Subgroup analyses and pre-specification.

Large clinical trials provide the opportunity to assess treatment effects in subgroups of patients, based on baseline demographic and disease-related factors, and there is always great interest in these analyses. Generally, the term "pre-specification" has major ramifications for clinical trials, particularly for adequate and well-controlled trials that are designed for formal hypothesis testing. Pre-specification is the "holy grail" of modern trials, as choosing analytical approaches with data in-hand will inflate the type I error rate. But "pre-specification" often has a different meaning with respect to subgroup analyses.

Functional and Symptomatic Clinical Trial Endpoints: The HFC-ARC Scientific Expert Panel.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations.

Consideration-of-concept of EvolvRehab-Body for upper limb virtual rehabilitation at home for people late after stroke.

OBJECTIVE: EvolvRehab-Body is a non-immersive virtual rehabilitation system that could provide high-dose, exercise-based upper limb therapy after stroke. This consideration-of-concept study investigated: adherence rate to prescribed repetitions; viability of repeated measures in preparation for a dose-articulation study; and preliminary signal of potential benefit. METHODS: Pre-post and repeated measures with people at least six months after stroke. Twelve-week intervention: exercise-based therapy via EvolvRehab-Body. Pre-post-intervention measures: Wolf Motor Function Test (WMFT); hand grip force. Repeated-during-intervention measures: Motricity Index (MI) and Action Research Arm Test (ARAT). ANALYSIS: adherence rate (%) to set repetitions; percentage of total possible measures collected; pre-to-post-intervention change estimated in relation to published minimally detectable changes of WMFT and hand grip force; and slope of plotted data for MI and ARAT (linear regression). RESULTS: Eight of twelve participants completed the 12-week intervention phase. Adherence: 88% (1710-9377 repetitions performed). Viability repeated measures: 88 of 96 (92%) ARAT and MI scores collected. Preliminary signal of potential benefit was observed in five participants but not always for the same measures. Three participants improved WMFT-time (-7.9 to -27.2 s/item), four improved WMFT-function (0.2-1.1 points/item), and nobody changed grip force. Slope of plotted data over the 12-week intervention ranged from: - 1.42 (p = 0.26) to 1.36 (p = 0.24) points-per-week for MI and - 0.30 (p = 0.40) to 1.71 (p < 0.001) points-per-week for ARAT. CONCLUSION: Findings of good adherence rate in home settings and preliminary signal of benefit for some participants gives support to proceed to a dose-articulation study. These findings cannot inform clinical practice. CONTRIBUTION OF THE PAPER.

Effect of PSSE on postural sway in AIS using center of pressure.

We haven't known whether the center of pressure (COP) could be considered as a better indicator in the evaluation of posture and balance change after the physiotherapeutic scoliosis specific exercise (PSSE) during level walking. The objective of this study was: 1) to determine changes in COP displacement in anterior-posterior (COP-AP) and medial-lateral (COP-ML) for AIS following the PSSE; 2) to find out COP oscillation(COP-OS) from the midline for the left and right foot; 3) to investigate max pressure at the forefoot, midfoot and hindfoot bilaterally. AIS patients with three reflective markers on their back walked on the pressure sensors embedded treadmill at 2 km/h and their trunks were also registered by DIERS Formetric 4D system. Each child received the PSSE for 12 weeks by the same physical therapist and had a dynamic pressure analysis before and after the PSSE. Six AIS children at a mean age of 13 years and with averaged major Cobb angle of 26° were enrolled. There was an increase in COP-AP (15%) and a decrease in the COP-ML (-25%) following the PSSE. COP-OS on the left foot shifted farther away from the midline (about 16%) as the right side moved closer (-1%), which becomes more symmetrical (Pre-PSSE: 0.86mm & Post-PSSE: 0.32mm). There were increased pressures on the left (35%) and right (26%) hallux after PSSE. Pressure metrics, especially including COP-ML, COP-AP, COP-OS, and peak pressures on the forefoot, may be opted as optimal predictors to posture improvements by the means of PSSE.

Gaining Efficiency in Clinical Trials With Cardiac Biomarkers: JACC Review Topic of the Week.

The momentum of cardiovascular drug development has slowed dramatically. Use of validated cardiac biomarkers in clinical trials could accelerate development of much-needed therapies, but biomarkers have been used less for cardiovascular drug development than in therapeutic areas such as oncology. Moreover, there are inconsistences in biomarker use in clinical trials, such as sample type, collection times, analytical methods, and storage for future research. With these needs in mind, participants in a Cardiac Safety Research Consortium Think Tank proposed the development of international guidance in this area, together with improved quality assurance and analytical methods, to determine what biomarkers can reliably show. Participants recommended the development of systematic methods for sample collection, and the archiving of samples in all cardiovascular clinical trials (including creation of a biobank or repository). The academic and regulatory communities also agreed to work together to ensure that published information is fully and clearly expressed.

Athletic Trainers' Perceptions of Accessibility to Necessary Resources for Those Working Per Diem Services.

CONTEXT: As the demand for athletic training services has grown, the per diem athletic training setting has expanded to fulfill this need. Per diem services are provided by athletic trainers (ATs) who are hired as independent contractors for short time periods. These service opportunities help to increase access to care for medically underserved populations; however, due to the transient nature of the work, the quality of care may be compromised. OBJECTIVE: To examine current practices in per diem services and evaluate ATs' accessibility to resources. DESIGN: Cross-sectional study. SETTING: Online survey. PATIENTS OR OTHER PARTICIPANTS: A total of 448 participants responded (access rate = 9.57%), of whom 210 were ineligible (46.9%). Of those who were eligible, 192 participants completed the entire tool (completion rate = 80.7%, age = 38 ± 12 years, years certified = 14 ± 11, years providing per diem services = 8 ± 8). MAIN OUTCOME MEASURE(S): The survey comprised 3 sections: (1) demographics, (2) accessibility to resources and influence on patient care, and (3) domains of athletic training while providing per diem services. Resources assessed included those that are relevant to ATs practicing in accordance with the Board of Certification "Standards of Professional Practice." The final instrument included approximately 30 questions (depending on display logic) and took an average of 12 minutes to complete. RESULTS: Of the 11 primary resources assessed, participants had limited accessibility to 6. Critical resources related to informatics, legalities, and health care delivery were often not available, were seen as unimportant to providing medical services, or both. CONCLUSIONS: Participants indicated varied perceptions about the need for and access to these resources. Yet such resources contribute to the creation of a safe infrastructure for providing medical services and should be part of the routine dialogue regarding independent contracting.

Standardized Definitions for Evaluation of Heart Failure Therapies: Scientific Expert Panel From the Heart Failure Collaboratory and Academic Research Consortium.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

Standardized definitions for evaluation of heart failure therapies: scientific expert panel from the Heart Failure Collaboratory and Academic Research Consortium.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation.

Epidemiology of Boys' Club Lacrosse Injuries During the 2018 Summer Lacrosse Season.

CONTEXT: In the past 10 years, participation in boys' youth and high school lacrosse has increased by 33%. Among many club teams and tournaments, athletes may not have access to medical coverage. Additionally, these athletes face a higher volume of play than in traditional scholastic sport settings. OBJECTIVE: To describe the injury characteristics of boys' nonscholastic youth and high school club lacrosse athletes over the course of a summer season. DESIGN: Descriptive epidemiology study. PATIENTS OR OTHER PARTICIPANTS: Boys' nonscholastic youth and high school lacrosse athletes, aged 8 to 18 years, who competed in tournaments. MAIN OUTCOME MEASURE(S): Athletic trainers at tournaments were given standardized injury report forms to document patient encounters. These reports were then entered into the Datalys Injury Surveillance Tool. RESULTS: Over the summer tournament season, 233 injuries were reported in 109 342 athlete-exposures (AEs) for an injury rate of 2.13 per 1000 AEs (95% confidence interval = 1.87, 2.42). The most frequently injured body parts were the head and/or face (n = 51, 22%), arm and/or elbow (n = 34, 15%), and hand and/or wrist (n = 29, 12%). The most common diagnoses were contusions (n = 63, 27%), concussions (n = 44, 19%), fractures (n = 39, 17%), and sprains (n = 35, 15%). The most often injured position was midfielder (n = 65, 41%), followed by defense (n = 48, 30%), attack (n = 36, 23%), and goalkeeper (n = 9, 6%). The concussion rate was 0.4 per 1000 AEs (95% confidence interval = 0.28, 0.52). CONCLUSIONS: The injury rate experienced by boys' nonscholastic club lacrosse athletes was similar to the rates of their high school counterparts as well as school-sponsored football and wrestling athletes. Because of the risk of injury, athletic training services should be available for youth and high school club lacrosse tournaments.

Design of a "Lean" Case Report Form for Heart Failure Therapeutic Development.

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.

Continuous and bolus intraventricular topotecan prolong survival in a mouse model of leptomeningeal medulloblastoma.

Leptomeningeal metastasis remains a difficult clinical challenge. Some success has been achieved by direct administration of therapeutics into the cerebrospinal fluid (CSF) circumventing limitations imposed by the blood brain barrier. Here we investigated continuous infusion versus bolus injection of therapy into the CSF in a preclinical model of human Group 3 medulloblastoma, the molecular subgroup with the highest incidence of leptomeningeal disease. Initial tests of selected Group 3 human medulloblastoma cell lines in culture showed that D283 Med and D425 Med were resistant to cytosine arabinoside and methotrexate. D283 Med cells were also resistant to topotecan, whereas 1 µM topotecan killed over 99% of D425 Med cells. We therefore introduced D425 Med cells, modified to express firefly luciferase, into the CSF of immunodeficient mice. Mice were then treated with topotecan or saline in five groups: continuous intraventricular (IVT) topotecan via osmotic pump (5.28 µg/day), daily bolus IVT topotecan injections with a similar daily dose (6 µg/day), systemic intraperitoneal injections of a higher daily dose of topotecan (15 µg/day), daily IVT pumped saline and daily intraperitoneal injections of saline. Bioluminescence analyses revealed that both IVT topotecan treatments effectively slowed leptomeningeal tumor growth in the brains. Histological analysis showed that they were associated with localized brain necrosis, possibly due to backtracking of topotecan around the catheter. In the spines, bolus IVT topotecan showed a trend towards slower tumor growth compared to continuous (pump) IVT topotecan, as measured by bioluminescence. Both continuous and bolus topotecan IVT showed longer survival compared to other groups. Thus, both direct IVT topotecan CSF delivery methods produced better anti-medulloblastoma effect compared to systemic therapy at the dosages used here.

The simplest supramolecular helix.

Diethylamine is the smallest and simplest molecule that features a supramolecular helix as its lowest energy aggregate. Structural studies and large scale sampling simulations show that the helical arrangement is more stable than cyclic structures, which are the dominant species for other small hydrogen bonding molecules.

Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs.

BACKGROUND: Concerns exist that women are underrepresented in trials of cardiovascular medications. OBJECTIVES: The authors sought to examine women's participation and the reported safety and efficacy by gender for pivotal cardiovascular disease (CVD) trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. METHODS: On the basis of publicly available FDA reviews, the authors assessed enrollment of women in trials supporting 36 drug approvals from 2005 to 2015. Prevalence-corrected estimates for the participation of women were calculated as the percentage of women among trial participants divided by the percentage of women in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of women in the trial and disease population. Sex differences in efficacy and safety were assessed. RESULTS: The proportion of women enrolled ranged from 22% to 81% (mean 46%). The calculated PPR by disease area was within or above the desirable range for atrial fibrillation (0.8 to 1.1), hypertension (0.9), and pulmonary arterial hypertension (1.4); PPR was <0.8 for heart failure (0.5 to 0.6), coronary artery disease (0.6), and acute coronary syndrome/myocardial infarction (0.6). The authors found little indication of clinically meaningful gender differences in efficacy or safety. Gender differences in efficacy or safety were described in labeling for 4 drugs. CONCLUSIONS: Women were well represented in trials of drugs for hypertension and atrial fibrillation, and overrepresented for pulmonary arterial hypertension. Representation of women fell below a PPR of 0.8 for trials in heart failure, coronary artery disease, and acute coronary syndrome. Minimal gender differences in drug efficacy and safety profiles were observed.

Improving Heart Failure Therapeutics Development in the United States: The Heart Failure Collaboratory.

The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including patients; investigators; academic leaders; pharmaceutical and device industry representatives; society representatives; third-party payers; and government representatives from the U.S. Food and Drug Administration, National Institutes of Health, and Centers for Medicare and Medicaid Services convened in March of 2017. This paper summarizes the discussions, outlines current challenges and actionable opportunities, and makes targeted recommendations to achieve the goals of improving efficiency in clinical trials and speeding the development of effective heart failure therapies, including the formation of an organized Heart Failure Collaboratory.

Experimental Realization of Floquet PT-Symmetric Systems.

We provide an experimental framework where periodically driven PT-symmetric systems can be investigated. The setup, consisting of two ultra high frequency oscillators coupled by a time-dependent capacitance, demonstrates a cascade of PT-symmetric broken domains bounded by exceptional point degeneracies. These domains are analyzed and understood using an equivalent Floquet frequency lattice with local PT symmetry. Management of these PT-phase transition domains is achieved through the amplitude and frequency of the drive.

Personalized Cardiovascular Medicine Today: A Food and Drug Administration/Center for Drug Evaluation and Research Perspective.

Over the past decade, personalized medicine has received considerable attention from researchers, drug developers, and regulatory agencies. Personalized medicine includes identifying patients most likely to benefit and those most likely to experience adverse reactions in response to a drug, and tailoring therapy based on pharmacokinetics or pharmacodynamic response, as well. Perhaps most exciting is finding ways to identify likely responders through genetic, proteomic, or other tests, so that only likely responders will be treated. However, less precise methods such as identifying historical, demographic, or other indicators of increased or reduced responsiveness are also important aspects of personalized medicine. The cardiovascular field has not used many genetic or proteomic markers, but has regularly used prognostic variables to identify likely responders. The development of biomarker-based approaches to personalized medicine in cardiovascular disease has been challenging, in part, because most cardiovascular therapies treat acquired syndromes, such as acute coronary syndrome and heart failure, which develop over many decades and represent the end result of several pathophysiological mechanisms. More precise disease classification and greater understanding of individual variations in disease pathology could drive the development of targeted therapeutics. Success in designing clinical trials for personalized medicine will require the selection of patient populations with attributes that can be targeted or that predict outcome, and the use of appropriate enrichment strategies once such attributes are identified. Here, we describe examples of personalized medicine in cardiovascular disease, discuss its impact on clinical trial design, and provide insight into the future of personalized cardiovascular medicine from a regulatory perspective.

Regulatory and scientific issues in studies to evaluate sexual dysfunction in antidepressant drug trials.

OBJECTIVE: Sexual dysfunction is an important side effect of serotonergic antidepressants, as it often leads to treatment nonadherence. However, sexual dysfunction is often underestimated in clinical trials submitted in support of drug approval. This is because such assessments are based mainly on unsolicited reporting. As a result, the characterization of sexual adverse events has become an important component of many of the development programs for new antidepressants. The purpose of this article is to discuss US Food and Drug Administration's (FDA's) current thinking on possible approaches to characterizing the effects of drugs on sexual function in depression drug trials. PARTICIPANTS: FDA's Division of Psychiatry Products, together with the Division of Biometrics I, in particular the authors of this article. EVIDENCE: The above-referenced FDA divisions conducted a regulatory science forum on measuring sexual dysfunction in depression trials. CONSENSUS PROCESS: Considering the evidence presented and discussed at the forum, we developed our preliminary regulatory views on the scientific issues with regard to study design, study population, use of available scales, testing strategy, and statistical analysis plans. CONCLUSIONS: Sexual dysfunction associated with antidepressants is an important entity that should be adequately assessed during clinical trials with the use of available instruments and described in product labels. It is important to appreciate the need for a positive control to establish assay sensitivity for any trial evaluating the impact of antidepressant medications on sexual function. Methodological improvement and additional data as well as experience with these approaches will be needed prior to further consideration of a formal regulatory guidance document by the FDA.

European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility.

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings.