Association Between Cardiovascular Health Status and Healthcare Utilization in a Large Integrated Healthcare System.

Introduction: The American Heart Association Life's Simple 7 schema can be used to categorize patients' cardiovascular health status as poor, intermediate, or ideal on the basis of smoking, BMI, physical activity, dietary patterns, blood pressure, cholesterol, and fasting blood sugar. This study examined the association between cardiovascular health status and subsequent healthcare utilization. Methods: This was an observational cohort study of adults from an integrated healthcare delivery system-Kaiser Permanente Northern California-that had outpatient care between 2013 and 2014. Patients were categorized by American Heart Association cardiovascular health status: poor, intermediate, or ideal. Individual-level healthcare utilization and costs in 2015 were accumulated for each patient and compared across the 3 cardiovascular health categories and stratified by age groups. Results: A total of 991,698 patients were included in the study. A total of 194,003 (19.6%) were aged 18-39 years; 554,129 (55.9%) were aged 40-64 years; and 243,566 (24.6%) were aged ≥65 years. A total of 259,931 (26.2%) had ideal cardiovascular health; 521,580 (52.6%) had intermediate cardiovascular health; and 210,187 (21.2%) had poor cardiovascular health. Healthcare utilization measured by average relative cost per patient increased monotonically across age categories (p<0.001). In addition, cardiovascular health category was inversely associated with lower cost in each age group (p<0.001). Conclusions: Adults who were younger and had more ideal cardiovascular health had relatively lower healthcare costs across age groups. Interventions to promote better cardiovascular health may improve patient outcomes and reduce overall healthcare expenditures.

Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice.

The recent emergence of a causal link between Epstein-Barr virus (EBV) and multiple sclerosis has generated considerable interest in the development of an effective vaccine against EBV. Here we describe a vaccine formulation based on a lymph node targeting Amphiphile vaccine adjuvant, Amphiphile-CpG, admixed with EBV gp350 glycoprotein and an engineered EBV polyepitope protein that includes 20 CD8+ T cell epitopes from EBV latent and lytic antigens. Potent gp350-specific IgG responses are induced in mice with titers >100,000 in Amphiphile-CpG vaccinated mice. Immunization including Amphiphile-CpG also induces high frequencies of polyfunctional gp350-specific CD4+ T cells and EBV-specific CD8+ T cells that are 2-fold greater than soluble CpG and are maintained for >7 months post immunization. This combination of broad humoral and cellular immunity against multiple viral determinants is likely to provide better protection against primary infection and control of latently infected B cells leading to protection against the development of EBV-associated diseases.

P2Y12 Inhibitors in Acute Coronary Syndromes: A Real-World, Community-Based Comparison of Ischemic and Bleeding Outcomes.

Background: Randomized trials have shown superiority of the novel P2Y12 inhibitors over clopidogrel in patients with acute coronary syndrome (ACS), but clinical benefit in the community remains controversial. Our objective was to compare the safety and efficacy of clopidogrel to ticagrelor and prasugrel in patients with ACS undergoing percutaneous coronary intervention (PCI) in a real-world population. Methods: We conducted a retrospective cohort study of patients with ACS who underwent PCI and were discharged with clopidogrel, ticagrelor, or prasugrel from 2012 to 2018 within Kaiser Permanente Northern California. We used Cox proportional hazard models with propensity-score matching to evaluate the association of the P2Y12 agent with the primary outcomes of all-cause mortality, myocardial infarction (MI), stroke, and bleeding events. Results: The study included 15,476 patients (93.1% on clopidogrel, 3.6% on ticagrelor and 3.2% on prasugrel). Compared to the clopidogrel group, ticagrelorand prasugrel patients were younger with less comorbidities. In multivariable models with propensity-score matching, we found a lower risk of all-cause mortality in the ticagrelor vs the clopidogrel group (HR (95% CI) 0.43 (0.20-0.92)), but no differences in the other endpoints, and no difference between prasugrel and clopidogrel among any endpoints. A larger proportion of patients on ticagrelor or prasugrel switched to an alternative P2Y12 agent vs. clopidogrel (p < 0.01), and a higher level of persistence was seen among patients on clopidogrel vs. ticagrelor (p = 0.03) or prasugrel (p < 0.01). Conclusion: Among patients with ACS who underwent PCI, we observed a lower risk of all-cause mortality in patients treated with ticagrelor vs clopidogrel, but no difference in other clinical endpoints nor any differences in endpoints between prasugrel vs. clopidogrel users. These results suggest that further study is needed to identify an optimal P2Y12 inhibitor in a real-world population.

Risk of cardiac events after elective versus urgent or emergent noncardiac surgery: Implications for quality measurement and improvement.

INTRODUCTION: Patient populations differ for elective vs urgent and emergent surgery. The effect of this difference on surgical outcome is not well understood and may be important for improving surgical safety. Our primary hypothesis was that there is an association of surgical acuity with risk of postoperative cardiac events. Secondarily, we examined elective vs urgent and emergent patients separately to understand patient characteristics that are associated with postoperative cardiac events. METHODS: We performed a retrospective cohort study of patients ≥65 years undergoing noncardiac elective or urgent/emergent surgery. Logistic regression estimated the association of surgical acuity with a postoperative cardiac event, which was defined as myocardial infarction or cardiac arrest within 30 days of surgery. For the secondary analysis, we modeled the outcome after stratifying by acuity. RESULTS: The study included 161,177 patients with 1014 cardiac events. The unadjusted risk of a postoperative cardiac event was 3.2 per 1000 among elective patients and 28.7 per 1000 among urgent and emergent patients (adjusted odds ratio 4.10, 95% confidence interval 3.56-4.72). After adjustment, increased age, higher baseline cardiac risk, peripheral vascular disease, hypertension, worse American Society of Anesthesiologist (ASA) physical classification, and longer operative time were associated with a postoperative cardiac event. Higher baseline cardiac risk was more strongly associated with postoperative cardiac events in elective patients. In contrast, worse ASA physical classification was more strongly associated with postoperative cardiac events in urgent and emergent patients. Black patients had higher odds of a postoperative cardiac event only in urgent and emergent patients compared to White patients. CONCLUSIONS: Quality measurement and improvement to address postoperative cardiac risk should consider patients based on surgical acuity.

Association of Thoracic Aortic Aneurysm Size With Long-term Patient Outcomes: The KP-TAA Study.

Importance: The risk of adverse events from ascending thoracic aorta aneurysm (TAA) is poorly understood but drives clinical decision-making. Objective: To evaluate the association of TAA size with outcomes in nonsyndromic patients in a large non-referral-based health care delivery system. Design, Setting, and Participants: The Kaiser Permanente Thoracic Aortic Aneurysm (KP-TAA) cohort study was a retrospective cohort study at Kaiser Permanente Northern California, a fully integrated health care delivery system insuring and providing care for more than 4.5 million persons. Nonsyndromic patients from a regional TAA safety net tracking system were included. Imaging data including maximum TAA size were merged with electronic health record (EHR) and comprehensive death data to obtain demographic characteristics, comorbidities, medications, laboratory values, vital signs, and subsequent outcomes. Unadjusted rates were calculated and the association of TAA size with outcomes was evaluated in multivariable competing risk models that categorized TAA size as a baseline and time-updated variable and accounted for potential confounders. Data were analyzed from January 2018 to August 2021. Exposures: TAA size. Main Outcomes and Measures: Aortic dissection (AD), all-cause death, and elective aortic surgery. Results: Of 6372 patients with TAA identified between 2000 and 2016 (mean [SD] age, 68.6 [13.0] years; 2050 female individuals [32.2%] and 4322 male individuals [67.8%]), mean (SD) initial TAA size was 4.4 (0.5) cm (828 individuals [13.0% of cohort] had initial TAA size 5.0 cm or larger and 280 [4.4%] 5.5 cm or larger). Rates of AD were low across a mean (SD) 3.7 (2.5) years of follow-up (44 individuals [0.7% of cohort]; incidence 0.22 events per 100 person-years). Larger initial aortic size was associated with higher risk of AD and all-cause death in multivariable models, with an inflection point in risk at 6.0 cm. Estimated adjusted risks of AD within 5 years were 0.3% (95% CI, 0.3-0.7), 0.6% (95% CI, 0.4-1.3), 1.5% (95% CI, 1.2-3.9), 3.6% (95% CI, 1.8-12.8), and 10.5% (95% CI, 2.7-44.3) in patients with TAA size of 4.0 to 4.4 cm, 4.5 to 4.9 cm, 5.0 to 5.4 cm, 5.5 to 5.9 cm, and 6.0 cm or larger, respectively, in time-updated models. Rates of the composite outcome of AD and all-cause death were higher than for AD alone, but a similar inflection point for increased risk was observed at 6.0 cm. Conclusions and Relevance: In a large sociodemographically diverse cohort of patients with TAA, absolute risk of aortic dissection was low but increased with larger aortic sizes after adjustment for potential confounders and competing risks. Our data support current consensus guidelines recommending prophylactic surgery in nonsyndromic individuals with TAA at a 5.5-cm threshold.

Limitations to Health Care Quality Measurement: Assessing Hospital Variation in Risk of Cardiac Events After Noncardiac Surgery.

Limited sample size, incomplete measures, and inadequate risk adjustment adversely influence accurate health care quality measurements, surgical quality measurements, and accurate comparisons among hospitals. Since these measures are linked to resources for quality improvement and reimbursement, improving the accuracy of measurement has substantial implications for patients, clinicians, hospital administrators, insurers, and purchasers. The team examined risk-adjusted differences of postoperative cardiac events among 20 geographically dispersed, community-based medical centers within an integrated health care system and compared it with the National Surgical Quality Improvement Program (NSQIP) hospital-specific differences. The exposure included the hospital at which patients received noncardiac surgical care, with stratification of patients by the acuity of surgery (elective vs. urgent/emergent). Among 157,075 surgery patients, the unadjusted risk of cardiac event per 1000 ranged among hospitals from 2.1 to 6.9 for elective surgery and from 10.3 to 44.5 for urgent/emergent surgery. Across the 20 hospitals, hospital rankings estimated in the present analysis differed significantly from ranking reported by NSQIP (P for difference: elective, P = 0.0001; urgent/emergent, P < 0.0001) with significantly and substantially lower variation after risk adjustment. Current surgical quality measures may not adequately account for limitations of sample size, data capture, adequate risk adjustment, and surgical acuity in a given hospital, particularly for rare outcomes. These differences have implications for quality reporting and may introduce bias into hospital comparisons, particularly for hospitals with incomplete capture of their patients' baseline risk and acuity.

Comparison of coronary revascularization strategies in older adults presenting with acute coronary syndromes.

BACKGROUND: The optimal coronary revascularization strategy to maximize the patient-centered outcome of days alive and out of hospital (DAOH), in multimorbid older (≥65-years) adults after an acute coronary syndrome (ACS) is incompletely understood. METHODS: Using Kaiser Permanente Northern California Health Plan databases, we identified 3871 patients ≥65-years presenting with ACS between 1/1/2010-3/1/2018 who underwent coronary revascularization with either coronary artery bypass grafting (CABG, N = 1575) or multivessel percutaneous coronary intervention (PCI, N = 2296). Selection bias was accounted for through propensity score modeling techniques and inverse probability of treatment weighting. Cox proportional hazards models were fit to evaluate the association of revascularization type with outcomes. PRIMARY OUTCOMES: Absolute DAOH and the relative risk of achieving ≥90%DAOH during three time intervals. SECONDARY OUTCOMES: All-cause mortality, recurrent MI, stroke, rehospitalization, repeat revascularization, and dialysis initiation. RESULTS: CABG (compared to PCI) was associated with greater absolute number of DAOH, significant after the first year (mean difference at 1-year: +5.8 days, 95% confidence interval [CI], -1.6 to 13 days; 3-years: +56 days, 95%CI, +25 to +88 days; 5-years: + 131 days, 95%CI, +57 to +205 days). The relative risk of achieving ≥90% DAOH significantly favored CABG after the first year (1-year:1.02, 95%CI, 0.98-1.05; 3-years:1.06, 95%CI 1.002-1.11, 5-years:1.12, 95%CI, 1.03-1.22), and was related to lower incidences of all-cause mortality, repeat revascularization, rehospitalization, incident dialysis, and nonfatal MI with CABG. CONCLUSIONS: In older adults with multivessel or left main coronary artery disease who presented with ACS, CABG, after the first year, was associated with a greater absolute number of DAOH-a geriatric and patient-centered outcome, compared to PCI. CABG patients also had a higher probability of achieving ≥90%DAOH-with lower all-cause mortality, recurrent MI, repeat revascularization, new dialysis, and rehospitalization rates. Future randomized trials should study the impact of optimal revascularization strategies on the quality of life of older adults with multimorbidity.

SARS-CoV-2-specific T cells generated for adoptive immunotherapy are capable of recognizing multiple SARS-CoV-2 variants.

Adoptive T-cell immunotherapy has provided promising results in the treatment of viral complications in humans, particularly in the context of immunocompromised patients who have exhausted all other clinical options. The capacity to expand T cells from healthy immune individuals is providing a new approach to anti-viral immunotherapy, offering rapid off-the-shelf treatment with tailor-made human leukocyte antigen (HLA)-matched T cells. While most of this research has focused on the treatment of latent viral infections, emerging evidence that SARS-CoV-2-specific T cells play an important role in protection against COVID-19 suggests that the transfer of HLA-matched allogeneic off-the-shelf virus-specific T cells could provide a treatment option for patients with active COVID-19 or at risk of developing COVID-19. We initially screened 60 convalescent individuals and based on HLA typing and T-cell response profile, 12 individuals were selected for the development of a SARS-CoV-2-specific T-cell bank. We demonstrate that these T cells are specific for up to four SARS-CoV-2 antigens presented by a broad range of both HLA class I and class II alleles. These T cells show consistent functional and phenotypic properties, display cytotoxic potential against HLA-matched targets and can recognize HLA-matched cells infected with different SARS-CoV-2 variants. These observations demonstrate a robust approach for the production of SARS-CoV-2-specific T cells and provide the impetus for the development of a T-cell repository for clinical assessment.

The natural history of large abdominal aortic aneurysms in patients without timely repair.

OBJECTIVE: Contemporary data on the natural history of large abdominal aortic aneurysms (AAAs) in patients undergoing delayed or no repair are lacking. In this study, we examine the impact of large AAA size on the incidence of rupture and mortality. METHODS: From a prospectively maintained aneurysm surveillance registry, patients with an unrepaired, large AAA (≥5.5 cm in men and ≥5.0 cm in women) at baseline (ie, index imaging) or who progressed to a large size from 2003 to 2017 were included, with follow-up through March 2020. Outcomes of interest obtained by manual chart review included rupture (confirmed by imaging/autopsy), probable rupture (timing/findings consistent with rupture without more likely cause of death), repair, reasons for either no or delayed (>1 year after diagnosis of large AAA) repair and total mortality. Cumulative incidence of rupture was calculated using a nonparametric cumulative incidence function, accounting for the competing events of death and aneurysm repair and was stratified by patient sex. RESULTS: Of the 3248 eligible patients (mean age, 83.6 ± 9.1 years; 71.2% male; 78.1% white; and 32.0% current smokers), 1423 (43.8%) had large AAAs at index imaging, and 1825 progressed to large AAAs during the follow-up period, with a mean time to qualifying size of 4.3 ± 3.4 years. In total, 2215 (68%) patients underwent repair, of which 332 were delayed >1 year; 1033 (32%) did not undergo repair. The most common reasons for delayed repair were discrepancy in AAA measurement between surgeon and radiologist (34%) and comorbidity (20%), whereas the most common reasons for no repair were patient preference (48%) and comorbidity (30%). Among patients with delayed repair (mean time to repair, 2.6 ± 1.8 years), nine (2.7%) developed symptomatic aneurysms, and an additional 11 (3.3%) ruptured. Of patients with no repair, 94 (9.1%) ruptured. The 3-year cumulative incidence of rupture was 3.4% for initial AAA size 5.0 to 5.4 cm (women only), 2.2% for 5.5 to 6.0 cm, 6.0% for 6.1 to 7.0 cm, and 18.4% for >7.0 cm. Women with AAA size 6.1 to 7.0 cm had a 3-year cumulative incidence of rupture of 12.8% (95% confidence interval, 7.5%-19.6%) compared with 4.5% (95% confidence interval, 3.0%-6.5%) in men (P = .002). CONCLUSIONS: In this large cohort of AAA registry patients over 17 years, annual rupture rates for large AAAs were lower than previously reported, with possible increased risk in women. Further analyses are ongoing to identify those at increased risk for aneurysm rupture and may provide targeted surveillance regimens and improve patient counseling.

Testicular Germ Cell Tumor Presenting to the Emergency Department.

The authors report on a case of a patient who presented to the emergency department (ED) and was ultimately diagnosed with stage IV testicular non-seminomatous germ cell tumor. The patient was cachectic with a tumor on the neck, abdomen, and scrotum. Germ cell tumors (GCTs) exhibit characteristic symptoms at different points in development. Appropriate treatment can cure most GCTs. While cancer may not be thought of as an ED diagnosis, it can often be the place where patients first present, even when advanced. Recognizing it is important for prompt treatment.

'Off-the-shelf' allogeneic antigen-specific adoptive T-cell therapy for the treatment of multiple EBV-associated malignancies.

BACKGROUND: Epstein-Barr virus (EBV), an oncogenic human gammaherpesvirus, is associated with a wide range of human malignancies of epithelial and B-cell origin. Recent studies have demonstrated promising safety and clinical efficacy of allogeneic 'off-the-shelf' virus-specific T-cell therapies for post-transplant viral complications. METHODS: Taking a clue from these studies, we developed a highly efficient EBV-specific T-cell expansion process using a replication-deficient AdE1-LMPpoly vector that specifically targets EBV-encoded nuclear antigen 1 (EBNA1) and latent membrane proteins 1 and 2 (LMP1 and LMP2), expressed in latency II malignancies. RESULTS: These allogeneic EBV-specific T cells efficiently recognized human leukocyte antigen (HLA)-matched EBNA1-expressing and/or LMP1 and LMP2-expressing malignant cells and demonstrated therapeutic potential in a number of in vivo models, including EBV lymphomas that emerged spontaneously in humanized mice following EBV infection. Interestingly, we were able to override resistance to T-cell therapy in vivo using a 'restriction-switching' approach, through sequential infusion of two different allogeneic T-cell therapies restricted through different HLA alleles. Furthermore, we have shown that inhibition of the programmed cell death protein-1/programmed death-ligand 1 axis in combination with EBV-specific T-cell therapy significantly improved overall survival of tumor-bearing mice when compared with monotherapy. CONCLUSION: These findings suggest that restriction switching by sequential infusion of allogeneic T-cell therapies that target EBV through distinct HLA alleles may improve clinical response.

Acute Hypoxic Respiratory Failure and Septic Shock Secondary to Mycoplasma Pneumoniae Pneumonia Complicated by Heroin Overdose.

We present the case of a woman with a past medical history of intravenous drug use and tobacco abuse who was brought into the emergency department by emergency medical services after a heroin overdose. She was found to be in acute hypoxic respiratory failure and developed septic shock secondary to Mycoplasma pneumonia. In this case report, the presentation and management of fulminant Mycoplasma pneumonia are discussed, along with plain chest radiography findings.

Stevens Johnson Syndrome Initiated by an Adverse Reaction to Trimethoprim-Sulfamethoxazole.

The authors present a case of a 54-year-old male who presented to the ED with Stevens Johnson syndrome (SJS) beginning on his upper lips, then spreading to his glans penis, airway, and buttocks. After using trimethoprim-sulfamethoxazole (TMP-SMX) to treat a pilonidal cyst diagnosed seven days prior to presentation, the patient began to have desquamating lesions on his upper and lower lips. Subsequently, he noticed desquamation on the glans penis and then between his buttocks. Before being referred to dermatology, he was treated with a high dosage of corticosteroids.

Cumulative Adherence to Secondary Prevention Guidelines and Mortality After Acute Myocardial Infarction.

Background The survival benefit associated with cumulative adherence to multiple clinical and lifestyle-related guideline recommendations for secondary prevention after acute myocardial infarction (AMI) is not well established. Methods and Results We examined adults with AMI (mean age 68 years; 64% men) surviving at least 30 (N=25 778) or 90  (N=24 200) days after discharge in a large integrated healthcare system in Northern California from 2008 to 2014. The association between all-cause death and adherence to 6 or 7 secondary prevention guideline recommendations including medical treatment (prescriptions for ß-blockers, renin-angiotensin-aldosterone system inhibitors, lipid medications, and antiplatelet medications), risk factor control (blood pressure <140/90 mm Hg and low-density lipoprotein cholesterol <100 mg/dL), and lifestyle approaches (not smoking) at 30 or 90 days after AMI was evaluated with Cox proportional hazard models. To allow patients time to achieve low-density lipoprotein cholesterol <100 mg/dL, this metric was examined only among those alive 90 days after AMI. Overall guideline adherence was high (35% and 34% met 5 or 6 guidelines at 30 days; and 31% and 23% met 6 or 7 at 90 days, respectively). Greater guideline adherence was independently associated with lower mortality (hazard ratio, 0.57 [95% CI, 0.49-0.66] for those meeting 7 and hazard ratio, 0.69 [95% CI, 0.61-0.78] for those meeting 6 guidelines versus 0 to 3 guidelines in 90-day models, with similar results in the 30-day models), with significantly lower mortality per each additional guideline recommendation achieved. Conclusions In a large community-based population, cumulative adherence to guideline-recommended medical therapy, risk factor control, and lifestyle changes after AMI was associated with improved long-term survival. Full adherence was associated with the greatest survival benefit.

Truncus arteriosus with retrograde aortic flow: a unique case.

Truncus arteriosus is a rare cyanotic congenital heart defect that involves septation failure of the heart's main arterial outflow tract. Varying morphologies of the truncal valve and aorta have been reported; however, the ascending aorta is typically supplied via anterograde blood flow through the truncal valve. We present the first reported case of neonatal truncus arteriosus with the ascending aorta being supplied entirely by retrograde flow.

An improved method for examining fat taste.

PURPOSE: The detection of fat taste in humans requires the delivery of hydrophobic stimuli to the oral cavity. Due to their low solubility in water, these fat taste stimuli are difficult to administer to test subjects by means of aqueous solutions or dispersions. These hydrophobic stimuli are also difficult to prepare in sufficient amounts to generate an appreciable chemosensory response. METHODS: An improved procedure for preparing thin edible strips that contain 18-carbon fatty acids as representative fat taste stimuli is described. This protocol includes the addition of low amounts of the dispersing agent xanthan gum and high drying temperature during film formation. These edible strips can be prepared in 4-5 h, are highly flexible, and evenly disperse long-chain fatty acids at micromole amounts. Due to the rapid dissolving time of these strips in the oral cavity, this delivery method generates minimal tactile responses. RESULTS: Psychophysical studies with edible strips indicate that nearly all individuals detected linoleic acid, with intensity responses in the weak to moderate range. Fewer individuals perceived stearic acid, with most intensity responses in the barely detectable range. Both fatty acids caused a fatty/oily or bitter taste response in the majority of test subjects. Finally, these intensity responses allowed the development of edible circles for regional testing of the tongue. CONCLUSION: This novel delivery method for hydrophobic stimuli should be useful for examining human fat taste perception, characterizing variations in fat taste perception, and identifying the emerging role of fat taste in human health.

T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response.

BACKGROUNDImpaired T cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients.METHODSIn the present study, we used high-throughput T cell receptor Vß sequencing and T cell functional profiling to delineate the impact of ACT on T cell repertoire remodeling in the context of pretherapy immunity and ACT products.RESULTSThese analyses indicated that a clinical response was coincident with significant changes in the T cell receptor Vß landscape after therapy. This restructuring was associated with the emergence of effector memory T cells in responding patients, while nonresponders displayed dramatic pretherapy T cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products.CONCLUSIONThese observations demonstrate that immune control following ACT requires significant repertoire remodeling, which may be impaired in nonresponders because of the preexisting immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.TRIAL REGISTRATIONAustralian New Zealand Clinical Trial Registry, ACTRN12613000981729.FUNDINGThis study was supported by funding from the National Health and Medical Research Council, Australia (APP1132519 and APP1062074).

Autologous Adoptive T-cell Therapy for Recurrent or Drug-resistant Cytomegalovirus Complications in Solid Organ Transplant Recipients: A Single-arm Open-label Phase I Clinical Trial.

Background: Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection. Methods: In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution. Results: Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy. Conclusions: The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease. Clinical Trials Registration: ACTRN12613000981729.

Cardiac Metastasis of Nonvisceral Soft-tissue Leiomyosarcoma.

Metastasis of a nonvisceral leiomyosarcoma to the heart is rare. We present the case of a man with a history of an upper extremity cancerous lesion that was completely resected with appropriate surveillance monitoring, which then metastasized to the heart 14 years later, presenting as superior vena cava syndrome. Full evaluation found no other metastatic lesions, including no residual sarcoma at the former primary site. We include transthoracic echocardiography and computed tomography images of unusual presentation of the large mass extending from the caudal superior vena cava to the right atrium and into the right ventricle across the tricuspid valve.

Proinflammatory signaling regulates voluntary alcohol intake and stress-induced consumption after exposure to social defeat stress in mice.

Proinflammatory activity has been postulated to play a role in addictive processes and stress responses, but the underlying mechanisms remain largely unknown. Here, we examined the role of interleukin 1 (IL-1) and tumor necrosis factor-α (TNF-α) in regulation of voluntary alcohol consumption, alcohol reward and stress-induced drinking. Mice with a deletion of the IL-1 receptor I gene (IL-1RI KO) exhibited modestly decreased alcohol consumption. However, IL-1RI deletion affected neither the rewarding properties of alcohol, measured by conditioned place preference (CPP), nor stress-induced drinking induced by social defeat stress. TNF-α signaling can compensate for phenotypic consequences of IL1-RI deletion. We therefore hypothesized that double deletion of both IL-1RI and TNF-1 receptors (TNF-1R) may reveal the role of these pathways in regulation of alcohol intake. Double KOs consumed significantly less alcohol than control mice over a range of alcohol concentrations. The combined deletion of TNF-1R and IL-1RI did not influence alcohol reward, but did prevent increased alcohol consumption resulting from exposure to repeated bouts of social defeat stress. Taken together, these data indicate that IL-1RI and TNF-1R contribute to regulation of stress-induced, negatively reinforced drinking perhaps through overlapping signaling events downstream of these receptors, while leaving rewarding properties of alcohol largely unaffected.