Change in forced vital capacity and associated subsequent outcomes in patients with newly diagnosed idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare and serious disease characterized by progressive lung-function loss. Limited evidence has been published on the impact of lung-function loss on subsequent patient outcomes. This study examined change in forced vital capacity (FVC) across IPF patients in the 6 months after diagnosis and its association with clinical and healthcare resource utilization (HRU) outcomes in a real-world setting in the U.S. METHODS: A retrospective chart review was conducted of patients diagnosed with IPF by U.S. pulmonologists. Patient eligibility criteria included: 1) 40 years or older with a confirmed date of first IPF diagnosis with high-resolution computed tomography and/or lung biopsy between 01/2011 and 06/2013; 2) FVC results recorded at first diagnosis (±1 month) and at 6 months (±3 months) following diagnosis. Based on relative change in FVC percent predicted (FVC%), patients were categorized as stable (decline <5%), marginal decline (decline ≥5% and <10%), or significant decline (decline ≥10%). Physician-reported clinical and HRU outcomes were assessed from ~6 months post-diagnosis until the last contact date with the physician and compared between FVC% change groups. Multivariable Cox proportional-hazards models were constructed to assess risk of mortality, suspected acute exacerbation (AEx), and hospitalization post-FVC% change. Generalized estimating equations were used to account for multiple patients contributed by individual physicians. RESULTS: The sample included 490 IPF patients contributed by 168 pulmonologists. The mean (SD) age was 61 (11) years, 68% were male, and the mean (SD) baseline FVC% was 60% (26%). 250 (51%) patients were categorized as stable, 98 (20%) as marginal decline, and 142 (29%) as significant decline. The mean (SD) observation time was 583 (287) days. In both unadjusted analysis and multivariable models, significantly worse clinical outcomes and increased HRU were observed with greater lung-function decline. CONCLUSIONS: These findings suggest that nearly half of IPF patients experienced decline in FVC% within ~6 months following IPF diagnosis. Greater FVC% decline was associated with an increased risk of further IPF progression, suspected AEx, mortality, and higher rate of HRU. Management options that slow FVC decline may help improve future health outcomes in IPF.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Impact of misspecifying the distribution of a prognostic factor on power and sample size for testing treatment interactions in clinical trials.

BACKGROUND: Interaction in clinical trials presents challenges for design and appropriate sample size estimation. Here we considered interaction between treatment assignment and a dichotomous prognostic factor with a continuous outcome. Our objectives were to describe differences in power and sample size requirements across alternative distributions of a prognostic factor and magnitudes of the interaction effect, describe the effect of misspecification of the distribution of the prognostic factor on the power to detect an interaction effect, and discuss and compare three methods of handling the misspecification of the prognostic factor distribution. METHODS: We examined the impact of the distribution of the dichotomous prognostic factor on power and sample size for the interaction effect using traditional one-stage sample size calculation. We varied the magnitude of the interaction effect, the distribution of the prognostic factor, and the magnitude and direction of the misspecification of the distribution of the prognostic factor. We compared quota sampling, modified quota sampling, and sample size re-estimation using conditional power as three strategies for ensuring adequate power and type I error in the presence of a misspecification of the prognostic factor distribution. RESULTS: The sample size required to detect an interaction effect with 80% power increases as the distribution of the prognostic factor becomes less balanced. Misspecification such that the actual distribution of the prognostic factor was more skewed than planned led to a decrease in power with the greatest loss in power seen as the distribution of the prognostic factor became less balanced. Quota sampling was able to maintain the empirical power at 80% and the empirical type I error at 5%. The performance of the modified quota sampling procedure was related to the percentage of trials switching the quota sampling scheme. Sample size re-estimation using conditional power was able to improve the empirical power under negative misspecifications (i.e. skewed distributions) but it was not able to reach the target of 80% in all situations. CONCLUSIONS: Misspecifying the distribution of a dichotomous prognostic factor can greatly impact power to detect an interaction effect. Modified quota sampling and sample size re-estimation using conditional power improve the power when the distribution of the prognostic factor is misspecified. Quota sampling is simple and can prevent misspecification of the prognostic factor, while maintaining power and type I error.

Patient-reported outcomes and tolerability in patients receiving ripretinib versus sunitinib after treatment with imatinib in INTRIGUE, a phase 3, open-label study.

PURPOSE: In the INTRIGUE trial, ripretinib showed no significant difference versus sunitinib in progression-free survival for patients with advanced gastrointestinal stromal tumour (GIST) previously treated with imatinib. We compared the impact of these treatments on health-related quality of life (HRQoL). PATIENTS AND METHODS: Patients were randomised 1:1 to once-daily ripretinib 150 mg or once-daily sunitinib 50 mg (4 weeks on/2 weeks off). Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer-30 (EORTC QLQ-C30) questionnaire at day (D)1, and D29 of all cycles until treatment discontinuation. Change from baseline was calculated. Time without symptoms or toxicity (TWiST) was estimated as the mean number of days without progression, death, or grade ≥3 treatment-emergent adverse events per patient over 1 year of follow-up. RESULTS: Questionnaire completion at baseline was 88.1% (199/226) for ripretinib and 87.7% (199/227) for sunitinib and remained high for enrolled patients throughout treatment. Patients receiving sunitinib demonstrated within-cycle variation in self-reported HRQoL, corresponding to the on/off dosing regimen. Patients receiving ripretinib reported better HRQoL at D29 assessments than patients receiving sunitinib on all scales except constipation. HRQoL was similar between treatments at D1 assessments, following 2 weeks without treatment for sunitinib patients. TWiST was greater for ripretinib patients (173 versus 126 days). CONCLUSION: Patients receiving ripretinib experienced better HRQoL than patients receiving sunitinib during the dosing period and similar HRQoL to patients who had not received sunitinib for 2 weeks for all QLQ-C30 domains except constipation. Ripretinib may provide clinically meaningful benefit to patients with advanced GIST previously treated with imatinib.

Does a modified gap-balancing technique result in medial-pivot knee kinematics in cruciate-retaining total knee arthroplasty? A pilot study.

BACKGROUND: Normal knee kinematics is characterized by posterior femorotibial rollback with tibial internal rotation and medial-pivot rotation in flexion. Cruciate-retaining TKAs (CR-TKAs) do not reproduce normal knee kinematics. QUESTIONS/PURPOSES: We hypothesized a more anatomic reconstruction of the medial femoral condyle, simultaneously preserving the tension of the PCL and medial collateral ligament, resulted in (1) medial-pivot rotation and tibial internal rotation, (2) lateral femoral rollback, and (3) reduced liftoff. PATIENTS AND METHODS: We compared 10 patients who underwent CR-TKA using the new technique at their 1-year followup to a matched control group of nine patients using a traditional gap-balancing technique at their 2- to 4-year followup. All patients received lateral radiographs in extension and flexion, which we utilized for three-dimensional implant matching to calculate tibial internal rotation, lateral rollback, and lateral liftoff in extension and flexion. RESULTS: The new gap-balancing technique resulted in a median of 3.5° tibial internal rotation with 2.7-mm rollback of the lateral femoral condyle relative to the medial condyle in flexion, which was different from the control group. We found no differences in liftoff between the groups. CONCLUSIONS: The new technique resulted in tibial internal rotation with flexion and lateral rollback comparing the lateral to the medial condyle in flexion, but no differences in condylar liftoff. These preliminary results were comparable to published kinematic results of an asymmetric CR-TKA or medial-pivot CR-TKA but not to symmetric CR-TKA.

Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans.

BACKGROUND: Obesity and knee osteoarthritis are among the most frequent chronic conditions affecting Americans aged 50 to 84 years. OBJECTIVE: To estimate quality-adjusted life-years lost due to obesity and knee osteoarthritis and health benefits of reducing obesity prevalence to levels observed a decade ago. DESIGN: The U.S. Census and obesity data from national data sources were combined with estimated prevalence of symptomatic knee osteoarthritis to assign persons aged 50 to 84 years to 4 subpopulations: nonobese without knee osteoarthritis (reference group), nonobese with knee osteoarthritis, obese without knee osteoarthritis, and obese with knee osteoarthritis. The Osteoarthritis Policy Model, a computer simulation model of knee osteoarthritis and obesity, was used to estimate quality-adjusted life-year losses due to knee osteoarthritis and obesity in comparison with the reference group. SETTING: United States. PARTICIPANTS: U.S. population aged 50 to 84 years. MEASUREMENTS: Quality-adjusted life-years lost owing to knee osteoarthritis and obesity. RESULTS: Estimated total losses of per-person quality-adjusted life-years ranged from 1.857 in nonobese persons with knee osteoarthritis to 3.501 for persons affected by both conditions, resulting in a total of 86.0 million quality-adjusted life-years lost due to obesity, knee osteoarthritis, or both. Quality-adjusted life-years lost due to knee osteoarthritis and/or obesity represent 10% to 25% of the remaining quality-adjusted survival of persons aged 50 to 84 years. Hispanic and black women had disproportionately high losses. Model findings suggested that reversing obesity prevalence to levels seen 10 years ago would avert 178,071 cases of coronary heart disease, 889,872 cases of diabetes, and 111,206 total knee replacements. Such a reduction in obesity would increase the quantity of life by 6,318,030 years and improve life expectancy by 7,812,120 quality-adjusted years in U.S. adults aged 50 to 84 years. LIMITATIONS: Comorbidity incidences were derived from prevalence estimates on the basis of life expectancy of the general population, potentially resulting in conservative underestimates. Calibration analyses were conducted to ensure comparability of model-based projections and data from external sources. CONCLUSION: The number of quality-adjusted life-years lost owing to knee osteoarthritis and obesity seems to be substantial, with black and Hispanic women experiencing disproportionate losses. Reducing mean body mass index to the levels observed a decade ago in this population would yield substantial health benefits. PRIMARY FUNDING SOURCE: The National Institutes of Health and the Arthritis Foundation.

Emergency provider attitudes and barriers to universal HIV testing in the emergency department.

BACKGROUND: The Centers for Disease Control and Prevention (CDC) recently published recommendations for routine, voluntary human immunodeficiency virus (HIV) testing of adults in all health care settings, including the emergency department (ED). STUDY OBJECTIVE: The objective of this study was to examine the willingness of ED providers to offer HIV testing, as well as their perceived barriers to implementation of these guidelines. METHODS: Before the establishment of a routine HIV testing program in the ED, a 21-item survey was used to assess ED providers' knowledge, attitudes, and perceived challenges to HIV testing. Six months after program initiation, the identical survey was re-administered to determine whether HIV testing program experience altered providers' perceptions. RESULTS: There were 108 of 146 (74%) providers who completed both the pre- and post-implementation surveys. Although the majority of emergency providers at 6 months were supportive of an ED-based HIV testing program (59/108 [55%]), only 38% (41/108) were willing to offer the HIV test most or all of the time. At 6 months, the most frequently cited barriers to offering a test were: inadequate time (67/108 [62%]), inadequate resources (65/108 [60%]), and concerns regarding provision of follow-up care (64/108 [59%]). CONCLUSIONS: After the implementation of a large-scale HIV testing program in an ED, the majority of emergency providers were supportive of routine HIV testing. Nevertheless, 6 months after program initiation, providers were still reluctant to offer the test due to persistent barriers. Further studies are needed to identify feasible implementation strategies that minimize barriers to routine HIV testing in the ED.

Evaluation of exposure-specific risks from two independent samples: a simulation study.

BACKGROUND: Previous studies have proposed a simple product-based estimator for calculating exposure-specific risks (ESR), but the methodology has not been rigorously evaluated. The goal of our study was to evaluate the existing methodology for calculating the ESR, propose an improved point estimator, and propose variance estimates that will allow the calculation of confidence intervals (CIs). METHODS: We conducted a simulation study to test the performance of two estimators and their associated confidence intervals: 1) current (simple product-based estimator) and 2) proposed revision (revised product-based estimator). The first method for ESR estimation was based on multiplying a relative risk (RR) of disease given a certain exposure by an overall risk of disease. The second method, which is proposed in this paper, was based on estimates of the risk of disease in the unexposed. We then multiply the updated risk by the RR to get the revised product-based estimator. A log-based variance was calculated for both estimators. Also, a binomial-based variance was calculated for the revised product-based estimator. 95% CIs were calculated based on these variance estimates. Accuracy of point estimators was evaluated by comparing observed relative bias (percent deviation from the true estimate). Interval estimators were evaluated by coverage probabilities and expected length of the 95% CI, given coverage. We evaluated these estimators across a wide range of exposure probabilities, disease probabilities, relative risks, and sample sizes. RESULTS: We observed more bias and lower coverage probability when using the existing methodology. The revised product-based point estimator exhibited little observed relative bias (max: 4.0%) compared to the simple product-based estimator (max: 93.9%). Because the simple product-based estimator was biased, 95% CIs around this estimate exhibited small coverage probabilities. The 95% CI around the revised product-based estimator from the log-based variance provided better coverage in most situations. CONCLUSION: The currently accepted simple product-based method was only a reasonable approach when the exposure probability is small (< 0.05) and the RR is ≤ 3.0. The revised product-based estimator provides much improved accuracy.

Factors associated with refusal of rapid HIV testing in an emergency department.

HIV screening studies in the emergency department (ED) have demonstrated rates of HIV test refusal ranging from 40-67%. This study aimed to determine the factors associated with refusal to undergo routine rapid HIV testing in an academic ED in Boston. HIV counselors offered routine testing to 1,959 patients; almost one-third of patients (29%) refused. Data from a self-administered survey were used to determine independent correlates of HIV testing refusal. In multivariate analysis, women and patients with annual household incomes of $50,000 or more were more likely to refuse testing, as were those who reported not engaging in HIV risk behaviors, those previously HIV tested and those who did not perceive a need for testing. Enrollment during morning hours was also associated with an increased risk of refusal. Increased educational efforts to convey the rationale and benefits of universal screening may improve testing uptake among these groups.

Patient satisfaction with rapid HIV testing in the emergency department.

OBJECTIVE: Patient satisfaction with HIV screening is crucial for sustainable implementation of the Centers for Disease Control and Prevention (CDC) HIV testing recommendations. This investigation assesses patient satisfaction with rapid HIV testing in the emergency department (ED) of an urban tertiary academic medical center. METHODS: After receiving HIV test results, participants in the Universal Screening for HIV Infection in the Emergency Room (USHER) randomized controlled trial were offered a patient satisfaction survey. Questions concerned overall satisfaction with ED visit, time spent on primary medical problem, time spent on HIV testing, and test provider's ability to answer HIV-related questions. Responses were reported on a 4-point Likert scale, ranging from very dissatisfied to very satisfied (defined as optimal satisfaction). RESULTS: Of 4,860 USHER participants, 2,025 completed testing and were offered the survey: 1,616 (79.8%) completed the survey. Overall, 1,478 (91.5%) were very satisfied. Satisfaction was less than optimal for 34.5% (10 of 29) of participants with reactive results and for 7.5% (115 of 1,542) with nonreactive results. The independent factors associated with less than optimal satisfaction were reactive test result, aged 60 years or older, black race, Hispanic/Latino ethnicity, and testing by ED provider instead of HIV counselor. CONCLUSION: Most participants were very satisfied with the ED-based rapid HIV testing program. Identification of independent factors that correlate with patient satisfaction will help guide best practices as EDs implement CDC recommendations. It is critical to better understand whether patients with reactive results were negatively affected by their results or truly had concerns about the testing process.

Counselor- versus provider-based HIV screening in the emergency department: results from the universal screening for HIV infection in the emergency room (USHER) randomized controlled trial.

OBJECTIVE: We compare rates of rapid HIV testing, test offer, and acceptance in an urban emergency department (ED) when conducted by dedicated HIV counselors versus current members of the ED staff. METHODS: The Universal Screening for HIV Infection in the Emergency Room [USHER] trial is a prospective randomized controlled trial that implemented an HIV screening program in the ED of an urban tertiary medical center. ED patients were screened and consented for trial enrollment by an USHER research assistant. Eligible subjects were randomized to rapid HIV testing (oral OraQuick) offered by a dedicated counselor (counselor arm) or by an ED provider (provider arm). In the counselor arm, counselors-without other clinical responsibilities-assumed nearly all testing-related activities (consent, counseling, delivery of test results). In the provider arm, trained ED emergency service assistants (nursing assistants) consented and tested the participant in the context of other ED-related responsibilities. In this arm, ED house officers, physician assistants, or attending physicians provided HIV test results to trial participants. Outcome measures were rates of HIV testing and test offer among individuals consenting for study participation. Among individuals offered the test, test acceptance was also measured. RESULTS: From February 2007 through July 2008, 8,187 eligible patients were approached in the ED, and 4,855 (59%) consented and were randomized to trial participation. The mean age was 37 years, 65% were women, and 42% were white. The overall testing rate favored the counselor arm (57% versus 27%; P<.001); 80% (1,959/2,446) of subjects in the counselor arm were offered an HIV test compared with 36% (861/2,409) in the provider arm (P<.001). HIV test acceptance was slightly higher in the provider arm (counselor arm 71% versus provider arm 75%; P = .025). CONCLUSION: Routine rapid HIV testing in the ED was accomplished more frequently by dedicated HIV counselors than by ED staff in the course of routine clinical work. Without dedicated staff, HIV testing in this setting may not be truly routine.

Overall survival with oral selinexor plus low-dose dexamethasone versus real-world therapy in triple-class-refractory multiple myeloma.

Triple-class-refractory multiple myeloma (MM) describes MM refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 monoclonal antibodies. In the Phase IIb STORM study (NCT02336815), oral selinexor plus low-dose dexamethasone (Sel-dex) demonstrated a 26.2% overall response rate in triple-class-refractory MM. Here, we compare overall survival (OS) of 122 patients with triple-class-refractory MM who received Sel-dex in STORM Part 2 with that of 64 similar patients treated with other available therapies in a Flatiron Health Analytic Database (FHAD) cohort. OS from the date that the patients' MM became triple-class-refractory was longer in STORM versus FHAD, with an unadjusted hazard ratio (HR) of 0.43 (P =  .0002; adjusted HR 0.35 [P  =  .011]). In a subset analysis of highly resistant patients receiving further therapies after their MM first became at least triple-class-refractory (i.e., who received Sel-dex in STORM, n = 64, and non-Sel-dex in FHAD, n = 36), the OS was significantly longer in STORM with an unadjusted HR of 0.52 (P = .0331; adjusted HR 0.33 [P = .041]). Within the limits of this analysis, the OS of patients with at least triple-class-refractory MM was significantly better with Sel-dex versus available therapies, suggesting that Sel-dex may be associated with a meaningful OS benefit in these patients.

Factors affecting bony impingement in hip arthroplasty.

Computer modeling of 10 patients' computed tomographic scans was used to study the variables affecting hip arthroplasty range of motion before bony impingement (ROMBI) including acetabular offset and height, femoral offset, height and anteversion, and osteophyte removal. The ROMBI was compared with the ROM before component impingement and the native hip ROM. The ROMBI decreased with decreased total offset and limb shortening. Acetabular offset and height had a greater effect on ROMBI than femoral offset and height. The ROMBI lost with decreased acetabular offset was not fully recoverable with an increase in femoral offset or osteophyte removal. Bony impingement increased and component impingement decreased with decreased acetabular offset and increased head diameter.

A Novel Treatment of Opioid Cravings With an Effect Size of .73 for Unilateral Transcranial Photobiomodulation Over Sham.

BACKGROUND: Opioid use disorders (OUDs) are an epidemic causing catastrophic consequences to individuals, families, and society despite treatments including psychotherapy, substitution therapy or receptor blockers, and psychoeducation. We have developed a novel treatment that combines unilateral transcranial photobiomodulation (t-PBM) to the hemisphere with a more positive valence by Dual Brain Psychology (DBP). METHODS: We used a randomized, double blind, placebo-controlled protocol in which 22 patients with significant opioid cravings and a history of recent or current OUD attended three 1-h weekly sessions. After baseline measures of opioid craving and other psychometrics, subjects received two unilateral t-PBM applications (810 nm CW LED, 250 mW/cm2, 60 J/cm2, 4 min) or a sham (foil-covered LED) at F3 or F4. Prior to any treatment we used two tests to determine which hemisphere was more associated with a negative outlook and cravings and treated that side before the more positive hemisphere. Primary outcome measure was an opioid craving scale (OCS). Secondary outcomes were weekly Hamilton Depression (HDRS) and Anxiety (HARS) Rating Scales prior to treatments and at follow-up. RESULTS: Immediately after treatment the OCS improved significantly for both the sham and active treatments, but one week later the active treatment showed a 51.0% (SD 33.7) decrease in OCS while a week after the sham treatments there was a decrease of only 15.8% (SD 35.0) (by Wilcoxon Sign Rank Test, p = 0.004) and by a mixed model it was p = 0.0071. The effect size for the differences between active and sham was 0.73. For the active treatment from before and after treatment the effect size was 1.51 and for the sham, 0.45. The HDRS improved from a baseline of 15.1 to 8.8 (SD 10.3) a week after the active treatment and to 13.3 (SD 12.9) after the sham (p = 0.0071). HARS improved from 14.7 to 8.0 (SD 13.2) after the active treatments and to 14.3 (SD 16.0) after the sham, p = 0.08. Active treatment of the positive hemisphere after the negative hemisphere significantly improved the OCS, but there was no significant difference after the sham treatment. One patient complained of 2 h of abdominal bloating and dropped out; no other adverse effects were observed. DISCUSSION: Unilateral t-PBM to the hemisphere with a more positive hemispheric emotional valence was an effective and safe treatment for opioid cravings as well as for depression and anxiety. Our results also lend support to the underlying premises of DBP.

Revising expectations from rapid HIV tests in the emergency department.

BACKGROUND: Expanded HIV screening efforts in the United States have increased the use of rapid HIV tests in emergency departments. The reported sensitivity and specificity of rapid HIV tests exceed 99%. OBJECTIVE: To assess whether a reactive rapid oral HIV test result correctly identifies adults with HIV infection in the emergency department. DESIGN: Diagnostic test performance assessment within the framework of a randomized, clinical trial. SETTING: Brigham and Women's Hospital emergency department (Boston, Massachusetts) from 7 February to 1 October 2007. PATIENTS: 849 adults with valid rapid oral HIV test results. INTERVENTION: Rapid HIV testing with the OraQuick ADVANCE Rapid HIV-1/2 Antibody Test (OraSure Technologies, Bethlehem, Pennsylvania). Patients with reactive rapid test results were offered enzyme-linked immunoassay, Western blot, and plasma HIV-1 RNA testing for confirmation. MEASUREMENTS: Specificity and positive likelihood ratio. RESULTS: 39 patients had reactive results (4.6% [95% CI, 3.2% to 6.0%]). On confirmation, 5 patients were HIV-infected (prevalence, 0.6% [CI, 0.1% to 1.1%]) and 26 were non-HIV-infected (8 patients declined confirmation). The estimated rapid test specificity was 96.9% (CI, 95.7% to 98.1%). Sensitivity analyses of the true HIV status of unconfirmed cases and test sensitivity resulted in a positive likelihood ratio of 8 to 32. Western blot alone as a confirmation test provided conclusive HIV status in only 50.0% (CI, 30.8% to 69.2%) of patients at first follow-up. The addition of HIV-1 RNA testing to the confirmation protocol improved this rate to 96.2% (CI, 88.8% to 100.0%). LIMITATION: Test sensitivity cannot be assessed because nonreactive OraQuick test results were not confirmed. CONCLUSION: Although patients with a reactive oral OraQuick HIV screening test in the emergency department had an 8- to 32-fold increased odds of HIV infection compared with the pretest odds, the specificity of the test was lower than anticipated.

Comparative efficacy of brigatinib versus ceritinib and alectinib in patients with crizotinib-refractory anaplastic lymphoma kinase-positive non-small cell lung cancer.

OBJECTIVE: Brigatinib, ceritinib, and alectinib are approved to treat crizotinib-refractory anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC), but no trial has compared them head-to-head. A matching-adjusted indirect comparison (MAIC) was conducted to estimate the relative efficacy of these agents in the crizotinib-refractory setting. METHODS: MAIC is a propensity score-type method that adjusts for differences in baseline characteristics between trials to estimate relative efficacy. Analyses were based on patient-level data from the ALTA trial for brigatinib and published summary-level trial data from ASCEND-1 and ASCEND-2 for ceritinib and NP28761 and NP28673 for alectinib. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared. RESULTS: After matching, all key baseline characteristics were balanced between trials. Compared with ceritinib, brigatinib was associated with longer PFS (ASCEND-1: median 15.7 vs 6.9 months, hazard ratio (HR) [95% confidence interval] = 0.38 [0.26-0.57]; ASCEND-2: median = 18.3 vs 7.2 months, HR = 0.33 [0.20-0.56]) and OS (ASCEND-1: not available; ASCEND-2: median 27.6 vs 14.9 months, HR = 0.33 [0.17-0.63]). Versus alectinib, brigatinib was associated with longer PFS (NP28761: median = 17.6 vs 8.2 months, HR = 0.56 [0.36-0.86]; NP28673: median = 17.6 vs 8.9 months, HR = 0.61 [0.40-0.93]); results for OS were inconclusive (NP28761: median = 27.6 vs 22.7 months, HR = 0.70 [0.42-1.16]; NP28673: median = 27.6 vs 26.0 months, HR = 0.66 [0.39-1.09]). ORR was similar. CONCLUSION: In crizotinib-refractory ALK + NSCLC patients, relative efficacy estimates suggest brigatinib may have prolonged PFS and OS vs ceritinib and prolonged PFS vs alectinib.

A retrospective comparison of the incidence of bacterial infection following anterior cruciate ligament reconstruction with autograft versus allograft.

PURPOSE: To compare the incidence of bacterial infection in anterior cruciate ligament (ACL) reconstruction with autograft versus allograft. METHODS: We completed a retrospective medical record review of ACL reconstructions performed at our institutions between 2001 and 2005. These included 170 autograft, 628 allograft, and 3 combined autograft/allograft reconstructions. Data collection included patient demographics, comorbidities, preoperative antibiotics, fixation type, and the occurrence of deep postoperative infection. RESULTS: Of the 801 patients who underwent ACL reconstruction, 6 (0.75%) developed a confirmed deep infection. There were 2 confirmed deep infections in 170 autograft reconstructions (1.2%) compared with 4 confirmed deep infections in 628 allograft reconstructions (0.6%). Multivariate analysis revealed that ACL reconstruction using autograft had a nearly twice the risk of infection compared to allograft reconstructions (adjusted odds ratio, 1.83; 95% confidence interval, 0.16 to 12.94). CONCLUSIONS: This study failed to find a higher rate of deep bacterial infection in ACL reconstructions when allograft tissue was used. We therefore feel that surgeons should consider allograft tissue as an alternative to autograft when there is a concern about donor-site morbidity, or for revision reconstructions. LEVEL OF EVIDENCE: Level III, therapeutic retrospective comparative study.

Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer and Brain Metastases in Two Clinical Trials.

Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (≥ 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).

Correction to: The Toronto cognitive assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

Upon publication of this article [1], it was brought to our attention that one of the 303 participants in the normative study should have been deleted from the database.

The Toronto Cognitive Assessment (TorCA): normative data and validation to detect amnestic mild cognitive impairment.

BACKGROUND: A need exists for easily administered assessment tools to detect mild cognitive changes that are more comprehensive than screening tests but shorter than a neuropsychological battery and that can be administered by physicians, as well as any health care professional or trained assistant in any medical setting. The Toronto Cognitive Assessment (TorCA) was developed to achieve these goals. METHODS: We obtained normative data on the TorCA (n = 303), determined test reliability, developed an iPad version, and validated the TorCA against neuropsychological assessment for detecting amnestic mild cognitive impairment (aMCI) (n = 50/57, aMCI/normal cognition). For the normative study, healthy volunteers were recruited from the Rotman Research Institute registry. For the validation study, the sample was comprised of participants with aMCI or normal cognition based on neuropsychological assessment. Cognitively normal participants were recruited from both healthy volunteers in the normative study sample and the community. RESULTS: The TorCA provides a stable assessment of multiple cognitive domains. The total score correctly classified 79% of participants (sensitivity 80%; specificity 79%). In an exploratory logistic regression analysis, indices of Immediate Verbal Recall, Delayed Verbal and Visual Recall, Visuospatial Function, and Working Memory/Attention/Executive Control, a subset of the domains assessed by the TorCA, correctly classified 92% of participants (sensitivity 92%; specificity 91%). Paper and iPad version scores were equivalent. CONCLUSIONS: The TorCA can improve resource utilization by identifying patients with aMCI who may not require more resource-intensive neuropsychological assessment. Future studies will focus on cross-validating the TorCA for aMCI, and validation for disorders other than aMCI.