Citations

Longitudinal trends demonstrate an increase in the prevalence of cardiovascular (CV) risk factors in the general population; however, the burden of CV risk factors or established disease in patients across WSPH groups remains unknown. Accordingly, we examined the prevalence of CV risk factors and established disease in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) cohort. PVDOMICS enrolled 1,097 subjects with pulmonary hypertension (PH) (mPA ≥ 25 mmHg) and at-risk disease comparators (mPa < 25 mmHg) from six US centers. Compared to participants with PH attributable to left heart disease (LHD-PH; WSPH Group 2, n=145) who are expected to have a high burden of CV risk factors and disease, patients with WSPH Groups 1,3,4,and 5 (non-LHD-PH)(n=618) were younger (56.2 ± 14.5 vs 67.7 ± 11.7 yrs, p<0.02) with no difference in %female or race. Non-LHD-PH had a lower prevalence of the CV disease risk factors hypertension (38.6% vs. 66.7%, p<0.02), diabetes mellitus (21.4 vs. 41.0%, p<0.02), and metabolic syndrome (30.8 vs. 48.4%, p<0.02) compared to LHD-PH, while smoking, hypercholesterolemia, and family history of CV disease were similar between groups. The prevalence of established CV disease, including myocardial infarction, CABG or stent, stroke, arrhythmia, or peripheral arterial disease was significantly lower in non-LHD-PH than in LHD-PH. At right heart catheterization, although mPA pressures were similar between the groups, PVR (5.5[3.3, 8.7] vs. 3.7[7.2, 5.7] WU, p<0.02), and cardiac output were higher (5.4 ± 1.9 vs. 4.9 ± 1.6 L/min, p<0.02) in non-LHD-PH compared to LHD-PH. This corresponded to a higher left ventricular ejection fraction by echo (62.2 ± 8.2 vs. 54.0 ± 14.0 %, p<0.02) and greater 6-minute walk distance (361.8 ± 134.7 vs. 294.7 ± 118.7 m, p<0.02). Non-LHD-PH also had better cardiovascular health compared to LHD-PH with higher modified American Heart Association Life’s Simple 7 scores (6.7 ± 1.6 vs. 5.8 ± 1.5, P<0.02). Taken together, these data demonstrate that CV disease risk factors and CV disease are frequent comorbidities that occur in patients with non-LHD-PH, although CV health is not as impaired as in patients with LHD-PH. How this affects PH-related outcomes remains to be determined.

Introduction: The magnitude of pericardial delayed hyperenhancement (DHE) by cardiac magnetic resonance imaging (CMR) illustrates the severity of inflammation in pericarditis. We report exploratory CMR data from an open-label Phase 2 study of rilonacept (IL-1α/IL-1β inhibitor) in recurrent pericarditis (RP). Methods: Patients (pts) with idiopathic RP or post-pericardiotomy syndrome (PPS) enrolled in the study. A subset had CMR at baseline (BL) and final visit (FV, 6 mo). Pain (NRS) and inflammation (CRP) were also collected. CMR images were graded (none, mild, moderate, or severe DHE) by a central core lab blinded to clinical data. Results: Of 25 study pts, 11 had CMR at BL and FV; 6 active idiopathic RP, and 5 corticosteroid (CS)-dependent non-active RP (4 idiopathic, 1 PPS). At BL, DHE was severe (3), moderate (2), and none (1) in active RP pts and moderate (1) or mild/none (4) in CS-dependent pts (Figure 1). At FV, DHE was improved (2), resolved (2; one pt example in Figure C/D), or unchanged (2) in active RP pts and was improved (1), resolved (1), unchanged (2) or worsened from none to mild (1) in CS-dependent pts. DHE improvements were associated with decreased pain and CRP and occurred despite discontinuation of CS or reduction in dose level. One pt with severe DHE at baseline and mild DHE at FV experienced a recurrence ~8 weeks after rilonacept discontinuation and enrolled a second time with severe DHE; the patient had reduced CRP and pain NRS during both enrollments and ended the second enrollment with moderate DHE. Conclusions: Serial CMR demonstrated improvement in pericardial DHE after 6 mo of rilonacept treatment, consistent with clinical improvement, while corticosteroids were tapered/discontinued. Recurrence in one pt with incompletely resolved DHE after 6 months of rilonacept treatment could indicate that a longer treatment duration is warranted in patients with unresolved DHE. These preliminary results may inform future CMR-guided treatment studies in RP.

Abstract: Sports ultrasound is commonly used by sports medicine physicians to enhance diagnostic and procedural accuracy. This expert consensus statement serves as an update to the 2015 American Medical Society for Sports Medicine recommended sports ultrasound curriculum for sports medicine fellowships. Although written in the context of the American sports medicine fellowship training model, we present a stepwise progression in both diagnostic and interventional sports ultrasound that may be applicable to the broader sports medicine community. The curriculum is divided into 12 units with each unit including didactic instructional sessions, practical hands-on instruction, independent scanning practice sessions, and mentored clinical experience. To assist with prioritization of learning, we have organized relevant pathology and procedures as essential, desirable, and optional. The expanded content can serve as an outline for continuing education postfellowship or for any physician to further advance their sports ultrasound knowledge and skill. We also provide updated scanning protocols, sample milestones, and a sample objective structured clinical examination (OSCE) to aid fellowships with implementation of the curriculum and ongoing assessment of fellow progress.

ABSTRACTBackgroundCurrently available structural variant (SV) detection methods do not span the complete spectrum of disease‐causing SVs. Optical genome mapping (OGM), an emerging technology with the potential to resolve diagnostic dilemmas, was performed to investigate clinically‐relevant SVs in a 4‐year‐old male with an epileptic encephalopathy of undiagnosed molecular origin.MethodsOGM was utilized to image long, megabase‐size DNA molecules, fluorescently labeled at specific sequence motifs throughout the genome with high sensitivity for detection of SVs greater than 500 bp in size. OGM results were confirmed in a CLIA‐certified laboratory via mate‐pair sequencing.ResultsOGM identified a mosaic, de novo 90 kb deletion and inversion on the X chromosome disrupting the CDKL5 gene. Detection of the mosaic deletion, which had been previously undetected by chromosomal microarray, an infantile epilepsy panel including exon‐level microarray for CDKL5, exome sequencing as well as genome sequencing, resulted in a diagnosis of X‐linked dominant early infantile epileptic encephalopathy‐2.ConclusionOGM affords an effective technology for the detection of SVs, especially those that are mosaic, since these remain difficult to detect with current NGS technologies and with conventional chromosomal microarrays. Further research in undiagnosed populations with OGM is warranted.

Critically ill patients with severe hypoxemia are often treated in the intensive care unit (ICU) with inhaled nitric oxide (iNO). These patients are at higher risk when they require intrahospital transportation. In this study, we collected clinical and laboratory data from 221 patients who were hospitalized in the general ICU and treated with iNO at Soroka Medical Center, Israel, between January 2010 and December 2019. We retrospectively compared the 65 patients who received iNO during intrahospital transportation to the 156 patients who received iNO without transportation. Among critically ill patients who were transported while being administered iNO, only one patient had an adverse event (atrial fibrillation) on transport. We found that maximal iNO dosage during ICU stay, duration of mechanical ventilation, and percent of vasopressor support were the only independent risk factors for ICU mortality in both study groups. No difference in primary outcome of ICU mortality rate was found between the critically ill patients treated with iNO during intrahospital transportation and those who were treated with iNO but not transported during the ICU stay. We anticipate that this study will advise clinical decision-making in the ICU, especially when treating patients who are administered iNO.

Abstract Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.

Newborn screening for congenital hypothyroidism remains challenging decades after broad implementation worldwide. Testing protocols are not uniform in terms of targets (TSH and/or T4) and protocols (parallel vs. sequential testing; one or two specimen collection times), and specificity (with or without collection of a second specimen) is overall poor. The purpose of this retrospective study is to investigate the potential impact of multivariate pattern recognition software (CLIR) to improve the post-analytical interpretation of screening results. Seven programs contributed reference data (N = 1,970,536) and two sets of true (TP, N = 1369 combined) and false (FP, N = 15,201) positive cases for validation and verification purposes, respectively. Data were adjusted for age at collection, birth weight, and location using polynomial regression models of the fifth degree to create three-dimensional regression surfaces. Customized Single Condition Tools and Dual Scatter Plots were created using CLIR to optimize the differential diagnosis between TP and FP cases in the validation set. Verification testing correctly identified 446/454 (98%) of the TP cases, and could have prevented 1931/5447 (35%) of the FP cases, with variable impact among locations (range 4% to 50%). CLIR tools either as made here or preferably standardized to the recommended uniform screening panel could improve performance of newborn screening for congenital hypothyroidism.

ObjectiveThis multilanguage study used simple speech recording and high‐end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α‐synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early‐stage Parkinson disease (PD).MethodsWe performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5–3.4 years), 149 with PD (mean duration of disease across language groups 1.7–2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12‐month follow‐up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria.ResultsNo differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12‐month follow‐up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups.InterpretationAutomated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62–75

AbstractBackgroundDiabetes is a risk factor for poor COVID‐19 outcomes, but pediatric patients with type 1 diabetes are poorly represented in current studies.MethodsT1D Exchange coordinated a US type 1 diabetes COVID‐19 registry. Forty‐six diabetes centers submitted pediatric cases for patients with laboratory confirmed COVID‐19. Associations between clinical factors and hospitalization were tested with Fisher's Exact Test. Logistic regression was used to calculate odds ratios for hospitalization.ResultsData from 266 patients with previously established type 1 diabetes aged <19 years with COVID‐19 were reported. Diabetic ketoacidosis (DKA) was the most common adverse outcome (n = 44, 72% of hospitalized patients). There were four hospitalizations for severe hypoglycemia, three hospitalizations requiring respiratory support (one of whom was intubated and mechanically ventilated), one case of multisystem inflammatory syndrome in children, and 10 patients who were hospitalized for reasons unrelated to COVID‐19 or diabetes. Hospitalized patients (n = 61) were more likely than nonhospitalized patients (n = 205) to have minority race/ethnicity (67% vs 39%, P < 0.001), public insurance (64% vs 41%, P < 0.001), higher A1c (11% [97 mmol/mol] vs 8.2% [66 mmol/mol], P < 0.001), and lower insulin pump and lower continuous glucose monitoring use (26% vs 54%, P < 0.001; 39% vs 75%, P < 0.001). Age and gender were not associated with risk of hospitalization. Higher A1c was significantly associated with hospitalization, with an odds ratio of 1.56 (1.34‐1.84) after adjusting for age, gender, insurance, and race/ethnicity.ConclusionsHigher A1c remained the only predictor for hospitalization with COVID‐19. Diabetic ketoacidosis is the primary concern among this group.