A taxing problem: The impacts of research payment practices on participants and inclusive research.

Empirical data regarding payments to participants in research is limited. This lack of information constrains our understanding of the effectiveness of payments to achieve scientific goals with respect to recruitment, retention, and inclusion. We conducted a content analysis of consent forms and protocols available on clinicaltrials.gov to determine what information researchers provide regarding payment. We extracted data from HIV (n = 101) and NIMH-funded studies (n = 65) listed on clinicaltrials.gov that had publicly posted a consent form. Using a manifest content analysis approach, we then coded the language regarding payment from the consent document and, where available, protocol for purpose and method of the payment. Although not part of our original planned analysis, the tax-related information that emerged from our content analysis of the consent form language provided additional insights into researcher payment practices. Accordingly, we also recorded whether the payment section mentioned social security numbers (or other tax identification number) in connection with payments and whether it made any statements regarding the Internal Revenue Service or the tax status of payments. We found studies commonly offered payment, but did not distinguish between the purposes for which payment may be offered (i.e., compensation, reimbursement, incentive, or appreciation). We also found studies that excluded some participants from receiving payment or treated them differently from other participants in the study. Differential treatment was typically linked to US tax laws and other legal requirements. A number of US studies also discussed the need to collect Social Security numbers and income reporting based on US tax laws. Collectively, these practices disadvantage some participants and may interfere with efforts to conduct more inclusive research.

Certificates of Confidentiality and Mandatory Reporting.

This Viewpoint discusses the importance of obtaining federal certificates of confidentiality to free researchers to perform important research into child sexual abuse.

Performance Characteristics of a Real-Time PCR Assay for Direct Detection of Streptococcus pneumoniae in Clinical Specimens.

Community-acquired pneumonia and complications, such as bacteremia and meningitis due to Streptococcus pneumoniae infection, still occur in at-risk populations, despite the availability of effective vaccines. Laboratory confirmation of S. pneumoniae remains challenging despite advances in blood culture techniques and the availability of nucleic acid-amplification tests. The goal of this study was to determine the performance characteristics of a molecular assay designed as a diagnostic test using primary clinical specimens for invasive pneumococcal disease. The molecular assay adapted for the Luminex Aries instrument targets an S. pneumoniae-specific gene (autolysin, lytA) in clinical specimens. Using real-time PCR MultiCode technology, four different clinical specimen types were evaluated. Specimen types included bronchoalveolar lavage, whole blood, cerebrospinal fluid, and urine to cover the various presentations and appropriate specimen types for invasive pneumococcal infections. The lower limit of detection in urine was 10 colony forming units (CFU)/mL, while in bronchoalveolar lavage, cerebrospinal fluid, and whole blood, it was 100 CFU/mL. Accuracy and specificity were both 100%, and all specimen types were stable for 8 days at 4°C. Finally, 38 clinical specimens were tested to further evaluate the assay. The performance characteristics met Clinical Laboratory Improvement Amendments standards for a clinical diagnostic assay, and the assay offers a sensitive and specific real-time PCR test for direct detection of S. pneumoniae in relevant clinical specimens.

Certificates of confidentiality: privileging research data.

With the Supreme Court's decision in Dobbs, reproductive research now joins other sensitive research topics that present legal risks to research participants, underscoring the role of Certificates in protecting them. Yet, stakeholders question whether Certificates will hold up in court. In this article, we describe the essential arguments supporting Congress's regulation of biomedical research and, thus, Certificates, under its authority to regulate interstate commerce. Our analysis should reassure researchers and Institutional review boards who rely on Certificates to protect the confidentiality of research participants' data. We conclude with recommendations for stakeholders based on our analysis.

Persistent SARS-CoV-2 Infection in a Multiple Sclerosis Patient on Ocrelizumab: A Case Report.

A 44-year-old female patient with multiple sclerosis (MS) treated with ocrelizumab was hospitalized with SARS-CoV-2 pneumonia three times over the course of five months, eventually expiring. Viral sequencing of samples from her first and last admissions suggests a single persistent SARS-CoV-2 infection. We hypothesize that her immunocompromised state, due to MS treatment with an immunosuppressive monoclonal antibody, prevented her from achieving viral clearance.

"Choice of law" in precision medicine research.

Large-scale precision medicine research requires massive amounts of data representing people from all walks of life; thus, in the US, it is often multistate research. Significant legal and ethical quandaries arise as a result of the patchwork of laws states have enacted that may apply to research, are not preempted by federal law, and may impose requirements or provide participant rights and protections that differ from other states. Determining which state's laws apply, and under what circumstances, is not solved by the transition to a single-IRB model and researchers cannot simply choose one state's laws to apply uniformly. At a minimum, the current process of meeting each state's requirements could be made more reliable and efficient. To fundamentally change this status quo, however, requires action at multiple levels. Federally, well-known gaps in the Genetic Information Nondiscrimination Act should be closed, and a coherent system of compensation for research injury-including non-physical injuries-should be developed. States should clarify which of their laws are intended to apply to research and work collaboratively to harmonize them. At the level of individual research projects, numerous policies and procedures could be standardized through authoritative guidelines. Examples include clarifying the scope of broad consent, understanding and upholding Certificates of Confidentiality, offering individual research results responsibly, and consistently disseminating aggregate results to participants and the public. Overall, development of a choice of law framework specific to the research context could significantly promote clarity and consistency.

Addressing choice of law challenges in multi-state precision medicine research: experts' assessment of key factors.

Precision medicine research implicates numerous state laws that may affect participants' rights and protections and are not preempted by federal law. The choice of which state's laws apply, and under what circumstances, can have significant impact on research design and oversight. But neither of the traditional approaches to choice of law issues-contractual agreement or determination by a court after a dispute arises-fit the research context well. We hosted a series of workshops with choice of law experts and research law and ethics experts to identify factors that are most crucial to account for in a future choice of law precision medicine research framework. Our workshops focused on precision medicine 'places' and choice of law factors; there was consensus that 'place where the harm occurred' was relevant and best represented by where the participant resides and/or where the research/institution is located. Our experts identified factors that need to be accounted for in a future choice of law framework. They also identified potential approaches, including a federal law or model state law as ways of achieving more uniformity of protections and a comprehensive database of laws, which merit further consideration to provide IRBs and researchers the guidance they require.

Perspectives on choice of law challenges in multistate precision medicine research.

Federal law establishes minimum standards for protecting human research participants, but many states have enacted laws that may apply to research. Precision medicine research in particular implicates state laws that govern an array of topics, including human subjects research, genetic testing, and both general and genetic privacy and discrimination. Thus, the determination of which state's laws apply, and under what circumstances, can substantially alter participant rights and protections. To shed light on this topic, we conducted interviews with experts in law, human research protections, and precision medicine research. Our goal was to better understand their experiences with choice of law issues, the effects of state law variation on research practices and stakeholder groups, and approaches to addressing such variation. Interviewees were aware of state-based variation in laws that could be applied to research. However, the extent to which they perceived such variability as problematic differed, as did their perceptions of stakeholder roles and responsibilities for addressing state law variation, and their estimations of requisite knowledge among IRBs and researchers. These divergent perspectives create an ethical and legal quandary, and further empirical and normative work is needed to fully characterize the implications of substantive differences in participant rights and protections.

Ending the evidence gap for pregnancy, HIV and co-infections: ethics guidance from the PHASES project.

INTRODUCTION: While pregnant people have been an important focus for HIV research, critical evidence gaps remain regarding prevention, co-infection, and safety and efficacy of new antiretroviral therapies in pregnancy. Such gaps can result in harm: without safety data, drugs used may carry unacceptable risks to the foetus or pregnant person; without pregnancy-specific dosing data, pregnant people face risks of both toxicity and undertreatment; and delays in gathering evidence can limit access to beneficial next-generation drugs. Despite recognition of the need, numerous barriers and ethical complexities have limited progress. We describe the process, ethical foundations, recommendations and applications of guidance for advancing responsible inclusion of pregnant people in HIV/co-infections research. DISCUSSION: The 26-member international and interdisciplinary Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) Working Group was convened to develop ethics-centred guidance for advancing timely, responsible HIV/co-infections research with pregnant people. Deliberations over 3 years drew on extensive qualitative research, stakeholder engagement, expert consultation and a series of workshops. The guidance, initially issued in July 2020, highlights conceptual shifts needed in framing research with pregnant people, and articulates three ethical foundations to ground recommendations: equitable protection from drug-related risks, timely access to biomedical advances and equitable respect for pregnant people's health interests. The guidance advances 12 specific recommendations, actionable within the current regulatory environment, addressing multiple stakeholders across drug development and post-approval research, and organized around four themes: building capacity, supporting inclusion, achieving priority research and ensuring respect. The recommendations describe strategies towards ethically redressing the evidence gap for pregnant people around HIV and co-infections. The guidance has informed key efforts of leading organizations working to advance needed research, and identifies further opportunities for impact by a range of stakeholder groups. CONCLUSIONS: There are clear pathways towards ethical inclusion of pregnant people in the biomedical research agenda, and strong agreement across the HIV research community about the need for - and the promise of - advancing them. Those who fund, conduct, oversee and advocate for research can use the PHASES guidance to facilitate more, better and earlier evidence to optimize the health and wellbeing of pregnant people and their children.

Induction of interferon response by high viral loads at early stage infection may protect against severe outcomes in COVID-19 patients.

Key elements for viral pathogenesis include viral strains, viral load, co-infection, and host responses. Several studies analyzing these factors in the function of disease severity of have been published; however, no studies have shown how all of these factors interplay within a defined cohort. To address this important question, we sought to understand how these four key components interplay in a cohort of COVID-19 patients. We determined the viral loads and gene expression using high throughput sequencing and various virological methods. We found that viral loads in the upper respiratory tract in COVID-19 patients at an early phase of infection vary widely. While the majority of nasopharyngeal (NP) samples have a viral load lower than the limit of detection of infectious viruses, there are samples with an extraordinary amount of SARS-CoV-2 RNA and a high viral titer. No specific viral factors were identified that are associated with high viral loads. Host gene expression analysis showed that viral loads were strongly correlated with cellular antiviral responses. Interestingly, however, COVID-19 patients who experience mild symptoms have a higher viral load than those with severe complications, indicating that naso-pharyngeal viral load may not be a key factor of the clinical outcomes of COVID-19. The metagenomics analysis revealed that the microflora in the upper respiratory tract of COVID-19 patients with high viral loads were dominated by SARS-CoV-2, with a high degree of dysbiosis. Finally, we found a strong inverse correlation between upregulation of interferon responses and disease severity. Overall our study suggests that a high viral load in the upper respiratory tract may not be a critical factor for severe symptoms; rather, dampened antiviral responses may be a critical factor for a severe outcome from the infection.

Movement System Diagnoses for Balance Dysfunction: Recommendations From the Academy of Neurologic Physical Therapy's Movement System Task Force.

The movement system was identified as the focus of our expertise as physical therapists in the revised vision statement for the profession adopted by the American Physical Therapy Association in 2013. Attaining success with the profession's vision requires the development of movement system diagnoses that will be useful in clinical practice, research, and education. To date, only a few movement system diagnoses have been identified and described, and none of these specifically address balance dysfunction. Over the past 2 years, a Balance Diagnosis Task Force, a subgroup of the Movement System Task Force of the Academy of Neurologic Physical Therapy, focused on developing diagnostic labels (or diagnoses) for individuals with balance problems. This paper presents the work of the task force that followed a systematic process to review available diagnostic frameworks related to balance, identify 10 distinct movement system diagnoses that reflect balance dysfunction, and develop complete descriptions of examination findings associated with each balance diagnosis. A standardized approach to movement analysis of core tasks, the Framework for Movement Analysis developed by the Academy of Neurologic Physical Therapy Movement Analysis Task Force, was integrated into the examination and diagnostic processes. The aims of this perspective paper are to (1) summarize the process followed by the Balance Diagnosis Task Force to develop an initial set of movement system (balance) diagnoses; (2) report the recommended diagnostic labels and associated descriptions; (3) demonstrate the clinical decision-making process used to determine a balance diagnosis and develop a plan of care; and (4) identify next steps to validate and implement the diagnoses into physical therapist practice, education, and research. IMPACT: The development and use of diagnostic labels to classify distinct movement system problems is needed in physical therapy. The 10 balance diagnosis proposed can aid in clinical decision making regarding intervention.

Development and Evaluation of a Fully Automated Molecular Assay Targeting the Mitochondrial Small Subunit rRNA Gene for the Detection of Pneumocystis jirovecii in Bronchoalveolar Lavage Fluid Specimens.

The fungal pathogen Pneumocystis jirovecii causes Pneumocystis pneumonia. Although the mitochondrial large subunit rRNA gene (mtLSU) is commonly used as a PCR target, a mitochondrial small subunit rRNA gene (mtSSU)-targeted MultiCode PCR assay was developed on the fully automated ARIES platform for detection of P. jirovecii in bronchoalveolar lavage fluid specimens in 2.5 hours. The assay showed a limit of detection of 800 copies/mL (approximately equal to 22 organisms/mL), with no cross-reactivity with other respiratory pathogens. Compared with the reference Pneumocystis-specific direct fluorescent antibody assay (DFA) and mtLSU-targeted PCR assay, the new assay demonstrated sensitivity of 96.9% (31/32) and specificity of 94.6% (139/147) in detecting P. jirovecii in 180 clinical bronchoalveolar lavage fluid specimens. This assay was concordant with all DFA-positive samples and all but one mtLSU PCR-positive sample, and detected eight positive samples that were negative by DFA and mtLSU PCR. Receiver operating characteristic curve analysis revealed an area under the curve of 0.98 and a threshold cycle (CT) cutoff of 39.1 with sensitivity of 90.9% and specificity of 99.3%. The detection of 39.1

Performance of the ImmuView and BinaxNOW assays for the detection of urine and cerebrospinal fluid Streptococcus pneumoniae and Legionella pneumophila serogroup 1 antigen in patients with Legionnaires' disease or pneumococcal pneumonia and meningitis.

The performances of the ImmuView Streptococcus pneumoniae (Sp) and Legionella pneumophila (Lp) urinary antigen test were compared to that of the BinaxNOW Sp and Lp assays, using frozen urine from 166 patients with Legionnaires' disease (LD) and 59 patients with pneumococcal pneumonia. Thirty Sp-positive or contrived cerebrospinal fluids (CSF) were also tested. Test specimens were collected and tested at different sites, with each site testing unique specimens by technologists blinded to expected results. No significant differences in test concordances were detected for the ImmuView and BinaxNOW assays for the Sp or Lp targets for urine from patients with pneumococcal pneumonia or LD when performance from both sites were combined. At one of two test sites the ImmuView Lp assay was more sensitive than the BinaxNOW assay, with no correlation between test performance and Lp serogroup 1 monoclonal type. Urines from six of seven patients with LD caused by Legionella spp. bacteria other than Lp serogroup 1 were negative in both assays. Both tests had equivalent performance for Sp-positive CSF. The clinical sensitivities for pneumococcal pneumonia were 88.1 and 94.4% for the ImmuView and Binax assays, and 87.6 and 84.2% for the Lp assays, respectively. Test specificities for pneumococcal pneumonia were 96.2 and 97.0% for the ImmuView and Binax assays, and 99.6 and 99.1% for the Lp assays. Both assays were highly specific for Sp in pediatric urines from children with nasopharyngeal colonization by the bacterium. ImmuView and BinaxNOW assay performance was equivalent in these studies.

Protecting Participants in Genomic Research: Understanding the "Web of Protections" Afforded by Federal and State Law.

Researchers now commonly collect biospecimens for genomic analysis together with information from mobile devices and electronic health records. This rich combination of data creates new opportunities for understanding and addressing important health issues, but also intensifies challenges to privacy and confidentiality. Here, we elucidate the "web" of legal protections for precision medicine research by integrating findings from qualitative interviews with structured legal research and applying them to realistic research scenarios involving various privacy threats.

Detection of Ehrlichia spp. and Anaplasma phagocytophilum in whole blood specimens using a duplex real-time PCR assay on the ARIES instrument.

Cases of tick-borne diseases are increasing in the United States, and new tick-borne pathogen species causing human illness are being discovered. The specific etiology is generally difficult to diagnose based on clinical signs and symptoms alone, because of their generalized nature and often lack of a known tick bite. For some infections, such as Lyme disease and spotted fever group rickettsioses, serology remains the most appropriate laboratory diagnostic tool, but for others such as anaplasmosis, ehrlichiosis, and babesiosis, direct detection in the blood is preferred for rapid diagnosis. In Kentucky, USA, the area served by our laboratory, the most commonly reported tick-borne illnesses include spotted fever group rickettsiosis, ehrlichiosis and Lyme disease, but of these three diseases, only ehrlichiosis is well-suited for direct detection using PCR methods during the acute stage of illness. We report here the validation of a duplex real-time PCR assay using whole blood specimens on the Luminex ARIES® instrument, combining DNA extraction, amplification and detection into a one-step process. This method allows for rapid and sensitive detection of acute infections with Ehrlichia spp. and Anaplasma phagocytophilum using whole blood specimens. We included A. phagocytophilum to monitor emergence of this pathogen in Kentucky, since surrounding states have reported many more cases than Kentucky.

The Web of Legal Protections for Participants in Genomic Research.

The identification and arrest of the Golden State Killer using DNA uploaded to an ancestry database occurred shortly before recruitment for the National Institutes of Health's (NIH) All of Us Study commenced, with a goal of enrolling and collecting DNA, health, and lifestyle information from one million Americans. It also highlighted the need to ensure prospective research participants that their confidentiality will be protected and their materials used appropriately. But there are questions about how well current law protects against these privacy risks. This article is the first to consider comprehensively and simultaneously all the federal and state laws offering protections to participants in genomic research. The literature typically focuses on the federal laws in isolation, questioning the strengths of federal legal protections for genomic research participants provided in the Common Rule, the HIPAA Privacy Rule, or the Genetic Information Nondiscrimination Act. Nevertheless, we found significant numbers and surprising variety among state laws that provide greater protections than federal laws, often filling in federal gaps by broadening the applicability of privacy or nondiscrimination standards or by providing important remedies for individuals harmed by breaches. Identifying and explaining the protections these laws provide is significant both to allow prospective participants to accurately weigh the risks of enrolling in these studies and as models for how federal legal protections could be expanded to fill known gaps.