness beyond that for the first dipping cycle had little effect on the transparent-properties. Static contact angle measurements proved to be an effective means for evaluating the surface morphology of CNT coatings. The interfacial durability of the CNT coatings on a glass substrate was much better than that of ITO coatings over the temperature range from -150°C to +150°C.

Determining access to assisted reproductive technology: reactions of clinic directors to ethically complex case scenarios.

BACKGROUND: Our aim was to increase understanding of how patient selection is handled by assisted reproductive technology (ART) clinicians. METHODS: Ethically complex case scenarios were evaluated by the directors of USA ART clinics. Scenarios included using a son as sperm donor for his father, sex selection without associated disease, treatment of morally irresponsible couples, and a dispute over embryo disposition. Respondents reviewed eight scenarios and gave their opinions on whether to offer treatment. Reasons given for these decisions were placed into one of 13 categories. RESULTS: Survey response rate was 57%. Between 3 and 50% of respondents would treat in each case. Of reasons given, 'conditional' responses (requiring counselling, blood tests or agreement to other 'conditions') were common (31.4%). Non-maleficence (risk) accounted for 29.4% of responses, philosophy of medicine 18.9%, respect for patient autonomy 5.9% and legal concerns 4.6%. Discrimination and threats were each significant in one case. Reasons evoking absolutist beliefs, personal discomfort, commitment to justice, religion and ethical relativism were rare. CONCLUSIONS: Clinicians felt conflict between a desire to respect patient autonomy and their discomfort over the risk associated with the procedure. They raised concerns about misuse of medical technology. Attempts to resolve complex issues through negotiation and compromise were common.

Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.

Piriqualone (1) was found to be an antagonist of AMPA receptors. Structure activity optimization was conducted on each of the three rings in 1 to afford a series of potent and selective antagonists. The sterically crowded environment surrounding the N-3 aryl group provided sufficient thermal stability for atropisomers to be isolated. Separation of these atropisomers resulted in the identification of (+)-38 (CP-465,022), a compound that binds to the AMPA receptor with high affinity (IC50 = 36 nM) and displays potent anticonvulsant activity.

Biphasic patterns of memory deficits following moderate-dose partial-brain irradiation: neuropsychologic outcome and proposed mechanisms.

PURPOSE: To identify the longitudinal neurobehavioral characteristics of the early-delayed and late-delayed effects of partial-brain radiotherapy for patients with supratentorial brain tumors with favorable histology. This study improves on previous attempts to identify radiation effects, because of the inclusion of baseline measures and the use of subjects as their own controls. PATIENTS AND METHODS: Ten neuropsychologic domains were measured in 12 patients at baseline (post-surgery and immediately before initiation of radiotherapy), and followed trimonthly for 1 year. Four to six patients were examined at 2 and 3 years postbaseline. RESULTS: Patients were impaired at baseline compared with controls only in visual memory and sentence recall, but demonstrated significant improvement in visual memory by 2 years postbaseline. Speed of processing information also showed a slope of improvement over 2 years. Retrieval from verbal long-term memory was impaired at 1.5 months postcompletion of radiotherapy, but recovered to baseline levels by 1 year. At 2 years postbaseline, long-term memory retrieval demonstrated a decline, but remained unchanged at 3 years. CONCLUSION: Long-term memory appears to be sensitive to the effects of radiotherapy. We confirmed our previous findings of a decrement with rebound during the early-delayed period, and propose that these findings are consistent with demyelination/remyelination. Decrement was observed again at 2 years postbaseline, which suggests that memory retrieval may be the earliest marker of late-delayed effects. These neurocognitive patterns are consistent with leukoencephalopathy. Confirmation of these observations will be possible if neuropsychologic testing with the same sensitivity can be incorporated into national collaborative trials.

Gene conversion between red and defective green opsin gene in blue cone monochromacy.

Blue cone monochromacy is an X-linked condition in which the function of both the red pigment gene (RCP) and the green pigment gene (GCP) is impaired. Blue cone monochromacy can be due to a red/green gene array rearrangement existing of a single red/green hybrid gene and an inactivating C203R point mutation in GCP. We describe here a family with blue cone monochromacy due to the presence of the C203R mutation in both RCP and GCP. The flanking sequences of the C203R mutation in exon 4 of RCP were characteristic for GCP, indicating that this mutation was transferred from GCP into RCP by gene conversion.

Effect of increased intra-aortic balloon pressure on catheter volume: relationship to changing altitudes.

OBJECTIVE: To evaluate the effect of intra-aortic balloon membrane response under increasing intracatheter pressure by indexing these data to associated barometric pressures that occur with changes in altitude. DESIGN: A static compliance test was performed to assess the effect of internal pressure on intra-aortic balloon compliance (simulating helium gas within the intra-aortic balloon affected by barometric pressure). Testing consisted of incrementally increasing pressure within eight percutaneous intra-aortic balloons from four leading manufacturers. SETTING: The University of Utah Department of Mechanical Engineering Laboratory. PATIENTS: No patients were involved. This study was a bench test lab study. INTERVENTIONS: No patient interventions were utilized. RESULTS: Results for all trials showed a curvilinear relationship between intracatheter pressure and balloon volume. Clinically significant balloon expansion data were obtained, with manufacturer variation observed at moderate-to-high pressures. CONCLUSIONS: Based on the results of this study, recommendations for operation of intra-aortic balloon pumps during altitude ascent and descent are proposed, from which individual institutional protocols may be developed.

Spinal cord localization and characterization of the neurons which give rise to the accessory phrenic nerve in the adult rat.

This study describes the spinal cord location and morphology of the neurons which give rise to the accessory phrenic nerve in the rat. The results indicate that the cell bodies of the accessory phrenic nerve are a caudal extension of the phrenic nucleus. These cell bodies are located from cervical spinal cord levels C5 to upper C6 and comprise approximately 11% of the total phrenic motoneuron pool. The substantial phrenic contribution indicates the importance of the accessory phrenic nerve in both experimental and clinical manipulations of diaphragm innervation.

[Monotherapy of endemic Kaposi sarcoma with long-term vincristine infusion]. / Monotherapie des endemischen Kaposi-Sarkoms mit Vincristin-Dauerinfusion.

Twelve patients with endemic Kaposi's sarcoma (KS) were entered into a clinical trial of vincristine (VCR) infusion. Patients received 5-day courses of VCR, 0.25 mg/m2/day by continuous infusion, after an 0.5 mg intravenous bolus injection. Courses were repeated every four weeks. Stabilization of disease occurred in nine patients and could be maintained for a mean of 3 months (range: 2-7 months). Complete or partial remissions were not achieved with this protocol. Complications of therapy consisted of development of moderate neurotoxicity and paralytic ileus in one patient. Two patients developed opportunistic infections while on therapy. Hematologic toxicity, nausea or emesis did not occur. Single agent VCR by infusion is well tolerated by patients with the acquired immunodeficiency syndrome (AIDS) but appears to have only limited activity in the treatment of AIDS-related KS.