Agreement and concurrent validity between telehealth and in-person diagnosis of musculoskeletal conditions: a systematic review.

OBJECTIVES: To assess the concurrent validity and inter-rater agreement of the diagnosis of musculoskeletal (MSK) conditions using synchronous telehealth compared to standard in-person clinical diagnosis. METHODS: We searched five electronic databases for cross-sectional studies published in English in peer-reviewed journals from inception to 28 September 2023. We included studies of participants presenting to a healthcare provider with an undiagnosed MSK complaint. Eligible studies were critically appraised using the QUADAS-2 and QAREL criteria. Studies rated as overall low risk of bias were synthesized descriptively following best-evidence synthesis principles. RESULTS: We retrieved 6835 records and 16 full-text articles. Nine studies and 321 patients were included. Participants had MSK conditions involving the shoulder, elbow, low back, knee, lower limb, ankle, and multiple conditions. Comparing telehealth versus in-person clinical assessments, inter-rater agreement ranged from 40.7% agreement for people with shoulder pain to 100% agreement for people with lower limb MSK disorders. Concurrent validity ranged from 36% agreement for people with elbow pain to 95.1% agreement for people with lower limb MSK conditions. DISCUSSION: In cases when access to in-person care is constrained, our study implies that telehealth might be a feasible approach for the diagnosis of MSK conditions. These conclusions are based on small cross-sectional studies carried out by similar research teams with similar participant demographics. Additional research is required to improve the diagnostic precision of telehealth evaluations across a larger range of patient groups, MSK conditions, and diagnostic accuracy statistics.

Retinal Artery Reperfusion After Translumenal YAG Laser Embolysis in a Case of Branch Retinal Artery Occlusion.

Purpose: To present a potential treatment for embolic branch retinal artery occlusion (BRAO). Methods: A case and its findings were analyzed. Results: A 75-year-old man with a 5-day history of an acute superior visual field defect in the right eye was found to have a BRAO secondary to a Hollenhorst plaque and was treated with translumenal YAG laser embolysis. Reperfusion of the retinal artery was observed on dislodging the Hollenhorst plaque, and improvements were seen in the patient's superior visual field defect. Conclusions: Translumenal YAG laser embolysis could potentially reverse ischemia secondary to embolic RAOs. This case report and the current literature cited suggest a rationale for treatment and supports further study of this technique.

Dysregulation of CD4+ and CD8+ resident memory T, myeloid, and stromal cells in steroid-experienced, checkpoint inhibitor colitis.

BACKGROUND: Colitis caused by checkpoint inhibitors (CPI) is frequent and is treated with empiric steroids, but CPI colitis mechanisms in steroid-experienced or refractory disease are unclear. METHODS: Using colon biopsies and blood from predominantly steroid-experienced CPI colitis patients, we performed multiplexed single-cell transcriptomics and proteomics to nominate contributing populations. RESULTS: CPI colitis biopsies showed enrichment of CD4+resident memory (RM) T cells in addition to CD8+ RM and cytotoxic CD8+ T cells. Matching T cell receptor (TCR) clonotypes suggested that both RMs are progenitors that yield cytotoxic effectors. Activated, CD38+ HLA-DR+ CD4+ RM and cytotoxic CD8+ T cells were enriched in steroid-experienced and a validation data set of steroid-naïve CPI colitis, underscoring their pathogenic potential across steroid exposure. Distinct from ulcerative colitis, CPI colitis exhibited perturbed stromal metabolism (NAD+, tryptophan) impacting epithelial survival and inflammation. Endothelial cells in CPI colitis after anti-TNF and anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) upregulated the integrin α4ß7 ligand molecular vascular addressin cell adhesion molecule 1 (MAdCAM-1), which may preferentially respond to vedolizumab (anti-α4ß7). CONCLUSIONS: These findings nominate CD4+ RM and MAdCAM-1+ endothelial cells for targeting in specific subsets of CPI colitis patients.

Utility of a fusion protein T-cell co-stimulation blocker Belatacept in heart transplant recipients: Real world experience from a high volume center.

BACKGROUND: Belatacept (BTC), a fusion protein, selectively inhibits T-cell co-stimulation by binding to the CD80 and CD86 receptors on antigen-presenting cells (APCs) and has been used as immunosuppression in adult renal transplant recipients. However, data regarding its use in heart transplant (HT) recipients are limited. This retrospective cohort study aimed to delineate BTC's application in HT, focusing on efficacy, safety, and associated complications at a high-volume HT center. METHODS: A retrospective cohort study was conducted of patients who underwent HT between January 2017 and December 2021 and subsequently received BTC as part of their immunosuppressive regimen. Twenty-one HT recipients were identified. Baseline characteristics, history of rejection, and indication for BTC use were collected. Outcomes included renal function, graft function, allograft rejection and mortality. Follow-up data were collected through December 2023. RESULTS: Among 776 patients monitored from January 2017 to December 2021 21 (2.7%) received BTC treatment. Average age at transplantation was 53 years (± 12 years), and 38% were women. BTC administration began, on average, 689 [483, 1830] days post-HT. The primary indications for BTC were elevated pre-formed donor-specific antibodies in highly sensitized patients (66.6%) and renal sparing (23.8%), in conjunction with reduced calcineurin inhibitor dosage. Only one (4.8%) patient encountered rejection within a year of starting BTC. Graft function by echocardiography remained stable at 6 and 12 months posttreatment. An improvement was observed in serum creatinine levels (76.2% of patients), decreasing from a median of 1.58 to 1.45 (IQR [1.0-2.1] to [1.1-1.9]) over 12 months (p = .054). eGFR improved at 3 and 6 months compared with 3 months pre- BTC levels; however, this was not statistically significant (p = .24). Treatment discontinuation occurred in seven patients (33.3%) of whom four (19%) were switched back to full dose CNI. Infections occurred in 11 patients (52.4%), leading to BTC discontinuation in 4 patients (19%). CONCLUSION: In this cohort, BTC therapy was used as alternative immunosuppression for management of highly sensitized patients or for renal sparing. BTC therapy when combined with CNI dose reduction resulted in stabilization in renal function as measured through renal surrogate markers, which did not, however, reach statistical significance. Patients on BTC maintained a low rejection rate and preserved graft function. Infections were common during BTC therapy and were associated with medication pause/discontinuation in 19% of patients. Further randomized studies are needed to assess the efficacy and safety of BTC in HT recipients.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we perform single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Oral Toxicities of PSMA-Targeted Immunotherapies for The Management of Prostate Cancer.

INTRODUCTION: Prostate Specific Membrane Antigen (PSMA)-targeted radionucleotide therapy has been shown to cause dry mouth, but the oral manifestations of PSMA-targeted immunotherapy have not been extensively studied. The aim of this study was to describe and quantify the oral manifestations of PSMA-targeted immunotherapies (bispecific antibodies or Chimeric Antigen Receptor T cell therapies) in the management of metastatic castration resistant prostate cancer. PATIENTS AND METHODS: We performed a retrospective analysis of the oral toxicities of PSMA-targeted immunotherapies of the patients seen at a single institution's cancer center between 2020 and 2023. Descriptive statistics were used to summarize the data. RESULTS: In a total of 19 patients treated with PSMA-targeted immunotherapies between 2020 and 2023, 9 patients (47%) experienced the following oral toxicities: xerostomia (n = 6; 32%), mucositis (n = 2; 10%), dysgeusia, dry throat and teeth sensitivity in (n = 1 each; 5%), respectively. Oral infections, such as candidiasis and herpes simplex, were not observed in any patients. Mucositis was managed with salt rinses and resolved within few months from onset. Xerostomia persisted in all the patients (median: 306 days, range: 98-484 days) among those who reported dry mouth at the time of data collection, despite treatment with salivary stimulants (n = 5; 83%). Dysgeusia was also persistent, although it was not specifically treated. CONCLUSIONS: Patients treated with PSMA-targeted immunotherapies for prostate cancer can present with various short-term and long-term off-tumor on-target oral toxicities including xerostomia and dysgeusia that may affect quality of life. This study serves as a foundation to future prospective studies with a larger sample size and also helps oncologists managing prostate cancer patients with targeted immunotherapies to familiarize common oral toxicities. Furthermore, we emphasize the importance of oral medicine consultation for a comprehensive oral examination and management of oral complications.

Single-cell and spatial multi-omics highlight effects of anti-integrin therapy across cellular compartments in ulcerative colitis.

Ulcerative colitis (UC) is driven by immune and stromal subsets, culminating in epithelial injury. Vedolizumab (VDZ) is an anti-integrin antibody that is effective for treating UC. VDZ is known to inhibit lymphocyte trafficking to the intestine, but its broader effects on other cell subsets are less defined. To identify the inflammatory cells that contribute to colitis and are affected by VDZ, we performed single-cell transcriptomic and proteomic analyses of peripheral blood and colonic biopsies in healthy controls and patients with UC on VDZ or other therapies. Here we show that VDZ treatment is associated with alterations in circulating and tissue mononuclear phagocyte (MNP) subsets, along with modest shifts in lymphocytes. Spatial multi-omics of formalin-fixed biopsies demonstrates trends towards increased abundance and proximity of MNP and fibroblast subsets in active colitis. Spatial transcriptomics of archived specimens pre-treatment identifies epithelial-, MNP-, and fibroblast-enriched genes related to VDZ responsiveness, highlighting important roles for these subsets in UC.

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Utilization of Regional Anesthesia in the Electrophysiology Lab: A Narrative Review.

PURPOSE OF REVIEW: The electrophysiology lab is an important source of growth of anesthetic volume as the indications and evidence for catheter ablations and various cardiac implantable electronic devices improve. Paired with this increase in volume is an increasing number of patients with substantial comorbid conditions presenting for their EP procedures. For these patients, the interaction between their comorbidities and traditional anesthesia practices may create the risk of hemodynamic instability, cardiovascular or respiratory complications, and potential need for prolonged post-operative monitoring negatively impacting length of hospital stay. RECENT FINDINGS: Regional anesthetic techniques, including pectoralis, serratus, and erector spinae plane blocks, offer options for both regional analgesia and surgical anesthesia for a variety of EP procedures. Existing case reports and extrapolations from other areas support these techniques as viable, safe, and effective components of an anesthetic plan. In this article, we will review the development and challenges of various EP procedures and how different regional anesthetic techniques can function as a component of the anesthesia plan.

Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results.

The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852 .

Impact of anemia on acute ischemic stroke outcomes: A systematic review of the literature.

INTRODUCTION: Anemia has been reported in nearly 40% of acute ischemic stroke (AIS) patients and is linked to significant morbidity and disability. The presence of anemia is associated with worse outcomes in AIS, specifically in the presence of large vessel occlusion (LVO). An optimal hemoglobin (Hb) target specific to this pathology has not yet been established. The goal of this review is to systematically review literature that observes the association that exists between AIS outcomes and hemoglobin (Hb) levels. METHODS: A systematic review was performed in accordance with guidelines for the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) to identify studies from 2008-2022. The following inclusion and exclusion criteria were used: studies of adult patients with AIS; must describe outcomes with regard to Hb levels in AIS (not limited to LVO); must be written in English. The clinical variables extracted included Length of Stay (LOS), modified rankin score (mRS), Hb levels, and mortality. RESULTS: A total of 1,154 studies were gathered, with 116 undergoing full text review. 31 studies were included in this review. The age of patients ranged from 61.4 to 77.8. The presence of anemia in AIS increased LOS by 1.7 days on average and these patients also have a 15.2% higher rate of mortality at one year, on average. DISCUSSION: This data suggests that the contemporary thresholds for treating anemia in AIS patients may be inadequate because anemia is strongly associated with poor outcomes (e.g., mRS>2 or mortality) and increased LOS in AIS patients. The current generalized Hb threshold for transfusion (7 g/dL) is also used in AIS patients, however, a more aggressive transfusion parameter should be further explored based on these findings. Further studies are required to confirm these findings and to determine if a more liberal RBCT threshold will result in clinical benefits.

The Association of Chinese Ethnicity and Language Preference with Advance Directive Completion Among Older Patients in an Integrated Health System.

BACKGROUND: Little is known about possible differences in advance directive completion (ADC) based on ethnicity and language preference among Chinese Americans on a regional level. OBJECTIVE: To understand the association of ethnicity and language preference with ADC among Chinese Americans. DESIGN: Retrospective cohort analysis with direct standardization. PARTICIPANTS: A total of 31,498 Chinese and 502,991 non-Hispanic White members enrolled in Kaiser Permanente Northern California during the entire study period between 2013 and 2017 who were 55 or older as of January 1, 2018. MAIN MEASURES: We compared the proportion of ADC among non-Hispanic White and Chinese patients, and also analyzed the rates according to language preference within the Chinese population. We calculated ADC rates with direct standardization using covariates previously found in literature to be significant predictors of ADC such as age and utilization. KEY RESULTS: Among Chinese members, 60% preferred English, 16% preferred another language without needing an interpreter, and 23% needed an interpreter. After standardizing for age and utilization, non-Hispanic Whites were more than twice as likely to have ADC as Chinese members (20.6% (95% confidence interval (CI): 20.5-20.7%) vs. 10.0% (95% CI: 9.6-10.3%), respectively). Among Chinese members, there was an inverse association between preference for a language other than English and ADC (13.3% (95% CI: 12.8-13.8%) if preferring English, 6.1% (95% CI: 5.4-6.7%) if preferring non-English language but not needing an interpreter, and 5.1% (95% CI: 4.6-5.6%) if preferring non-English language and needing an interpreter). CONCLUSIONS: Chinese members are less likely to have ADC relative to non-Hispanic White members, and those preferring a language other than English are most affected. Further studies can assess reasons for lower ADC among Chinese members, differences in other Asian American populations, and interventions to reduce differences among Chinese members especially among those preferring a language other than English.

Non-viral precision T cell receptor replacement for personalized cell therapy.

T cell receptors (TCRs) enable T cells to specifically recognize mutations in cancer cells1-3. Here we developed a clinical-grade approach based on CRISPR-Cas9 non-viral precision genome-editing to simultaneously knockout the two endogenous TCR genes TRAC (which encodes TCRα) and TRBC (which encodes TCRß). We also inserted into the TRAC locus two chains of a neoantigen-specific TCR (neoTCR) isolated from circulating T cells of patients. The neoTCRs were isolated using a personalized library of soluble predicted neoantigen-HLA capture reagents. Sixteen patients with different refractory solid cancers received up to three distinct neoTCR transgenic cell products. Each product expressed a patient-specific neoTCR and was administered in a cell-dose-escalation, first-in-human phase I clinical trial ( NCT03970382 ). One patient had grade 1 cytokine release syndrome and one patient had grade 3 encephalitis. All participants had the expected side effects from the lymphodepleting chemotherapy. Five patients had stable disease and the other eleven had disease progression as the best response on the therapy. neoTCR transgenic T cells were detected in tumour biopsy samples after infusion at frequencies higher than the native TCRs before infusion. This study demonstrates the feasibility of isolating and cloning multiple TCRs that recognize mutational neoantigens. Moreover, simultaneous knockout of the endogenous TCR and knock-in of neoTCRs using single-step, non-viral precision genome-editing are achieved. The manufacture of neoTCR engineered T cells at clinical grade, the safety of infusing up to three gene-edited neoTCR T cell products and the ability of the transgenic T cells to traffic to the tumours of patients are also demonstrated.

Risk factors of multiple pulmonary emboli in an elite Ironman triathlete: a case report.

Objective: To present a unique case of pulmonary embolism (PE) in an elite-Ironman triathlete and review athlete-specific risk factors associated with venous thromboembolism (VTE). Case presentation: A 57-year-old male triathlete presented for chiropractic care of midback pain and dyspnea one day before competition. During competition, he was removed and unable to complete the event with dyspnea, chest, and midback pain. Vitals revealed prolonged elevated resting heart rate. He was triaged to the hospital with a high index of suspicion for PE. He was diagnosed with multiple PE in both lungs. Summary: VTE is not normally considered in athletes. A combination of athlete-specific risk factors may predispose athletes to a higher propensity of VTE. Due to life-threatening consequences, it is important to include a differential diagnosis of VTE in patients presenting with midback pain and dyspnea.

Objectif: Présenter un cas unique d'embolie pulmonaire (EP) chez un triathlète Ironman d'élite et passer en revue les facteurs de risque spécifiques aux athlètes associés à la thrombo-embolie veineuse. Présentation du cas: Un triathlète de 57 ans s'est présenté pour des soins chiropratiques en raison de douleurs au milieu du dos et de dyspnée un jour avant la compétition. Pendant la compétition, il a été évacué et incapable de terminer l'épreuve en raison d'une dyspnée, d'une douleur thoracique et d'une douleur lombaire. Les signes vitaux ont révélé une élévation prolongée de la fréquence cardiaque au repos. Il a été transféré à l'hôpital avec une forte suspicion d'EP. On lui a diagnostiqué une EP multiple dans les deux poumons. Synthèse: La thrombo-embolie veineuse n'est normalement pas envisagée chez les athlètes. Une combinaison de facteurs de risque spécifiques aux athlètes peut les prédisposer à une plus grande propension à la thrombo-embolie veineuse. En raison des conséquences potentiellement mortelles, il est important d'inclure un diagnostic différentiel de la thrombo-embolie veineuse chez les patients souffrant de douleurs lombaires et de dyspnée.

Investigating the research capacity and productivity of Canadian sports chiropractors.

Objectives: To investigate the research capacity and productivity of Canadian sports chiropractors. Methods: A cross-sectional survey (phase one) and scoping review (phase two) investigated the research capacity and productivity (from 2015-2020) of the Canadian sports chiropractic field. Results: Most respondents (72%) reported obtaining research training from fellowship and master's programs, with only 2 (1%) PhD qualifications identified. Approximately, 30% reported active involvement in research, with 28% being part-time clinician researchers. Access to human and technological research resources were limited. We identified 67 publications and 16 conference presentations within a five-year period, with clinical, population health, and basic science research as the areas most studied. Conclusion: The research effort of Canadian sports chiropractors is primarily conducted by clinicians involved in research on a part-time basis. Its research outputs predominantly reflect the research requirements of the RCCSS(C) Sports Sciences Residency Program, highlighting its contribution in developing capacity and producing research for the Canadian sports chiropractic field.

Objectifs: Étudier la capacité de recherche et la productivité des chiropraticiens du sport Canadiens. Méthodes: Une enquête transversale (première phase) et un examen de la portée (deuxième phase) ont permis d'étudier la capacité de recherche et la productivité (de 2015 à 2020) du domaine de la chiropratique sportive au Canada. Résultats: La plupart des répondants (72 %) ont déclaré avoir obtenu une formation en recherche dans le cadre de programmes de bourses et de maîtrises, et seulement 2 (1 %) ont indiqué avoir obtenu un doctorat. Environ 30 % des répondants ont déclaré participer activement à la recherche, 28 % d'entre eux étant des cliniciens-chercheurs à temps partiel. L'accès aux ressources humaines et technologiques de la recherche était limité. Nous avons recensé 67 publications et 16 présentations de conférences sur une période de cinq ans, les domaines les plus étudiés étant la recherche clinique, la recherche sur la santé des populations et la recherche en sciences fondamentales. Conclusion: L'effort de recherche des chiropraticiens du sport canadiens est principalement mené par des cliniciens impliqués dans la recherche à temps partiel. Leurs résultats de recherche reflètent surtout les exigences de recherche du programme de résidence en sciences du sport du Collège royal des sciences chiropratiques du sport du Canada (RCCSS(C)), soulignant leur contribution au développement des capacités et à la production de recherches pour le domaine de la chiropratique du sport au Canada.

Do-not-resuscitate (DNR) status and major depressive disorder (MDD): Clinical association and hospitalization outcomes.

OBJECTIVES: To understand (1) the association of Major Depressive Disorder (MDD) and do-not-resuscitate (DNR) status among hospitalized patients and (2) the association of MDD and hospitalization outcomes among DNR patients. METHODS: This was a cross-sectional analysis of United States Healthcare Cost and Utilization Project, Nationwide Inpatient Sample data from 2009 to 2013 for patients >18 years. To address the first objective, we used multivariable logistic regression among all hospitalized patients to compute the adjusted odds ratio (aOR) of having DNR status if patients have active MDD of varying severities after controlling for age, sex, race, suicidal ideation, and Elixhauser Comorbidity Index. To address the second objective, we used multivariable regression among patients with DNR status to compute aOR of having hospitalization outcomes such as increased length of stay, higher total charges, leaving against medical advice, and mortality if patients have MDD. RESULTS: Among all hospitalizations, 2.3% had DNR status. There was an inverse association between severity of MDD and having DNR status. Relative to those without MDD, patients with moderate recurrent MDD episode (aOR 0.74 (95% confidence interval (CI): 0.65-0.85) and severe recurrent MDD episode (aOR of 0.42 (95% CI: 0.37-0.48)) were significantly less likely to have DNR status. Among DNR patients, those with all severities of MDD except mild single episode MDD were >40% less likely to die during hospitalization. Among DNR patients, patients with MDD had 0.7 day longer length of stay, and >$4,500 higher total charges. SIGNIFICANCE OF RESULTS: Patients are less likely to have DNR status if they have active MDD. Among patients with DNR status, those with MDD are less likely to die during hospitalization than those without MDD. With current practice, depression is not associated with increased likelihood of death due to foregoing resuscitation prematurely, though the exact mechanisms of these findings need further investigation.

Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer.

Sex bias exists in the development and progression of nonreproductive organ cancers, but the underlying mechanisms are enigmatic. Studies so far have focused largely on sexual dimorphisms in cancer biology and socioeconomic factors. Here, we establish a role for CD8+ T cell-dependent antitumor immunity in mediating sex differences in tumor aggressiveness, which is driven by the gonadal androgen but not sex chromosomes. A male bias exists in the frequency of intratumoral antigen-experienced Tcf7/TCF1+ progenitor exhausted CD8+ T cells that are devoid of effector activity as a consequence of intrinsic androgen receptor (AR) function. Mechanistically, we identify a novel sex-specific regulon in progenitor exhausted CD8+ T cells and a pertinent contribution from AR as a direct transcriptional transactivator of Tcf7/TCF1. The T cell-intrinsic function of AR in promoting CD8+ T cell exhaustion in vivo was established using multiple approaches including loss-of-function studies with CD8-specific Ar knockout mice. Moreover, ablation of the androgen-AR axis rewires the tumor microenvironment to favor effector T cell differentiation and potentiates the efficacy of anti-PD-1 immune checkpoint blockade. Collectively, our findings highlight androgen-mediated promotion of CD8+ T cell dysfunction in cancer and imply broader opportunities for therapeutic development from understanding sex disparities in health and disease.

West Nile Virus Transmission by Solid Organ Transplantation and Considerations for Organ Donor Screening Practices, United States.

West Nile virus (WNV) is the most common domestic arbovirus in the United States. During 2018, WNV was transmitted through solid organ transplantation to 2 recipients who had neuroinvasive disease develop. Because of increased illness and death in transplant recipients, organ procurement organizations should consider screening during region-specific WNV transmission months.