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Aging results for the immune system in a departure from the optimal homeostatic state seen in young organisms. This divergence regrettably contributes to a higher frequency of compromised responses to infections and inefficient classical vaccination in aged populations. In B cells, the cornerstone of humoral immunity, the development and distribution of the various mature B cell subsets are impacted by aging in both humans and mice. In addition, aged mature B cells demonstrate limited capacity to mount efficient antibody responses. An expected culprit for the decline in effective immunity is the rise of the systemic levels of pro-inflammatory molecules during aging, establishing a chronic low-grade inflammation. Indeed, numerous alterations affecting directly or indirectly B cells in old people and mice are reminiscent of various effects of acute inflammation on this cell type in young adults. The present mini-review will highlight the possible adverse contributions of the persistent low-level inflammation observed in susceptible older organisms to the inadequate B-cell physiology. [ABSTRACT FROM AUTHOR]

Objective: To compare effects of the dipeptidyl peptidase 4 (DPP-4) inhibitor linagliptin with those of a sulfonylurea on renal physiology in metformin-treated patients with type 2 diabetes mellitus (T2DM).Research Design and Methods: In this double-blind randomized trial, 46 overweight T2DM patients without renal impairment received once-daily linagliptin (5 mg) or glimepiride (1 mg) for 8 weeks. Fasting glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined by inulin and para-aminohippuric acid clearances. Fractional excretions, urinary damage markers, and circulating DPP-4 substrates (among others, glucagon-like peptide 1 and stromal cell-derived factor-1α [SDF-1α]) were measured.Results: HbA1c reductions were similar with linagliptin (-0.45 ± 0.09%) and glimepiride (-0.65 ± 0.10%) after 8 weeks (P = 0.101). Linagliptin versus glimepiride did not affect GFR, ERPF, estimated intrarenal hemodynamics, or damage markers. Only linagliptin increased fractional excretion (FE) of sodium (FENa) and potassium, without affecting FE of lithium. Linagliptin-induced change in FENa correlated with SDF-1α (R = 0.660) but not with other DPP-4 substrates.Conclusions: Linagliptin does not affect fasting renal hemodynamics compared with glimepiride in T2DM patients. DPP-4 inhibition promotes modest natriuresis, possibly mediated by SDF-1α, likely distal to the macula densa. [ABSTRACT FROM AUTHOR]

Background: Studies indicate that standard doses of hypnotics reduce or do not change the apnea-hypopnea index (AHI) or pharyngeal muscle activity. A 1-month trial of nightly zopiclone (7.5 mg) modestly reduced the AHI vs baseline without changing other sleep parameters or next-day sleepiness.Research Question: This study aimed to determine the effects of high-dose zopiclone (15 mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds without major overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI but may come at the expense of increased hypoxemia and next-day impairment.Study Design and Methods: Twenty-eight participants (AHI = 29 ± 20 events/h) suspected to have low to moderate arousal thresholds were studied during two in-laboratory polysomnographies, separated by 1 week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15 mg of zopiclone or placebo at each visit according to a double-blind, randomized, crossover design. Each morning, subjective sleepiness and alertness via a driving simulator task were assessed.Results: The AHI did not change from placebo to zopiclone (-1.5 events/h; 95% CI, -6.6 to 3.5 events/h; P = .54). Arousal threshold, genioglossus muscle responsiveness, and most other sleep parameters and measures of next-day sleepiness and alertness also did not change with zopiclone.Interpretation: A single night of treatment with high-dose zopiclone does not systematically reduce the AHI or increase the arousal threshold in selected people with OSA. The mechanisms for these unexpected findings require further investigation.Trial Registry: Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au. [ABSTRACT FROM AUTHOR]

Anatomical and physiological adaptations of animals to extreme environments provide insight into basic physiological principles and potential therapies for human disease. In that regard, the diving physiology of marine mammals and seabirds is especially relevant to pulmonary and cardiovascular function, and to the pathology and potential treatment of patients with hypoxaemia and/or ischaemia. This review highlights past and recent progress in the field of comparative diving physiology with emphasis on its potential relevance to human medicine. [ABSTRACT FROM AUTHOR]

Aim: Retrospective analysis of different contact lens wearing groups suggests lens surface lubricity is the main factor influencing contact lens comfort. However, the examined commercially available contact lenses differ in material and design as well as surface properties. Hence this study isolates the contribution of lens surface properties using an ultra-thin coating technology.Methods: Nineteen habitual contact lens wearers (21.6±1.7years) wore formofilcon B soft monthly disposable contact lenses with and without coating technology modified surface properties for a month each in a randomised double-masked cross-over study. OBJECTIVE NON-INVASIVE: breakup time (NIKBUT), NIKBUT average and ocular redness (Jenvis grading scale) were evaluated (Keratograph 5M) after 1 week and 1 month of wear. Symptoms were assessed using the Contact Lens Dry Eye Questionnaire (CLDEQ-8); perceived vision quality and subjective lens comfort at insertion, mid-day and end of the day were rated with four Visual Analog Scales.Results: Perceived visual quality (F=5.049,p=0.037), contact lens dry eye symptoms (F=14.408,p=0.001) and subjective lens comfort (F=28.447,p<0.001) were better for coated compared to uncoated lenses. The surface coating postponed the lens dewetting (F=8.518,p=0.009) and increased the pre-lens tear film stability (F=5.626,p=0.029), but bulbar (F=0.340,p=0.567) and limbal (F=0.110,p=0.744) redness were similar for both contact lenses. No parameter changed significantly between a weeks' and months' wear (p>0.05). Lens surface wettability and ocular redness were not correlated to changes in symptoms (p>0.05).Conclusion: As previously hypothesised, enhancing the physical surface properties of a soft contact lens improves subjectively rated wearer comfort, which, in turn, should result in reduced contact lens discontinuation. [ABSTRACT FROM AUTHOR]

In the prospective, randomized, controlled multicenter study, 100 patients who were clinically diagnosed with sarcopenia were assigned to either a home-based exercise group or a control group. The home-based training program included exercises with gradually increasing intensity comprising posture, stretching and upper- and lower-extremity muscle-strengthening exercises, balance and coordination exercises, and gait training. Before and 3 months after the exercise program, all the patients were evaluated. The 6-min walking test and Berg Balance Scale scores increased significantly after 3 months in the home-based exercise group compared with the controls. There was also a significant decrease in timed up and go test scores and a significant improvement in quality of life in the exercise group compared with the control group. Our findings indicated that a home-based exercise program can have a positive effect on physical function, balance, and quality of life in patients with sarcopenia. [ABSTRACT FROM AUTHOR]

Introduction: Transcranial magnetic stimulation (TMS) is widely used to explore cortical physiology in health and disease. Surface electromyography (sEMG) is appropriate for superficial muscles, but cannot be applied easily to less accessible muscles. Muscle ultrasound (mUS) may provide an elegant solution to this problem, but fundamental questions remain. We explore the relationship between TMS evoked muscle potentials and TMS evoked muscle contractions measured with mUS.Methods: In 10 participants, we performed a TMS recruitment curve, simultaneously measuring motor evoked potentials (MEPs) and mUS in biceps (BI), first dorsal interosseous (FDI), tibialis anterior (TA), and the tongue (TO).Results: Resting motor threshold (RMT) measurements and recruitment curves were found to be consistent across sEMG and mUS.Discussion: This work supports the use of TMS-US to study less accessible muscles. The implications are broad but could include the study of a new range of muscles in disorders such as amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

Aim: The Safe Passage Study, conducted by the Prenatal Alcohol in SIDS and Stillbirth Network, is investigating contributions of prenatal alcohol exposure to foetal and infant demise. This current report presents physiological data from full-term infants with no prenatal exposure to alcohol or maternal smoking.Methods: Data are from 666 infants from the Northern Plains (North and South Dakota) and South Africa. A standardised protocol assessed cardiorespiratory function during baseline and head-up tilts shortly after birth and at one month of age.Results: Analyses revealed significant increases in heart rate and decreases in BP from the newborn to one-month time period as well as diminished heart rate responses to head-up tilt in one-month-old infants.Conclusion: The Safe Passage Study was successful in characterising physiology in a large number of infants at sites known to have elevated risks for SIDS. Results demonstrate that even with low prenatal adverse exposures, there are significant changes in cardiorespiratory function as infants enter the window of increased risk for SIDS. [ABSTRACT FROM AUTHOR]

Background: Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia.Methods: Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin-dependent protein kinase 2α-positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg-1 · min-1 for 45 min, eight rats; high dose: 4.5 µg · kg-1 · min-1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg-1 · min-1 for 30 min, seven rats; high dose: 4 mg · kg-1 · min-1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed.Results: Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide - saline] during dexmedetomidine infusion = -6.06 [99% CI = -12.36 to -1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [-1.93, -0.87] dB, 99% CI = [-4.16 to -0.56, -1.62 to -0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [-20.06 to 14.14, -20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: -3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016).Conclusions: These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic's molecular target.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Objective: To assess characteristics of active motor units (MUs) during volitional vastus medialis (VM) activation in adults with symptomatic knee osteoarthritis (OA) across the spectrum of radiographic severity and age-comparable healthy control volunteers.Methods: We evaluated 39 participants (age 65+/-3 years) in whom weight-bearing knee X-rays were assigned a Kellgren & Lawrence (KL) grade (18 with KL grade=0; four each with KL grades=1, 2 and 4; nine with grade 3). Electromyography (EMG) signals were simultaneously acquired using surface [surface EMG (S-EMG)] and intramuscular needle electrodes, and analyzed by decomposition-enhanced spike-triggered averaging to obtain estimates of size [surface-represented MU action potentials (S-MUAP) area], number [MU recruitment index (MURI)] and firing rates [MU firing rates (mFR)] of active MUs at 10%, 20%, 30% and 50% effort relative to maximum voluntary force [maximal voluntary isometric contraction (MVIC)] during isometric knee extension.Results: Knee extensor MVIC was lower in OA participants, especially at higher KL grades (P=0.05). Taking the observed force differences into account, OA was also associated with activation of larger MUs (S-MUAP area/MVICx%effort; P<0.0001). In contrast, the estimated number of active units (MURI/MVICx%effort) changed differently as effort increased from 10% to 50% and was higher with advanced OA (KL=3, 4) than controls (P=0.0002).Conclusion: VM activation changes at the level of the MU with symptomatic knee OA, and this change is influenced by radiographic severity. Poor muscle quality may explain the pattern observed with higher KL grades, but alternative factors (e.g., nerve or joint injury, physical inactivity or muscle composition changes) should be examined in early OA. [ABSTRACT FROM AUTHOR]

Cervical orthosis is used to immobilize the neck in various disorders such as trauma and post-operation. However, it is still uncertain how cervical orthosis restricts the degree of movement of the cervical spine during swallowing and how they affect swallowing physiology. The purpose of this study was to evaluate these issues using the Philadelphia(®) Collar. We conducted videofluorography of swallowing in 39 healthy subjects (23 men, 16 women; mean age of 34.3 years) with and without cervical orthosis. To compare the two conditions regarding the cervical spine motion, we determined the angular and positional changes of the occipital bone (C0) and each cervical vertebra (C1-C7) from the oral phase to the pharyngeal phase. Similarly, to compare swallowing physiology, we assessed the start and end times and the durations of soft palate elevation, rapid hyoid anterosuperior movement, epiglottis inversion, closure of the laryngeal vestibule, and pharyngoesophageal segment (PES) opening. Finally, we compared the transit times of contrast agent in the two conditions. The respective extensions of C1, C2, and C3 were 0.31°, 0.07°, and 0.05° (mean) with cervical orthosis, and the respective flexions of C1, C2, and C3 were 0.98°, 1.42°, and 0.85° (mean) without. These results suggested that cervical orthosis restricted the flexion of C1-C3. Analysis of swallowing physiology revealed that the average durations of hyoid anterosuperior elevation, epiglottic inversion, and PES opening were prolonged by 0.09, 0.19, and 0.05 s, respectively. In conclusion, the cervical orthosis restricted the movement of the cervical spine during swallowing and changed swallowing physiology. [ABSTRACT FROM AUTHOR]

The prevention of perioperative neurocognitive disorders is a priority for patients, families, clinicians, and researchers. Given the multiple risk factors present throughout the perioperative period, a multicomponent preventative approach may be most effective. The objectives of this narrative review are to highlight the importance of sleep, pain, and cognition on the risk of perioperative neurocognitive disorders and to discuss the evidence behind interventions targeting these modifiable risk factors. Sleep disruption is associated with postoperative delirium, but the benefit of sleep-related interventions is uncertain. Pain is a risk factor for postoperative delirium, but its impact on other postoperative neurocognitive disorders is unknown. Multimodal analgesia and opioid avoidance are emerging as best practices, but data supporting their efficacy to prevent delirium are limited. Poor preoperative cognitive function is a strong predictor of postoperative neurocognitive disorder, and work is ongoing to determine whether it can be modified to prevent perioperative neurocognitive disorders. [ABSTRACT FROM AUTHOR]

Background: Previous studies have established the role of various tissue compartments in the kinetics of inhaled anesthetic uptake and elimination. The role of normal lungs in inhaled anesthetic kinetics is less understood. In juvenile pigs with normal lungs, the authors measured desflurane and sevoflurane washin and washout kinetics at three different ratios of alveolar minute ventilation to cardiac output value. The main hypothesis was that the ventilation/perfusion ratio (VA/Q) of normal lungs influences the kinetics of inhaled anesthetics.Methods: Seven healthy pigs were anesthetized with intravenous anesthetics and mechanically ventilated. Each animal was studied under three different VA/Q conditions: normal, low, and high. For each VA/Q condition, desflurane and sevoflurane were administered at a constant, subanesthetic inspired partial pressure (0.15 volume% for sevoflurane and 0.5 volume% for desflurane) for 45 min. Pulmonary arterial and systemic arterial blood samples were collected at eight time points during uptake, and then at these same times during elimination, for measurement of desflurane and sevoflurane partial pressures. The authors also assessed the effect of VA/Q on paired differences in arterial and mixed venous partial pressures.Results: For desflurane washin, the scaled arterial partial pressure differences between 5 and 0 min were 0.70 ± 0.10, 0.93 ± 0.08, and 0.82 ± 0.07 for the low, normal, and high VA/Q conditions (means, 95% CI). Equivalent measurements for sevoflurane were 0.55 ± 0.06, 0.77 ± 0.04, and 0.75 ± 0.08. For desflurane washout, the scaled arterial partial pressure differences between 0 and 5 min were 0.76 ± 0.04, 0.88 ± 0.02, and 0.92 ± 0.01 for the low, normal, and high VA/Q conditions. Equivalent measurements for sevoflurane were 0.79 ± 0.05, 0.85 ± 0.03, and 0.90 ± 0.03.Conclusions: Kinetics of inhaled anesthetic washin and washout are substantially altered by changes in the global VA/Q ratio for normal lungs.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Background: Patients undergoing surgical procedures are vulnerable to repetitive evoked or ongoing nociceptive barrage. Using functional near infrared spectroscopy, the authors aimed to evaluate the cortical hemodynamic signal power changes during ongoing nociception in healthy awake volunteers and in surgical patients under general anesthesia. The authors hypothesized that ongoing nociception to heat or surgical trauma would induce reductions in the power of cortical low-frequency hemodynamic oscillations in a similar manner as previously reported using functional magnetic resonance imaging for ongoing pain.Methods: Cortical hemodynamic signals during noxious stimuli from the fontopolar cortex were evaluated in two groups: group 1, a healthy/conscious group (n = 15, all males) where ongoing noxious and innocuous heat stimulus was induced by a contact thermode to the dorsum of left hand; and group 2, a patient/unconscious group (n = 13, 3 males) receiving general anesthesia undergoing knee surgery. The fractional power of low-frequency hemodynamic signals was compared across stimulation conditions in the healthy awake group, and between patients who received standard anesthesia and those who received standard anesthesia with additional regional nerve block.Results: A reduction of the total fractional power in both groups-specifically, a decrease in the slow-5 frequency band (0.01 to 0.027 Hz) of oxygenated hemoglobin concentration changes over the frontopolar cortex-was observed during ongoing noxious stimuli in the healthy awake group (paired t test, P = 0.017; effect size, 0.70), and during invasive procedures in the surgery group (paired t test, P = 0.003; effect size, 2.16). The reduction was partially reversed in patients who received a regional nerve block that likely diminished afferent nociceptive activity (two-sample t test, P = 0.002; effect size, 2.34).Conclusions: These results suggest common power changes in slow-wave cortical hemodynamic oscillations during ongoing nociceptive processing in conscious and unconscious states. The observed signal may potentially promote future development of a surrogate signal to assess ongoing nociception under general anesthesia.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Background: Triple antimalarial combination therapies combine potent and rapidly cleared artemisinins or related synthetic ozonides, such as arterolane, with two, more slowly eliminated partner drugs to reduce the risk of resistance. We aimed to assess the safety, tolerability, and efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine and artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Kenyan children.Methods: In this single-centre, open-label, randomised, non-inferiority trial done in Kilifi County Hospital, Kilifi, coastal Kenya, children with uncomplicated Plasmodium falciparum malaria were recruited. Eligible patients were aged 2-12 years and had an asexual parasitaemia of 5000-250 000 parasites per μL. The exclusion criteria included the presence of an acute illness other than malaria, the inability to tolerate oral medications, treatment with an artemisinin derivative in the previous 7 days, a known hypersensitivity or contraindication to any of the study drugs, and a QT interval corrected for heart rate (QTc interval) longer than 450 ms. Patients were randomly assigned (1:1:1), by use of blocks of six, nine, and 12, and opaque, sealed, and sequentially numbered envelopes, to receive either arterolane-piperaquine, arterolane-piperaquine-mefloquine, or artemether-lumefantrine. Laboratory staff, but not the patients, the patients' parents or caregivers, clinical or medical officers, nurses, or trial statistician, were masked to the intervention groups. For 3 days, oral artemether-lumefantrine was administered twice daily (target dose 5-24 mg/kg of bodyweight of artemether and 29-144 mg/kg of bodyweight of lumefantrine), and oral arterolane-piperaquine (arterolane dose 4 mg/kg of bodyweight; piperaquine dose 20 mg/kg of bodyweight) and oral arterolane-piperaquine-mefloquine (mefloquine dose 8 mg/kg of bodyweight) were administered once daily. All patients received 0·25 mg/kg of bodyweight of oral primaquine at hour 24. All patients were admitted to Kilifi County Hospital for at least 3 consecutive days and followed up at day 7 and, thereafter, weekly for up to 42 days. The primary endpoint was 42-day PCR-corrected efficacy, defined as the absence of treatment failure in the first 42 days post-treatment, of arterolane-piperaquine-mefloquine versus artemether-lumefantrine, and, along with safety, was analysed in the intention-to-treat population, which comprised all patients who received at least one dose of a study drug. The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine versus arterolane-piperaquine was an important secondary endpoint and was also analysed in the intention-to-treat population. The non-inferiority margin for the risk difference between treatments was -7%. The study is registered in ClinicalTrials.gov, NCT03452475, and is completed.Findings: Between March 7, 2018, and May 2, 2019, 533 children with P falciparum were screened, of whom 217 were randomly assigned to receive either arterolane-piperaquine (n=73), arterolane-piperaquine-mefloquine (n=72), or artemether-lumefantrine (n=72) and comprised the intention-to-treat population. The 42-day PCR-corrected efficacy after treatment with arterolane-piperaquine-mefloquine (100%, 95% CI 95-100; 72/72) was non-inferior to that after treatment with artemether-lumefantrine (96%, 95% CI 88-99; 69/72; risk difference 4%, 95% CI 0-9; p=0·25). The 42-day PCR-corrected efficacy of arterolane-piperaquine-mefloquine was non-inferior to that of arterolane-piperaquine (100%, 95% CI 95-100; 73/73; risk difference 0%). Vomiting rates in the first hour post-drug administration were significantly higher in patients treated with arterolane-piperaquine (5%, 95% CI 2-9; ten of 203 drug administrations; p=0·0013) or arterolane-piperaquine-mefloquine (5%, 3-9; 11 of 209 drug administrations; p=0·0006) than in patients treated with artemether-lumefantrine (1%, 0-2; three of 415 drug administrations). Upper respiratory tract complaints (n=26 for artemether-lumefantrine; n=19 for arterolane-piperaquine-mefloquine; n=23 for arterolane-piperaquine), headache (n=13; n=4; n=5), and abdominal pain (n=7; n=5; n=5) were the most frequently reported adverse events. There were no deaths.Interpretation: This study shows that arterolane-piperaquine-mefloquine is an efficacious and safe treatment for uncomplicated falciparum malaria in children and could potentially be used to prevent or delay the emergence of antimalarial resistance.Funding: UK Department for International Development, The Wellcome Trust, The Bill & Melinda Gates Foundation, Sun Pharmaceutical Industries. [ABSTRACT FROM AUTHOR]

Background: The paucity of easy-to-use, reliable objective neuromuscular monitors is an obstacle to universal adoption of routine neuromuscular monitoring. Electromyography (EMG) has been proposed as the optimal neuromuscular monitoring technology since it addresses several acceleromyography limitations. This clinical study compared simultaneous neuromuscular responses recorded from induction of neuromuscular block until recovery using the acceleromyography-based TOF-Watch SX and EMG-based TetraGraph.Methods: Fifty consenting patients participated. The acceleromyography and EMG devices analyzed simultaneous contractions (acceleromyography) and muscle action potentials (EMG) from the adductor pollicis muscle by synchronization via fiber optic cable link. Bland-Altman analysis described the agreement between devices during distinct phases of neuromuscular block. The primary endpoint was agreement of acceleromyography- and EMG-derived normalized train-of-four ratios greater than or equal to 80%. Secondary endpoints were agreement in the recovery train-of-four ratio range less than 80% and agreement of baseline train-of-four ratios between the devices.Results: Acceleromyography showed normalized train-of-four ratio greater than or equal to 80% earlier than EMG. When acceleromyography showed train-of-four ratio greater than or equal to 80% (n = 2,929), the bias was 1.3 toward acceleromyography (limits of agreement, -14.0 to 16.6). When EMG showed train-of-four ratio greater than or equal to 80% (n = 2,284), the bias was -0.5 toward EMG (-14.7 to 13.6). In the acceleromyography range train-of-four ratio less than 80% (n = 2,802), the bias was 2.1 (-16.1 to 20.2), and in the EMG range train-of-four ratio less than 80% (n = 3,447), it was 2.6 (-14.4 to 19.6). Baseline train-of-four ratios were higher and more variable with acceleromyography than with EMG.Conclusions: Bias was lower than in previous studies. Limits of agreement were wider than expected because acceleromyography readings varied more than EMG both at baseline and during recovery. The EMG-based monitor had higher precision and greater repeatability than acceleromyography. This difference between monitors was even greater when EMG data were compared to raw (nonnormalized) acceleromyography measurements. The EMG monitor is a better indicator of adequate recovery from neuromuscular block and readiness for safe tracheal extubation than the acceleromyography monitor.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Background: Fluid overload is associated with poor outcomes. Clinicians might be reluctant to initiate diuretic therapy for patients with recent vasopressor use. We estimated the effect on 30-day mortality of withholding or delaying diuretics after vasopressor use in patients with probable fluid overload.Methods: This was a retrospective cohort study of adults admitted to ICUs of an academic medical centre between 2008 and 2012. Using a database of time-stamped patient records, we followed individuals from the time they first required vasopressor support and had >5 L cumulative positive fluid balance (plus additional inclusion/exclusion criteria). We compared mortality under usual care (the mix of care actually delivered in the cohort) and treatment strategies restricting diuretic initiation during and for various durations after vasopressor use. We adjusted for baseline and time-varying confounding via inverse probability weighting.Results: The study included 1501 patients, and the observed 30-day mortality rate was 11%. After adjusting for observed confounders, withholding diuretics for at least 24 h after stopping most recent vasopressor use was estimated to increase 30-day mortality rate by 2.2% (95% confidence interval [CI], 0.9-3.6%) compared with usual care. Data were consistent with moderate harm or slight benefit from withholding diuretic initiation only during concomitant vasopressor use; the estimated mortality rate increased by 0.5% (95% CI, -0.2% to 1.1%).Conclusions: Withholding diuretic initiation after vasopressor use in patients with high cumulative positive balance (>5 L) was estimated to increase 30-day mortality. These findings are hypothesis generating and should be tested in a clinical trial. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is one of the most challenging diseases causing an increasing burden worldwide. Although the neuropathologic diagnosis of AD has been established for many years, the metabolic changes in neuropathologic diagnosed AD samples have not been fully investigated.Objective: To elucidate the potential metabolism dysregulation in the postmortem human brain samples assessed by AD related pathological examination.Methods: We performed untargeted and targeted metabolomics in 44 postmortem human brain tissues. The metabolic differences in the hippocampus between AD group and control (NC) group were compared.Results: The results show that a pervasive metabolic dysregulation including phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, biotin metabolism, and purine metabolism are associated with AD pathology. Targeted metabolomics reveal that phenylalanine, phenylpyruvic acid, and N-acetyl-L-phenylalanine are upregulated in AD samples. In addition, the enzyme IL-4I1 catalyzing transformation from phenylalanine to phenylpyruvic acid is also upregulated in AD samples.Conclusion: There is a pervasive metabolic dysregulation in hippocampus with AD-related pathological changes. Our study suggests that the dysregulation of phenylalanine metabolism in hippocampus may be an important pathogenesis for AD pathology formation. [ABSTRACT FROM AUTHOR]

Background: The γ-aminobutyric acid-mediated (GABAergic) inhibitory system in the brain is critical for regulation of sleep-wake and general anesthesia. The lateral septum contains mainly GABAergic neurons, being cytoarchitectonically divided into the dorsal, intermediate, and ventral parts. This study hypothesized that GABAergic neurons of the lateral septum participate in the control of wakefulness and promote recovery from anesthesia.Methods: By employing fiber photometry, chemogenetic and optogenetic neuronal manipulations, anterograde tracing, in vivo electrophysiology, and electroencephalogram/electromyography recordings in adult male mice, the authors measured the role of lateral septum GABAergic neurons to the control of sleep-wake transition and anesthesia emergence and the corresponding neuron circuits in arousal and emergence control.Results: The GABAergic neurons of the lateral septum exhibited high activities during the awake state by in vivo fiber photometry recordings (awake vs. non-rapid eye movement sleep: 3.3 ± 1.4% vs. -1.3 ± 1.2%, P < 0.001, n = 7 mice/group; awake vs. anesthesia: 2.6 ± 1.2% vs. -1.3 ± 0.8%, P < 0.001, n = 7 mice/group). Using chemogenetic stimulation of lateral septum GABAergic neurons resulted in a 100.5% increase in wakefulness and a 51.2% reduction in non-rapid eye movement sleep. Optogenetic activation of these GABAergic neurons promoted wakefulness from sleep (median [25th, 75th percentiles]: 153.0 [115.9, 179.7] s to 4.0 [3.4, 4.6] s, P = 0.009, n = 5 mice/group) and accelerated emergence from isoflurane anesthesia (514.4 ± 122.2 s vs. 226.5 ± 53.3 s, P < 0.001, n = 8 mice/group). Furthermore, the authors demonstrated that the lateral septum GABAergic neurons send 70.7% (228 of 323 cells) of monosynaptic projections to the ventral tegmental area GABAergic neurons, preferentially inhibiting their activities and thus regulating wakefulness and isoflurane anesthesia depth.Conclusions: The results uncover a fundamental role of the lateral septum GABAergic neurons and their circuit in maintaining awake state and promoting general anesthesia emergence time.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes-thus impeding Lafora bodies accumulation in this cell type-prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons. [ABSTRACT FROM AUTHOR]

Background: Studies performed shortly after anti-reflux surgery have demonstrated that the reduction of reflux episodes is caused by a decrease in the rate of transient lower esophageal sphincter relaxations (TLESRs) and a decrease in the distensibility of the esophagogastric junction (EGJ). We aimed to assess the long-term effects of surgical fundoplication on the physiology of the EGJ.Methods: We included 18 patients who underwent surgical fundoplication >5 years before and 10 GERD patients who did not have surgery. Patients underwent 90-min combined high-resolution manometry and pH-impedance monitoring, and EGJ distensibility was assessed.Results: Post-fundoplication patients exhibited a lower frequency of reflux events than GERD patients (2.0 ± 0.5 vs 15.1 ± 4.3, p < 0.05). The rate of TLESRs (6.1 ± 0.9 vs 12.6 ± 1.0, p < 0.05) and their association with reflux (28.3 ± 9.0 vs 74.9 ± 6.9 %, p < 0.05) was lower in post-fundoplication patients than in GERD patients. EGJ distensibility was significantly lower in post-fundoplication patients than in GERD patients. Recurrence of GERD symptoms after fundoplication was not associated with an increased number of reflux episodes, nor was it associated with an increased distensibility of the EGJ or an increase in the number of TLESRs.Conclusion: More than 5 years after anti-reflux surgery, patients still exhibit a lower rate of TLESRs and a reduced distensibility of the EGJ compared with medically treated GERD patients. These data suggest that the effects of surgical fundoplication on EGJ physiology persist at the long term and underlie the persistent reduction of reflux events. [ABSTRACT FROM AUTHOR]

Purpose: To establish the optimum grading increment which ensured parity between practitioners while maximising clinical precision.Methods: Second year optometry students (n = 127, 19.5 ± 1.4 years, 55 % female) and qualified eye care practitioners (n = 61, 40.2 ± 14.8 years, 52 % female) had 30 s to grade each of bulbar, limbal and palpebral hyperaemia of the upper lid of 4 patients imaged live with a digital slit lamp under 16× magnification, diffuse illumination, with the image projected on a screen. The patients were presented in a randomised sequence 3 times in succession, during which the graders used the Efron printed grading scale once to the nearest 0.1 increment, once to nearest 0.5 increment and once to the nearest integer grade in a randomised order. Graders were masked to their previous responses.Results: For most grading conditions less than 20 % of clinicians showed a ≤0.1 difference in grade from the mean. In contrast, more than 50 % of the student graders and 40 % of experienced graders showed a difference in grade from the mean within 0.5 for all conditions under measurement. Student precision in grading was better with both 0.1 and 0.5 grading increments than grading to the nearest unit, except for limbal hyperaemia where they performed more accurately with 0.5 unit increment grading. Limbal grading precision was not affected by grading step increment for experienced practitioners, but 0.1 and 0.5 grading increments were both better than the 1.0 grading increment for bulbar hyperaemia and the 0.1 grading increment was better than the 0.5 grading increment and both were better than the 1.0 grading increment for palpebral hyperaemia.Conclusion: Although narrower interval scales maximise the ability to detect smaller clinical changes, the grading increment should not exceed one standard deviation of the discrepancy between measurements. Therefore, 0.5 grading increments are recommended for subjective anterior eye physiology grading (limbal, bulbar and palpebral redness). [ABSTRACT FROM AUTHOR]

Study Question: Is there a relationship between blastocyst metabolism and biomarkers of embryo viability?Summary Answer: Blastocysts with higher developmental potential and a higher probability of resulting in a viable pregnancy consume higher levels of glucose and exhibit distinct amino acid profiles.What Is Known Already: Morphological and morphokinetic analyses utilized in embryo selection provide insight into developmental potential, but alone are unable to provide a direct measure of embryo physiology and inherent health. Glucose uptake is a physiological biomarker of viability and amino acid utilization is different between embryos of varying qualities.Study Design, Size, Duration: Two hundred and nine human preimplantation embryos from 50 patients were cultured in a time-lapse incubator system in both freeze all and fresh transfer cycles. A retrospective analysis of morphokinetics, morphology (Gardner grade), KIDScore, artificial intelligence grade (EmbryoScore), glucose and amino acid metabolism, and clinical pregnancies was conducted.Participants/materials, Setting, Methods: ICSI was conducted in all patients, who were aged ≤37 years and previously had no more than two IVF cycles. Embryos were individually cultured in a time-lapse incubator system, and those reaching the blastocyst stage had their morphokinetics annotated and were each assigned a Gardner grade, KIDScore and EmbryoScore. Glucose and amino acid metabolism were measured. Clinical pregnancies were confirmed by the presence of a fetal heartbeat at 6 weeks of gestation.Main Results and the Role Of Chance: Glucose consumption was at least 40% higher in blastocysts deemed of high developmental potential using either the Gardner grade (P < 0.01, n = 209), KIDScore (P < 0.05, n = 207) or EmbryoScore (P < 0.05, n = 184), compared to less viable blastocysts and in blastocysts that resulted in a clinical pregnancy compared to those that failed to implant (P < 0.05, n = 37). Additionally, duration of cavitation was inversely related to glucose consumption (P < 0.05, n = 200). Total amino acid consumption was significantly higher in blastocysts with an EmbryoScore higher than the cohort median score (P < 0.01, n = 185). Furthermore, the production of amino acids was significantly lower in blastocysts with a high Gardner grade (P < 0.05, n = 209), KIDScore (P < 0.05, n = 207) and EmbryoScore (P < 0.01, n = 184).Limitations, Reasons For Caution: Samples were collected from patients who had ICSI treatment and from only one clinic.Wider Implications Of the Findings: These results confirm that metabolites, such as glucose and amino acids, are valid biomarkers of embryo viability and could therefore be used in conjunction with other systems to aid in the selection of a healthy embryo.Study Funding/competing Interest(s): Work was supported by Virtus Health. D.K.G is contracted with Virtus Health. The other authors have no conflict of interest to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Understanding the physiological mechanisms by which common variants predispose to type 2 diabetes requires large studies with detailed measures of insulin secretion and sensitivity. Here we performed the largest genome-wide association study of first-phase insulin secretion, as measured by intravenous glucose tolerance tests, using up to 5,567 individuals without diabetes from 10 studies. We aimed to refine the mechanisms of 178 known associations between common variants and glycemic traits and identify new loci. Thirty type 2 diabetes or fasting glucose-raising alleles were associated with a measure of first-phase insulin secretion at P < 0.05 and provided new evidence, or the strongest evidence yet, that insulin secretion, intrinsic to the islet cells, is a key mechanism underlying the associations at the HNF1A, IGF2BP2, KCNQ1, HNF1B, VPS13C/C2CD4A, FAF1, PTPRD, AP3S2, KCNK16, MAEA, LPP, WFS1, and TMPRSS6 loci. The fasting glucose-raising allele near PDX1, a known key insulin transcription factor, was strongly associated with lower first-phase insulin secretion but has no evidence for an effect on type 2 diabetes risk. The diabetes risk allele at TCF7L2 was associated with a stronger effect on peak insulin response than on C-peptide-based insulin secretion rate, suggesting a possible additional role in hepatic insulin clearance or insulin processing. In summary, our study provides further insight into the mechanisms by which common genetic variation influences type 2 diabetes risk and glycemic traits. [ABSTRACT FROM AUTHOR]

Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer's disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β peptide (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility needs further exploration.Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction.Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in slices. Olfaction was assessed through the habituation/dishabituation test.Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in slices.Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD. [ABSTRACT FROM AUTHOR]

Objective: To examine children's sugar-sweetened beverage (SSB) and water intakes in relation to implemented intervention activities across the social ecological model (SEM) during a multilevel community trial.Design: Children's Healthy Living was a multilevel, multicomponent community trial that reduced young child obesity (2013-2015). Baseline and 24-month cross-sectional data were analysed from nine intervention arm communities. Implemented intervention activities targeting reduced SSB and increased water consumption were coded by SEM level (child, caregiver, organisation, community and policy). Child SSB and water intakes were assessed by caregiver-completed 2-day dietary records. Multilevel linear regression models examined associations of changes in beverage intakes with activity frequencies at each SEM level.Setting: US-Affiliated Pacific region.Participants: Children aged 2-8 years (baseline: n 1343; 24 months: n 1158).Results: On average (± sd), communities implemented 74 ± 39 SSB and 72 ± 40 water activities. More than 90 % of activities targeted both beverages together. Community-level activities (e.g. social marketing campaign) were most common (61 % of total activities), and child-level activities (e.g. sugar counting game) were least common (4 %). SSB activities across SEM levels were not associated with SSB intake changes. Additional community-level water activities were associated with increased water intake (0·62 ml/d/activity; 95 % CI: 0·09, 1·15) and water-for-SSB substitution (operationalised as SSB minus water: -0·88 ml/d/activity; 95 % CI: -1·72, -0·03). Activities implemented at the organization level (e.g. strengthening preschool wellness guidelines) and policy level (e.g. SSB tax advocacy) also suggested greater water-for-SSB substitution (P < 0·10).Conclusions: Community-level intervention activities were associated with increased water intake, alone and relative to SSB intake, among young children in the Pacific region. [ABSTRACT FROM AUTHOR]

Hippo pathway is a master regulator of development, cell proliferation, stem cell function, tissue regeneration, homeostasis, and organ size control. Hippo pathway relays signals from different extracellular and intracellular events to regulate cell behavior and functions. Hippo pathway is conserved from Protista to eukaryotes. Deregulation of the Hippo pathway is associated with numerous cancers. Alteration of the Hippo pathway results in cell invasion, migration, disease progression, and therapy resistance in cancers. However, the function of the various components of the mammalian Hippo pathway is yet to be elucidated in detail especially concerning tumor biology. In the present review, we focused on the Hippo pathway in different model organisms, its regulation and deregulation, and possible therapeutic targets for cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease. One of the pathologies of AD is the accumulation of amyloid-β (Aβ) to form senile plaques, leading to a decline in cognitive ability and a lack of learning and memory. However, the cause leading to Aβ aggregation is not well understood. Dendritic cell factor 1 (Dcf1) shows a high expression in the entorhinal cortex neurons and neurofibrillary tangles in AD patients.Objective: Our goal is to investigate the effect of Dcf1 on Aβ aggregation and memory deficits in AD development.Methods: The mouse and Drosophila AD model were used to test the expression and aggregation of Aβ, senile plaque formation, and pathological changes in cognitive behavior during dcf1 knockout and expression. We finally explored possible drug target effects through intracerebroventricular delivery of Dcf1 antibodies.Results: Deletion of Dcf1 resulted in decreased Aβ42 level and deposition, and rescued AMPA Receptor (GluA2) levels in the hippocampus of APP-PS1-AD mice. In Aβ42 AD Drosophila, the expression of Dcf1 in Aβ42 AD flies aggravated the formation and accumulation of senile plaques, significantly reduced its climbing ability and learning-memory. Data analysis from all 20 donors with and without AD patients aged between 80 and 90 indicated a high-level expression of Dcf1 in the temporal neocortex. Dcf1 contributed to Aβ aggregation by UV spectroscopy assay. Intracerebroventricular delivery of Dcf1 antibodies in the hippocampus reduced the area of senile plaques and reversed learning and memory deficits in APP-PS1-AD mice.Conclusion: Dcf1 causes Aβ-plaque accumulation, inhibiting dcf1 expression could potentially offer therapeutic avenues. [ABSTRACT FROM AUTHOR]

Background: Further exploration of the possible effects of vegetable intake on kidney function is warranted.Objective: We aimed to study the causality of the association between vegetable intake and kidney function by implementing Mendelian randomization (MR) analysis.Methods: This study comprised a cross-sectional dietary investigation using UK Biobank data and MR analysis. For the cross-sectional investigation, 432,732 participants aged 40-69 y from the UK Biobank cohort were included. Self-reported vegetable intake was the exposure, and the outcomes were the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). Next, we included 337,138 participants of white British ancestry in the UK Biobank, and a genome-wide association study (GWAS) was performed to generate a genetic instrument. For MR, we first performed polygenic score (PGS)-based 1-sample MR. In addition, 2-sample MR was performed with CKDGen GWAS for kidney function traits, and the inverse variance weighted method was the main MR method.Results: Higher vegetable intake was cross-sectionally associated with a higher eGFR (per heaped tablespoon increase; β: 0.154; 95% CI: 0.144, 0.165) and lower odds of CKD (OR: 0.975; 95% CI: 0.968, 0.982). A PGS for vegetable intake was significantly associated with a higher eGFR [per ordinal category increase (0, 1-3, 4-6, ≥7 tablespoons per day); β: 4.435; 95% CI: 2.337, 6.533], but the association with CKD remained nonsignificant (OR: 0.468; 95% CI: 0.143, 1.535). In the 2-sample MR, the causal estimates indicated that a higher genetically predicted vegetable intake was associated with a higher eGFR (percent change; β: 3.071; 95% CI: 0.602, 0.560) but nonsignificantly associated with the risk of CKD (OR: 0.560; 95% CI: 0.289, 1.083) in the European ancestry data from the CKDGen.Conclusions: This study suggests that higher vegetable intake may have a causal effect on higher eGFRs in the European population. [ABSTRACT FROM AUTHOR]

Background: OSA is common in chronic kidney disease (CKD) and may accelerate a decline in kidney function. It is not clear whether treatment of OSA with CPAP improves kidney function.Research Question: Does treatment with CPAP improve kidney function in patients with CKD and coexisting OSA?Study Design and Methods: A randomized, controlled, nonblinded, parallel clinical trial was performed of patients with stages 3 and 4 CKD and coexisting OSA comparing the effect of CPAP vs usual care on the estimated glomerular filtration rate (eGFR) and the urine albumin to creatinine ratio (ACR) over 12 months.Results: Fifty-seven patients were enrolled and 30 were randomized to CPAP. They had moderately severe CKD (eGFR, 38.4 ± 1.5 mL/min/1.73 m2) and significant OSA and nocturnal hypoxemia (oxygen desaturation index: 23.9 events/h; interquartile range [IQR], 20.3 events/h; mean peripheral capillary oxygen saturation: 89.5%; IQR, 1.7%); 60% had baseline albuminuria (ACR, > 3 mg/mmol). No significant difference was found between CPAP and usual care in the change in eGFR and ACR over 12 months. Although some improvement in eGFR occurred with CPAP therapy in patients with a lower risk of CKD progression, this did not reach statistical significance.Interpretation: Although CPAP did not provide additional renal benefits over usual care in all CKD patients, some evidence suggested that CPAP slowed the decline in eGFR in CKD patients with a lower risk of CKD progression. These preliminary data support the need for larger clinical trials exploring the effects of CPAP on kidney function.Trial Registry: ClinicalTrials.gov; No.: NCT02420184; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Objective: Exercise-induced cardiac dysfunction and corollary biomarker release have been documented following long-distance running events. To what degree these processes occur during shorter distance running events is unknown.Methods: 72 healthy recreational runners (54% male/46% female) recruited by age (group 1 (18-20 years old, N=19); group 2 (45-50 years old, N=27); group 3 (70-75 years old, N=26)) were studied with echocardiography and biochemical profiling during participation in a 10 km running race.Results: Despite age-dependent baseline differences in ventricular size and diastolic tissue velocities, there were no significant within group or across group decrements in ventricular systolic or diastolic function following race completion. Postrace increases in cardiac troponin-I (cTnI), B-type natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP) were common and demonstrated distinct age dependent profiles. Specifically, BNP increases were most pronounced among older runners (group 3Δ: 16±22 pg/mL, p=0.001), hs-CRP increased only among younger runners (group 1Δ: 1.5±2.7 mg/L, p=0.03) and cTnI increased in both younger (group 1Δ: 0.01±0.02 ng/mL, p=0.028) and older (group 3Δ: 0.01±0.01 ng/mL, p=0.007) runners, but not middle aged runners (group 2Δ: 0.00±0.00 ng/mL, p=0.57).Conclusions: Moderate distance recreational running leads to distinct age-dependent biomarker release but is not associated with cardiac fatigue, a proposed stimulus for pathologic cardiac remodelling that has been observed following longer distance running events. [ABSTRACT FROM AUTHOR]

Background: Noninvasive monitoring of fetal development and the early detection of pregnancy-associated complications is challenging, largely because of the lack of information about the molecular spectrum during pregnancy. Recently, cell-free DNA in plasma was found to reflect the global nucleosome footprint and status of gene expression and showed potential for noninvasive health monitoring during pregnancy.Objective: We aimed to test the relationships between plasma cell-free DNA profiles and pregnancy biology and evaluate the use of a cell-free DNA profile as a noninvasive method for physiological and pathologic status monitoring during pregnancy.Study Design: We used genome cell-free DNA sequencing data generated from noninvasive prenatal testing in a total of 2937 pregnant women. For each physiological and pathologic condition, features of the cell-free DNA profile were identified using the discovery cohort, and support vector machine classifiers were built and evaluated using independent training and validation cohorts.Results: We established nucleosome occupancy profiles at transcription start sites in different gestational trimesters, demonstrated the relationships between gene expression and cell-free DNA coverage at transcription start sites, and showed that the cell-free DNA profiles at transcription start sites represented the biological processes of pregnancy. In addition, using cell-free DNA data, nucleosome profiles of transcription factor binding sites were identified to reflect the transcription factor footprint, which may help to reveal the molecular mechanisms underlying pregnancy. Finally, by using machine-learning models on low-coverage noninvasive prenatal testing data, we evaluated the use of cell-free DNA nucleosome profiles for distinguishing gestational trimesters, fetal sex, and fetal trisomy 21 and highlighted its potential utility for predicting physiological and pathologic fetal conditions by using low-coverage noninvasive prenatal testing data.Conclusion: Our analyses profiled nucleosome footprints and regulatory networks during pregnancy and established a noninvasive proof-of-principle methodology for health monitoring during pregnancy. [ABSTRACT FROM AUTHOR]

Background: Veno-arterial extracorporeal membrane oxygenation therapy is a growing treatment modality for acute cardiorespiratory failure. Cardiac output monitoring during veno-arterial extracorporeal membrane oxygenation therapy remains challenging. This study aims to validate a new thermodilution technique during veno-arterial extracorporeal membrane oxygenation therapy using a pig model.Methods: Sixteen healthy pigs were centrally cannulated for veno-arterial extracorporeal membrane oxygenation, and precision flow probes for blood flow assessment were placed on the pulmonary artery. After chest closure, cold boluses of 0.9% saline solution were injected into the extracorporeal membrane oxygenation circuit, right atrium, and right ventricle at different extracorporeal membrane oxygenation flows (4, 3, 2, 1 l/min). Rapid response thermistors in the extracorporeal membrane oxygenation circuit and pulmonary artery recorded the temperature change. After calculating catheter constants, the distributions of injection volumes passing each circuit were assessed and enabled calculation of pulmonary blood flow. Analysis of the exponential temperature decay allowed assessment of right ventricular function.Results: Calculated blood flow correlated well with measured blood flow (r2 = 0.74, P < 0.001). Bias was -6 ml/min [95% CI ± 48 ml/min] with clinically acceptable limits of agreement (668 ml/min [95% CI ± 166 ml/min]). Percentage error varied with extracorporeal membrane oxygenation blood flow reductions, yielding an overall percentage error of 32.1% and a percentage error of 24.3% at low extracorporeal membrane oxygenation blood flows. Right ventricular ejection fraction was 17 [14 to 20.0]%. Extracorporeal membrane oxygenation flow reductions increased end-diastolic and end-systolic volumes with reductions in pulmonary vascular resistance. Central venous pressure and right ventricular ejection fractions remained unchanged. End-diastolic and end-systolic volumes correlated highly (r2 = 0.98, P < 0.001).Conclusions: Adapted thermodilution allows reliable assessment of cardiac output and right ventricular behavior. During veno-arterial extracorporeal membrane oxygenation weaning, the right ventricle dilates even with stable function, possibly because of increased venous return.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a disease of the entire joint involving synovial fibrosis and inflammation. Pathological changes to the synovium can accelerate the progression of OA. Pirfenidone (PFD) is a potent anti-fibrotic drug with additional anti-inflammatory properties. However, the influence of PFD on OA is unknown.Methods: Proliferation of human fibroblast-like synoviocytes (FLSs) after treatment with TGF-β1 or PFD was evaluated using a Cell Counting Kit-8 assay and their migration using a Transwell assay. The expression of fibrosis-related genes (COL1A1, TIMP-1, and ACTA-2) and those related to inflammation (IL-6 and TNF-α) was quantified by real-time quantitative PCR. The protein expression levels of COL1A1, α-SMA (coded by ACTA-2), IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay. A rabbit model of OA was established and then PFD was administered by gavage. The expression of genes related to fibrosis (COL1A1, TIMP-1, and ADAM-12) and inflammation (IL-6 and TNF-α) was measured using RNA extracted from the synovium. Synovial tissue was examined histologically after staining with H&E, Masson's trichrome, and immunofluorescence. Synovitis scores, the volume fraction of collagen, and mean fluorescence intensity were calculated. Degeneration of articular cartilage was analyzed using a Safranin O-fast green stain and OARSI grading.Results: The proliferation of FLSs was greatest when induced with 2.5 ng/ml TGF-β1 although it did not promote their migration. Therefore, 2.5 ng/ml TGF-β1 was used to stimulate the FLSs and evaluate the effects of PFD, which inhibited the migration of FLSs at concentrations as low as 1.0 mg/ml. PFD decreased the expression of COL1A1 while TGF-β1 increased both mRNA and protein expression levels of IL-6 but had no effect on α-SMA or TNF-α expression. PFD decreased mRNA expression levels of COL1A1, IL-6, and TNF-α in vivo. H&E staining and synovitis scores indicated that PFD reduced synovial inflammation, while Masson's trichrome and immunofluorescence staining suggested that PFD decreased synovial fibrosis. Safranin O-Fast Green staining and the OARSI scores demonstrated that PFD delayed the progression of OA.Conclusions: PFD attenuated synovial fibrosis and inflammation, and postponed the progression of osteoarthritis in a modified Hulth model of OA in rabbits, which was related to its anti-fibrotic and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Background: In-season return to play after anterior glenohumeral instability is associated with high rates of recurrent instability and the need for surgical stabilization. We are not aware of previous studies that have investigated in-season return to play after posterior glenohumeral instability; furthermore, as posterior shoulder instability in collision athletes occurs frequently, understanding the expected outcome of in-season athletes may improve the ability of physicians to provide athletes with a better understanding of the expected outcome of their injury and their ability to return to sport.Questions/purposes: (1) What proportion of athletes returned to play during the season after posterior instability in collegiate football players? (2) How much time did athletes lose to injury, what proportion of athletes opted to undergo surgery, and what proportion of athletes experienced recurrent instability after a posterior instability episode during a collegiate football season?Methods: A multicenter, prospective, observational study of National Collegiate Athletic Association (NCAA) Division 1 Football Bowl Subdivision athletes was performed at three US Military Service Academies. Ten athletes who sustained a posterior instability event during the regular football season and who pursued a course of nonoperative treatment were identified and prospectively observed through the subsequent season. All athletes in the observed cohort attempted an initial course of nonoperative treatment during the season. All athletes sustained subluxation events initially identified through history and physical examination at the time of injury. None of the athletes sustained a dislocation event requiring a manual reduction. Intraarticular pathology consisting of posterior labral pathology was further subsequently identified in all subjects via MRI arthrogram. Return to play was the primary outcome of interest. Time lost to injury, surgical intervention, and subsequent instability were secondary outcomes.Results: Of the 10 athletes who opted for a trial of initial nonoperative management, seven athletes were able to return to play during the same season. Although these seven athletes returned within 1 week of their injury (median of 1 day), 5 of 7 athletes sustained recurrent subluxation events with a median (range) of four subluxation events per athlete (0 to 8) during the remainder of the season. Seven athletes were treated surgically after the completion of their season, four of whom returned to football.Conclusion: This study suggests that although collegiate football players are able to return to in-season sport after a posterior glenohumeral instability event, they will likely sustain multiple recurrent instability events and undergo surgery after the season is completed. The results of this study can help guide in-season management of posterior shoulder instability by allowing more appropriate postinjury counseling and decision making through the identification of those athletes who may require additional attention from medical staff during the season and possible modifications to training regimens to minimize long-term disability. Further prospective studies involving a larger cohort over several seasons should be performed through collaborative studies across the NCAA that better assess function and injury risk factors before beginning collegiate athletics. This would better characterize the natural history and associated functional limitations that athletes may encounter during their collegiate careers.Level Of Evidence: Level IV, prognostic study. [ABSTRACT FROM AUTHOR]

Objective: To determine whether follicle flushing during oocyte retrieval improves live birth or secondary outcomes in assisted reproductive technology (ART).Design: Systematic review and meta-analysis.Setting: Not applicable.Patient(s): Women undergoing ART using autologous gametes.Intervention(s): A systematic search of PubMed, EMBASE, Cochrane Database, and Web of Science for randomized controlled trials comparing follicle flushing to direct aspiration during oocyte retrieval published in English between 1989 to 2020.Main Outcome Measure(s): Live birth as primary outcome, and clinical and ongoing pregnancy, total and mature metaphase II (MII) oocytes retrieved, and operating time as secondary outcomes.Result(s): Eleven studies were included totaling 1,178 cases. No difference in live birth was demonstrated between follicle flushing and direct aspiration. Clinical pregnancy and ongoing pregnancy were not improved with flushing. Total oocyte and MII yield were lower with flushing compared with direct aspiration. Procedure time was increased with flushing by 2 minutes in poor responders and 9 minutes in normal responders. Other sensitivity analyses did not demonstrate any changes, except the difference in MII yield was no longer statistically significant.Conclusion(s): Follicle flushing during oocyte retrieval increases procedure time and does not improve live birth or secondary ART outcomes. Randomized data do not support the use of follicle flushing as an intervention in ART. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) comprise a class of RNAs that do not code for proteins but are critical in regulating diverse cellular processes and maintaining cell function. In doing so, they have, in recent years, added a potentially new and significant layer of biological regulation. These are more than 200 nucleotides in length and are implicated in a range of diseases and therefore have emerged as potential tools for possible therapeutic intervention. For a disease as complex as cancer, emerging technologies suggest the presence of mutations on genomic loci that do not encode proteins, but give rise to lncRNAs. Aberrant signatures of lncRNAs are now a consistent feature of almost all types of cancers and their associated complications. Analysis and characterisation of functional pathways that lncRNAs are involved with suggest that lncRNAs interact with the chromatin, the protein or with the RNA to demonstrate their cellular effects to modulate proliferation, migration, differentiation, apoptosis and cell death. This review summarizes the current knowledge of lncRNAs, their implications in diverse types of cancer and their possible therapeutic utility. [ABSTRACT FROM AUTHOR]

Background: Treatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood.Objectives: The purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF.Methods: In 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term.Results: WRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF.Conclusions: Among HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF. [ABSTRACT FROM AUTHOR]

The 24 kD form of secreted phosphoprotein (SPP-24), a cytokine-binding bone matrix protein with various truncated C-terminal products, is primarily synthesized by the liver. SPP-24 shares homology with fetuin-A, a potent vascular and soft tissue calcification inhibitor and SPP-24 is one component of calciprotein particles (CPPs), a circulating fetuin-mineral complex. The limited molecular evidence to date suggests that SPP-24 may also function as an inhibitor of bone formation and ectopic vascular calcification, potentially through bone morphogenic protein 2 (BMP-2) and Wnt-signaling mediated actions. The C-terminal products of SPP-24 bind to BMP-2 and attenuate BMP-2-induced bone formation. The aim of this study was to assess circulating SPP-24 in relation to kidney function and in concert with markers of mineral metabolism in humans. SPP-24 was measured in the serum of total of 192 subjects using ELISA-based measurements. Subjects were participants of one of two cohorts: (1) mGFR Cohort (n = 80) was participants of a study of measured GFR (mGFR) using inulin urinary clearance, recruited mostly from a chronic kidney disease clinic with low-range kidney function (eGFR 38.7 ± 25.0 mL/min/1.73 m2) and (2) CaMOS Cohort (n = 112) was a subset of randomly selected, community-dwelling participants of year 10 of the Canadian Multicentre Osteoporosis Study with eGFR in the normal range of 75.0 ± 15.9 mL/min/1.73 m2. In the combined cohort, the mean SPP-24 was 167.7 ± 101.1 ng/mL (range 33.4-633.6 ng/mL). The mean age was 66.5 ± 11.3, 57.1% female and mean eGFR (CKD-EPI) was 59.9 ± 27.0 mL/min/1.73 m2 (range 8-122 mL/min/1.73 m2). There was a strong inverse correlation between SPP-24 and eGFR (R = - 0.58, p < 0.001) that remained after adjustment for age. Following adjustment for age, eGFR, and sex, SPP-24 was significantly associated with phosphate (R = - 0.199), PTH (R = 0.298), and the Wnt-signaling inhibitor Dickkopf-related protein 1 (R = - 0.156). The results of this study indicate that SPP-24 is significantly altered by kidney function and is the first human data linking levels of SPP-24 to other biomarkers involved in mineral metabolism. Whether there is a role for circulating SPP-24 in bone formation and ectopic mineralization requires further study. [ABSTRACT FROM AUTHOR]

Background: The ultimate validation of a clinical marker for Alzheimer's disease (AD) is its association with AD neuropathology.Objective: To identify clinical measures that predict pathology, we evaluated the relationships of the picture version of the Free and Cued Selective Reminding Test (pFCSRT + IR), the Mini-Mental State Exam (MMSE), and the Clinical Dementia Rating scale Sum of Boxes (CDR-SB) to Braak stage.Methods: 315 cases from the clinicopathologic series at the Knight Alzheimer's Disease Research Center were classified according to Braak stage. Boxplots of each predictor were compared to identify the earliest stage at which decline was observed and ordinal logistic regression was used to predict Braak stage.Results: Looking at the assessment closest to death, free recall scores were lower in individuals at Braak stage III versus Braak stages 0 and I (combined) while MMSE and CDR scores for individuals did not differ from Braak stages 0/I until Braak stage IV. The sum of free recall and total recall scores independently predicted Braak stage and had higher predictive validity than MMSE and CDR-SB in models including all three.Conclusion: pFCSRT + IR scores may be more sensitive to early pathological changes than either the CDR-SB or the MMSE. [ABSTRACT FROM AUTHOR]

Importance: Thigh muscle weakness is associated with knee discomfort and osteoarthritis disease progression. Little is known about the efficacy of high-intensity strength training in patients with knee osteoarthritis or whether it may worsen knee symptoms.Objective: To determine whether high-intensity strength training reduces knee pain and knee joint compressive forces more than low-intensity strength training and more than attention control in patients with knee osteoarthritis.Design, Setting, and Participants: Assessor-blinded randomized clinical trial conducted at a university research center in North Carolina that included 377 community-dwelling adults (≥50 years) with body mass index (BMI) ranging from 20 to 45 and with knee pain and radiographic knee osteoarthritis. Enrollment occurred between July 2012 and February 2016, and follow-up was completed September 2017.Interventions: Participants were randomized to high-intensity strength training (n = 127), low-intensity strength training (n = 126), or attention control (n = 124).Main Outcomes and Measures: Primary outcomes at the 18-month follow-up were Western Ontario McMaster Universities Osteoarthritis Index (WOMAC) knee pain (0 best-20 worst; minimally clinically important difference [MCID, 2]) and knee joint compressive force, defined as the maximal tibiofemoral contact force exerted along the long axis of the tibia during walking (MCID, unknown).Results: Among 377 randomized participants (mean age, 65 years; 151 women [40%]), 320 (85%) completed the trial. Mean adjusted (sex, baseline BMI, baseline outcome values) WOMAC pain scores at the 18-month follow-up were not statistically significantly different between the high-intensity group and the control group (5.1 vs 4.9; adjusted difference, 0.2; 95% CI, -0.6 to 1.1; P = .61) or between the high-intensity and low-intensity groups (5.1 vs 4.4; adjusted difference, 0.7; 95% CI, -0.1 to 1.6; P = .08). Mean knee joint compressive forces were not statistically significantly different between the high-intensity group and the control group (2453 N vs 2512 N; adjusted difference, -58; 95% CI, -282 to 165 N; P = .61), or between the high-intensity and low-intensity groups (2453 N vs 2475 N; adjusted difference, -21; 95% CI, -235 to 193 N; P = .85). There were 87 nonserious adverse events (high-intensity, 53; low-intensity, 30; control, 4) and 13 serious adverse events unrelated to the study (high-intensity, 5; low-intensity, 3; control, 5).Conclusions and Relevance: Among patients with knee osteoarthritis, high-intensity strength training compared with low-intensity strength training or an attention control did not significantly reduce knee pain or knee joint compressive forces at 18 months. The findings do not support the use of high-intensity strength training over low-intensity strength training or an attention control in adults with knee osteoarthritis.Trial Registration: ClinicalTrials.gov Identifier: NCT01489462. [ABSTRACT FROM AUTHOR]

De novo phospholipogenesis, mediated by choline-ethanolamine phosphotransferase 1 (CEPT1), is essential for phospholipid activation of transcription factors such as peroxisome proliferator-activated receptor α (PPARα) in the liver. Fenofibrate, a PPARα agonist and lipid-lowering agent, decreases amputation incidence in patients with diabetes. Because we previously observed that CEPT1 is elevated in carotid plaque of patients with diabetes, we evaluated the role of CEPT1 in peripheral arteries and PPARα phosphorylation (Ser12). CEPT1 was found to be elevated in diseased lower-extremity arterial intima of individuals with peripheral arterial disease and diabetes. To evaluate the role of Cept1 in the endothelium, we engineered a conditional endothelial cell (EC)-specific deletion of Cept1 via induced VE-cadherin-CreERT2-mediated recombination (Cept1Lp/LpCre+). Cept1Lp/LpCre+ ECs demonstrated decreased proliferation, migration, and tubule formation, and Cept1Lp/LpCre+ mice had reduced perfusion and angiogenesis in ischemic hind limbs. Peripheral ischemic recovery and PPARα signaling were further compromised by streptozotocin-induced diabetes and ameliorated by feeding fenofibrate. Cept1 endoribonuclease-prepared siRNA decreased PPARα phosphorylation in ECs, which was rescued with fenofibrate but not PC16:0/18:1. Unlike Cept1Lp/LpCre+ mice, Cept1Lp/LpCre+Ppara-/- mice did not demonstrate hind-paw perfusion recovery after feeding fenofibrate. Therefore, we demonstrate that CEPT1 is essential for EC function and tissue recovery after ischemia and that fenofibrate rescues CEPT1-mediated activation of PPARα. [ABSTRACT FROM AUTHOR]

BACKGROUNDWe investigated residual β cell function in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study participants with an average 35-year duration of type 1 diabetes mellitus (T1DM).METHODSSerum C-peptide was measured during a 4-hour mixed-meal tolerance test. Associations with metabolic outcomes and complications were explored among nonresponders (all C-peptide values after meal <0.003 nmol/L) and 3 categories of responders, classified by peak C-peptide concentration (nmol/L) as high (>0.2), intermediate (>0.03 to ≤0.2), and low (≥ 0.003 to ≤0.03).RESULTSOf the 944 participants, 117 (12.4%) were classified as responders. Residual C-peptide concentrations were associated with higher DCCT baseline concentrations of stimulated C-peptide (P value for trend = 0.0001). Residual C-peptide secretion was not associated with current or mean HbA1c, HLA high-risk haplotypes for T1DM, or the current presence of T1DM autoantibodies. The proportion of subjects with a history of severe hypoglycemia was lower with high (27%) and intermediate (48%) residual C-peptide concentrations than with low (74%) and no (70%) residual C-peptide concentrations (P value for trend = 0.0001). Responders and nonresponders demonstrated similar rates of advanced microvascular complications.CONCLUSIONβ Cell function can persist in long-duration T1DM. With a peak C-peptide concentration of >0.03 nmol/L, we observed clinically meaningful reductions in the prevalence of severe hypoglycemia.TRIAL REGISTRATIONClinicalTrials.gov NCT00360815 and NCT00360893.FUNDINGDivision of Diabetes Endocrinology and Metabolic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (DP3-DK104438, U01 DK094176, and U01 DK094157). [ABSTRACT FROM AUTHOR]

Background: Pressure measurement for the duration of the wave-free period (WFP) is considered essential for resting-state physiological assessment of coronary stenosis severity using the instantaneous wave-free ratio (iFR).Objectives: The aim of this study was to compare other diastolic resting indexes to iFR.Methods: In the population of the VERIFY2 (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography) study, iFR calculated by proprietary software (Volcano Harvest, Volcano Corporation, Rancho Cordova, California) was compared with the ratio of resting distal coronary pressure and aortic pressure during the complete duration of diastole (dPR), 25% to 75% of diastole (dPR25-75), and midpoint of diastole (dPRmid), along with Matlab calculated iFR (iFRmatlab) and iFR-like indexes shortening the length of the WFP by 50 and 100 ms (iFR-50ms and iFR-100ms), respectively. Mutual differences, Spearman correlations, area under the curve values from receiver-operating characteristic analyses, and diagnostic performance with respect to iFR and fractional flow reserve (FFR) were calculated for all indexes.Results: Median iFR in 197 patients with 257 vessels was 0.91 with an interquartile range of 0.87 to 0.95. The mutual differences (± SD) with iFR were 0.006 ± 0.011 (dPR), 0.001 ± 0.007 (dPR25-75), 0.001 ± 0.008 (dPRmid), 0.005 ± 0.009 (iFRmatlab), 0.003 ± 0.008 (iFR-50ms), and 0.001 ± 0.009 (iFR-100ms). Correlations for all indexes with iFR were >0.99 (p < 0.001 for all). Area under the curve values for predicting iFR were >0.99 for all indexes as well. Diagnostic accuracy compared with FFR was 76% to 77% for all indexes including iFR.Conclusions: All diastolic resting indexes tested were identical to iFR, both numerically and with respect to their agreement with FFR. A numerically equal value to iFR can be determined without restriction to the WFP. Cutoff values, guidelines, and clinical recommendations for iFR can therefore be extended to these other indexes. (Pd/Pa vs iFR in an Unselected Population Referred for Invasive Angiography [VERIFY2]; NCT02377310). [ABSTRACT FROM AUTHOR]

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1) withdrawal of neural ventilatory drive or 2) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA. [ABSTRACT FROM AUTHOR]

Controllable genetic manipulation is an indispensable tool in research, greatly advancing our understanding of cell biology and physiology. However in β-cells, transgene silencing, low inducibility, ectopic expression, and off-targets effects are persistent challenges. In this study, we investigated whether an inducible Tetracycline (Tet)-Off system with β-cell-specific mouse insulin promoter (MIP)-itTA-driven expression of tetracycline operon (TetO)-CreJaw/J could circumvent previous issues of specificity and efficacy. Following assessment of tissue-specific gene recombination, β-cell architecture, in vitro and in vivo glucose-stimulated insulin secretion, and whole-body glucose homeostasis, we discovered that expression of any tetracycline-controlled transactivator (e.g., improved itTA, reverse rtTA, or tTA) in β-cells significantly reduced Insulin gene expression and decreased insulin content. This translated into lower pancreatic insulin levels and reduced insulin secretion in mice carrying any tTA transgene, independent of Cre recombinase expression or doxycycline exposure. Our study echoes ongoing challenges faced by fundamental researchers working with β-cells and highlights the need for consistent and comprehensive controls when using the tetracycline-controlled transactivator systems (Tet-On or Tet-Off) for genome editing. [ABSTRACT FROM AUTHOR]

Introduction: Many reports have indicated that adipose-derived stem cells (ADSCs) are effective for nerve regeneration. We investigated nerve regeneration by combining a polyglycolic acid collagen (PGA-c) tube, which is approved for clinical use, and Schwann cell-like differentiated ADSCs (dADSCs).Methods: Fifteen-millimeter-long gaps in the sciatic nerve of rats were bridged in each group using tubes (group I), with tubes injected with dADSCs (group II), or by resected nerve (group III).Results: Axonal outgrowth was greater in group II than in group I. Tibialis anterior muscle weight revealed recovery only in group III. Latency in nerve conduction studies was equivalent in group II and III, but action potential was lower in group II. Transplanted dADSCs maintained Schwann cell marker expression. ATF3 expression level in the dorsal root ganglia was equivalent in groups II and III.Discussion: dADSCs maintained their differentiated state in the tubes and are believed to have contributed to nerve regeneration. [ABSTRACT FROM AUTHOR]

Purpose: To determine whether improvements in cardiorespiratory fitness (CRF), blood pressure (BP) and body composition previously seen after a 16-week exercise intervention (POST) with hypocaloric diet are maintained following six months (6M) of unsupervised exercise time. Methods: Overweight/obese, physically inactive participants with primary hypertension (HTN) (n = 190) were randomly assigned into an attention control group (physical activity recommendations) or one of three supervised exercise groups. After POST, all participants received diet and physical activity advice for the following 6M but no supervision. All anthropometric and physiological measurements were taken pre and post the 16-week supervised intervention period, as well as after 6M of no supervision. Results: After 6M: 1) body mass (BM) (Δ = 2.5%) and waist circumference (Δ = 1.8%) were higher (P < .005) than POST, but lower (P < .005) than pre-intervention (BM, Δ = -5.1%; waist circumference, Δ = -4.7%), with high-volume and high-intensity interval training group revealing a higher BM reduction (Δ = -6.4 kg) compared to control group (Δ = -3.5 kg); 2) BP variables were higher (P < .001) compared to POST with no change from pre-intervention; and 3) CRF was higher compared to pre-intervention (Δ = 17.1%, P < .001) but lower than POST (Δ = -5.7%, P < .001). Conclusions: When an overweight/obese population with HTN attains significant improvements in cardiometabolic health POST intervention with diet restriction, there is a significant reduction following 6M when exercise and diet supervision is removed, and only recommendations were applied. These results suggest the need for a regular, systematic and supervised diet and exercise programs to avoid subsequent declines in cardiometabolic health. [ABSTRACT FROM AUTHOR]

Introduction: Immobility of the upper limbs has been associated with reduction of F-wave frequency. However, there are no similar studies on lower limb (LL) F-waves. We investigated the impact of LL rest on F-wave and H-reflex parameters.Methods: The LLs of 14 healthy participants were studied after 90 minutes rest. F-waves (frequency, latencies, chronodispersion, and mean amplitude) and H-reflexes (latency and recruitment curve) were investigated bilaterally. In seven participants the protocol was repeated, but the temperature of one limb was reduced.Results: Immobility only changed F-wave latencies, which increased significantly (mean value of 2 ms, P < .01). Limb cooling did not influence results.Discussion: Contrary to what occurred in cervical lower motor neurons (LMN), LL LMNs did not show a reduced F-wave response to immobility, but their latency increased significantly. This could have been due to reduced Renshaw inhibition of small LMNs, thus facilitating their response to antidromic stimulation and causing delayed late responses. [ABSTRACT FROM AUTHOR]