Melioidosis, caused by the environmental gram-negative bacterium Burkholderia pseudomallei, usually develops in adults with predisposing conditions and in Australia more commonly occurs during the ...monsoonal wet season. We report an outbreak of 7 cases of melioidosis in immunocompetent children in Australia. All the children had participated in a single-day sporting event during the dry season in a tropical region of Australia, and all had limited cutaneous disease. All case-patients had an adverse reaction to oral trimethoprim/sulfamethoxazole treatment, necessitating its discontinuation. We describe the clinical features, environmental sampling, genomic epidemiologic investigation, and public health response to the outbreak. Management of this outbreak shows the potential benefits of making melioidosis a notifiable disease. The approach used could also be used as a framework for similar outbreaks in the future.
Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only ...sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures.
The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed.
In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected.
Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.
•In a cohort of >21 000 patients, tumor-only sequencing failed to detect 10.5% of pathogenic germline variants in 16 CSGs.•18.8%, 12.8% and 7.3% of pathogenic germline variants in MMR, DDR and HRD genes were not detected by tumor-only sequencing.•These undetected P/LP variants may affect the use of targeted therapies, preventative measures and familial surveillance.•For patients with negative tumor sequencing results, genetic testing is needed to guide therapy and genetic counseling.
Presence of a germline BRCA1 and/or BRCA2 mutation (gBRCAm) may sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition via inactivation of the second allele, resulting in gene-specific ...loss of heterozygosity (gsLOH) and homologous recombination deficiency (HRD). Here we explore whether tissue sample testing provides an additional route to germline testing to inform treatment selection for PARP inhibition.
In this prespecified exploratory analysis, BRCA1 and/or BRCA2 mutations in blood samples (gBRCAm) and tumor tissue (tBRCAm) were analyzed from patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer and known gBRCAm, enrolled in the phase III OlympiAD trial. The frequency and nature of tBRCAm, HRD score status HRD-positive (score ≥42) versus HRD-negative (score <42) using the Myriad myChoice® CDx test and rates of gsLOH were determined, and their impact on clinical efficacy (objective response rate and progression-free survival) was explored.
Tissue samples from 161/302 patients yielded tBRCAm, HRD and gsLOH data for 143 (47%), 129 (43%) and 125 (41%) patients, respectively. Concordance between gBRCAm and tBRCAm was 99%. gsLOH was observed in 118/125 (94%) patients BRCA1m, 73/76 (96%); BRCA2m, 45/49 (92%). A second mutation event was recorded for two of the three BRCA1m patients without gsLOH. The incidence of HRD-negative was 16% (21/129) and was more common for BRCA2m (versus BRCA1m) and/or for hormone receptor-positive (versus triple-negative) disease. Olaparib antitumor activity was observed irrespective of HRD score.
gBRCAm identified in patients with HER2-negative metastatic breast cancer by germline testing in blood was also identified by tumor tissue testing. gsLOH was common, indicating a high rate of biallelic inactivation in metastatic breast cancer. Olaparib activity was seen regardless of gsLOH status or HRD score. Thus, additional tumor testing to inform PARP inhibitor treatment selection may not be supported for these patients.
•We investigated if there is a role for tumor testing in HER2-negative metastatic breast cancer with germline BRCA mutations.•Tumor testing was able to detect known germline BRCA mutations, with 99% concordance for tumor tissue and blood.•HRD scores were mostly high and gsLOH was >90%.•Olaparib activity was seen in the few tumors with low HRD scores or lacking LOH.•Additional measurement of genome instability and gene-specific LOH may not inform PARP inhibitor treatment selection.
This study sought to understand barriers and facilitators for preparing and eating dinner at home in families who report eating dinner away from home ≥3 times per week. Cross-sectional, mixed methods ...(focus groups, questionnaires) study. Twenty-seven parents with a child 3–10 years-old who reported eating dinner away from home ≥3 times per week from a pediatric medical center in the Midwest participated. The key concepts analytic framework guided focus group analysis. Descriptive statistics were used to characterize parent demographics, anthropometrics, attitudes and confidence toward cooking, perceptions of dinner costs and portions, and parent and child dinners. Parents reported confidence in cooking a home prepared meal, but that eating away from home was reinforcing because it provided quality family time and diminished barriers such as picky eating and perceived costs. Home cooking was also hindered by early school lunch and after-school sports as children were not hungry or home at the typical dinner hour and parents did not want to cook after 8pm. Parents estimated preparing and eating a meal at home took significantly more time than driving and eating out (80.7 min vs. 30.3 min, p < 0.001). Parents significantly (F (3, 104) = 8.80, p < 0.001) overestimated the cost of home-prepared meals compared to take-out and frozen meals. Portion size was also overestimated for a protein serving. Findings are limited to predominantly married, female parents whom are highly educated and working. To reduce eating out, interventions should address family factors (e.g., time management, quality time) and child behavior (e.g., picky eating). Innovative interventions that include experiential cooking opportunities that incorporate time management, address picky eating and enthusiasm for cooking with education on decreasing costs may be particularly beneficial for middle-to high-income families.
•Focus groups with affluent parents who reported eating away from home often.•Societal factors, cost, and parent expectations of meal times influence eating out.•Competing priorities with preparing food at home may differ by income-status.•Interventions need to address time management and child eating behavior.
The token economy is a well-established and widely used behavioral intervention. A token economy is comprised of six procedural components: the target response(s), a token that functions as a ...conditioned reinforcer, backup reinforcers, and three interconnected schedules of reinforcement. Despite decades of applied research, the extent to which the procedures of a token economy are described in complete and replicable detail has not been evaluated. Given the inherent complexity of a token economy, an analysis of the procedural descriptions may benefit future token economy research and practice. Articles published between 2000 and 2015 that included implementation of a token economy within an applied setting were identified and reviewed with a focus on evaluating the thoroughness of procedural descriptions. The results show that token economy components are regularly omitted or described in vague terms. Of the articles included in this analysis, only 19% (18 of 96 articles reviewed) included replicable and complete descriptions of all primary components. Missing or vague component descriptions could negatively affect future research or applied practice. Recommendations are provided to improve component descriptions.
Burkholderia pseudomallei is resistant to most antibiotics. Decreased susceptibility to the reserve antibiotic meropenem would dramatically decrease treatment options. We document the first cases of ...decreased meropenem susceptibility and identify its molecular basis. Decreased susceptibility was associated with poorer outcomes.
Abstract
Background
Burkholderia pseudomallei, the causative agent of the high-mortality disease melioidosis, is a gram-negative bacterium that is naturally resistant to many antibiotics. There is no vaccine for melioidosis, and effective eradication is reliant on biphasic and prolonged antibiotic administration. The carbapenem drug meropenem is the current gold standard option for treating severe melioidosis. Intrinsic B. pseudomallei resistance toward meropenem has not yet been documented; however, resistance could conceivably develop over the course of infection, leading to prolonged sepsis and treatment failure.
Methods
We examined our 30-year clinical collection of melioidosis cases to identify B. pseudomallei isolates with reduced meropenem susceptibility. Isolates were subjected to minimum inhibitory concentration (MIC) testing toward meropenem. Paired isolates from patients who had evolved decreased susceptibility were subjected to whole-genome sequencing. Select agent-compliant genetic manipulation was carried out to confirm the molecular mechanisms conferring resistance.
Results
We identified 11 melioidosis cases where B. pseudomallei isolates developed decreased susceptibility toward meropenem during treatment, including 2 cases not treated with this antibiotic. Meropenem MICs increased from 0.5-0.75 µg/mL to 3-8 µg/mL. Comparative genomics identified multiple mutations affecting multidrug resistance-nodulation-division (RND) efflux pump regulators, with concomitant overexpression of their corresponding pumps. All cases were refractory to treatment despite aggressive, targeted therapy, and 2 were associated with a fatal outcome.
Conclusions
This study confirms the role of RND efflux pumps in decreased meropenem susceptibility in B. pseudomallei. These findings have important ramifications for the diagnosis, treatment, and management of life-threatening melioidosis cases.
In recent years, new human magnetic resonance imaging systems operating at static magnetic fields strengths of 7 Tesla or higher have become available, providing better signal sensitivity compared ...with lower field strengths. However, imaging human-sized objects at such high field strength and associated precession frequencies is limited due to the technical challenges associated with the wavelength effect, which substantially disturb the transmit field uniformity over the human body when conventional coils are used. Here we report a novel passive inductively-coupled radiofrequency resonator array design with a simple structure that works in conjunction with conventional coils and requires only to be tuned to the scanner's operating frequency. We show that inductive-coupling between the resonator array and the coil improves the transmit efficiency and signal sensitivity in the targeted region. The simple structure, flexibility, and cost-efficiency make the proposed array design an attractive approach for altering the transmit field distribution specially at high field systems, where the wavelength is comparable with the tissue size.
This study investigated how the VR experience (immersion and presence) and design features (narrative, guidance, and feedback) were related to participants’ engagement and perceptions of learning ...with a desktop Virtual Reality field trip (dVFT) in public outreach settings as used by environmental education centers. Data was collected from 139 participants at three different types of public outreach settings. The results found that immersion, presence, engagement, learning about local environment, VR design features, and affective learning were perceived favorably by the majority of the study’s participants. Design features, engagement, learning about the local environment, and affective learning were significantly lower for young participants (≤ 18 years old) compared to adults. Environmental education center festival participants had higher favorable mean responses for each subscale followed by Web location participants, followed by Homework Club participants. Results from the path analysis highlighted the importance of presence and the design features for engagement and perceived learning. Our findings support that learning about one’s local environment with a dVFT can have a positive impact on engagement and learning, particularly in public outreach learning environments.
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