Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19.

BACKGROUND: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days. METHODS: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183. RESULTS: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group. CONCLUSIONS: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.).

Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.

BACKGROUND: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known. METHODS: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru. RESULTS: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose. CONCLUSIONS: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.).

Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant.

BACKGROUND: Assessment of the safety and efficacy of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in different populations is essential, as is investigation of the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. METHODS: We conducted a multicenter, double-blind, randomized, controlled trial to assess the safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) in people not infected with the human immunodeficiency virus (HIV) in South Africa. Participants 18 to less than 65 years of age were assigned in a 1:1 ratio to receive two doses of vaccine containing 5×1010 viral particles or placebo (0.9% sodium chloride solution) 21 to 35 days apart. Serum samples obtained from 25 participants after the second dose were tested by pseudovirus and live-virus neutralization assays against the original D614G virus and the B.1.351 variant. The primary end points were safety and efficacy of the vaccine against laboratory-confirmed symptomatic coronavirus 2019 illness (Covid-19) more than 14 days after the second dose. RESULTS: Between June 24 and November 9, 2020, we enrolled 2026 HIV-negative adults (median age, 30 years); 1010 and 1011 participants received at least one dose of placebo or vaccine, respectively. Both the pseudovirus and the live-virus neutralization assays showed greater resistance to the B.1.351 variant in serum samples obtained from vaccine recipients than in samples from placebo recipients. In the primary end-point analysis, mild-to-moderate Covid-19 developed in 23 of 717 placebo recipients (3.2%) and in 19 of 750 vaccine recipients (2.5%), for an efficacy of 21.9% (95% confidence interval [CI], -49.9 to 59.8). Among the 42 participants with Covid-19, 39 cases (95.1% of 41 with sequencing data) were caused by the B.1.351 variant; vaccine efficacy against this variant, analyzed as a secondary end point, was 10.4% (95% CI, -76.8 to 54.8). The incidence of serious adverse events was balanced between the vaccine and placebo groups. CONCLUSIONS: A two-dose regimen of the ChAdOx1 nCoV-19 vaccine did not show protection against mild-to-moderate Covid-19 due to the B.1.351 variant. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT04444674; Pan African Clinical Trials Registry number, PACTR202006922165132).

Gaps in Patient-Centered Decision-Making Related to Complex Surgery: A Mixed-Methods Study.

INTRODUCTION: We sought to understand the perceptions of surgeons around patient preferred roles in decision-making and their approaches to patient-centered decision-making (PCDM). METHODS: A concurrent embedded mixed-methods design was utilized among a cohort of surgeons performing complex surgical procedures. Data were collected through online surveys. Associations between perceptions and PCDM approaches were examined. RESULTS: Among 241 participants, most respondents were male (67.2%) with an average age of 47.6 y (standard deviation = 10.3); roughly half (52.4%) had practiced medicine for 10 or more years. Surgeons most frequently agreed (94.2%) with the statement, "Patients prefer to make health decisions on their own after seriously considering their physician's opinion." Conversely, surgeons most frequently disagreed (73.0%) with the statement, "Patients prefer that their physician make health decisions for them." Nearly one-third (30.4%) of surgeon qualitative responses (n = 115) indicated that clinical/biological information would help them tailor their approach to PCDM. Only 12.2% of respondents indicated that they assess patient preferences regarding both decision-making and information needs. CONCLUSIONS: Surgeons most frequently agree that patients want to make their own health decisions after seriously considering their physicians opinion. A greater focus on what information surgeons should know before treatment decision-making may help optimize patient experience and outcomes related to complex surgical procedures.

A single-arm pilot of MyInspiration: a novel digital resource to support spiritual needs of patients undergoing cancer-directed surgery.

PURPOSE: This study aimed to assess the feasibility, acceptability, and satisfaction associated with the MyInspiration intervention, a digital spiritual support tool for patients undergoing cancer surgery. Additionally, we evaluated changes in spiritual well-being and the ability to find meaning in their experience with cancer before and after the intervention. METHODS: This was a prospective, single-arm pilot study. Feasibility and acceptability were assessed by ratio of participants who completed all assessments among individuals who had signed consent forms. Satisfaction was assessed with 5 Likert-style questions around user experience. Patient spiritual well-being and finding meaning in their experience with cancer were measured at baseline and post-intervention. RESULTS: Forty patients were enrolled, the majority of whom were female (80.0%) and diagnosed with breast cancer (52.5%), with an average age of 54.4 years (SD = 13.7, range 29.0-82.0). Regarding feasibility and acceptability, 76.9% of patients who consented to participate completed the full study protocol. In assessing satisfaction, 59% of patients were satisfied with the overall experience of MyInspiration. There was no difference in spiritual well-being pre-/post-intervention. There was a difference in pre (M = 1.95, SD = .95) and post (M = 2.23, SD = .86) scores relative to "finding meaning in the cancer experience" with a mean difference of 0.28 (p = 0.008). CONCLUSION: MyInspiration was feasible and acceptable to patients, and the majority were satisfied with the tool. The intervention was associated with changes in patients' ability to find meaning within their cancer experience. A randomized control trial is needed to evaluate the efficacy of the tool in a broader population of patients with cancer.

Influence of Pregnancy Intention on Postpartum Contraceptive Choice at an Urban Academic Medical Center.

OBJECTIVE: This study aimed to describe postpartum contraception preferences in the context of pregnancy intention (PI). STUDY DESIGN: A prospective cohort study analyzing postpartum contraceptive choice (PCC) in 431 postpartum women who delivered at a single academic medical center. PCC in women with an unintended or mistimed pregnancy was compared to contraceptive choice in women with an intended pregnancy using the adapted National Survey of Family Growth categorization. Mistimed and unintended pregnancies were grouped for analysis. Generalized linear modeling estimated the relative influence of PI on PCC adjusting for maternal age, race, and parity. RESULTS: Nearly three out of four (71.9%) pregnancies were mistimed or unintended. These pregnancies were more likely in women who were non-Hispanic Black (62.3%), unmarried (86.3%), 18 to 24 years (51.3%), and insured by Medicaid or Medicare (82.1%), compared to women with an intended pregnancy, p-value <0.001. Women with mistimed or unintended pregnancy were 83% more likely to choose highly effective, user-independent methods compared to any other or no method, adjusted relative risk (aRR) = 1.83 (95% confidence interval [CI]: 1.36, 2.47), and more likely to desire voluntary sterilization, aRR = 2.70 (95% CI: 1.58, 4.59). Additionally, women with these pregnancies were 56% more likely to use user-independent methods compared to user-dependent methods, aRR = 1.56 (95% CI: 1.18, 2.06). CONCLUSION: Women with mistimed or unintended pregnancies are 83% more likely to choose highly effective postpartum contraception or voluntary sterilization, and thus initiatives are necessary to increase access and affordability to these methods before hospital discharge after delivery. KEY POINTS: · Nearly three out of four pregnancies in this study were mistimed or unintended.. · Women with mistimed or unintended pregnancies are more likely to choose highly effective postpartum contraception or voluntary sterilization.. · Public health initiatives to improve access to family planning services and postpartum contraception, including surgery for bilateral tubal ligation before discharge from the hospital postdelivery, are important areas of focus to help attenuate the rates of unintended pregnancy in the United States..

Factors Associated with Maternal Morbidity among Black Women in the United States.

OBJECTIVE: Non-Hispanic Black people (NHBP) have a three-fold higher rate of maternal mortality compared to other racial groups. Racial disparities in maternal morbidity are well-described; however, there are substantial differences in cultural, economic, and social determinants of health among racial groups. We thus sought to study the at-risk, non-Hispanic Black population as its own cohort to identify factors most associated with severe maternal morbidity (SMM). STUDY DESIGN: This is a population-based retrospective case-control study of all live births in the United States between 2017 and 2019 using birth records obtained from the National Center for Health Statistics. The primary outcome for this study was to determine demographic, social, medical, and obstetric factors associated with maternal morbidity among NHBP who did and did not experience an SMM event. Multivariable logistic regression was used to estimate the adjusted odds ratio between each individual factor and the outcome of SMM among NHBP. RESULTS: Of the 1,624,744 NHBP who delivered between 2017 and 2019, 1.1% experienced an SMM event defined as a composite of blood product transfusion, eclamptic seizure, intensive care unit admission, unplanned hysterectomy, and uterine rupture. The rates of these individual SMM events per 10,000 deliveries were 50, 40, 20, 5, and 4 among NHBP, respectively. Among NHBP, factors associated in multivariable regression analysis with SMM in order of strength of association included cesarean delivery, earlier gestational age at delivery, preeclampsia, induction of labor, chronic hypertension, prior preterm birth, lower educational attainment, multifetal gestation, advanced maternal age, pregestational diabetes, and cigarette smoking. The population attributable fraction for cesarean delivery, preterm birth, and pregnancy-induced hypertensive disease for the outcome of SMM were 0.46, 0.23, and 0.07, respectively. CONCLUSION: The three factors most associated with SMM among NHBP are potentially avoidable or modifiable by aggressive screening, prevention, and treatment of preeclampsia and preterm birth as well as reducing cesarean rates in this population. KEY POINTS: · The rate of SMM in NHBP may be modifiable.. · NHBP have a three-fold higher rate of maternal mortality.. · Preeclampsia, preterm birth, and cesarean sections are most associated with maternal morbidity..

Use of Next-Generation Sequencing in a State-Wide Strategy of HIV-1 Surveillance: Impact of the SARS-COV-2 Pandemic on HIV-1 Diagnosis and Transmission.

BACKGROUND: The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic posed an unpreceded threat to the management of other pandemics such as human immunodeficiency virus-1 (HIV-1) in the United States. The full impact of the SARS-CoV-2 pandemic on the HIV-1 pandemic needs to be evaluated. METHODS: All individuals with newly reported HIV-1 diagnoses from NC State Laboratory of Public Health were enrolled in this prospective observational study, 2018-2021. We used a sequencing-based recency assay to identify recent HIV-1 infections and to determine the days postinfection (DPI) for each person at the time of diagnosis. RESULTS: Sequencing used diagnostic serum samples from 814 individuals with new HIV-1 diagnoses spanning this 4-year period. Characteristics of individuals diagnosed in 2020 differed from those in other years. People of color diagnosed in 2021 were on average 6 months delayed in their diagnosis compared to those diagnosed in 2020. There was a trend that genetic networks were more known for individuals diagnosed in 2021. We observed no major integrase resistance mutations over the course of the study. CONCLUSIONS: SARS-CoV-2 pandemic may contribute to the spread of HIV-1. Public health resources need to focus on restoring HIV-1 testing and interrupting active, ongoing, transmission.

Breakthrough SARS-CoV-2 Infections in the PROVENT Prevention Trial Were Not Associated With AZD7442 (Tixagevimab/Cilgavimab) Resistant Variants.

BACKGROUND: We report spike protein-based lineage and AZD7442 (tixagevimab/cilgavimab) neutralizing activity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants identified from breakthrough infections in the PROVENT preexposure prophylaxis trial. METHODS: Variants identified from PROVENT participants with reverse-transcription polymerase chain reaction-positive symptomatic illness were phenotypically assessed to determine neutralization susceptibility of variant-specific pseudotyped virus-like particles. RESULTS: At completion of 6 months' follow-up, no AZD7442-resistant variants were observed in breakthrough coronavirus disease 2019 (COVID-19) cases. SARS-CoV-2 neutralizing antibody titers were similar in breakthrough and nonbreakthrough cases. CONCLUSIONS: Symptomatic COVID-19 breakthrough cases in PROVENT were not due to resistance-associated substitutions in AZD7442 binding sites or lack of AZD7442 exposure. CLINICAL TRIALS REGISTRATION: NCT04625725.

AZD7442 (Tixagevimab/Cilgavimab) for Post-Exposure Prophylaxis of Symptomatic Coronavirus Disease 2019.

BACKGROUND: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19). METHODS: Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183. RESULTS: A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo. CONCLUSIONS: This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972.

Coding long COVID: characterizing a new disease through an ICD-10 lens.

BACKGROUND: Naming a newly discovered disease is a difficult process; in the context of the COVID-19 pandemic and the existence of post-acute sequelae of SARS-CoV-2 infection (PASC), which includes long COVID, it has proven especially challenging. Disease definitions and assignment of a diagnosis code are often asynchronous and iterative. The clinical definition and our understanding of the underlying mechanisms of long COVID are still in flux, and the deployment of an ICD-10-CM code for long COVID in the USA took nearly 2 years after patients had begun to describe their condition. Here, we leverage the largest publicly available HIPAA-limited dataset about patients with COVID-19 in the US to examine the heterogeneity of adoption and use of U09.9, the ICD-10-CM code for "Post COVID-19 condition, unspecified." METHODS: We undertook a number of analyses to characterize the N3C population with a U09.9 diagnosis code (n = 33,782), including assessing person-level demographics and a number of area-level social determinants of health; diagnoses commonly co-occurring with U09.9, clustered using the Louvain algorithm; and quantifying medications and procedures recorded within 60 days of U09.9 diagnosis. We stratified all analyses by age group in order to discern differing patterns of care across the lifespan. RESULTS: We established the diagnoses most commonly co-occurring with U09.9 and algorithmically clustered them into four major categories: cardiopulmonary, neurological, gastrointestinal, and comorbid conditions. Importantly, we discovered that the population of patients diagnosed with U09.9 is demographically skewed toward female, White, non-Hispanic individuals, as well as individuals living in areas with low poverty and low unemployment. Our results also include a characterization of common procedures and medications associated with U09.9-coded patients. CONCLUSIONS: This work offers insight into potential subtypes and current practice patterns around long COVID and speaks to the existence of disparities in the diagnosis of patients with long COVID. This latter finding in particular requires further research and urgent remediation.

Influence of social determinants of health on breastfeeding intent in the United States.

BACKGROUND: Breastfeeding rates in the United States are suboptimal despite public health recommendations that infants are fed breastmilk for their first year of life. This study aimed to characterize the influence of social determinants of health on intended breastfeeding duration. METHODS: This case-control study analyzed breastfeeding intent in 421 postpartum women. Data on social determinants and medical history were obtained from medical records and participant self-report. Logistic regression estimated the influence of demographic factors and social determinants on intent to breastfeed for durations of <6 months, 6-12 months, and at least 1 year. RESULTS: Thirty-five percent of mothers intended to breastfeed for at least 6 months, and 15% for 1 year. Social determinants that negatively predicted breastfeeding intent included not owning transportation and living in a dangerous neighborhood (p < 0.05). Women were more likely to intend to breastfeed for 12 months if they had knowledge of breastfeeding recommendations (adjusted odds ratio [aOR] 6.19, 95% confidence interval [CI 2.67-14.34]), an identifiable medical provider (aOR 2.64 [CI 1.22-5.72]), familial support (aOR 2.80 [CI 1.01-7.80]), or were married (aOR 2.55 [CI 1.01-6.46]). Sociodemographic factors that negatively influenced breastfeeding intent included non-Hispanic Black race, no high school diploma, cigarette use, income below $20,000, fewer than five prenatal visits, and WIC or Medicaid enrollment (p < 0.05). CONCLUSIONS: Women who lack familial support, an identifiable healthcare provider, or knowledge of breastfeeding guidelines are less likely to intend to breastfeed. Public health initiatives should address these determinants to improve breastfeeding and infant outcomes.

Genomics of sorghum local adaptation to a parasitic plant.

Host-parasite coevolution can maintain high levels of genetic diversity in traits involved in species interactions. In many systems, host traits exploited by parasites are constrained by use in other functions, leading to complex selective pressures across space and time. Here, we study genome-wide variation in the staple crop Sorghum bicolor (L.) Moench and its association with the parasitic weed Striga hermonthica (Delile) Benth., a major constraint to food security in Africa. We hypothesize that geographic selection mosaics across gradients of parasite occurrence maintain genetic diversity in sorghum landrace resistance. Suggesting a role in local adaptation to parasite pressure, multiple independent loss-of-function alleles at sorghum LOW GERMINATION STIMULANT 1 (LGS1) are broadly distributed among African landraces and geographically associated with S. hermonthica occurrence. However, low frequency of these alleles within S. hermonthica-prone regions and their absence elsewhere implicate potential trade-offs restricting their fixation. LGS1 is thought to cause resistance by changing stereochemistry of strigolactones, hormones that control plant architecture and below-ground signaling to mycorrhizae and are required to stimulate parasite germination. Consistent with trade-offs, we find signatures of balancing selection surrounding LGS1 and other candidates from analysis of genome-wide associations with parasite distribution. Experiments with CRISPR-Cas9-edited sorghum further indicate that the benefit of LGS1-mediated resistance strongly depends on parasite genotype and abiotic environment and comes at the cost of reduced photosystem gene expression. Our study demonstrates long-term maintenance of diversity in host resistance genes across smallholder agroecosystems, providing a valuable comparison to both industrial farming systems and natural communities.

Food Insecurity in an Urban Pregnancy Cohort.

OBJECTIVE: Food insecurity is a prominent problem and has been implicated in adverse maternal and neonatal outcomes. This study aims to describe the food insecure population in an urban academic health center perinatal cohort. STUDY DESIGN: We enrolled 451 postpartum inpatients at the University of Cincinnati Medical Center who completed a questionnaire and were then categorized as food insecure based on U.S. Department of Agriculture standardized survey questions. Generalized linear models estimated the relative influence of maternal characteristics on food insecurity. RESULTS: Among the study population (n = 426), 18.6% (95% confidence interval: 15.2-22.4%) were classified as food insecure. Factors with increased adjusted relative risk on food insecurity include annual household income <$40,000, obesity, and smoking. Food insecure women also reported lower levels of love, satisfaction, and joy, and higher levels of despair. CONCLUSION: We recommend the use of a validated screening tool on all pregnant women with the associated psychosocial stressors and social determinants of health. KEY POINTS: · Food insecurity is prevalent among pregnant women.. · Nearly one in five women (18.6%) in the study cohort were classified as food insecure.. · Food insecure pregnant women were more likely to have additional risks for adverse health outcomes..

Challenges in diagnosis and biomarker testing for RET-altered lung and thyroid cancer care: an international mixed-method study.

BACKGROUND: The introduction of new targeted therapies for RET-altered lung and thyroid cancers (LC/TC) has impacted pathologists' practice by making genomic testing more relevant. Variations in health systems and treatment access result in distinct clinical challenges and barriers. This study aimed to assess practice gaps and challenges experienced by pathologists involved in the diagnosis of RET-altered LC/TC, including biomarker testing, to inform educational solutions. METHODS: Pathologists in Germany, Japan, the UK, and US participated in this ethics-approved mixed-methods study, which included interviews and surveys (data collected January-March 2020). Qualitative data was thematically analysed, quantitative data was analysed with chi-square and Kruskal-Wallis H-tests, and both were triangulated. RESULTS: A total of 107 pathologists took part in this study. Knowledge gaps were reported regarding genomic testing for LC/TC in Japan (79/60%), the UK (73/66%), and the US (53/30%). Skill gaps were reported when selecting genomic biomarker tests to diagnose TC in Japan (79%), the UK (73%) and US (57%) and when performing specific biomarker tests, especially in Japan (82% for RET) and in the UK (75% for RET). Japanese participants (80%) reported uncertainty about what information to share with the multidisciplinary team to ensure optimal patient-centered care. At the time of data collection, pathologists in Japan faced access barriers to using RET biomarker tests: only 28% agreed that there are relevant RET genomic biomarker tests available in Japan, versus 67% to 90% in other countries. CONCLUSIONS: This study identified areas where pathologists need additional continuing professional development opportunities to enhance their competencies and better support delivery of care to patients with RET-altered lung or thyroid tumours. Addressing identified gaps and improving competencies of pathologists in this field should be emphasised in continuing medical education curricula and through quality improvement initiatives. Strategies deployed on an institutional and health system level should aim to improve interprofessional communication and genetic biomarker testing expertise.

Assessing the Impact of Provider Training and Perceived Barriers on the Provision of Spiritual Care: a Mixed Methods Study.

The current study evaluated formal training around spiritual care for healthcare providers and the relationships between that training, perceived barriers to spiritual care, and frequency of inquiry around spiritual topics. A mixed methods explanatory sequential design was used. Quantitative methods included an online survey administered to providers at The Ohio State University Comprehensive Cancer Center. Main and interactive effects of formal training and barriers to spiritual care on frequency of inquiry around spiritual topics were assessed with two-way ANOVA. Qualitative follow-up explored provider strategies to engage spiritual topics. Among 340 quantitative participants, most were female (82.1%) or White (82.6%) with over one-half identifying as religious (57.5%). The majority were nurses (64.7%) and less than 10% of all providers (n = 26) indicated formal training around spiritual care. There were main effects on frequency of inquiry around spiritual topics for providers who indicated "personal discomfort" as a barrier (p < 0.001), but not formal training (p = 0.526). Providers who indicated "personal discomfort" as a barrier inquired about spirituality less frequently, regardless of receiving formal training (M = 8.0, SD = 1.41) or not (M = 8.76, SD = 2.96). There were no interactive effects between training and "may offend patients" or "personal discomfort" (p = 0.258 and 0.125, respectively). Qualitative analysis revealed four strategies with direct and indirect approaches: (1) permission-giving, (2) self-awareness/use-of-self, (3) formal assessment, and (4) informal assessment. Training for providers should emphasize self-awareness to address intrapersonal barriers to improve the frequency and quality of spiritual care for cancer patients.

Intersection of Syphilis and Human Immunodeficiency Virus (HIV) Networks to Identify Opportunities to Enhance HIV Prevention.

BACKGROUND: Human immunodeficiency virus (HIV) and syphilis infection continue at disproportionate rates among minority men who have sex with men (MSM) in the United States. The integration of HIV genetic clustering with partner services can provide important insight into local epidemic trends to guide interventions and control efforts. METHODS: We evaluated contact networks of index persons defined as minority men and transgender women diagnosed with early syphilis and/or HIV infection between 2018 and 2020 in 2 North Carolina regions. HIV clusters were constructed from pol sequences collected through statewide surveillance. A combined "HIV-risk" network, which included persons with any links (genetic or sexual contact) to HIV-positive persons, was evaluated by component size, demographic factors, and HIV viral suppression. RESULTS: In total, 1289 index persons were identified and 55% named 1153 contacts. Most index persons were Black (88%) and young (median age 30 years); 70% had early syphilis and 43% had prevalent HIV infection. Most people with HIV (65%) appeared in an HIV cluster. The combined HIV-risk network (1590 contact network and 1500 cluster members) included 287 distinct components; however, 1586 (51%) were in a single component. Fifty-five percent of network members with HIV had no evidence of viral suppression. Overall, fewer index persons needed to be interviewed to identify 1 HIV-positive member without viral suppression (1.3 vs 4.0 for contact tracing). CONCLUSIONS: Integration of HIV clusters and viral loads illuminate networks with high HIV prevalence, indicating recent and ongoing transmission. Interventions intensified toward these networks may efficiently reach persons for HIV prevention and care re-engagement.

Pango lineage designation and assignment using SARS-CoV-2 spike gene nucleotide sequences.

BACKGROUND: More than 2 million SARS-CoV-2 genome sequences have been generated and shared since the start of the COVID-19 pandemic and constitute a vital information source that informs outbreak control, disease surveillance, and public health policy. The Pango dynamic nomenclature is a popular system for classifying and naming genetically-distinct lineages of SARS-CoV-2, including variants of concern, and is based on the analysis of complete or near-complete virus genomes. However, for several reasons, nucleotide sequences may be generated that cover only the spike gene of SARS-CoV-2. It is therefore important to understand how much information about Pango lineage status is contained in spike-only nucleotide sequences. Here we explore how Pango lineages might be reliably designated and assigned to spike-only nucleotide sequences. We survey the genetic diversity of such sequences, and investigate the information they contain about Pango lineage status. RESULTS: Although many lineages, including the main variants of concern, can be identified clearly using spike-only sequences, some spike-only sequences are shared among tens or hundreds of Pango lineages. To facilitate the classification of SARS-CoV-2 lineages using subgenomic sequences we introduce the notion of designating such sequences to a "lineage set", which represents the range of Pango lineages that are consistent with the observed mutations in a given spike sequence. CONCLUSIONS: We find that many lineages, including the main variants-of-concern, can be reliably identified by spike alone and we define lineage-sets to represent the lineage precision that can be achieved using spike-only nucleotide sequences. These data provide a foundation for the development of software tools that can assign newly-generated spike nucleotide sequences to Pango lineage sets.

Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Intersectionality in cancer care: A systematic review of current research and future directions.

OBJECTIVES: The objective of the current review was to synthesize the literature on intersectionality relative to disparities across the cancer care continuum. A model to support future intersectional cancer research was proposed. METHODS: Web-based discovery services and discipline-specific databases were queried for both peer-reviewed and gray literature. Study screening and data extraction were facilitated through the Covidence software platform. RESULTS: Among 497 screened studies, 28 met study inclusion criteria. Most articles were peer-reviewed empirical studies (n = 22) that focused on pre-diagnosis/screening (n = 19) and included marginalized racial/ethnic (n = 22) identities. Pre-cancer diagnosis, sexual orientation and race influenced women's screening and vaccine behaviors. Sexual minority women, particularly individuals of color, were less likely to engage in cancer prevention behaviors prior to diagnosis. Race and socioeconomic status (SES) were important factors in patient care/survivorship with worse outcomes among non-white women of low SES. Emergent themes in qualitative results emphasized the importance of patient intersectional identities, as well as feelings of marginalization, fears of discrimination, and general discomfort with providers as barriers to seeking cancer care. CONCLUSIONS: Patients with intersectional identities often experience barriers to cancer care that adversely impact screening, diagnosis, treatment, as well as survivorship. The use of an "intersectional lens" as a future clinical and research framework will facilitate a more multidimensional and holistic approach to the care of cancer patients.