In their own words: Perspectives of IPV survivors on obtaining support within the healthcare system.

BACKGROUND: Almost half of all women in the US experience intimate partner violence (IPV) in their lifetime. The US Preventive Services Task Force recommends IPV screening paired with intervention for women of reproductive age. We aim to understand clinical practices and policies that are beneficial, detrimental, or insufficient to support survivors of IPV in a safety-net healthcare system. METHODS: We sampled 45 women who were 18-64 years old, had experienced IPV within the prior year and were patients in the San Francisco Health Network. We conducted in-depth, semi-structured interviews to elicit their perspectives on disclosing IPV and obtaining support within the healthcare system. We analyzed our data using thematic analysis and grounded theory practices informed by ecological systems theory. FINDINGS: We identified four themes regarding factors that impeded or facilitated discussing and addressing IPV across interpersonal and systemic levels relating to relationship-building, respect, autonomy and resources. (1) Interpersonal barriers included insufficient attention to relationship-building, lack of respect or concern for survivor circumstances, and feeling pressured to disclose IPV or to comply with clinicians' recommended interventions. (2) Interpersonal facilitators consisted of patient-centered IPV inquiry, attentive listening, strength-based counseling and transparency regarding confidentiality. (3) Systemic barriers such as visit time limitations, clinician turn-over and feared loss of autonomy from involvement of governmental systems leading to separation from children or harm to partners, negatively affected interpersonal dynamics. (4) Systemic facilitators involved provision of resources through IPV universal education, on-site access to IPV services, and community partnerships. CONCLUSIONS: Women experiencing IPV in our study reported that relationship-building, respect, autonomy, and IPV-related resources were essential components to providing support, promoting safety, and enabling healing in the healthcare setting. Successful trauma-informed transformation of healthcare systems must optimize interpersonal and systemic factors that improve survivor wellbeing while eliminating barriers.

Association between primary Spanish language and quality of intrapartum care among Latina women: a secondary analysis of the Listening to Mothers in California survey.

BACKGROUND: Language barriers play significant roles in quality of healthcare. Limited studies have examined the relationships between Spanish language and quality of intrapartum care. The objective was to determine the association between primary Spanish language and quality of intrapartum care so as to further inform best practices for non-English speaking patients in the labor and delivery setting. METHODS: We used the 2016 Listening to Mothers in California survey data, which included a statewide representative sample of women who gave birth in hospitals. Our analytical sample included 1202 Latina women. Multivariable logistic regression was used to examine the association between primary language (monolingual English vs. monolingual Spanish vs. bilingual Spanish/English) and perceived discrimination due to language, perceived pressure for medical interventions, and mistreatment during labor, adjusting for maternal sociodemographics and other maternal and neonatal factors. RESULTS: Over one-third of the study population spoke English (35.6%), less than one-third spoke Spanish (29.1%), and greater than one-third spoke bilingual Spanish/English (35.3%). Overall, 5.4% of Latina women perceived discrimination due to language spoken, 23.1% perceived pressure for any medical intervention, and 10.1% experienced either form of mistreatment. Compared to English-speakers, Spanish-speakers were significantly more likely to report discrimination due to language (aOR 4.36; 95% CI 1.15-16.59), but were significantly less likely to experience pressure for certain medical interventions (labor induction or cesarean delivery) during labor (aOR 0.34; 95% CI 0.15-0.79 for induction; aOR 0.44; 95% CI 0.18-0.97 for cesarean delivery). Bilingual Spanish/English-speakers also significantly reported discrimination due to language to a lesser extent than monolingual Spanish-speakers (aOR 3.37; 95% CI 1.12-10.13). Any form of Spanish language (monolingual or bilingual) was not significantly associated with mistreatment. CONCLUSIONS: Spanish language may contribute to experiences of discrimination during intrapartum care among Latina women. Future research is needed to explore perceptions of pressure, discrimination and mistreatment, among patients with limited English proficiency.

Advocating for a New Residency Application Process: A Student Perspective.

OBJECTIVE: The COVID-19 pandemic provided an opportunity for surgical residency programs to rethink their methods of evaluating and recruiting candidates. However, the past year has not been seamless, with a soaring number of applications, reports of programs and applicants having difficulty evaluating each other, and an increasingly uneven distribution of interviews among applicants. Consequently, many have called for national changes to the residency application process to address these longstanding concerns. RESULTS: Here, we review the evolving literature and advocate for the permanent adoption of visiting rotations, virtual interviews with a universal release date and data-driven attendance limits, and opportunities for in-person applicant visits. CONCLUSIONS: We believe these changes leverage the strengths of each format, allow for satisfactory bidirectional evaluation, and promote principles of justice, equity, diversity, and inclusion.

Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing.

Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. SIGNIFICANCE: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945.

Knowledge Is Power: Benefits, Risks, Hopes, and Decision-Making Reported by Parents Consenting to Next-Generation Sequencing for Children and Adolescents with Cancer.

OBJECTIVES: To qualitatively describe parent perspectives of next-generation genomic sequencing (NGS) for their children with cancer, including perceived benefits, risks, hopes/expectations, and decision-making process when consenting or not consenting to NGS and prior to result disclosure. DATA SOURCES: Qualitative interviews were used. CONCLUSION: Altruism is an important factor in parents consenting to NGS testing, as well as making sense of their child's cancer and legacy building. Parents described realistic hopes and expectations associated with NGS participation. Although parents endorsed the likelihood of no medical benefit, those consenting to NGS felt there was no reason not to participate. Parents declining participation expressed avoidance of worry and parent guilt if a germline variant were to be disclosed. IMPLICATIONS FOR NURSING PRACTICE: As NGS evolves into a component of the routine diagnostic workup for pediatric cancer patients, genetic nurses play a role in conducting informed consent conversations and ensuring that patients and families have realistic hopes and expectations associated with NGS.

Creating a cancer genomics curriculum for pediatric hematology-oncology fellows: A national needs assessment.

BACKGROUND: With the advent of next generation sequencing, tumor and germline genomic testing are increasingly being used in the management of pediatric cancer patients. Despite this increase in testing, many pediatric hematology-oncology (PHO) providers are not confident interpreting or utilizing tumor or germline genomic results to care for their patients. METHODS: We developed and delivered a needs assessment survey to PHO program directors, attendings, and fellows in the United States to understand this deficiency, gather data on existing cancer genomics educational initiatives, and query preferences for creating a future curriculum. RESULTS: The survey includes 31 (41%) of 74 invited PHO program directors, 110 (11%) of 1032 invited attendings, and 79 fellows. The majority of attending physicians and fellows responding to the survey agree that understanding tumor (95% attending physicians; 95% fellows) and germline (86% attending physicians; 94% fellows) genomic information is essential for their practice. However, only 9 of 31 (29%) responding programs report that they have an existing cancer genomics curriculum. Most program directors indicated that the ideal genomics curriculum would occur during the first year of fellowship and incorporate direct patient care, online modules, and problem-based learning. Attending physicians and fellows identified that addressing indications for ordering tumor and germline genomic testing, counseling about the risks and benefits of such testing, and interpreting and individualizing clinical management based on tumor and germline results should be included in a future curriculum. CONCLUSION: The results of this study reveal a great need to develop a curriculum that can be offered across PHO fellowship programs to expand knowledge in the area of cancer genomics.

Amphotericin B Penetrates into the Central Nervous System Through Focal Disruption of the Blood Brain Barrier in Experimental Hematogenous Candida Meningoencephalitis.

Hematogenous Candida meningoencephalitis (HCME) is a life-threatening complication of neonates and immunocompromised children. Amphotericin B (AmB) shows poor permeability and low cerebrospinal fluid (CSF) concentrations, but is effective in treatment of HCME. In order to better understand the mechanism of CNS penetration of AmB, we hypothesized that AmB may achieve focally higher concentrations in infected CNS lesions. An in vitro BBB model was serially infected with C. albicans. Liposomal AmB (LAMB) or deoxycholate AmB (DAMB) at 5 µg/ml were then provided, vascular and CNS compartments were sampled 4h later. For in vivo correlation, rabbits with experimental HCME received a single dose of DAMB 1 mg/kg or LAMB 5 mg/kg, and were euthanized after 1, 3, 6 and 24h. Evans blue solution (2%) 2 ml/kg administered IV one hour prior to euthanasia stained infected regions of tissue but not histologically normal areas. AmB concentrations in stained and unstained tissue regions were measured using UPLC. For selected rabbits, MRI scans performed on days 1-7 postinoculation were acquired before and after IV bolus Gd-DTPA at 15min intervals through 2h post-injection. The greatest degree of penetration of DAMB and LAMB through the in vitro BBB occurred after 24h of exposure (P=0.0022). In vivo the concentrations of LAMB and DAMB in brain abscesses were 4.35±0.59 and 3.14±0.89-times higher vs. normal tissue (P≤0.019). MRI scans demonstrated that Gd-DTPA accumulated in infected areas with disrupted BBB. Localized BBB disruption in HCME allows high concentrations of AmB within infected tissues, despite the presence of low CSF concentrations.

Speaking genomics to parents offered germline testing for cancer predisposition: Use of a 2-visit consent model.

BACKGROUND: Patients with cancer are increasingly offered genomic sequencing, including germline testing for cancer predisposition or other disorders. Such testing is unfamiliar to patients and families, and clear communication is needed to introduce genomic concepts and convey risk and benefit information. METHODS: Parents of children with cancer were offered the opportunity to have their children's tumor and germline examined with clinical genomic sequencing. Families were introduced to the study with a 2-visit informed consent model. Baseline genetic knowledge and self-reported literacy/numeracy were collected before a study introduction visit, during which basic concepts related to genomic sequencing were discussed. Information was reinforced during a second visit, during which informed consent was obtained and a posttest was administered. RESULTS: As reflected by the percentage of correct answers on the pretest and posttest assessments, this model increased genetic knowledge by 11.1% (from 77.8% to 88.9%; P < .0001) in 121 parents participating in both the study introduction and consent visits. The percentage of parents correctly identifying the meaning of somatic and germline mutations increased significantly (from 18% to 59% [somatic] and from 31% to 64% [germline]; P < .0001). Nevertheless, these concepts remained unfamiliar to one-third of the parents. No relation was identified between the change in the overall percentage of correct answers and self-reported literacy, numeracy, or demographics. CONCLUSIONS: The use of a 2-visit communication model improved knowledge of concepts relevant to genomic sequencing, particularly differences between somatic and germline testing; however, these areas remained confusing to many participants, and reinforcement may be necessary to achieve complete understanding.

Identification of novel pathogenic variants and novel gene-phenotype correlations in Mexican subjects with microphthalmia and/or anophthalmia by next-generation sequencing.

Severe congenital eye malformations, particularly microphthalmia and anophthalmia, are one of the main causes of visual handicap worldwide. They can arise from multifactorial, chromosomal, or monogenic factors and can be associated with extensive clinical variability. Genetic analysis of individuals with these defects has allowed the recognition of dozens of genes whose mutations lead to disruption of normal ocular embryonic development. Recent application of next generation sequencing (NGS) techniques for genetic screening of patients with congenital eye defects has greatly improved the recognition of monogenic cases. In this study, we applied clinical exome NGS to a group of 14 Mexican patients (including 7 familial and 7 sporadic cases) with microphthalmia and/or anophthalmia. Causal or likely causal pathogenic variants were demonstrated in ~60% (8 out of 14 patients) individuals. Seven out of 8 different identified mutations occurred in well-known microphthalmia/anophthalmia genes (OTX2, VSX2, MFRP, VSX1) or in genes associated with syndromes that include ocular defects (CHD7, COL4A1) (including two instances of CHD7 pathogenic variants). A single pathogenic variant was identified in PIEZO2, a gene that was not previously associated with isolated ocular defects. NGS efficiently identified the genetic etiology of microphthalmia/anophthalmia in ~60% of cases included in this cohort, the first from Mexican origin analyzed to date. The molecular defects identified through clinical exome sequencing in this study expands the phenotypic spectra of CHD7-associated disorders and implicate PIEZO2 as a candidate gene for major eye developmental defects.

Parent-child communication surrounding genetic testing for Li-Fraumeni syndrome: Living under the cloud of cancer.

BACKGROUND: Advances in the application of genetic technologies reveal a growing number of heritable disorders associated with an increased risk to develop cancer during childhood. As genetic testing is increasingly employed in the clinical setting, it is essential to understand whether parents communicate with their children about test results and to elucidate the factors that influence the content and outcomes of these conversations. METHODS: Semistructured interviews were conducted with 14 parents whose children tested positive for Li-Fraumeni syndrome (LFS). Semantic content analysis was performed on transcribed interviews, focusing on questions related to parent-child conversations about the genetic testing process and disclosure of positive test results. RESULTS: All parents emphasized the importance of involving children in conversations about LFS. The majority (93%) identified as being part of "cancer families" in which prior experiences with cancer created opportunities for communication. While all had spoken with their children about cancer, only seven (50%) specifically disclosed to their children that they had tested positive for LFS. The most common reason cited for nondisclosure at the time of this study was the young age of the children. CONCLUSION: Parents of children with LFS desire open conversations about genetic testing and cancer risk. These conversations are challenging yet essential to enable child understanding of genetic risk status and enhance compliance with health-promoting and cancer surveillance measures. Development of age-appropriate educational materials and novel clinical models to facilitate parent-child conversations about genetic test results and risk status for cancer are needed.

Sclerocornea-Microphthalmia-Aphakia Complex: Description of Two Additional Cases Associated With Novel FOXE3 Mutations and Review of the Literature.

PURPOSE: To describe 2 sporadic Mexican patients having congenital bilateral, total sclerocornea, aphakia, and microphthalmia associated with novel mutations in the FOXE3 gene. METHODS: Two affected individuals with congenital bilateral, total sclerocornea, aphakia, and microphthalmia underwent detailed examinations including slit-lamp examination, visual acuity, and intraocular pressure measurements. Ocular ultrasonography and ultrasound biomicroscopy were performed. Genomic DNA was isolated from blood leukocytes in each subject, and molecular analysis of the FOXE3 gene was performed. For cosegregation analysis, presumable pathogenic variants were tested by Sanger sequencing in parental DNA. RESULTS: Molecular screening of FOXE3 was performed in 2 cases with congenital bilateral, total sclerocornea, aphakia, and microphthalmia. In patient 1, genetic analysis demonstrated a novel homozygous c.291C>G (p.Ile97Met) FOXE3 pathogenic variant. In patient 2, compound heterozygosity for the novel c.387C>G (p.Phe129Leu) transversion and for the previously reported c.244A>G (p.Met82Val) transition, was recognized. CONCLUSIONS: The sclerocornea-microphthalmia-aphakia complex is a severe malformative ocular phenotype resulting from mutations in the FOXE3 transcription factor. To date, patients from at least 14 families with this uncommon ocular disorder have been described. The identification of 2 novel pathogenic variants in our patients expands the mutational spectrum in FOXE3-related congenital eye disorders. In addition, we performed a review of the clinical and genotypic characteristics of all published patients carrying biallelic FOXE3 mutations.

Ethical considerations surrounding germline next-generation sequencing of children with cancer.

INTRODUCTION: The advent of next-generation sequencing (NGS) has introduced an exciting new era in biomedical research. NGS forms the foundation of current genetic testing approaches, including targeted gene panel testing, as well as more comprehensive whole-exome and whole-genome sequencing. Together, these approaches promise to provide critical insights into the understanding of health and disease. However, with NGS testing come many ethical questions and concerns, particularly when testing involves children. These concerns are especially relevant for children with cancer, where the testing of tumor and germline tissues is increasingly being incorporated into clinical care. Areas covered: In this manuscript, we explore the key ethical considerations related to conducting germline NGS testing in pediatric oncology, focusing on the four main principles of beneficence, non-maleficence, autonomy and justice. Expert commentary: The ethical issues surrounding germline NGS testing are complex and result in part from our limited understanding of the medical relevance of many of the results obtained and poor knowledge of the impacts of testing, both beneficial and detrimental, on patients and their families. In this article we discuss the risks and benefits of germline NGS testing and the arguments for and against such testing in children with cancer.

Should Genetic Testing be Offered for Children? The Perspectives of Adolescents and Emerging Adults in Families with Li-Fraumeni Syndrome.

Whether children should be offered genetic testing for cancer risk is much debated but young voices are rarely heard in these conversations. The current study explored perspectives of genetic testing held by adolescents and emerging adults in families with Li Fraumeni syndrome (LFS). Twelve 12- to 25-year-olds in families with LFS completed qualitative interviews for this study. All believed that testing should be offered for children but many qualified this statement saying parental approval would be needed and testing should be optional. Genetic testing was seen as way to learn of risk status, allow for disease prevention efforts, and reduce uncertainty and anxiety. Perceived disadvantages included negative emotions associated with the testing result. Participants generally felt that children should be involved in the testing decision, but that parents could unilaterally decide to have a child tested in certain circumstances (e.g., young age, high risk). All who were aware of having been tested and of their test result (n = 7; 4 positive) said testing had no negative impact on their outlook and they agreed with the decision to undergo testing. Implications of these findings for clinical practice and future research are discussed.

Integrating next-generation sequencing into pediatric oncology practice: An assessment of physician confidence and understanding of clinical genomics.

BACKGROUND: The incorporation of genomic testing to identify targetable somatic alterations and predisposing germline mutations into the clinical setting is becoming increasingly more common. Despite its potential usefulness, to the authors' knowledge physician confidence with regard to understanding and applying genomic testing remains unclear, particularly within the realm of pediatric oncology. METHODS: Before initiating an institutional feasibility study regarding the integration of clinical genomic testing, the authors surveyed pediatric oncologists regarding their confidence around understanding of genomic testing, perceived usefulness of test results, preferences around the disclosure of germline test results, and possible risks and benefits of testing. RESULTS: Among survey respondents (52 of 88 contacted; response rate of 59%), only a minority were confident in interpreting, using, and discussing somatic (35%) or germline (27%) genomic test results. Providers who were confident in interpreting somatic results were significantly more likely to anticipate using the results to plan the treatment of patients with relapsed or refractory cancers (P = .009). Similarly, providers who reported confidence in interpreting germline results were significantly more likely to discuss and use these results as part of clinical care (P<.0001). The majority of physicians (93%), regardless of their level of confidence, wanted to speak to a genetic counselor before disclosing germline test results. CONCLUSIONS: Among physicians at a comprehensive pediatric cancer center, confidence in the interpretation, use, and discussion of oncology-based genomic test results appears to be low, both in terms of somatic and germline testing. To optimize the integration of genomic sequencing into cancer care, methods must be developed to improve basic competencies around cancer-based genomic testing. Given the complexities surrounding variant interpretation and genotype-phenotype relationships, interdisciplinary collaborations are warranted. Cancer 2017;123:2352-2359. © 2017 American Cancer Society.

Li-Fraumeni syndrome: a paradigm for the understanding of hereditary cancer predisposition.

Li-Fraumeni syndrome (LFS) is a rare cancer predisposing condition caused by germline mutations in TP53, the gene encoding the TP53 transcription factor. LFS is typified by the development of a wide spectrum of childhood and adult-onset malignancies, which includes, among others, the lymphoid and myeloid leukaemias, myelodysplastic syndrome and, to a lesser extent, lymphoma. Accordingly, it is important that haematologists/oncologists be familiar with this pleiotropic hereditary cancer syndrome. The high cancer risk and variability in type and age of cancer onset have raised questions about the underlying biology and optimal treatment approaches for individuals with LFS. Since its description almost 50 years ago, many clinical and basic research investigations have provided insights into the pathogenesis, manifestations, genetic testing and management strategies for individuals with LFS. Here we provide an update on the current state of knowledge regarding LFS with an emphasis, where possible, on information relevant to practicing haematologists.

An Evaluation of the Ho'ouna Pono Curriculum: A Pilot Study of Culturally Grounded Substance Abuse Prevention for Rural Hawaiian Youth.

This pilot study evaluated the Ho'ouna Pono curriculum, which is a culturally grounded, school-based, drug prevention curriculum tailored to rural Native Hawaiian youth. The curriculum focuses on culturally relevant drug resistance skills training and is aligned with the State of Hawai'i academic standards. Six Hawai'i Island public middle/intermediate schools randomly assigned to intervention or treatment-as-usual comparison conditions (N = 213) were evaluated in this study. Paired sample t-tests separating intervention and comparison groups were conducted, as well as mixed models that adjusted for random effects (nesting) at the school level. Findings suggested that the curriculum was effective in maintaining youths' use of culturally relevant drug resistance skills, as well as decreasing girls' aggressive behaviors, at six-month follow-up. Unanticipated findings also suggested areas for curricular improvement, including more emphasis on normative drug education. Implications for future research and development of the curriculum are discussed.

Culturally Grounded Prevention for Minority Youth Populations: A Systematic Review of the Literature.

Contemporary prevention science has focused on the application of cultural adaptations of evidence-based prevention programs for minority youth populations. Far less is known about culturally grounded methods that are intended to organically develop prevention programs within specific populations and communities. This article systematically reviews recent literature on culturally grounded interventions used to prevent health disparities in ethnic minority youth populations. In this review, we assessed 31 peer-reviewed articles published in 2003 or later that fit inclusionary criteria pertaining to the development and evaluation of culturally grounded prevention programs. The evaluated studies indicated different approaches toward cultural grounding, as well as specific populations, geographic regions, and health issues that have been targeted. Specifically, the findings indicated that most of the studies focused on the development and evaluation of culturally grounded HIV/STI and substance abuse prevention programs for Mexican-American, African American, and American Indian/Alaska Native youth residing in the South or Southwestern US. These studies largely relied on community-based participatory or qualitative research methods to develop programs from the "ground up." This review has implications for the development of future culturally grounded and culturally adapted prevention programs targeting underserved minority youth populations and geographic regions. Specifically, it identifies populations and regions where culturally grounded prevention efforts are underdeveloped or non-existent, providing some scientific direction for the future development of these types of programs.

Gender differences in the use of drug resistance strategies: an analysis of rural Asian/Pacific Islander youth.

This study examines gender differences in the use of drug resistance strategies for rural Asian/Pacific Islander youth. Multiethnic Asian/Pacific Islander youth (N = 213) from six middle/intermediate schools on the Island of Hawai'i participated in the study, and gender differences in their real-world use of specific strategies (e.g., refuse, explain, avoid, leave) were examined. Despite similar levels of exposure to situations where drugs and/or alcohol were offered, girls indicated significantly lower usage of most of the resistance strategies compared to boys, suggesting girls' increased risk in dealing with drug-related problem situations. Implications for gender-and culture-specific health promotion and drug prevention curricula are discussed.