Leveraging CTSA hubs for rapid, large-scale, high-impact research: A case study during a global public health emergency.

As the COVID-19 pandemic took hold in the USA in early 2020, it became clear that knowledge of the prevalence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among asymptomatic individuals could inform public health policy decisions and provide insight into the impact of the infection on vulnerable populations. Two Clinical and Translational Science Award (CTSA) Hubs and the National Institutes of Health (NIH) set forth to conduct a national seroprevalence survey to assess the infection's rate of spread. This partnership was able to quickly design and launch the project by leveraging established research capacities, prior experiences in large-scale, multisite studies and a highly skilled workforce of CTSA hubs and unique experimental capabilities at the NIH to conduct a diverse prospective, longitudinal observational cohort of 11,382 participants who provided biospecimens and participant-reported health and behavior data. The study was completed in 16 months and benefitted from transdisciplinary teamwork, information technology innovations, multimodal communication strategies, and scientific partnership for rigor in design and analytic methods. The lessons learned by the rapid implementation and dissemination of this national study is valuable in guiding future multisite projects as well as preparation for other public health emergencies and pandemics.

Racial and ethnic differences in severe maternal morbidity among singleton stillbirth deliveries.

BACKGROUND: Despite growing evidence suggesting racial or ethnic disparities in the risk of severe maternal morbidity among live births, there is little research investigating potential differences in severe maternal morbidity risk among stillbirths across race and ethnicity. OBJECTIVE: This study aimed to compare the risk of severe maternal morbidity by race and ethnicity among patients with singleton stillbirth pregnancies. STUDY DESIGN: We used the California Linked Birth File database to perform a retrospective analysis of singleton stillbirth pregnancies delivered at 20 to 42 weeks' gestation between 2007 and 2011. The database contained information from fetal death certificates linked to maternal hospital discharge records. We defined severe maternal morbidity using the Centers for Disease Control and Prevention composite severe maternal morbidity indicator and compared rates of severe maternal morbidity across racial and ethnic groups. Multivariable regression analysis was used to examine how race and ethnicity were associated with severe maternal morbidity risk after accounting for the influence of patients' clinical risk factors, socioeconomic characteristics, and attributes of the delivery hospital. RESULTS: Of the 9198 patients with singleton stillbirths, 533 (5.8%) experienced severe maternal morbidity. Non-Hispanic Black patients had a significantly higher risk of severe maternal morbidity (10.6% vs 5.2% in non-Hispanic White patients, 5.2% in Hispanic patients, and 5.1% in patients with other race or ethnicity; P<.001). The higher risk of severe maternal morbidity among non-Hispanic Black patients persisted even after adjusting for patients' clinical, socioeconomic, and hospital characteristics (adjusted odds ratio for non-Hispanic Black vs non-Hispanic White patients, 1.74; 95% confidence interval, 1.21-2.50). Further analysis separating blood-transfusion and nontransfusion severe maternal morbidity showed a higher risk of blood transfusion in non-Hispanic Black patients, which remained significant after adjusting for patients' clinical, socioeconomic, and hospital characteristics (adjusted odds ratio for non-Hispanic Black vs non-Hispanic White patients, 1.64; 95% confidence interval, 1.11-2.43). However, the higher risk of nontransfusion severe maternal morbidity in non-Hispanic Black patients was no longer significant after adjusting for patients' clinical risk factors (adjusted odds ratio for non-Hispanic Black vs non-Hispanic White patients, 1.38; 95% confidence interval, 0.83-2.30). CONCLUSION: Severe maternal morbidity occurred in 5.8% of patients with a singleton stillbirth. Risk of severe maternal morbidity in stillbirth was higher in patients with non-Hispanic Black race, which was likely owing to a higher risk of hemorrhage, as evidenced by increased rate of blood transfusion.

Mode of Delivery in Antepartum Singleton Stillbirths and Associated Risk Factors.

OBJECTIVE: This study was aimed to investigate delivery management of patients with antepartum stillbirth. STUDY DESIGN: Using data from fetal death certificates and linked maternal hospital discharge records, we identified a population-based sample of patients with singleton antepartum stillbirth at 20 to 42 weeks of gestation in California in 2007 to 2011. Primary outcomes were intended mode of delivery and actual mode of delivery. We used multivariable regressions to examine the association between patient demographic, clinical, and hospital characteristics and their mode of delivery. Separate analysis was performed for patients who had prior cesarean delivery versus those who did not. RESULTS: Of 7,813 patients with singleton antepartum stillbirth, 1,356 had prior cesarean, while 6,457 had no prior cesarean. Labor was attempted in 51.8% of patients with prior cesarean and 93.7% of patients without prior cesarean, with 76.2 and 95.8% of these patients, respectively, delivered vaginally. Overall, 18.9% of patients underwent a cesarean delivery (60.5% among those with prior cesarean and 10.2% among those without prior cesarean). Multivariable regression analysis identified several factors associated with the risk of cesarean delivery that were not medically indicated. For instance, among patients without prior cesarean, malpresentation (of which the vast majority was breech presentation) was associated with an increased likelihood of planned cesarean (adjusted odds ratio [OR] = 3.26, 95% confidence interval [CI]: 2.53-4.22) and cesarean delivery after attempting labor (adjusted OR = 3.09, 95% CI: 2.25-4.25). For both patients with and without prior cesarean, delivery at an urban teaching hospital was associated with a lower likelihood of planned cesarean and a lower likelihood of cesarean delivery after attempting labor (adjusted ORs ranged from 0.28 to 0.56, p < 0.001 for all). CONCLUSION: Over one in six patients with antepartum stillbirth underwent cesarean delivery. Among patients who attempted labor, rate of vaginal delivery was generally high, suggesting a potential opportunity to increase vaginal delivery in this population. KEY POINTS: · In singleton antepartum stillbirths, 18.9% underwent cesarean delivery.. · Rate of vaginal delivery was high when labor was attempted.. · Both clinical and non-clinical factors were associated with risk of cesarean delivery..

Hydroquinidine Prevents Life-Threatening Arrhythmic Events in Patients With Short QT Syndrome.

BACKGROUND: Short QT syndrome (SQTS) is a rare and life-threatening arrhythmogenic syndrome characterized by abbreviated repolarization. Hydroquinidine (HQ) prolongs the QT interval in SQTS patients, although whether it reduces cardiac events is currently unknown. OBJECTIVES: This study investigated whether long-term treatment with HQ reduces the occurrence of life-threatening arrhythmic events (LAE) (cardiac arrest or sudden cardiac death) in SQTS patients. METHODS: In this cohort study on consecutive SQTS patients, 2 analyses were performed: 1) a matched-period analysis for the occurrence of LAE in 17 SQTS patients who received long-term HQ; and 2) a comparison of the annual incidence of LAE off- and on-HQ in 16 SQTS patients who survived a cardiac arrest. RESULTS: A total of 17 patients (82% male, age 29 ± 3 years, QTc before treatment 331 ± 3 ms) received HQ therapy (584 ± 53 mg/day). Therapy was stopped in 2 cases (12%) due to gastrointestinal intolerance, and 15 patients continued treatment for 6 ± 1 year. QTc prolongation was observed in all patients (by 60 ± 6 ms; p < 0.001). We compared the occurrence of LAE during 6 ± 1 years before and after HQ, observing that patients on HQ experienced a reduction in both the rate of LAE from 40% to 0% (p = 0.03) and the number of LAE per patient from 0.73 ± 0.3 to 0 (p = 0.026). Furthermore, the annual rate of LAE in the 16 patients with a previous cardiac arrest dropped from 12% before HQ to 0 on therapy (p = 0.028). CONCLUSIONS: We demonstrated for the first time that treatment with HQ was associated with a lower incidence of LAE in SQTS patients. These data point to the importance that quinidine, that in several countries has been removed from the market, remains available worldwide for patients with SQTS. In the present study, therapy with HQ has been proven to be safe, with a relatively low rate of side effects.

The new kids on the block of arrhythmogenic disorders: Short QT syndrome and early repolarization.

Short QT syndrome (SQTS) is one of the rarest inheritable cardiac channelopathies, characterized by an accelerated cardiac repolarization, which is also the substrate for the development of life-threatening ventricular arrhythmias. Up to this date, fewer than 200 SQTS cases have been reported in the literature worldwide. Patients with SQTS may experience a cardiac arrest as early as in the neonatal period or as late as 80 years old. The cumulative probability of experiencing a cardiac arrest by the fifth decade of life approaches 40%, highlighting the importance of early recognition and management. SQTS is an autosomal dominant disease with five identified causative genes, including three that encode for potassium channels (KCNH2, KCNQ1, and KCNJ2) and two that encode for subunits of the L-type calcium channels (CACNA1C and CACNB2). The term "early repolarization" (ER) has long been used to refer to a heterogeneous group of specific QRS-T junction patterns that are commonly found on the electrocardiograms of young healthy subjects. In the last decade, it has been suggested that in some individuals, the presence of ER may be associated with an increased risk of sudden cardiac death, and thus the term "early repolarization syndrome" (ERS) has progressively entered into use. Up to this point, however, whether ER constitutes a true primary arrhythmic disorder or whether it is simply a predisposing substrate that facilitates arrhythmias in the presence of other triggers remains an unresolved issue. In this review paper, we aim to integrate the current literature on SQTS and ERS. For each, we will describe the key steps that first led to the identification of the syndrome before moving into a discussion of our current understanding of each entity, including the epidemiology, genetics, diagnosis, clinical manifestations, and management.

Positional Right Ventricular Obstruction in Pectus Excavatum.

Pectus excavatum is one of the most common congenital chest wall deformities. The degree of sternal depression, which may result in compression of the right heart by the chest wall, is variable. While typically asymptomatic, there are various symptoms that can result from severe pectus excavatum. We report on a patient with severe pectus excavatum leading to dynamic obstruction of the right ventricular outflow tract in the seated position.

Is There a Role for Genetics in the Prevention of Sudden Cardiac Death?

The identification of patients at risk for sudden cardiac death (SCD) is fundamental for both acquired cardiovascular diseases (such as coronary artery diseases, CAD) and inherited arrhythmia syndromes (such as the long-QT syndrome, LQTS). Genetics may play a role in both situations, although the potential to exploit this information to reduce the burden of SCD varies among these two groups. Concerning acquired cardiovascular diseases, which affect most of the general population, preliminary data suggest an association between genetics and the risk of dying suddenly. The maximal utility, instead, is reached in inherited arrhythmia syndromes, where the discovery of monogenic diseases such as LQTS tracked the way for the first genotype-phenotype correlations. The aim of this review is to provide a general overview focusing on the current genetic knowledge and on the present and future applicability for prevention in these two populations at risk for SCD.

Glycolytic Enzymes Localize to Synapses under Energy Stress to Support Synaptic Function.

Changes in neuronal activity create local and transient changes in energy demands at synapses. Here we discover a metabolic compartment that forms in vivo near synapses to meet local energy demands and support synaptic function in Caenorhabditis elegans neurons. Under conditions of energy stress, glycolytic enzymes redistribute from a diffuse localization in the cytoplasm to a punctate localization adjacent to synapses. Glycolytic enzymes colocalize, suggesting the ad hoc formation of a glycolysis compartment, or a "glycolytic metabolon," that can maintain local levels of ATP. Local formation of the glycolytic metabolon is dependent on presynaptic scaffolding proteins, and disruption of the glycolytic metabolon blocks the synaptic vesicle cycle, impairs synaptic recovery, and affects locomotion. Our studies indicate that under energy stress conditions, energy demands in C. elegans synapses are met locally through the assembly of a glycolytic metabolon to sustain synaptic function and behavior. VIDEO ABSTRACT.

Clinical Challenges in Catecholaminergic Polymorphic Ventricular Tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inheritable cardiac disorder associated with exercise- and stress-induced sudden death in young individuals. Although important steps forward have been made in the comprehension and treatment of this disease, several aspects remain unclear. Firstly, from an epidemiological standpoint the actual prevalence of CPVT is still unknown and possibly underestimated. In addition, the diagnostic process remains very challenging and can be supported by genetic analysis in only about half of the cases. Finally, up to one third of CPVT patients continue to present complex arrhythmias despite beta blocker treatment; the role of newer therapeutic options, such as flecainide and left cardiac sympathetic denervation, needs to be further elucidated. All these points constitute challenges for the cardiologist in the management of CPVT patients and fuel research into new diagnostic, prognostic and therapeutic approaches.

Occupational therapists prefer combining multiple intervention approaches for children with learning difficulties.

BACKGROUND/AIM: Research to date has not fully explored how occupational therapists provide intervention for children with learning difficulties in their day-to-day practice. The purpose of this study was to provide an in-depth description of the approaches and techniques used and how they are applied and combined to meet the complex and multifaceted needs of these children. METHODS: In-depth interviews and short questionnaires were completed by seven occupational therapists who had provided intervention to children with learning difficulties. Observations of therapy sessions were also conducted. Thematic analysis gained insight into the approaches and techniques therapists used and how these were applied in practice. RESULTS: Therapists use a wide range of approaches in various combinations because they feel that these best meet the needs of individual children. Sensory-based and cognitive approaches were most frequently drawn from and combined with other approaches such as visual information analysis, biomechanical and psychosocial approaches added for particular purposes. Approaches were usually combined simultaneously within an activity or session. CONCLUSIONS: Therapists create their own 'multimodel' approach in order to best meet the needs of their clients. They are able to articulate the theoretical basis behind these choices, although lack of clarity exists about the frames of reference being used.

Factors influencing therapists' interventions for children with learning difficulties.

BACKGROUND: Occupational therapists use a range of intervention approaches with children with learning difficulties. PURPOSE: This study aimed to identify factors influencing therapists' clinical decisions when choosing and combining these interventions. METHODS: Seven occupational therapists participated. Data were collected through in-depth interviews, short questionnaires, and therapy observations and analysed thematically. FINDINGS: Therapists used a combination of child, therapist, and service-related factors to individually tailor a combination of intervention techniques drawn from different theoretical approaches. Therapists also used embedded practices with all children to engage and motivate them, promote task mastery, encourage application of strategies at home and school, and evolve intervention through ongoing evaluation. IMPLICATIONS: The child and family's home and school context and, to a lesser extent, the therapist's past experience and service context are primary factors considered when choosing interventions. Therapists continually move between theoretical and practical levels of thinking to best meet each child's needs.