Major cardiovascular events after COVID-19, event rates post-vaccination, antiviral or anti-inflammatory therapy, and temporal trends: Rationale and methodology of the CORONA-VTE-Network study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied. METHODS: Adult patients, aged ≥18 years, with polymerase chain reaction-confirmed COVID-19 who received inpatient or outpatient care at the participating centers of the registry are eligible for inclusion. A total of 10,000 patients have been included in this multicenter study, with Brigham and Women's Hospital (Boston, MA) serving as the coordinating center. Other sites include Beth Israel Deaconess Medical Center, Anne Arundel Medical Center, University of Virginia Medical Center, University of Colorado Health System, and Thomas Jefferson University Health System. Data elements will be ascertained manually for accuracy. The two main outcomes are 1) a composite of venous or arterial thrombotic events, and 2) a composite of major cardiovascular events, defined as venous or arterial thrombosis, myocarditis or heart failure with inpatient treatment, new atrial fibrillation/flutter, or cardiovascular death. Clinical outcomes are adjudicated by independent physicians. Vaccination status and time of inclusion in the study will be ascertained for subgroup-specific analyses. Outcomes are pre-specified to be reported separately for hospitalized patients versus those who were initially receiving outpatient care. Outcomes will be reported at 30-day and 90-day follow-up. Data cleaning at the sites and the data coordinating center and outcomes adjudication process are in-progress. CONCLUSIONS: The CORONA-VTE-Network study will share contemporary information related to rates of cardiovascular and thrombotic events in patients with COVID-19 overall, as well as within key subgroups, including by time of inclusion, vaccination status, patients undergoing hemodialysis, the elderly, and sex-informed analyses such as comparison of women and men, or among pregnant and breastfeeding women.

Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.

D-Dimer elevation and adverse outcomes.

D-Dimer is a biomarker of fibrin formation and degradation. While a D-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated D-dimer with adverse outcomes has received far less emphasis. An elevated D-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated D-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the D-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

Continuous Positive Airway Pressure (CPAP) for prevention of recurrent pneumonia in the Neuromyelitis Optica patient.

INTRODUCTION: Traumatic spinal cord injury patients with quadriplegia associated respiratory compromise are at an immediately increased risk of developing pneumonia, but the onset of pneumonia risk and use of prevention strategies in the patient with quadriplegia due to Neuromyelitis Optica has not been described. CASE REPORT: This is a case of a Neuromyelitis Optica patient with quadriplegia, dysphagia and tracheostomy that suffered recurrent fevers due to respiratory infections. The non-specific presentation and test results led to extensive testing, while the frequent recurrence resulted in the patient residing in the acute care hospital 201 days and outside of this hospital only 118 days during the period of August 2011 to June 2012. The initiation of CPAP 10 cm while sleeping overnight for 8-10 h eliminated the recurrence of respiratory infections and thereby reduced both the frequency and duration of the patient's hospital stays. CONCLUSIONS: Patients with Neuromyelitis Optica differ from those with traumatic spinal cord injury as they have a chronic progressive systemic illness that causes continued deterioration of their nervous system resulting in the need for routine monitoring that ensures the timely addition of CPAP for the prevention of pneumonia and its associated medical expenses.

Randomized trial of physician alerts for thromboprophylaxis after discharge.

BACKGROUND: Many hospitalized Medical Service patients are at risk for venous thromboembolism in the months after discharge. We conducted a multicenter randomized controlled trial to test whether a hospital staff member's thromboprophylaxis alert to an Attending Physician before discharge will increase the rate of extended out-of-hospital prophylaxis and, in turn, reduce the incidence of symptomatic venous thromboembolism at 90 days. METHODS: From April 2009 to January 2010, we enrolled hospitalized Medical Service patients using the point score system developed by Kucher et al to identify those at high risk for venous thromboembolism who were not ordered to receive thromboprophylaxis after discharge. There were 2513 eligible patients from 18 study sites randomized by computer in a 1:1 ratio to the alert group or the control group. RESULTS: Patients in the alert group were more than twice as likely to receive thromboprophylaxis at discharge as controls (22.0% vs 9.7%, P <.0001). Based on an intention-to-treat analysis, symptomatic venous thromboembolism at 90 days (99.9% follow-up) occurred in 4.5% of patients in the alert group, compared with 4.0% of controls (hazard ratio 1.12; 95% confidence interval, 0.74-1.69). The rate of major bleeding at 30 days in the alert group was similar to that of the control group (1.2% vs 1.2%, hazard ratio 0.94; 95% confidence interval, 0.44-2.01). CONCLUSIONS: Alerting providers to extend thromboprophylaxis after hospital discharge in Medical Service patients increased the rate of prophylaxis but did not decrease the rate of symptomatic venous thromboembolism.

Toxin assay is more reliable than ICD-9 data and less time-consuming than chart review for public reporting of Clostridium difficile hospital case rates.

OBJECTIVE: Clostridium difficile-associated disease (CDAD) is common and has a 6.1% mortality. Governmental agencies have recommended surveillance, but reporting increases health care costs. We sought to identify a reliable method of reporting CDAD that will not significantly increase health care costs. METHODS: Patients were identified via database query for International Statistical Classification of Diseases and Related Health Problems, 9th Edition (ICD-9) codes and C. difficile toxin positivity. All identified patients underwent a chart review, which was used to determine the accuracy of the database query methods. Methods of determining whether CDAD was acquired at the reporting institution were studied, and time required to perform each method was measured. RESULTS: The toxin assay reported 96.1% (369/384) of cases and had a positive predictive value of 100%. No difference was found in comparison of the toxin assay case rate of 15.7 per 1000 discharged patients to the rate of 16.3 identified by chart review (P = 0.440; 95% confidence interval [CI], 14.1-17.4), whereas the ICD-9 method was found to be significantly different by reporting 116.1% (446/384) of cases for a case rate of 19.0 per 1000 discharges (P = 0.001; 95% CI, 17.3-20.8). The time for data extraction via the toxin assay method required only 842 minutes, while the chart review method consumed 21,899 minutes. CONCLUSION: A positive C. difficile toxin assay accurately reports the institutional incidence of disease and is more reliable than ICD-9 query. This process can be instituted at a fraction of the cost of the standard chart review, and enables governmental agencies to inexpensively add CDAD to their list of reportable diseases.

Telling her story: narrating a Japanese lesbian community.

This article explores queer Japanese women's narratives of their own histories and the history of the "Japanese lesbian community," which has been constructed as a space outside the heterosexual mainstream, a space where queer women can find at least temporary refuge. It begins with the acknowledgment that the evolution and the shape of the community, along with the identities of the women who comprise it, are shifting and contested. This article specifically looks at the long history of the lesbian bar scene as well as more recent history of lesbian dance parties; the early role of lesbian feminism and activism; lesbian community-based and commercial publications, paying special attention to the critical role translation has played in Japanese lesbian discourse and the construction of multiple lesbian identities; and, finally, lesbian, gay, bisexual, and transgender (LGBT) pride events and film festivals, through which the larger LGBT community has been gaining increasing visibility. This article argues that while some of the building blocks of the community are borrowed, from the "West" as well as from the Japanese gay community, there has also been creative translation, adaptation, and resistance to these imports. The resulting Japanese lesbian community is a complex and local construct, an innovative bricolage firmly sited in Japan.

Antibiotic timing and errors in diagnosing pneumonia.

BACKGROUND: The percentage of patients with community-acquired pneumonia (CAP) whose time to first antibiotic dose (TFAD) is less than 4 hours of presentation to the emergency department (ED) has been made a core quality measure, and public reporting has been instituted. We asked whether these time pressures might also have negative effects on the accuracy of diagnosis of pneumonia. METHODS: We performed a retrospective review of adult admissions for CAP for 2 periods: group 1, when the core quality measure was a TFAD of less than 8 hours; and group 2, when the TFAD was lowered to less than 4 hours. We examined the accuracy of diagnosis of CAP by ED physicians. RESULTS: A total of 548 patients diagnosed as having CAP were studied (255 in group 1 and 293 in group 2). At admission, group 2 patients were 39.0% less likely to meet predefined diagnostic criteria for CAP than were group 1 patients (odds ratio, 0.61; 95% confidence interval, 0.42-0.86) (P = .004). At discharge, there was agreement between the ED physician's diagnosis and the predefined criteria for CAP in 62.0% of group 1 and 53.9% of group 2 patients (P = .06) and between the ED physician's admitting diagnosis and that of the discharging physician in 74.5% of group 1 and 66.9% of group 2 patients (P = .05). The mean (SD) TFAD was similar in group 1 (167.0 [118.6] minutes) and group 2 (157.8 [96.3] minutes). CONCLUSION: Reduction in the required TFAD from 8 to 4 hours seems to reduce the accuracy by which ED physicians diagnose pneumonia, while failing to reduce the actual TFAD achieved for patients.

Implementation of electronic data capture systems: barriers and solutions.

Although increasing in pace, the conversion to Electronic Data Capture (EDC) has been a slow progression. The use of EDC systems should confer improved data integrity, cost savings and a shorter time to study database closure. This will reduce the time to market and cost of new medications. With the current sentiment of the industry suggesting the cost analysis has been accepted to be in favor of EDC, the likely limitation to disseminated use is an inability to implement these systems. If the leadership at the sponsor, clinical research organization and investigator site is cognizant of the barriers to implementation, they can anticipate and mitigate them prior to the users becoming disgruntled and resistant to the new method of data capture. Once understood, barriers such as user input, technical support, user motivation, regulatory requirements, communication with users, timing of implementation, software installation, graphical user interface, identification of bridgers, patient participation, availability of technology, and costs can be better addressed at the beginning of the implementation process and successfully averted. This review discusses these barriers and potential solutions that can assist the clinical trial industry in achieving more wide-spread EDC use and the resulting improvement in operating efficiencies.

Authorship versus "credit" for participation in research: a case study of potential ethical dilemmas created by technical tools used by researchers and claims for authorship by their creators.

The distinction between authorship and other forms of credit for contribution to a publication has been a persisting controversy that has resulted in numerous guidelines outlining the expected contributions of those claiming authorship. While there have been flagrant, well-publicized deviations from widely accepted standards, they are largely outnumbered by cases that are not publicity-worthy, and therefore remain known to only those directly involved with the inappropriate conduct. We discuss the definition and ethical requirements of authorship, offer a case example of the authorship debate created by a technical tool at our institution, and review parallels that support and dispute the authorship claims of our software developers. Ultimately, we conclude that development of a technical tool that enables data collection does not adequately substitute for contributions to study design and manuscript preparation for authorship purposes. Unless the designers of such a technical tool prospectively participate as a part of the project, they would not have an adequate understanding of the publication's genesis to defend it publicly and cannot be listed as authors. Therefore, it is incumbent upon project members to invite tool developers to participate at the beginning of such projects, and for tool developers to contribute to study design and manuscript preparation when they desire authorship listings.

Repeat needle biopsies combined with clinical observation are safe and accurate in the management of a solitary pulmonary nodule.

BACKGROUND: Sixty percent of removed solitary pulmonary nodules (SPNs) are benign. An approach that reduces the unnecessary excision of benign nodules is consistent with the oncologic objective of organ preservation. METHODS: A prospective observational study was performed at a lung cancer referral center in which consecutive patients were evaluated who presented with SPNs measuring < 4 cm on computed tomography (CT) scans. Patients underwent transbronchial biopsy (TBB), percutaneous needle aspiration (PCNA), clinical observation, repeat CT scans, and repeat biopsies. Patients were observed clinically and underwent repeat biopsies in an effort to reduce unnecessary surgical intervention. RESULTS: One hundred eighteen patients underwent 194 biopsy sessions, including 137 TBB sessions and 57 PCNA sessions. The mean follow-up was 4 years. The shortest follow-up of a benign lesion was 3 years. The incidence of malignancy was 61%. The positive predictive value, negative predictive value, sensitivity, specificity, and accuracy all were 100%. Five patients had a delayed change in diagnosis from benign to malignant. This delay in diagnosis neither resulted in a change in tumor stage nor had an impact on patient management or survival. CONCLUSIONS: Repeat needle biopsies combined with clinical observation and repeat CT scans can classify an SPN as benign versus malignant with 100% accuracy (95% confidence interval, 96.1-100.0%). An SPN diagnostic approach that includes a TBB, then PCNA, clinical observation, repeat CT scans, and repeat biopsies for continued suspicion of malignancy appears to reduce the unnecessary surgical excision of benign nodules from the current rate of 60% to 5% of SPN resections without affecting the survival of patients who have malignant SPNs.

An approach to the diagnosis and treatment of cryofibrinogenemia.

Cryofibrinogenemia is a rarely symptomatic disorder that is underrecognized due to the infrequency with which it causes symptoms. Although completely reversible, this disorder can be life threatening when untreated. In this review, the classification, pathophysiology, and clinical presentation of cryofibrinogenemia are described, based on case reports and prospective observational data. Diagnostic criteria are outlined, and therapies are assessed critically. This information should help clinicians in establishing a diagnosis of cryofibrinogenemia and initiating treatment.

Diagnosis of primary bone tumors with image-guided percutaneous biopsy: experience with 110 tumors.

PURPOSE: To determine the diagnostic accuracy of image-guided percutaneous biopsy in 110 primary bone tumors of varying internal compositions. MATERIALS AND METHODS: One hundred ten consecutive patients with primary bone tumors underwent biopsy with computed tomography (CT) or fluoroscopy. Ninety-one patients underwent surgical follow-up and 19 received medical treatment and underwent subsequent imaging studies. Final analysis of bone biopsy results included tumor type, malignancy, final tumor grade, biopsy complications, and effect on eventual treatment outcome. RESULTS: Seventy-seven tumors were malignant and 33 were benign. Most common tumors at biopsy were osteosarcoma (n = 20), lymphoma (n = 18), chondrosarcoma (n = 16), and giant cell tumor (n = 16). Correct final diagnosis was attained in 97 (88%) patients. Sixty-three lesions were solid nonsclerotic; 26, sclerotic; and 21, lytic with cystic centers containing internal areas of fluid, hemorrhage, or necrosis. In six of 21 lesions with a predominant cystic internal composition, problems occurred in determining a final diagnosis. In 13 patients, definite correct diagnosis was not obtained with initial percutaneous bone biopsy. Of these patients, benign bone tumors were better defined with surgical specimens in seven, a diagnosis of malignancy was changed to that of another malignancy in four, and the diagnosis was changed from benign to malignant in two. Nine patients underwent open surgical biopsy. Seven of the difficult cases were of cystic tumors with hemorrhagic fluid levels visible at CT or magnetic resonance imaging. The only complication was a small hematoma. CONCLUSION: Percutaneous biopsy of primary bone tumors is safe and accurate for diagnosis and grade of specific tumor. In cases with nondiagnostic biopsy, open-procedure biopsy is likely to be associated with similar diagnostic difficulties.