Retention of hemostatic and immunological properties of frozen plasma and COVID-19 convalescent apheresis fresh-frozen plasma produced and freeze-dried in Canada.

BACKGROUND: Randomized clinical trial data show that early plasma transfusion may save lives among trauma patients. Supplying plasma in remote environments is logistically challenging. Freeze-dried plasma (FDP) offers a possible solution. STUDY DESIGN AND METHODS: A Terumo BCT plasma freeze-drying system was evaluated. We compared pooled frozen plasma (FP) units with derived Terumo BCT FDP (TFDP) units and pooled COVID-19 convalescent apheresis fresh-frozen plasma (CC-AFFP) with derived CC-TFDP units. Parameters measured were: coagulation factors (F) II; V; VII; VIII; IX; XI; XIII; fibrinogen; Proteins C (PC) and S (PS); antithrombin (AT); α2 -antiplasmin (α2 AP); ADAMTS13; von Willebrand Factor (vWF); thrombin-antithrombin (TAT); D-dimer; activated complement factors 3 (C3a) and 5 (C5a); pH; osmolality; prothrombin time (PT); and activated partial thromboplastin time (aPTT). Antibodies to SARS-CoV-2 in CC-AFFP and CC-TFDP units were compared by plaque reduction assays and viral protein immunoassays. RESULTS: Most parameters were unchanged in TFDP versus FP or differed ≤15%. Mean aPTT, PT, C3a, and pH were elevated 5.9%, 6.9%, 64%, and 0.28 units, respectively, versus FP. CC-TFDP showed no loss of SARS-CoV-2 neutralization titer versus CC-AFFP and no mean signal loss in most pools by viral protein immunoassays. CONCLUSION: Changes in protein activities or clotting times arising from freeze-drying were <15%. Although C3a levels in TFDP were elevated, they were less than literature values for transfusable plasma. SARS-CoV-2-neutralizing antibody titers and viral protein binding levels were largely unaffected by freeze-drying. In vitro characteristics of TFDP or CC-TFDP were comparable to their originating plasma, making future clinical studies appropriate.

A Miniaturized MicroRNA Sensor Identifies Targets Associated with Weight Loss in a Diet and Exercise Intervention among Healthy Overweight Individuals.

Weight loss through dietary and exercise intervention is commonly prescribed but is not effective for all individuals. Recent studies have demonstrated that circulating microRNA (miR) biomarkers could potentially be used to identify individuals who will likely lose weight through diet and exercise and attain a healthy body weight. However, accurate detection of miRs in clinical samples is difficult, error-prone, and expensive. To address this issue, we recently developed iLluminate-a low-cost and highly sensitive miR sensor suitable for point-of-care testing. To investigate if miR testing and iLluminate can be used in real-world obesity applications, we developed a pilot diet and exercise intervention and utilized iLluminate to evaluate miR biomarkers. We evaluated the expression of miRs-140, -935, -let-7b, and -99a, which are biomarkers for fat loss, energy metabolism, and adipogenic differentiation. Responders lost more total mass, tissue mass, and fat mass than non-responders. miRs-140, -935, -let-7b, and -99a, collectively accounted for 6.9% and 8.8% of the explained variability in fat and lean mass, respectively. At the level of the individual coefficients, miRs-140 and -935 were significantly associated with fat loss. Collectively, miRs-140 and -935 provide an additional degree of predictive capability in body mass and fat mass alternations.

Contribution of changes in atmospheric circulation patterns to extreme temperature trends.

Surface weather conditions are closely governed by the large-scale circulation of the Earth's atmosphere. Recent increases in the occurrence of some extreme weather phenomena have led to multiple mechanistic hypotheses linking changes in atmospheric circulation to increasing probability of extreme events. However, observed evidence of long-term change in atmospheric circulation remains inconclusive. Here we identify statistically significant trends in the occurrence of atmospheric circulation patterns, which partially explain observed trends in surface temperature extremes over seven mid-latitude regions of the Northern Hemisphere. Using self-organizing map cluster analysis, we detect robust circulation pattern trends in a subset of these regions during both the satellite observation era (1979-2013) and the recent period of rapid Arctic sea-ice decline (1990-2013). Particularly substantial influences include the contribution of increasing trends in anticyclonic circulations to summer and autumn hot extremes over portions of Eurasia and North America, and the contribution of increasing trends in northerly flow to winter cold extremes over central Asia. Our results indicate that although a substantial portion of the observed change in extreme temperature occurrence has resulted from regional- and global-scale thermodynamic changes, the risk of extreme temperatures over some regions has also been altered by recent changes in the frequency, persistence and maximum duration of regional circulation patterns.

Sleeping time is associated with functional limitations in a national sample of older Americans.

BACKGROUND: Engaging in healthy behaviors may help to preserve function during aging; however, it is not well understood how sleeping time is associated with functional capacity in older adults. AIMS: We sought to determine the association of sleeping time on functional limitation in a national sample of older Americans. METHODS: The analytical sample included 6020 adults aged at least 65 years who participated in the 2007-2016 waves of the National Health and Nutrition Examination Survey. Respondents indicated their hours of sleep/weeknight and were categorized as < 5, 5-6.5, 7-8, 8.5-9, and > 9 h of sleep/weeknight. Ability to complete 19 functional tasks including basic activities of daily living, instrumental activities of daily living, leisure and social activities, lower extremity mobility activities, and general physical activities were also self-reported. A covariate-adjusted logistic model analyzed the associations between each sleeping time category and functional limitation. RESULTS: Relative to those reporting 7-8 h of sleep/weeknight, older Americans reporting < 5, 5-6.5, 8.5-9, and > 9 h of sleep/weeknight had 1.66 [95% confidence interval (CI): 1.05, 2.62], 1.25 (CI: 1.02, 1.52), 1.59 (CI: 1.19, 2.12), and 2.99 (CI: 1.96, 4.56) greater odds for functional limitation, respectively. DISCUSSION: Sleep should be recognized as a health factor that may reflect functional capacity in older adults. Healthcare providers should discuss the importance of optimal sleep with their older patients and older adults should practice healthy sleeping behaviors for preserving function. CONCLUSIONS: Not meeting optimal sleep recommendations is associated with functional limitations in older Americans.

In-Hospital Telehealth Supports Care for Neonatal Patients in Strict Isolation.

The aim of this study is to determine the feasibility of "in-hospital" inpatient telemedicine within a children's referral hospital to facilitate inpatient care activities such as interprofessional rounding and the provision of supportive services such as lactation consultations to pediatric patients in strict isolation. To test the feasibility of in-hospital video telemedicine, a dedicated telemedicine device was set up in the patient's room. This device and the accompanying Bluetooth stethoscope were used by the health care team located just outside the room for inpatient rounding and consultations from supportive services. Video telemedicine facilitated inpatient care and interactions with support services, reducing the number of health care providers with potential exposure to infection and decreasing personal protective equipment use. In the setting of strict isolation for highly infectious viral illness, telemedicine can be used for inpatient care activities such as interprofessional rounding and provision of supportive services. KEY POINTS: · Telehealth supports patient care in isolation.. · Telehealth reduced health care provider exposures.. · Telehealth conserves personal protective equipment..

Doxorubicin-induced neurotoxicity is associated with acute alterations in synaptic plasticity, apoptosis, and lipid peroxidation.

Cognitive deficits are commonly reported by patients following treatment with chemotherapeutic agents. Anthracycline-containing chemotherapy regimens are associated with cognitive impairment and reductions in neuronal connectivity in cancer survivors, and doxorubicin (Dox) is a commonly used anthracycline. Although it has been reported that Dox distribution to the central nervous system (CNS) is limited, considerable Dox concentrations are observed in the brain with co-administration of certain medications. Additionally, pro-inflammatory cytokines, which are overproduced in cancer or in response to chemotherapy, can reduce the integrity of the blood-brain barrier (BBB). Therefore, the aim of this study was to evaluate the acute neurotoxic effects of Dox on hippocampal neurons. In this study, we utilized a hippocampal cell line (H19-7/IGF-IR) along with rodent hippocampal slices to evaluate the acute neurotoxic effects of Dox. Hippocampal slices were used to measure long-term potentiation (LTP), and expression of proteins was determined by immunoblotting. Cellular assays for mitochondrial complex activity and lipid peroxidation were also utilized. We observed reduction in LTP in hippocampal slices with Dox. In addition, lipid peroxidation was increased as measured by thiobarbituric acid reactive substances content indicating oxidative stress. Caspase-3 expression was increased indicating an increased propensity for cell death. Finally, the phosphorylation of signaling molecules which modulate LTP including extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase, and Akt were increased. This data indicates that acute Dox exposure dose-dependently impairs synaptic processes associated with hippocampal neurotransmission, induces apoptosis, and increases lipid peroxidation leading to neurotoxicity.

Establishing Transcriptional Signatures to Differentiate PXR-, CAR-, and AhR-Mediated Regulation of Drug Metabolism and Transport Genes in Cryopreserved Human Hepatocytes.

The potential for drug-drug interactions (DDIs) arising from transcriptional regulation of drug-disposition genes via activation of nuclear receptors (NRs), such as pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR), remains largely unexplored, as highlighted in a recent guidance document from the European Medicines Agency. The goal of this research was to establish PXR-/CAR-/AhR-specific drug-metabolizing enzyme (DME) and transporter gene expression signatures in sandwich-cultured cryopreserved human hepatocytes using selective activators of PXR (rifampin), CAR (CITCO), and AhR (omeprazole). Dose response for ligand-induced changes to 38 major human DMEs and critical hepatobiliary transporters were assessed using a custom gene expression array card. We identified novel differentially expressed drug-disposition genes for PXR (↑ABCB1/MDR1, CYP2C9, CYP2C19, and EPHX1, ↓ABCB11), CAR [↑sulfotransferase (SULT) 1E1, uridine glucuronosyl transferase (UGT) 2B4], and AhR (↑SLC10A1/NTCP, SLCO1B1/OATP1B1], and coregulated genes (CYP1A1, CYP2B6, CYP2C8, CYP3A4, UGT1A1, UGT1A4). Subsequently, DME gene expression signatures were generated for known CYP3A4 inducers PF-06282999 and pazopanib. The former produced an induction signature almost identical to that of rifampin, suggesting activation of the PXR pathway, whereas the latter produced an expression signature distinct from those of PXR, CAR, or AhR, suggesting involvement of an alternate pathway(s). These results demonstrate that involvement of PXR/CAR/AhR can be identified via expression changes of signature DME/transporter genes. Inclusion of such signature genes could serve to simultaneously identify potential inducers and inhibitors, and the NRs involved in the transcriptional regulation, thus providing a more holistic and mechanism-based assessment of DDI risk for DMEs and transporters beyond conventional cytochrome P450 isoforms.

A Study on Pharmacokinetics of Bosentan with Systems Modeling, Part 1: Translating Systemic Plasma Concentration to Liver Exposure in Healthy Subjects.

Understanding liver exposure of hepatic transporter substrates in clinical studies is often critical, as it typically governs pharmacodynamics, drug-drug interactions, and toxicity for certain drugs. However, this is a challenging task since there is currently no easy method to directly measure drug concentration in the human liver. Using bosentan as an example, we demonstrate a new approach to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically based pharmacokinetic modeling. The prediction was verified to be both accurate and precise using sensitivity analysis. For bosentan, the predicted pseudo steady-state unbound liver-to-unbound systemic plasma concentration ratio was 34.9 (95% confidence interval: 4.2, 50). Drug-drug interaction (i.e., CYP3A and CYP2B6 induction) and inhibition of hepatic transporters (i.e., bile salt export pump, multidrug resistance-associated proteins, and sodium-taurocholate cotransporting polypeptide) were predicted based on the estimated unbound liver tissue or plasma concentrations. With further validation and refinement, we conclude that this approach may serve to predict human liver exposure and complement other methods involving tissue biopsy and imaging.

Induction of human cytochrome P450 3A4 by the irreversible myeloperoxidase inactivator PF-06282999 is mediated by the pregnane X receptor.

1. 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide (PF-06282999) is a member of the thiouracil class of irreversible inactivators of human myeloperoxidase enzyme and a candidate for the treatment of cardiovascular disease. PF-06282999 is an inducer of CYP3A4 mRNA and midazolam-1'-hydroxylase activity in human hepatocytes, which is consistent with PF-06282999-dose dependent decreases in mean maximal plasma concentrations (Cmax) and area under the plasma concentration time curve (AUC) of midazolam in humans following 14-day treatment with PF-06282999. 2. In the present study, the biochemical mechanism(s) of CYP3A4 induction by PF-06282999 was studied. Incubations in reporter cells indicated that PF-06282999 selectively activated human pregnane X receptor (PXR). Treatment of human HepaRG cells with PF-06282999 led to ∼14-fold induction in CYP3A4 mRNA and 5-fold increase in midazolam-1'-hydroxylase activity, which was nullified in PXR-knock out HepaRG cells. TaqMan® gene expression analysis of human hepatocytes treated with PF-06282999 and the prototypical PXR agonist rifampin demonstrated increases in mRNA for CYP3A4 and related CYPs that are regulated by PXR. 3. Docking studies using a published human PXR crystal structure provided insights into the molecular basis for PXR activation by PF-06282999. Implementation of PXR transactivation assays in a follow-on discovery campaign should aid in the identification of back-up compounds devoid of PXR activation and CYP3A4 induction liability.

In vitro studies with two human organic anion transporters: OAT2 and OAT7.

1. Penciclovir, ganciclovir, creatinine, para-aminohippuric acid (PAH), ketoprofen, estrone 3-O-sulfate (E3S), dehydroepiandrosterone 3-O-sulfate (DHEAS) and cyclic guanosine monophosphate (cGMP) were screened as substrates of human liver organic anion transporters OAT2 and OAT7. 2. For OAT7, high uptake ratios (versus mock transfected HEK293 cells) of 29.6 and 15.3 were obtained with E3S and DHEAS. Less robust uptake ratios (≤3.6) were evident with the other substrates. OAT2 (transcript variant 1, OAT2-tv1) presented high uptake ratios of 30, 13, ∼35, ∼25, 8.5 and 9 with cGMP, PAH, penciclovir, ganciclovir, creatinine and E3S, respectively. No uptake was observed with DHEAS. 3. Although not a substrate of either transporter, ketoprofen did inhibit transfected OAT2-tv1 (IC50 of 17, 22, 23, 24, 35 and 586 µM; creatinine, ganciclovir, penciclovir, cGMP, E3S and prostaglandin F2α, respectively) and penciclovir uptake (IC50 = 27 µM; >90% inhibition) by plated human hepatocytes (PHH). 4. It is concluded that penciclovir and ketoprofen may serve as useful tools for the assessment of OAT2 activity in PHH. However, measurement of OAT7 activity therein will prove more challenging, as high uptake rates are evident with E3S and DHEAS only and both sulfoconjugates are known to be substrates of organic anion transporting polypeptides.

Not all mindfulness is equal: certain facets of mindfulness have important implications for well-being and mental health across the lifespan.

The connections between the five facets of mindfulness, well-being, and mental health across the lifespan have traditionally been investigated using variable-centered approaches. Less research has investigated these relationships from a person-centered, profile-based approach. In this work, we aimed to identify the profiles of mindfulness in a Canadian lifespan sample (14 to 90 years of age) and investigate how these profiles compared on age, well-being, and mental health. An age- and gender-balanced sample of 1,600 participants completed a questionnaire that measured the five facets of mindfulness; life satisfaction; existential well-being; and anxiety, depression, and stress symptoms. A latent profile analysis was conducted. Five profiles based on the five-facet model of mindfulness were identified: high mindfulness, moderate mindfulness, low mindfulness, nonjudgmentally aware, and judgmentally observing. The 3-step approach to profile comparisons was used to assess age, mental health, and well-being differences across the profiles. Those in the high mindfulness and nonjudgmentally aware profiles were generally older, while the judgmentally observing profile contained younger individuals. Those in the high mindfulness and nonjudgmentally aware profiles reported the greatest mental health and well-being. Conversely, those in the low mindfulness and judgmentally observing profiles had worse mental health than the other profiles. The moderate mindfulness profile was situated between these profile groups on age, mental health, and well-being outcomes. This pattern of results has implications for mindfulness-based intervention research and practice to better account for heterogeneity in mindfulness and better support well-being across the lifespan.

The subjective value of genuine smiles guides real-world social behaviour.

The mechanisms that underpin human social behaviour are poorly understood, in part because natural social behaviour is challenging to study. The task of linking the mechanisms thought to drive social behaviour to specific social behaviours in a manner that maintains ecological validity poses an even greater challenge. Here we report evidence that the subjective value people assign to genuine smiles, as measured in the laboratory, determines their responsiveness to genuine smiles encountered in a naturalistic social interaction. Specifically, participants (university undergraduates; age 17 to 36) who valued genuine smiles to a greater degree also showed stronger attention capture effects to neutral faces that were previously associated with genuine smiles and faster reciprocity of a social partner's smiles in a real social interaction. Additionally, the faster participants responded to the partner's genuine smiles the higher the partner's ratings of interaction quality were after the interaction. These data suggest that individual differences in subjective value of genuine smiles, measured in the lab, is one element that underpins responsiveness to natural genuine smiles and subsequent social outcomes.

Obstructing Ureteral Calculi and Presumed Infection: Impact of Antimicrobial Duration and Time From Decompression to Stone Treatment in Developing Urosepsis.

OBJECTIVE: To determine whether the duration of antibiotic treatment and timing between urgent renal decompression and stone intervention impacts the risk of developing urosepsis following definitive stone treatment. MATERIALS & METHODS: A retrospective review of patients who were diagnosed with obstructive urolithiasis and underwent urgent decompression with a ureteral double J stent or percutaneous nephrostomy at our institution between 2012 and 2018 was performed. We narrowed our analysis to the subset of patients who had suspected infection and received definitive stone treatment at our institution. Demographic, infection and antimicrobial data, and initial admission to stone treatment characteristics were collected. Factors associated with developing urosepsis were analyzed. RESULTS: We identified 872 patients who were treated with urgent renal decompression, of which 215 were analyzed that had suspected infection and also received definitive stone removal at our institution. Thirty-three had fevers, 64.2% had a positive urine culture, and 45.6% had urosepsis at the initial presentation. The median antibiotics duration post decompression was 13 days (IQR 8-18). The median duration from decompression to stone treatment was 17 days (IQR 12-27). Of all, 4.6% of the patients developed urosepsis post ureteroscopy and 5% post percutaneous nephrolithotomy. No factors were associated with developing urosepsis post stone treatment on logistic regression analyses. CONCLUSION: In patients requiring urgent decompression for obstructing urolithiasis and suspected infection, the time between decompression and stone treatment and the length of antibiotic exposure did not impact rates of postoperative urosepsis. This highlights the importance of maintaining high clinical suspicion for prolonged use of antibiotics, to prevent overtreatment and possible exacerbation of antibiotic resistance.

Investigation of CYP3A induction by PF-05251749 in early clinical development: comparison of linear slope physiologically based pharmacokinetic prediction and biomarker response.

PF-05251749 is a dual inhibitor of casein kinase 1 δ/ε under clinical development to treat disruption of circadian rhythm in Alzheimer's and Parkinson's diseases. In vitro, PF-05251749 (0.3-100 µM) induced CYP3A in cryopreserved human hepatocytes, demonstrating non-saturable, dose-dependent CYP3A mRNA increases, with induction slopes in the range 0.036-0.39 µM-1 . In a multiple-dose study (B8001002) in healthy participants, CYP3A activity was explored by measuring changes in 4ß-hydroxycholesterol/cholesterol ratio. Following repeated oral administration of PF-05251749, up to 400 mg q.d., no significant changes were observed in 4ß-hydroxycholesterol/cholesterol ratio; this ratio increased significantly (~1.5-fold) following administration of PF-05251749 at 750 mg q.d., suggesting potential CYP3A induction at this dose. Physiologically based pharmacokinetic (PBPK) models were developed to characterize the observed clinical pharmacokinetics (PK) of PF-05251749 at 400 and 750 mg q.d.; the PBPK induction model was calibrated using the in vitro linear fit induction slope, with rifampin as reference compound (Indmax  = 8, EC50  = 0.32 µM). Clinical trial simulation following co-administration of PF-05251749, 400 mg q.d. with oral midazolam 2 mg, predicted no significant drug interaction risk. PBPK model predicted weak drug interaction following co-administration of PF-05251749, 750 mg q.d. with midazolam 2 mg. In conclusion, good agreement was obtained between CYP3A drug interaction risk predicted using linear-slope PBPK model and exploratory biomarker trends. This agreement between two orthogonal approaches enabled assessment of drug interaction risks of PF-05251749 in early clinical development, in the absence of a clinical drug-drug interaction study.

Does tamsulosin decrease postoperative urinary retention in spine surgery? A double-blind, randomized controlled trial.

OBJECTIVE: The authors' objective was to determine whether preoperative administration of tamsulosin decreases postoperative urinary retention after spine surgery. METHODS: In this randomized, double-blind, placebo-controlled clinical trial performed at a single institution between 2016 and 2019, eligible males aged 50 to 85 years were administered tamsulosin or placebo for 5 days prior to elective spine surgery. Patients were excluded if they were taking alpha adrenergic blocking drugs; were allergic to tamsulosin, lactose, or sulfa drugs; had a preexisting indwelling urinary catheter, orthostatic hypotension, history of urological surgery, or renal failure; or were scheduled for cataract surgery within 2 weeks. Screening identified 1051 eligible patients (140 declined participation, 150 did not meet the inclusion criteria, and 151 did not enroll for other reasons). A total of 610 patients were randomly assigned to receive 0.4 mg oral tamsulosin or an identical placebo capsule for 5 days preoperatively and 2 days postoperatively. RESULTS: A total of 497 patients were included in the final statistical analysis. The overall rate of postoperative urinary retention was 9.7%, and tamsulosin had no observed effect on reducing the rate of postoperative urinary retention as compared with placebo (9.4% vs 9.9%, p = 0.96). There were no significant differences in the reported adverse events between groups. Multivariate logistic regression was performed to model the effects of patient, surgical, and anesthetic factors on postoperative urinary retention, and the study drug remained an insignificant factor. CONCLUSIONS: This study did not detect an effect of perioperative tamsulosin on reducing the rate of postoperative urinary retention in male patients aged 50 to 85 years who underwent elective spine surgery. This study does not support the routine use of tamsulosin to reduce postoperative urinary retention in patients without a previous prescription. It is unknown if subpopulations exist for which prophylactic tamsulosin may reduce postoperative urinary retention.

Animal-Based Dietary Protein Intake Is Not A Risk Factor For Metabolic Syndrome Among Young Or Middle-Aged Females.

Background: Metabolic syndrome (MetS) increases risk for morbidity and premature mortality. Blood pressure, waist circumference, and fasting triglycerides (TG), blood glucose (BG), and high-density lipoprotein cholesterol (HDL) are factors for determining MetS. The Simple Method for Quantifying Metabolic Syndrome (siMS) score and risk score estimate risk of MetS. The purpose for this study was to exam the relationship of animal-based (ABP) and plant-based protein (PLP) with MetS as estimated by siMS score and risk score. Physical activty is another important consideration in MetS as it can reduce blood pressure, waist circumference and blood glucose, and affect blood lipid and lipoprotein concentrations. Methods: A cross-sectional study examined whether physical activity (PA) level and dietary protein source (i.e., animal- or plant-based) among young (18-24 years) and middle-aged (45-60 years) females were associated with siMS score and siMS risk score. Average time spent in sedentary, light, and moderate-to-vigorous PA (MVPA; min/wk), steps (steps/day), energy intake (kcal/day), percent dietary protein to total energy intake, ABP and PLP dietary intake, and ABP:PLP ratio (g/day) were included in the analysis. Volunteers were recruited from North Dakota and Minnesota from 2017 to 2019. Results: Eighty-one female participants (mean ± SD; young, n = 38, 20.4 ± 1.7 years, middle-aged, 52.5 ± 4.8 years) were included in the independent t-tests used to examine group differences in age, body mass index, HDL, BG, TG, systolic blood pressure, waist circumference, energy intake, energy intake percentage of total carbohydrates, fat, protein, ABP, and PLP, ABP:PLP, siMS score, and siMS risk score. Stepwise linear regressions were used to evaluate whether PA level and dietary protein source were predictors of siMS score and siMS risk score among young and middle-aged adult females. There was an inverse relationship between PLP intake and siMS score. The model explained 6.9% of the variance in siMS risk score (F1, 80 = 5.93). Plant-based protein intake was inversely related to siMS risk score while light PA was positively associated with siMS risk score. The model explained 16% of the variance in siMS risk score (F1, 80 = 7.53). Animal-based dietary protein intake did not impact siMS score (p = 0.180) and siMS risk score (p = 0.283). Conclusions: Plant-based protein intake was associated with a lower risk of MetS via siMS scores, while ABP was not associated. Given the nature of the cross-sectional design of this study, no causal relationship can be determined, but longitudinal studies or randomized control trials to confirm the results from this study are needed in the future.

SARS-CoV-2 Delta Variant N Gene Mutations Reduce Sensitivity to the TaqPath COVID-19 Multiplex Molecular Diagnostic Assay.

As the SARS-CoV-2 virus evolves, mutations may result in diminished sensitivity to qRT-PCR diagnostic assays. We investigated four polymorphisms circulating in the SARS-CoV-2 Delta lineage that result in N gene target failure (NGTF) on the TaqPath COVID-19 Combo Kit. These mutations were detected from the SARS-CoV-2 genome sequences that matched with the diagnostic assay results of saliva specimens. Full length N genes from the samples displaying NGTF were cloned into plasmids and assayed using three SARS-CoV-2 qRT-PCR assays. These constructs resulted in reduced sensitivity to the TaqPath COVID-19 Combo Kit compared to the controls (mean Ct differences of 3.06, 7.70, 12.46, and 14.12), but were detected equivalently on the TaqPath COVID-19 Fast PCR Combo 2.0 or CDC 2019_nCoV_N2 assays. This work highlights the importance of genomic sequencing to monitor circulating mutations and provide guidance in improving diagnostic assays.

Evenness of Dietary Protein Intake Is Positively Associated with Lean Mass and Strength in Healthy Women.

Background: Evenness of protein intake is associated with increased lean mass, but its relationship with muscle strength and performance is uncertain. Objectives: We determined the association of evenness of protein intake with lean mass, muscle strength and endurance, and functional ability. Design: This was a cross-sectional study. Setting: Data were collected at a research university in the upper midwestern United States. Participants: One hundred ninety-two healthy women, aged 18 to 79 years, mean ± SEM 41.9 ± 1.3, completed the study. Measurements: Dietary intake was assessed using 3-day food diaries verified with food frequency questionnaires. To assess evenness of protein intake, the day was divided into 3 periods: waking to 11:30, 11:31 to 16:30, and after 16:30. Lean mass was measured with dual energy X-ray absorptiometry. Lower-body muscle strength and endurance were determined using isokinetic dynamometry. Upper-body muscle strength was maximal handgrip strength. Functional ability was assessed using 6-m gait speed and 30-second chair stand tests. Accelerometry measured physical activity. Results: Intakes of 25 g or more of protein at 1 or more of the 3 periods was positively associated with lean mass (ß ± S.E.; 1.067 ± 0.273 kg, P < .001) and upper-body (3.274 ± 0.737 kg, P < .001) and lower-body strength (22.858 ± 7.918 Nm, P = .004) when controlling for age, body mass index, physical activity, and energy and protein intakes. Consuming at least 0.24 g/kg/period for those under 60 years and 0.4 g/kg/period for those 60 years and older was related to lean mass (0.754 ± 0.244 kg, P = .002), upper-body strength (2.451 ± 0.658 kg, P < .001), and lower-body endurance (184.852 ± 77.185 J, P = .018), controlling for the same variables. Conclusions: Evenness of protein intake is related to lean mass, muscle strength, and muscular endurance in women. Spreading protein intake throughout the day maximizes the anabolic response to dietary protein, benefiting muscle mass and performance.

East Antarctic cooling induced by decadal changes in Madden-Julian oscillation during austral summer.

While West Antarctica has experienced the most significant warming in the world, a profound cooling trend in austral summer was observed over East Antarctica (30°W to 150°E, 70° to 90°S) from 1979 to 2014. Previous studies attributed these changes to high-latitude atmospheric dynamics, stratospheric ozone change, and tropical sea surface temperature anomalies. We show that up to 20 to 40% of the observed summer cooling trend in East Antarctica was forced by decadal changes of the Madden-Julian oscillation (MJO). Both observational analysis and climate model experiments indicate that the decadal changes in the MJO, characterized by less (more) atmospheric deep convection in the Indian Ocean (western Pacific) during the recent two decades, led to the net cooling trend over East Antarctica through modifying atmospheric circulations linked to poleward-propagating Rossby wave trains. This study highlights that changes in intraseasonal tropical climate patterns may result in important climate change over Antarctica.

Evaluation of Nigerian Medicinal Plants Extract on Human P-glycoprotein and Cytochrome P450 Enzyme Induction: Implications for Herb-drug Interaction.

BACKGROUND: Herbal medicine represents a significant component of disease prevention and therapy in most African countries. Herb-drug interactions (HDI) can arise from the co-administration of herbal and orthodox medicines. OBJECTIVE: This study assessed the potential for HDI of V. amygdalina, O. gratissimum, M. oleifera, A. indica, and P. nitida extracts using in vitro assays. Little is known about these medicinal plants' potential for drug interaction despite their extensive use in Nigeria for several disease conditions. METHOD: The medicinal plant crude extracts were evaluated for Cytochrome P450 (CYP) enzyme induction using cryopreserved human hepatocytes. Enzyme activity was determined by quantifying probe substrate metabolism and metabolite formation using liquid chromatography-mass spectrometry/mass spectrometry. The extracts were evaluated for the potential to inhibit P-glycoprotein (P-gp) activity using human embryonic kidney membrane vesicles over-expressing human P-gp. The herbal extracts in vivo drug interaction potential was predicted based on the USFDA drug interaction guidance. RESULT: O. gratissimum and P. nitida methanol extracts induced CYP1A2 enzyme activity by greater than 3-fold. P. nitida methanol extracts showed over 2-fold induction of CYP1A2 mRNA expression. O. gratissimum methanol extract induced CYP2B6 mRNA expression over 2-fold. P. nitida and A. indica methanol extracts showed potent inhibition of P-gp activity (IC50: 3.8 and 5.4 µg/mL), respectively, while V. amygdalina and M. oleifera methanol extracts showed moderate P-gp inhibition (IC50: 12.1 and 37.2 µg/mL, respectively). CONCLUSION: Our studies suggested that the medicinal plants' extracts can modulate CYP enzymes and P-gp activity with the potential to cause herb-drug interaction in vivo.