COVID-19 and Alzheimer's disease: Impact of lockdown and other restrictive measures during the COVID-19 pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection initially results in respiratory distress symptoms but can also lead to central nervous system (CNS) and neurological manifestations, significantly impacting coronavirus disease 2019 (COVID-19) patients with neurodegenerative diseases. Additionally, strict lockdown measures introduced to curtail the spread of COVID-19 have raised concerns over the wellbeing of patients with dementia and/or Alzheimer's disease. The aim of this review was to discuss the overlapping molecular pathologies and the potential bidirectional relationship between COVID-19 and Alzheimer's dementia, as well as the impact of lockdown/restriction measures on the neuropsychiatric symptoms (NPS) of patients with Alzheimer's dementia. Furthermore, we aimed to assess the impact of lockdown measures on the NPS of caregivers, exploring its potential effects on the quality and extent of care they provide to dementia patients.We utilized the PubMed and Google Scholar databases to search for articles on COVID-19, dementia, Alzheimer's disease, lockdown, and caregivers. Our review highlights that patients with Alzheimer's disease face an increased risk of COVID-19 infection and complications. Additionally, these patients are likely to experience greater cognitive decline. It appears that these issues are primarily caused by the SARS-CoV-2 infection and appear to be further exacerbated by restrictive/lockdown measures. Moreover, lockdown measures introduced during the pandemic have negatively impacted both the NPSs of caregivers and their perception of the wellbeing of their Alzheimer's patients. Thus, additional safeguard measures, along with pharmacological and non-pharmacological approaches, are needed to protect the wellbeing of dementia patients and their caregivers in light of this and possible future pandemics.

Real-World Effectiveness of the Varicella Vaccine among Children and Adolescents in Qatar: A Case-Control Study.

BACKGROUND: Despite the availability of a highly efficacious vaccine, varicella outbreaks are still being reported globally. In this study, we evaluated the real-world effectiveness of varicella vaccination among children between the ages of 1 and 18 years old during the period 2017 to 2019 in Qatar. METHODS: A matched case-control study was conducted that included all reported varicella-infected children who visited the primary healthcare system in Qatar from January 2017 to December 2019. The cases were children under the age of 18 years who were clinically diagnosed with varicella. The controls were of the same age, who visited the Primary Health Care Corporation (PHCC) during 2017-2019 with a skin rash where varicella infection was ruled out. The data on varicella vaccination for each participant were obtained from the electronic database in the PHCC during the study period. RESULTS: We included 862 cases of varicella and 5454 matched controls, with a median age of 8 years (IQR 3-12); 47.4% were female and almost 50% were of Qatari nationality. The year 2019 had the highest varicella infection count with a total of 416 cases. The cases were less likely to be vaccinated against varicella, with approximately a quarter (25.6%) of cases and 36.7% of the controls having either one or two doses of the vaccine (p < 0.001). Compared to not being vaccinated, a single dose vaccination showed a 56% reduction in the odds of varicella infection [OR 0.44, 95% CI: 0.34-0.55; p < 0.000], and a two-dose vaccination showed an 86% reduction in the odds of varicella infection [OR 0.13, 95% CI: 0.06-0.29; p < 0.000]. CONCLUSION: In this multicultural setting, a two-dose varicella vaccination shows reasonable protection against varicella infection.

The prevalence of adaptive immunity to COVID-19 and reinfection after recovery - a comprehensive systematic review and meta-analysis.

This study aims to estimate the prevalence and longevity of detectable SARS-CoV-2 antibodies and T and B memory cells after recovery. In addition, the prevalence of COVID-19 reinfection and the preventive efficacy of previous infection with SARS-CoV-2 were investigated. A synthesis of existing research was conducted. The Cochrane Library, the China Academic Journals Full Text Database, PubMed, and Scopus, and preprint servers were searched for studies conducted between 1 January 2020 to 1 April 2021. Included studies were assessed for methodological quality and pooled estimates of relevant outcomes were obtained in a meta-analysis using a bias adjusted synthesis method. Proportions were synthesized with the Freeman-Tukey double arcsine transformation and binary outcomes using the odds ratio (OR). Heterogeneity was assessed using the I2 and Cochran's Q statistics and publication bias was assessed using Doi plots. Fifty-four studies from 18 countries, with around 12,000,000 individuals, followed up to 8 months after recovery, were included. At 6-8 months after recovery, the prevalence of SARS-CoV-2 specific immunological memory remained high; IgG - 90.4% (95%CI 72.2-99.9, I2 = 89.0%), CD4+ - 91.7% (95%CI 78.2-97.1y), and memory B cells 80.6% (95%CI 65.0-90.2) and the pooled prevalence of reinfection was 0.2% (95%CI 0.0-0.7, I2 = 98.8). Individuals previously infected with SARS-CoV-2 had an 81% reduction in odds of a reinfection (OR 0.19, 95% CI 0.1-0.3, I2 = 90.5%). Around 90% of recovered individuals had evidence of immunological memory to SARS-CoV-2, at 6-8 months after recovery and had a low risk of reinfection.RegistrationPROSPERO: CRD42020201234.

Prasugrel Versus Ticagrelor in Patients With CYP2C19 Loss-of-Function Genotypes: Results of a Randomized Pharmacodynamic Study in a Feasibility Investigation of Rapid Genetic Testing.

The feasibility of rapid genetic testing in patients undergoing percutaneous coronary intervention (PCI) and the comparison of the pharmacodynamic effects of prasugrel versus ticagrelor among carriers of cytochrome P450 2C19 loss-of-function alleles treated with PCI has been poorly explored. Rapid genetic testing using the Spartan assay was shown to be feasible and provides results in a timely fashion in a real-world setting of patients undergoing coronary angiography (n = 781). Among patients (n = 223, 28.5%), carriers of at least 1 loss-of-function allele treated with PCI (n = 65), prasugrel, and ticagrelor achieve similar levels of platelet inhibition. (A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function [NCT02065479]).

Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y12 Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study.

Background Vorapaxar as an adjunct to dual antiplatelet therapy (DAPT) reduces thrombotic events in patients with prior myocardial infarction at the expense of increased bleeding. Withdrawal of aspirin has emerged as a bleeding reduction strategy. The pharmacodynamic effects of vorapaxar with potent P2Y12 inhibitors as well as the impact of dropping aspirin is unexplored and represented the aim of the VORA-PRATIC (Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y12 Receptor Inhibitors Prasugrel and Ticagrelor) study. Methods and Results Post-myocardial infarction patients (n=130) on standard DAPT (aspirin+prasugrel or ticagrelor) were randomized to 1 of 3 arms: (1) triple therapy: aspirin+prasugrel/ticagrelor+vorapaxar; (2) dual therapy (drop aspirin): prasugrel/ticagrelor+vorapaxar; (3) DAPT: aspirin+prasugrel/ticagrelor. Pharmacodynamic assessments were performed at 3 time points (baseline and 7 and 30 days). Vorapaxar reduced CAT (collagen-ADP-TRAP)-induced platelet aggregation, a marker of platelet-mediated global thrombogenicity (triple therapy versus DAPT at 30 days: mean difference=-27; 95% CI,-35 to -19; P<0.001; primary end point). This effect was attenuated but still significant in the absence of aspirin (dual therapy versus DAPT at 30 days: mean difference=-15; 95% CI,-23 to -7; P<0.001; between-group comparisons, P<0.05). Vorapaxar abolished TRAP-induced aggregation (P<0.001), without affecting thrombin generation and clot strength. There were no differences in markers of P2Y12 reactivity. Markers sensitive to aspirin-induced effects increased (P<0.001) in the dual-therapy arm. Conclusions In post-myocardial infarction patients treated with potent P2Y12 inhibitors, vorapaxar reduces platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y12 reactivity or clot kinetics. The clinical implications of these PD observations warrant future investigation. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02545933.

Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: The platelet inhibitory effects induced by oral P2Y12 receptor antagonists are delayed in patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention (P-PCI). In turn, this leads to a gap in platelet inhibition, exposing patients to an increased risk of early thrombotic complications and underscoring the need to define strategies associated with more effective platelet inhibition in the peri-primary percutaneous coronary intervention period. Cangrelor is an intravenous P2Y12 inhibitor with prompt and potent antiplatelet effects. However, to date, there are limited data on the effects of cangrelor used in combination with ticagrelor in patients undergoing primary percutaneous coronary intervention. Moreover, questions have emerged on the potential for drug-drug interactions during the transition from cangrelor to oral P2Y12 inhibitors. METHODS: This was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2Y12 reaction units by VerifyNow and platelet reactivity index by vasodilator-stimulated phosphoprotein. RESULTS: Compared with placebo, cangrelor was associated with reduced P2Y12 reaction units as early as 5 minutes after bolus, which persisted during the entire duration of drug infusion, including at 30 minutes (63 [32-93] versus 214 [183-245]; mean difference, 152 [95% CI, 108-195]; P<0·001; primary end point). Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with cangrelor. After discontinuation of cangrelor/placebo infusion, there were no differences in levels of platelet reactivity between groups, ruling out a drug-drug interaction when cangrelor and ticagrelor are concomitantly administered. CONCLUSIONS: In patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y12 inhibition induced by ticagrelor. Ticagrelor can be administered as a crushed formulation concomitantly with cangrelor without any apparent drug-drug interaction. The clinical implications of these pharmacodynamic findings warrant investigation in an adequately powered clinical trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03247738.

Pharmacodynamic Effects of Vorapaxar in Patients With and Without Diabetes Mellitus: Results of the OPTIMUS-5 Study.

Vorapaxar reduces thrombotic cardiovascular events at the expense of increased bleeding. However, the differential pharmacodynamic (PD) effects of vorapaxar according to diabetes mellitus (DM) status are unknown. Moreover, although withdrawal of aspirin has emerged as a bleeding reduction strategy, the PD effects of stopping aspirin in patients treated with vorapaxar also are unknown. In this prospective PD investigation, vorapaxar was associated with reduced platelet-mediated thrombogenicity without affecting clot kinetics irrespective of DM status. However, platelet-mediated thrombogenicity increased after aspirin withdrawal, particularly among patients with DM. (Optimizing anti-Platelet Therapy In diabetes MellitUS-5 Study [OPTIMUS-5]; NCT02548650).

Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease: Results of the SWAP-4 Study.

BACKGROUND: Switching between different classes of P2Y12 inhibitors, including de-escalation from ticagrelor to clopidogrel, commonly occurs in clinical practice. However, the pharmacodynamic profiles of this strategy have been poorly explored. METHODS: This was a prospective, randomized, open-label study conducted in patients on maintenance dosing (MD) of aspirin (81 mg/d) and clopidogrel (75 mg/d). After a 7-day run-in with ticagrelor (180 mg loading dose [LD] followed by 90 mg twice daily MD), patients (n=80) were randomized into 1 of 4 groups: group A, clopidogrel 600 mg LD 24 hours after the last MD of ticagrelor (C-600 mg-24h); group B, clopidogrel 600 mg LD 12 hours after the last MD of ticagrelor (C-600 mg-12h); group C, clopidogrel 75 mg/d MD 24 hours after the last MD of ticagrelor (C-75 mg-24h); and group D, ticagrelor 90 mg twice daily MD (T-90 mg twice daily). MD of the randomized treatment was maintained for 10±3 days. Pharmacodynamic assessments were performed at baseline, after run-in, and at 2, 24, 48, and 72 hours and 10 days with P2Y12 reaction units by VerifyNow; platelet reactivity index was assessed by vasodilator-stimulated phosphoprotein; and maximal platelet aggregation was determined by light transmittance aggregometry. RESULTS: T-90 mg twice daily led to lower platelet reactivity than any clopidogrel regimen using all assays at all time points. P2Y12 reaction unit levels were similar between the C-600 mg-24h (group A) and the C-75 mg-24h (group C) (P=0.29), including at 48 hours (primary end point; least mean difference, -6.9; 95% confidence interval, -38.1 to 24.3; P=0.66). P2Y12 reaction unit levels were lower with C-600 mg-12h (group B) than with C-75 mg-24h (group C; P=0.024). Maximal platelet aggregation over time was lower with both C-600 mg-24h (group A; P=0.041) and C-600 mg-12h (group B; P=0.028) compared with C-75 mg-24h (group C). Platelet reactivity index profiles paralleled those observed with P2Y12 reaction units. There were no pharmacodynamic differences for all tests between C-600 mg-24h (group A) and C-600 mg-12h (group B). In group C (C-75 mg-24h), platelet reactivity increased compared with baseline as early as 24 hours, reaching statistical significance at 48 and 72 hours and up to 10 days. These pharmacodynamic findings were delayed and blunted in magnitude with the administration of an LD, regardless of the timing of administration. CONCLUSIONS: De-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity. The use of an LD before the initiation of an MD regimen of clopidogrel mitigates these observations, although this is not affected by the timing of its administration after ticagrelor discontinuation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02287909.

Degradation of poly(ε-caprolactone) (PCL) by a newly isolated Brevundimonas sp. strain MRL-AN1 from soil.

A poly(ε-caprolactone) (PCL)-degrading bacterium designated as strain MRL-AN1 was isolated from soil. The bacterium was identified as Brevundimonas sp. strain MRL-AN1 through biochemical tests and 16S rRNA gene sequencing. Scanning electron microscopy and Fourier transform infrared spectroscopy results confirmed the degradation of PCL by strain MRL-AN1. An extracellular PCL depolymerase was purified to homogeneity by column chromatography and molecular weight was estimated to be approximately 63.49 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. PCL depolymerase could degrade not only PCL but also other aliphatic polyesters. The enzyme was stable at wide range of temperature (20-45°C) and pH (5-9) as well as stable in the presence of various metal ions, surfactants and organic solvents. Phenylmethylsulfonyl fluoride inhibited enzyme activity that indicates this enzyme belongs to the serine hydrolase family. It is concluded from the results that the enzymes from strain MRL-AN1 might be applied in the process of biochemical monomer recycling in the polyester-contaminated environments.

Intravenous dexmedetomidine versus clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: A randomized double-blind study.

BACKGROUND: Alpha2-adrenergic agonists have synergistic action with local anesthetics and may prolong the duration of sensory, motor blockade and postoperative analgesia obtained with spinal anesthesia. AIM: The objectives of this study are to compare and evaluate the efficacy of intravenous dexmedetomidine premedication with clonidine and placebo on spinal blockade duration, postoperative analgesia and sedation in patients undergoing surgery under bupivacaine intrathecal block. MATERIALS AND METHODS: In this prospective, randomized, double-blind placebo-controlled study, 75 patients of the American Society of Anesthesiologists status I or II, scheduled for orthopedic lower limb surgery under spinal anesthesia, were randomly allocated into three groups of 25 each. Group DE received dexmedetomidine 0.5 µgkg(-1), group CL received clonidine 1.0 µgkg(-1) and placebo group PL received 10 ml of normal saline intravenously before subarachnoid anesthesia with 15 mg of 0.5% hyperbaric bupivacaine. Onset time and regression times of sensory and motor blockade, the maximum upper level of sensory blockade were recorded. Duration of postoperative analgesia and sedation scores along with side effects were also recorded. Data was analyzed using analysis of variance or Chi-square test, and the value of P < 0.05 was considered statistically significant. RESULTS: The sensory block level was higher with dexmedetomidine (T4 ± 1) than clonidine (T6 ± 1) or placebo (T6 ± 2). Dexmedetomidine also increased the time (243.35 ± 56.82 min) to first postoperative analgesic request compared with clonidine (190.93 ± 42.38 min, P < 0.0001) and placebo (140.75 ± 28.52 min, P < 0.0001). The maximum Ramsay sedation score was greater in the dexmedetomidine group than other two groups (P < 0.0001). CONCLUSION: Premedication with intravenous dexmedetomidine is better than intravenous clonidine to provide intraoperative sedation and postoperative analgesia during bupivacaine spinal anesthesia.

Effectiveness of butorphanol as an adjuvant to lidocaine for haematoma or periosteal block: A prospective, randomised, double blind study.

BACKGROUND: The peripheral nerve endings carrying pain contains opiod receptors. Blocking these receptors during haematoma block or periosteal block may provide better analgesia. AIM: Evaluation of effectiveness and safety of butorphanol as an adjuvant to lidocaine for haematoma block. SETTINGS AND DESIGN: This is a two centre, prospective, individually randomised, two group, parallel, double-blind clinical trial. METHODS: In this study, 115 American society of anaesthesiologist grade I and II adult patients scheduled for closed reduction of fractures were randomly allocated into two groups; Group A received 1% lidocaine (2 mg/kg) where as Group B received 1% lidocaine (2 mg/kg) with butorphanol (0.02 mg/kg) during haematoma block. Pain was assessed before, during and after manipulation of fracture by using visual analogue scale (VAS 0-10). Onset time of block, time for first rescue analgesic, 24 hour analgesic requirement and sedation levels were noted. STATISTICAL ANALYSIS: Data analysed with the unpaired t-test with Welch correction assuming unequal variances and Fisher's exact test using Graph pad Prism 5.02 version. RESULTS: Onset time of haematoma block was significantly less in the butorphanol group compared to the lidocaine group (P=0.0003). The mean time for first rescue analgesic was significantly higher and total analgesic requirement was significantly lower in the butorphanol group (P<0.0001). Mean VAS scores were lower and sedation scores were higher in the butorphanol group. CONCLUSIONS: Addition of butorphanol to lidocaine quickens onset of haematoma block, provides excellent post manipulation analgesia and decreases 24 hour total analgesic requirement without excessive sedation.

Wogonin ameliorates lipotoxicity-induced apoptosis of cultured vascular smooth muscle cells via interfering with DAG-PKC pathway.

AIM: To investigate the effects of wogonin (5,7-dihydroxy-8-methoxyflavone) extracted from Scutellaria baicalensis Georgi (S baicalensis) on lipotoxicity-induced apoptosis of vascular smooth muscle cells (VSMCs) and the underlying mechanisms. METHODS: Cultured VSMCs were used. Apoptosis of VSMCs was induced by palmitate (0.75 mmol/L), and detected using TUNEL assay. The expression levels of protein and phosphorylated protein were measured using Western blot analysis. RESULTS: Treatment of VSMCs with wogonin (10, 25 and 50 µmol/L) significantly attenuated the apoptosis and endoplasmic reticulum (ER) stress induced by palmitate in concentration- and time-dependent manners. Wogonin (50 µmol/L) decreased palmitate-induced reactive oxygen species (ROS) generation. The ER stress inhibitor 4-phenyl butyric acid (5 mmol/L) significantly decreased palmitate-induced apoptotic cells, and occluded the anti-apoptotic effect of wogonin (25 µmol/L). Wogonin (10, 25 and 50 µmol/L) significantly reduced the intracellular diacylglycerol (DAG) accumulation and expression levels of phosphorylated PKCs in palmitate-treated VSMCs. CONCLUSION: Our results suggest that wogonin inhibits lipotoxicity-induced apoptosis of VSMCs via suppressing the intracellular DAG accumulation and subsequent inhibition of PKC phosphorylation. Wogonin has therapeutic potential for the prevention and treatment of atherosclerosis.

Arctigenin suppresses unfolded protein response and sensitizes glucose deprivation-mediated cytotoxicity of cancer cells.

The involvement of unfolded protein response (UPR) activation in tumor survival and resistance to chemotherapies suggests a new anticancer strategy targeting UPR pathway. Arctigenin, a natural product, has been recently identified for its antitumor activity with selective toxicity against cancer cells under glucose starvation with unknown mechanism. Here we found that arctigenin specifically blocks the transcriptional induction of two potential anticancer targets, namely glucose-regulated protein-78 (GRP78) and its analog GRP94, under glucose deprivation, but not by tunicamycin. The activation of other UPR pathways, e.g., XBP-1 and ATF4, by glucose deprivation was also suppressed by arctigenin. A further transgene experiment showed that ectopic expression of GRP78 at least partially rescued arctigenin/glucose starvation-mediated cell growth inhibition, suggesting the causal role of UPR suppression in arctigenin-mediated cytotoxicity under glucose starvation. These observations bring a new insight into the mechanism of action of arctigenin and may lead to the design of new anticancer therapeutics.