Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Elucidating the Heterogeneity of Immunotherapy Response and Immune-Related Toxicities by Longitudinal ctDNA and Immune Cell Compartment Tracking in Lung Cancer.

PURPOSE: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect-especially in the setting of stable disease-calls for the development of molecularly informed real-time minimally invasive approaches. In addition to capturing tumor regression, liquid biopsies may be informative in capturing immune-related adverse events (irAE). EXPERIMENTAL DESIGN: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. RESULTS: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank P = 0.0003) and overall survival (log-rank P = 0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, on-treatment peripheral blood T-cell repertoire reshaping, assessed by significant T-cell receptor (TCR) clonotypic expansions and regressions, was identified on average 5 months prior to clinical diagnosis of an irAE. CONCLUSIONS: Molecular responses assist with the interpretation of heterogeneous clinical responses, especially for patients with stable disease. Our complementary assessment of the peripheral tumor and immune compartments provides an approach for monitoring of clinical benefits and irAEs during immunotherapy.

Improved lung cancer clinical outcomes in patients with autoimmune rheumatic diseases.

PURPOSE: Concomitant autoimmune rheumatic diseases (ARD) can add morbidity and complicate treatment decisions for patients with lung cancer. We evaluated the tumour characteristics at diagnosis and clinical outcomes in lung cancer patients with or without ARD. METHODS: This retrospective cohort study included 10 963 patients with lung cancer, treated at Johns Hopkins. Clinical data including tumour characteristics and outcomes were extracted from the cancer registry. Data on patients' history of 20 ARD were extracted from the electronic medical record. Logistic regression was used to compare tumour characteristics between those with and without ARD; Kaplan-Meier curves and Cox proportional hazards models were performed to compare survival outcomes. RESULTS: ARD was present in 3.6% of patients (n=454). The mean age at diagnosis was 69 (SD 10) and 68 (SD 12) in patients with and without ARD (p=0.02). Female sex and smoking history were significantly associated with a history of ARD (OR: 1.75, OR: 1.46, p<0.05). Patients with ARD were more likely to be diagnosed with stage 1 lung cancer (36.8% vs 26.9%, p<0.001) and with smaller tumour size (OR: 0.76, p=0.01), controlling for sex, race and histology. Notably, lung cancer patients with ARD had a significantly prolonged median overall survival (OS) (7.11 years vs 1.7 years, p<0.001), independent of stage. CONCLUSION: Patients with ARD and lung cancer had better OS compared with their counterparts, independent of cancer stage and treatments and were less likely to have advanced stage lung cancer at diagnosis. Additional studies are needed to investigate the differential immunological anti-tumour immune activity and genomic variations in patients with and without ARD.

Elucidating the heterogeneity of immunotherapy response and immune-related toxicities by longitudinal ctDNA and immune cell compartment tracking in lung cancer.

Purpose: Although immunotherapy is the mainstay of therapy for advanced non-small cell lung cancer (NSCLC), robust biomarkers of clinical response are lacking. The heterogeneity of clinical responses together with the limited value of radiographic response assessments to timely and accurately predict therapeutic effect -especially in the setting of stable disease-call for the development of molecularly-informed real-time minimally invasive predictive biomarkers. In addition to capturing tumor regression, liquid biopsies may be informative in evaluating immune-related adverse events (irAEs). Experimental design: We investigated longitudinal changes in circulating tumor DNA (ctDNA) in patients with metastatic NSCLC who received immunotherapy-based regimens. Using ctDNA targeted error-correction sequencing together with matched sequencing of white blood cells and tumor tissue, we tracked serial changes in cell-free tumor load (cfTL) and determined molecular response for each patient. Peripheral T-cell repertoire dynamics were serially assessed and evaluated together with plasma protein expression profiles. Results: Molecular response, defined as complete clearance of cfTL, was significantly associated with progression-free (log-rank p=0.0003) and overall survival (log-rank p=0.01) and was particularly informative in capturing differential survival outcomes among patients with radiographically stable disease. For patients who developed irAEs, peripheral blood T-cell repertoire reshaping, assessed by significant TCR clonotypic expansions and regressions were noted on-treatment. Conclusions: Molecular responses assist with interpretation of heterogeneous clinical responses especially for patients with stable disease. Our complementary assessment of the tumor and immune compartments by liquid biopsies provides an approach for monitoring of clinical benefit and immune-related toxicities for patients with NSCLC receiving immunotherapy. Statement of translational relevance: Longitudinal dynamic changes in cell-free tumor load and reshaping of the peripheral T-cell repertoire capture clinical outcomes and immune-related toxicities during immunotherapy for patients with non-small cell lung cancer.

Translocation of bacterial LPS is associated with self-reported cognitive abilities in men living with HIV receiving antiretroviral therapy.

BACKGROUND: Gut damage allows translocation of bacterial lipopolysaccharide (LPS) and fungal ß-D-glucan (BDG) into the blood. This microbial translocation contributes to systemic inflammation and risk of non-AIDS comorbidities in people living with HIV, including those receiving antiretroviral therapy (ART). We assessed whether markers of gut damage and microbial translocation were associated with cognition in ART-treated PLWH. METHODS: Eighty ART-treated men living with HIV from the Positive Brain Health Now Canadian cohort were included. Brief cognitive ability measure (B-CAM) and 20-item patient deficit questionnaire (PDQ) were administered to all participants. Three groups were selected based on their B-CAM levels. We excluded participants who received proton pump inhibitors or antiacids in the past 3 months. Cannabis users were also excluded. Plasma levels of intestinal fatty acid binding protein (I-FABP), regenerating islet-derived protein 3 α (REG3α), and lipopolysaccharides (LPS = were quantified by ELISA, while 1-3-ß-D-glucan BDG) levels were assessed using the Fungitell assay. Univariable, multivariable, and splines analyses were performed. RESULTS: Plasma levels of I-FABP, REG3α, LPS and BDG were not different between groups of low, intermediate and high B-CAM levels. However, LPS and REG3α levels were higher in participants with PDQ higher than the median. Multivariable analyses showed that LPS association with PDQ, but not B-CAM, was independent of age and level of education. I-FABP, REG3α, and BDG levels were not associated with B-CAM nor PDQ levels in multivariable analyses. CONCLUSION: In this well characterized cohort of ART-treated men living with HIV, bacterial but not fungal translocation was associated with presence of cognitive difficulties. These results need replication in larger samples.

Comutations and KRASG12C Inhibitor Efficacy in Advanced NSCLC.

Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

Dynamics of Sequence and Structural Cell-Free DNA Landscapes in Small-Cell Lung Cancer.

PURPOSE: Patients with small-cell lung cancer (SCLC) have an exceptionally poor prognosis, calling for improved real-time noninvasive biomarkers of therapeutic response. EXPERIMENTAL DESIGN: We performed targeted error-correction sequencing on 171 serial plasmas and matched white blood cell (WBC) DNA from 33 patients with metastatic SCLC who received treatment with chemotherapy (n = 16) or immunotherapy-containing (n = 17) regimens. Tumor-derived sequence alterations and plasma aneuploidy were evaluated serially and combined to assess changes in total cell-free tumor load (cfTL). Longitudinal dynamic changes in cfTL were monitored to determine circulating cell-free tumor DNA (ctDNA) molecular response during therapy. RESULTS: Combined tiered analyses of tumor-derived sequence alterations and plasma aneuploidy allowed for the assessment of ctDNA molecular response in all patients. Patients classified as molecular responders (n = 9) displayed sustained elimination of cfTL to undetectable levels. For 14 patients, we observed initial molecular responses, followed by ctDNA recrudescence. A subset of patients (n = 10) displayed a clear pattern of molecular progression, with persistence of cfTL across all time points. Molecular responses captured the therapeutic effect and long-term clinical outcomes in a more accurate and rapid manner compared with radiographic imaging. Patients with sustained molecular responses had longer overall (log-rank P = 0.0006) and progression-free (log-rank P < 0.0001) survival, with molecular responses detected on average 4 weeks earlier than imaging. CONCLUSIONS: ctDNA analyses provide a precise approach for the assessment of early on-therapy molecular responses and have important implications for the management of patients with SCLC, including the development of improved strategies for real-time tumor burden monitoring. See related commentary by Pellini and Chaudhuri, p. 2176.

Development of a Frailty Ladder Using Rasch Analysis: If the Shoe Fits.

Background: The current measurement approach to frailty is to create an index of frailty status, rather than measure it. The purpose of this study is to test the extent to which a set of items identified within the frailty concept fit a hierarchical linear model (e.g., Rasch model) and form a true measure reflective of the frailty construct. Methods: A sample was assembled from three sources: community organization for at-risk seniors (n=141); colorectal surgery group assessed post-surgery (n=47); and hip fracture assessed post-rehabilitation (n=46). The 234 individuals (age 57 to 97) contributed 348 measurements. The frailty construct was defined according to the named domains within commonly used frailty indices, and items drawn to reflect the frailty came from self-report measures. Performance tests were tested for the extent to which they fit the Rasch model. Results: Of the 68 items, 29 fit the Rasch model: 19 self-report items on physical function and 10 performance tests, including one for cognition; patient reports of pain, fatigue, mood, and health did not fit; nor did body mass index (BMI) nor any item representing participation. Conclusion: Items that are typically identified as reflecting the frailty concept fit the Rasch model. The Frailty Ladder would be an efficient and statistically robust way of combining results of different tests into one outcome measure. It would also be a way of identifying which outcomes to target in a personalized intervention. The rungs of the ladder, the hierarchy, could be used to guide treatment goals.

The Families First Program to Prevent Child Abuse: Results of a Cluster Randomized Controlled Trial in West Java, Indonesia.

The Families First parenting program is a 10-week paraprofessional-administered adaptation of the Positive Discipline in Everyday Parenting program for West Java, Indonesia. It has not been tested in a randomized controlled trial. The objective was to evaluate the effects of Families First on physical and emotional punishment. We conducted a cluster randomized controlled trial and randomly assigned 20 rural and urban villages in West Java, Indonesia, to intervention or waitlist. Caregivers of children aged 0-7 years in intervention villages received Families First. Between 2017 and 2018, measurements were taken before randomization, immediately post-intervention, and 6 months post-intervention. Primary outcome was presence versus absence of caregiver-reported physical or emotional punishment immediately post-intervention. Intention-to-treat regression models accounted for clustering within villages and were run to compare between groups. Participants and study personnel could not be blinded. There were 374 caregivers in the 10 intervention villages and 362 in the 10 waitlist villages included in the trial and in outcome analyses. The intervention did not result in a lower proportion of intervention families using punishment immediately post-intervention (odds ratio [OR] for physical or emotional punishment immediately post intervention = 1.20 (95% CI 0.79-1.82). There were no significant differences for positive and involved parenting, setting limits, and opinion on discipline, but caregivers in the intervention group had significantly lower odds of using positive discipline (OR = 0.65 (95% CI 0.53-0.80). Families First did not prevent punishment in a setting with low levels of reported punishment but should be tested in a setting with higher levels or among people selected for risk or presence.

Sex-specific differences in immunogenomic features of response to immune checkpoint blockade.

Introduction: The magnitude of response to immune checkpoint inhibitor (ICI) therapy may be sex-dependent, as females have lower response rates and decreased survival after ICI monotherapy. The mechanisms underlying this sex dimorphism in ICI response are unknown, and may be related to sex-driven differences in the immunogenomic landscape of tumors that shape anti-tumor immune responses in the context of therapy. Methods: To investigate the association of immunogenic mutations with HLA haplotypes, we leveraged whole exome sequence data and HLA genotypes from 482 non-small cell lung cancer (NSCLC) tumors from The Cancer Genome Atlas (TCGA). To explore sex-specific genomic features linked with ICI response, we analyzed whole exome sequence data from patients with NSCLC treated with ICI. Tumor mutational burden (TMB), HLA class I and II restricted immunogenic missense mutation (IMM) load, and mutational smoking signature were defined for each tumor. IMM load was combined with HLA class I and II haplotypes and correlated with therapeutic response and survival following ICI treatment. We examined rates of durable clinical benefit (DCB) for at least six months from ICI treatment initiation. Findings were validated utilizing whole exome sequence data from an independent cohort of ICI treated NSCLC. Results: Analysis of whole exome sequence data from NSCLC tumors of females and males revealed that germline HLA class II diversity (≥9 unique HLA alleles) was associated with higher tumor class II IMM load in females (p=0.01) and not in males (p=0.64). Similarly, in tumors of female patients, somatic HLA class II loss of heterozygosity was associated with increased IMM load (p=0.01) while this association was not observed in tumors in males (p=0.20). In females, TMB (p=0.005), class I IMM load (p=0.005), class II IMM load (p=0.004), and mutational smoking signature (p<0.001) were significantly higher in tumors responding to ICI as compared to non-responding tumors. In contrast, among males, there was no significant association between DCB and any of these features. When IMM was considered in the context of HLA zygosity, high MHC-II restricted IMM load and high HLA class II diversity was significantly associated with overall survival in males (p=0.017). Conclusions: Inherent sex-driven differences in immune surveillance affect the immunogenomic determinants of response to ICI and likely mediate the dimorphic outcomes with ICI therapy. Deeper understanding of the selective pressures and mechanisms of immune escape in tumors in males and females can inform patient selection strategies and can be utilized to further hone immunotherapy approaches in cancer.

Validation of a rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of vistusertib.

Vistusertib is an orally bioavailable mTOR inhibitor that is being studied in clinical trials. A novel reliable method was developed to quantitate vistusertib using LC-MS/MS to explore drug exposure-response relationships. Sample preparation involved protein precipitation using acetonitrile. Separation of vistusertib and the internal standard, AZD8055, was achieved with a Waters Acquity UPLC BEH C18 column utilizing isocratic elution over a 3 min total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of vistusertib. The assay range was 5-5000 ng/mL and proved to be accurate (98.7-105.7%) and precise (CV ≤ 10.5%). A 40,000 ng/mL sample that was diluted 1:10 (v/v) with plasma was accurately quantitated. Long-term frozen plasma stability for vistusertib at -70 °C has been determined for at least 29 months. The method was applied for the measurement of plasma concentrations of vistusertib in a patient a solid tumor receiving 35 mg twice daily dose orally.

A Short-term Psychological Intervention for People Living with HIV During the First Wave of COVID-19.

Research on the psychosocial impact of COVID-19 has found significant levels of distress among the general population, and among those especially vulnerable due to chronic social or health challenges. Among these are individuals aging with HIV infection, who are encountering COVID-19 as a new infectious threat to their health and wellbeing. In a longitudinal observational study of the psychosocial impact of COVID-19 in middle-aged and older people living with HIV, we identified a subset of participants who expressed heightened levels of distress and were referred for clinical intervention. This paper describes the supportive and contemporary cognitive-behavioral interventions that were provided and presents data on changes in distress in this case series. This work provides a model for identifying people in at-risk groups in acute need of psychological intervention and for implementing an individualized clinical response that can be safely delivered in the context of COVID-19 and future crisis situations.

Validation of a robust and rapid liquid chromatography tandem mass spectrometric method for the quantitative analysis of navitoclax.

The Bcl-2 family small molecule inhibitor navitoclax is being clinically evaluated to treat multiple cancers including lymphoid malignancies and small cell lung cancer. A sensitive and reliable method was developed to quantitate navitoclax in human plasma using liquid chromatography with tandem mass spectrometry with which to perform detailed pharmacokinetic studies. Sample preparation involved protein precipitation using acetonitrile. Separation of navitoclax and the internal standard, navitoclax-d8, was achieved with a Waters Acquity UPLC BEH C18 column using isocratic flow over a 3 min total analytical run time. A SCIEX 4500 triple quadrupole mass spectrometer operated in positive electrospray ionization mode was used for the detection of navitoclax. The assay range was 5-5,000 ng/ml and proved to be accurate (89.5-104.9%) and precise (CV ≤ 11%). Long-term frozen plasma stability for navitoclax at -70°C was at least 34 months. The method was applied for the measurement of total plasma concentration of navitoclax in a patient receiving a 250 mg daily oral dose.

Poly(ADP-Ribose) Polymerase Inhibition in Small Cell Lung Cancer: A Review.

ABSTRACT: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy with high and rapid relapse rates and poor outcomes. Treatment for SCLC has historically been limited by the lack of targetable driver genomic lesions, however recent developments in the underpinnings of genomic instability in SCLC and understanding of its transcriptional subtypes have led to increased interest in the use of poly(ADP-ribose) polymerase (PARP) inhibitors as a rationale therapy. Poly(ADP-ribose) polymerase inhibitors, historically designed to target BRCA1/2-mutated malignancies, capitalize on synthetic lethality in homologous recombination-deficient tumors. In this review, we outline the mechanistic rationale for the use of PARP inhibitors in treating SCLC and detail key clinical trials investigating their use in combination with chemotherapy and immunotherapy. We describe developments in the understanding of biomarkers for sensitivity to therapy and highlight further investigational directions for the use of PARP inhibitors in treating SCLC.

Targeted Treatment of Non-Small Cell Lung Cancer: Focus on Capmatinib with Companion Diagnostics.

MET dysregulation promoting tumorigenesis in non-small cell lung cancer (NSCLC) is associated with worse outcomes following chemotherapy as compared to non-driver mutated NSCLC and occurs either through mutations causing MET exon 14 skipping (METex14) or gene amplification and overexpression that result in enhanced receptor signaling. Capmatinib is the first FDA-approved targeted therapy for NSCLC with METex14 skipping mutations, approved in 2020. FoundationOne® CDx, a comprehensive genomic profiling test for solid tumors, was concurrently approved as a companion diagnostic for capmatinib use. The GEOMETRY mono-1 phase II trial of capmatinib monotherapy demonstrated an overall response rate (ORR) of 68% in treatment naïve (n=28) and 41% in pre-treated (n=69) METex14 skipping advanced NSCLC; in MET amplified advanced NSCLC (gene copy number ≥ 10) ORRs of 40% in treatment naïve and 29% in pre-treated disease was seen. This review outlines the clinical data supporting capmatinib approval in the treatment of NSCLC and FoundationOne® CDx approval as a companion diagnostic. We detail the practical clinical administration of capmatinib, including dosing and toxicity management, compare capmatinib to other approved and investigational MET-targeted therapies, discuss limitations of capmatinib, and highlight ongoing trials of capmatinib in combinatorial approaches.

Immunotherapy for small cell lung cancer: established applications and novel approaches.

Small cell lung cancer (SCLC) is a devastating disease that has a case fatality rate of more than 90% despite best available treatments. As a result, patients with SCLC are in critical need of improved therapeutic approaches. Immunotherapies, in particular immune checkpoint inhibitors (ICIs), have transformed the treatment of many cancers and are of great interest in SCLC. In recent years, the addition of anti-programmed death ligand 1 (PD-L1) inhibitors to frontline platinum-based chemotherapy in extensive-stage SCLC has improved survival, and combination chemoimmunotherapy is now approved as the standard of care. ICIs are also under investigation in other settings, including as consolidation therapy in limited-stage SCLC following chemoradiation and in combination with chemoradiation. PD-L1 expression and tumor mutational burden are not reliably associated with ICI benefit in SCLC, and predictive biomarkers of ICI response in SCLC are actively sought. Novel immunotherapeutic approaches are under investigation in SCLC. Rational targets and combinations, which stem from investigations of SCLC biology and the immune tumor microenvironment, include combinations with inhibitors of TIGIT or LAG3; targeting alternative signaling pathways, such as DNA damage repair; and co-targeting SCLC-specific tumor antigens, such as fucosyl-GM1 and DLL3. This review summarizes approaches to immunotherapy in SCLC, including current evidence and approvals, as well as key questions and future directions.

Higher Grit Scores Associated With Less Burnout in a Cohort of Internal Medicine Residents.

BACKGROUND: The association between grit, defined as perseverance and passion for long-term goals, and professional burnout has not been studied in internal medicine residents. Our objective was to examine whether internal medicine residents' scores on a grit scale were associated with various measures of burnout. METHODS: All residents from a single internal medicine program were invited to participate in a study of grit and burnout. Grit and burnout were measured using the Short Grit Scale and modified Maslach Burnout Inventory, respectively. In addition, demographics, last In-Training Examination (ITE) score, and interest in a subspecialty were captured. RESULTS: A total of 139 of 168 eligible residents (83%) participated. Emotional exhaustion and depersonalization (i.e., burn out) were identified in 63% and 42% of residents, respectively. Endorsement of emotional exhaustion was higher for residents living with family members, postgraduate year (PGY)1 and PGY2 compared with PGY3 residents, and residents scoring above the 50th percentile on the last ITE. Grit scores were higher for residents not reporting emotional exhaustion. As grit score increases, the odds of reporting emotional exhaustion significantly decreased, after adjustments for demographics, ITE scores, type of medical school, PGY level, and interest in a subspecialty (odds ratio = 0.36, 95% CI 0.15-0.84). CONCLUSIONS: Grit appeared to be an independent predictor of burnout in internal medicine residents in this sample, with lower grit scores associated with higher burnout scores. By measuring grit early in residency, programs can potentially identify residents at risk for symptoms of burnout, specifically emotional exhaustion, and implement targeted interventions.

Impact of Loneliness on Brain Health and Quality of Life Among Adults Living With HIV in Canada.

BACKGROUND: People aging with HIV are at risk for loneliness, with stigmatization and economic marginalization added to the health challenges arising from chronic infection. This study provides evidence for the extent, contributors, and consequences of loneliness in people living with HIV, focusing on brain health and quality of life. SETTING: Cross-sectional data from 856 middle-aged and older adults living with HIV recruited from 5 urban specialty clinics in Canada were drawn from the inaugural visit of the Positive Brain Health Now cohort study. METHODS: Participants completed an extensive assessment of biopsychosocial variables. The prevalence, severity, and quality of life impact of self-reported loneliness were described. Clinical and environmental factors hypothesized as contributing to loneliness, and the consequences of loneliness on health and function were identified using logistic, ordinal, and linear regression. RESULTS: Eighteen percent reported being "quite often" and 46% "sometimes" lonely. Those with more loneliness were younger, less mobile, suffered more financial hardship, and were more likely to use opioids. HIV symptoms, pain, fatigue, low motivation, stigma, and unemployment were related to loneliness. Loneliness increased the odds of cognitive impairment, low mood, stress, and poor physical health. Those who were "quite often" lonely were over 4 times more likely to report poor or very poor quality of life than those who were "almost never" lonely. CONCLUSION: Loneliness is common in middle-aged and older people living with HIV in Canada. Many of the associated factors are modifiable, offering novel targets for improving brain health, general health, and quality of life in HIV.

Relationships between cognition, function, and quality of life among HIV+ Canadian men.

OBJECTIVE: To estimate the extent to which HIV-related variables, cognition, and other brain health factors interrelate with other HIV-associated symptoms to influence function, health perception, and QOL in older HIV+ men in Canada. DESIGN: Cross-sectional structural equation modelling (SEM) of data from the inaugural visit to the Positive Brain Health Now Cohort. SETTING: HIV clinics at 5 Canadian sites. SUBJECTS: 707 men, age ≥ 35 years, HIV+ for at least one year, without clinically diagnosed dementia. MAIN OUTCOME MEASURES: Five latent and 21 observed variables from the World Health Organization's biopsychosocial model for functioning and disability and the Wilson-Cleary Model were analysed. SEM was used to link disease factors to symptoms, impairments, function, health perception, and QOL with a focus on cognition. RESULTS: QOL was explained directly by depression, social role, health perception, social support, and quality of the environment. Measured cognitive performance had direct effects on activity/function and indirect effects on participation, HP and QOL, acting through self-reported cognitive difficulties and meaningful activities. CONCLUSION: The biopsychosocial model showed good fit, with RMSEA < 0.05. This is the first time the full model has been tested in HIV. All of the domains included in the model are theoretically amenable to intervention and many have evidence-based interventions that could be harnessed to improve QOL.