Short structural variants as informative genetic markers for ALS disease risk and progression

There is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1, SCAF4, and STMN2, we hope to improve the outcomes of future ALS clinical trials.

A practice game changer: Impact of tenecteplase for acute ischemic stroke in a multicenter quality improvement project

Purpose Tenecteplase is a thrombolytic that is more fibrin specific, has a longer half-life, and is easier to administer than alteplase for acute ischemic stroke (AIS). This article outlines the pharmacy experience and perspective on implementation of tenecteplase as the treatment of choice for AIS. Summary Tenecteplase has been of increasing interest for AIS and is currently being studied in several clinical trials. Although it is not indicated by the Food and Drug Administration for AIS, several published studies and an update to stroke guidelines from the American Heart Association and American Stroke Association support its use in this setting. In January 2021, Cedars-Sinai Health System made the decision to add tenecteplase to the formulary for AIS in addition to keeping alteplase for patients who met the criterion of being outside the 4.5-hour window following stroke onset. Along with the added benefits of having tenecteplase on formulary come challenges of managing multiple thrombolytics for the same indication. Identifying key stakeholders and creating an interdisciplinary team are critical to ensure safe transitions. Conclusion Institutions can safely transition from alteplase to tenecteplase as a thrombolytic of choice for AIS.

The Application of Beta-Tricalcium Phosphate in Implant Dentistry: A Systematic Evaluation of Clinical Studies

The demand for synthetic graft materials in implant dentistry is rising. This systematic review aims to evaluate the survival rate of dental implants placed simultaneously with bone regeneration procedures using the material β-tricalcium phosphate, one of the most promising synthetic graft materials. The electronic search was conducted in PubMed, Scielo, and the Cochrane Central Register of Controlled Trials. There were five randomized clinical trials, one of which was a non-randomized controlled clinical trial and four of which were observational studies without a control group included. Implant survival rate and other clinical, radiographic, and histological parameters did not differ from those of implants placed simultaneously with another type of graft material, or placed in blood clots or natural alveolar ridges. Based on the available literature, β-tricalcium phosphate seems to be a promising graft material in implant dentistry. Nevertheless, more randomized clinical trials, with long follow-up periods, preoperative and postoperative CBCT, and histological analysis, are necessary to assess its long-term behavior.

Clinical Trials Targeting Neurofibromatoses-associated Tumors: A Systematic Review

Background There is a paucity of literature that comprehensively analyzes previous and current clinical trials targeting neurofibromatoses-related tumors. This article aims to provide readers of drug development efforts targeting these tumors by analyzing translational and clinical findings. Methods This systematic review was written according to the PRISMA guidelines. Inclusion criteria were clinical trials involving patients with neurofibromatosis type 1, type 2, or schwannomatosis that were treated with therapies targeting neurofibromatoses-associated tumors and that were registered on clinicaltrials.gov. In addition, a search was performed in PubMed, Web of Science, Google Scholar, and Embase European for articles fully describing these clinical trials. Results A total of 265 clinical trials were registered and screened for eligibility. Ninety-two were included in this systematic review involving approximately 4,636 participants. The number of therapies analyzed was more than 50. Drugs under investigation mainly act on the MAPK/ERK and PI3K/AKT/mTOR pathways, tumor microenvironment, or aberrantly over-expressed cell surface receptors. Selumetinib was the most effective medication for treating a neurofibromatosis type 1-associated tumor with approximately 68-71% partial response for inoperable or progressive plexiform neurofibromas in children 2 years of age and older and bevacizumab for a neurofibromatosis type 2-related tumor with approximately 36-41% partial response for vestibular schwannomas in patients 12 years of age and older. Conclusions This systematic review presents the results of previous clinical investigations and those under development for neurofibromatoses-associated tumors. Clinicians may use this information to strategize patients to appropriate clinical trials.

Research conducted on gestating women globally during trials

The aim of clinical research is to impart knowledge that will improve human health or improve understanding of human physiology. Although, till the end of 20 century pregnancy was always under exclusion criteria, now pervasive exclusion of pregnant women in clinical trials is currently not justified. Pregnancy brings in an array of anatomical, physiological and biochemical changes that can impact the pharmacokinetics of important medications. Pregnancy is often accompanied by chronic diseases like diabetes, hypertension, tuberculosis, HIV, depression which can require long term therapy. This indicates a need for studies being conducted exclusively in pregnant women. Current communication narrates ethical and regulatory aspects of inclusion of pregnant women in clinical trials.

Point-of-care cell therapy manufacturing; it’s not for everyone

The use of cellular therapies to treat cancer, inherited immune deficiencies, hemoglobinopathies and viral infections is growing rapidly. The increased interest in cellular therapies has led to the development of reagents and closed-system automated instruments for the production of these therapies. For cellular therapy clinical trials involving multiple sites some people are advocating a decentralized model of manufacturing where patients are treated with cells produced using automated instruments at each participating center using a single, centrally held Investigational New Drug Application (IND). Many academic centers are purchasing these automated instruments for point-of-care manufacturing and participation in decentralized multiple center clinical trials. However, multiple site manufacturing requires harmonization of product testing and manufacturing in order to interpret the clinical trial results. Decentralized manufacturing is quite challenging since all centers should use the same manufacturing protocol, the same or comparable in-process and lot release assays and the quality programs from each center must work closely together. Consequently, manufacturing cellular therapies using a decentralized model is in many ways more difficult than manufacturing cells in a single centralized facility. Before an academic center decides to establish a point-of-care cell processing laboratory, they should consider all costs associated with such a program. For many academic cell processing centers, point-of-care manufacturing may not be a good investment.