Illness Perception and the Impact of a Definitive Diagnosis on Women With Ischemia and No Obstructive Coronary Artery Disease: A Qualitative Study.

BACKGROUND: Ischemia and no obstructive coronary artery disease (INOCA) disproportionately impacts women, yet the underlying pathologies are often not distinguished, contributing to adverse health care experiences and poor quality of life. Coronary function testing at the time of invasive coronary angiography allows for improved diagnostic accuracy. Despite increased recognition of INOCA and expanding access to testing, data lack on first-person perspectives and the impact of receiving a diagnosis in women with INOCA. METHODS: From 2020 to 2021, we conducted structured telephone interviews with 2 groups of women with INOCA who underwent invasive coronary angiography (n=29) at Yale New Haven Hospital, New Haven, CT: 1 group underwent coronary function testing (n=20, of whom 18 received a mechanism-based diagnosis) and the other group who did not undergo coronary function testing (n=9). The interviews were analyzed using the constant comparison method by a multidisciplinary team. RESULTS: The mean age was 59.7 years, and 79% and 3% were non-Hispanic White and non-Hispanic Black, respectively. Through iterative coding, 4 themes emerged and were further separated into subthemes that highlight disease experience aspects to be addressed in patient care: (1) distress from symptoms of uncertain cause: symptom constellation, struggle for sensemaking, emotional toll, threat to personal and professional identity; (2) a long journey to reach a definitive diagnosis: self-advocacy and fortitude, healthcare interactions brought about further uncertainty and trauma, therapeutic alliance, sources of information; (3) establishing a diagnosis enabled a path forward: relief and validation, empowerment; and (4) commitment to promoting awareness and supporting other women: recognition of sex and racial/ethnic disparities, support for other women. CONCLUSIONS: Insights about how women experience the symptoms of INOCA and their interactions with clinicians and the healthcare system hold powerful lessons for more patient-centered care. A coronary function testing-informed diagnosis greatly influences the healthcare experiences, quality of life, and emotional states of women with INOCA.

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.

Strengthening Public Health Scholarship in Sudan: The Role of Leadership and Mentorship Development.

A robust public health workforce in Sudan is essential for accelerating progress toward the Sustainable Development Goals, and strengthening public health education is a priority for the Ministries of Health and Higher Education. Faculty at public health training institutions are a critical resource. Globally, development programs for junior to midlevel public health faculty have been well documented. However, most involved direct partnership between a university from the Global North and only one or two universities from the Global South, only one included an explicit focus on creation of a leadership network, and none were launched as fully virtual collaborations. Therefore, we conducted a mixed-method evaluation of the fully virtual Yale-Sudan Program for Research Leadership in Public Health. We used program records, participant feedback, competency assessment, and network analysis to evaluate 1) participant engagement, 2) change in skill, and 3) change in collaboration. The program achieved a 93% graduation rate. All participants would "definitely" recommend the program and described the live virtual sessions as engaging, effective, and accessible. We observed progress toward learning objectives and significant increases in 13 of 14 leadership and mentorship competency domains. Collaboration across Sudanese institutions increased, including an almost doubling in the number of pairs reporting scholarly collaboration. Eight authorship teams are actively working toward peer-reviewed publications. The program engaged scholars and policymakers from across Sudan and the Sudanese diaspora achieved high levels of co-creation and continues despite significant political unrest in the country, serving as a promising model for strengthening of public health education in Sudan.

Severe Phenotype in Patients with X-linked Hydrocephalus Caused by a Missense Mutation in L1CAM.

OBJECTIVE: The study aimed to show the clinical characteristics and prognosis of the L1 syndrome in patients with L1CAM mutations in the extracellular region. MATERIALS AND METHODS: Three affected boys and their siblings and parents from a large family were included in this study. Genetic etiology was investigated by whole-exome sequencing in the index patient. The pathogenic variant was detected by whole-exome sequencing and was validated by Sanger sequencing in 3 patients and other family members. RESULTS: We present 2 brothers and their cousin with prenatal onset hydrocephalus, severe developmental and speech delay, corpus callosum agenesis/hypogenesis, epilepsia, and adducted thumbs. A hemizygous missense mutation NM_024003 (c.A2351G:p.Y784C) on exon 18 of L1CAM gene was found in the 3 patients and their carrier mother. This missense mutation in the conserved region of the second fibronectin type III-like repeats located in the extracellular region of L1CAM resulted in the severe phenotype of X-linked inherited L1 syndrome in the patients. CONCLUSION: L1 syndrome should be considered in the differential diagnosis of male children with intellectual disability, hydrocephalus, and adducted thumbs. While truncating mutations of L1CAM may cause a more severe phenotype, missense mutations cause milder forms. However, pathogenic missense mutations affecting key amino acid residues lead to severe phenotype likely.

PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans.

Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA.

Strengthening the Mentorship and Leadership Capacity of HIV/AIDS and Tuberculosis Researchers in South Africa.

Programs to increase emerging and established HIV and tuberculosis (TB) researchers' capacity to be more effective leaders and mentors are urgently needed in low- and middle-income countries (LMICs). Although conceptual frameworks of mentoring and mentoring toolkits have been developed by and for researchers in LMIC settings, few mentor training programs have been implemented and evaluated in these settings. We created, implemented, and evaluated a 9-month, certificate-level mentorship training program to strengthen the pipeline of HIV and TB researchers in South Africa. Differentiating features of the program included careful contextualization of mentorship tools and approaches, inclusion of a leadership curriculum to improve participant ability to work effectively in teams and organizations, and attention to processes that promote interinstitutional collaboration in mentorship. Twelve mid-career researchers graduated from the first cohort of the program. Among participants, we observed significant longitudinal improvement in mentorship competencies, increased numbers of network connections in multiple domains of collaboration, and high levels of satisfaction. We anticipate that the program description and results will be useful to researchers, research institutions, and funders seeking to build research mentorship and leadership capacity in LMIC settings.

Novel compound heterozygous mutations in GPT2 linked to microcephaly, and intellectual developmental disability with or without spastic paraplegia.

We here describe novel compound heterozygous missense variants, NM_133443:c.[400C>T] and NM_133443:[1435G>A], in the glutamic-pyruvic transaminase 2 (GPT2) gene in a large consanguineous family with two affected siblings diagnosed with microcephaly intellectual disability and developmental delay (IDD). In addition to these clinical phenotypes, the male sibling has spastic paraplegia, and the female sibling has epilepsy. Their four extended family members have IDD and microcephaly. Both of these variants, c.400C>T (p.R134C) and c.1435G>A (p.V479M), reside in the pyridoxal phosphate-dependent aminotransferase domain. The missense variants affect highly conserved amino acids and are classified to be disease-causing by meta-SVM. The candidate variants were not found in the Exome Aggregation Consortium (ExAC) dataset or in dbSNP. Both GPT2 variants have an allele frequency of 0% (0/ ∼ 600) in the whole-exome sequenced Turkish cohort. Upon Sanger sequencing, we confirmed these mutations in all affected family members and showed that the index patient and his affected sister inherited one mutant allele from each unaffected parent. To the best of our knowledge, this is the first family in which a novel compound heterozygous variant in the GPT2 gene was identified.