Confidence score: a data-driven measure for inclusive systematic reviews considering unpublished preprints.

OBJECTIVES: COVID-19, since its emergence in December 2019, has globally impacted research. Over 360 000 COVID-19-related manuscripts have been published on PubMed and preprint servers like medRxiv and bioRxiv, with preprints comprising about 15% of all manuscripts. Yet, the role and impact of preprints on COVID-19 research and evidence synthesis remain uncertain. MATERIALS AND METHODS: We propose a novel data-driven method for assigning weights to individual preprints in systematic reviews and meta-analyses. This weight termed the "confidence score" is obtained using the survival cure model, also known as the survival mixture model, which takes into account the time elapsed between posting and publication of a preprint, as well as metadata such as the number of first 2-week citations, sample size, and study type. RESULTS: Using 146 preprints on COVID-19 therapeutics posted from the beginning of the pandemic through April 30, 2021, we validated the confidence scores, showing an area under the curve of 0.95 (95% CI, 0.92-0.98). Through a use case on the effectiveness of hydroxychloroquine, we demonstrated how these scores can be incorporated practically into meta-analyses to properly weigh preprints. DISCUSSION: It is important to note that our method does not aim to replace existing measures of study quality but rather serves as a supplementary measure that overcomes some limitations of current approaches. CONCLUSION: Our proposed confidence score has the potential to improve systematic reviews of evidence related to COVID-19 and other clinical conditions by providing a data-driven approach to including unpublished manuscripts.

Impact of Stigma on Clinician Training for Opioid Use Disorder Care: A Qualitative Study in a Primary Care Learning Collaborative.

PURPOSE: We undertook a study to examine how stigma influences the uptake of training on medication for opioid use disorder (MOUD) in primary care academic programs. METHODS: We conducted a qualitative study of 23 key stakeholders responsible for implementing MOUD training in their academic primary care training programs that were participants in a learning collaborative in 2018. We assessed barriers to and facilitators of successful program implementation and used an integrated approach to develop a codebook and analyze the data. RESULTS: Participants represented the family medicine, internal medicine, and physician assistant fields, and they included trainees. Most participants described clinician and institutional attitudes, misperceptions, and biases that enabled or hindered MOUD training. Perceptions included concerns that patients with OUD are "manipulative" or "drug seeking." Elements of stigma in the origin domain (ie, beliefs by primary care clinicians or the community that OUD is a choice and not a disease), the enacted domain (eg, hospital bylaws banning MOUD and clinicians declining to obtain an X-Waiver to prescribe MOUD), and the intersectional domain (eg, inadequate attention to patient needs) were perceived as major barriers to MOUD training by most respondents. Participants described strategies that improved the uptake of training, including giving attention to clinician concerns, clarifying the biology of OUD, and ameliorating clinician fears of being ill equipped to provide care for patients. CONCLUSIONS: OUD-related stigma was commonly reported in training programs and impeded the uptake of MOUD training. Potential strategies to address stigma in the training context, beyond providing content on effective evidence-based treatments, include addressing the concerns of primary care clinicians and incorporating the chronic care framework into OUD treatment.

Decision-making Among Hepatitis C Virus-negative Transplant Candidates Offered Organs from Donors with HCV Infection.

Background: Historically, many organs from deceased donors with hepatitis C virus (HCV) were discarded. The advent of highly curative direct-acting antiviral (DAA) therapies motivated transplant centers to conduct trials of transplanting HCV-viremic organs (nucleic acid amplification test positive) into HCV-negative recipients, followed by DAA treatment. However, the factors that influence candidates' decisions regarding acceptance of transplant with HCV-viremic organs are not well understood. Methods: To explore patient-level perceptions, influences, and experiences that inform candidate decision-making regarding transplant with organs from HCV-viremic donors, we conducted a qualitative semistructured interview study embedded within 3 clinical trials investigating the safety and efficacy of transplanting lungs and kidneys from HCV-viremic donors into HCV-negative recipients. The study was conducted from June 2019 to March 2021. Results: Among 44 HCV-negative patients listed for organ transplant who were approached for enrollment in the applicable clinical trial, 3 approaches to decision-making emerged: positivist, risk analyses, and instinctual response. Perceptions of risk contributed to conceptualizations of factors influencing decisions. Moreover, most participants relied on multiple decision-making approaches, either simultaneously or sequentially. Conclusions: Understanding how different decisional models influence patients' choices regarding transplant with organs from HCV-viremic donors may promote shared decision-making among transplant patients and providers.

Clinic screening for adverse childhood experiences in people living with HIV to Improve Care Delivery.

Adverse childhood experiences (ACEs) are associated with negative health outcomes; however, screening for ACEs is not routinely performed among people living with HIV (PLWH). We conducted a single-center, cross-sectional pilot study to define the (1) prevalence of ACEs in PLWH and (2) acceptability of ACEs screening in routine out-patient clinical care. One hundred participants completed screening: median age of participants was 49 years (interquartile range: 38.5-59.5), 73% male, 66% Non-Hispanic Black/African American, and 47% gay/lesbian. Clinically significant ACEs score, defined as ≥4, was reported in 51%. High ACEs score was more common among participants <50 years old (64.7% vs. 36.7%; p < 0.01), but the prevalence of ACEs ≥4 did not differ by gender, race, ethnicity, or sexual orientation. Among participants with ≥4 ACEs, 44.4% screened negative on both PHQ-9 and PC-PTSD screens. The majority of participants (89%) reported a positive experience with ACEs screening. The prevalence of clinically significant ACEs in this clinic population of PLWH was more than twice that reported in the general population. Routine ACEs screening can improve delivery of trauma-informed care in the HIV primary care setting.

The impact of disease-related knowledge on perceptions of stigma among patients with Hepatitis C Virus (HCV) infection.

Most patients with hepatitis C virus (HCV) infection perceive some degree of disease-related stigma. Misunderstandings about diseases may contribute to disease-related stigma. The objective of this study was to evaluate patient-level knowledge about HCV infection transmission and natural history and its association with HCV-related stigma among HCV-infected patients. We conducted a cross-sectional survey study among 265 patients with HCV in Philadelphia using the HCV Stigma Scale and the National Health and Nutrition Examination Survey (NHANES) Hepatitis C Follow-up Survey (2001-2008). The association between HCV knowledge and HCV-related stigma was evaluated via linear regression. Overall knowledge about HCV transmission and natural history was high, with >80% of participants answering ≥9 of 11 items correctly (median number of correct responses, 9 [82%]), HCV-related knowledge was similar between HIV/HCV-coinfected and HCV-monoinfected participants (p = 0.30). A higher level of HCV-related knowledge was associated with greater perceived HCV-related stigma (ß, 2.34 ([95% CI, 0.51-4.17]; p = 0.013). Results were similar after adjusting for age, race, ethnicity, HIV status, education level, stage of HCV management, time since diagnosis, and history of injection drug use. In this study, increased HCV-related knowledge was associated with greater perceptions of HCV stigma. Clinicians may consider allotting time to address common misconceptions about HCV when educating patients about HCV infection, which may counterbalance the stigmatizing impact of greater HCV-related knowledge.

Determinants of stigma among patients with hepatitis C virus infection.

Stigma around hepatitis C virus (HCV) infection is an important and understudied barrier to HCV treatment and elimination. The determinants of HCV-related stigma, including the impacts of stage of HCV treatment (ie spontaneously cleared; diagnosed, untreated; previously treated, not cured; currently being treated; and treated, cured) and coinfection with human immunodeficiency virus (HIV), remain unknown. To address these gaps, we conducted a cross-sectional study among patients with a history of HCV infection (n = 270) at outpatient clinics in Philadelphia from July 2018 to May 2019. We evaluated stigma using the validated HCV Stigma Scale, adapted from the Berger HIV Stigma Scale. Associations among HCV-related stigma and hypothesized demographic, behavioural, and clinical risk factors were evaluated by multivariable linear regression. Most participants (95.5%) experienced HCV-related stigma. Mean stigma scores did not differ significantly between HCV-monoinfected and HIV/HCV-coinfected participants (P = .574). However, we observed significant interactions between HIV status and multiple determinants; therefore, we stratified analyses by HIV status. Among HIV/HCV-coinfected participants, previous HCV treatment without cure, female gender, Hispanic/Latinx ethnicity and some college education were significantly associated with higher HCV-stigma scores. An annual income of $10 000-$40 000 was associated with significantly lower stigma scores. No significant associations were observed among HCV-monoinfected participants. We found that most participants experienced stigma associated with HCV diagnosis. While stigma scores were similar between HCV-monoinfected and HIV/HCV-coinfected participants, the determinants associated with HCV stigma differed by HIV status. Understanding how experiences of stigma differ between HCV-monoinfected and HIV/HCV-coinfected patients may aid in the development of targeted interventions to address the HCV epidemic.

Validation of a modified Berger HIV stigma scale for use among patients with hepatitis C virus (HCV) infection.

BACKGROUND: Stigma around hepatitis C virus (HCV) infection is an important and understudied barrier to HCV prevention, treatment, and elimination. To date, no validated instrument exists to measure patients' experiences of HCV stigma. This study aimed to revise the Berger (2001) HIV stigma scale and evaluate its psychometric properties among patients with HCV infection. METHODS: The Berger HIV stigma scale was revised to ask about HCV and administered to patients with HCV (n = 270) in Philadelphia, Pennsylvania. Scale reliability was evaluated as internal consistency by calculating Cronbach's alpha. Exploratory factor analysis was performed to evaluate construct validity by comparing item clustering to the Berger HIV stigma scale subscales. Item response theory was employed to further evaluate individual items and to calibrate items for simulated computer adaptive testing sessions in order to identify potential shortened instruments. RESULTS: The revised HCV Stigma Scale was found to have good reliability (α = 0.957). After excluding items for low loadings, the exploratory factor analysis indicated good construct validity with 85% of items loading on pre-defined factors. Analyses strongly suggested the predominance of an underlying unidimensional factor solution, which yielded a 33-item scale after items were removed for low loading and differential item functioning. Adaptive simulations indicated that the scale could be substantially shortened without detectable information loss. CONCLUSIONS: The 33-item HCV Stigma Scale showed sufficient reliability and construct validity. We also conducted computer adaptive testing simulations and identified shortened six- and three-item scale alternatives that performed comparably to the original 40-item scale.

Concordance of hospitalizations between Clinical Practice Research Datalink and linked Hospital Episode Statistics among patients treated with oral antidiabetic therapies.

PURPOSE: The ability of the Clinical Practice Research Datalink (CPRD) to ascertain all-cause hospitalizations remains unknown. We determined the proportion of hospitalizations in CPRD that were also recorded in Hospital Episode Statistics (HES), and vice versa, among patients initiating oral antidiabetic (OAD) therapy. METHODS: We conducted a retrospective cohort study from October 2009 to September 2012 among OAD-treated patients registered with general practitioners who contribute to CPRD and consent to HES linkage. In CPRD, we identified initial hospitalizations for each calendar year by an Inpatient Referral, Consultation Type code, or Read code indicating an inpatient episode and determined if an admission date was recorded in HES within ±30 days. We then identified initial HES admission dates and determined if a hospitalization was documented in CPRD within ±30 days. Sensitivity analyses were conducted utilizing HES discharge, rather than admission, dates. RESULTS: Among 8574 OAD-treated HES-linked patients in CPRD, 6574 initial hospitalizations across the study period were identified in CPRD, and 5188 (78.9% [95% CI, 77.9%-79.9%]) were confirmed by a HES admission date within ±30 days (median difference, ±3 days [IQR, 1-7 days]). Among 8609 initial hospital admissions in HES, 4803 (55.7% [95% CI, 54.7%-56.8%]) hospitalizations were recorded in CPRD within ±30 days (median difference, ±4 days [IQR, 1-9 days]). Similar results were observed using HES discharge dates. CONCLUSION: A substantial minority of patient-level hospitalization data are nonconcordant between HES and CPRD. Pharmacoepidemiologic studies within CPRD that seek to identify hospitalizations should consider linkage with HES to ensure adequate ascertainment of inpatient events.

Absolute Insurer Denial of Direct-Acting Antiviral Therapy for Hepatitis C: A National Specialty Pharmacy Cohort Study.

BACKGROUND: Despite the availability of new direct-acting antiviral (DAA) regimens, changes in DAA reimbursement criteria, and a public health focus on hepatitis C virus (HCV) elimination, it remains unclear if public and private insurers have increased access to these therapies over time. We evaluated changes in the incidence of absolute denial of DAA therapy over time and by insurance type. METHODS: We conducted a prospective cohort study among patients who had a DAA prescription submitted from January 2016 to April 2017 to Diplomat Pharmacy, Inc., which provides HCV pharmacy services across the United States. The main outcome was absolute denial of DAA prescription, defined as lack of fill approval by the insurer. We calculated the incidence of absolute denial, overall and by insurance type (Medicaid, Medicare, commercial), for the 16-month study period and each quarter. RESULTS: Among 9025 patients from 45 states prescribed a DAA regimen (4702 covered by Medicaid, 1821 Medicare, 2502 commercial insurance), 3200 (35.5%; 95% confidence interval, 34.5%-36.5%) were absolutely denied treatment. Absolute denial was more common among patients covered by commercial insurance (52.4%) than Medicaid (34.5%, P < .001) or Medicare (14.7%, P < .001). The incidence of absolute denial increased across each quarter of the study period, overall (27.7% in first quarter to 43.8% in last quarter; test for trend, P < .001) and for each insurance type (test for trend, P < .001 for each type). CONCLUSIONS: Despite the availability of new DAA regimens and changes in restrictions of these therapies, absolute denials of DAA regimens by insurers have remained high and increased over time, regardless of insurance type.

Validity of diagnostic codes to identify hospitalizations for infections among patients treated with oral anti-diabetic drugs.

PURPOSE: Identification of hospitalizations for infection is important for post-marketing surveillance of drugs, but the validity of using diagnosis codes to identify these events is unknown. Differentiating between hospitalization for and with infection is important, as the latter is common and less likely to arise from pre-admission exposure to drugs. We determined positive predictive values (PPVs) of diagnostic coding-based algorithms to identify hospitalization for infection among patients prescribed oral anti-diabetic drugs (OADs). METHODS: We identified patients initiating OADs within 2 United States claims databases (Medicare, HealthCore Integrated Research DatabaseSM [HIRDSM ]) and 2 United Kingdom electronic medical record databases (Clinical Practice Research Datalink [CPRD], The Health Improvement Network [THIN]) from 2009 to 2014. To identify potential hospitalizations for infection, we selected patients with a hospital diagnosis of infection and, within 7 days prior to hospitalization, either an outpatient/emergency department visit with an infection diagnosis or outpatient antimicrobial treatment. Hospital records were reviewed by infectious disease specialists to adjudicate hospital admissions for infection. PPVs for confirmed outcomes were determined for each database. RESULTS: Code-based algorithms to identify hospitalization for infection had PPVs exceeding 80% within Medicare (PPV, 83% [90/109]; 95% CI, 74-89%), HIRDSM (PPV, 89% [73/82]; 95% CI, 80-95%), and THIN (PPV, 86% [12/14]; 95% CI, 57-98%) but not within CPRD (PPV, 67% [14/21]; 95% CI, 43-85%). CONCLUSIONS: Algorithms identifying hospitalization for infection utilizing hospital diagnoses along with antecedent outpatient/emergency infection diagnoses or antimicrobial therapy had sufficiently high PPVs for confirmed events within Medicare, HIRDSM , and THIN to enable their use for pharmacoepidemiologic research.

Postauthorization safety study of the DPP-4 inhibitor saxagliptin: a large-scale multinational family of cohort studies of five outcomes.

OBJECTIVE: To evaluate the risk of serious adverse events among patients with type 2 diabetes mellitus initiating saxagliptin compared with oral antidiabetic drugs (OADs) in classes other than dipeptidyl peptidase-4 (DPP-4) inhibitors. RESEARCH DESIGN AND METHODS: Cohort studies using 2009-2014 data from two UK medical record data sources (Clinical Practice Research Datalink, The Health Improvement Network) and two USA claims-based data sources (HealthCore Integrated Research Database, Medicare). All eligible adult patients newly prescribed saxagliptin (n=110 740) and random samples of up to 10 matched initiators of non-DPP-4 inhibitor OADs within each data source were selected (n=913 384). Outcomes were hospitalized major adverse cardiovascular events (MACE), acute kidney injury (AKI), acute liver failure (ALF), infections, and severe hypersensitivity events, evaluated using diagnostic coding algorithms and medical records. Cox regression was used to determine HRs with 95% CIs for each outcome. Meta-analyses across data sources were performed for each outcome as feasible. RESULTS: There were no increased incidence rates or risk of MACE, AKI, ALF, infection, or severe hypersensitivity reactions among saxagliptin initiators compared with other OAD initiators within any data source. Meta-analyses demonstrated a reduced risk of hospitalization/death from MACE (HR 0.91, 95% CI 0.85 to 0.97) and no increased risk of hospitalization for infection (HR 0.97, 95% CI 0.93 to 1.02) or AKI (HR 0.99, 95% CI 0.88 to 1.11) associated with saxagliptin initiation. ALF and hypersensitivity events were too rare to permit meta-analysis. CONCLUSIONS: Saxagliptin initiation was not associated with increased risk of MACE, infection, AKI, ALF, or severe hypersensitivity reactions in clinical practice settings. TRIAL REGISTRATION NUMBER: NCT01086280, NCT01086293, NCT01086319, NCT01086306, and NCT01377935; Results.

Evaluation of methods to estimate missing days' supply within pharmacy data of the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN).

PURPOSE: The extent to which days' supply data are missing in pharmacoepidemiologic databases and effective methods for estimation is unknown. We determined the percentage of missing days' supply on prescription and patient levels for oral anti-diabetic drugs (OADs) and evaluated three methods for estimating days' supply within the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN). METHODS: We estimated the percentage of OAD prescriptions and patients with missing days' supply in each database from 2009 to 2013. Within a random sample of prescriptions with known days' supply, we measured the accuracy of three methods to estimate missing days' supply by imputing the following: (1) 28 days' supply, (2) mode number of tablets/day by drug strength and number of tablets/prescription, and (3) number of tablets/day via a machine learning algorithm. We determined incidence rates (IRs) of acute myocardial infarction (AMI) using each method to evaluate the impact on ascertainment of exposure time and outcomes. RESULTS: Days' supply was missing for 24 % of OAD prescriptions in CPRD and 33 % in THIN (affecting 48 and 57 % of patients, respectively). Methods 2 and 3 were very accurate in estimating days' supply for OADs prescribed at a consistent number of tablets/day. Method 3 was more accurate for OADs prescribed at varying number of tablets/day. IRs of AMI were similar across methods for most OADs. CONCLUSIONS: Missing days' supply is a substantial problem in both databases. Method 2 is easy and very accurate for most OADs and results in IRs comparable to those from method 3.

Use of demographic and pharmacy data to identify patients included within both the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN).

PURPOSE: Pharmacoepidemiology researchers often utilize data from two UK electronic medical record databases, the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN), and may choose to combine the two in an effort to increase sample size. To minimize duplication of data, previous studies examined the practice-level overlap between these databases. However, the proportion of overlapping patients remains unknown. We developed a method using demographic and pharmacy variables to identify patients included in both CPRD and THIN, and applied this method to measure the proportion of overlapping patients who initiated the oral anti-diabetic drug saxagliptin. METHODS: We conducted a cross-sectional study among patients initiating saxagliptin in CPRD and THIN between October 2009 and September 2012. Within both databases, we identified patients: (i) ≥18 years, (ii) newly prescribed saxagliptin, and (iii) with ≥180 days enrollment prior to saxagliptin initiation. Demographic data (birth year, sex, patient registration date, family number, and marital status) and prescriptions (including dates) for the first two oral anti-diabetic drugs prescribed within the study period were used to identify matching patients. RESULTS: Among 4202 CPRD and 3641 THIN patients initiating saxagliptin, 2574 overlapping patients (61% of CPRD saxagliptin initiators; 71% of THIN saxagliptin initiators) were identified. Among these patients, 2474 patients (96%) perfectly matched on all demographic and prescription data. CONCLUSIONS: Within each database, over 60% of patients initiating saxagliptin were included within both CPRD and THIN. Combined demographic and prescription data can be used to identify patients included in both CPRD and THIN.

Determinants of saxagliptin use among patients with type 2 diabetes mellitus treated with oral anti-diabetic drugs.

BACKGROUND: The patterns and determinants of saxagliptin use among patients with type 2 diabetes mellitus (T2DM) are unknown in real-world settings. We compared the characteristics of T2DM patients who were new initiators of saxagliptin to those who were new initiators of non-dipeptidyl peptidase-4 (DPP-4) inhibitor oral anti-diabetic drugs (OADs) and identified factors associated with saxagliptin use. METHODS: We conducted a cross-sectional study within the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), US Medicare, and the HealthCore Integrated Research Database (HIRD(SM)) across the first 36 months of saxagliptin availability (29 months for US Medicare). Patients were included if they were: 1) ≥18 years old, 2) newly prescribed saxagliptin or a non-DPP-4 inhibitor OAD, and 3) enrolled in their respective database for 180 days. For each saxagliptin initiator, we randomly selected up to ten non-DPP-4 inhibitor OAD initiators matched on age, sex, and geographic region. Conditional logistic regression was used to identify determinants of saxagliptin use. RESULTS: We identified 64,079 saxagliptin initiators (CPRD: 1,962; THIN: 2,084; US Medicare: 51,976; HIRD(SM): 8,057) and 610,660 non-DPP-4 inhibitor OAD initiators (CPRD: 19,484; THIN: 19,936; US Medicare: 493,432; HIRD(SM): 77,808). Across all four data sources, prior OAD use, hypertension, and hyperlipidemia were associated with saxagliptin use. Saxagliptin initiation was also associated with hemoglobin A1c results >8% within the UK data sources, and a greater number of hemoglobin A1c measurements in the US data sources. CONCLUSIONS: In these UK and US data sources, initiation of saxagliptin was associated with prior poor glycemic control, prior OAD use, and diagnoses of hypertension and hyperlipidemia. TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT01086280 , NCT01086293 , NCT01086319 , NCT01086306 , and NCT01377935.