Breast cancer molecular diagnostics in Rwanda: a cost-minimization study of immunohistochemistry versus a novel GeneXpert® mRNA expression assay.

Objective: To compare the financial and time cost of breast cancer biomarker analysis by immunohistochemistry with that by the Xpert® STRAT4 assay. Methods: We estimated costs (personnel, location, consumables and indirect) and time involved in breast cancer diagnosis at the Butaro Cancer Centre of Excellence, Rwanda, using time-driven activity-based costing. We performed a cost-minimization analysis to compare the cost of biomarker analysis for estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2 status with immunohistochemistry versus STRAT4. We performed sensitivity analyses by altering laboratory-specific parameters for the two methods. Findings: We estimated that breast cancer diagnosis in Rwanda costs 138.29 United States dollars (US$) per patient when conducting biomarker analysis by immunohistochemistry. At a realistic immunohistochemistry antibody utilization efficiency of 70%, biomarker analysis comprises 48.7% (US$ 67.33) of diagnostic costs and takes 33 min. We determined that biomarker analysis with STRAT4 yields a reduction in diagnosis cost of US$ 7.33 (10.9%; 7.33/67.33), and in pathologist and technician time of 20 min (60.6%; 20/33), per patient. Our sensitivity analysis revealed that no cost savings would be made in laboratories with antibody utilization efficiencies over 90%, or where only estrogen and/or progesterone receptor status are assessed; however, such operational efficiencies are unlikely, and more laboratories are pursuing human epidermal growth factor receptor-2 analysis as targeted therapies become increasingly available. Conclusion: Breast cancer biomarker analysis with STRAT4 has the potential to reduce the required human and capital resources in sub-Saharan African laboratories, leading to improved treatment selection and better clinical outcomes.

Assessment of approaches to estimate scapular orientation in children with brachial plexus birth injury.

BACKGROUND: Challenges in measuring dynamic scapular orientation limit assessment of scapulothoracic and glenohumeral contributions to shoulder function in children with brachial plexus birth injury (BPBI). Double calibration acromion marker cluster (D-AMC) and linear model approaches have been validated to estimate scapular motion in healthy adults, but neither has been evaluated in BPBI. RESEARCH QUESTION: Are the linear model and D-AMC approaches able to accurately estimate scapular orientation in children with BPBI at functional arm postures? METHODS: Seventeen children with BPBI positioned their affected limbs in 11 static positions while their segment orientations were measured with motion capture. Linear model and D-AMC estimates of scapular orientation were compared against palpation at six of the static positions with functional relevance to BPBI using a three-way repeat measures ANOVA and a comparison of root mean square errors (RMSE) against literature AMC values for healthy adults. RESULTS: The D-AMC was similar to palpation across all positions and scapular axes while the linear model differed from palpation in a few instances. RMSEs of the D-AMC (3.7-14.8°) and particularly the linear model (4.6-24.8°) were generally at or beyond the upper range of past AMC analyses on healthy adults (1.6-14.2°), especially for more complex, multiplanar arm postures. Despite the D-AMC outperforming the linear model, this approach still produced clinically meaningful (>10°) errors for roughly (12.7-22.5%) of subjects. SIGNIFICANCE: Current methods for estimating dynamic scapular orientation remain less than ideal for BPBI. Use of the D-AMC may be appropriate to gain broad insights into general dynamic scapulothoracic and glenohumeral function; however, given their potential for producing clinically meaningful errors, the D-AMC and linear model are not recommended for diagnostic purposes or outcomes assessment on an individual patient basis unless their patient-specific accuracy has been evaluated and confirmed prior to use.

Assessment of the relationship between Brachial Plexus Profile activity short form scores and modified Mallet scores.

INTRODUCTION: This study aims to assess the relationship between the modified Mallet classification and the Brachial Plexus Profile activity short form (BP-PRO activity SF). The therapist or surgeon classifies upper extremity movement for the modified Mallet classification, while the BP-PRO assesses parents' perceptions of difficulty performing activities. PURPOSE: To provide a deeper understanding of the relationship of functional and perceived outcome measurements. STUDY DESIGN: Prospective, correlational design. METHODS: Eighty children with brachial plexus birth injuries were evaluated using the modified Mallet classification, while parents simultaneously answered the BP-PRO activity SF questions. All patients had undergone one of three surgical interventions to improve shoulder function. The relationship between the two measures, patient injury levels, and surgical histories were assessed. RESULTS: The average modified Mallet scores and BP-PRO activity SF scores weakly correlated (r = 0.312, P = .005) and both measures differentiated between C5-6 and C5-7 injury levels (P = .03 and P = .02, respectively). Conversely, the modified Mallet scores could differentiate between the three surgical groups (F = 8.2, P < .001), while the BP-PRO activity SF could not (P = .54). CONCLUSION: The results suggest that these tools measure different aspects of patient outcomes. The Mallet classification may be more focused on shoulder motion than the BP-PRO activity SF. Additional questions that specifically require shoulder function could be incorporated into the BP-PRO activity SF to improve understanding of patient/parent perceptions of shoulder function for children with brachial plexus injuries. Clinicians should be aware of the strengths, weaknesses, and limitations of each outcome assessment tool for appropriate use and interpretation of results.

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.

Immunogenicity Assessment of Inotersen, a 2'-O-(2-Methoxyethyl) Antisense Oligonucleotide in Animals and Humans: Effect on Pharmacokinetics, Pharmacodynamics, and Safety.

Inotersen (TEGSEDI™) is a 2'-O-(2-methoxyethyl)-modified antisense oligonucleotide, intended for treating hereditary transthyretin (TTR) amyloidosis with polyneuropathy. The potential immunogenicity (IM) response to inotersen was evaluated in chronic nonclinical safety studies and the pivotal phase 2/3 clinical study. The evaluation was designed to assess the characteristics of antidrug antibodies (ADAs) and their effects on the pharmacokinetics, pharmacodynamics, clinical efficacy, and safety in animals and humans. No immunogenic response was observed after long-term treatment with inotersen in mice. In monkeys, the incidence rate of IM to inotersen appeared to be dose dependent, with 28.6%-50.0% of animals developing ADAs after 36 weeks of treatment. This was characterized as late onset (median onset of 185 days) with low titers (median titer of 8, or 400 if minimum required dilution of 50 is included). The overall incidence rate of patients who developed ADAs was 30% after 65 weeks of treatment with median onset of 203 days and median peak titer of 300. IM had minimal effect on plasma peak (Cmax) and total exposure (i.e. area under curve, AUC) of inotersen, but showed elevated plasma trough levels in both IM-positive animals and humans. However, ADAs had no effect on tissue exposure, TTR messenger RNA, or plasma TTR levels in the long-term monkey study. Similarly, IM showed no effect on plasma TTR levels in clinical studies. Thus, ADAs antibodies were binding antibodies, but not neutralizing antibodies. Finally, no association was observed between IM and toxicity findings (eg, platelet, complement activation, and histopathology findings) in the inotersen 9-month monkey study. In humans, no difference was observed in hematology, including platelets, kidney function tests, or incidence of adverse events between IM-positive and -negative patients. Overall, IM showed no effect on toxicity or safety of inotersen evaluated in both monkeys and humans. ClinicalTrials.gov Identifier: NCT01737398.

Acute Myeloid Leukemia iPSCs Reveal a Role for RUNX1 in the Maintenance of Human Leukemia Stem Cells.

Leukemia stem cells (LSCs) are believed to have more distinct vulnerabilities than the bulk acute myeloid leukemia (AML) cells, but their rarity and the lack of universal markers for their prospective isolation hamper their study. We report that genetically clonal induced pluripotent stem cells (iPSCs) derived from an AML patient and characterized by exceptionally high engraftment potential give rise, upon hematopoietic differentiation, to a phenotypic hierarchy. Through fate-tracking experiments, xenotransplantation, and single-cell transcriptomics, we identify a cell fraction (iLSC) that can be isolated prospectively by means of adherent in vitro growth that resides on the apex of this hierarchy and fulfills the hallmark features of LSCs. Through integrative genomic studies of the iLSC transcriptome and chromatin landscape, we derive an LSC gene signature that predicts patient survival and uncovers a dependency of LSCs, across AML genotypes, on the RUNX1 transcription factor. These findings can empower efforts to therapeutically target AML LSCs.

Occupational Injuries Involving Medical Imaging and Radiation Therapy Professionals.

PURPOSE: To determine the types of occupational injuries medical imaging and radiation therapy professionals experience in addition to the length of medical leave of absence, receipt of financial compensation, and ability to perform the same job duties on returning to work. METHODS: Using a quantitative approach, a random sample of 10 000 American Society of Radiologic Technologists members was invited to complete a survey detailing occupational injuries experienced while working as a medical imaging or radiation therapy professional. Data were collected using Qualtrics and analyzed with IBM's SPSS. RESULTS: Of the 401 participants in this study, more than half (251, 62.6%) experienced occupational injuries, with the majority of those being muscular injuries (205, 81.7%). Of the 251 participants who experienced an occupational injury, 109 (43.4%) reported a medical leave of absence of less than 1 week, 61 (24.3%) received financial assistance from their employer, and 231 (92%) indicated they were able to resume their previous job duties on returning to work. DISCUSSION: Many study participants acknowledged that despite being injured they continued to work impaired without taking a medical leave of absence or did not report the injury to administration or risk management. Impaired employees can further aggravate pre-existing medical conditions and possibly trigger a permanent disability or chronic ailment by continuing to perform the same work activities as when they were injured initially. Department managers and supervisors should encourage medical imaging and radiation therapy professionals to report all injuries so that appropriate measures (eg, informing risk management, filing a workers' compensation claim, or modifying job responsibilities) can be initiated. CONCLUSION: Additional research is warranted to explore strategies for preventing or decreasing the incidence of occupational injuries in the medical imaging and radiation therapy profession that can be implemented individually (eg, practicing proper patient handling techniques) or organizationally (eg, staffing an appropriate number of personnel for the workload).

A global assessment of marine heatwaves and their drivers.

Marine heatwaves (MHWs) can cause devastating impacts to marine life. Despite the serious consequences of MHWs, our understanding of their drivers is largely based on isolated case studies rather than any systematic unifying assessment. Here we provide the first global assessment under a consistent framework by combining a confidence assessment of the historical refereed literature from 1950 to February 2016, together with the analysis of MHWs determined from daily satellite sea surface temperatures from 1982-2016, to identify the important local processes, large-scale climate modes and teleconnections that are associated with MHWs regionally. Clear patterns emerge, including coherent relationships between enhanced or suppressed MHW occurrences with the dominant climate modes across most regions of the globe - an important exception being western boundary current regions where reports of MHW events are few and ocean-climate relationships are complex. These results provide a global baseline for future MHW process and prediction studies.

Self-Awareness and Cultural Identity as an Effort to Reduce Bias in Medicine.

In response to persistently documented health disparities based on race and other demographic factors, medical schools have implemented "cultural competency" coursework. While many of these courses have focused on strategies for treating patients of different cultural backgrounds, very few have addressed the impact of the physician's own cultural background and offered methods to overcome his or her own unconscious biases. In hopes of training physicians to contextualize the impact of their own cultural background on their ability to provide optimal patient care, the authors created a 14-session course on culture, self-reflection, and medicine. After completing the course, students reported an increased awareness of their blind spots and that providing equitable care and treatment would require lifelong reflection and attention to these biases. In this article, the authors describe the formation and implementation of a novel medical school course on self-awareness and cultural identity designed to reduce unconscious bias in medicine. Finally, we discuss our observations and lessons learned after more than 10 years of experience teaching the course.

Self-reported Conflicts of Interest and Trial Sponsorship of Clinical Trials in Prostate Cancer Involving Radiotherapy.

OBJECTIVES: To examine the association between trial sponsorship and conflicts of interest (COI) with clinical trial conclusions for prostate cancer trials related to radiotherapy. MATERIALS AND METHODS: The MEDLINE database was searched for all prostate cancer clinical trials published between 2004 and 2013 and identified 1396 studies. Two investigators independently identified trials published in the English language of ≥30 patients, and extracted relevant data. Clinical trials were classified according to trial characteristics, sponsorship source and type, COI, and study conclusion, and analyzed by univariable and multivariable logistic regression. RESULTS: Of 240 eligible trials, 160 (67.5%) evaluated drugs without radiotherapy, 60 (25%) involved radiotherapy, and 18 (7.5%) involved procedures without radiotherapy. Of the 60 radiotherapy trials eligible for analysis, positive sponsorship and potential COI were present in 58.3% and 20% of trials, respectively. Study conclusions were positive, negative, or neutral in 78.3%, 5%, and 16.7% of trials, respectively. No association was found between positive conclusions and either industry support of potential COI. Positive conclusions were reported in 86.7% and 83.3% of trials with sponsorship and COI, respectively, as compared with 75.6% and 77.1% of those without sponsorship (P=0.37) and COI (P=0.64). Sponsorship was significantly associated with radiotherapy trials combined with drugs (odds ratio 5.5, P=0.01) and higher-risk disease (odds ratio 4.71, P=0.01). CONCLUSIONS: The presence of sponsorship was associated with radiotherapy trials involving drugs or studying higher-risk prostate cancer. However, there were no identified associations between study conclusion and sponsorship type or COI.

The Methuselah Effect: The Pernicious Impact of Unreported Deaths on Old-Age Mortality Estimates.

We examine inferences about old-age mortality that arise when researchers use survey data matched to death records. We show that even small rates of failure to match respondents can lead to substantial bias in the measurement of mortality rates at older ages. This type of measurement error is consequential for three strands in the demographic literature: (1) the deceleration in mortality rates at old ages; (2) the black-white mortality crossover; and (3) the relatively low rate of old-age mortality among Hispanics, often called the "Hispanic paradox." Using the National Longitudinal Survey of Older Men matched to death records in both the U.S. Vital Statistics system and the Social Security Death Index, we demonstrate that even small rates of missing mortality matching plausibly lead to an appearance of mortality deceleration when none exists and can generate a spurious black-white mortality crossover. We confirm these findings using data from the National Health Interview Survey matched to the U.S. Vital Statistics system, a data set known as the "gold standard" (Cowper et al. 2002) for estimating age-specific mortality. Moreover, with these data, we show that the Hispanic paradox is also plausibly explained by a similar undercount.

Current Approaches for Absorption, Distribution, Metabolism, and Excretion Characterization of Antibody-Drug Conjugates: An Industry White Paper.

An antibody-drug conjugate (ADC) is a unique therapeutic modality composed of a highly potent drug molecule conjugated to a monoclonal antibody. As the number of ADCs in various stages of nonclinical and clinical development has been increasing, pharmaceutical companies have been exploring diverse approaches to understanding the disposition of ADCs. To identify the key absorption, distribution, metabolism, and excretion (ADME) issues worth examining when developing an ADC and to find optimal scientifically based approaches to evaluate ADC ADME, the International Consortium for Innovation and Quality in Pharmaceutical Development launched an ADC ADME working group in early 2014. This white paper contains observations from the working group and provides an initial framework on issues and approaches to consider when evaluating the ADME of ADCs.

Cardiovascular and Musculoskeletal Assessment of Elite US Volleyball Players.

OBJECTIVE: The aim of this study was to characterize the cardiovascular and musculoskeletal systems of elite volleyball players, including aortic dimensions. Previous studies have shown that the upper limit of normal aortic sinus diameter for male and female athletes is 4 and 3.4 cm, respectively. DESIGN: Cross-sectional analysis. SETTING: United States Olympic Volleyball Training Facility and Rady Children's Hospital San Diego. PARTICIPANTS: Seventy (37 male) members of the US national volleyball team. MAIN OUTCOME MEASURES: Athletes underwent evaluation that included medical and family histories, targeted physical examinations specifically focusing on abnormalities present in Marfan syndrome (MFS), and transthoracic echocardiograms. Cardiac chamber and great artery size, valve function, and coronary artery origins were assessed. RESULTS: Three male athletes (8%) had an aortic sinus diameter ≥4 cm, one of whom also had an ascending aorta >4 cm. Two female athletes (6%) had aortic sinus diameter ≥3.4 cm, and another had an ascending aorta of 3.4 cm. There were no other intracardiac or arterial abnormalities. Individual musculoskeletal characteristics of MFS were common among the athletes but not more frequent or numerous in those with aortic dilation. CONCLUSIONS: The prevalence of aortic root dilation in this population of athletes was higher than what has previously been reported in other similar populations. Further study is needed to determine whether these represent pathological changes or normal variations in tall athletes. CLINICAL RELEVANCE: This study adds to the existing knowledge base of athlete's heart, with specific attention to aortic dimensions in elite volleyball players. The data are relevant to similar athletes' medical care and to preparticipation cardiac screening in general.

The AOA-JOA 2014 exchange traveling fellowship: Banzai and beyond.

The American Orthopaedic Association-Japanese Orthopaedic Association (AOA-JOA) traveling fellowship was established in 1992 as a method for creating collaboration between the American and Japanese orthopaedic communities and providing a friendly exchange of current practices and scientific endeavors. The fellowship is designed to allow early-career orthopaedic surgeons the opportunity to participate in international travel and scholarship. This year's traveling fellows (Hassan Mir, Wakenda Tyler, Leo Kroonen, and Dan Zlotolow) all hail from different parts of the United States and have a variety of practice subspecialties. During the fellowship, the fellows were able to visit five academic centers that spanned the entire country of Japan as well as the JOA meeting in Kobe. The experience is one that contributed to the growth and development of each fellow's practices and depth of understanding of orthopaedic surgery.

The WASOG Sarcoidosis Organ Assessment Instrument: An update of a previous clinical tool.

INTRODUCTION: A Case Control Etiology of Sarcoidosis Study (ACCESS) sarcoidosis organ assessment instrument has been used for more than a decade to establish uniform standards for the probability of sarcoidosis organ involvement. The ACCESS instrument has become increasingly outdated as new technologies have been developed. Furthermore, the ACCESS instrument failed to address all possible organs involved with sarcoidosis. For these reasons, the World Association of Sarcoidosis and Other Granulomatous Diseases (WASOG) developed a new sarcoidosis organ assessment instrument. METHODS: Clinical sarcoidosis experts assessed various clinical manifestations for the probability of sarcoidosis organ involvement. Two criteria were required to apply this assessment: 1) histologic evidence of granulomatous inflammation of unknown cause in an organ that was not being assessed; 2) the clinical manifestation being addressed required that alternative causes other than sarcoidosis had been reasonably excluded. Clinical manifestations were assessed as either: a) highly probable: likelihood of sarcoidosis causing this manifestation of at least 90%.; b) probable: likelihood of sarcoidosis causing this manifestation of between 50 and 90%; c) possible: likelihood of sarcoidosis causing this manifestation of less than 50%. The sarcoidosis experts voted on the likelihood of sarcoidosis causing each manifestation using Delphi study methodology where at least 70% agreement of the experts was needed for consensus. RESULTS: Various clinical manifestations were classified as highly probable, at least probable, possible, or indeterminate when no consensus could be reached. CONCLUSION: An instrument was developed by expert opinion that may be useful for the clinician and researcher in establishing criteria for sarcoidosis organ involvement.

THE ROLE OF LOCATION IN EVALUATING RACIAL WAGE DISPARITY.

A standard object of empirical analysis in labor economics is a modified Mincer wage function in which an individual's log wage is specified to be a function of education, experience, and an indicator variable identifying race. We analyze this approach in a context in which individuals live and work in different locations (and thus face different housing prices and wages). Our model provides a justification for the traditional approach, but with the important caveat that the regression should include location-specific fixed effects. Empirical analyses of men in U.S. labor markets demonstrate that failure to condition on location causes us to (i) overstate the decline in black-white wage disparity over the past 60 years, and (ii) understate racial and ethnic wage gaps that remain after taking into account measured cognitive skill differences that emerge when workers are young.

Using Lancaster's mid-P correction to the Fisher's exact test for adverse impact analyses.

Adverse impact is often assessed by evaluating whether the success rates for 2 groups on a selection procedure are significantly different. Although various statistical methods have been used to analyze adverse impact data, Fisher's exact test (FET) has been widely adopted, especially when sample sizes are small. In recent years, however, the statistical field has expressed concern regarding the default use of the FET and has proposed several alternative tests. This article reviews Lancaster's mid-P (LMP) test (Lancaster, 1961), an adjustment to the FET that tends to have increased power while maintaining a Type I error rate close to the nominal level. On the basis of Monte Carlo simulation results, the LMP test was found to outperform the FET across a wide range of conditions typical of adverse impact analyses. The LMP test was also found to provide better control over Type I errors than the large-sample Z-test when sample size was very small, but it tended to have slightly lower power than the Z-test under some conditions.

Role of common biochemical markers for the assessment of fracture union.

The progress of fracture union requires close monitoring. Whereas, clinical examination and radiographic studies assess the outcome, biochemical markers like serum alkaline phosphatase and urinary hydroxyproline reflect the actual status of bone resorption and bone formation over a short time frame. 36 patients of long bone fracture were randomly allocated for the study. When the patient reported to the Department of Orthopedics after fracture, serum and urinary samples were collected and X-ray of the affected part were taken. Subsequent samples were collected and X-ray taken just after management (either operative or conservative), after 3rd, 5th, 8th and 12th week, respectively after onset of fracture. According to the course of callus formation the patients were divided into two groups that progressed to proper union or malunion. The levels of serum alkaline phosphatase, urinary total and free hydroxyproline levels were measured and statistically analysed and compared. A statistically significant positive correlation between total urinary hydroxyproline excretion and serum alkaline phosphatase indicate progress towards satisfactory union. Thus, serial monitoring of biochemical markers of bone turnover can be used as an adjunct to clinical and radiological evidence of fracture healing.