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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The Impact of a Telehealth Intervention on Activity Profiles in Older Adults during the COVID-19 Pandemic: A Pilot Study.

BACKGROUND: Physical inactivity during the COVID-19 pandemic is a public health concern for older adults. Telehealth presents a safe platform for conducting health-related interventions that may have additional benefits such as widespread reach. Our pilot study sought to examine how a telehealth intervention changed activity profiles in older adults during the COVID-19 pandemic. METHODS: There were n =13 adults aged 70.6 ± 4.5 years that participated in a 6 week telehealth intervention during the COVID-19 pandemic. The didactic intervention contents were shared online, and participants worked with trained interviewers over the telephone to discuss physical activity. At baseline and post-intervention, the Multimedia Activity Recall for Children and Adults examined activity profiles, while accelerometry estimated time spent sedentary and in physical activity. RESULTS: Relative to the baseline measures, there was an 88 min/day (95% confidence interval (CI): 39, 137) increase in computer time and 36 min/day (CI: 10, 62) reduction in time spent in active transport at post-intervention. Moderate-to-vigorous physical activity participation also increased by an estimated 2 min/day (CI: -21, 26) and 12 min/week (CI: -154, 180), but this trend was not statistically significant. CONCLUSION: We recommend that support be provided to older adults transitioning to telehealth, especially as migration to telehealth progresses.

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.

Time-restricted eating and concurrent exercise training reduces fat mass and increases lean mass in overweight and obese adults.

The purpose of this study was to determine whether time-restricted eating (TRE), also known as time-restricted feeding, was an effective dietary strategy for reducing fat mass and preserving fat-free mass while evaluating changes in cardiometabolic biomarkers, hormones, muscle performance, energy intake, and macronutrient intake after aerobic and resistance exercise training in physically inactive and overweight or obese adults. This study was a randomized, controlled trial. Overweight and obese adults (mean ± SD; age: 44 ± 7 years; body mass index [BMI]: 29.6 ± 2.6 kg/m2 ; female: 85.7%) were randomly assigned to a TRE or normal eating (NE) dietary strategy group. The TRE participants consumed all calories between 12:00 p.m. and 8:00 p.m., whereas NE participants maintained their dietary habits. Both groups completed 8 weeks of aerobic exercise and supervised resistance training. Body composition, muscle performance, energy intake, macronutrient intake, physical activity, and physiological variables were assessed. A total of 21 participants completed the study (NE: n = 10; TRE: n = 11). A mild energy restriction was observed for TRE (~300 kcal/day, 14.5%) and NE (~250 kcal/day, 11.4%). Losses of total body mass were significantly greater for TRE (3.3%) relative to NE (0.2%) pre- to post-intervention, of which TRE had significantly greater losses of fat mass (9.0%) compared to NE (3.3%). Lean mass increased during the intervention for both TRE (0.6%) and NE (1.9%), with no group differences. These data support the use of TRE and concurrent exercise training as a short-term dietary strategy for reducing fat mass and increasing lean mass in overweight and obese adults.

Measures Derived from Panoramic Ultrasonography and Animal-Based Protein Intake Are Related to Muscular Performance in Middle-Aged Adults.

Ultrasonography advantageously measures skeletal muscle size and quality, but some muscles may be too large to capture with standardized brightness mode (B-mode) imaging. Panoramic ultrasonography can capture more complete images and may more accurately measure muscle size. We investigated measurements made using panoramic compared to B-mode ultrasonography images of the rectus femoris with muscular performance. Concurrently, protein intake plays an important role in preventing sarcopenia; therefore, we also sought to investigate the association between animal-based protein intake (ABPI) and muscular performance. Ninety-one middle-aged adults were recruited. Muscle cross-sectional area (CSA) and thickness were obtained using B-mode and panoramic ultrasound and analyzed with Image J software. Muscular performance was assessed using isokinetic dynamometry, a 30-s chair test, and handgrip strength. Three-day food diaries estimated dietary intakes. Linear regression models determined relationships between measures from ultrasonography and muscular performance. Mixed linear models were used to evaluate the association between ABPI and muscular performance. Muscle CSA from panoramic ultrasonography and ABPI were positively associated with lower-body strength (ß ± S.E.; CSA, 42.622 ± 20.024, p = 0.005; ABPI, 65.874 ± 19.855, p = 0.001), lower-body endurance (ß ± S.E.; CSA, 595 ± 200.221, p = 0.001; ABPI, 549.944 ± 232.478, p = 0.020), and handgrip strength (ß ± S.E.; CSA, 6.966 ± 3.328, p = 0.004; ABPI, 0.349 ± 0.171, p = 0.045). Panoramic ultrasound shows promise as a method for assessing sarcopenia. ABPI is related to better muscular performance.

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.

Depression and Impulsivity Self-Assessment Tools to Identify Dopamine Agonist Side Effects in Patients With Pituitary Adenomas.

Background: Dopamine agonists (DA) are the first line therapy for prolactinoma and symptomatic hyperprolactinemia; use as an adjuvant treatment for acromegaly and Cushing's disease is rare. Some patients develop de novo psychiatric symptoms or have exacerbation of pre-existing conditions during DA therapy. A practical, clinically sensitive depression and impulse control disorders (ICD; particularly hypersexuality and gambling disorders) detection tool is important for identifying at risk patients. The Barratt Impulsivity Scale (BIS-11) and the 9-item Patient Health Questionnaire (PHQ-9) are sensitive in identifying impulsivity and depression. Objective: Detail use of the BIS-11 and PHQ-9 as screening tools for depression and ICD in patients with pituitary disease at a high-volume academic pituitary center. Methods: DA-treated and naïve patients with pituitary disease were included. Patients with a known history of depression or psychiatric disorder were excluded. PHQ-9 standardized interpretation criteria were utilized to classify depression severity. For BIS-11, threshold was established based on previous studies. Statistical analysis was with SPSS version 25. Results: Seventy-six DA-treated and 27 naïve patients were included. Moderate and moderately severe depression were more prevalent in DA-treated patients; severe depression only found in DA-treated patients. A normal BIS-11 score was noted in 76.69%; higher scores (not significant) were noted in DA-treated patients. There was a positive correlation between higher BIS-11 and PHQ-9 scores; higher in DA-treated patients (r = 0.52, p < 0.001) than DA-naïve patients. Patients with BIS-11 scores ≥60 were younger and received lower cumulative DA doses compared to patients with BIS scores <60. There was no association between male sex and BIS-11 ≥60 and male sex did not increase the odds of increased scores (OR = 0.66, CI95% 0.25-1.76, p = 0.41). No significant difference was found for macroadenoma, prolactin levels, testosterone levels, hypogonadism, testosterone replacement in men, and increased impulsivity or depression scores. Conclusion: Use of PHQ-9 and BIS-11 is practical for routine screening of depression and ICD during outpatient pituitary clinic visits for patients with pituitary disease both naïve to treatment and during DA therapy. We recommend close follow-up after initiation of DA therapy for younger patients, regardless of dose.

Mechanistic insights on clearance and inhibition discordance between liver microsomes and hepatocytes when clearance in liver microsomes is higher than in hepatocytes.

Human liver microsomes (HLM) and human hepatocytes (HHEP) are two common in vitro systems used in metabolic stability and inhibition studies. The comparison between the assays using the two systems can provide mechanistic insights on the interplay of metabolism, passive permeability and transporters. This study investigated the critical factors impacting the unbound intrinsic clearance (CLint,u) and IC50 of CYP3A inhibition between HLM and HHEP. The HLM/HHEP CLint,u ratio and HHEP/HLM IC50 ratio are inversely correlated to passive permeability, but have no correlation with P-gp efflux ratio. Cofactor-supplemented permeabilized HHEP (MetMax™) collapses the IC50 differences between HHEP and HLM. P-gp inhibitor, encequidar, shows minimal impact on CLint,u and IC50 in HHEP. This is the first study that is able to separately investigate the effects of passive permeability and efflux transport. These data collectively show that passive permeability plays a critical role in metabolism and enzyme inhibition in HHEP, while P-gp efflux has a minor role. This may be due to low functional P-gp activity in suspension HHEP under the assay conditions. Low passive permeability may limit metabolism and enzyme inhibition in HHEP, leading to lower CLint,u and higher IC50 in HHEP compared to HLM. When liver microsomes give higher CLint,u than hepatocytes, microsomes are more predictive of in vivo clearance than hepatocytes.

Comparison of Fraction Unbound Between Liver Homogenate and Hepatocytes at 4°C.

Fraction unbound (fu) values obtained from liver or hepatocyte homogenate with equilibrium dialysis (fu,homo) or the hepatocyte partition coefficient method at 4°C (fu,c) are both frequently used to estimate unbound drug concentrations (Cu) and unbound partition coefficient (Kpuu) of the liver. Literature data are somewhat controversial on this topic: some reported that the two methods gave comparable fu values, while others showed that they had no correlation. To better understand the two approaches, 44 structurally diverse compounds with wide ranges of fu values were used for the comparison study. The results indicate that fu values from the two methods are comparable with an average fold error of 2.9-fold and a bias of 1.0. Although some outliers were observed, the reasons are not entirely clear and further investigations are needed. As the fu data from both methods are correlated, fu,homo measurement using tissue homogenate is recommended over cells at 4°C (fu,c) in early drug discovery. This is because fu,homo method is more reliable, has good in vivo predictability, and feasibility for any tissue types where representative cells may not be readily available. The approach can be used to estimate Cu and Kpuu of tissues in order to develop pharmacokinetic/pharmacodynamic relationships, and to estimate therapeutic indices, as well as to predict drug-drug interactions.

Handgrip Strength Asymmetry and Weakness are Differentially Associated with Functional Limitations in Older Americans.

Background: Handgrip strength (HGS) is a convent measure of strength capacity and associated with several age-related health conditions such as functional disability. Asymmetric strength between limbs has been linked to diminished function. Therefore, both HGS asymmetry and weakness could be associated with functional disability. We examined the associations of HGS asymmetry and weakness on functional limitations in a nationally representative sample of older Americans. Methods: Data were analyzed from 2689 adults ≥ 60 years who participated in the 2011-2012 and 2013-2014 waves of the National Health and Nutrition Examination Survey. Weakness was defined as HGS < 26 kg for men and < 16 kg for women. Asymmetry was determined from the ratio of the dominant and non-dominant HGS. Those with HGS ratio 0.9-1.1 were considered as having HGS symmetry, and those outside this range had asymmetry. Results: Compared to those with symmetric HGS and were not weak, those with weakness alone, and both weakness and HGS asymmetry had 2.47 (95% confidence interval [CI]: 1.14-5.35) and 3.93 (CI: 1.18-13.07) greater odds for functional limitations, respectively. However, HGS asymmetry alone was not associated with functional limitations (odds ratio: 0.80; CI: 0.62-1.03). Conclusion: The use of HGS asymmetry in protocols could improve the prognostic value of handgrip dynamometers.