A consensus-based classification workflow to determine genetically inferred ancestry from comprehensive genomic profiling of patients with solid tumors.

Disparities in cancer diagnosis, treatment, and outcomes based on self-identified race and ethnicity (SIRE) are well documented, yet these variables have historically been excluded from clinical research. Without SIRE, genetic ancestry can be inferred using single-nucleotide polymorphisms (SNPs) detected from tumor DNA using comprehensive genomic profiling (CGP). However, factors inherent to CGP of tumor DNA increase the difficulty of identifying ancestry-informative SNPs, and current workflows for inferring genetic ancestry from CGP need improvements in key areas of the ancestry inference process. This study used genomic data from 4274 diverse reference subjects and CGP data from 491 patients with solid tumors and SIRE to develop and validate a workflow to obtain accurate genetically inferred ancestry (GIA) from CGP sequencing results. We use consensus-based classification to derive confident ancestral inferences from an expanded reference dataset covering eight world populations (African, Admixed American, Central Asian/Siberian, European, East Asian, Middle Eastern, Oceania, South Asian). Our GIA calls were highly concordant with SIRE (95%) and aligned well with reference populations of inferred ancestries. Further, our workflow could expand on SIRE by (i) detecting the ancestry of patients that usually lack appropriate racial categories, (ii) determining what patients have mixed ancestry, and (iii) resolving ancestries of patients in heterogeneous racial categories and who had missing SIRE. Accurate GIA provides needed information to enable ancestry-aware biomarker research, ensure the inclusion of underrepresented groups in clinical research, and increase the diverse representation of patient populations eligible for precision medicine therapies and trials.

Fetal Intraparenchymal Hemorrhage Imaging Patterns, Etiology, and Outcomes: A Single Center Cohort Study.

OBJECTIVE: This study examines associations among fetal brain magnetic resonance imaging (MRI) injury patterns, etiologies, and outcomes in fetal intraparenchymal hemorrhage (IPH). METHODS: This is a retrospective, single-center cohort study of IPH diagnosed on fetal MRI (1996-2022). IPH and associated abnormalities were categorized by 2 pediatric neuroradiologists; electronic medical records were reviewed by 2 pediatric neurologists to classify etiology and outcomes including cerebral palsy, epilepsy, developmental delay, and death. RESULTS: Forty-four fetuses with IPH were identified (34 singleton and 10 twin gestations) with MRI at median 24 weeks gestation (interquartile range [IQR] = 22-28 weeks). IPH was commonly supratentorial (84%) and focal (50%) or focal with diffuse injury (43%) and was often associated with germinal matrix hemorrhage (GMH; 75%) and/or intraventricular hemorrhage (IVH; 52%). An etiology was identified in 75%, including twin-twin transfusion syndrome (TTTS, n = 10), COL4A1/2 variants (n = 8), or other fetal/maternal conditions (n = 15). COL4A1/2 variants were associated with focal IPH and the presence of hemorrhagic porencephaly, and intrauterine transfusion was associated with infratentorial hemorrhage. Twenty-two fetuses were liveborn, and 18 pregnancies were terminated. Among those with follow-up ≥ 12 months (median = 7 years), 12 of 13 had cerebral palsy, 6 of 13 had developmental delay, and 5 of 13 had epilepsy. INTERPRETATION: An etiology for fetal IPH with or without GMH-IVH is identified in most cases in our cohort and is commonly TTTS, COL4A1/2 variants, or other maternal/fetal comorbidities. Pattern of fetal IPH on MRI is associated with etiology. Cerebral palsy and neurodevelopmental impairment were common in liveborn infants. Genetic studies should be considered in cases of fetal IPH without an otherwise apparent cause. ANN NEUROL 2024.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Multicenter Study of Long-Term Outcomes and Quality of Life in PHACE Syndrome after Age 10.

OBJECTIVE: To characterize long-term outcomes of PHACE syndrome. STUDY DESIGN: Multicenter study with cross-sectional interviews and chart review of individuals with definite PHACE syndrome ≥10 years of age. Data from charts were collected across multiple PHACE-related topics. Data not available in charts were collected from patients directly. Likert scales were used to assess the impact of specific findings. Patient-Reported Outcomes Measurement Information System (PROMIS) scales were used to assess quality of life domains. RESULTS: A total of 104/153 (68%) individuals contacted participated in the study at a median of 14 years of age (range 10-77 years). There were infantile hemangioma (IH) residua in 94.1%. Approximately one-half had received laser treatment for residual IH, and the majority (89.5%) of participants were satisfied or very satisfied with the appearance. Neurocognitive manifestations were common including headaches/migraines (72.1%), participant-reported learning differences (45.1%), and need for individualized education plans (39.4%). Cerebrovascular arteriopathy was present in 91.3%, with progression identified in 20/68 (29.4%) of those with available follow-up imaging reports. Among these, 6/68 (8.8%) developed moyamoya vasculopathy or progressive stenoocclusion, leading to isolated circulation at or above the level of the circle of Willis. Despite the prevalence of cerebrovascular arteriopathy, the proportion of those with ischemic stroke was low (2/104; 1.9%). PROMIS global health scores were lower than population norms by at least 1 SD. CONCLUSIONS: PHACE syndrome is associated with long-term, mild to severe morbidities including IH residua, headaches, learning differences, and progressive arteriopathy. Primary and specialty follow-up care is critical for PHACE patients into adulthood.

Cost-effectiveness analysis of endovascular vs surgical arteriovenous fistula creation in the United States.

OBJECTIVE: In the United States, an estimated $2.8 billion annually is spent on vascular access and its complications. Endovascular arteriovenous fistula (endoAVF) creation is a novel, minimally invasive alternative to traditional surgical AV fistula (sAVF) creation in ≤60% of patients. Although cost effective in single-payer systems, the clinical and financial impact of endoAVF in the United States remains uncertain. METHODS: We constructed a decision tree followed by a probabilistic cohort state-transition model to study the cost effectiveness of endoAVF vs sAVF creation. We conducted a systematic review to obtain input parameters including technical success, maturation, patency, and utility values. We derived costs from the Medicare 2022 fee schedule and from the literature. We used a 5-year time horizon, an annual discount rate of 3% for costs and utilities (measured in quality-adjusted life-years [QALYs]), and the common willingness-to-pay threshold of $50,000. One-way and Monte Carlo probabilistic sensitivity analyses were performed varying technical success, patency, reintervention, cost, and utility parameters. RESULTS: In the base-case scenario, endoAVF ($30,129 average per-person costs, 2.19 QALYs gained, 65% patent at 5 years) was not cost effective compared with sAVF ($12.987 average per-person costs, 2.11 QALYs gained, 66% patent at 5 years), generating an incremental cost-effectiveness ratio of $227,504 per QALY gained. In one-way sensitivity analyses, endoAVF becomes cost effective when the initial cost of sAVF creation exceeds endoAVF by ≥$600 (eg, if endoAVF creation costs ≤$3000 relative to the base-case sAVF cost of $3600), the additional QALYs gained from endoAVF exceeds 0.12 QALYs/year (eg, 0.81 QALYs gained/year from endoAVF compared with base-case sAVF 0.69 QALYs/year), the endoAVF maturation rate is >90% (base case 78%), or the sAVF maturation rate is <65% (base case 78%). Probabilistic sensitivity analysis demonstrated that sAVF remained the optimal strategy in 71% of iterations. CONCLUSIONS: EndoAVF is not cost effective compared with sAVF when modeling 5-year outcomes. The main driver of sAVF remaining cost effective is the four times higher up-front cost for endoAVF creation, as well as a relatively low additional increase in quality of life for endoAVF. It will be important to establish how the endoAVF learning curve contributes to upfront costs and, given the annual cost attributed to vascular access nationally, a randomized controlled trial is warranted.

Use of point-of-care haemoglobin tests to diagnose childhood anaemia in low- and middle-income countries: A systematic review.

OBJECTIVES: Anaemia is a major cause of mortality and transfusion in children in low- and middle-income countries (LMICs); however, current diagnostics are slow, costly and frequently unavailable. Point-of-care haemoglobin tests (POC(Hb)Ts) could improve patient outcomes and use of resources by providing rapid and affordable results. We systematically reviewed the literature to investigate what, where and how POC(Hb)Ts are being used by health facilities in LMICs to diagnose childhood anaemia, and to explore challenges to their use. METHODS: We searched a total of nine databases and trial registries up to 10 June 2022 using the concepts: anaemia, POC(Hb)T, LMIC and clinical setting. Adults ≥21 years and literature published >15 years ago were excluded. A single reviewer conducted screening, data extraction and quality assessment (of diagnostic studies) using QUADAS-2. Outcomes including POC(Hb)T used, location, setting, challenges and diagnostic accuracy were synthesised. RESULTS: Of 626 records screened, 41 studies were included. Evidence is available on the use of 15 POC(Hb)Ts in hospitals (n = 28, 68%), health centres (n = 9, 22%) and clinics/units (n = 10, 24%) across 16 LMICs. HemoCue (HemoCue AB, Ängelholm, Sweden) was the most used test (n = 31, 76%). Key challenges reported were overestimation of haemoglobin concentration, clinically unacceptable limits of agreement, errors/difficulty in sampling, environmental factors, cost, inter-observer variability and supply of consumables. Five POC(Hb)Ts (33%) could not detect haemoglobin levels below 4.5 g/dL. Diagnostic accuracy varied, with sensitivity and specificity to detect anaemia ranging from 24.2% to 92.2% and 70% to 96.7%, respectively. CONCLUSIONS: POC(Hb)Ts have been successfully utilised in health facilities in LMICs to diagnose childhood anaemia. However, limited evidence is available, and challenges exist that must be addressed before wider implementation. Further research is required to confirm accuracy, clinical benefits and cost-effectiveness.

Legume-supplemented feed for children hospitalised with severe malnutrition: a phase II trial.

Children hospitalised with severe malnutrition have high mortality and readmission rates post-discharge. Current milk-based formulations target restoring ponderal growth but not the modification of gut barrier integrity or microbiome which increases the risk of gram-negative sepsis and poor outcomes. We propose that legume-based feeds rich in fermentable carbohydrates will promote better gut health and improve overall outcomes. We conducted an open-label phase II trial at Mbale and Soroti Regional Referral Hospitals, Uganda, involving 160 children aged 6 months to 5 years with severe malnutrition (mid-upper arm circumference (MUAC) < 11·5 cm and/or nutritional oedema). Children were randomised to a lactose-free, chickpea-enriched legume paste feed (LF) (n 80) v. WHO standard F75/F100 feeds (n 80). Co-primary outcomes were change in MUAC and mortality to day 90. Secondary outcomes included weight gain (> 5 g/kg/d), de novo development of diarrhoea, time to diarrhoea and oedema resolution. Day 90 MUAC increase was marginally lower in LF v. WHO arm (1·1 cm (interquartile range (IQR) 1·1) v. 1·4 cm (IQR 1·40), P = 0·09); day 90 mortality was similar (11/80 (13·8 %) v. 12/80 (15 %), respectively, OR 0·91 (95 % CI 0·40, 2·07), P = 0·83). There were no differences in any of the other secondary outcomes. Owing to initial poor palatability of the LF, ten children switched to WHO feeds. Per-protocol analysis indicated a trend to lower day 90 mortality and readmission rates in the LF (6/60 (10 %) and 2/60(3 %)) v. WHO feeds (12/71(17·5 %) and 4/71(6 %)). Further refinement of LF and clinical trials are warranted, given the poor outcomes in children with severe malnutrition.

Association of inpatient and outpatient pediatric palliative care with healthcare utilization and end-of-life outcomes in pediatric oncology.

BACKGROUND: Pediatric palliative care (PPC) is associated with improved end-of-life (EOL) outcomes. Inpatient and outpatient PPC have unique roles during the disease course. Yet, it is unknown whether the location of PPC receipt (inpatient vs. outpatient) is associated with healthcare utilization and EOL outcomes for pediatric and adolescent and young adult oncology patients. PROCEDURE: A retrospective single-institution chart review of pediatric patients (age 0-28) with cancer who died between January 2015 and December 2022 was performed to compare EOL outcomes and healthcare utilization metrics among inpatient PPC, any outpatient PPC, and non-PPC recipients. Demographics and clinical factors were analyzed by PPC receipt location. RESULTS: Among 450 patients, 292 (64.9%) received PPC (inpatient only 35%, any outpatient 65%). Patients who died without receiving PPC dropped from 69% to 22% following development of an outpatient PPC clinic (p < .001). In the last 6 months, 1 month, and last week of life, inpatient PPC recipients spent more days admitted to the hospital and intensive care unit (all p < .001), and had more intensive medical interventions performed (p < .01). Outpatient PPC recipients were less likely to receive intravenous (IV) chemotherapy (p < .01) or intubation (p = .05), and more likely to receive hospice, die at home, and have an outpatient do-not-resuscitate order (all p < .001). CONCLUSIONS: PPC receipt substantially increased after the creation of an outpatient PPC clinic, suggesting that outpatient PPC is critical in the provision of PPC to children with cancer. Outpatient PPC was associated with fewer hospital days, IV chemotherapy, and intubation at EOL, while increasing hospice enrollment and home death.

Experimental competition induces immediate and lasting effects on the neurogenome in free-living female birds.

Periods of social instability can elicit adaptive phenotypic plasticity to promote success in future competition. However, the underlying molecular mechanisms have primarily been studied in captive and laboratory-reared animals, leaving uncertainty as to how natural competition among free-living animals affects gene activity. Here, we experimentally generated social competition among wild, cavity-nesting female birds (tree swallows, Tachycineta bicolor). After territorial settlement, we reduced the availability of key breeding resources (i.e., nest boxes), generating heightened competition; within 24 h we reversed the manipulation, causing aggressive interactions to subside. We sampled females during the peak of competition and 48 h after it ended, along with date-matched controls. We measured transcriptomic and epigenomic responses to competition in two socially relevant brain regions (hypothalamus and ventromedial telencephalon). Gene network analyses suggest that processes related to energy mobilization and aggression (e.g., dopamine synthesis) were up-regulated during competition, the latter of which persisted 2 d after competition had ended. Cellular maintenance processes were also down-regulated after competition. Competition additionally altered methylation patterns, particularly in pathways related to hormonal signaling, suggesting those genes were transcriptionally poised to respond to future competition. Thus, experimental competition among free-living animals shifts gene expression in ways that may facilitate the demands of competition at the expense of self-maintenance. Further, some of these effects persisted after competition ended, demonstrating the potential for epigenetic biological embedding of the social environment in ways that may prime individuals for success in future social instability.

Association of Frailty and the Expanded Operative Stress Score with Preoperative Acute Serious Conditions, Complications, and Mortality in Males Compared to Females: A Retrospective Observational Study.

OBJECTIVE: The aim of this study was to expand Operative Stress Score (OSS) increasing procedural coverage and assessing OSS and frailty association with Preoperative Acute Serious Conditions (PASC), complications and mortality in females versus males. SUMMARY BACKGROUND DATA: Veterans Affairs male-dominated study showed high mortality in frail veterans even after very low stress surgeries (OSS1). METHODS: Retrospective cohort using NSQIP data (2013-2019) merged with 180-day postoperative mortality from multiple hospitals to evaluate PASC, 30-day complications and 30-, 90-, and 180-day mortality. RESULTS: OSS expansion resulted in 98.2% case coverage versus 87.0% using the original. Of 82,269 patients (43.8% male), 7.9% were frail/very frail. Males had higher odds of PASC [adjusted odds ratio (aOR) = 1.31, 95% confidence interval (CI) = 1.21-1.41, P < 0.001] and severe/life-threatening Clavien-Dindo IV (CDIV) complications (aOR = 1.18, 95% CI = 1.09-1.28, P < 0.001). Although mortality rates were higher (all time-points, P < 0.001) in males versus females, mortality was similar after adjusting for frailty, OSS, and case status primarily due to increased male frailty scores. Additional adjustments for PASC and CDIV resulted in a lower odds of mortality in males (30-day, aOR = 0.81, 95% CI = 0.71-0.92, P = 0.002) that was most pronounced for males with PASC compared to females with PASC (30-day, aOR = 0.75, 95% CI = 0.56-0.99, P = 0.04). CONCLUSIONS: Similar to the male-dominated Veteran population, private sector, frail patients have high likelihood of postoperative mortality, even after low-stress surgeries. Preoperative frailty screening should be performed regardless of magnitude of the procedure. Despite males experiencing higher adjusted odds of PASC and CDIV complications, females with PASC had higher odds of mortality compared to males, suggesting differences in the aggressiveness of care provided to men and women.

Female sex is independently associated with reduced inpatient mortality after endovascular repair of blunt thoracic aortic injury.

BACKGROUND: Female sex has been associated with decreased mortality after blunt trauma, but whether sex influences the outcomes of thoracic endovascular aortic repair (TEVAR) for traumatic blunt thoracic aortic injury (BTAI) is unknown. METHODS: In this retrospective study of a prospectively maintained database, the Vascular Quality Initiative registry was queried from 2013 to 2020 for patients undergoing TEVAR for BTAI. Univariate Student's t-tests and χ2 tests were performed, followed by multivariate logistic regression for variables associated with inpatient mortality. RESULTS: Of 806 eligible patients, 211 (26.2%) were female. Female patients were older (47.9 vs 41.8 years, P < .0001) and less likely to smoke (38.3% vs 48.2%, P = .044). Most patients presented with grade III BTAI (54.5% female, 53.6% male), followed by grade IV (19.0% female, 19.5% male). Mean Injury Severity Scores (30.9 + 20.3 female, 30.5 + 18.8 male) and regional Abbreviated Injury Score did not vary by sex. Postoperatively, female patients were less likely to die as inpatients (3.8% vs 7.9%, P = .042) and to be discharged home (41.4% vs 52.2%, P = .008). On multivariate logistic regression, female sex (odds ratio [OR]: 0.05, P = .002) was associated with reduced inpatient mortality. Advanced age (OR: 1.06, P < .001), postoperative transfusion (OR: 1.05, P = .043), increased Injury Severity Score (OR: 1.03, P = .039), postoperative stroke (OR: 9.09, P = .016), postoperative myocardial infarction (OR: 9.9, P = .017), and left subclavian coverage (OR: 2.7, P = .029) were associated with inpatient death. CONCLUSIONS: Female sex is associated with lower odds of inpatient mortality after TEVAR for BTAI, independent of age, injury severity, BTAI grade, and postoperative complications. Further study of the influence of sex on postdischarge outcomes is needed.

Most privately insured patients do not receive federally recommended abdominal aortic aneurysm screening.

OBJECTIVE: Since 2005, the United States Preventative Services Task Force has recommended abdominal aortic aneurysm (AAA) ultrasound screening for 65- to 75-year-old male ever-smokers. Integrated health systems such as Kaiser Permanente and the Veterans Affairs (VA) health care system report 74% to 79% adherence, but compliance rates in the private sector are unknown. METHODS: The IBM Marketscan Commercial and Medicare Supplemental databases (2006-2017) were queried for male ever-smokers continuously enrolled from age 65 to 75 years. Exclusion criteria were previous history of AAA, connective tissue disorder, and aortic surgery. Patients with abdominal computed tomographic or magnetic resonance imaging from ages 65 to 75 years were also excluded. Screening was defined as a complete abdominal, retroperitoneal, or aortic ultrasound. A logistic mixed-effects model utilizing state as a random intercept was used to identify patient characteristics associated with screening. RESULTS: Of 35,154 eligible patients, 13,612 (38.7%) underwent screening. Compliance varied by state, ranging from 24.4% in Minnesota to 51.6% in Montana (P < .05). Screening activity increased yearly, with 0.7% of screening activity occurring in 2008 vs 22.2% in 2016 (P <.05). In a logistic mixed-effects model adjusting for state as a random intercept, history of hypertension (odds ratio [OR], 1.07; 95% confidence interval [CI], 1.03-1.13), coronary artery disease (OR, 1.17; 95% CI, 1.10-1.22), congestive heart failure (OR, 1.14; 95% CI, 1.01-1.22), diabetes (OR, 1.1; 95% CI, 1.06-1.16), and chronic kidney disease (OR, 1.4; 95% CI, 1.24-1.53) were associated with screening. Living outside of a census-designated metropolitan area was negatively associated with screening (OR, 0.92; 95% CI, 0.87-0.97). CONCLUSIONS: In a private claims database representing 250 million claimants, 38.7% of eligible patients received United States Preventative Services Task Force-recommended AAA screening. Compliance was nearly one-half that of integrated health systems and was significantly lower for patients living outside of metropolitan areas. Efforts to improve early detection of AAA should include targeting non-metropolitan areas and modifying Medicare reimbursement and incentivization strategies to improve guideline adherence.

Precocious Rupture of Abdominal Aortic Aneurysms Below Size Criteria for Repair: Risk Factors and Outcomes.

BACKGROUND: Practice guidelines recommend elective repair for abdominal aortic aneurysms (AAAs) ≥ 5.5 cm in men and ≥ 5 cm in women to prevent rupture; however, some rupture at smaller diameters. We identify risk factors for rupture AAA (rAAA) below this threshold and compare outcomes following rAAA repair above/below size criteria. METHODS: The Vascular Quality Initiative (2013-2019) was queried for patients undergoing repair for rAAA and stratified based on diameter into small and large cohorts [Small: < 5.5 cm (men), < 5.0 cm (women)]. Univariate analysis was performed, and Kaplan-Meier analysis compared overall survival, aneurysm-related mortality, and reintervention at 12 months. RESULTS: Five thousand one hundred sixty two rAAA were identified. Small rAAA patients [n = 588] were more likely to have hypertension (81.3% vs. 77.0%, P < 0.02), diabetes (18.2% vs. 14.9%, P < 0.04), and end-stage renal disease (2.9% vs. 0.9%, P < 0.01) and be on optimal medical therapy (32.1% vs. 26.8%, P < 0.01). Women were more likely to rupture at smaller diameters compared to men (P < 0.01). Small rAAA patients were more likely to undergo endovascular aortic repair (EVAR) (70.2% vs. 56.0%, P < 0.01) and had lower in-hospital mortality (17.7% vs. 27.7%, P < 0.01) and fewer perioperative complications across all categories. At 12 months, small rAAA patients had better overall survival, freedom from aneurysm-related mortality, and freedom from reintervention, largely driven by EVAR approach. CONCLUSIONS: More than 11% of patients presenting with ruptured AAA were below the recommended size threshold for repair, and they tended to be younger, non-White, and have hypertension, diabetes, and/or renal failure. Patients with small rAAA experienced lower in-hospital morbidity and mortality and improved 1-year survival, and EVAR was associated with better outcomes than open repair. However, women more frequently rupture at smaller diameters compared to men. Given contemporary elective outcomes for women, a randomized controlled trial for EVAR versus surveillance at a sex-specific size threshold is needed.

Simplifying Hospital Quality Comparisons for Vascular Surgery Using Center-Level Frailty Burden Rather Than Comorbidities.

BACKGROUND: Failure to rescue (FtR), or inpatient death following complication, is a publicly reported hospital quality measure. Previous work has demonstrated significant variation in the proportion of frail patients across hospitals. However, frailty is not incorporated into risk-adjustment algorithms for hospital quality comparisons and risk adjustment is made by comorbidity scores. Our aim was to assess the impact of frailty on FtR quality measurement and as a means of risk adjustment. METHODS: Patients undergoing open or endovascular aneurysm repair or lower extremity bypass in the Vascular Quality Initiative (VQI) at centers performing ≥ 25 vascular procedures annually (2003-2019) were included. Multivariable logistic regression evaluated in-hospital death using scaled hierarchical modeling clustering at the center level. Center FtR observed/expected ratios were compared with expected values adjusted for either standard comorbidity profiles or frailty as measured by the VQI Risk Analysis Index. Centers were divided into quartiles using VQI-linked American Hospital Association data to describe the hospital characteristics of centers whose ranks changed. RESULTS: A total of 63,143 patients (213 centers) were included; 1,630 patients (2.58%) were classified as FtR. After accounting for center-level variability, frailty was associated with FtR [scaled odds ratio 1.9 (1.8-2.0), P < 0.001]. The comorbidity-centric and frailty-based models performed similarly in predicting FtR with C-statistics of 0.85 (0.84-0.86) and 0.82 (0.82-0.84), respectively. Overall changes in ranking based on observed/expected ratios were not statistically significant (P = 0.48). High and low performing centers had similar ranking using comorbidity-centric and frailty-based methods; however, centers in the middle of the performance spectrum saw more variability in ranking alterations. Forty nine (23%) of hospitals improved their ranking by five or more positions when using frailty versus comorbidity risk adjustment. The centers in Quartile 4, those who performed the highest number of vascular procedures annually, experience on average a significant improvement in hospital ranking when frailty was used for risk adjustment, whereas centers performing the fewest number of vascular procedures and the lowest proportion of vascular surgery cases annually (Quartile 1) saw a significant worsening of ranking position (all P < 0.05). However, total number of surgical procedures annually, total hospital beds, for-profit status, and teaching hospital status were not significantly associated with changes in rank. CONCLUSIONS: A simple frailty-adjusted model has similar predictive abilities as a comorbidity-focused model for predicting a common quality metric that influences reimbursement. In addition to distilling the risk-adjustment algorithm to a few variables, frailty can be assessed preoperatively to develop quality improvement efforts for rescuing frail patients. Centers treating a greater proportion of frail patients and those who perform higher volumes of vascular surgery benefit from a risk adjustment strategy based on frailty.

Transfusion Volume for Children with Severe Anemia in Africa.

BACKGROUND: Severe anemia (hemoglobin level, <6 g per deciliter) is a leading cause of hospital admission and death in children in sub-Saharan Africa. The World Health Organization recommends transfusion of 20 ml of whole-blood equivalent per kilogram of body weight for anemia, regardless of hemoglobin level. METHODS: In this factorial, open-label trial, we randomly assigned Ugandan and Malawian children 2 months to 12 years of age with a hemoglobin level of less than 6 g per deciliter and severity features (e.g., respiratory distress or reduced consciousness) to receive immediate blood transfusion with 20 ml per kilogram or 30 ml per kilogram. Three other randomized analyses investigated immediate as compared with no immediate transfusion, the administration of postdischarge micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. The primary outcome was 28-day mortality. RESULTS: A total of 3196 eligible children (median age, 37 months; 2050 [64.1%] with malaria) were assigned to receive a transfusion of 30 ml per kilogram (1598 children) or 20 ml per kilogram (1598 children) and were followed for 180 days. A total of 1592 children (99.6%) in the higher-volume group and 1596 (99.9%) in the lower-volume group started transfusion (median, 1.2 hours after randomization). The mean (±SD) volume of total blood transfused per child was 475±385 ml and 353±348 ml, respectively; 197 children (12.3%) and 300 children (18.8%) in the respective groups received additional transfusions. Overall, 55 children (3.4%) in the higher-volume group and 72 (4.5%) in the lower-volume group died before 28 days (hazard ratio, 0.76; 95% confidence interval [CI], 0.54 to 1.08; P = 0.12 by log-rank test). This finding masked significant heterogeneity in 28-day mortality according to the presence or absence of fever (>37.5°C) at screening (P=0.001 after Sidak correction). Among the 1943 children (60.8%) without fever, mortality was lower with a transfusion volume of 30 ml per kilogram than with a volume of 20 ml per kilogram (hazard ratio, 0.43; 95% CI, 0.27 to 0.69). Among the 1253 children (39.2%) with fever, mortality was higher with 30 ml per kilogram than with 20 ml per kilogram (hazard ratio, 1.91; 95% CI, 1.04 to 3.49). There was no evidence of differences between the randomized groups in readmissions, serious adverse events, or hemoglobin recovery at 180 days. CONCLUSIONS: Overall mortality did not differ between the two transfusion strategies. (Funded by the Medical Research Council and Department for International Development, United Kingdom; TRACT Current Controlled Trials number, ISRCTN84086586.).

Immediate Transfusion in African Children with Uncomplicated Severe Anemia.

BACKGROUND: The World Health Organization recommends not performing transfusions in African children hospitalized for uncomplicated severe anemia (hemoglobin level of 4 to 6 g per deciliter and no signs of clinical severity). However, high mortality and readmission rates suggest that less restrictive transfusion strategies might improve outcomes. METHODS: In this factorial, open-label, randomized, controlled trial, we assigned Ugandan and Malawian children 2 months to 12 years of age with uncomplicated severe anemia to immediate transfusion with 20 ml or 30 ml of whole-blood equivalent per kilogram of body weight, as determined in a second simultaneous randomization, or no immediate transfusion (control group), in which transfusion with 20 ml of whole-blood equivalent per kilogram was triggered by new signs of clinical severity or a drop in hemoglobin to below 4 g per deciliter. The primary outcome was 28-day mortality. Three other randomizations investigated transfusion volume, postdischarge supplementation with micronutrients, and postdischarge prophylaxis with trimethoprim-sulfamethoxazole. RESULTS: A total of 1565 children (median age, 26 months) underwent randomization, with 778 assigned to the immediate-transfusion group and 787 to the control group; 984 children (62.9%) had malaria. The children were followed for 180 days, and 71 (4.5%) were lost to follow-up. During the primary hospitalization, transfusion was performed in all the children in the immediate-transfusion group and in 386 (49.0%) in the control group (median time to transfusion, 1.3 hours vs. 24.9 hours after randomization). The mean (±SD) total blood volume transfused per child was 314±228 ml in the immediate-transfusion group and 142±224 ml in the control group. Death had occurred by 28 days in 7 children (0.9%) in the immediate-transfusion group and in 13 (1.7%) in the control group (hazard ratio, 0.54; 95% confidence interval [CI], 0.22 to 1.36; P = 0.19) and by 180 days in 35 (4.5%) and 47 (6.0%), respectively (hazard ratio, 0.75; 95% CI, 0.48 to 1.15), without evidence of interaction with other randomizations (P>0.20) or evidence of between-group differences in readmissions, serious adverse events, or hemoglobin recovery at 180 days. The mean length of hospital stay was 0.9 days longer in the control group. CONCLUSIONS: There was no evidence of differences in clinical outcomes over 6 months between the children who received immediate transfusion and those who did not. The triggered-transfusion strategy in the control group resulted in lower blood use; however, the length of hospital stay was longer, and this strategy required clinical and hemoglobin monitoring. (Funded by the Medical Research Council and Department for International Development; TRACT Current Controlled Trials number, ISRCTN84086586.).

Trends in annual open abdominal aortic surgical volumes for vascular trainees compared with annual national volumes in the endovascular era.

OBJECTIVE: A prior analysis predicted a shortfall in open abdominal aortic repair (OAR) experience for vascular trainees resulting from the rapid adoption, and increased anatomic suitability, of endovascular aortic aneurysm repair (EVAR) technology. We explored how EVAR has transformed contemporary open aortic surgical education for vascular trainees. METHODS: We examined the Accreditation Council for Graduate Medical Education case volumes of open abdominal aortic aneurysm (AAA) repair and reconstruction for aortoiliac occlusive disease via aortoiliac or femoral bypass (AFB) from integrated vascular surgery residents (VSRs) and fellows (VSFs) graduating from 2006 to 2017 and compared them to the national estimates of total OAR (open AAA repair plus AFB) in the Agency for Healthcare Research and Quality National Inpatient Sample using the International Classification of Diseases, 9th and 10th revision, procedural codes. Changes over time were assessed using the χ2 test, Student's t test, and linear regression. RESULTS: During the 12-year study period, the national annual total OAR and open AAA repair estimates had decreased: total OAR by 72.5% (estimate ± standard error: 2006, 24,255 ± 1185; vs 2017, 6690 ± 274; P < .001) and open AAA repair by 84.7% (estimate ± standard error: 2006, 18,619 ± 924; vs 2017, 2850 ± 168; P < .001). The AFB estimates had decreased by 33.0% (P < .001). The percentage of total OAR, open AAA repair, and AFB performed at teaching hospitals had significantly increased, from ∼55% to 80% (P < .001 for all). A 40.9% decrease was found for open AAA repairs performed by graduating VSFs (mean, 18.6 vs 11) but only a 6.9% decrease in total OAR cases (mean, 27.6 vs 25.7) owing to increasing AFB volumes (mean, 9.0 vs 14.7). The VSR graduates had consistently logged an average of ∼10 open AAA repairs, with a 31.0% increase in total OARs (mean, 23.2 vs 30.4), again secondary to increasing AFB volumes (mean, 11.4 vs 17.5). Although an absolute decrease was found in open aortic experience for VSFs, the rate of decline for the total OAR case volumes was not significantly different after VSR programs had been established (P = .40). CONCLUSIONS: As the incidence has decreased nationally, the use of OAR has been shifting toward teaching hospitals. Although open AAA procedures for trainees have been declining with the increased use of EVAR, open aortic reconstruction for aortoiliac occlusive disease has been increasing, playing an important role in ensuring that vascular trainees continue to have satisfactory OAR experience sufficient for meeting minimum graduation requirements. Strategies to maintain and maximize the education and experience from these cases should be the top priority for vascular surgery program directors.

CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

Author Correction: CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Outcomes reported in trials of treatments for severe malaria: The need for a core outcome set.

OBJECTIVES: Malaria is one of the most important parasitic infectious diseases worldwide. Despite the scale-up of effective antimalarials, mortality rates from severe malaria (SM) remain significantly high; thus, numerous trials are investigating both antimalarials and adjunctive therapy. This review aimed to summarise all the outcome measures used in trials in the last 10 years to see the need for a core outcome set. METHODS: A systematic review was undertaken to summarise outcomes of individually randomised trials assessing treatments for SM in adults and children. We searched key databases and trial registries between 1 January 2010 and 30 July 2020. Non-randomised trials were excluded to allow comparison of similar trials. Trial characteristics including phase, region, population, interventions, were summarised. All primary and secondary outcomes were extracted and categorised using a taxonomy table. RESULTS: Twenty-seven of 282 screened trials met our inclusion criteria, including 10,342 patients from 19 countries: 19 (70%) trials from Africa and 8 (30%) from Asia. A large amount of heterogeneity was observed in the selection of outcomes and instruments, with 101 different outcomes measures recorded, 78/101 reported only in a single trial. Parasitological outcomes (17 studies), neurological status (14 studies), death (14 studies) and temperature (10 studies), were the most reported outcomes. Where an outcome was reported in >1 study it was often measured differently: temperature (4 different measures), renal function (7 measures), nervous system (13 measures) and parasitology (10 measures). CONCLUSION: Outcomes used in SM trials are inconsistent and heterogeneous. Absence of consensus for outcome measures used impedes research synthesis and comparability of different interventions. This systematic review demonstrates the need to develop a standardised collection of core outcomes for clinical trials of treatments for SM and next steps to include the development of a panel of experts in the field, a Delphi process, and a consensus meeting.