In vitro antimicrobial activities of novel anilinouracils which selectively inhibit DNA polymerase III of gram-positive bacteria

The 6-anilinouracils are novel dGTP analogs that selectively inhibit the replication-specific DNA polymerase III of gram-positive eubacteria. Two specific derivatives, IMAU (6-[3\u27-iodo-4\u27-methylanilino]uracil) and EMAU (6-[3\u27-ethyl-4\u27-methylanilino]uracil), were substituted with either a hydroxybutyl (HB) or a methoxybutyl (MB) group at their N3 positions to produce four agents: HB-EMAU, MB-EMAU, HB-IMAU, and MB-IMAU. These four new agents inhibited Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, and Enterococcus faecium. Time-kill assays and broth dilution testing confirmed bactericidal activity. These anilinouracil derivatives represent a novel class of antimicrobials with promising activities against gram-positive bacteria that are resistant to currently available agents, validating replication-specific DNA polymerase III as a new target for antimicrobial development

Phomopsis bougainvilleicola prepatellar bursitis in a renal transplant recipient

Prepatellar bursitis is typically a monomicrobial bacterial infection. A fungal cause is rarely identified. We describe a 61-year-old man who had received a renal transplant 21 months prior to presentation whose synovial fluid and surgical specimens grew Phomopsis bougainvilleicola, a pycnidial coelomycete

Child and family experiences of a whole-systems approach to physical activity in a multiethnic UK city: a citizen science evaluation protocol.

YesWhole-systems approaches are being adopted to tackle physical inactivity. The mechanisms contributing to changes resulting from whole-systems approaches are not fully understood. The voices of children and families that these approaches are designed for need to be heard to understand what is working, for whom, where and in what context. This paper describes the protocol for the children and families' citizen science evaluation of the Join Us: Move, Play (JU:MP) programme, a whole-systems approach to increasing physical activity in children and young people aged 5-14 years in Bradford, UK. The evaluation aims to understand the lived experiences of children and families' relationship with physical activity and participation in the JU:MP programme. The study takes a collaborative and contributory citizen science approach, including focus groups, parent-child dyad interviews and participatory research. Feedback and data will guide changes within this study and the JU:MP programme. We also aim to examine participant experience of citizen science and the suitability of a citizen science approach to evaluate a whole-systems approach. Data will be analysed using framework approach alongside iterative analysis with and by citizen scientists in the collaborative citizen science study. Ethical approval has been granted by the University of Bradford: study one (E891-focus groups as part of the control trial, E982-parent-child dyad interviews) and study two (E992). Results will be published in peer-reviewed journals and summaries will be provided to the participants, through schools or directly. The citizen scientists will provide input to create further dissemination opportunities

The Effect of Various Doses of Phenylalanine Supplementation on Blood Phenylalanine and Tyrosine Concentrations in Tyrosinemia Type 1 Patients

Tyrosinemia type 1 (TT1) treatment with 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) and a phenylalanine-tyrosine restricted diet is associated with low phenylalanine concentrations. Phenylalanine supplementation is prescribed without comprehensive consideration about its effect on metabolic control. We investigated the effect of phenylalanine supplementation on bloodspot phenylalanine, tyrosine, NTBC and succinylacetone. Eleven TT1 patients received 0, 20 and 40 mg/kg/day phenylalanine supplementation with the phenylalanine-tyrosine free L-amino acid supplements. Bloodspots were collected before breakfast, midday and evening meal. Differences between study periods, sample times and days within a study period were studied using (generalized) linear mixed model analyses. Twenty and 40 mg/kg/day phenylalanine supplementation prevented daytime phenylalanine decreases (p = 0.05) and most low phenylalanine concentrations, while tyrosine concentrations increased (p <0.001). Furthermore, NTBC and succinylacetone concentrations did not differ between study periods. To conclude, 20 mg/kg/day phenylalanine supplementation can prevent most low phenylalanine concentrations without increasing tyrosine to concentrations above the target range or influencing NTBC and succinylacetone concentrations, while 40 mg/kg/day increased tyrosine concentrations to values above the targeted range. Additionally, this study showed that the effect of phenylalanine supplementation, and a possible phenylalanine deficiency, should be assessed using pre-midday meal blood samples that could be combined with an overnight fasted sample when in doubt

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome

<p>Abstract</p> <p>Background</p> <p>Individuals who carry deleterious BRCA mutations face significantly elevated risks of breast, ovarian, and other cancers. These individuals are also responsible for informing relatives of their increased risk for carrying the family BRCA mutation. Few interventions have been developed to facilitate this family communication process.</p> <p>Methods</p> <p>We developed the Sharing Risk Information Tool (ShaRIT), a personalized educational intervention, to support BRCA carriers as they discuss BRCA positive results and their implications with relatives. We conducted a pilot study of 19 BRCA carriers identified through the University of California San Francisco Cancer Risk Program. Our study had two aims: 1) to assess the feasibility and acceptability of ShaRIT, and 2) describe characteristics associated with increased family communication and BRCA testing. Participants in our study were divided into two groups: those who had not received ShaRIT as part of their genetic counseling protocol (control group, n = 10) and those who received ShaRIT (n = 9).</p> <p>Results</p> <p>All 9 women who received ShaRIT reported that it was a useful resource. Characteristics associated with increased sharing and testing included: female gender, degree of relationship, and frequency of communication. Increased pedigree knowledge showed a trend toward higher rates of sharing.</p> <p>Conclusions</p> <p>Both participants and genetic counselors considered ShaRIT a well-received, comprehensive tool for disseminating individual risk information and clinical care guidelines to Hereditary Breast and Ovarian Cancer Syndrome families. Because of this, ShaRIT has been incorporated as standard of care at our institution. In the future we hope to evaluate the effects of ShaRIT on family communication and family testing in larger populations of BRCA positive families.</p

Drug-Induced Liver Injury due to Flucloxacillin:Relevance of Multiple Human Leukocyte Antigen Alleles

© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics Some patients prescribed flucloxacillin (~0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR)=36.62; P=2.67×10−97). HLA-B*57:03 also showed an association (OR=79.21; P=1.2×10−6). Within the HLA-B protein sequence, imputation showed valine97, common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR=38.1; P=9.7×10−97). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n=6) or amoxicillin (n=15) and no significant non-HLA signals for any penicillin-related DILI

A cross-sectional survey of the prevalence of environmental tobacco smoke preventive care provision by child health services in Australia

Background: Despite the need for a reduction in levels of childhood exposure to environmental tobacco smoke (ETS) being a recognised public health goal, the delivery of ETS preventive care in child health service settings remains a largely unstudied area. The purpose of this study was to determine the prevalence of ETS preventive care in child health services; differences in the provision of care by type of service; the prevalence of strategies to support such care; and the association between care support strategies and care provision. Method: One-hundred and fifty-one (83%) child health service managers within New South Wales, Australia completed a questionnaire in 2002 regarding the: assessment of parental smoking and child ETS exposure; the provision of parental smoking cessation and ETS-exposure reduction advice; and strategies used to support the provision of such care. Child health services were categorised based on their size and case-mix, and a chi-square analysis was performed to compare the prevalence of ETS risk assessment and ETS prevention advice between service types. Logistic regression analysis was used to examine associations between the existence of care support strategies and the provision of ETS risk assessment and ETS exposure prevention advice. Results: A significant proportion of services reported that they did not assess parental smoking status (26%), and reported that they did not assess the ETS exposure (78%) of any child. Forty four percent of services reported that they did not provide smoking cessation advice and 20% reported they did not provide ETS exposure prevention advice. Community based child and family health services reported a greater prevalence of ETS preventive care compared to other hospital based units. Less than half of the services reported having strategies to support the provision of ETS preventive care. The existence of such support strategies was associated with greater odds of care provision. Conclusions: The existence of major gaps in recommended ETS preventive care provision suggests a need for additional initiatives to increase such care delivery. The low prevalence of strategies that support such care delivery suggests a potential avenue to achieve this outcome

Factors associated with testicular self-examination among unaffected men from multiple-case testicular cancer families

<p>Abstract</p> <p>Background</p> <p>The lifetime testicular cancer (TC) risk in the general population is relatively low (~1 in 250), but men with a family history of TC are at 4 to 9 times greater risk than those without. Some health and professional organizations recommend consideration of testicular self-examination (TSE) for certain high-risk groups (e.g. men with a family history of TC). Yet little is known about factors associated with TSE behaviors in this at-risk group.</p> <p>Methods</p> <p>We collected information on this subject during an on-going NCI multidisciplinary, etiologically-focused, cross-sectional Familial Testicular Cancer (FTC) study. We present the first report specifically targeting TSE behaviors among first- and second-degree relatives (n = 99) of affected men from families with ≥ 2 TC cases. Demographic, medical, knowledge, health belief, and psychological factors consistent with the Health Belief Model (HBM) were evaluated as variables related to TSE behavior, using chi-square tests of association for categorical variables, and t-tests for continuous variables.</p> <p>Results</p> <p>For men in our sample, 46% (n = 46) reported performing TSE regularly and 51% (n = 50) reported not regularly performing TSE. Factors associated (p < .05) with regularly performing TSE in multivariate analysis were physician recommendation and testicular cancer worry. This is the first study to examine TSE in unaffected men from FTC families.</p> <p>Conclusion</p> <p>The findings suggest that, even in this high-risk setting, TSE practices are sub-optimal. Our data provide a basis for further exploring psychosocial issues that are specific to men with a family history of TC, and formulating intervention strategies aimed at improving adherence to TSE guidelines.</p

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A&gt;T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management