Rehabilitation in the intensive care unit: How amount of physical and occupational therapy affects patients' function and hospital length of stay.

BACKGROUND: Patients in the intensive care unit (ICU) often experience extended periods of immobility. Following hospital discharge, many face impaired mobility and never return to their baseline function. Although the benefits of physical and occupational rehabilitation are well established in non-ICU patients, a paucity of work describes effective practices to alleviate ICU-related declines in mobility. OBJECTIVE: To assess how rehabilitation with physical and occupational therapy (PT-OT) during ICU stays affects patients' mobility, self-care, and length of hospital stay. DESIGN: Retrospective cohort study. SETTING: Inpatient ICU. PARTICIPANTS: A total of 6628 adult patients who received physical rehabilitation across multiple sites (Arizona, Florida, Minnesota, and Wisconsin) of a single institution between January 2018 and December 2021. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Descriptive statistics, linear regression models, and gradient boosting machine methods were used to determine the relationship between the amount of PT-OT received and outcomes of hospital length of stay (LOS), Activity Measure for Post-Acute Care Daily Activity and Basic Mobility scores. RESULTS: The 6628 patients who met inclusion criteria received an average (median) of 23 (range: 1-89) minutes of PT-OT per day. Regression analyses showed each additional 10 minutes of PT-OT per day was associated with a 1.0% (95% confidence interval [CI]: 0.41-1.66, p < .001) higher final Basic Mobility score, a 1.8% (95% CI: 1.30%-2.34%, p < .001) higher final Daily Activity score, and a 1.2-day (95% CI: -1.28 to -1.09, p < .001) lower hospital LOS. One-dimensional partial dependence plots revealed an exponential decrease in predicted LOS as minutes of PT-OT received increased. CONCLUSION: Higher rehabilitation minutes provided to patients in the ICU may reduce the LOS and improve patients' functional outcomes at discharge. The benefits of rehabilitation increased with increasing amounts of time of therapy received.

Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

Germline Genetic Testing in Unselected Squamous and Non-Squamous Head and Neck Cancers.

OBJECTIVE: This study describes the prevalence of pathogenic germline variants (PGVs) in head and neck cancer patients, the incremental yield compared to a guideline-based approach to genetic evaluation, and the uptake of family variant testing. STUDY DESIGN: Prospective cohort study. SETTING: Three tertiary academic medical centers. METHODS: Germline sequencing using an 84-gene screening platform among unselected head and neck cancer patients who received care at Mayo Clinic Cancer Centers between April 2018 and March 2020. RESULTS: Amongst 200 patients, the median age was 62.0 years (Q1, Q3: 55, 71), 23.0% were female, 89.0% white/non-Hispanic, 5.0% Hispanic/Latinx, 6% of another race, and 42.0% had prognostic stage IV disease. The most common subsites were the oropharyngeal (45.0%) and salivary glands (12.0%). The most common histology was squamous cell carcinoma (74.5%). Twenty-one patients (10.5%) had a total of 22 PGVs; 20 of the 21 patients (95.2%) did not meet criteria for testing by current guidelines. Regarding penetrance of the 22 PGVs, 11 were high or moderate (most common PMS2 or HOXB13), and 11 were low or recessive (most common MUTYH, WNR, or RECQL4). One patient had a change in care based on an identified PGV. Family variant testing was completed at a rate of 4.8%. CONCLUSIONS: Universal gene panel testing identified a PGV in 10.5% of head and neck cancer patients; almost all would have been missed by current guideline-based testing. One of 21 patients had a treatment change due to their PGV, indicating that head and neck cancer treatment decisions are not yet widely informed by germline alterations. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3378-3388, 2023.

Universal Genetic Testing vs. Guideline-Directed Testing for Hereditary Cancer Syndromes Among Traditionally Underrepresented Patients in a Community Oncology Program.

Background Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognosis, treatment selection, clinical trial enrollment, and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but their applicability in an ethnically and racially diverse community hospital population is unknown. This study describes the diagnostic and incremental yield of universal multi-gene panel testing in a diverse population in a community cancer practice. Methods We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL, between June 2020 and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene next-generation sequencing (NGS) tumor genomic testing platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines determined incremental PGV rates. Results Two hundred twenty-three patients were enrolled, with a median age of 63 years, 78.5% female. 32.7% were Black/African American, and 5.4% were Hispanic. 39.9% of patients were commercially insured, Medicare/Medicaid insured 52.5%, and 2.7% were uninsured. The most common cancers in this cohort were breast (61.9%), lung (10.3%), and colorectal (7.2%). Twenty-three patients (10.3%) carried one or more PGVs, and 50.2% carried a variant of uncertain significance (VUS). Though there was no significant difference in the rate of PGVs based on race/ethnicity, African Americans were numerically more likely to have a VUS reported than whites (P=0.059). Eighteen (8.1%) patients had incremental clinically actionable findings that practice guidelines would not have detected, which was higher in non-whites. Conclusions In this racially/ethnically and socioeconomically diverse cohort, universal multi-gene panel testing (MGPT) increased diagnostic yield over targeted guideline-informed testing. Rates of VUS and incremental PGV were higher in non-white populations.

Association of Neutralizing Antispike Monoclonal Antibody Treatment With Coronavirus Disease 2019 Hospitalization and Assessment of the Monoclonal Antibody Screening Score.

Objective: To test the hypothesis that the Monoclonal Antibody Screening Score performs consistently better in identifying the need for monoclonal antibody infusion throughout each "wave" of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant predominance during the coronavirus disease 2019 (COVID-19) pandemic and that the infusion of contemporary monoclonal antibody treatments is associated with a lower risk of hospitalization. Patients and Methods: In this retrospective cohort study, we evaluated the efficacy of monoclonal antibody treatment compared with that of no monoclonal antibody treatment in symptomatic adults who tested positive for SARS-CoV-2 regardless of their risk factors for disease progression or vaccination status during different periods of SARS-CoV-2 variant predominance. The primary outcome was hospitalization within 28 days after COVID-19 diagnosis. The study was conducted on patients with a diagnosis of COVID-19 from November 19, 2020, through May 12, 2022. Results: Of the included 118,936 eligible patients, hospitalization within 28 days of COVID-19 diagnosis occurred in 2.52% (456/18,090) of patients who received monoclonal antibody treatment and 6.98% (7,037/100,846) of patients who did not. Treatment with monoclonal antibody therapies was associated with a lower risk of hospitalization when using stratified data analytics, propensity scoring, and regression and machine learning models with and without adjustments for putative confounding variables, such as advanced age and coexisting medical conditions (eg, relative risk, 0.15; 95% CI, 0.14-0.17). Conclusion: Among patients with mild to moderate COVID-19, including those who have been vaccinated, monoclonal antibody treatment was associated with a lower risk of hospital admission during each wave of the COVID-19 pandemic.

The Pitfalls of Mining for QuantiFERON Gold in Severely Ill Patients With COVID-19.

Objective: To assess the proportion of indeterminate QuantiFERON-TB Gold Plus (QFT-Plus) results in patients admitted for severe coronavirus disease 2019 (COVID-19) pneumonia and evaluate the factors associated with indeterminate QFT-Plus results. Patients and Methods: Data on COVID-19 admissions at Mayo Clinic in Florida were extracted between October 13, 2020, and September 20, 2021, and data from a prepandemic cohort were extracted between October 13, 2018, and September 20, 2019. A secondary analysis of the COVID-19 cohort was performed using gradient boosting modeling to generate variable importance and SHapley Additive exPlanations plots. Results: Our findings demonstrated more indeterminate QFT-Plus test results in patients hospitalized for severe COVID-19 infection than in patients without COVID-19 (139 of 495, 28.1%). The factors associated with indeterminate QFT-Plus test results included elevated levels of C-reactive protein, ferritin, lactate dehydrogenase and interleukin-6 and included lower levels of leukocyte, lymphocyte, and platelet counts. Conclusion: The patients with severe COVID-19 had a higher likelihood of indeterminate QFT-Plus results, which were associated with elevated levels of inflammatory markers consistent with severe infection. Interferon-gamma release assay screening tests are likely confounded by COVID-19 infection itself, limiting the screening ability for latent tuberculosis infection reactivation. Indeterminate QFT-Plus results may also require follow-up QFT-Plus testing after patient recovery from COVID-19, increasing the cost and complexity of medical decision making and management. Additional risk assessments may be needed in this patient population for screening for latent tuberculosis infection in patients with severe COVID-19.

Adoption of High-sensitivity Troponin Testing and Emergency Physician Ordering Behavior.

INTRODUCTION: Emergency departments (ED) are rapidly replacing conventional troponin assays with high-sensitivity troponin tests. We sought to evaluate emergency physician utilization of troponin tests before and after high-sensitivity troponin introduction in our ED. METHODS: We retrospectively examined 9,477 ED encounters, identifying the percentage in which physicians ordered a serum troponin both before and after our institution adopted a high-sensitivity troponin test. RESULTS: After introduction of high-sensitivity troponin testing, the percentage of ED encounters in which physicians ordered troponin studies decreased (28.3% before vs 22% after; P <.001), with the drop most pronounced in admitted patients (decrease of 10.9% [95% confidence interval [CI]: 7.3%-14.5%] in admitted patients vs decrease of 3.6% [95% CI: 1.7%-5.4%] in discharged patients; P<.001) CONCLUSION: Introduction of high-sensitivity troponin testing was associated with a decrease in troponin ordering. While the reasons for this are unclear, it is possible that physicians became more selective in their ordering behavior because of the lower specificity of high-sensitivity troponin.

Clinical and laboratory profiles of the SARS-CoV-2 Delta variant compared with pre-Delta variants.

OBJECTIVES: The emergence of SARS-CoV-2 variants of concern has led to significant phenotypical changes in transmissibility, virulence, and public health measures. Our study used clinical data to compare characteristics between a Delta variant wave and a pre-Delta variant wave of hospitalized patients. METHODS: This single-center retrospective study defined a wave as an increasing number of COVID-19 hospitalizations, which peaked and later decreased. Data from the United States Department of Health and Human Services were used to identify the waves' primary variant. Wave 1 (August 8, 2020-April 1, 2021) was characterized by heterogeneous variants, whereas Wave 2 (June 26, 2021-October 18, 2021) was predominantly the Delta variant. Descriptive statistics, regression techniques, and machine learning approaches supported the comparisons between waves. RESULTS: From the cohort (N = 1318), Wave 2 patients (n = 665) were more likely to be younger, have fewer comorbidities, require more care in the intensive care unit, and show an inflammatory profile with higher C-reactive protein, lactate dehydrogenase, ferritin, fibrinogen, prothrombin time, activated thromboplastin time, and international normalized ratio compared with Wave 1 patients (n = 653). The gradient boosting model showed an area under the receiver operating characteristic curve of 0.854 (sensitivity 86.4%; specificity 61.5%; positive predictive value 73.8%; negative predictive value 78.3%). CONCLUSION: Clinical and laboratory characteristics can be used to estimate the COVID-19 variant regardless of genomic testing availability. This finding has implications for variant-driven treatment protocols and further research.

Low antispike antibody levels correlate with poor outcomes in COVID-19 breakthrough hospitalizations.

BACKGROUND: While COVID-19 immunization programs attempted to reach targeted rates, cases rose significantly since the emergence of the delta variant. This retrospective cohort study describes the correlation between antispike antibodies and outcomes of hospitalized, breakthrough cases during the delta variant surge. METHODS: All patients with positive SARS-CoV-2 polymerase chain reaction hospitalized at Mayo Clinic Florida from 19 June 2021 to 11 November 2021 were considered for analysis. Cases were analyzed by vaccination status. Breakthrough cases were then analyzed by low and high antibody titers against SARS-CoV-2 spike protein, with a cut-off value of ≥132 U/ml. Outcomes included hospital length of stay (LOS), need for intensive care unit (ICU), mechanical ventilation, and mortality. We used 1:1 nearest neighbor propensity score matching without replacement to assess for confounders. RESULTS: Among 627 hospitalized patients with COVID-19, vaccine breakthrough cases were older with more comorbidities compared to unvaccinated. After propensity score matching, the unvaccinated patients had higher mortality (27 [28.4%] vs. 12 [12.6%], p = 0.002) and LOS (7 [1.0-57.0] vs. 5 [1.0-31.0] days, p = 0.011). In breakthrough cases, low-titer patients were more likely to be solid organ transplant recipients (16 [34.0%] vs. 9 [12.3%], p = 0.006), with higher need for ICU care (24 [51.1%] vs. 22 [11.0%], p = 0.034), longer hospital LOS (median 6 vs. 5 days, p = 0.013), and higher mortality (10 [21.3%] vs. 5 [6.8%], p = 0.025) than high-titer patients. CONCLUSIONS: Hospitalized breakthrough cases were more likely to have underlying risk factors than unvaccinated patients. Low-spike antibody titers may serve as an indicator for poor prognosis in breakthrough cases admitted to the hospital.

The role research gap years play in a successful dermatology match.

BACKGROUND: A new trend includes taking a dedicated year away from medical school to complete a research fellowship. There is minimal data on the benefit of a gap year. We aimed to identify if a gap year makes a dermatology applicant more successful in The Match. METHODS: Dermatology applicants who applied to Mayo Clinic Arizona for the 2018-2019 application cycle and Mayo Clinic Rochester, Arizona, and Florida for the 2019-2020 application cycle were surveyed. RESULTS: In total, 291 dermatology applicants completed the initial survey, and 236 completed the follow-up survey. Ninety applicants took a gap year, 198 applicants did not. There was no significant difference in match rates. When comparing match rates at top dermatology residency programs, 40.6% of gap-year applicants matched to these residencies versus 19.0% of no gap-year applicants (P < 0.01). CONCLUSION: Applicants should weigh the opportunity costs before pursuing research gap years as they may not be universally helpful. Applicants who want to match at a top dermatology program may benefit from a research gap year. This data may have limited generalizability outside of the United States.

The role of race and ethnicity in the dermatology applicant match process.

OBJECTIVE: The field of dermatology is one of the least racially diverse specialties. We aimed to identify ways in which minorities become underrepresented within dermatology. METHODS: We surveyed dermatology applicants who applied to Mayo Clinic in Scottsdale, AZ during the 2018-2019 application cycle and Mayo Clinic in Rochester, Scottsdale, and Jacksonville during the 2019-2020 application cycles. Underrepresented minorities (URM) were defined as Latino/Latina, African American, American Indian/Alaska Native, or Native Hawaiian/Pacific Islander. RESULTS: In total, 149 and 142 dermatology applicants completed the initial 2019 and 2020 surveys, 112 and 124 completed the follow-up surveys. The racial breakdown was 69.9% Caucasian, 23.7% Asian, 5.4% African American, 0.4% American Indian/Alaska Native, and 0.7% Native Hawaiian/Pacific Islander. Eight percent identified as Hispanic/Latino. Median Step 1 scores were lower for URM (p<0.01). URM had more publications (p=0.01). There were no observed differences in away rotations or interviews attended. URM were less likely to match (76.7%) vs. Whites (88.4%) and Asians (96.0%; p=0.03). CONCLUSION: URM are taking out more loans, pursuing research fellowships more often than their White counterparts, publishing more, completing the same number of away rotations and interviews, yet have lower match rates leading to underrepresentation in the field. It is important to realize how Step scores might reflect and reproduce disparities between different racial/ethnic backgrounds, in turn influencing the racial composition of dermatology residency programs.

Germline Cancer Susceptibility Gene Testing in Unselected Patients With Colorectal Adenocarcinoma: A Multicenter Prospective Study.

BACKGROUND & AIMS: Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. This study aimed to determine the prevalence of pathogenic germline variants (PGVs) in CRC patients using a universal testing approach, association with clinical outcomes, and the uptake of family variant testing. METHODS: We performed a prospective multisite study of germline sequencing using a more than 80-gene next-generation sequencing platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: Of 361 patients, the median age was 57 years (SD, 12.4 y), 43.5% were female, 82% were white, and 38.2% had stage IV disease. PGVs were found in 15.5% (n = 56) of patients, including 44 in moderate- and high-penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC-specific gene panel. Only younger age at diagnosis was associated with the presence of PGVs (odds ratio, 1.99; 95% CI, 1.12-3.56). After a median follow-up period of 20.7 months, no differences in overall survival were seen between those with or without a PGV (P = .2). Eleven percent of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%). CONCLUSIONS: Universal multigene panel testing in CRC was associated with a modest, but significant, detection of heritable mutations over guideline-based testing. One in 10 patients had changes in their management based on test results. Uptake of cascade family testing was low, which is a concerning observation that warrants further study.

Germline Cancer Susceptibility Gene Testing in Unselected Patients with Hepatobiliary Cancers: A Multi-Center Prospective Study.

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. PREVENTION RELEVANCE: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

Access to and safety of COVID-19 convalescent plasma in the United States Expanded Access Program: A national registry study.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to coronavirus disease 2019 (COVID-19) convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents. The objective of this study is to report on the demographic, geographical, and chronological characteristics of patients in the EAP, and key safety metrics following transfusion of COVID-19 convalescent plasma. METHODS AND FINDINGS: Mayo Clinic served as the central institutional review board for all participating facilities, and any US physician could participate as a local physician-principal investigator. Eligible patients were hospitalized, were aged 18 years or older, and had-or were at risk of progression to-severe or life-threatening COVID-19; eligible patients were enrolled through the EAP central website. Blood collection facilities rapidly implemented programs to collect convalescent plasma for hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal patterns in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate at the state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions, as well as assessing enrollment in metropolitan areas and less populated areas that did not have access to COVID-19 clinical trials. From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. The majority of patients were 60 years of age or older (57.8%), were male (58.4%), and had overweight or obesity (83.8%). There was substantial inclusion of minorities and underserved populations: 46.4% of patients were of a race other than white, and 37.2% of patients were of Hispanic ethnicity. Chronologically and geographically, increases in the number of both enrollments and transfusions in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled and transfused patients in the EAP, including both in metropolitan and in less populated areas. The incidence of serious adverse events was objectively low (<1%), and the overall crude 30-day mortality rate was 25.2% (95% CI, 25.0% to 25.5%). This registry study was limited by the observational and pragmatic study design that did not include a control or comparator group; thus, the data should not be used to infer definitive treatment effects. CONCLUSIONS: These results suggest that the EAP provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The study design of the EAP may serve as a model for future efforts when broad access to a treatment is needed in response to an emerging infectious disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT#: NCT04338360.

Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors.

Successful therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have harnessed the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Evidence that SARS-CoV-2 exists as locally evolving variants suggests that immunological differences may impact the effectiveness of antibody-based treatments such as convalescent plasma and vaccines. Considering that near-sourced convalescent plasma likely reflects the antigenic composition of local viral strains, we hypothesize that convalescent plasma has a higher efficacy, as defined by death within 30 days of transfusion, when the convalescent plasma donor and treated patient were in close geographic proximity. Results of a series of modeling techniques applied to approximately 28,000 patients from the Expanded Access to Convalescent Plasma program (ClinicalTrials.gov number: NCT04338360) support this hypothesis. This work has implications for the interpretation of clinical studies, the ability to develop effective COVID-19 treatments, and, potentially, for the effectiveness of COVID-19 vaccines as additional locally-evolving variants continue to emerge.

Shoulder-Specific Patient-Reported Outcome Measures for Use in Patients With Head and Neck Cancer: An Assessment of Reliability, Construct Validity, and Overall Appropriateness of Test Score Interpretation Using Rasch Analysis.

OBJECTIVES: The purpose of this study was to investigate the construct validity and overall appropriateness of test score interpretation of 4 shoulder-related patient-reported outcome (PRO) measures for use in a population of patients with head and neck cancer using Rasch analysis. METHODS: One hundred eighty-two individuals who had received a neck dissection procedure within the past 2 weeks to 18 months were recruited for this cross-sectional psychometric study. Rasch methodologies were used to investigate scale dimensionality, scale hierarchy, response scale structure, and reliability of Disabilities of the Arm, Shoulder and Hand (DASH), QuickDASH, Shoulder Pain and Disability Index (SPADI), and Neck Dissection Impairment Index (NDII). RESULTS: DASH did not meet criteria for unidimensionality and was deemed inappropriate for use in this sample. The QuickDASH, SPADI, and NDII were all determined to be unidimensional. All scales had varying issues with person and item misfit, differential item functioning, coverage of ability levels, and optimal rating scale requirements. The NDII met most requirements. All measures were found to meet thresholds for person and item separation as well as reliability statistics. CONCLUSIONS: Rasch analysis indicates the NDII is the most appropriate measure studied for this population. The QuickDASH and SPADI are recommended with reservation, whereas the DASH is not recommended. IMPACT: This study demonstrates the use of objective methodologies, using Rasch analysis, to validate PRO recommendations provided by clinical experts in forums such as the Evaluation Database to Guide Effectiveness (EDGE) TaskForce, which are based upon a comprehensive literature review, consideration of published psychometric properties, and expert consensus. Use of Rasch methodologies demonstrates weaknesses in this model and provides opportunities to strengthen recommendations for clinicians.

SARS-CoV-2 Serologic Assays Dependent on Dual-Antigen Binding Demonstrate Diverging Kinetics Relative to Other Antibody Detection Methods.

Longitudinal studies assessing durability of the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) humoral immune response have generated conflicting results. This has been proposed to be due to differences in patient populations, the lack of standardized methodologies, and the use of assays that measure distinct aspects of the humoral response. SARS-CoV-2 antibodies were serially measured in sera from a cohort of 44 well-characterized convalescent plasma donors over 120 days post-COVID-19 symptom onset, utilizing eight assays, which varied according to antigen source, the detected antibody isotype, and the activity measured (i.e., binding, blocking, or neutralizing). While the majority of assays demonstrated a gradual decline in antibody titers over the course of 120 days, the two electrochemiluminescence immunoassay Roche assays (Roche Diagnostics Elecsys anti-SARS-CoV-2 [qualitative, nucleocapsid based] and Roche Diagnostics Elecsys anti-SARS-CoV-2 S [semiquantitative, spike based]), which utilize dual-antigen binding for antibody detection, demonstrated stable and/or increasing antibody titers over the study period. This study is among the first to assess longitudinal, rather than cross-sectional, SARS-CoV-2 antibody profiles among convalescent COVID-19 patients, primarily using commercially available serologic assays with Food and Drug Administration emergency use authorization. We show that SARS-CoV-2 antibody detection is dependent on the serologic method used, which has implications for future assay utilization and clinical value.

Program and patient characteristics for the United States Expanded Access Program to COVID-19 convalescent plasma.

BACKGROUND: The United States (US) Expanded Access Program (EAP) to COVID-19 convalescent plasma was initiated in response to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease-2019 (COVID-19). While randomized clinical trials were in various stages of development and enrollment, there was an urgent need for widespread access to potential therapeutic agents particularly for vulnerable racial and ethnic minority populations who were disproportionately affected by the pandemic. The objective of this study is to report on the demographic, geographic, and chronological access to COVID-19 convalescent plasma in the US via the EAP. METHODS AND FINDINGS: Mayo Clinic served as the central IRB for all participating facilities and any US physician could participate as local physician-principal investigator. Registration occurred through the EAP central website. Blood banks rapidly developed logistics to provide convalescent plasma to hospitalized patients with COVID-19. Demographic and clinical characteristics of all enrolled patients in the EAP were summarized. Temporal trends in access to COVID-19 convalescent plasma were investigated by comparing daily and weekly changes in EAP enrollment in response to changes in infection rate on a state level. Geographical analyses on access to convalescent plasma included assessing EAP enrollment in all national hospital referral regions as well as assessing enrollment in metropolitan and less populated areas which did not have access to COVID-19 clinical trials.From April 3 to August 23, 2020, 105,717 hospitalized patients with severe or life-threatening COVID-19 were enrolled in the EAP. A majority of patients were older than 60 years of age (57.8%), male (58.4%), and overweight or obese (83.8%). There was substantial inclusion of minorities and underserved populations, including 46.4% of patients with a race other than White, and 37.2% of patients were of Hispanic ethnicity. Severe or life-threatening COVID-19 was present in 61.8% of patients and 18.9% of patients were mechanically ventilated at time of convalescent plasma infusion. Chronologically and geographically, increases in enrollment in the EAP closely followed confirmed infections across all 50 states. Nearly all national hospital referral regions enrolled patients in the EAP, including both in metropolitan and less populated areas. CONCLUSIONS: The EAP successfully provided widespread access to COVID-19 convalescent plasma in all 50 states, including for underserved racial and ethnic minority populations. The efficient study design of the EAP may serve as an example framework for future efforts when broad access to a treatment is needed in response to a dynamic disease affecting demographic groups and areas historically underrepresented in clinical studies.

Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19.

BACKGROUND: Convalescent plasma has been widely used to treat coronavirus disease 2019 (Covid-19) under the presumption that such plasma contains potentially therapeutic antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be passively transferred to the plasma recipient. Whether convalescent plasma with high antibody levels rather than low antibody levels is associated with a lower risk of death is unknown. METHODS: In a retrospective study based on a U.S. national registry, we determined the anti-SARS-CoV-2 IgG antibody levels in convalescent plasma used to treat hospitalized adults with Covid-19. The primary outcome was death within 30 days after plasma transfusion. Patients who were enrolled through July 4, 2020, and for whom data on anti-SARS-CoV-2 antibody levels in plasma transfusions and on 30-day mortality were available were included in the analysis. RESULTS: Of the 3082 patients included in this analysis, death within 30 days after plasma transfusion occurred in 115 of 515 patients (22.3%) in the high-titer group, 549 of 2006 patients (27.4%) in the medium-titer group, and 166 of 561 patients (29.6%) in the low-titer group. The association of anti-SARS-CoV-2 antibody levels with the risk of death from Covid-19 was moderated by mechanical ventilation status. A lower risk of death within 30 days in the high-titer group than in the low-titer group was observed among patients who had not received mechanical ventilation before transfusion (relative risk, 0.66; 95% confidence interval [CI], 0.48 to 0.91), and no effect on the risk of death was observed among patients who had received mechanical ventilation (relative risk, 1.02; 95% CI, 0.78 to 1.32). CONCLUSIONS: Among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti-SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT04338360.).