Association Between SARS-CoV-2 Viral Load and COVID-19 Vaccination in 4 Phase 3 Trials.

Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802.

Selection of HIV Envelope Strains for Standardized Assessments of Vaccine-Elicited Antibody-Dependent Cellular Cytotoxicity-Mediating Antibodies.

Antibody-dependent cellular cytotoxicity (ADCC) has been correlated with reduced risk of human immunodeficiency virus type 1 (HIV-1) infection in several preclinical vaccine trials and in the RV144 clinical trial, indicating that this is a relevant antibody function to study. Given the diversity of HIV-1, the breadth of vaccine-induced antibody responses is a critical parameter to understand if a universal vaccine is to be realized. Moreover, the breadth of ADCC responses can be influenced by different vaccine strategies and regimens, including adjuvants. Therefore, to accurately evaluate ADCC and to compare vaccine regimens, it is important to understand the range of HIV Envelope (Env) susceptibility to these responses. These evaluations have been limited because of the complexity of the assay and the lack of a comprehensive panel of viruses for the assessment of these humoral responses. Here, we used 29 HIV-1 infectious molecular clones (IMCs) representing different Envelope subtypes and circulating recombinant forms to characterize susceptibility to ADCC from antibodies in plasma from infected individuals, including 13 viremic individuals, 10 controllers, and six with broadly neutralizing antibody responses. We found in our panel that ADCC susceptibility of the IMCs in our panel did not cluster by subtype, infectivity, level of CD4 downregulation, level of shedding, or neutralization sensitivity. Using partitioning around medoids (PAM) clustering to distinguish smaller groups of IMCs with similar ADCC susceptibility, we identified nested panels of four to eight IMCs that broadly represent the ADCC susceptibility of the entire 29-IMC panel. These panels, together with reagents developed to specifically accommodate circulating viruses at the geographical sites of vaccine trials, will provide a powerful tool to harmonize ADCC data generated across different studies and to detect common themes of ADCC responses elicited by various vaccines. IMPORTANCE Antibody-dependent cellular cytotoxicity (ADCC) responses were found to correlate with reduced risk of infection in the RV144 trial of the only human HIV-1 vaccine to show any efficacy to date. However, reagents to understand the breadth and magnitude of these responses across preclinical and clinical vaccine trials remain underdeveloped. In this study, we characterize HIV-1 infectious molecular clones encoding 29 distinct Envelope strains (Env-IMCs) to understand factors that impact virus susceptibility to ADCC and use statistical methods to identify smaller nested panels of four to eight Env-IMCs that accurately represent the full set. These reagents can be used as standardized reagents across studies to fully understand how ADCC may affect efficacy of future vaccine studies and how studies differ in the breadth of responses developed.

Promoting Informed Decisions About Colorectal Cancer Screening in Older Adults (PRIMED Study): a Physician Cluster Randomized Trial.

BACKGROUND: For adults aged 76-85, guidelines recommend individualizing decision-making about whether to continue colorectal cancer (CRC) testing. These conversations can be challenging as they need to consider a patient's CRC risk, life expectancy, and preferences. OBJECTIVE: To promote shared decision-making (SDM) for CRC testing decisions for older adults. DESIGN: Two-arm, multi-site cluster randomized trial, assigning physicians to Intervention and Comparator arms. Patients were surveyed shortly after the visit to assess outcomes. Analyses were intention-to-treat. PARTICIPANTS AND SETTING: Primary care physicians affiliated with 5 academic and community hospital networks and their patients aged 76-85 who were due for CRC testing and had a visit during the study period. INTERVENTIONS: Intervention arm physicians completed a 2-h online course in SDM communication skills and received an electronic reminder of patients eligible for CRC testing shortly before the visit. Comparator arm received reminders only. MAIN MEASURES: The primary outcome was patient-reported SDM Process score (range 0-4 with higher scores indicating more SDM); secondary outcomes included patient-reported discussion of CRC screening, knowledge, intention, and satisfaction with the visit. KEY RESULTS: Sixty-seven physicians (Intervention n=34 and Comparator n=33) enrolled. Patient participants (n=466) were on average 79 years old, 50% with excellent or very good self-rated overall health, and 66% had one or more prior colonoscopies. Patients in the Intervention arm had higher SDM Process scores (adjusted mean difference 0.36 (95%CI (0.08, 0.64), p=0.01) than in the Comparator arm. More patients in the Intervention arm reported discussing CRC screening during the visit (72% vs. 60%, p=0.03) and had higher intention to follow through with their preferred approach (58.0% vs. 47.1, p=0.03). Knowledge scores and visit satisfaction did not differ significantly between arms. CONCLUSION: Physician training plus reminders were effective in increasing SDM and frequency of CRC testing discussions in an age group where SDM is essential. TRIAL REGISTRATION: The trial is registered on clinicaltrials.gov (NCT03959696).

Paleocene latitude of the Kohistan-Ladakh arc indicates multistage India-Eurasia collision.

We report paleomagnetic data showing that an intraoceanic Trans-Tethyan subduction zone existed south of the Eurasian continent and north of the Indian subcontinent until at least Paleocene time. This system was active between 66 and 62 Ma at a paleolatitude of 8.1 ± 5.6 °N, placing it 600-2,300 km south of the contemporaneous Eurasian margin. The first ophiolite obductions onto the northern Indian margin also occurred at this time, demonstrating that collision was a multistage process involving at least two subduction systems. Collisional events began with collision of India and the Trans-Tethyan subduction zone in Late Cretaceous to Early Paleocene time, followed by the collision of India (plus Trans-Tethyan ophiolites) with Eurasia in mid-Eocene time. These data constrain the total postcollisional convergence across the India-Eurasia convergent zone to 1,350-2,150 km and limit the north-south extent of northwestern Greater India to <900 km. These results have broad implications for how collisional processes may affect plate reconfigurations, global climate, and biodiversity.

High Asymptomatic Carriage With the Omicron Variant in South Africa.

We report a 23% asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Omicron carriage rate in participants being enrolled into a clinical trial in South Africa, 15-fold higher than in trials before Omicron. We also found lower CD4 + T-cell counts in persons with human immunodeficiency virus (HIV) strongly correlated with increased odds of being SARS-CoV-2 polymerase chain reaction (PCR) positive.

Colorectal Cancer Screening During the COVID-19 Pandemic.

Shared decision-making (SDM) can help patients make good decisions about preventive health interventions such as cancer screening. We illustrate the use of SDM in the case of a 53-year-old man who had a new patient visit with a primary care physician and had never been screened for colorectal cancer (CRC). The patient had recently recovered from a serious COVID-19 infection requiring weeks of mechanical ventilation. When the primary care physician initially offered a screening colonoscopy, the man expressed great reluctance to return to the hospital for the exam. The PCP then offered a stool test, which could be completed at home, but emphasized that if it were positive, a colonoscopy would be required. He agreed to complete the stool test, and unfortunately, it was positive. He then agreed to undergo colonoscopy, which uncovered a large rectal cancer. The carcinoma had invaded the mesorectal fat but there were no metastases. After undergoing neoadjuvant chemotherapy followed by a low anterior resection of the tumor, he has no evidence of recurrence so far. Many clinicians favor colonoscopy for CRC screening, but evidence suggests that patients who are offered more than one reasonable option are more likely to undergo screening. If screening had been delayed in this patient until he was willing to accept a screening colonoscopy, there was the potential the cancer may have been more advanced when diagnosed, with a worse outcome. Shared decision-making was a key approach to understanding the patient's feelings related to this screening decision and making a decision consistent with his preferences.

Robotic Peritoneal Flap vs. Perineal Penile Inversion Techniques for Gender-Affirming Vaginoplasty.

PURPOSE OF REVIEW: To discuss perineal and robotic approaches to gender-affirming vaginoplasty. RECENT FINDINGS: The Davydov peritoneal vaginoplasty has its origins in neovaginal reconstruction for vaginal agenesis. It has been adapted as a robotic-assisted laparoscopic procedure and provides an alternative to perineal canal dissection in gender-affirming vaginoplasty. Both techniques represent variations of penile inversion vaginoplasty with successful outcomes and overall low rates of major complications reported in the literature. However, there are differing advantages and considerations to each approach. A perineal approach has been the gold standard to gender-affirming vaginoplasty for many decades. Robotic peritoneal gender-affirming vaginoplasty (RPGAV) is an emerging alternative, with potential advantages including less reliance on extragenital skin grafts in individuals with minimal genital tissue, especially among patients presenting with pubertal suppression, and safer dissection in revision vaginoplasty for stenosis of the proximal neovaginal canal. Additional risks of RPGAV include those associated with robotic abdominal surgeries.

A Systematic Review and Meta-Analysis of Preoperative Frailty Instruments Derived From Electronic Health Data.

BACKGROUND: Frailty is a strong predictor of adverse outcomes in the perioperative period. Given the increasing availability of electronic medical data, we performed a systematic review and meta-analysis with primary objectives of describing available frailty instruments applied to electronic data and synthesizing their prognostic value. Our secondary objectives were to assess the construct validity of frailty instruments that have been applied to perioperative electronic data and the feasibility of electronic frailty assessment. METHODS: Following protocol registration, a peer-reviewed search strategy was applied to Medline, Excerpta Medica dataBASE (EMBASE), Cochrane databases, and the Comprehensive Index to Nursing and Allied Health literature from inception to December 31, 2019. All stages of the review were completed in duplicate. The primary outcome was mortality; secondary outcomes included nonhome discharge, health care costs, and length of stay. Effect estimates adjusted for baseline illness, sex, age, procedure, and urgency were of primary interest; unadjusted and adjusted estimates were pooled using random-effects models where appropriate or narratively synthesized. Risk of bias was assessed. RESULTS: Ninety studies were included; 83 contributed to the meta-analysis. Frailty was defined using 22 different instruments. In adjusted data, frailty identified from electronic data using any instrument was associated with a 3.57-fold increase in the odds of mortality (95% confidence interval [CI], 2.68-4.75), increased odds of institutional discharge (odds ratio [OR], 2.40; 95% CI, 1.99-2.89), and increased costs (ratio of means, 1.54; 95% CI, 1.46-1.63). Most instruments were not multidimensional, head-to-head comparisons were lacking, and no feasibility data were reported. CONCLUSIONS: Frailty status derived from electronic data provides prognostic value as it is associated with adverse outcomes, even after adjustment for typical risk factors. However, future research is required to evaluate multidimensional instruments and their head-to-head performance and to assess their feasibility and clinical impact.

Ecological inference for infectious disease data, with application to vaccination strategies.

Disease surveillance systems provide a rich source of data regarding infectious diseases, aggregated across geographical regions. The analysis of such ecological data is fraught with difficulties, and, unless care and suitable data summaries are available, will lead to biased estimates of individual-level parameters. We consider using surveillance data to study the impacts of vaccination. To catalog the problems of ecological inference, we start with an individual-level model, which contains familiar parameters, and derive an ecologically consistent model for infectious diseases in partially vaccinated populations. We compare with other popular model classes and highlight deficiencies. We explore the properties of the new model through simulation and demonstrate that, under standard assumptions, the ecological model provides less biased estimates. We then fit the new model to data collected on measles outbreaks in Germany from 2005-2007.

Transforming Research and Clinical Knowledge in Spinal Cord Injury (TRACK-SCI): an overview of initial enrollment and demographics.

OBJECTIVE: Traumatic spinal cord injury (SCI) is a dreaded condition that can lead to paralysis and severe disability. With few treatment options available for patients who have suffered from SCI, it is important to develop prospective databases to standardize data collection in order to develop new therapeutic approaches and guidelines. Here, the authors present an overview of their multicenter, prospective, observational patient registry, Transforming Research and Clinical Knowledge in SCI (TRACK-SCI). METHODS: Data were collected using the National Institute of Neurological Disorders and Stroke (NINDS) common data elements (CDEs). Highly granular clinical information, in addition to standardized imaging, biospecimen, and follow-up data, were included in the registry. Surgical approaches were determined by the surgeon treating each patient; however, they were carefully documented and compared within and across study sites. Follow-up visits were scheduled for 6 and 12 months after injury. RESULTS: One hundred sixty patients were enrolled in the TRACK-SCI study. In this overview, basic clinical, imaging, neurological severity, and follow-up data on these patients are presented. Overall, 78.8% of the patients were determined to be surgical candidates and underwent spinal decompression and/or stabilization. Follow-up rates to date at 6 and 12 months are 45% and 36.3%, respectively. Overall resources required for clinical research coordination are also discussed. CONCLUSIONS: The authors established the feasibility of SCI CDE implementation in a multicenter, prospective observational study. Through the application of standardized SCI CDEs and expansion of future multicenter collaborations, they hope to advance SCI research and improve treatment.

Choose who's in your circle: how women's relationship actions during and following residential treatment help create recovery-oriented networks.

Women in recovery from substance use disorders often have difficulty establishing recovery-supportive networks. This exploratory study uses qualitative thematic analysis to examine how 88 women in recovery describe the actions they take to manage their personal social networks 12 months after intake into residential substance use treatment. Participants describe disconnecting or limiting contact with recovery-endangering people and adding recovery-supportive people to their networks as primary relationship actions for maintaining recovery. Their actions to build recovery-supportive networks can provide a focus for clinical work to help them become integrated into their communities.

Role of patient-provider communication on older adults' preferences for continuing colorectal cancer testing and visit satisfaction.

OBJECTIVE: To identify possible predictors of older adults' preferences for stopping or continuing colorectal cancer (CRC) testing and satisfaction with medical visits. METHODS: Cross-sectional, secondary analysis of patient data. The parent study was a two-arm, multi-site clustered randomized trial, assigning primary care physicians to receive shared decision making training plus a reminder, or reminders alone for patients who were due for CRC testing. For the current analysis, patient data were pooled and analyzed without regard to study arm. Patients were aged 76-85 years. RESULTS: In total, 375 patients reported their preference: 74 % preferred continued testing while 26 % preferred no further testing. In multivariable models, patients were more likely to prefer CRC testing if they had more maximizing preferences for health care, higher anticipated regret at missing a diagnosis, and lower anticipated regret about colonoscopy complications. Patients were more likely to report being extremely satisfied with the visit with longer duration spent discussing testing options. CONCLUSION: Anticipated decision regret and medical maximizing were associated with preferences for CRC testing. Time spent discussing CRC testing was associated with visit satisfaction. PRACTICE IMPLICATIONS: To support informed decision making, older adults should be given thorough information about CRC testing, treatments, and post-treatment follow up.

Deciphering Mechanochemical Influences of Emergent Actomyosin Crosstalk using QCM-D.

Cytoskeletal protein ensembles exhibit emergent mechanics where behavior exhibited in teams is not necessarily the sum of the components' single molecule properties. In addition, filaments may act as force sensors that distribute feedback and influence motor protein behavior. To understand the design principles of such emergent mechanics, we developed an approach utilizing QCM-D to measure how actomyosin bundles respond mechanically to environmental variables that alter constituent myosin II motor behavior. We demonstrate that QCM-D can detect changes in actomyosin viscoelasticity due to molecular-level alterations, such as motor concentration and nucleotide state, thus providing evidence for actin's role as a mechanical force-feedback sensor and a new approach for deciphering the fundamental mechanisms of emergent cytoskeletal ensemble crosstalk. Justification: Cytoskeletal ensembles exhibit mechanics that are not necessarily the sum of the components' single molecule properties, and this emergent behavior is not well understood. Cytoskeletal filaments may also act as force sensors that influence constituent motor protein behavior. To understand the elusive design principles of such emergent mechanics, we innovated an approach using QCM-D to measure how actomyosin bundles sense and respond mechanically to environmental variables. We demonstrate for the first time that QCM-D can detect changes in actomyosin viscoelasticity due to molecular-level alterations, thus providing evidence for actin's role as a mechanical force-feedback sensor and a new approach for deciphering the fundamentals of emergent cytoskeletal ensemble crosstalk.

Shared Decision-Making in Colorectal Cancer Screening for Older Adults: A Secondary Analysis of a Cluster Randomized Clinical Trial.

Importance: Decisions about whether to stop colorectal cancer (CRC) screening tests in older adults can be difficult and may benefit from shared decision-making (SDM). Objective: To evaluate the effect of physician training in SDM and electronic previsit reminders (intervention) vs reminders only (comparator) on receipt of the patient-preferred approach to CRC screening and on overall CRC screening rates of older adults at 12 months. Design, Setting, and Participants: This was a secondary analysis of the Promoting Informed Decisions About Colorectal Cancer Screening in Older Adults (PRIMED) cluster randomized clinical trial. In the PRIMED trial, primary care physicians (PCPs) from 36 primary care practices in Massachusetts and Maine were enrolled between May 1 and August 30, 2019, and were randomized to the intervention group or the comparator group. Patients aged 76 to 85 years who were overdue for CRC screening and did not have a prior diagnosis of CRC enrolled between October 21, 2019, and April 8, 2021. Data analysis was performed between May 24, 2022, and May 10, 2023. Interventions: Primary care physicians in the intervention group completed an SDM training course and received previsit reminders of patients eligible for CRC testing discussion, whereas PCPs in the comparator group received reminders only. Main Outcomes and Measures: The primary outcome was concordance, or the percentage of patients who received their preferred screening approach. Postvisit surveys were administered to assess patient preference for testing, and electronic health record review was used to assess CRC testing at 12 months. Heterogeneity of treatment effect analyses examined interaction between study groups and different factors on concordance rates. Results: This study included 59 physicians and 466 older adults. Physicians had a mean (SD) age of 52.7 (9.4) years and a mean (SD) of 21.6 (10.2) years in practice; 30 (50.8%) were women and 16 (27.1%) reported prior training in SDM. Patients had a mean (SD) age of 80.3 (2.8) years; 249 (53.4%) were women and 238 (51.1%) reported excellent or very good overall health. Patients preferred stool-based tests (161 [34.5%]), followed by colonoscopy (116 [24.8%]) or no further screening (97 [20.8%]); 75 (16.1%) were not sure. The distribution of patient preferences was similar across groups (P = .36). At 12 months, test uptake was also similar for both the intervention group (29 [12.3%] for colonoscopy, 62 [26.3%] for stool-based tests, and 145 [61.4%] for no testing) and the comparator group (32 [13.9%] for colonoscopy, 35 [15.2%] for stool-based tests, and 163 [70.9%] for no testing; P = .08). Approximately half of patients in the intervention group received their preferred approach vs the comparator group (115 of 226 [50.9%] vs 103 of 223 [46.2%]; P = .47). Heterogeneity of treatment effect analyses found significantly higher rates with the intervention vs the comparator for patients with a strong intention to follow through with the preferred approach (adjusted odds ratio [AOR], 1.79 [95% CI, 1.11-2.89]; P = .02, P = .05 for interaction) and for patients who reported more than 5 minutes (AOR, 3.27 [95% CI, 1.25-8.59]; P = .02, P = .05 for interaction) of discussion with their PCP regarding screening. Higher rates were also observed among patients who reported 2 to 5 minutes of discussion with their PCP, although this finding was not significant (AOR, 1.89 [95% CI, 0.93-3.84]; P = .08, P = .05 for interaction). Conclusions and Relevance: In this secondary analysis of a cluster randomized clinical trial, approximately half of older patients received their preferred approach to CRC screening. Physician training in SDM did not result in higher concordance rates overall but may have benefitted some subgroups. Future work to refine and evaluate clinical decision support (in the form of an electronic advisory or reminder) as well as focused SDM skills training for PCPs may promote high-quality, preference-concordant decisions about CRC testing for older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT03959696.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials.

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity. Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease. Design, Setting, and Participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023. Main Outcomes and Measures: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis. Results: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity. Conclusions and Relevance: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.