Neurophysiological effects of human-derived pathological tau conformers in the APPKM670/671NL.PS1/L166P amyloid mouse model of Alzheimer's disease

Alzheimer's Disease (AD) is a neurodegenerative disease characterized by two main pathological hallmarks: amyloid plaques and intracellular tau neurofibrillary tangles. However, a majority of studies focus on the individual pathologies and seldom on the interaction between the two pathologies. Herein, we present the longitudinal neuropathological and neurophysiological effects of a combined amyloid-tau model by hippocampal seeding of human-derived tau pathology in the APP.PS1/L166P amyloid animal model. We statistically assessed both neurophysiological and pathological changes using linear mixed modelling to determine if factors such as the age at which animals were seeded, genotype, seeding or buffer, brain region where pathology was quantified, and time-post injection differentially affect these outcomes. We report that AT8-positive tau pathology progressively develops and is facilitated by the amount of amyloid pathology present at the time of injection. The amount of AT8-positive tau pathology was influenced by the interaction of age at which the animal was injected, genotype, and time after injection. Baseline pathology-related power spectra and Higuchi Fractal Dimension (HFD) score alterations were noted in APP.PS1/L166P before any manipulations were performed, indicating a baseline difference associated with genotype. We also report immediate localized hippocampal dysfunction in the electroencephalography (EEG) power spectra associated with tau seeding which returned to comparable levels at 1 month-post-injection. Longitudinal effects of seeding indicated that tau-seeded wild-type mice showed an increase in gamma power earlier than buffer control comparisons which was influenced by the age at which the animal was injected. A reduction of hippocampal broadband power spectra was noted in tau-seeded wild-type mice, but absent in APP.PS1 animals. HFD scores appeared to detect subtle effects associated with tau seeding in APP.PS1 animals, which was differentially influenced by genotype. Notably, while tau histopathological changes were present, a lack of overt longitudinal electrophysiological alterations was noted, particularly in APP.PS1 animals that feature both pathologies after seeding, reiterating and underscoring the difficulty and complexity associated with elucidating physiologically relevant and translatable biomarkers of Alzheimer's Disease at the early stages of the disease

Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection.

BACKGROUND: Long-acting injectable regimens may simplify therapy for patients with human immunodeficiency virus type 1 (HIV-1) infection. METHODS: We conducted a phase 3, randomized, open-label trial in which adults with HIV-1 infection who had not previously received antiretroviral therapy were given 20 weeks of daily oral induction therapy with dolutegravir-abacavir-lamivudine. Participants who had an HIV-1 RNA level of less than 50 copies per milliliter after 16 weeks were randomly assigned (1:1) to continue the current oral therapy or switch to oral cabotegravir plus rilpivirine for 1 month followed by monthly injections of long-acting cabotegravir plus rilpivirine. The primary end point was the percentage of participants who had an HIV-1 RNA level of 50 copies per milliliter or higher at week 48 (Food and Drug Administration snapshot algorithm). RESULTS: At week 48, an HIV-1 RNA level of 50 copies per milliliter or higher was found in 6 of 283 participants (2.1%) who received long-acting therapy and in 7 of 283 (2.5%) who received oral therapy (adjusted difference, -0.4 percentage points; 95% confidence interval [CI], -2.8 to 2.1), a result that met the criterion for noninferiority for the primary end point (margin, 6 percentage points). An HIV-1 RNA level of less than 50 copies per milliliter at week 48 was found in 93.6% who received long-acting therapy and in 93.3% who received oral therapy (adjusted difference, 0.4 percentage points; 95% CI, -3.7 to 4.5), a result that met the criterion for noninferiority for this end point (margin, -10 percentage points). Of the participants who received long-acting therapy, 86% reported injection-site reactions (median duration, 3 days; mild or moderate severity, 99% of cases); 4 participants withdrew from the trial for injection-related reasons. Grade 3 or higher adverse events and events that met liver-related stopping criteria occurred in 11% and 2%, respectively, who received long-acting therapy and in 4% and 1% who received oral therapy. Treatment satisfaction increased after participants switched to long-acting therapy; 91% preferred long-acting therapy at week 48. CONCLUSIONS: Therapy with long-acting cabotegravir plus rilpivirine was noninferior to oral therapy with dolutegravir-abacavir-lamivudine with regard to maintaining HIV-1 suppression. Injection-site reactions were common. (Funded by ViiV Healthcare and Janssen; FLAIR ClinicalTrials.gov number, NCT02938520.)

Week 96 Extension Results of a Phase 3 Study Evaluating Long-Acting Cabotegravir with Rilpivirine for HIV-1 Treatment

BACKGROUND: ATLAS (NCT02951052), a phase 3, multicenter, open-label study, demonstrated that switching to injectable cabotegravir (CAB) with rilpivirine (RPV) long-acting dosed every 4 weeks was noninferior at week (W) 48 to continuing three-drug daily oral current antiretroviral therapy (CAR). Results from the W 96 analysis are presented. METHODS AND DESIGN: Participants completing W 52 of ATLAS were given the option to withdraw, transition to ATLAS-2M (NCT03299049), or enter an Extension Phase to continue long-acting therapy (Long-acting arm) or switch from CAR to long-acting therapy (Switch arm). Endpoints assessed at W 96 included proportion of participants with plasma HIV-1 RNA less than 50 copies/ml, incidence of confirmed virologic failure (CVF; two consecutive HIV-1 RNA ≥200 copies/ml), safety and tolerability, pharmacokinetics, and patient-reported outcomes. RESULTS: Most participants completing the Maintenance Phase transitioned to ATLAS-2M (88%, n = 502/572). Overall, 52 participants were included in the W 96 analysis of ATLAS; of these, 100% (n = 23/23) and 97% (n = 28/29) in the Long-acting and Switch arms had plasma HIV-1 RNA less than 50 copies/ml at W 96, respectively. One participant had plasma HIV-1 RNA 50 copies/ml or higher in the Switch arm (173 copies/ml). No participants met the CVF criterion during the Extension Phase. No new safety signals were identified. All Switch arm participants surveyed preferred long-acting therapy to their previous daily oral regimen (100%, n = 27/27). CONCLUSION: In this subgroup of ATLAS, 98% (n = 51/52) of participants at the Extension Phase W 96 analysis maintained virologic suppression with long-acting therapy. Safety, efficacy, and participant preference results support the therapeutic potential of long-acting CAB+RPV treatment for virologically suppressed people living with HIV-1

Long-acting injectable Cabotegravir + Rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression

Brettanomyces bruxellensis yeasts: impact on wine and winemaking

Yeasts belonging to the Brettanomyces/Dekkera genus are non-conventional yeasts, which affect winemaking by causing wine spoilage all over the world. This mini-review focuses on recent results concerning the presence of Brettanomyces bruxellensis throughout the wine processing chain. Here, culture-dependent and independent methods to detect this yeast on grapes and at the very early stage of wine production are encompassed. Chemical, physical and biological tools, devised for the prevention and control of such a detrimental species during winemaking are also presented. Finally, the mini-review identifies future research areas relevant to the improvement of wine safety and sensory profiles

Hybrid Genetic Bees Algorithm applied to Single Machine Scheduling with Earliness and Tardiness Penalties

This paper presents a hybrid Genetic-Bees Algorithm based optimised solution for the single machine scheduling problem. The enhancement of the Bees Algorithm (BA) is conducted using the Genetic Algorithm's (GA's) operators during the global search stage. The proposed enhancement aims to increase the global search capability of the BA gradually with new additions. Although the BA has very successful implementations on various type of optimisation problems, it has found that the algorithm suffers from weak global search ability which increases the computational complexities on NP-hard type optimisation problems e.g. combinatorial/permutational type optimisation problems. This weakness occurs due to using a simple global random search operation during the search process. To reinforce the global search process in the BA, the proposed enhancement is utilised to increase exploration capability by expanding the number of fittest solutions through the genetical variations of promising solutions. The hybridisation process is realised by including two strategies into the basic BA, named as â\u80\u9creinforced global searchâ\u80\u9d and â\u80\u9cjumping functionâ\u80\u9d strategies. The reinforced global search strategy is the first stage of the hybridisation process and contains the mutation operator of the GA. The second strategy, jumping function strategy, consists of four GA operators as single point crossover, multipoint crossover, mutation and randomisation. To demonstrate the strength of the proposed solution, several experiments were carried out on 280 well-known single machine benchmark instances, and the results are presented by comparing to other well-known heuristic algorithms. According to the experiments, the proposed enhancements provides better capability to basic BA to jump from local minima, and GBA performed better compared to BA in terms of convergence and the quality of results. The convergence time reduced about 60% with about 30% better results for highly constrained jobs