Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy.

The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic T cell therapies remains a time- and cost-intensive endeavor. Current approaches to identify tumor-reactive TCRs analyze tumor mutations to predict T cell activating (neo)antigens and use these to either enrich tumor infiltrating lymphocyte (TIL) cultures or validate individual TCRs for transgenic autologous therapies. Here we combined high-throughput TCR cloning and reactivity validation to train predicTCR, a machine learning classifier that identifies individual tumor-reactive TILs in an antigen-agnostic manner based on single-TIL RNA sequencing. PredicTCR identifies tumor-reactive TCRs in TILs from diverse cancers better than previous gene set enrichment-based approaches, increasing specificity and sensitivity (geometric mean) from 0.38 to 0.74. By predicting tumor-reactive TCRs in a matter of days, TCR clonotypes can be prioritized to accelerate the manufacture of personalized T cell therapies.

A K(ATP) channel gene effect on sleep duration: from genome-wide association studies to function in Drosophila.

Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 × 10(-8)) in the ABCC9 gene that explains ≈5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3 h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism.

Down's syndrome, complete atrioventricular canal, and pulmonary vascular obstructive disease.

We reviewed our experience over a 10-year period to determine whether children with Down's syndrome and complete atrioventricular canal develop pulmonary vascular obstructive disease earlier than children with normal chromosomes and this defect. Comparisons were made between Down's syndrome and normal chromosome children regarding (1) pulmonary blood flow and pulmonary vascular resistance at initial catheterization, (2) operability as related to elevation in pulmonary vascular resistance, and (3) age at diagnosis of fixed pulmonary vascular obstructive disease. The 45 patients with Down's syndrome catheterized under 1 year of age had a lower mean pulmonary blood flow (3.2 versus 5.7; p = 0.0001) and higher mean pulmonary vascular resistance (8.3 versus 4.6 Wood units.m2; p = 0.0003) than their 34 normal chromosome counterparts. When all ages were included, 38 of 81 (47%) of the children with Down's syndrome and 32 of 40 (80%) of the normal children were considered operable. Non-Down's syndrome patients who had operations had a higher pulmonary blood flow (5.8 versus 3.3; p = 0.004) and lower pulmonary vascular resistance (3.6 versus 6.0 Wood units.m2; p = 0.005) than Down's syndrome patients. Of the 34 patients who did not have operations because of pulmonary vascular obstructive disease, 31 had Down's syndrome. In 10 of 81 children with Down's syndrome, fixed pulmonary vascular obstructive disease was diagnosed before the age of 1 year, while this was found in none of 40 normal children. Our data demonstrate that Down's syndrome patients with complete atrioventricular canal have a greater degree of elevation of pulmonary vascular resistance in the first year of life and more rapid progression to fixed pulmonary vascular obstructive disease than children with normal chromosomes.

GRATEFUL MED searching: a hospital library perspective.

The Health Sciences Information Center of Cedars-Sinai Medical Center implemented an end user search service utilizing NLM's GRATEFUL MED software. A librarian-taught seminar is required of all end users. The course's teaching strategies are described. A survey of users was conducted and results are shared.

Pacing in children and young adults with nonsurgical atrioventricular block: comparison of single-rate ventricular and dual-chamber modes.

A prospective comparison of physiologic response to single-rate ventricular and dual-chamber atrioventricular pacing was conducted in 14 pediatric patients (age 1 to 24 years, median 14) with symptomatic nonsurgical second- or third-degree atrioventricular block. All patients were studied acutely during cardiac catheterization before and after 1 hour of both pacing modes. Following pacemaker implant, eight patients were reevaluated after 1 month of each mode with symptom questionnaire, resting ECG, resting echocardiogram, and Doppler cardiac output measurement at rest and at peak treadmill exercise. Cardiac outputs (mean +/- standard error) increased acutely (n = 14) with both ventricular (32 +/- 12%) and dual-chamber (39 +/- 10%) pacing over intrinsic rhythm values (p less than 0.01 in both). During chronic pacing (n = 8), symptoms were reported only with the ventricular mode. Dual-chamber synchronous pacing was associated with improved mean resting shortening fraction and cardiac output, slower mean resting sinus rate (89 +/- 5 compared to 73 +/- 4 bpm (p less than 0.02), and a 23% increase in mean excerise cardiac output (4.2 +/- 0.4 compared to 3.4 +/- 0.3 L/min/m2) compared to single-rate ventricular pacing. Exercise-induced dysrhythmias occurred only with ventricular pacing. This study demonstrates that pediatric patients with nonsurgical atrioventricular block can compensate for loss of atrioventricular synchrony at rest but exhibit improved cardiac function with chronic dual-chamber atrioventricular compared to single-rate ventricular pacing.

Surgical and medical results of complete atrioventricular canal: a ten year review.

The files of 121 patients who presented to Children's Hospital of Michigan over the last 10 years with complete atrioventricular (AV) canal were reviewed to evaluate long-term management and overall outcome. Of 121 patients, 70 underwent corrective surgery, 21 (30%) of whom died perioperatively. The surgical mortality rate was 13% when patients with hypoplastic left or right ventricle (n = 6), double-orifice mitral valve or extreme deficiency of mitral tissue (n = 5), and pulmonary vascular obstructive disease (n = 5) were excluded. Of the 49 patients who survived operation, 36 are in New York Heart Association class I, 1 patient requires a pacemaker and 3 died late. In 34 of the 51 patients (28%) who did not undergo operation, pulmonary vascular obstructive disease developed; it occurred within 12 months in 10 patients (8%). Eight other patients who did not undergo operation died before planned surgery (age 1 to 9 months). Although surgical prognosis in good candidates is acceptable, the overall prognosis for children with complete AV canal is guarded because of the risk of early death or early pulmonary vascular obstructive disease and frequently unfavorable anatomy.

Myocardial dysfunction in hypothyroid children.

Eleven children with primary hypothyroidism were studied by echocardiography. Eight patients had pericardial effusion. Systolic time intervals (preejection period-ejection time ratio and left ventricular isovolumic contraction time) were suggestive of abnormal myocardial function. Asymmetric septal hypertrophy without left ventricular out-flow obstruction (ventricular septal-left ventricular posterior wall diastolic thickness ratio, greater than 1.3) was present in two hypothyroid children. After full replacement therapy, these cardiac abnormalities reversed to normal. Our data suggest that the myopericardial response to hypothyroidism in children is similar to that seen in adults.

Classic shunting operations for congenital cyanotic heart defects.

A total of 297 consecutive classic systemic artery-pulmonary artery shunts were performed in 281 patients over the past 9 years. This experience includes 200 Blalock-Taussig shunts (67.3%), 84 Waterston shunts (28.2%), and 13 Potts shunts (4.3%). The overall early mortality after the Blalock-Taussig shunt (5.5%) was significantly lower (p less than 0.02) than for the Waterston shunt (13%). The early mortality after either the Blalock-Taussig or Waterston shunt was not statistically related to the age of the patient at operation. Both the Blalock-Taussig and Waterston shunts demonstrated a higher mortality (p less than 0.02) among patients in Group II (complex defects) than in patients in Group I (tetralogy of Fallot and pulmonary atresia with ventricular septal defect [VSD]). However, the Blalock-Taussig shunt had a significantly lower (p less than 0.04) probability of early postoperative death than the Waterston shunt among patients with complex lesions. The Blalock-Taussig shunt also revealed a lower incidence of important late postoperative complications and did not affect adversely the hemodynamic result after intracardiac correction, as evidenced by late postoperative cardiac catheterization. This study also confirms the feasibility of the Blalock-Taussig shunt during the neonatal period without significantly increased age-related risk of postoperative death (p = 0.13) and with good early and late long-term patency rates.

Surgical treatment of cor triatriatum.

Six patients with cor triatriatum underwent surgical correction. They ranged for 1.5 to 93 months old (mean, 22 months). Congestive heart failure was present in 3 patients. Cardiomegaly and increased pulmonary vascularity were evident roentgenographically in all patients. Cardiac cineangiography demonstrated the subdividing left atrial membrane in 5 patients and suggested the correct diagnosis by revealing an abnormal configuration of the left atrium in the other patient. The opening in the anomalous left atrial membrane was stenotic in every instance. The proximal left atrial chamber communicated with the right atrium through an atrial septal defect in 5 patients and with the systemic venous circuit through a persistent left superior vena cava in the other patient, in whom the atrial septum was intact. A right atrial-transseptal approach provided ample exposure for complete excision of the obstructing membrane and repair of the atrial septum in all patients. One patient died of low cardiac output during the early postoperative period. The other 5 are alive and well at an average of 48 months after operation.

Searching the MEDLARS file for information on the elderly.

As the elderly population in the United States increases, the consequences for the health care system are significant. The Veterans Administration (VA) has created a Geriatric Research, Education, and Clinical Centers program to provide care, support research, and train practitioners in geriatric medicine. Through the participation of the Wadsworth VA Medical Center library in this program, methodologies have been developed for searching National Library of Medicine (NLM) data bases for information on the elderly. These methodologies are described; terms and definitions in geriatrics are explicated; sample search requests are explored; and on-line strategies are indicated. Review and comparison of NLM data bases, as they relate to geriatrics, are offered.

Results of total correction of tetralogy of Fallot with complete atrioventricular canal.

Four patients with tetralogy of Fallot (TF) and complete atrioventricular canal (CAVC) underwent successful intracardiac repair. All patients had undergone preliminary palliative shunts. Associated cardiovascular lesions included muscular ventricular septal defect (VSD) and left superior vena cava (one patient), bilateral main pulmonary artery stenosis (one patient), and right aortic arch (two patients). The diagnosis was suspected clinically by electrocardiographic evidence of right ventricular hypertrophy and left anterior hemiblock, by echocardiographic findings suggestive of CAVC with aortic dextroposition, and by the association with trisomy 21. The diagnosis was confirmed by cardiac catheterization and cineangiography. Total correction consisted of closure of the VSD and atrial septal defect (ASD), reconstruction of the atrioventricular valves, and relief of the right ventricular outflow tract obstruction (RVOTO). There were no early or late postoperative deaths. Surgically induced complete heart block did not occur. One patient underwent successful reoperation for residual VSD and right ventricular outflow aneurysm. Late hemodynamic evaluation revealed good results in all patients. We recommend a staged treatment plan consisting of preliminary systemic--pulmonary artery shunting for symptomatic children under 4 to 5 years of age and total correction for older children. With proper preoperative diagnosis and accurate intracardiac repair, good results may be obtained after total correction of TF and CAVC.

Results of the Mustard operation for dextro-transposition of the great arteries.

One hundred twenty patients with dextro-transposition of the great arteries (TGA) underwent intra-arterial baffle repair using thin Dacron fabric from 1971 to 1979. The ages of the patients ranging from 29 days to 17 years (mean age 28 months). Thirty-five patients had undergone 49 preliminary palliative operations. Early postoperative mortality was 4.8% for patients with simple TGA but was higher among patients with associated ventricular septal defect (26%), VSD and left ventricular outflow tract obstruction (28.5%) and intact ventricular septum with left ventricular outflow tract obstruction (12.5%). Early nonfatal postoperative complications included low cardiac output (23.3%), respiratory insufficiency (35.8%), junctional rhythm (34.1%), superior vena caval (SVC) obstruction (9.1%), and chylothorax (7.5%). Late postoperative mortality for all groups was 7.5% (nine patients). Late cardiac dysrhythmias occurred in 33 patients (40.7%). Normal sinus rhythm has been preserved in all patients since direct, high SVC cannulation was instituted. Late postoperative hemodynamic and angiographic evaluation in 61 patients revealed severe to total SVC obstruction in 12 patients (20.2%) and pulmonary venous obstruction in four patients (6.5%). Among the latter, two patients died following reoperation and another patient died without operation. SVC obstruction was clinically important in only three patients, two of whom have undergone successful reoperation. All other late survivors are acyanotic and clinically well. The Mustard operation has dramatically improved the survival rate and quality of life for patients with TGA. However, postoperative caval and pulmonary venous obstruction are problems which require additional technical modifications and stimulate the search for alternative corrective operations.

Early and late results of total correction of tetralogy of Fallot.

Two hundred and nine patients underwent total repair of tetralogy of Fallot without congenital pulmonary atresia from 1971 to 1979. The age of the patients ranged from 22 months to 27 years (mean 6.8 years). Previous palliative shunts were present in 130 patients (62.2%). The right ventricular outflow tract obstruction was relieved by infundibulectomy in 31 patients (14.8%), by transannular patching in 142 patients (67.9%), and by insertion of a right ventricular--to--pulmonary artery prosthetic conduit in 10 patients (4.7%) with associated coronary artery anomalies. A porcine valve was inserted after transannular patching only in patients with undersized pulmonary arteries, unilateral pulmonary artery, or congenitally absent pulmonary valve. There were 10 early postoperative deaths (4.7%). Previous palliative shunts did not adversely affect early postoperative mortality rate. Surgically induced permanent complete heart block occurred in one patient (0.4%). Six patients (3%) died in the late postoperative period, three of them of unrelated causes. Late results were good in 170 patients (87%), fair in 10 patients (5.1%), and poor in 15 patients (7.6%). Poor results were due to residual stenosis at the origin of the pulmonary arteries in 13 patients (6.5%) and to residual ventricular septal defect in two patients (1%). The mean cardiothoracic ratio was 0.61 for patients with poor results and 0.54 for the entire group. Pulmonary valvular insufficiency was well tolerated postoperatively in the absence of distal pulmonary artery obstruction. This experience supports a policy of aggressive relief of the right ventricular outflow tract obstruction including liberal use of transannular patching and, when indicated, extensive reconstruction of the pulmonary artery branches. We also recommend a two-stage treatment program for symptomatic infants with unfavorable anatomy consisting of initial Blalock-Taussig shunt followed by total repair at about 3 years of age.

Results of two-stage surgical treatment of tetralogy of Fallot.

One hundred nine consecutive patients underent 115 palliative shunts between 1971 and 1979 for the initial management of symptomatic tetralogy of Fallot. A single Blalock-Taussig shunt was done in 78 patients, including 38 infants below 12 months of age, with two deaths (2.5% mortality rate). Thirty-two patients underwent a Waterston shunt, with one death (3.1% mortality rate). The total early shunt mortality rate was 2.7% (three deaths among 109 patients). There was one later noncardiac death and one instance of nonfatal brain abscess between the two stages. Fifty-nine of the previously shunted patients have undergone total correction at a mean postshunt interval of 37.1 months, with one early postoperative death (1.6% mortality rate). The mean patient age at total repair was 4.8 years. The two-stage combined operative mortality rate was 3.6% (four deaths among 109 patients). The Waterston shunt is considered undesirable because it complicated the total repair and was associated with a high incidence of residual right pulmonary artery obstruction at postoperative cardiac catheterization. The Blalock-Taussig shunt had a low mortality rate, high long-term patency rate, absence of interval complications, and no adverse effect at the time of total correction. It is considered the shunt of choice in all symptomatic infants and small children with tetralogy of Fallot. Our experience suggests that, at the present time, the two-stage surgical approach compares favorably with primary total correction, especially in infants under 1 year of age.