A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.

INTRODUCTION: Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. METHODS: De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. RESULTS: Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations. CONCLUSION: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.

Comparative genomic analysis of PIK3R1-mutated and wild-type breast cancers.

PURPOSE: The PIK3R1 gene encodes the regulatory subunit-p85a-of the PI3K signaling complex. Prior studies have found that pathogenic somatic alterations in PIK3R1 are enriched in human breast cancers but the genomic landscape of breast cancer patients harboring PIK3R1 mutations has not been extensively characterized. METHODS: We retrospectively analyzed 6,009 patient records that underwent next-generation sequencing (NGS) using the Tempus xT solid tumor assay. All patients had breast cancer with known HER2 (+/-) and hormone receptor (HR; +/-) status and were classified according to the presence of PIK3R1 mutations including short variants and copy number alterations. RESULTS: The frequency of PIK3R1 mutations varied according to subtype: 6% in triple negative (TNBC, 89/1,475), 2% in HER2-/HR+ (80/3,893) and 2.3% in HER2+ (15/641) (p < 0.001). Co-mutations in PTEN, TP53 and NF1 were significantly enriched, co-mutations in PIK3CA were significantly less prevalent, and tumor mutational burden was significantly higher in PIK3R1-mutated HER2- samples relative to PIK3R1 wild-type. At the transcriptional-level, PIK3R1 RNA expression in HER2- disease was significantly higher in PIK3R1-mutated (excluding copy number loss) samples, regardless of subtype. CONCLUSION: This is the largest investigation of the PIK3R1 mutational landscape in breast cancer patients (n = 6,009). PIK3R1 mutations were more common in triple-negative breast cancer (~ 6%) than in HER2 + or HER2-/HR + disease (approximately 2%). While alterations in the PI3K/AKT pathway are often actionable in HER2-/HR + breast cancer, our study suggests that PIK3R1 could be an important target in TNBC as well.

RNA-Based Homologous Recombination Deficiency Signature Detects Homologous Recombination Deficiency-RNA+ Patients With and Without Homologous Recombination Repair Gene Pathogenic Alterations in Men With Prostate Cancer.

PURPOSE: Homologous recombination deficiency (HRD) is a well-described phenotype of some prostate cancers; however, current biomarkers for HRD are imperfect and rely on detection of single gene alterations in the homologous recombination repair (HRR) pathway, which may not capture the complexity of HRD biology. RNA signature-based methods of HRD identification present a potentially dynamic assessment of the HRD phenotype; however, its relationship with HRR gene alterations is not well characterized in prostate cancer. METHODS: A HRD assay on the basis of an RNA signature associated with biallelic BRCA1/2 loss was applied to a retrospective cohort study of 985 men with prostate cancer analyzed on the Tempus xT platform. HRD status was defined by a binary threshold on a continuous scale. RESULTS: In this cohort, of the 126 (13%) patients found to be HRD+ by RNA signature (HRD-RNA+), 100 (79%) had no coexisting HRR gene alteration. Among samples with biallelic BRCA1/2 loss, 78% (7/9) were classified as HRD-RNA+, while 8% (2/25) of samples with BRCA1/2 monoallelic loss were HRD-RNA+. Biallelic and monoallelic ATM loss exhibited HRD-RNA+ at a lower prevalence: 6.7% (1/15) and 7.1% (1/14), respectively, compared with HRD-RNA+ prevalence among samples without any HRR gene loss (13%; 100/782). HRD-RNA+ was associated with a significantly higher prevalence of TP53 and AR gene alterations relative to HRD-RNA- after correction for multiple comparisons, 59% versus 39% (q = 0.003) and 23% versus 12% (q = 0.024), respectively. CONCLUSION: Use of an RNA-based HRD signature significantly expands the fraction of patients with prostate cancer who may derive benefit from poly (ADP-ribose) polymerase inhibitors (PARPis) compared with using HRR gene mutations alone. Further studies are needed to evaluate functional HRD significance and inform future usage as a predictive biomarker for PARPi selection.

Advanced Age in Humans and Mouse Models of Glioblastoma Show Decreased Survival from Extratumoral Influence.

PURPOSE: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. EXPERIMENTAL DESIGN: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. RESULTS: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. CONCLUSIONS: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.

Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency-Related Loss of Heterozygosity.

There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

Association between Platelet Transfusion and Delirium in Critically Ill Children.

Delirium is a frequent, serious, and preventable complication in critically ill children. Inflammation has been implicated as a mechanism for the development of delirium. Platelet transfusions may potentiate the body's pro-inflammatory responses. We hypothesized that receipt of platelets would be associated with delirium development in a pediatric intensive care unit (PICU). We performed a single-center retrospective cohort analysis including children admitted to the PICU between 2014 and 2018 who were transfused platelets within the first 14 days of admission. Data obtained included severity of illness, level of respiratory support, exposure to medications and blood products, as well as daily cognitive status. To account for time-dependent confounding, a marginal structural model (MSM) was constructed to delineate the relationship between platelet transfusion and next-day delirium. MSM demonstrated a 75% increase in the development of next-day delirium after transfusion of platelets (aOR 1.75, 95% CI 1.03-2.97). For every 1 cc/kg of platelet transfused, odds of next-day delirium increased by 9% (odds ratio 1.09, 95% CI 1.03-1.51). We reported an independent association between platelet transfusion and next-day delirium/coma after accounting for time-dependent confounders, with a dose-response effect. Minimizing platelet transfusions as much as clinically feasible may decrease delirium risk in critically ill children.

Does the Type of Reconstruction Matter? A Propensity Score Analysis of Immediate Postmastectomy Implant and Flap Reconstruction.

BACKGROUND: No randomized controlled trials have compared implant and flap reconstruction. Recently, worse longitudinal outcomes have been suggested for flap reconstruction. The authors compared long-term oncologic outcomes of postmastectomy breast reconstruction using propensity score matching. METHODS: A retrospective study of postmastectomy reconstruction was achieved using the Weill Cornell Breast Cancer Registry between 1998 and 2019. Patients were matched using propensity scores based on demographic, clinical, and surgical characteristics. Kaplan-Meier estimates, Cox-regression models, and restricted mean survival times (RMST) were used to evaluate patient outcomes. RESULTS: Before matching, 1395 implant and 586 flap patients were analyzed. No difference in overall survival and recurrence were observed. Multivariable models showed decreased survival for Medicare/Medicaid [hazard ratio (HR), 3.09; 95% CI, 1.63 to 5.87; P < 0.001], pathologic stage II (HR, 2.98; 95% CI, 1.12 to 7.90; P = 0.028), stage III (HR, 4.88; 95% CI, 1.54 to 15.5; P = 0.007), 11 to 20 lymph nodes positive (HR, 3.66; 95% CI, 1.31 to 10.2; P = 0.013), more than 20 lymph nodes positive (HR, 6.41; 95% CI, 1.49 to 27.6; P = 0.013). RMST at 10 years after flap reconstruction showed 2 months of decreased survival time compared with implants (9.56 versus 9.74 years; 95% CI, -0.339 to -0.024; P = 0.024). After matching, 563 implant and 563 flap patients were compared. Reconstruction was not associated with overall survival and recurrence. RMST between implant and flap reconstruction showed no difference in each 5-year interval over 20 years. CONCLUSION: Postmastectomy breast reconstruction was not associated with a difference in long-term oncologic outcomes over a 20-year period. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Actionable genomic landscapes from a real-world cohort of urothelial carcinoma patients.

BACKGROUND: Recent targeted therapies for advanced and metastatic urothelial cancer have generated enthusiasm, but the actionable genomic landscape of early-stage disease remains largely unknown. Here, we utilized a large, real-world cohort to comprehensively investigate the incidence of genetic alterations with potential therapeutic implications at all stages of bladder cancer. MATERIALS AND METHODS: We retrospectively analyzed next-generation sequencing (NGS) data from 1,562 bladder cancer patients (stages I-IV) with formalin-fixed, paraffin-embedded tumor biopsies sequenced using the Tempus xT solid tumor assay. Incidence of genetic alterations, tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 status were assessed and stratified by bladder cancer stage. For patients with tumor-normal match sequencing (n=966), incidental germline alterations in 50 genes were assessed. RESULTS: The cohort was composed of 165 stage I-II, 211 stage III, and 1,186 stage IV tumors. TMB-high, PD-L1 positive, and MSI-high status were noted in 14%, 33%, and 0.7% of tumors, respectively, and were similar across stages. Alterations in fibroblast growth factor receptor (FGFR)2/3, homologous recombination repair genes, additional DNA repair gene mutations (ERCC2, RB1, FANCC), and NTRK fusions were detected at similar frequencies across disease stages. We identified a low rate of incidental germline mutations in all tumors (5.2%) and in specific genes: MUTYH (1.9%), BRCA2 (0.5%), and ATM (0.8%). CONCLUSIONS: Important subsets of patients demonstrate genetic alterations in potentially actionable molecular pathways at all stages. This analysis found minimal variability in these alterations across stages, providing rationale for early identification of genetic alterations and personalization of therapies at all stages for patients with bladder cancer.

Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity.

BACKGROUND: Adolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT). METHODS: Retrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017. RESULTS: In 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]). CONCLUSIONS: In a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.

Pediatric Delirium and All-Cause PICU Readmissions Within 1 Year.

OBJECTIVES: Delirium in critically ill children is associated with increased in-hospital morbidity and mortality. Little is known about the lingering effects of pediatric delirium in survivors after hospital discharge. The primary objective of this study was to determine whether children with delirium would have a higher likelihood of all-cause PICU readmission within 1 calendar year, when compared with children without delirium. DESIGN: Retrospective cohort study. SETTING: Tertiary care, mixed PICU at an urban academic medical center. PATIENTS: Index admissions included all children admitted between September 2014 and August 2015. For each index admission, any readmission occurring within 1 year after PICU discharge was captured. INTERVENTION: Every child was screened for delirium daily throughout the PICU stay. MEASUREMENTS AND MAIN RESULTS: Among 1,145 index patients, 166 children (14.5%) were readmitted at least once. Bivariate analyses compared patients readmitted within 1 year of discharge with those not readmitted: complex chronic conditions (CCCs), increased severity of illness, longer PICU length of stay, need for mechanical ventilation, age less than 6 months, and a diagnosis of delirium were all associated with subsequent readmission. A multivariable logistic regression model was constructed to describe adjusted odds ratios for readmission. The primary exposure variable was number of delirium days. After controlling for confounders, critically ill children who experienced greater than 2 delirium days on index admission were more than twice as likely to be readmitted (adjusted odds ratio, 2.2; CI, 1.1-4.4; p = 0.023). A dose-response relationship was demonstrated as children with longer duration of delirium had increased odds of readmission. CONCLUSIONS: In this cohort, delirium duration was an independent risk factor for readmission in critically ill children. Future research is needed to determine if decreasing prevalence of delirium during hospitalization can decrease need for PICU readmission.

Cervical spine ligamentum flavum gaps: MR characterisation and implications for interlaminar epidural injection therapy.

BACKGROUND: Cervical epidural steroid injections are commonly performed to manage pain from cervical spine disease. Cadaveric studies have demonstrated incomplete ligamentum flavum fusion in the central interlaminar region with resultant midline gaps. We performed an MR-based characterization of cervical ligamentum flavum midline gaps to improve understanding of their prevalence and guide interventionalists in procedural planning. METHODS: Fifty patients were retrospectively reviewed following institutional review board approval. Axial T2-weighted spinecho sequences were used to evaluate ligamentum flavum integrity at the interlaminar spaces of C5-C6, C6-C7 and C7-T1. Interlaminar spaces were further subdivided into superior, middle, and inferior portions, yielding 150 interlaminar regions characterized from C5 to T1. Subsequently, a novel categorization of gap morphology was performed, highlighting gap morphology (anterior, posterior, full, or no gap). RESULTS: Full gaps of the ligamentum flavum, with direct epidural space exposure, were observed with variable prevalence at all three levels evaluated. The highest incidence of full ligamentum flavum gaps were observed at C7-T1, occurring in 71.4% of patients at both its middle and inferior portions. The inferior aspect of C5-C6 demonstrated the lowest observed rates of full ligamentum flavum gap (2%). CONCLUSIONS: Ligamentum flavum gaps occur in the lower cervical spine at high rates, with the highest prevalence of full thickness ligamentum flavum gaps at C7-T1. Interventionists must be aware of these important normal variants and evaluate preprocedural MRI to plan interventions.

Prevalence of Germline Findings Among Tumors From Cancer Types Lacking Hereditary Testing Guidelines.

Importance: Germline testing guidelines are suggested for specific disease types or a family history of cancer, yet alterations are found in cancer types in which germline testing is not routinely indicated. The clinical role of identifying germline variants in these populations is valuable to patients and their at-risk relatives. Objective: To evaluate the prevalence of germline findings in patients undergoing tumor/normal matched sequencing among cancer types lacking guidelines. Design, Setting, and Participants: This retrospective cross-sectional study took place on August 18, 2021, and included data from deidentified records of patients tested, using the Tempus xT tumor/normal matched approach from November 2017 to August 2021. Records included in this study were from 34 642 patients treated in geographically diverse oncology practices in the US with a diagnosis of any of the following cancers: bladder, brain, lung, esophagus, cholangiocarcinoma, head and neck, breast, ovarian, pancreatic, prostate, endometrial, and colorectal. Main Outcomes and Measures: The rate of germline findings (ie, single-nucleotide variants and small insertions or deletions) detected in 50 reportable hereditary cancer genes was calculated for cancer types lacking guidelines for germline testing (bladder, brain, lung, esophagus, cholangiocarcinoma, and head and neck) and cancer types for which germline testing is frequently performed (breast, ovarian, pancreatic, prostate, endometrial, and colorectal). Same-gene second somatic hits were assessed to provide a comprehensive assessment on genomic drivers. Results: Of 34 642 patients, 18 888 were female (54.5%); of 27 498 patients whose age at diagnosis was known, mean (SD) age was 62.23 (3.36) years. A total of 2534 of 34 642 patients (7.3%) harbored pathogenic or likely pathogenic germline variants. Within the tumor types lacking testing guidelines, germline mutations were at 6.6% (79/1188) in bladder cancer and 5.8% (448/7668) in lung cancer. Conclusions and Relevance: This study may present the largest retrospective analysis to date of deidentified real-world data from patients diagnosed with advanced cancer with tumor/normal matched sequencing data and the prevalence of pathogenic or likely pathogenic germline variants in cancer types lacking hereditary cancer testing guidelines. The findings suggest there may be clinical implications for patients and their at-risk family members in cancers for which germline assessment primarily based on the cancer diagnosis is rarely obtained.

Polysomnography-guided mandibular distraction osteogenesis in Pierre Robin sequence patients.

STUDY OBJECTIVES: Craniofacial malformations with micrognathia cause high grades of obstructive sleep apnea (OSA) measured by polysomnography (PSG). Mandibular distraction osteogenesis is a novel procedure for upper airway obstruction relief. Our primary objective was to describe the utilization of PSGs to improve obstruction in patients undergoing mandibular distraction. METHODS: This is a retrospective study. Patients with micrognathia and severe upper airway obstruction, presenting with severe OSA diagnosed by PSG, were included from a single tertiary care center between 2015 and 2019. PSGs were done (1) prior to surgery, (2) once the cosmetic goal was achieved (Post-Op 1), and (3) if residual moderate-to-severe OSA was seen, every 2 nights until mild or no OSA was achieved (Post-Op 2). RESULTS: Thirteen patients were included. The median age at surgery was 1.1 months (10 days-3 months). All 13 patients had baseline severe OSA, with a median obstructive apnea-hypopnea index of 33 events/h and a median O2 nadir of 73%. Post-Op 1 PSG was done at a median of 6 days after surgery. Median first postoperative obstructive apnea-hypopnea index in all 13 patients was 6.8 events/h, with a median O2 nadir of 87%. A median additional distraction of 3 mm was needed beyond the traditionally recommended advancement. Long-term follow-up studies at or after 1 year were done in 5 patients, all showing persistent nonsevere OSA. CONCLUSIONS: This is the first case series utilizing PSGs as a guide for mandibular distraction osteogenesis in patients with micrognathia showing the need for jaw overcorrection to achieve resolution of OSA. CITATION: Kochhar R, Modi V, de Silva N, et al. Polysomnography-guided mandibular distraction osteogenesis in Pierre Robin sequence patients. J Clin Sleep Med. 2022;18(7):1749-1755.

Scholarly activity training in pediatric pulmonology fellowship programs.

BACKGROUND: Scholarly activity training is a required component of pediatric pulmonology fellowship programs. However, there are no data on resources and barriers to training and factors associated with fellow productivity. METHODS: We surveyed US pediatric pulmonology fellowship program directors (FPDs) between March and October 2019. Our primary outcome was fellow productivity (>75% of fellows in the past 5 years had a manuscript accepted in a peer-reviewed journal). Analyses included descriptive statistics, χ2 and Fisher's exact tests for categorical values, and t-test or Wilcoxon rank-sum test for numerical values. RESULTS: Sixty-one percent (33/54) of FPDs completed the survey. Seventy-nine percent reported that most fellows completed clinical, basic science, or translational research. However, only 21% reported that most fellows pursued research positions after graduation; academic clinical positions were more common. For 21%, lack of funding and competing clinical responsibilities were barriers to completing the scholarly activity. Only 39% had highly productive programs; those FPDs were more likely to be highly satisfied with fellow scholarly activity products (p = 0.049) and have >6 publications in the previous 3 years (p = 0.03). Fifty-two percent of FPDs believed that pediatric pulmonary training should be shortened to 2 years for those pursuing clinical or clinician-educator careers. CONCLUSIONS: Barriers to scholarly activity training in pediatric pulmonology programs threaten the pipeline of academic pediatric pulmonologists and physician-investigators. Aligning fellow scholarly activity and clinical training with the skills required in their postgraduate positions could optimize the utilization of limited resources and better support career development.

Modifiable predictors of suicidal ideation during psychotherapy for late-life major depression. A machine learning approach.

This study aimed to identify subgroups of depressed older adults with distinct trajectories of suicidal ideation during brief psychotherapy and to detect modifiable predictors of membership to the trajectories of suicidal ideation. Latent growth mixed models were used to identify trajectories of the presence of suicidal ideation in participants to a randomized controlled trial comparing Problem Solving Therapy with "Engage" therapy in older adults with major depression over 9 weeks. Predictors of membership to trajectories of suicidal ideation were identified by the convergence of four machine learning models, i.e., least absolute shrinkage and selection operator logistic regression, random forest, gradient boosting machine, and classification tree. The course of suicidal ideation was best captured by two trajectories, a favorable and an unfavorable trajectory comprising 173 and 76 participants respectively. Members of the favorable trajectory had no suicidal ideation by week 8. In contrast, members of the unfavorable trajectory had a 60% probability of suicidal ideation by treatment end. Convergent findings of the four machine learning models identified hopelessness, neuroticism, and low general self-efficacy as the strongest predictors of membership to the unfavorable trajectory of suicidal ideation during psychotherapy. Assessment of suicide risk should include hopelessness, neuroticism, and general self-efficacy as they are predictors of an unfavorable course of suicidal ideation in depressed older adults receiving psychotherapy. Psychotherapeutic interventions exist for hopelessness, emotional reactivity related to neuroticism, and low self-efficacy, and if used during therapy, may improve the course of suicidal ideation.

Cross-sectional study of correlates and prevalence of functional and high-risk multimorbidity in an academic HIV practice in New York City.

OBJECTIVES: People with HIV have high levels of multimorbidity, but studies often focus on high-risk comorbidities such as hypertension or coronary artery disease. We examined both high-risk and functional comorbidities in an ethnically diverse clinic population to compare the prevalence of comorbidities and different patterns of multimorbidity. DESIGN: Retrospective cross-sectional study. SETTING: University-based primary care HIV clinic with two locations in New York City. PARTICIPANTS: Patients who had been seen by a physician at least once between 1 June 2016 and 31 May 2017. PRIMARY AND SECONDARY OUTCOME MEASURES: Data regarding demographics, diagnoses and lab values were downloaded in a one-time data import from the electronic medical record. Comorbidities were classified as high-risk (with major impact on mortality) or functional (with major impact on function), and multimorbidity was determined for both classes in the total sample of 2751. Factors associated with high-risk and functional multimorbidity were determined first through bivariate analysis and then through multivariable median regression in 2013 patients with complete data. RESULTS: Median age was 52 years (IQR 43-59). Cisgendered women comprised 24.6% of the sample, and 31.7% were African-American. Both functional and high-risk comorbidities were common and risk increased with age. Among those 75 and older, median number of both functional and high-risk comorbidities was 3 (IQR 2-4). High-risk comorbidities were associated with age (p<0.001), more years with an HIV diagnosis (p<0.001) and being an African-American (p<0.001). Associated with a higher number of functional comorbidities were age (p<0.001), being a cisgender female (p<0.001), being Hispanic (p=0.01) and more years with an HIV diagnosis (p<0.001). CONCLUSIONS: Comorbidities with functional impact increase with age in parallel to those with a more direct impact on mortality and should be assessed and monitored, especially as the population with HIV ages.

The effect of obesity on pain severity and pain interference.

Aim: Obesity is one of the most prevalent comorbidities associated with chronic pain, which can severely interfere with daily living and increase utilization of clinical resources. We hypothesized that a higher level of obesity, measured by BMI, would be associated with increased pain severity (intensity) and interference (pain related disability). Materials & methods: Participant data was pulled from a multisite chronic pain outpatient database and categorized based on BMI. Results: A total of 2509 patients were included in the study. We found significant differences between BMI groups for all pain severity scores (worst, least, average, current) and total pain interference score. Obese patients had significantly higher scores than normal weight patients. Conclusion: We found obesity to be associated with increased pain severity and pain interference.

Delirium in Children Undergoing Hematopoietic Cell Transplantation: A Multi-Institutional Point Prevalence Study.

Introduction: Delirium occurs frequently in adults undergoing hematopoietic cell transplantation, with significant associated morbidity. Little is known about the burden of delirium in children in the peri-transplant period. This study was designed to determine delirium rates, define risk factors (demographic and treatment related), and establish feasibility of multi-institutional bedside screening for delirium in children undergoing hematopoietic cell transplant. Methods: This is a multi-institutional point prevalence study. All subjects were prospectively screened for delirium twice daily using the Cornell Assessment of Pediatric Delirium over a 10-day period. De-identified data, including basic demographics and daily characteristics, were extracted from the electronic medical record. Results: Eleven North American institutions were included, 106 children were enrolled, and 883 hospital days were captured. Delirium screening was successfully completed on more than 98% of the study days. Forty-eight children (45%) developed delirium over the course of the 10-day study. Children were diagnosed with delirium on 161/883 study days, for an overall delirium rate of 18% per day. Higher delirium rates were noted in children <5 years old (aOR 0.41 for children over 5 years), and in association with specific medications (melatonin, steroids, and tacrolimus). Conclusion: Delirium was a frequent occurrence in our study cohort, with identifiable risk factors. Delirium screening is highly feasible in the pediatric hematopoietic cell transplant patient population. A large-scale prospective longitudinal study following children throughout their transplant course is urgently needed to fully describe the epidemiology of pediatric delirium, explore the effects of delirium on patient outcomes, and establish guidelines to prevent and treat delirium in the peri-transplant period.

A predictive model of clinical deterioration among hospitalized COVID-19 patients by harnessing hospital course trajectories.

From early March through mid-May 2020, the COVID-19 pandemic overwhelmed hospitals in New York City. In anticipation of ventilator shortages and limited ICU bed capacity, hospital operations prioritized the development of prognostic tools to predict clinical deterioration. However, early experience from frontline physicians observed that some patients developed unanticipated deterioration after having relatively stable periods, attesting to the uncertainty of clinical trajectories among hospitalized patients with COVID-19. Prediction tools that incorporate clinical variables at one time-point, usually on hospital presentation, are suboptimal for patients with dynamic changes and evolving clinical trajectories. Therefore, our study team developed a machine-learning algorithm to predict clinical deterioration among hospitalized COVID-19 patients by extracting clinically meaningful features from complex longitudinal laboratory and vital sign values during the early period of hospitalization with an emphasis on informative missing-ness. To incorporate the evolution of the disease and clinical practice over the course of the pandemic, we utilized a time-dependent cross-validation strategy for model development. Finally, we validated our prediction model on an external validation cohort of COVID-19 patients served in a demographically distinct population from the training cohort. The main finding of our study is the identification of risk profiles of early, late and no clinical deterioration during the course of hospitalization. While risk prediction models that include simple predictors at ED presentation and clinical judgement are able to identify any deterioration vs. no deterioration, our methodology is able to isolate a particular risk group that remain stable initially but deteriorate at a later stage of the course of hospitalization. We demonstrate the superior predictive performance with the utilization of laboratory and vital sign data during the early period of hospitalization compared to the utilization of data at presentation alone. Our results will allow efficient hospital resource allocation and will motivate research in understanding the late deterioration risk group.