The impact of clinical genome sequencing in a global population with suspected rare genetic disease.

There is mounting evidence of the value of clinical genome sequencing (cGS) in individuals with suspected rare genetic disease (RGD), but cGS performance and impact on clinical care in a diverse population drawn from both high-income countries (HICs) and low- and middle-income countries (LMICs) has not been investigated. The iHope program, a philanthropic cGS initiative, established a network of 24 clinical sites in eight countries through which it provided cGS to individuals with signs or symptoms of an RGD and constrained access to molecular testing. A total of 1,004 individuals (median age, 6.5 years; 53.5% male) with diverse ancestral backgrounds (51.8% non-majority European) were assessed from June 2016 to September 2021. The diagnostic yield of cGS was 41.4% (416/1,004), with individuals from LMIC sites 1.7 times more likely to receive a positive test result compared to HIC sites (LMIC 56.5% [195/345] vs. HIC 33.5% [221/659], OR 2.6, 95% CI 1.9-3.4, p < 0.0001). A change in diagnostic evaluation occurred in 76.9% (514/668) of individuals. Change of management, inclusive of specialty referrals, imaging and testing, therapeutic interventions, and palliative care, was reported in 41.4% (285/694) of individuals, which increased to 69.2% (480/694) when genetic counseling and avoidance of additional testing were also included. Individuals from LMIC sites were as likely as their HIC counterparts to experience a change in diagnostic evaluation (OR 6.1, 95% CI 1.1-∞, p = 0.05) and change of management (OR 0.9, 95% CI 0.5-1.3, p = 0.49). Increased access to genomic testing may support diagnostic equity and the reduction of global health care disparities.

Birth Care Gaps in the Childbirth Options, Information, and Person-Centered Explanation (CHOICEs) Measure.

PURPOSE: The objective of this study was to revise and improve the intrapartum items of the shared decision-making (SDM) measure, CH ildbirth O ptions, I nformation and person- C entered E xplanation (CHOICEs). STUDY DESIGN AND METHODS: Methodological sequential triangulation was used to select a purposive sample of 29 people who gave birth in the United States between August 2019 and June 2021. A qualitative descriptive approach was used to analyze and interpret the data. We used an interview guide with questions related to the nine intrapartum items in CHOICEs to address the question: How did decision-making occur during your most recent birth? RESULTS: Four major themes were identified: provider told me what to do ; communication about interventions during labor and birth ; preferences overlooked ; multiple team members . Under the theme of provider told me what to do , there was one sub-theme of induction of labor . CLINICAL IMPLICATIONS: Participants noted lack of shared decision-making, poor communication, and obstetric violence. We found the need for perinatal providers to improve communication with birthing people on topics such as fetal monitoring, induction of labor, and multiple team members who may participate in their care. Revisions of CHOICEs will include seven new items to further address birth preferences, feeling heard, and multiple team members.

Cross-Sectional Study of the Frequency and Severity of Traumatic Childbirth Events and How They Affect Maternity Care Clinicians.

OBJECTIVE: To describe the frequency and severity of traumatic childbirth events (TCEs) and how they affected the professional practice and personal lives of maternity care clinicians, including registered nurses (RNs), certified nurse-midwives, attending physicians, and resident physicians. DESIGN: Descriptive cross-sectional study. SETTING: Maternity units across five hospitals in the Baltimore metropolitan area. PARTICIPANTS: Maternity care clinicians (N = 160) including RNs (n = 104), certified nurse-midwives (n = 17), attending physicians (n = 28), and resident physicians (n = 11). METHODS: Participants completed an online survey to measure the frequency and severity of TCEs and how they affect participants' professional practice and personal lives. We used descriptive statistics to characterize maternity care clinicians and bivariate analysis and linear regression to examine relationships. RESULTS: Most participants were women (92.5%), White (62.5%), between the ages of 21 and 54 years (89.4%), RNs (65.0%), and employed full-time (79.2%). Shoulder dystocia was the most frequently observed TCE (90.6%), and maternal death was the most severe TCE (M = 4.82, SD = 0.54). Attending physicians (50.0%) reported a significantly greater frequency of exposure to TCEs than the other participants, χ2(6) = 23.8 (n = 159), p <. 001. The frequency of TCEs had a significant medium correlation with perceived effect on professional practice, r(154) = 0.415, p < .001, and personal life, r(155) = 0.386, p < .001. Perception of severity was strongly associated with professional practice, ß = 0.52, p < .001, and personal life, ß = 0.46, p < .001. CONCLUSION: If severe, TCE exposure can affect the professional practice and personal life of maternity care clinicians.

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial.

Importance: Whole-genome sequencing (WGS) shows promise as a first-line genetic test for acutely ill infants, but widespread adoption and implementation requires evidence of an effect on clinical management. Objective: To determine the effect of WGS on clinical management in a racially and ethnically diverse and geographically distributed population of acutely ill infants in the US. Design, Setting, and Participants: This randomized, time-delayed clinical trial enrolled participants from September 11, 2017, to April 30, 2019, with an observation period extending to July 2, 2019. The study was conducted at 5 US academic medical centers and affiliated children's hospitals. Participants included infants aged between 0 and 120 days who were admitted to an intensive care unit with a suspected genetic disease. Data were analyzed from January 14 to August 20, 2020. Interventions: Patients were randomized to receive clinical WGS results 15 days (early) or 60 days (delayed) after enrollment, with the observation period extending to 90 days. Usual care was continued throughout the study. Main Outcomes and Measures: The main outcome was the difference in the proportion of infants in the early and delayed groups who received a change of management (COM) 60 days after enrollment. Additional outcome measures included WGS diagnostic efficacy, within-group COM at 90 days, length of hospital stay, and mortality. Results: A total of 354 infants were randomized to the early (n = 176) or delayed (n = 178) arms. The mean participant age was 15 days (IQR, 7-32 days); 201 participants (56.8%) were boys; 19 (5.4%) were Asian; 47 (13.3%) were Black; 250 (70.6%) were White; and 38 (10.7%) were of other race. At 60 days, twice as many infants in the early group vs the delayed group received a COM (34 of 161 [21.1%; 95% CI, 15.1%-28.2%] vs 17 of 165 [10.3%; 95% CI, 6.1%-16.0%]; P = .009; odds ratio, 2.3; 95% CI, 1.22-4.32) and a molecular diagnosis (55 of 176 [31.0%; 95% CI, 24.5%-38.7%] vs 27 of 178 [15.0%; 95% CI, 10.2%-21.3%]; P < .001). At 90 days, the delayed group showed a doubling of COM (to 45 of 161 [28.0%; 95% CI, 21.2%-35.6%]) and diagnostic efficacy (to 56 of 178 [31.0%; 95% CI, 24.7%-38.8%]). The most frequent COMs across the observation window were subspecialty referrals (39 of 354; 11%), surgery or other invasive procedures (17 of 354; 4%), condition-specific medications (9 of 354; 2%), or other supportive alterations in medication (12 of 354; 3%). No differences in length of stay or survival were observed. Conclusions and Relevance: In this randomized clinical trial, for acutely ill infants in an intensive care unit, introduction of WGS was associated with a significant increase in focused clinical management compared with usual care. Access to first-line WGS may reduce health care disparities by enabling diagnostic equity. These data support WGS adoption and implementation in this population. Trail Registration: ClinicalTrials.gov Identifier: NCT03290469.

Health status of southern Arizona border counties: a Healthy Border 2010 midterm review.

OBJECTIVE: The region on the United States (US) side of the US-Mexico border consists of 44 counties in four states; populations on both sides of the border have similar health problems. Healthy Border 2010: An Agenda for Improving Health on the US-Mexico Border (HB 2010) is a binational agenda of health promotion and disease prevention for individuals in the region. This study reports on the health status of the four southern Arizona border counties. METHODS: Data on health indicators for Cochise, Pima, Santa Cruz, and Yuma Counties were collected from the Arizona Department of Health Services Vital Records and Statistics. Progress was calculated as a percentage made toward or away from the 2010 target. Comparisons were made between the border counties and Arizona. RESULTS: Progress toward the HB 2010 targets varied among the border counties. All border counties made progress toward the targets with the cervical cancer, hepatitis A, and teenage birthrate objectives. Most border counties moved toward the goals for breast cancer, diabetes mortality, tuberculosis, motor vehicle crashes, infant mortality from congenital abnormalities, and prenatal care. Border counties moved away from the target with the human immunodeficiency virus and infant mortality objectives. CONCLUSIONS: Assessment of the HB 2010 objectives provided a comprehensive description of the health status of the population. Although the southern Arizona border counties have shown improvement in some areas, monitoring is still needed to identify the disparities that remain.

Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.

Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the "diagnostic odyssey". Patients in resource-limited areas face even greater challenges-a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.

Twelve-month frequency of drug-metabolizing enzyme and transporter-based drug-drug interaction potential in patients receiving oral enzyme-targeted kinase inhibitor antineoplastic agents.

OBJECTIVE: To describe 12-month rates and patterns of coprescription of drugs that potentially create drug-drug interactions (DDIs) through shared metabolic or transport pathways for 9 enzyme-targeted kinase inhibitor oral antineoplastic drugs (OADs). PATIENTS AND METHODS: We used a deidentified pharmacy claims database identifying patients prescribed dasatinib, erlotinib, everolimus, imatinib, lapatinib, nilotinib, pazopanib, sorafenib, or sunitinib between January 1, 2008, and May 31, 2010. Coprescribing was 1 or more overlapping days of supply between the OAD and potential DDI drugs during the 12-month period beginning on the OAD index date. Product labels identified the cytochrome P450 metabolic enzymes used and whether P-glycoprotein was used by the OADs. Drugs that induce and/or inhibit these pathways were identified from the label and online resources. RESULTS: Sample sizes ranged from 96 (pazopanib group) to 4617 (imatinib group). Coprescribing rates with drugs that may decrease OAD effectiveness were 359/1546 (23%) (sunitinib group) to 1851/3263 (57%) (erlotinib group). Coprescribing rates with drugs that may increase OAD toxicity were 364/1546 (24%) (sunitinib group) to 71/96 (74%) (pazopanib group). Patients coprescribed DDI drugs had a median of 1 to 4 more medications present on the OAD index date than those not coprescribed a DDI drug. Most groups coprescribed DDI drugs had a median of 180 or more OAD days of supply during follow-up. The proportion of OAD days of supply with overlapping days of DDI drugs ranged from 7% to 85%. Generally, oncologists prescribed the OAD and nononcologists the DDI drug. CONCLUSION: Coprescription of drugs that induce or inhibit metabolic pathways used by enzyme-targeted kinase inhibitor OADs is high. The clinical consequences need further study.

High-risk HIV minorities in the United States: who gets tested and where?

OBJECTIVES: To assess characteristics of high-risk populations tested for HIV at particular testing sites. METHODS: BRFSS data (N=20,633) was used to quantify rates of HIV testing and identify specific racial/ethnic testing locations. RESULTS: Analysis determined associations existing among high-risk individuals based on demographics. Testing differences were identified in racial/ ethnic groups among those at high-risk in the United States. HIV testing was more likely among high-risk African Americans (OR=1.62), other races (OR=1.42), and multiracial participants (OR=1.89) than whites. CONCLUSIONS: Minorities were more likely to be tested at locations such as hospitals and clinics supporting the need for alternative testing locations.

Understanding the causal factors of obesity using the International Classification of Functioning, Disability and Health.

PURPOSE: Behavioural, personal, psychological, sociodemographic, environmental, biological and childbearing factors have been associated with obesity among women. This study quantitatively explored the effects of these factors on predicting body mass index (BMI) in U.S. women using the International Classification of Functioning, Disability and Health (ICF) and determined the effectiveness of using the ICF with population-level data. METHODS: We used the ICF Core Sets for Obesity, and data from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) in a sample of 8766 U.S. women to quantify the impact of all associated causal factors. Linear regression was used in the analyses. RESULTS: Body image perceptions (42%) was the most significant contributor, followed by hypertension (12%), general health condition (11%), diabetes/borderline diabetes (10%), arthritis (9%) and performing vigorous activity (9%). CONCLUSIONS: To decrease obesity prevalence rates in U.S. women, obesity prevention and treatment programmes should parallel the contributory effects of its most significant causal factors of psychological, biological and behavioural. In addition, more research and data are needed to explore the relationship between BMI in women and the multiple influencing factors by going beyond the more frequently available information of age, gender, race, education, income and parity.

Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L.

The antidepressant action of cannabis as well as the interaction between antidepressants and the endocannabinoid system has been reported. This study was conducted to assess the antidepressant-like activity of Delta(9)-THC and other cannabinoids. Cannabinoids were initially evaluated in the mouse tetrad assay to determine doses that do not induce hypothermia or catalepsy. The automated mouse forced swim (FST) and tail suspension (TST) tests were used to determine antidepressant action. At doses lacking hypothermic and cataleptic effects (1.25, 2.5, and 5 mg/kg, i.p.), both Delta(9)-THC and Delta(8)-THC showed a U-shaped dose response with only Delta(9)-THC showing significant antidepressant-like effects at 2.5 mg/kg (p<0.05) in the FST. The cannabinoids cannabigerol (CBG) and cannabinol (CBN) did not produce antidepressant-like actions up to 80 mg/kg in the mouse FST, while cannabichromene (CBC) and cannabidiol (CBD) exhibited significant effect at 20 and 200mg/kg, respectively (p<0.01). The antidepressant-like action of Delta(9)-THC and CBC was further confirmed in the TST. Delta(9)-THC exhibited the same U-shaped dose response with significant antidepressant-like action at 2.5 mg/kg (p<0.05) while CBC resulted in a significant dose-dependent decrease in immobility at 40 and 80 mg/kg doses (p<0.01). Results of this study show that Delta(9)-THC and other cannabinoids exert antidepressant-like actions, and thus may contribute to the overall mood-elevating properties of cannabis.

Health status of southern Arizona border counties: a Healthy Border 2010 midterm review / Situación de salud de los condados de la frontera sur de Arizona: examen a mitad de período del programa "Frontera saludable 2010"

OBJECTIVE: The region on the United States (US) side of the US-Mexico border consists of 44 counties in four states; populations on both sides of the border have similar health problems. Healthy Border 2010: An Agenda for Improving Health on the US-Mexico Border (HB 2010) is a binational agenda of health promotion and disease prevention for individuals in the region. This study reports on the health status of the four southern Arizona border counties. METHODS: Data on health indicators for Cochise, Pima, Santa Cruz, and Yuma Counties were collected from the Arizona Department of Health Services Vital Records and Statistics. Progress was calculated as a percentage made toward or away from the 2010 target. Comparisons were made between the border counties and Arizona. RESULTS: Progress toward the HB 2010 targets varied among the border counties. All border counties made progress toward the targets with the cervical cancer, hepatitis A, and teenage birthrate objectives. Most border counties moved toward the goals for breast cancer, diabetes mortality, tuberculosis, motor vehicle crashes, infant mortality from congenital abnormalities, and prenatal care. Border counties moved away from the target with the human immunodeficiency virus and infant mortality objectives. CONCLUSIONS: Assessment of the HB 2010 objectives provided a comprehensive description of the health status of the population. Although the southern Arizona border counties have shown improvement in some areas, monitoring is still needed to identify the disparities that remain.

OBJETIVO: La región estadounidense de la frontera entre México y los Estados Unidos consta de 48 condados distribuidos en cuatro estados, y las poblaciones que viven a uno y otro lado de la frontera tienen problemas de salud similares. El programa binacional "Frontera saludable 2010" está destinado a las poblaciones de la región y se propone mejorar la situación sanitaria en la frontera entre México y los Estados Unidos mediante actividades de promoción de la salud y prevención de enfermedades. Este estudio es un informe sobre la situación sanitaria de los cuatro condados de la frontera sur de Arizona. MÉTODOS. Los datos acerca de los indicadores de salud de los condados de Cochise, Pima, Santa Cruz y Yuma se obtuvieron del registro civil y estadísticas del Departamento de Servicios de Salud de Arizona. Se calculó el progreso mediante un porcentaje que refleja la cercanía o la lejanía del objetivo propuesto para el año 2010. Se compararon los datos correspondientes a los condados fronterizos con los del estado de Arizona. RESULTADOS: El progreso hacia los objetivos del programa "Frontera saludable 2010" no fue uniforme en los distintos condados fronterizos. Los cuatro condados lograron avances hacia los objetivos propuestos en materia de cáncer cervicouterino, hepatitis A y tasa de natalidad entre las adolescentes. La mayoría de los condados fronterizos están más próximos a cumplir con los objetivos en materia de cáncer de mama, mortalidad por diabetes, tuberculosis, colisiones de vehículos automotores, mortalidad infantil por anomalías congénitas y atención prenatal. Sin embargo, ninguno de los cuatro condados se está acercando al objetivo propuesto en cuanto al virus de la inmunodeficiencia humana y la mortalidad infantil. CONCLUSIONES: La evaluación de los objetivos del programa "Frontera saludable 2010" brindó una descripción integral de la situación de salud de la población. Aunque los condados de la frontera sur de Arizona han logrado avances en algunos aspectos, sigue siendo necesario mantener la vigilancia con el fin de detectar las disparidades aún presentes.