Perforation of the Heart During Elective Removal of an Inferior Vena Cava Filter.

ABSTRACT: A common treatment for venous thromboembolic disease in patients with contraindications to anticoagulation includes placement of an inferior vena cava (IVC) filter. Temporary filters are available to avoid the risk of long-term permanent placement. A woman in her 60s with a history of uterine serous carcinoma presented to the emergency department with cardiac arrest following elective attempted IVC filter removal. Three months prior, a temporary filter was placed because anticoagulation medication was stopped in preparation for a hysterectomy. During the IVC retrieval procedure, which was performed using an intravascular approach from the right jugular vein, the filter was tilted, requiring the use of a different retrieval sheath. During catheter reentry, the patient complained of discomfort in the chest and neck, after which she became hypotensive, lost consciousness, and died. Autopsy revealed 2 cardiac perforations, one in each ventricle. Approximately 600 mL of liquid and clotted blood was within the tense pericardial sac. An IVC filter was found in place, with no adjacent hemorrhage.To our knowledge, this is the first reported fatality due to cardiac perforation by an access sheath during intravascular removal of an IVC filter. This instance also documents the time course of the cardiac perforations to the resultant loss of consciousness.

Electrocatalytic CO2 reduction to formate by a cobalt phosphino-thiolate complex.

Electrochemical conversion of CO2 to value-added products serves as an attractive method to store renewable energy as energy-dense fuels. Selectivity in this type of conversion can be limited, often leading to the formation of side products such as H2. The activity of a cobalt phosphino-thiolate complex ([Co(triphos)(bdt)]+) towards the selective reduction of CO2 to formate is explored in this report. In the presence of H2O, selective production of formate (as high as 94%) is observed at overpotentials of 750 mV, displaying negligible current degradation during long-term electrolysis experiments ranging as long as 24 hours. Chemical reduction studies of [Co(triphos)(bdt)]+ indicates deligation of the apical phosphine moiety is likely before catalysis. Computational and experimental results suggest a metal-hydride pathway, indicating an ECEC based mechanism.

Whole-Genome Sequencing-Based Confirmatory Methods on RT-qPCR Results for the Detection of Foodborne Viruses in Frozen Berries.

Accurate detection, identification, and subsequent confirmation of pathogens causing foodborne illness are essential for the prevention and investigation of foodborne outbreaks. This is particularly true when the causative agent is an enteric virus that has a very low infectious dose and is likely to be present at or near the limit of detection. In this study, whole-genome sequencing (WGS) was combined with either of two non-targeted pre-amplification methods (SPIA and SISPA) to investigate their utility as a confirmatory method for RT-qPCR positive results of foods contaminated with enteric viruses. Frozen berries (raspberries, strawberries, and blackberries) were chosen as the food matrix of interest due to their association with numerous outbreaks of foodborne illness. The hepatitis A virus (HAV) and human norovirus (HuNoV) were used as the contaminating agents. The non-targeted WGS strategy employed in this study could detect and confirm HuNoV and HAV at genomic copy numbers in the single digit range, and in a few cases, identified viruses present in samples that had been found negative by RT-qPCR analyses. However, some RT-qPCR-positive samples could not be confirmed using the WGS method, and in cases with very high Ct values, only a few viral reads and short sequences were recovered from the samples. WGS techniques show great potential for confirmation and identification of virally contaminated food items. The approaches described here should be further optimized for routine application to confirm the viral contamination in berries.

Modifiable Cardiometabolic Risk Factors in Survivors of Childhood Cancer: JACC: CardioOncology State-of-the-Art Review.

The growing community of childhood cancer survivors faces a heavy burden of late onset morbidities and mortality, with cardiovascular diseases being the leading noncancer cause. In addition to demographics and cancer treatment exposures, which cannot be altered, cardiometabolic risk factors (obesity, hypertension, diabetes, and dyslipidemia) and frailty potentiate the risk of morbidity and mortality associated with chronic health conditions. Important opportunities exist to target these risk factors and improve late health outcomes for survivors. Unfortunately, limited evidence exists on the optimal methods to prevent, screen, and treat cardiometabolic risk factors among survivors, resulting in significant underdiagnosis and undertreatment. In this review, we discuss the prevalence of, risk factors for, current survivor-specific recommendations, and gaps in knowledge to mitigate potentially modifiable cardiometabolic risk factors and frailty among survivors of childhood cancer.

A loss-of-function mutation in KCNJ11 causing sulfonylurea-sensitive diabetes in early adult life.

AIMS/HYPOTHESIS: The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life. METHODS: A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays. RESULTS: Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation. CONCLUSIONS/INTERPRETATION: Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes.

'I'm still here, I'm alive and breathing': The experience of Black Americans with long COVID.

AIMS AND OBJECTIVES: In this study, we aimed to characterize the impact of long COVID on quality of life and approaches to symptom management among Black American adults. BACKGROUND: As a novel condition, qualitative evidence concerning long COVID symptoms and their impact on quality of life can inform the refinement of diagnostic criteria and care plans. However, the underrepresentation of Black Americans in long COVID research is a barrier to achieving equitable care for all long COVID patients. DESIGN: We employed an interpretive description study design. METHODS: We recruited a convenience sample of 15 Black American adults with long COVID. We analysed the anonymized transcripts from race-concordant, semi-structured interviews using an inductive, thematic analysis approach. We followed the SRQR reporting guidelines. RESULTS: We identified four themes: (1) The impact of long COVID symptoms on personal identity and pre-existing conditions; (2) Self-management strategies for long COVID symptoms; (3) Social determinants of health and symptom management; and (4) Effects on interpersonal relationships. CONCLUSION: Findings demonstrate the comprehensive ramifications of long COVID on the lives of Black American adults. Results also articulate how pre-existing conditions, social risk factors, distrust due to systemic racism, and the nature of interpersonal relationships can complicate symptom management. RELEVANCE TO CLINICAL PRACTICE: Care approaches that support access to and implementation of integrative therapies may be best suited to meet the needs of long COVID patients. Clinicians should also prioritize eliminating patient exposure to discrimination, implicit bias, and microaggressions. This is of particular concern for long COVID patients who have symptoms that are difficult to objectively quantify, such as pain and fatigue. NO PATIENT OR PUBLIC CONTRIBUTION: While patient perspectives and experiences were the focus of this study, patients were not involved with the design or conduct of the study, data analysis or interpretation, or writing the manuscript.

A qualitative study on opportunities to improve research engagement and inclusion of Black adults with systemic lupus erythematosus.

In response to racial inequities in systemic lupus erythematosus (SLE), we aimed to identify practical recommendations for increasing engagement and inclusion of Black adults in SLE research. We used a qualitative, interpretive description approach and recruited 30 Black adults diagnosed with SLE in Michigan to participate in semi-structured interviews. Theme development focused on what factors influenced research perceptions and how research did not meet participant needs and expectations. We developed five main themes: (1) Ethical and equitable research. Participants shared how the impacts of past and present-day racism impacted their willingness to participate in research. (2) Trusting researchers to conduct studies and translate findings to health care. Participants had concerns related to researcher intentions and expressed the importance of communicating research outcomes to participants and translating findings to health care. (3) Drug trial beneficence. When considering drug trials, several people did not consider the potential benefits worth the risk of side effects, and some said they would need to consult with their doctor before agreeing to participate. (4) Altruism. Participants explained how the desire to help others was a motivating factor for participating in research and donating biological samples. (5) Research priorities. Participants described a need for better treatments that value their overall health and well-being. Findings indicate that researchers can center the perspectives of Black people with SLE across the research life cycle-beyond a focus on adequate racial diversity among study participants.

Comparing the structures and photophysical properties of two charge transfer co-crystals.

Organic co-crystals have emerged as a promising class of semiconductors for next-generation optoelectronic devices due to their unique photophysical properties. This paper presents a joint experimental-theoretical study comparing the crystal structure, spectroscopy, and electronic structure of two charge transfer co-crystals. Reported herein is a novel co-crystal Npe:TCNQ, formed from 4-(1-naphthylvinyl)pyridine (Npe) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) via molecular self-assembly. This work also presents a revised study of the co-crystal composed of Npe and 1,2,4,5-tetracyanobenzene (TCNB) molecules, Npe:TCNB, herein reported with a higher-symmetry (monoclinic) crystal structure than previously published. Npe:TCNB and Npe:TCNQ dimer clusters are used as theoretical model systems for the co-crystals; the geometries of the dimers are compared to geometries of the extended solids, which are computed with periodic boundary conditions density functional theory. UV-Vis absorption spectra of the dimers are computed with time-dependent density functional theory and compared to experimental UV-Vis diffuse reflectance spectra. Both Npe:TCNB and Npe:TCNQ are found to exhibit neutral character in the S0 state and ionic character in the S1 state. The high degree of charge transfer in the S1 state of both Npe:TCNB and Npe:TCNQ is rationalized by analyzing the changes in orbital localization associated with the S1 transitions.

Recommendations for Improving Systemic Lupus Erythematosus Care From Black Adults: A Qualitative Study.

Importance: Racial inequities in incidence, morbidity, and mortality are a defining feature of systemic lupus erythematosus (SLE). Health care systems are integral to addressing these inequities. However, qualitative evidence that highlights Black SLE care experiences is limited. Objective: To identify opportunities for improving SLE care based on the experiences and perspectives of Black adults with SLE. Design, Setting, and Participants: In this qualitative study, an interpretive description approach was used and data were analyzed using inductive thematic analysis. Semistructured interviews with Black adults in Michigan who were diagnosed with SLE were conducted. Interviews occurred from November 2, 2021, to July 19, 2022, and data analysis occurred from May 6, 2022, to April 12, 2023. Main Outcomes and Measures: Deidentified transcripts from the interviews were analyzed to develop themes that focused on opportunities to improve quality of care and symptom management. Results: The participants included 30 Black adults with SLE (97% women; mean age, 41 years; range, 18-65 years). Four main themes were identified: (1) awareness of SLE signs and symptoms before diagnosis (participants emphasized delays in diagnosis and how knowledge concerning SLE could be limited in their families and communities); (2) patient-clinician interactions (participants faced discrimination in health care settings and talked about the value of coordinated and supportive health care teams); (3) medication adherence and health effects (participants experienced a range of adverse effects from medications that treat SLE and described how monitoring medication use and efficacy could inform tailored care approaches); and (4) comprehensive care plans after diagnosis (participants reported persistent pain and other symptoms despite treatment). In the context of disease management, participants emphasized the importance of behavioral change and the negative impact of social risk factors. Conclusions and Relevance: The findings of this qualitative study suggest how limited information about SLE, experiences of racism, treatment regimens, and social risk factors may affect Black people with SLE. Future research should further engage and include Black communities within the context of treatment and intervention development to reduce racial inequities.

Transition of young adults with metabolic bone diseases to adult care.

As more accurate diagnostic tools and targeted therapies become increasingly available for pediatric metabolic bone diseases, affected children have a better prognosis and significantly longer lifespan. With this potential for fulfilling lives as adults comes the need for dedicated transition and intentional care of these patients as adults. Much work has gone into improving the transitions of medically fragile children into adulthood, encompassing endocrinologic conditions like type 1 diabetes mellitus and congenital adrenal hyperplasia. However, there are gaps in the literature regarding similar guidance concerning metabolic bone conditions. This article intends to provide a brief review of research and guidelines for transitions of care more generally, followed by a more detailed treatment of bone disorders specifically. Considerations for such transitions include final adult height, fertility, fetal risk, heritability, and access to appropriately identified specialists. A nutrient-dense diet, optimal mobility, and adequate vitamin D stores are protective factors for these conditions. Primary bone disorders include hypophosphatasia, X-linked hypophosphatemic rickets, and osteogenesis imperfecta. Metabolic bone disease can also develop secondarily as a sequela of such diverse exposures as hypogonadism, a history of eating disorder, and cancer treatment. This article synthesizes research by experts of these specific disorders to describe what is known in this field of transition medicine for metabolic bone diseases as well as unanswered questions. The long-term objective is to develop and implement strategies for successful transitions for all patients affected by these various conditions.

Social determinants of depression in systemic lupus erythematosus: A systematic scoping review.

Social determinants of health (SDOH) influence inequities in systemic lupus erythematosus (SLE). While these inequities contribute to overall disease experience, there is little consensus guiding our understanding of the psychological implications of SDOH in SLE. Given the paucity of evidence in this area, the aim of this scoping review was to systematically assess the volume and features of available research literature on associations of SDOH with depression in SLE over the past 20 years, from 1 January 2000 to 16 November 2021. We developed a search strategy for PubMed and EMBASE that included keywords for depression and lupus. After screening 2188 articles, we identified 22 original articles that met our inclusion criteria. At least one SDOH was associated with depression in two of the six studies with unadjusted estimates and 13 of the 16 studies with adjusted estimates. Results provide consistent but sparse evidence that SDOH are associated with depression in SLE. Additionally, depression epidemiology in SLE may differ from the general population such that depression risk is more similar across genders and racial/ethnic groups. More work is needed to identify the SDOH that have the greatest impact on depression and mental health among SLE patients, as well as how and when to intervene.

Preclinical development of ZED8, an 89Zr immuno-PET reagent for monitoring tumor CD8 status in patients undergoing cancer immunotherapy.

BACKGROUND: ZED8 is a novel monovalent antibody labeled with zirconium-89 for the molecular imaging of CD8. This work describes nonclinical studies performed in part to provide rationale for and to inform expectations in the early clinical development of ZED8, such as in the studies outlined in clinical trial registry NCT04029181 [1]. METHODS: Surface plasmon resonance, X-ray crystallography, and flow cytometry were used to characterize the ZED8-CD8 binding interaction, its specificity, and its impact on T cell function. Immuno-PET with ZED8 was assessed in huCD8+ tumor-bearing mice and in non-human primates. Plasma antibody levels were measured by ELISA to determine pharmacokinetic parameters, and OLINDA 1.0 was used to estimate radiation dosimetry from image-derived biodistribution data. RESULTS: ZED8 selectively binds to human CD8α at a binding site approximately 9 Å from that of MHCI making mutual interference unlikely. The equilibrium dissociation constant (KD) is 5 nM. ZED8 binds to cynomolgus CD8 with reduced affinity (66 nM) but it has no measurable affinity for rat or mouse CD8. In a series of lymphoma xenografts, ZED8 imaging was able to identify different CD8 levels concordant with flow cytometry. In cynomolgus monkeys with tool compound 89Zr-aCD8v17, lymph nodes were conspicuous by imaging 24 h post-injection, and the pharmacokinetics suggested a flat-fixed first-in-human dose of 4 mg per subject. The whole-body effective dose for an adult human was estimated to be 0.48 mSv/MBq, comparable to existing 89Zr immuno-PET reagents. CONCLUSION: 89Zr immuno-PET with ZED8 appears to be a promising biomarker of tissue CD8 levels suitable for clinical evaluation in cancer patients eligible for immunotherapy.

Satisfaction With Telehealth Among Patients With Irritable Bowel Syndrome During COVID-19: Cross-Sectional Survey Findings.

INTRODUCTION: Coronavirus disease 2019 rapidly shifted health care toward telehealth. We assessed satisfaction with and preferences for telehealth among patients with irritable bowel syndrome (IBS). METHODS: We conducted a cross-sectional survey in an integrated healthcare system in Southern California with members aged 18-90 years with an International Classification of Diseases 9 and 10 codes for IBS from office-based encounters between June 1, 2018, and June 1, 2020. Eligible patients were emailed a survey assessing telehealth satisfaction overall and by patient-related factors, IBS characteristics, health and technologic literacy, utilization, and coronavirus disease 2019 perceptions. We identified perceived telehealth benefits and challenges. Multivariable logistic regression identified predictors of telehealth dissatisfaction. RESULTS: Of 44,789 surveys sent, 5,832 (13.0%) patients responded and 1,632 (3.6%) had Rome IV IBS. Among 1,314 (22.5%) patients with IBS and prior telehealth use (mean age 52.6 years [17.4]; 84.9% female; and 59.4% non-Hispanic White, 29.0% Hispanic, and 5.6% non-Hispanic Black), 898 (68.3%) were satisfied, 130 (9.9%) were dissatisfied, and 286 (21.8%) felt neutral. In addition, 78.6% would use telehealth again. Independent predictors of telehealth dissatisfaction include social media use of once a week or less (adjusted odds ratio [OR] = 2.1; 1.3-3.5), duration of IBS for <1 year (adjusted OR = 8.2; 1.9-35.8), and willingness to travel 60 plus minutes for face-to-face visits (adjusted OR = 2.6; 1.4-3.7). Patients' main concern with telehealth was a lack of physical examination. DISCUSSION: Most of the patients with IBS are satisfied with telehealth. Shorter duration of IBS diagnosis, comfort with technology, and increased willingness to travel were associated with telehealth dissatisfaction. These predictors may help identify a target population for a focused IBS-telehealth program.

Opportunities to Improve Long COVID Care: Implications from Semi-structured Interviews with Black Patients.

BACKGROUND: Long coronavirus disease (COVID) is an emerging condition that could considerably burden healthcare systems. Prior qualitative studies characterize the experience of having long COVID, which is valuable for informing care strategies. However, evidence comes from predominantly White samples. This is a concern because underrepresentation of Black patients in research and intervention development contribute to racial inequities. OBJECTIVE: To facilitate racial equity in long COVID care, the purpose of this qualitative study was to inform the development of care strategies that are responsive to the experiences and perspectives of Black patients with long COVID in the United States of America. METHODS: Using convenience sampling, we conducted race-concordant, semi-structured, and open-ended interviews with Black adults (80% female, mean age = 39) who had long COVID. We transcribed and anonymized the recorded interviews. We analyzed the transcripts using inductive, thematic analysis. Theme development focused on who can help or hinder strategies for reducing health inequities, what should be done to change care policies or treatment strategies, and when are the critical timepoints for intervention. RESULTS: We developed four main themes. Participants reported challenges before and after COVID testing. Many participants contacted primary care physicians as a first step for long COVID treatment. However, not all respondents had positive experiences and at times felt dismissed. Without a qualifying diagnosis, participants could not obtain disability benefits, which negatively influenced their employment and increased financial hardship. CONCLUSIONS: There are possible targets for improving long COVID care, from COVID testing through to long-term treatment plans. There is a need to increase long COVID awareness among physicians. Diagnosis and a standardized treatment plan could help patients avoid unnecessary healthcare utilization and obtain comprehensive support.

Incentives for Uptake of and Adherence to Outpatient Stroke Rehabilitation Services: A 3-Arm Randomized Controlled Trial.

OBJECTIVE: To determine if rehabilitation uptake and adherence can be increased by providing coordinated transportation (increased convenience) and eliminating out-of-pocket costs (reduced expense). DESIGN: Three-arm randomized controlled trial. SETTING: Stroke units of 2 Singapore tertiary hospitals. PARTICIPANTS: Singaporeans or permanent residents 21 years or older who were diagnosed as having stroke and were discharged home with physician's recommendation to continue outpatient rehabilitation (N=266). INTERVENTIONS: A Transportation Incentives arm (T), which provides free transportation services, a Transportation & Sessions Incentives arm (T&S), offering free transportation and prescribed stroke rehabilitation sessions, and a control arm, Education (E), consisting of a stroke rehabilitation educational program. MAIN OUTCOME MEASURES: The primary study outcome was uptake of outpatient rehabilitation services (ORS) among patients poststroke and key predefined secondary outcomes being number of sessions attended and adherence to prescribed sessions. RESULTS: Uptake rate of ORS was 73.0% for E (confidence interval [CI], 63.8%-82.3%), 81.8% for T (CI, 73.8%-89.8%), and 84.3% for T&S (CI, 76.7%-91.8%). Differences of T and T&S vs E were not statistically significant (P=.22 and P=.10, respectively). However, average number of rehabilitation sessions attended were significantly higher in both intervention arms: 5.50±7.65 for T and 7.51±9.52 for T&S vs 3.26±4.22 for control arm (E) (T vs E: P=.017; T&S vs E: P<.001). Kaplan-Meier analysis indicated that persistence was higher for T&S compared with E (P=.029). CONCLUSIONS: This study has demonstrated a possibility in increasing the uptake of and persistence to stroke ORS with free transportation and sessions. Incentivizing survivors of stroke to take up ORS is a new strategy worthy of further exploration for future policy change in financing ORS or other long-term care services.

The gleam-glum effect: /i:/ versus /λ/ phonemes generically carry emotional valence.

The gleam-glum effect is a novel sound symbolic finding that words with the /i:/-phoneme (like gleam) are perceived more positive emotionally than matched words with the /Λ/-phoneme (like glum). We provide data that not only confirm the effect but also are consistent with an explanation that /i:/ and /Λ/ articulation tend to co-occur with activation of positive versus negative emotional facial musculature respectively. Three studies eliminate selection bias by including all applicable English words from the English Lexicon Project (Balota et al., 2007) and the Warriner et al. (2013) database and every possible Mandarin Pinyin combination that differ only in the middle phoneme (/i:/ vs /Λ/). In Study 1, 61 U.S. undergraduates rated monosyllabic English /i:/ words as robustly more positive than matched /Λ/ words. Study 2 analyzed the Warriner et al. (2013) valence ratings, extending the gleam-glum effect to all applicable words in the database. In Study 3, 38 U.S. participants (using English) and 37 participants in China (using Mandarin Pinyin) rated word pairs under three conditions that moderate musculature activity: Read aloud (Enhance), read silently (Control), and read silently while chewing gum (Interfere). Indeed, the effect was both replicated and was significantly larger when facial musculature was enhanced than when interfered with, and the two language populations did not significantly differ. These findings confirm a robust gleam-glum effect, despite semantic noise, in English and Mandarin Pinyin. Furthermore, these data are consistent with the hypothesis that this type of sound symbolism arises from the overlap in muscles used both in articulation and emotion expression. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Patient Endothelial Colony-Forming Cells to Model Coronary Artery Disease Susceptibility and Unravel the Role of Dysregulated Mitochondrial Redox Signalling.

Mechanisms involved in the individual susceptibility to atherosclerotic coronary artery disease (CAD) beyond traditional risk factors are poorly understood. Here, we describe the utility of cultured patient-derived endothelial colony-forming cells (ECFCs) in examining novel mechanisms of CAD susceptibility, particularly the role of dysregulated redox signalling. ECFCs were selectively cultured from peripheral blood mononuclear cells from 828 patients from the BioHEART-CT cohort, each with corresponding demographic, clinical and CT coronary angiographic imaging data. Spontaneous growth occurred in 178 (21.5%) patients and was more common in patients with hypertension (OR 1.45 (95% CI 1.03-2.02), p = 0.031), and less likely in patients with obesity (OR 0.62 [95% CI 0.40-0.95], p = 0.027) or obstructive CAD (stenosis > 50%) (OR 0.60 [95% CI 0.38-0.95], p = 0.027). ECFCs from patients with CAD had higher mitochondrial production of superoxide (O2--MitoSOX assay). The latter was strongly correlated with the severity of CAD as measured by either coronary artery calcium score (R2 = 0.46; p = 0.0051) or Gensini Score (R2 = 0.67; p = 0.0002). Patient-derived ECFCs were successfully cultured in 3D culture pulsatile mini-vessels. Patient-derived ECFCs can provide a novel resource for discovering mechanisms of CAD disease susceptibility, particularly in relation to mitochondrial redox signalling.

Evidence That the Etiology of Congenital Hypopituitarism Has a Major Genetic Component but Is Infrequently Monogenic.

PURPOSE: Congenital hypopituitarism usually occurs sporadically. In most patients, the etiology remains unknown. METHODS: We studied 13 children with sporadic congenital hypopituitarism. Children with non-endocrine, non-familial idiopathic short stature (NFSS) (n = 19) served as a control group. Exome sequencing was performed in probands and both unaffected parents. A burden testing approach was used to compare the number of candidate variants in the two groups. RESULTS: First, we assessed the frequency of rare, predicted-pathogenic variants in 42 genes previously reported to be associated with pituitary gland development. The average number of variants per individual was greater in probands with congenital hypopituitarism than those with NFSS (1.1 vs. 0.21, mean variants/proband, P = 0.03). The number of probands with at least 1 variant in a pituitary-associated gene was greater in congenital hypopituitarism than in NFSS (62% vs. 21%, P = 0.03). Second, we assessed the frequency of rare, predicted-pathogenic variants in the exome (to capture undiscovered causes) that were inherited in a fashion that could explain the sporadic occurrence of the proband's condition with a monogenic etiology (de novo mutation, autosomal recessive, or X-linked recessive) with complete penetrance. There were fewer monogenic candidates in the probands with congenital hypopituitarism than those with NFSS (1.3 vs. 2.5 candidate variants/proband, P = 0.024). We did not find any candidate variants (0 of 13 probands) in genes previously reported to explain the phenotype in congenital hypopituitarism, unlike NFSS (8 of 19 probands, P = 0.01). CONCLUSION: Our findings provide evidence that the etiology of sporadic congenital hypopituitarism has a major genetic component but may be infrequently monogenic with full penetrance, suggesting a more complex etiology.