Notes

Hemophilia Gene Therapy Worth Examination: Methodological Difficulties and suggestions.
Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.
Our study demonstrates that the use of ATP infusion as therapy is feasible and safe. Larger studies are however needed to assess the efficacy of ATP in moderate to severe AD.
Previous meta-analyses did not explore the immediate and long-term effect of non-invasive brain stimulation (NIBS) on different cognitive domains in Alzheimer's disease (AD). The meta-analysis aimed to assess the therapy effect of repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on different cognitive domains in AD in randomized controlled trials (RCTs).

Studies published before December 2021 and exploring therapy effect of rTMS, tDCS on different cognitive domains in AD were searched in the following databases PubMed and Web of Science. We used STATA 12.0 software to compute the standard mean difference (SMD) and a 95% confidence interval (CI).

The present study included 16 articles (including 372 AD patients treated with rTMS and 310 treated with sham rTMS) for rTMS and 11 articles (including 152 AD patients treated with tDCS and 134 treated with sham tDCS) for tDCS. The present study showed better immediate and long-term general cognitive functionion in AD. More large-scale studies were essential to explore the effect of NIBS on various cognitive function in AD.
A key issue to Alzheimer's disease clinical trial failures is poor participant selection. Participants have heterogeneous cognitive trajectories and many do not decline during trials, which reduces a study's power to detect treatment effects. Trials need enrichment strategies to enroll individuals who are more likely to decline.

To develop machine learning models to predict cognitive trajectories in participants with early Alzheimer's disease and presymptomatic individuals over 24 and 48 months respectively.

Prognostic machine learning models were trained from a combination of demographics, cognitive tests, APOE genotype, and brain imaging data.

Data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), National Alzheimer's Coordinating Center (NACC), Open Access Series of Imaging Studies (OASIS-3), PharmaCog, and a Phase 3 clinical trial in early Alzheimer's disease were used for this study.

A total of 2098 participants who had demographics, cognitive tests, APOE genotype, and brain imaging rognostic models to recruit enriched cohorts of predicted decliners can reduce clinical trial sample sizes by as much as 51% while maintaining the same detection power.

Prognostic tools for predicting cognitive decline and enriching clinical trials with participants at the highest risk of decline can improve trial quality, derisk endpoint failures, and accelerate therapeutic development in Alzheimer's disease.
Prognostic tools for predicting cognitive decline and enriching clinical trials with participants at the highest risk of decline can improve trial quality, derisk endpoint failures, and accelerate therapeutic development in Alzheimer's disease.Aducanumab (ADUHELMTM) was approved for the treatment of Alzheimer's disease (AD) in the US. This approval was supported by an effect on the cerebral amyloid plaque load and evidence of cognitive efficacy to be confirmed in post-marketing trials. Other anti-amyloid antibodies are under investigation in phase III (donanemab, lecanemab, gantenerumab) and have shown preliminary evidence of a cognitive benefit in phase II trials. Although these agents target a small segment of patients with mild cognitive impairment due to AD or mild AD dementia, their advent will change the design of future clinical trials both for anti-amyloid and non-amyloid drugs. These changes will promote the selection of patients in clinical trials by amyloid and tau biomarkers that identify patients with appropriate biology and may follow the treatment response to approved amyloid antibodies. The use of these agents creates the opportunity to test combined drug therapies and to conduct comparative assessments with innovative therapies and newly approved drugs available in clinical practice. Blood-based AD biomarkers should be implemented in research and could facilitate the recruitment into clinical trials. Anti-amyloid antibodies will have positive (e.g., more early diagnosis) and negative impacts (some subjects will be reluctant to participate in trials and risk assignment to placebo) on AD trials in the immediate future. We present the results of the CTAD Task Force on this topic, in Boston, November 6, 2021.As the last opportunity to assess treatment effect modification in a controlled setting prior to formal approval, clinical trials are a critical tool for understanding the safety and efficacy of new treatments in diverse populations. Recruitment of diverse participants in Alzheimer's Disease (AD) clinical trials are therefore essential to increase the generalizability of study results, with diversity broadly described to be representative and inclusive. This representation of study participants is equally critical in longitudinal cohort (observational) studies, which will be key to understanding disease disparities and are often used to design adequately powered AD clinical trials. New and innovative recruitment initiatives and enhanced infrastructure facilitate increased participant diversity in AD clinical studies.Immunogenicity following an additional dose of Coronavirus disease 2019 (COVID-19) vaccine was investigated in an extended primary series among kidney transplant (KT) recipients. Eighty-five KT participants were randomized to receive either an mRNA (M group; n = 43) or viral vector (V group; n = 42) vaccine. Among them, 62% were male, with a median (IQR) age of 50 (43-59) years and post-transplantation duration of 46 (26-82) months. At 2 weeks post-additional dose, there was no difference in the seroconversion rate between the M and V groups (70% vs. 65%, p = .63). A median (IQR) of anti-RBD antibody level was not statistically different between the M group compared with the V group (51.8 [5.1-591] vs. 28.5 [2.9-119.3] BAU/ml, p = .18). Furthermore, the percentage of participants with positive SARS-CoV-2 surrogate virus neutralization test results was not statistically different between groups (20% vs. 15%, p = .40). S1-specific T cell and RBD-specific B cell responses were also comparable between the M and V groups (230 [41-420] vs. 268 [118-510], p = .65 and 2 [0-10] vs. 2 [0-13] spot-forming units/106 peripheral blood mononuclear cells, p = .60). selleck In conclusion, compared with an additional dose of viral vector COVID-19 vaccine, a dose of mRNA COVID-19 vaccine did not elicit significantly different responses in KT recipients, regarding either humoral or cell-mediated immunity. (TCTR20211102003).
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare treatment-resistant childhood epilepsies classed as developmental and epileptic encephalopathies. ELEKTRA investigated the efficacy and safety of soticlestat (TAK-935) as adjunctive therapy in children with DS or LGS (NCT03650452).

ELEKTRA was a phase 2, randomized, double-blind, placebo-controlled study of soticlestat (≤300 mg twice daily, weight-adjusted) in children (aged 2-17 years) with DS, demonstrating three or more convulsive seizures/month, or with LGS, demonstrating four or more drop seizures/month at baseline. The 20-week treatment period comprised an 8-week dose-optimization period and a 12-week maintenance period. Efficacy endpoints included change from baseline in seizure frequency versus placebo. Safety assessments included incidence of treatment-emergent adverse events (TEAEs).

ELEKTRA enrolled 141 participants; 126 (89%) completed the study. The modified intent-to-treat population included 139 participants who received one ency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.
Soticlestat treatment resulted in statistically significant, clinically meaningful reductions from baseline in median seizure frequency (combined patient population) and in convulsive seizure frequency (DS cohort). Drop seizure frequency showed a nonstatistically significant numerical reduction in children with LGS. Soticlestat had a safety profile consistent with previous studies.The Testudo graeca (i.e., Greek Tortoise or Spur-thighed Tortoise) origin in Western Europe is a subject of debate within the scientific community. The species is a part of the current Spanish biodiversity, with three isolated populations, located in the south-eastern (Almeria and Murcia) and south-western (Doñana National Park, Andalusia) areas of the Iberian Peninsula, and in the Mallorca Island (Balearic Islands). Throughout the 19th and 20th centuries, putative references to the presence of Testudo graeca in the Iberian paleontological and archaeozoological records were relatively common. However, many of them were refuted in subsequent papers and, those that were not, are currently considered as doubtful. The aim of this work is to present and describe the oldest indisputable remains of Testudo graeca in the Iberian Peninsula. They correspond to several individuals, hitherto unpublished, recovered as grave goods in two tombs at the Plaza Marqués de Busianos 5 site (Valencia, eastern Spain), dated between the first and second centuries AD.Hair follicles (HFs) play an essential role in sustaining a persistent hair growth cycle. The activities of dermal papilla cells (DPCs) and other cells inside the HFs dominate the process of hair growth. However, the detailed molecular mechanisms remain largely unknown. To investigate the role of citric acid (CA) metabolism in hair growth, we evaluated the effect of citrate synthase (CS)-CA axis on hair growth in vivo and in vitro. Mice hair growth was evaluated by morphology and histopathology analysis. The inflammation and apoptosis levels in mice, HFs, and DPCs were detected by immunohistofluorescence, qPCR, ELISA, western blot, and TUNEL assay. Cell proliferation, cell cycle, and cell apoptosis in DPCs were analyzed by real-time cell analysis and flow cytometer. We found that subcutaneous injection of CA in mice caused significant hair growth suppression, skin lesion, inflammatory response, cell apoptosis, and promotion of catagen entry, compared with the saline control, by activating p-p65 and apoptosis signaling in an NLRP3-dependent manner. In cultured human HFs, CA attenuated the hair shaft production and accelerated HF catagen entry by regulating the above-mentioned pathways. Additionally, CA hampered the proliferation rate of DPCs via inducing cell apoptosis and cell cycle arrest. Considering that citrate synthase (CS) is responsible for CA production and is a rate-limiting enzyme of the tricarboxylic acid cycle, we also investigated the role of CS in CA metabolism and hair growth. As expected, knockdown of CS reduced CA production and reversed CA-induced hair growth inhibition, anagen shrink, inflammation, and apoptosis both in HFs and DPCs. Our experiments demonstrated that CS-CA axis serves as an important mediator and might be a potential therapeutic target in hair growth.
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