Abstract Quality of life (QoL) in patients with myelofibrosis (MF) is severely compromised by severe constitutional symptoms (i.e. fatigue, night sweats, fever, weight loss), pruritus, and symptoms ...from frequently massive hepatosplenomegaly. Given that no current instrument of patient reported outcomes (PRO) exists that covers the unique spectrum of symptomatology seen in MF patients, we sought to develop a new PRO instrument for MF patients for use in therapeutic clinical trials. Utilizing data from an international Internet-based survey of 458 patients with MF we created a 20-item instrument (MFSAF: Myelofibrosis Symptom Assessment Form) which measures the symptoms reported by >10% of MF patients and includes a measure of QoL. We subsequently validated the MFSAF in a prospective trial of MF patients involving patient and provider feedback, as well as comparison to other validated instruments used in cancer patients. The MFSAF results were highly correlated with other instruments, judged comprehensive and understandable by patients, and should be considered for evaluation of MF symptoms in therapeutic trials.
Treatment of age-related macular degeneration (AMD) with anti-vascular endothelial growth factor (VEGF) biologic agents has been shown to restore and maintain visual acuity for many patients ...afflicted with wet AMD. These agents are usually administered via intravitreal injection at a dosing interval of 4–8 weeks. Employment of long-acting delivery (LAD) technologies could improve the therapeutic outcome, ensure timely treatment, and reduce burden on patients, caregivers, and the health care system. Development of LAD approaches requires thorough testing in pre-clinical species; however, therapeutic proteins of human origin may not be well tolerated during testing in non-human species due to immunogenicity. Here, we have engineered a surrogate porcine antibody Fab fragment (pigG6.31) from a human antibody for testing ocular LAD technologies in a porcine model. The engineered Fab retains the VEGF-A-binding and inhibition properties of the parental human Fab and has stability properties suitable for LAD evaluation. Upon intravitreal injection in minipigs, pigG6.31 showed first-order clearance from the ocular compartments with vitreal elimination rates consistent with other molecules of this size. Application of the surrogate molecule in an in vivo evaluation in minipigs of a prototype of the port delivery (PD) platform indicated continuous ocular delivery from the implant, with release kinetics consistent with both the results from in vitro release studies and the efficacy observed in human clinical studies of the PD system with ranibizumab (PDS). Anti-drug antibodies in the serum against pigG6.31 were not detected over exposure durations up to 16 weeks, suggesting that this molecule has low porcine immunogenicity.
Background The single patient (n-of-1) trial can be used to resolve therapeutic uncertainty for the individual patient. Treatment alternatives are systematically tested against each other, generating ...patient-specific data used to inform an individualized treatment plan. We hypothesize that clinical decisions informed by n-of-1 trials improve patient outcomes compared to usual care. Our objective was to provide an overview of the clinical trial evidence on the effect of n-of-1 trials on clinical outcomes. Methods A systematic search of medical databases, trial registries, and gray literature was performed to identify trials assessing clinical outcomes in a group of patients undergoing an n-of-1 trial compared to those receiving usual care for any clinical condition. We abstracted elements related to study design and results and assessed risk of bias for both the overall randomized trials and the n-of-1 trials. The review was registered on PROSPERO. (CRD: 42020166490). Findings Twelve randomized trials of the n-of-1 approach were identified in conditions spanning chronic pain, osteoarthritis, chronic irreversible airflow limitation, attention-deficit hyperactivity disorder, hyperlipidemia, atrial fibrillation, statin intolerance, and hypertension. One trial showed a statistically significant benefit in the primary outcome. Only one reached the pre-specified sample size target. Secondary outcomes showed modest benefits, including decreasing medication use, fewer atrial fibrillation episodes, and improved patient satisfaction. Interpretation Very few trials have been undertaken to assess the effectiveness of n-of-1 trials in improving clinical outcomes, and most trials were underpowered for the primary outcome. Barriers to enrollment and retention in these trials should be explored, as well-powered randomized trials are needed to clarify the clinical impact of n-of-1 trials and assess their utility in clinical practice.
Chronic hypersensitivity pneumonitis (CHP) is an immune-mediated interstitial lung disease (ILD) caused by inhalational exposure to environmental antigens, resulting in parenchymal fibrosis. By ...definition, a diagnosis of CHP assumes a history of antigen exposure, but only half of all patients eventually diagnosed with CHP will have a causative antigen identified. Individual clinician variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis.
A list of potential causative exposures were derived from a systematic review of the literature. A Delphi method was applied to an international panel of ILD experts to obtain consensus regarding technique for the elicitation of exposure to antigens relevant to a diagnosis of CHP. The consensus threshold was set at 80% agreement, and median ≤ 2, interquartile range = 0 on a 5-point Likert scale (1, strongly agree; 2, tend to agree; 3, neither agree nor disagree; 4, disagree; 5, strongly disagree).
In two rounds, 36/40 experts participated. Experts agreed on 18 exposure items to ask every patient with suspected CHP. Themes included CHP inducing exposures, features that contribute to an exposure’s relevance, and quantification of a relevant exposure. Based on the results from the literature review and Delphi process, a CHP exposure assessment instrument was derived. Using cognitive interviews, the instrument was revised by patients with ILD for readability and usability.
This Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP and provides basis for a systematically derived CHP exposure assessment instrument. Clinical utility of this exposure assessment instrument may be affected by different local prevalence patterns of exposures. Ongoing research is required to clinically validate these items and consider their impact in more geographically diverse settings.
An information technology governance (ITG) program has helped the National Institutes of Health (NIH) Clinical Center (CC) in the implementation of many systems and has guided the organization ...through the maturity of its project management methodology. The NIHCC Department of Clinical Research Informatics (DCRI) maintains an electronic health record (EHR) called the clinical research information system (CRIS) along with many clinical information systems (CIS) and research information systems, supporting approximately 3,200 users. ITG involves establishing processes to guide the review, selection, implementation, management, and setting of the IT strategy representing the business owners, stakeholders, and IT.
Research conducted by Levstek, Hovelja, and Pucihar
identified that different organizations may need different ITG structures, frameworks, and strategies. The path to achieving strong ITG is a continuous journey. This paper reviews the evolution of the NIHCC IT governance strategy.
This research project explores the effects of altering the structure of discussion board formats to increase student engagement and participation. This paper will present the findings of a ...two-university, two-class research project in which asynchronous discussion board entries were analyzed for substance. By using oral discourse analysis techniques, the postings of two distinct structures of discussion board entries were analyzed. A baseline of typical student interactions was established by using an Open-ended discussion board assignment. The requirements were then changed and an Experimental discussion board format was introduced--students were placed into smaller groups and expected to enact a 3R pattern of Respond, React, and Reply. The ways in which students made their thinking visible were coded and tabulated. Findings suggest that a Connected Stance, identified by a high level of participation coupled with a high level of engagement, was an optimal online discourse pattern.
We have mapped a Jagged/Serrate-binding site to specific residues within the 12th EGF domain of human and Drosophila Notch. Two critical residues, involved in a hydrophobic interaction, provide a ...ligand-binding platform and are adjacent to a Fringe-sensitive residue that modulates Notch activity. Our data suggest that small variations within the binding site fine-tune ligand specificity, which may explain the observed sequence heterogeneity in mammalian Notch paralogues, and should allow the development of paralogue-specific ligand-blocking antibodies. As a proof of principle, we have generated a Notch-1-specific monoclonal antibody that blocks binding, thus paving the way for antibody tools for research and therapeutic applications.
Background: The site of Jagged/Serrate ligand recognition by Notch is unknown.
Results: Two critical residues involved in an intramolecular hydrophobic interaction across the central β-sheet of EGF12 form a ligand-binding platform.
Conclusion: The ligand-binding region is adjacent to a Fringe-sensitive residue involved in modulating Notch activity.
Significance: The results have implications for understanding receptor/ligand recognition, Notch regulation by O-glycosylation, and the development of paralogue-specific antibodies.
The purpose of this project was to develop a best-practices document on chiropractic care for pregnant and postpartum patients with low back pain (LBP), pelvic girdle pain (PGP), or a combination.
A ...modified Delphi consensus process was conducted. A multidisciplinary steering committee of 11 health care professionals developed 71 seed statements based on their clinical experience and relevant literature. A total of 78 panelists from 7 countries were asked to rate the recommendations (70 chiropractors and representatives from 4 other health professions). Consensus was reached when at least 80% of the panelists deemed the statement to be appropriate along with a median response of at least 7 on a 9-point scale.
Consensus was reached on 71 statements after 3 rounds of distribution. Statements included informed consent and risks, multidisciplinary care, key components regarding LBP during pregnancy, PGP during pregnancy and combined pain during pregnancy, as well as key components regarding postpartum LBP, PGP, and combined pain. Examination, diagnostic imaging, interventions, and lifestyle factors statements are included.
An expert panel convened to develop the first best-practice consensus document on chiropractic care for pregnant and postpartum patients with LBP or PGP. The document consists of 71 statements on chiropractic care for pregnant and postpartum patients with LBP and PGP.
It is crucial that orthopaedic implant materials are tested in conditions that replicate the natural body’s environment as closely as possible. Bovine serum is currently recommended for use by the ...International Organisation for Standardisation (ISO) for the wear testing of these implant materials, however, the rheological properties of bovine serum do not match fully those of the body’s natural lubricant, synovial fluid. This study looks at a potential alternative to bovine serum for the testing of orthopaedic implant materials; 0.5% gellan gum fluid gel. Wear tests using multidirectional motion were conducted on ultra-high molecular weight polyethylene (UHMWPE) pins rubbing against stainless steel plates. Roughness measurements were performed during testing along with particle analysis of the testing lubricant. At two million cycles (equivalent to 121.3 km of sliding), the mean wear factor for the four UHMWPE pins was 0.25 (standard deviation (SD) 0.03) × 10−6 mm3/Nm and there was no evidence of any transfer film on the plate surfaces. The wear factor produced by 0.5% gellan gum fluid gel was lower than that measured in previous studies using bovine serum as the lubricant but greater than the wear factor shown in published work using a similar alternative lubricant (sodium alginate mixed with gellan gum). Work on the development of a suitable alternative lubricant to bovine serum will continue.
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