Effects of 8 weeks parent-accompanied swimming on physical capacity and intelligence in preschool children.

This study aimed to explore the potential effects of 8-week parents-accompanied swimming on the physical capacity and intelligence of preschool children in China. Thirty-six boys (mean age 3.56 ± 0.27 years) were divided into three groups: the traditional physical exercise group (TP, n = 12), the accompanied swimming group (AS, n = 12) and the independent swimming group (IS, n = 12). Participants' physical capacity was assessed before and after the intervention using the following indicators: height, weight, distance of tennis ball throw, standing long jump distance, time for the 10-meter shuttle run, time for a two-legged continuous jump, sit-and-reach distance, and time on the walking balance beam. Intelligence was assessed at three points: pre-test, mid-test after 4 weeks, and post-test. Data were analyzed using a two-way repeated measures ANOVA, Bonferroni test (p < 0.05) and effect size. The time of the AS and IS groups to walk the balance beam was significantly lower than the TP group, with a difference of 1.81 s (p < 0.01, [95% CI -3.22 to -0.40], ES = 1.53) and 1.25 s (p < 0.05, [95% CI -2.66 to 0.16], ES = 0.81). At the mid-test, the IQ scores of the TP group were lower than the AS group (p < 0.05, [95% CI -12.45 to -0.96], ES = 0.89). Additionally, at post-test, the IQ scores of the TP group were significantly lower than those of both AS (p < 0.01, [95% CI -14.12 to -2.74], ES = 1.15) and IS groups (p < 0.01, [95% CI -12.53 to -3.31], ES = 1.21). Swimming enhances children's balance and IQ scores more than traditional physical exercises. Involving parents in swimming leads to a more significant increase in IQ scores within 4 weeks of initial swimming exercise.

Dosing Cefazolin for Surgical Site Infection Prophylaxis in Adolescent Idiopathic Scoliosis Surgery: Intermittent Bolus or Continuous Infusion?-A Pilot Study.

Background: Cefazolin may minimize the risk of surgical site infection (SSI) following posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). Cefazolin dosing recommendations vary and there is limited evidence for achieved tissue concentrations. Methods: We performed a randomized, controlled, prospective pharmacokinetic pilot study of 12 patients given cefazolin by either intermittent bolus (30 mg/kg every 3 h) or continuous infusion (30 mg/kg bolus followed by 10/mg/kg per hour) during PSF for AIS. Results: Patients were well matched for demographic and perioperative variables. While total drug exposure, measured as area-under-the-curve (AUC), was similar in plasma for bolus and infusion dosing, infusion dosing achieved greater cefazolin exposure in subcutaneous and muscle tissue. Using the pharmacodynamic metric of time spent above minimal inhibitory concentration (MIC), both bolus and infusion dosing performed well. However, when targeting a bactericidal concentration of 32 µg/mL, patients in the bolus group spent a median of 1/5 and 1/3 of the typical 6 h operative time below target in subcutaneous and muscle tissue, respectively. Conclusions: We conclude that intraoperative determination of cefazolin tissue concentrations is feasible and both bolus and infusion dosing of cefazolin achieve concentrations in excess of typical MICs. Infusion dosing appears to more consistently achieve bactericidal concentrations in subcutaneous and muscle tissues.

Dose-response relationship between weekly physical activity level and the frequency of colds in Chinese middle-aged and elderly individuals.

Background: Engaging in appropriate physical activity can significantly lower the risk of various diseases among middle-aged and older adults. Investigating optimal levels of physical activity (PA) is crucial for enhancing the health of this demographic. This study aims to explore the dose-response relationship between weekly PA levels and the frequency of colds among Chinese middle-aged and elderly individuals, identifying the necessary PA level to effectively diminish the risk of colds. Methods: We conducted a cross-sectional study using a web-based survey targeting individuals aged 40 and older (n = 1, 683) in China. The survey collected information on PA and the frequency of colds. Data was analyzed using Kruskal-Wallis test and the χ2 test. We explored the dose-response relationship between weekly PA and cold frequency over the past year through an ordered multivariate logistic regression model and a restricted cubic spline model. Results: (1) Brisk walking emerged as the preferred physical exercise for those over 40. The findings suggest that engaging in moderate (odds ratio (OR) = 0.64, P < 0.001, 95% confidence interval (CI) [0.50-0.81]) and high (OR = 0.64, P < 0.001, 95% CI [0.51-0.79]) levels of PA weekly significantly reduces the risk of catching a cold. Individuals with one (OR = 1.47, P < 0.001, 95% CI [1.20-1.80]) or multiple chronic diseases (OR = 1.56, P < 0.001, 95% CI [1.21-2.00]) were at increased risk. Those residing in central (OR = 1.64, P < 0.001, 95% CI [1.33-02.01]) and western China (OR = 1.49, P = 0.008, 95% CI [1.11-02.00]) faced a higher risk compared to their counterparts in eastern China. (2) According to the restricted cubic spline model, adults who experienced one cold in the past year had a weekly PA level of 537.29 metabolic equivalent-minutes per week (MET-min/wk) with an OR value of 1. For those reporting two or more colds, the PA level was 537.76 MET-min/wk with an OR of 1. Conclusions: (1) Brisk walking is the most favored exercise among the Chinese middle-aged and elderly, with the prevalence of colds being affected by the number of chronic diseases and the geographic location. (2) Regular, moderate exercise is linked to a lower risk of colds. To effectively reduce cold frequency, it is recommended that middle-aged and elderly Chinese individuals engage in a minimum of 538 MET-min/wk of exercise.

Brisk walking improves motor function and lower limb muscle strength in Chinese women aged 80 years and older.

This study investigates the effects of a 12-week brisk walking exercise regimen on motor function improvements in elderly women. Twenty-six elderly women, aged 84.2 ± 3.2 years, participated in a 12-week brisk walking exercise program. Fitness assessments and blood biomarker analyses (including CHO, HDLC, LDLC, TC) were conducted pre- and post-intervention. Additionally, targeted metabolomics was employed to measure short-chain fatty acids, amino acids, and vitamin metabolites. The intervention led to significant enhancements in participants' flexibility (p < 0.05), lower limb muscle strength (p < 0.01), and cardiorespiratory endurance (p < 0.01), while muscle mass showed no significant changes. Fifteen significant differential metabolites were identified (VIP > 1.0, FC > 1.2 or < 0.8, and p < 0.05), with arginine, ornithine, aspartic acid, glutamine, phenylalanine, tyrosine, and pantothenic acid playing key roles across seven metabolic pathways. A 12-week brisk walking exercise program significantly enhanced flexibility, lower limb muscle strength, and cardiorespiratory endurance among elderly women. These improvements did not extend to muscle mass or upper limb muscle strength. The observed enhancement in exercise capacity may be attributed to improved regulation of neurotransmitters.

Human mutations in SLITRK3 implicated in GABAergic synapse development in mice.

This study reports on biallelic homozygous and monoallelic de novo variants in SLITRK3 in three unrelated families presenting with epileptic encephalopathy associated with a broad neurological involvement characterized by microcephaly, intellectual disability, seizures, and global developmental delay. SLITRK3 encodes for a transmembrane protein that is involved in controlling neurite outgrowth and inhibitory synapse development and that has an important role in brain function and neurological diseases. Using primary cultures of hippocampal neurons carrying patients' SLITRK3 variants and in combination with electrophysiology, we demonstrate that recessive variants are loss-of-function alleles. Immunostaining experiments in HEK-293 cells showed that human variants C566R and E606X change SLITRK3 protein expression patterns on the cell surface, resulting in highly accumulating defective proteins in the Golgi apparatus. By analyzing the development and phenotype of SLITRK3 KO (SLITRK3-/-) mice, the study shows evidence of enhanced susceptibility to pentylenetetrazole-induced seizure with the appearance of spontaneous epileptiform EEG as well as developmental deficits such as higher motor activities and reduced parvalbumin interneurons. Taken together, the results exhibit impaired development of the peripheral and central nervous system and support a conserved role of this transmembrane protein in neurological function. The study delineates an emerging spectrum of human core synaptopathies caused by variants in genes that encode SLITRK proteins and essential regulatory components of the synaptic machinery. The hallmark of these disorders is impaired postsynaptic neurotransmission at nerve terminals; an impaired neurotransmission resulting in a wide array of (often overlapping) clinical features, including neurodevelopmental impairment, weakness, seizures, and abnormal movements. The genetic synaptopathy caused by SLITRK3 mutations highlights the key roles of this gene in human brain development and function.

Can non-renal clearance and/or bioavailability of drugs be assessed reliably in renal impairment studies with oral drug administration?

OBJECTIVE: The causes for the variable susceptibility of renal clearance (CLr) and bioavailability (F) of drugs in renal impairment are still unknown. We investigated whether the impact of chronic kidney disease (CKD) on non-renal clearance (CLnr) or F can be appraised when drug administration is by the oral route only in dedicated renal impairment studies (DRIS), as is routinely done when developing drugs intended for oral use. MATERIALS AND METHODS: A literature search on DRIS administering drugs orally only or orally and intravenously was conducted. Seven drugs administered orally only with notable CLnr and 2 drugs administered by the oral and intravenous routes with negligible CLnr were identified. Regressions of oral clearance (CL/F), normalized by absolute bioavailability in healthy subjects (F1), on CLr were performed for the drugs with notable non-renal elimination to determine the impact of CKD on CLnr. Regressions of CL/F and CL on CLr were conducted for the drugs with negligible CLnr to determine F. RESULTS: Excessive variability in CL/F and CLr precluded evaluation of CLnr for 1 drug with notable CLnr and F1 < 0.01. A categorization based on the susceptibility of CLnr to CKD appeared possible for the 6 drugs with notable non-renal elimination if the parameters of the F1 normalized regressions of CL/F on CLr are taken at face value, i.e., if equality of F and F1 is assumed. However, the true relationship between F and F1 in subjects with varying renal function is unknowable for drugs with significant CLnr when administered orally only. F of drugs with significant CLnr may be altered by a reduced activity of uptake-transporters and/or enzymes so that in renal impaired subjects both absorption and first pass metabolism of intact drug may be reduced relative to healthy subjects, making it impossible to predict whether F in the former or latter population is greater. Bioavailability of drugs with negligible CLnr may depend primarily on the integrity of uptake-transporters so that F in healthy subjects is expected to be greater than in renal impaired subjects. Apparently accurate estimates of F for drugs with negligible CLnr may be obtained from DRIS with oral administration by using the reciprocal of the slope of the regressions. CONCLUSION: A reliable assessment of the impact of CKD on CLnr for drugs with significant non-renal elimination requires information after oral and intravenous administration in the same DRIS study. However, apparently accurate estimates of F for drugs with negligible non-renal elimination may be obtained in DRIS with oral drug administration only, but validation of the proposed method with other drugs exhibiting negligible non-renal elimination and variable F1 is required.

Changes in cardiac-driven perivascular fluid movement around the MCA in a pharmacological model of acute hypertension detected with non-invasive MRI.

Perivascular spaces mediate a complex interaction between cerebrospinal fluid and brain tissue that may be an important pathway for solute waste clearance. Their structural or functional derangement may contribute to the development of age-related neurogenerative conditions. Here, we employed a non-invasive low b-value diffusion-weighted ECG-gated MRI method to capture perivascular fluid movement around the middle cerebral artery of the anaesthetised rat brain. Using this method, we show that such MRI estimates of perivascular fluid movement directionality are highly sensitive to the cardiac cycle. We then show that these measures of fluid movement directionality are decreased in the angiotensin-II pharmacological model of acute hypertension, with an associated dampening of vessel pulsatility. This translational MRI method may, therefore, be useful to monitor derangement of perivascular fluid movement associated with cardiovascular pathologies, such as hypertension, in order to further our understanding of perivascular function in neurology.

Relationship between methods of monitoring training load and physiological indicators changes during 4 weeks cross-country skiing altitude training.

This study aimed to: (i) analyze the load characteristics of 4 weeks cross-country skiing altitude training; (ii) analyze the relationships between methods of monitoring training load and physiological indicators changes of elite male Chinese cross-country skiers during this period. Practitioners collected load data during 4 weeks of altitude training camp. Participants performed maximal oxygen uptake, lactate threshold, body composition, and skierg power test before and after the training camp to investigate the changes in physiological performance. Edwards TRIMP, Lucia TRIMP, and session rating of perceived exertion were collected as internal load. Training distance, time recorded by the Catapult module were collected as external load. The result revealed a " pyramid " pattern in the load characteristics during the altitude training camp. The correlation between luTRIMP and percent change in physiological indicators was highest. Percentage changes in lactate threshold velocity (r = .78 [95% CI -.01 to .98]), percentage changes in lactate threshold HR (r = .71 [95% CI .14- .99]), percentage changes in maximum HR (r = .83 [95% CI .19-1.00]), percentage changes in skierg power-to-weight ratio (r = .75 [95% CI -.28 to .98]) had very large relationships with luTRIMP. In cross-country skiing altitude training, training loads should be reasonably controlled to ensure that athletes do not become overly fatigued. Methods of training load monitoring that combine with athletes' physiological characteristics and program characteristics have the highest dose-response relationships, it is an important aspect of cross-country ski training load monitoring. The luTRIMP could be a good monitoring tool in cross-country skiing altitude training.

Image-Guided Magnetic Thermoseed Navigation and Tumor Ablation Using a Magnetic Resonance Imaging System.

Medical therapies achieve their control at expense to the patient in the form of a range of toxicities, which incur costs and diminish quality of life. Magnetic resonance navigation is an emergent technique that enables image-guided remote-control of magnetically labeled therapies and devices in the body, using a magnetic resonance imaging (MRI) system. Minimally INvasive IMage-guided Ablation (MINIMA), a novel, minimally invasive, MRI-guided ablation technique, which has the potential to avoid traditional toxicities, is presented. It comprises a thermoseed navigated to a target site using magnetic propulsion gradients generated by an MRI scanner, before inducing localized cell death using an MR-compatible thermoablative device. The authors demonstrate precise thermoseed imaging and navigation through brain tissue using an MRI system (0.3 mm), and they perform thermoablation in vitro and in vivo within subcutaneous tumors, with the focal ablation volume finely controlled by heating duration. MINIMA is a novel theranostic platform, combining imaging, navigation, and heating to deliver diagnosis and therapy in a single device.

Remote and Selective Control of Astrocytes by Magnetomechanical Stimulation.

Astrocytes play crucial and diverse roles in brain health and disease. The ability to selectively control astrocytes provides a valuable tool for understanding their function and has the therapeutic potential to correct dysfunction. Existing technologies such as optogenetics and chemogenetics require the introduction of foreign proteins, which adds a layer of complication and hinders their clinical translation. A novel technique, magnetomechanical stimulation (MMS), that enables remote and selective control of astrocytes without genetic modification is described here. MMS exploits the mechanosensitivity of astrocytes and triggers mechanogated Ca2+ and adenosine triphosphate (ATP) signaling by applying a magnetic field to antibody-functionalized magnetic particles that are targeted to astrocytes. Using purpose-built magnetic devices, the mechanosensory threshold of astrocytes is determined, a sub-micrometer particle for effective MMS is identified, the in vivo fate of the particles is established, and cardiovascular responses are induced in rats after particles are delivered to specific brainstem astrocytes. By eliminating the need for device implantation and genetic modification, MMS is a method for controlling astroglial activity with an improved prospect for clinical application than existing technologies.

Monitoring Physiological Performance over 4 Weeks Moderate Altitude Training in Elite Chinese Cross-Country Skiers: An Observational Study.

The current observational study aimed to monitor the physiological performance over 4 weeks of living and training at a moderate altitude in elite Chinese cross-country skiers (8 males, mean age 20.83 ± 1.08 years). Lactate threshold, maximal oxygen uptake, blood, and body composition tests were performed at different time points to investigate the changes in physiological performance. The data were analysed by a one-way repeated measures ANOVA and a paired sample T-test between the test results. During the training camp, systematic load monitoring was carried out. Lactate threshold velocity, lactate threshold heart rate, and upper body muscle mass increased significantly (p < 0.01) after moderate altitude training. Maximum oxygen uptake was reduced compared to pre-tests (p < 0.05). Aerobic capacity parameters (maximal oxygen uptake, haemoglobin, red blood cell count) did not significantly increase after athletes returned to sea level (p > 0.05). These findings suggest that 4 weeks of moderate altitude training can significantly improve athletes' lactate threshold and upper body muscle mass; no significant improvement in other aerobic capacity was seen. Exposure time, training load, and nutritional strategies should be thoroughly planned for optimal training of skiers at moderate altitudes.

Pooled Analysis of Gastric Emptying in Patients With Obesity: Implications for Oral Absorption Projection.

PURPOSE: Gastric emptying time is one of limiting factors that determines the pharmacokinetic properties of drugs administered by mouth. Despite the high prevalence of obesity worldwide, modifications in gastric emptying time have not been systematically addressed in this set of patients. The current analysis aims to quantitatively address obesity-related changes in gastric emptying time of solids, semisolids, and liquids compared with lean individuals, highlighting the relevant pharmacokinetic implications of oral drug absorption in patients with obesity. METHODS: We searched the Cochrane Library, PubMed, Web of Science, and Embase for all relevant articles published until November 1, 2020. Differences in gastrointestinal variables in relation to gastric emptying between obese and lean individuals were quantified by weighted mean difference (WMD) and ratio of means (RoM). Robustness of the analyses was evaluated by subgroup analysis and publication bias test. FINDINGS: A total of 17 studies with 906 participants were included. The gastric half-emptying time of solids (WMD, -10.4 minutes; P = 0.001; RoM, 0.90; P = 0.01) and liquids (WMD, -6.14 minutes; P < 0.001; RoM, 0.83, P = 0.03) was significantly shorter in individuals with obesity compared with lean individuals. These findings were confirmed by the subgroup analyses and publication bias tests. IMPLICATIONS: Our pooled analysis systemically quantifies the differences in gastric half-emptying time between individuals with obesity and lean individuals, facilitating better understanding and prediction of drug absorption in individuals with obesity through physiologically based pharmacokinetic approaches. Obesity is associated with a faster transit of both solids and liquids through the stomach.

Attitude is everything: keep probe pitch neutral during side-fire prostate biopsy. A simulator study.

OBJECTIVES: To develop and validate on a simulator a learnable technique to decrease deviation of biopsied cores from the template schema during freehand, side-fire systematic prostate biopsy (sPBx) with the goal of reducing prostate biopsy (PBx) false-negatives, thereby facilitating earlier sampling, diagnosis and treatment of clinically significant prostate cancer. PARTICIPANTS AND METHODS: Using a PBx simulator with real-time three-dimensional visualization, we devised a freehand, pitch-neutral (0°, horizontal plane), side-fire, transrectal ultrasonography (TRUS)-guided sPBx technique in the left lateral decubitus position. Thirty-four trainees on four Canadian and US urology programmes learned the technique on the same simulator, which recorded deviation from the intended template location in a double-sextant template as well as the TRUS probe pitch at the time of sampling. We defined deviation as the shortest distance in millimeters between a core centre and its intended template location, template deviation as the mean of all deviations in a template, and mastery as achieving a template deviation ≤5.0 mm. RESULTS: All results are reported as mean ± sd. The mean absolute pitch and template deviation before learning the technique (baseline) were 8.2 ± 4.1° and 8.0 ± 2.7 mm, respectively, and after mastering the technique decreased to 4.5 ± 2.7° (P = 0.001) and 4.5 ± 0.6 mm (P < 0.001). Template deviation was related to mean absolute pitch (P < 0.001) and increased by 0.5 mm on average with each 1° increase in mean absolute pitch. Participants achieved mastery after practising 3.9 ± 2.9 double-sextant sets. There was no difference in time to perform a double-sextant set at baseline (277 ± 102 s) and mastery (283 ± 101 s; P = 0.39). CONCLUSION: A pitch-neutral side-fire technique reduced template deviation during simulated freehand TRUS-guided sPBx, suggesting it may also reduce PBx false-negatives in patients in a future clinical trial. This pitch-neutral technique can be taught and learned; the University of Florida has been teaching it to all Urology residents for the last 2 years.

Assembly of a Rovibrational Ground State Molecule in an Optical Tweezer.

We demonstrate the coherent creation of a single NaCs molecule in its rotational, vibrational, and electronic (rovibronic) ground state in an optical tweezer. Starting with a weakly bound Feshbach molecule, we locate a two-photon transition via the |c^{3}Σ_{1},v^{'}=26⟩ excited state and drive coherent Rabi oscillations between the Feshbach state and a single hyperfine level of the NaCs rovibronic ground state |X^{1}Σ,v^{''}=0,N^{''}=0⟩ with a binding energy of D_{0}=h×147044.63(11) GHz. We measure a lifetime of 3.4±1.6 s for the rovibronic ground state molecule, which possesses a large molecule-frame dipole moment of 4.6D and occupies predominantly the motional ground state. These long-lived, fully quantum-state-controlled individual dipolar molecules provide a key resource for molecule-based quantum simulation and information processing.

Abundance and Associated Variations of Cytochrome P450 Drug-Metabolizing Enzymes in the Liver of East Asian Adults: A Meta-Analysis.

BACKGROUND: Cytochrome P450 (CYP) enzymes are one of the main sources of variability in drug metabolic clearance. Information on their abundance levels is therefore crucial to optimize scaling factors for in vitro-in vivo extrapolation (IVIVE) to predict metabolic clearance. OBJECTIVE: This study aims to quantify the abundance data of hepatic drug-metabolizing CYP enzymes in East Asian subjects reported from various sources in the literature using meta-analysis. METHOD: We conducted a meta-analysis on the abundance of drug-metabolizing CYP enzymes in the liver of East Asian adults. Eligible reports were identified based on predefined criteria-(1) individual liver microsomal samples, and (2) absolute protein abundance data from normal tissues of East Asian adult subjects. Subgroup and sensitivity analyses were also performed. RESULTS: Among the 11 CYP isoforms analyzed in East Asian subjects, CYP3A5 and CYP3A4 had the highest protein levels. In particular, the number of studies and the liver sample used to quantify the abundance of CYP3A4 were the largest. Of the isoforms involved, CYP2J2 and CYP2B6 had the lowest abundance level, i.e., <5 pmol/ mg of microsomal protein. For enzymes with abundance values available in both Chinese and Japanese subjects (CYP1A2, CYP2C9, CYP3A4, and CYP3A5), the abundance level of each CYP isoform appeared to be higher in Chinese than in Japanese subjects. The most distinct difference was observed in CYP3A5 abundance. CONCLUSION: The current meta-analysis shows that the abundance levels of CYP enzymes appear to vary greatly among different East Asian individuals who have similar ethnic backgrounds and food habits. The pooled data of CYP abundance can be used as preliminary reference values along with the associated variations for the projections of pharmacokinetics through physiologically based pharmacokinetic (PBPK) approaches.

Mechanosensory Signaling in Astrocytes.

Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signaling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca2+ responses in astrocytes of the rat brainstem were blocked by (1) antagonists of connexin channels, connexin 43 (Cx43) blocking peptide Gap26, or Cx43 gene knock-down; (2) antagonists of TRPV4 channels; (3) antagonist of P2Y1 receptors for ATP; and (4) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and Cx43 channels in astrocytes. Dye loading experiments showed that mechanical stimulation increased open probability of carboxyfluorescein-permeable membrane channels. These data suggest that mechanosensory Ca2+ responses in astrocytes are mediated by interaction between TRPV4 and Cx43 channels, leading to Cx43-mediated release of ATP which propagates/amplifies Ca2+ signals via P2Y1 receptors and Ca2+ recruitment from the intracellular stores. In astrocyte-specific Cx43 knock-out mice the magnitude of heart rate responses to acute increases in intracranial pressure was not affected by Cx43 deficiency. However, these animals displayed lower heart rates at different levels of cerebral perfusion, supporting the hypothesis of connexin hemichannel-mediated release of signaling molecules by astrocytes having an excitatory action on the CNS sympathetic control circuits.SIGNIFICANCE STATEMENT There is evidence suggesting that astrocytes may function as intracranial baroreceptors that play an important role in the control of systemic and cerebral circulation. To function as intracranial baroreceptors, astrocytes must possess a specialized membrane mechanism that makes them exquisitely sensitive to mechanical stimuli. This study shows that opening of connexin 43 (Cx43) hemichannels leading to the release of ATP is the key central event underlying mechanosensory Ca2+ responses in astrocytes. This astroglial mechanism plays an important role in the autonomic control of heart rate. These data add to the growing body of evidence suggesting that astrocytes function as versatile surveyors of the CNS metabolic milieu, tuned to detect conditions of potential metabolic threat, such as hypoxia, hypercapnia, and reduced perfusion.

Forming a Single Molecule by Magnetoassociation in an Optical Tweezer.

We demonstrate the formation of a single NaCs molecule in an optical tweezer by magnetoassociation through an s-wave Feshbach resonance at 864.11(5) G. Starting from single atoms cooled to their motional ground states, we achieve conversion efficiencies of 47(1)%, and measure a molecular lifetime of 4.7(7) ms. By construction, the single molecules are predominantly [77(5)%] in the center-of-mass motional ground state of the tweezer. Furthermore, we produce a single p-wave molecule near 807 G by first preparing one of the atoms with one quantum of motional excitation. Our creation of a single weakly bound molecule in a designated internal state in the motional ground state of an optical tweezer is a crucial step towards coherent control of single molecules in optical tweezer arrays.

Evaluation of Hemodialysis Effect on Pharmacokinetics of Meropenem/Vaborbactam in End-Stage Renal Disease Patients Using Modeling and Simulation.

The objectives of this study were to evaluate the effect of hemodialysis (HD) on the pharmacokinetics (PK) of meropenem/vaborbactam, an approved beta-lactam/beta-lactamase inhibitor combination, and provide the rationale for the recommended timing of meropenem/vaborbactam administration relative to HD in end-stage renal disease (ESRD) patients. Population PK models were developed separately for meropenem and vaborbactam in subjects with normal renal function and different degrees of renal impairment, including those receiving HD. Simulations were performed to evaluate the exposure of meropenem and vaborbactam in ESRD patients who received a fixed dose of 0.5 g/0.5 g meropenem/vaborbactam every 12 hours as a 3-hour intravenous infusion under various drug administration schedules relative to HD. The probability of target attainment (PTA) analyses were conducted with pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem and vaborbactam. Simulations showed that HD reduces the accumulation of vaborbactam, but the exposure of vaborbactam is still above the PK/PD target regardless of whether meropenem/vaborbactam is administered predialysis or postdialysis. For meropenem, drug infusion completed right prior to initiation of HD may substantially reduce exposure leading to poor PTA results. In contrast, drug infusion completed at least 2 hours prior to initiation of HD is not predicted to result in efficacy loss based on PTA analysis. The results of simulation indicate that meropenem/vaborbactam infusion completed at least 2 hours prior to initiation of HD or administered immediately after the end of HD can avoid potential efficacy loss in ESRD patients.