Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells.

Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.

Universal testing for severe acute respiratory syndrome coronavirus 2 in 2 Philadelphia hospitals: carrier prevalence and symptom development over 2 weeks.

Background: The coronavirus disease 2019 pandemic caused by the severe acute respiratory syndrome coronavirus 2 has challenged obstetrical care providers. Universal testing on labor and delivery units has been implemented by many hospitals to ensure patient and staff safety. Asymptomatic carrier rates are expected to vary based on geographic differences in disease prevalence, although differences within the same city have not been reported previously. In addition, clinical follow-up of women who had a negative result for severe acute respiratory syndrome coronavirus 2 during obstetrical hospitalization has not been included in any previous reports. Objective: This study aimed to describe the prevalence of positive severe acute respiratory syndrome coronavirus 2 test results among asymptomatic pregnant women at 2 Philadelphia obstetrical hospitals, characterize the clinical course of those who had a positive result, and report symptom development among all women tested in the 2 weeks after hospitalization. Study Design: This is an observational study of asymptomatic pregnant women who underwent severe acute respiratory syndrome coronavirus 2 testing at 2 academic health centers (Hospital of the University of Pennsylvania and Pennsylvania Hospital) in Philadelphia, Pennsylvania, between April 13, 2020, and April 26, 2020. All women tested were contacted via telephone for symptom follow-up at 1 and 2 weeks after discharge. Asymptomatic positive test rates are reported for the overall population and by hospital. The hospital and 2-week posthospital course are described for women who had a positive result for severe acute respiratory syndrome coronavirus 2. Posthospital symptom development among women who had a negative result for severe acute respiratory syndrome coronavirus 2 is also described. Results: A total of 318 asymptomatic women underwent severe acute respiratory syndrome coronavirus 2 testing during this 2-week period; 8 women had a positive result. The overall asymptomatic test positive rate was 2.5%. The rate at Hospital of the University of Pennsylvania was 3.8% compared with 1.3% at Pennsylvania Hospital (P=.283). Of note, 3 women (37.5%) who were initially asymptomatic developed mild symptoms in the 2 weeks after a positive test result. Repeat severe acute respiratory syndrome coronavirus 2 testing was performed in 14 of the 310 women (4.5%) who initially had a negative result; 2 women (0.6%) had a positive result on repeat testing. Moreover, 242 (78.1%) and 213 (68.7%) of the 310 women who had a negative result for severe acute respiratory syndrome coronavirus 2 at the time of the initial hospitalization were followed up via telephone at 1 and 2 weeks after admission, respectively. Viral symptoms, including fevers, chills, shortness of breath, or cough, were self-reported in 4.5% and 4.2% of these women at 1 and 2 weeks after discharge, respectively. Conclusion: The asymptomatic positive severe acute respiratory syndrome coronavirus 2 test rate among an obstetrical population in Philadelphia differed between 2 hospitals and was lower than that described in other geographic regions. This supports the importance of institution-specific testing protocols. The development of symptomatic severe acute respiratory syndrome coronavirus 2 infection after hospitalization among women with initial negative test results is uncommon.

The Psychological Experience of Obstetric Patients and Health Care Workers after Implementation of Universal SARS-CoV-2 Testing.

OBJECTIVE: This study was aimed to describe the hospitalization and early postpartum psychological experience for asymptomatic obstetric patients tested for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) as part of a universal testing program and report the impact of this program on labor and delivery health care workers' job satisfaction and workplace anxiety. STUDY DESIGN: This is a cohort study of asymptomatic pregnant women who underwent SARS-CoV-2 testing between April 13, 2020 and April 26, 2020. Semistructured interviews were conducted via telephone at 1 and 2 weeks posthospitalization to assess maternal mental health. Depression screening was conducted using the patient health questionnaire-2 (PHQ-2). An online survey of labor and delivery health care workers assessed job satisfaction and job-related anxiety before and during the novel coronavirus disease 2019 (COVID-19) pandemic, as well as employees' subjective experience with universal testing. Patient and employee responses were analyzed for recurring themes. RESULTS: A total of 318 asymptomatic women underwent SARS-CoV-2 testing during this 2-week period. Six of the eight women (75%) who tested positive reported negative in-hospital experiences secondary to perceived lack of provider and partner support and neonatal separation after birth. Among the 310 women who tested negative, 34.4% of multiparous women reported increased postpartum anxiety compared with their prior deliveries due to concerns about infectious exposure in the hospital and lack of social support. Only 27.6% of women, tested negative, found their test result to be reassuring. Job satisfaction and job-related anxiety among health care workers were negatively affected. Universal testing was viewed favorably by the majority of health care workers despite concerns about delays or alterations in patient care and maternal and neonatal separation. CONCLUSION: Universal testing for SARS-CoV-2 in obstetric units has mixed effects on maternal mental health but is viewed favorably by labor and delivery employees. Ongoing evaluation of new testing protocols is paramount to balance staff and patient safety with quality and equality of care. KEY POINTS: · Women with SARS-CoV-2 had a negative hospital experience.. · A negative SARS-CoV-2 test was not reassuring for patients.. · COVID-19 negatively impacts healthcare workers' well-being..

Neurobehavioral outcomes in young adults with perinatally acquired HIV.

BACKGROUND: With combination antiretroviral therapy (cART), infants with perinatally acquired HIV (pHIV) are living into adolescence and adulthood. Worldwide, many have not received cART in the first years of life, and challenges of adolescence complicate transition to adulthood. Neurobehavioral outcomes in pHIV young adults (pHIVAd) are infrequently reported. OBJECTIVES: To examine neurobehavioral characteristics of pHIVAd ages 21-30 years, and to compare them with age-matched young adults infected in the second or third decade of life (HIVagematch), and older adults with similar duration HIV disease (HIVOA). METHODS: A comprehensive neuropsychological test battery and questionnaires to determine cognitive function and mood, and reviews of neuromedical and behavioral records were undertaken in three groups of 13 individuals each. Descriptive analysis and bivariate techniques were used for comparisons. RESULTS: Rates of cognitive impairment were highest in pHIVAd (85%) compared with HIVagematch (38%) and HIVOA (62%). pHIVAd had the worst scores in global cognition, speed of information processing, working memory, and verbal fluency (0.5--1.0 SD below other groups). There was a trend for higher rates of psychiatric dysfunction (predominantly mood disorders) in pHIVAd (85%) compared with HIV-agematch (46%) and HIVOA (54%). Only four pHIVAd reported employment or enrollment in school. Four had autoimmune disorders. CONCLUSION: These pHIVAd displayed high rates of cognitive, psychiatric, and autoimmune dysfunction, greater than age-matched or HIV duration-matched comparators. Although this small study is largely descriptive in nature, it suggests that a lack of cART in early life may result in long-term neurobehavioral and immune abnormalities manifesting into adulthood.