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Development can proceed in “fits and starts”, with rapid transitions between cell states involving concerted transcriptome-wide changes in gene expression. However, it is not clear how these transitions are regulated in complex cell populations, in which cells receive multiple inputs. It is also not clear to what extent these rapid transitions represent developmental commitment. Here we address these issues usingDictyosteliumcells undergoing development in their physiological niche. A continuous single cell transcriptomics time series reveals a sharp “jump” in global gene expression marking functionally different cell states. By simultaneously live imaging the physiological dynamics of transcription and signalling over millimetre length scales, we show that the jump coincides with the onset of collective oscillations of cAMP, the positive feedback signal for multicellular development. Different jump genes respond to distinct dynamic features of signalling. The late gene expression changes of the jump are almost completely dependent on cAMP. In contrast, transcript changes at the onset of the jump require additional input. The spatial boundary marking the jump divides cells separated by only a few minutes of developmental time, with cells missing a jump then waiting several hours for the onset of the next wave of cAMP oscillations. This timing variability contrasts the prevailing developmental paradigm of a timed synchronous process and is associated with substantial pre-jump transcriptome variability. The coupling of collective signalling with gene expression is a potentially powerful strategy to drive robust cell state transitions in heterogeneous signalling environments. Based on the context of the jump, we also conclude that sharp gene expression transitions may not be sufficient for commitment.

Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. To this end, we used a novel volitional vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized Δ9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHCrats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CANTHCvapor dosing regimen that approximated CANTHCself-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHCrats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CANTHCself-administration as opposed to a sex difference in the effects of CANTHCvaporper se.

Nonminimum carbonic acid clusters provide excitation energies and oscillator strengths in line with observed ice-phase UV absorptions better than traditional optimized minima. This equation-of-motion coupled cluster quantum chemical analysis on carbonic acid monomers and dimers shows that shifts to the dihedral angle for the internal heavy atoms in the monomer produce UV electronic excitations close to 200 nm with oscillator strengths that would produce observable features. This τ(OCOO) dihedral is actually a relatively floppy motion unlike what is often expected for sp

The smallest Platonic hydrocarbon, tetrahedrane, has been subject to frequent theoretical and experimental study for 50 years, but its infrared spectrum and synthetic pathway remain a mystery. The recent partial attribution of the ultraviolet extinction bump observed in the interstellar medium (ISM) of the Milky Way galaxy to hydrogenated T-carbon, a larger tetrahedral cluster formed from tetrahedrane and C

The recent detection of ethynyl-functionalized cyclopropenylidene (c-C3HC2H) has initiated the search for other functional forms of cyclopropenylidene (c-C3H2) in space. There is existing gas-phase rotational spectroscopic data for cyano-cyclopropenylidene (c-C3HCN), but the present work provides the first anharmonic vibrational spectral data for that molecule, as well as the first full set of both rotational and vibrational spectroscopic data for fluoro- and chloro-cyclopropenylidenes (c-C3HF and c-C3HCl). All three molecules have fundamental vibrational frequencies with substantial infrared intensities. Namely, c-C3HCN has a moderately intense fundamental frequency at 1244.4 cm-1, while c-C3HF has two large intensity modes at 1765.4 and 1125.3 cm-1 and c-C3HCl again has two large intensity modes at 1692.0 and 1062.5 cm-1. All of these frequencies are well within the spectral range covered by the high-resolution EXES instrument on NASA's Stratospheric Observatory for Infrared Astronomy (SOFIA). Further, all three molecules have dipole moments of around 3.0 D in line with c-C3H2, enabling them to be observed by pure rotational spectroscopy, as well. Thus, the rovibrational spectral data presented herein should assist with future laboratory studies of functionalized cyclopropenylidenes and may lead to their interstellar or circumstellar detection.

Rovibrational spectral data for several tetra-atomic silicon carbide clusters (TASCCs) are computed in this work using a CCSD(T)-F12b/cc-pCVTZ-F12 quartic force field. Accurate theoretical spectroscopic data may facilitate the observation of TASCCs in the interstellar medium which may lead to a more complete understanding of how the smallest silicon carbide (SiC) solids are formed. Such processes are essential for understanding SiC dust grain formation. Due to SiC dust prevalence in the interstellar medium, this may also shed light on subsequent planetary formation. Rhomboidal Si2C2 is shown here to have a notably intense (247 km mol−1) anharmonic vibrational frequency at 988.1 cm−1 (10.1 μm) for ν2, falling into one of the spectral emission features typically associated with unknown infrared bands of various astronomical regions. Notable intensities are also present for several of the computed anharmonic vibrational frequencies including the cyclic forms of C4, SiC3, Si3C, and Si4. These features in the 6–10 μm range are natural targets for infrared observation with the James Webb Space Telescope (JWST)’s MIRI instrument. Additionally, t-Si2C2, d-Si3C, and r-SiC3 each possess dipole moments of greater than 2.0 D making them interesting targets for radioastronomical searches especially since d-SiC3 is already known in astrophysical media.

Background and aim Mortality of alcohol-related liver disease (ArLD) is increasing, and liver fibrosis stage is the best mortality predictor. Non-invasive tests (NITs) are increasingly used to detect fibrosis, but their value as prognostic tests in chronic liver disease, and in particular in ArLD, is less well recognized. We aimed to describe the prognostic performance of four widely used NITs (Fibrosis 4 test [FIB4], Enhanced Liver Fibrosis [ELF] test, FibroScan, and FibroTest) in ArLD. Methods Applying systematic review methodology, we searched four databases from inception to May 2020. Inclusion/exclusion criteria were applied to search using Medical Subject Heading terms and keywords. The first and second reviewers independently screened results, extracted data, and performed risk-of-bias assessment using Quality in Prognosis Studies tool. Results Searches produced 25 088 articles. After initial screening, 1020 articles were reviewed independently by both reviewers. Eleven articles remained after screening for eligibility: one on ELF, four on FibroScan, four on FIB4, one on FIB4 + FibroScan, and one on FibroTest + FIB4. Area under the receiver operating characteristic curves for outcome prediction ranged from 0.65 to 0.76 for FibroScan, 0.64 to 0.83 for FIB4, 0.69 to 0.79 for FibroTest, and 0.72 to 0.85 for ELF. Studies scored low-moderate risk of bias for most domains but high risk in confounding/statistical reporting domains. The results were heterogeneous for outcomes and reporting, making pooling of data unfeasible. Conclusions This systematic review returned 11 papers, six of which were conference abstracts and one unpublished manuscript. While the heterogeneity of studies precluded direct comparisons of NITs, each NIT performed well in individual studies in predicting prognosis in ArLD (area under the receiver operating characteristic curves >0.7 in each NIT category) and may add value to prognostication in clinical practice.

Aims. The detection of c-C3HC2H and possible future detection of c-C3HCN provide new molecules for reaction chemistry in the dense interstellar medium (ISM) where R-C2H and R-CN species are prevalent. Determination of chemically viable c-C3HC2H and c-C3HCN derivatives and their prominent spectral features can accelerate potential astrophysical detection of this chemical family. This work characterizes three such derivatives: c-C3(C2H)2, c-C3(CN)2, and c-C3(C2H)(CN). Methods. Interstellar reaction pathways of small carbonaceous species are well replicated through quantum chemical means. Highly accurate cc-pVXZ-F12/CCSD(T)-F12 (X = D,T) calculations generate the energetics of chemical formation pathways as well as the basis for quartic force field and second-order vibrational perturbation theory rovibrational analysis of the vibrational frequencies and rotational constants of the molecules under study. Results. The formation of c-C3(C2H)2 is as thermodynamically and, likely, as stepwise favorable as the formation of c-C3HC2H, rendering its detectability to be mostly dependent on the concentrations of the reactants. Both c-C3(C2H)2 and c-C3(C2H)(CN) will be detectable through radioastronomical observation with large dipole moments of 2.84 D and 4.26 D, respectively, while c-C3(CN)2 has an exceedingly small and likely unobservable dipole moment of 0.08 D. The most intense frequency for c-C3(C2H)2 is v2 at 3316.9 cm–1 (3.01 μm), with an intensity of 140 km mol–1. The mixed-substituent molecule c-C3(C2H)(CN) has one frequency with a large intensity, v1, at 3321.0 cm–1 (3.01 μm), with an intensity of 82 km mol–1. The molecule c-C3(CN)2 lacks intense vibrational frequencies within the range that current instrumentation can readily observe. Conclusions. Both c-C3(C2H)2 and c-C3(C2H)(CN) are viable candidates for astrophysical observation, with favorable reaction profiles and spectral data produced herein, but c-C3(CN)2 will not be directly observable through any currently available remote sensing means, even if it forms in large abundances.

From an ongoing multicenter effort toward differentiation of Parkinsonian spectrum disorders (PSD) from other types of neurodegenerative disorders, the sleep biomarker non-rapid-eye-movement sleep with hypertonia (NRH) emerged.This study included in the PSD group patients with dementia with Lewy bodies/Parkinson disease dementia (DLB/PDD = 16), Parkinson disease (PD = 16), and progressive supranuclear palsy (PSP = 13). The non-PSD group included patients with Alzheimer disease dementia (AD = 24), mild cognitive impairment (MCI = 35), and a control group with normal cognition (CG = 61). In-home, multi-night Sleep Profiler studies were conducted in all participants. Automated algorithms detected NRH, characterized by elevated frontopolar electromyographic power. Between-group differences in NRH were evaluated using Logistic regression, Mann-Whitney U and Chi-squared tests.NRH was greater in the PSD group compared to non-PSD (13.9 ± 11.0% vs. 3.1 ± 4.7%, P 0.0001). The threshold NRH≥5% provided the optimal between-group differentiation (AUC = 0.78, P 0.001). NRH was independently associated with the PSD group after controlling for age, sex, and SSRI/SNRI use (P 0.0001). The frequencies of abnormal NRH by subgroup were PSP = 92%, DLB/PDD = 81%, PD = 56%, MCI = 26%, AD = 17%, and CG = 16%. The odds of abnormal NRH in each PSD subgroup ranged from 3.7 to 61.2 compared to each non-PSD subgroup. The night-to-night and test-retest intraclass correlations were excellent (0.78 and 0.84, both P 0.0001).In this pilot study, NRH appeared to be a novel candidate sleep biomarker for PSD-related neurodegeneration. Future studies in larger cohorts are needed to confirm these findings, understand the etiology of NRH magnitude/duration, and determine whether it is an independent prodromal marker for specific neurodegenerative pathologies.

Benzvalyne (C

The low-frequency vibrational fundamentals of D2h inorganic oxides are readily modeled by heuristic scaling factors at fractions of the computational cost compared to explicit anharmonic frequency computations. Oxygen and the other elements in the present study are abundant in geochemical environments and have the potential to aggregate into minerals in planet-forming regions or in the remnants of supernovae. Explicit quartic force field computations at the CCSD(T)-F12b/cc-pVTZ-F12 level of theory generate scaling factors that accurately predict the anharmonic frequencies with an average error of less than 1.0 cm-1 for both the metal-oxygen stretching frequencies and the torsion and antisymmetric stretching frequencies. Inclusion of hydrogen motions is less absolutely accurate but is similarly relatively predictive. The fundamental vibrational frequencies for the seven tetra-atomic inorganic oxides examined presently fall below 876 cm-1 and most of the hydrogenated species do as well. Additionally, ν6 for the SiO dimer is shown to have an intensity of 562 km mol-1, with each of the other molecules having one or more frequencies with intensities greater than 80 km mol-1, again with most in the low-frequency infrared range. These intensities and the frequencies computed in the present study should assist in laboratory characterization and potential interstellar or circumstellar observation.

Survival rates for patients following liver transplantation exceed 90% at 12 months and approach 70% at 10 years. Part 1 of this guideline has dealt with all aspects of liver transplantation up to the point of placement on the waiting list. Part 2 explains the organ allocation process, organ donation and organ type and how this influences the choice of recipient. After organ allocation, the transplant surgery and the critical early post-operative period are, of necessity, confined to the liver transplant unit. However, patients will eventually return to their referring secondary care centre with a requirement for ongoing supervision. Part 2 of this guideline concerns three key areas of post liver transplantation care for the non-transplant specialist: (1) overseeing immunosuppression, including interactions and adherence; (2) the transplanted organ and how to initiate investigation of organ dysfunction; and (3) careful oversight of other organ systems, including optimising renal function, cardiovascular health and the psychosocial impact. The crucial significance of this holistic approach becomes more obvious as time passes from the transplant, when patients should expect the responsibility for managing the increasing number of non-liver consequences to lie with primary and secondary care.

Liver transplantation is a highly successful treatment for all types of liver failure, some non-liver failure indications and liver cancer. Most referrals come from secondary care. This first part of a two-part guideline outlines who to refer, and how that referral should be made, including patient details and additional issues such as those relevant to alcohol and drug misuse. The process of liver transplant assessment involves the confirmation of the diagnosis and non-reversibility, an evaluation of comorbidities and exclusion of contraindications. Finally, those making it onto the waiting list require monitoring and optimising. Underpinning this process is a need for good communication between patient, their carers, secondary care and the liver transplant service, synchronised by the transplant coordinator. Managing expectation and balancing the uncertainty of organ availability against the inevitable progression of underlying liver disease requires sensitivity and honesty from all healthcare providers and the assessment of palliative care needs is an integral part of this process.

The recent detection of ethynyl-functionalized cyclopropenylidene (c-C

Reparameterized semi-empirical methods can reproduce gas-phase experimental vibrational frequencies to within 24 cm−1 or better for a 100-fold decrease in computational cost in the anharmonic fundamental vibrational frequencies. To achieve such accuracy and efficiency, the default parameters in the PM6 semi-empirical model are herein optimized to reproduce the experimental and high-level theoretical vibrational spectra of three small hydrocarbon molecules, C2H2, c-C3H2, and C2H4, with the hope that these same parameters will be applicable to large polycyclic aromatic hydrocarbons (PAHs). This massive cost reduction allows for the computation of explicit anharmonic frequencies and the inclusion of resonance corrections that have been shown to be essential for accurate predictions of anharmonic frequencies. Such accurate predictions are necessary to help to disentangle the heretofore unidentified infrared spectral features observed around diverse astronomical bodies and hypothesized to be caused by PAHs, especially with the upcoming influx of observational data from the James Webb Space Telescope. The optimized PM6 parameters presented herein represent a substantial step in this direction with those obtained for ethylene (C2H4) yielding a 37% reduction in the mean absolute error of the fundamental frequencies compared to the default PM6 parameters.

This work provides the first full set of vibrational and rotational spectral data needed to aid in the detection of AlH$_3$OH$_2$, SiH$_3$OH, and SiH$_3$NH$_2$ in astrophysical or simulated laboratory environments through the use of quantum chemical computations at the CCSD(T)-F12b level of theory employing quartic force fields for the three molecules of interest. Previous work has shown that SiH$_3$OH and SiH$_3$NH$_2$ contain some of the strongest bonds of the most abundant elements in space. AlH$_3$OH$_2$ also contains highly abundant atoms and represents an intermediate along the reaction pathway from H$_2$O and AlH$_3$ to AlH$_2$OH. All three of these molecules are also polar with AlH$_3$OH$_2$ having the largest dipole of 4.58 D and the other two having dipole moments in the 1.10-1.30 D range, large enough to allow for the detection of these molecules in space through rotational spectroscopy. The molecules also have substantial infrared intensities with many of the frequencies being over 90 km mol$^{-1}$ and falling within the currently uncertain 12-17 $\mu$m region of the spectrum. The most intense frequency for AlH$_3$OH$_2$ is $\nu_9$ which has an intensity of 412 km mol$^{-1}$ at 777.0 cm$^{-1}$ (12.87 $\mu$m). SiH$-3$OH has an intensity of 183 km mol$^{-1}$ at 1007.8 cm$^{-1}$ (9.92 $\mu$m) for $\nu_5$, and SiH$_3$NH$_2$ has an intensity of 215 km mol$^{-1}$ at 1000.0 cm$^{-1}$ (10.00 $\mu$m) for $\nu_7$., Comment: 7 pages, 2 figures, accepted in MNRAS

Daniel J Levendowski,1 Erik K St. Louis,2 Luigi Ferini Strambi,3 Andrea Galbiati,3 Philip Westbrook,1 Chris Berka1 1Advanced Brain Monitoring, Carlsbad, CA,USA; 2Center for Sleep Medicine, Departments of Neurology and Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; 3Department of Clinical Neurosciences, San Raffaele Scientific Institute, Sleep Disorders Center Università Vita-Salute San Raffaele, Milan, Italy Objective: Submentalis electromyography (sEMG) and frontalis electromyography (fEMG) muscle activities have been used to assist in the staging of sleep and detection of disruptions in sleep. This study was designed to assess the concordance between sEMG and fEMG power, by and across sleep stages. Methods: Forty-three records with simultaneous acquisition of differential signals from the submental and frontalis muscles were evaluated. Sleep stages were assigned using the polysomnography signals based on majority agreement of five technicians. The sEMG and fEMG signals were identically filtered and aligned prior to cross-correlation analysis. Results: A strong concordance between sEMG and fEMG power was observed, with 95% of the records exhibiting at least moderate agreement. During rapid eye movement (REM) sleep, sEMG power was significantly less than fEMG power, but exhibited four times greater across-subject variability. fEMG power during wake and non-REM (NREM) sleep was greater than sEMG power, but with 50% less variability. Differences in wake and N1 mean power and between the other sleep stages were more distinct in the fEMG recordings. Relative changes in sEMG and fEMG power across wake, NREM, and REM stages were essentially ­identicalwith median by-subject cross correlations of 0.98 and interquartile ranges of 0.97 and 0.99, respectively. Conclusion: The fEMG and sEMG power values were similar during wakefulness and sleep; however, the frontalis exhibits substantially less between-subject variability. This study established face validity for the use of fEMG in the detection of wake and stages of sleep, and for future applications toward assessment of quantitative REM sleep muscle activity in REM sleep behavior disorder. Keywords: EMG, frontalis, submentalis, sleep stage, REM sleep without atonia

The ethynol (HCCOH) molecule has recently been shown to be present in simulated astrochemical ices possibly linking it to molecular building blocks for interstellar complex organic molecules like amino acids. The proposed reaction mechanism suggests the simultaneous formation of both ketene and ethynol from mixed carbon monoxide/water ice in simulated interstellar conditions. Rigorous anharmonic spectral data within both the IR and microwave regions are needed for possible detection of ethynol in the interstellar medium. This study provides the first such data for this molecule from high-level quantum chemical computations where experiment is currently lacking. Ethynol has a Beff comparable to, but distinct from acetonitrile at 9,652.1 MHz and three notable infrared features with two in the hydride stretching-regions and the C–C stretch at 2,212.8 cm−1. The ketene isomer has already been detected in the interstellar medium, and the possible detection of ethynol made possible by this work may lead to a deeper understanding of the proposed ice formation mechanism involving both species and how this relates to the molecular origins of life.

Background and aims Alcohol use disorders (AUD) cause 7.2% of UK hospital admissions/year. Most are not managed by hepatologists and liver disease may be missed. We used the Enhanced Liver Fibrosis (ELF) test to investigate prevalence and associations of occult advanced liver fibrosis in AUD patients not known to have liver fibrosis. Methods Liver fibrosis was assessed using ELF in prospective patients referred to the Royal Free Hospital Alcohol Specialist Nurse (November 2018–December 2019). Known cases of liver disease were excluded. Patient demographics, blood tests, imaging data and alcohol histories recorded. Advanced fibrosis was categorised as ELF ≥ 10.5. Results The study included 99 patients (69% male, mean age 53.1 ± 14.4) with median alcohol intake 140 units/week (IQR 80.9–280), and a mean duration of harmful drinking of 15 years (IQR 10–27.5). The commonest reason for admission was symptomatic alcohol withdrawal (36%). The median ELF score was 9.62, range 6.87–13.78. An ELF score ≥ 10.5 was recorded in 28/99 (29%) patients, of whom 28.6% had normal liver tests. Within previous 5-years, 76% had attended A&E without assessment of liver disease. The ELF score was not associated with recent alcohol intake (p = 0.081), or inflammation (p = 0.574). Conclusion Over a quarter of patients with AUD had previously undetected advanced liver fibrosis assessed by ELF testing. ELF was not associated with liver inflammation or recent alcohol intake. The majority had recent missed opportunities for investigating liver disease. We recommend clinicians use non-invasive tests to assess liver fibrosis in patients admitted to hospital with AUD.

Previous work suggests adolescent rats have deficient extinction consolidation relative to adults. Although the mechanisms underlying this age difference are currently unknown, studies in adult rats have implicated GluN2B-containing NMDA receptor function in extinction consolidation of drug-associated memory. Importantly, GluN2B neurotransmission emerges during adolescent development, and drugs of abuse during adolescence may delay the development of extinction consolidation by disrupting the ontogeny of GluN2B function. Here, we trained Sprague-Dawley rats of both sexes to self-administer methamphetamine (METH, 0.1 mg/kg/infusion i.v.) beginning during adolescence [postnatal (P) day 41] or adulthood (P91). Rats were given short access (2 h) to self-administer METH in seven daily sessions followed by fourteen sessions with long access (6 h). Subsequently, rats underwent four daily 30-min extinction sessions with immediate post-session injections of either a GluN2B antagonist (Ro25-6981; 6 mg/kg, i.p.) or a vehicle solution. After four daily 2-h extinction sessions, a priming injection (1 mg/kg METH, i.p.) was given prior to a final 2-h reinstatement session. During LgA, adolescent-onset rats earn more METH than adult-onset rats and display greater drug-loading behavior. Rats reduced their drug-seeking behavior across extinction sessions, with no significant group differences. Rats reinstated drug-seeking following the METH priming injection, with females displaying greater reinstatement than males. These results do not support oura priorihypothesis that adolescent-onset METH use disrupts the ontogeny of GluN2B transmission and contributes to age-of-onset differences in extinction of METH-seeking. However, our findings suggest that age-of-onset contributes to excessive METH-taking, while sex confers vulnerability to relapse to METH-seeking.

Adolescent use of amphetamine and its closely related, methylated version methamphetamine, is alarmingly high in those who use drugs for nonmedical purposes. This raises serious concerns about the potential for this drug use to have a long-lasting, detrimental impact on the normal development of the brain and behavior that is ongoing during adolescence. In this review, we explore recent findings from both human and laboratory animal studies that investigate the consequences of amphetamine and methamphetamine exposure during this stage of life. We highlight studies that assess sex differences in adolescence, as well as those that are designed specifically to address the potential unique effects of adolescent exposure by including groups at other life stages (typically young adulthood). We consider epidemiological studies on age and sex as vulnerability factors for developing problems with the use of amphetamines, as well as human and animal laboratory studies that tap into age differences in use, its short-term effects on behavior, and the long-lasting consequences of this exposure on cognition. We also focus on studies of drug effects in the prefrontal cortex, which is known to be critically important for cognition and is among the later maturing brain regions. Finally, we discuss important issues that should be addressed in future studies so that the field can further our understanding of the mechanisms underlying adolescent use of amphetamines and its outcomes on the developing brain and behavior.

The low-frequency vibrational fundamentals of

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h self-administration sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (NOR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats with a history of METH self-administration exhibited modest deficits in OiP compared to their adult-onset counterparts, but there was no sex difference and self-administration groups did not differ from naive control rats. All rats displayed intact novel object recognition memory. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and modest dysfunction in PFC-dependent cognition.

Liver transplant is a life-saving treatment with 1-year and 5-year survival rates of 90% and 70%, respectively. However, organ demand continues to exceed supply, such that many patients will die waiting for an available organ. This article reviews for the general gastroenterologist the latest developments in the field to reduce waiting list mortality and maximise utilisation of available organs. The main areas covered include legislative changes in organ donation and the new ‘opt-out’ systems being rolled out in the UK, normothermic machine perfusion to optimise marginal grafts, a new national allocation system to maximise benefit from each organ and developments in patient ‘prehabilitation’ before listing. Current areas of research interest, such as immunosuppression withdrawal, are also summarised.

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration (SA) in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h SA sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (OR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats exhibited modest deficits in OiP compared to adult-onset rats, but there was no sex difference in this effect and no groups differed in OR. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and subsequent dysfunction of PFC-dependent cognition.

Rodent models have been especially useful for investigating adolescent ethanol exposure. However, there is a paucity of studies examining sex differences in behavioral intoxication from adolescent ethanol drinking. Here, we used an ethanol drinking model to investigate if adolescent rats of both sexes readily drink ethanol to measurable behavioral intoxication, indicated by increased impulsive action and motor incoordination. Beginning on postnatal day (P) 28, male and female Long-Evans rats were given 30-min access to a solution of sucrose (20%) or sweetened ethanol (20% sucrose +15% ethanol) every other day until P60 and once after 2 weeks of forced abstinence (on P75). On alternate (nondrinking) days, rats were reinforced with a food pellet for making a cued nosepoke response. Beginning on P56, rats were tested in this task after drinking sessions to assess ethanol-induced changes in impulsive action, defined as premature responding prior to cue presentation. Motor coordination was assessed before and after drinking sessions using an incline plane test. Adolescent male and female rats readily consumed ethanol to behavioral intoxication, measured as reduced motor coordination. Following forced abstinence, females displayed greater ethanol-induced impulsive action. These studies provide evidence for sex differences in behavioral intoxication following adolescent ethanol drinking.

Water and hydrogen sulfide will bind with every atomic cation from the first three rows of the periodic table. While some atoms bind more tightly than others, explicitly correlated coupled cluster theory computations show that energy is required to be put into the system in order to dissociate these bonds even for noble gas atoms. The most promising systems have shallow entrance potential energy surfaces (PESs) that lie above deeper wells of a different spin. These wells are shown explicitly for H2OO+, H2SS+, and H2OS+ where relaxed PESs of the heavy atom bond lengths indicate that quartet states will cross more deeply-bound doublet states allowing for relatively easy association but much more difficult dissociation. In astrophysical regions that are cold and diffuse, such associations could lead to the formation of novel molecules utilizing water (or H2S) as the building blocks of more rich subsequent chemistry. Recent work has hypothesized that oxywater (H2OO) may be an intermediate in the formation of molecular oxygen in comets, and this work supports such a conclusion at least from a molecular cation perspective.

Daniel J Levendowski,1 Garun S Hamilton,2 Erik K St. Louis,3 Thomas Penzel,4 David Dawson,5 Philip R Westbrook11Advanced Brain Monitoring, Inc., Carlsbad, CA, USA; 2Monash Health & School of Clinical Sciences, Monash University, Clayton, VIC, Australia; 3Center for Sleep Medicine, Departments of Neurology and Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; 4Sleep Medicine Center, Charité Universitätsmedizin Berlin, GmbH, Berlin, Germany; 5Department of Anesthesiology, Bradford Teaching Hospitals NHS Foundation Trust, West Yorkshire, UKObjective: Evaluate the concordance between overall and positional oxygen desaturation indices (ODI) and apnea-hypopnea indices (AHI) according to two different definitions for positional obstructive sleep apnea (POSA).Methods: A total of 184 in-home polysomnograms were edited to simulate Level III home sleep apnea tests (HSAT) with the auto-scored AHI and ODI based on recording time. POSA was determined using 132 records with an AHI≥5 and at least 20 mins of recording time in both supine and non-supine positions. POSA was defined independently for the AHI and ODI based on ratios of overall/non-supine event/h ≥1.4 (O/NS) and supine/non-supine event/h≥2.0 (S/NS).Results: Correlation between the AHI and ODI was 0.97 overall, 0.94 for supine, and 0.96 for non-supine recording times (all p5/hr, and 6% exceeding >10 events/hr. The positive and negative percent agreements were uniformly good to excellent across varying clinical POSA cutoffs; percent agreements (positive, negative) were: AHI≥5=0.99, 0.78; AHI≥10=0.96, 0.89; and AHI≥15=0.96, 0.89. Cohen’s Kappa scores also showed substantial agreement for overall as well as supine and non-supine positions across varying clinical cutoffs of the AHI. Frequency of POSA was reproducibly uniform between 59% and 61% for both POSA criteria. When the O/NS and S/NS definitions conflicted in POSA characterization, O/NS was superior for identifying patients who might exhibit a greater response to supine restriction positional therapy.Conclusions: Auto-scored positional oximetry is a clinically viable alternative to an auto-scored Level III HSAT AHI in the characterization of POSA based on a 3% desaturation.Keywords: obstructive sleep apnea, positional, supine, apnea-hypopnea index, oxygen desaturation index

Objective To conduct an evidence-based review of adolescent self-report depression measures and to demonstrate how various measures can be rescored onto a harmonized metric. Method Six widely used person-reported outcome measures (PROMs) were reviewed. Psychometric properties were evaluated using previously published guidance for PROMs. Next, two secondary data sources (from an outpatient behavioral health clinic and from the general population) were evaluated to harmonize scores across three of the measures. Both item response theory and equipercentile linking methods were used and compared. Results All six PROMs demonstrated a high evidence base for widespread use depending on the purpose of the assessments. Adolescent involvement when developing the PROM for content validity and floor or ceiling effects were the least frequent available evidence. Three of the PROMs were linked to the PROMIS® Pediatric Depressive Symptoms v2.0 (PROMIS-PedDepSx) metric. The scales were highly correlated and essentially unidimensional when aggregated. All linking methods were broadly comparable. Group-level score conversions are recommended to minimize linking bias. Conclusions There are a number of strong, widely used PROMs for the evidence-based assessment (EBD) of adolescent depression. However, score comparability is a concern whenever there is a proliferation of measures. Harmonized score metrics support data aggregation and re-analysis. Using four PROMs, one of which served as the scoring metric, we demonstrated the possibility of harmonized depression scores. Future directions for EBD should evaluate whether harmonized PROMs for other pediatric health domains would be useful.

Successful exchange rate based stabilization programs in Europe, Israel and elsewhere have led many economists and policymakers to advocate the use of pegged exchange rates as an integral part of stabilization programs in the emerging market economies. This chapter discusses the ambiguous concept of "success" in stabilization. It examines the role of the exchange rate regime and other policies in stabilization programs in Argentina, Bolivia, Brazil, Chile, Ecuador, Mexico, Peru and Uruguay. Even allowing for considerable ambiguity in classifications, both of stabilization success and of exchange rate regimes, the Latin American experience amply demonstrates that use of the exchange rate as a nominal anchor is neither a necessary nor a sufficient condition for successful stabilization policy. The Latin American experience shows that fixed exchange rates are more likely to give way in the face of continued inflation than for inflation to be constrained by a fixed rate.

Background: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression. Objective: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions. Methods: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer's disease, and 6 with Lewy Body, Parkinson's, or other dementias) and 120 age-sex matched controls with normal cognition (NC). Results: The frequency of supine sleep 2 h/night was significantly greater in the NDD than in the NC group (p < 0.001, odds ratio = 3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis (p = 0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h. Conclusion: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain's ability to clear CNS neurotoxins and metabolites.

The CcCR quartic force field (QFF) methodology is capable of computing B 0 and C 0 rotational constants to within 35 MHz (0.14%) of experiment for triatomic and larger molecules with at least two heavy atoms. Additionally, the same constants for molecules with four or more atoms agree to within 20 MHz (0.12%) of experiment for the current test set. This work also supports previous claims that the same QFF methodology can produce fundamental vibrational frequencies with a deviation less than 5.7 cm−1 from experiment. Consequently, this approach of augmenting complete basis set extrapolated energies with treatments of core electron correlation and scalar relativity produces some of the most accurate rovibrational spectroscopic data available.

The fundamental vibrational frequency of the B–N stretch in BH3NH3 has eluded gas-phase experimental observation for decades. This work offers a theoretical anharmonic prediction of this mode to be 644 cm−1, using a Cartesian quartic force field at the CCSD(T)-F12/cc-pVTZ-F12 level of theory. The other fundamental frequencies reported herein have a mean absolute error of only 5 cm−1 from the seven available gas-phase experimental frequencies, making the anharmonic vibrational frequencies and rotational constants the most accurate computational data available for BH3NH3 to date. The inclusion of Fermi, Coriolis, and Darling–Dennison resonances is a major source of this accuracy, with the non-resonance-corrected frequencies having a mean absolute error of 10 cm−1. In particular, the inclusion of the 2ν6 = ν5 type 1 Fermi resonance increases the B–N stretching frequency by 14 cm−1 compared to previous work. Ammonia borane also represents one of the largest molecules ever studied by quartic force fields, making this work an important step in extending the breadth of application for these theoretical rovibrational techniques.

Rocky bodies are made of minerals comprised largely of silicon and oxygen. How these minerals are formed from their constituent atoms is not fully known. The rovibrational IR spectral data produced in this work may help to observe small molecules containing silicon and oxygen so that these potential molecular intermediates can be observed. These molecules have strong absorption features between 7.0 ​μm and 8.0 ​μm, most notably, and are fully characterized in the IR from the present quantum chemical data. The antisymmetric Si−O stretches of small silicon oxide clusters also fall in this range and have large intensities. Hence, this quantum chemical analysis provides spectral data for such molecules that may be of significance for astrochemical classification and could play a role in the formation or degradation of mineral nanocrystals from or into their constituent atoms. Both explicitly computed anharmonic fundamental vibrational frequencies and those determined from scaled harmonic frequencies agree well with known experimental data, and spectroscopic constants are provided herein such that astronomical rotational spectral characterization may also be possible for the C2v SiO3 and Si2O3 molecules.

This study investigates behavioral adaptation to vibrotactile position-avoidance therapy during sleep in patients with obstructive sleep apnea (n =135) across 15 to 52 weeks. The overall compliance, based on nights used ≥ 4 hr, was 71%. Overall regular use, that is, ≥ 4 hr/night over 70% of nights, was 88%. Poor early compliance strongly predicted poor long-term treatment adherence, with 92% of those noncompliant across the first 12 weeks of therapy remaining noncompliant. Conversely, 21% of those with compliant utilization in the short term became noncompliant in the long term. It appears that patients do not habituate to the stimulus during sleep, nor was there a training effect associated with long-term use.

We are not aware of a report detailing the complex obstetrical and medical management of twin pregnancy in the context of HIV infection and early post-liver transplantation period. Here we describe the successful outcome of a twin pregnancy in a 28-year-old HIV-positive female receiving antiretroviral therapy and immunosuppressive therapy who was the recipient of a liver transplant for previous drug-induced liver failure.

Introduction Vitamin D deficiency and reduced BMD are highly prevalent in patients with advanced chronic liver disease. For bisphosphonate treatment for osteoporosis to be effective vitamin D levels must be replete. Moreover, vitamin D deficiency has been associated with an increased risk of infections and increased rejection rates following liver transplantation. The optimal dose and route of vitamin D replacement in cirrhosis is unknown. BSG guidance currently recommends 800 IU/day orally for all patients with cirrhosis/cholestatic liver disease. Methods Retrospective review of 218 cirrhotic patients undergoing evaluation for liver transplant between 2016 and 2017. Vitamin D ‘severe deficiency’ was defined as 50 ng/ml. Response to oral vitamin D therapy was recorded. Results Out of 218 patients, 128/218 (59%) had low Vitamin D levels with 25% (n=55) ‘severely deficient’ and 33% (n=73) ‘deficient’. Overall 33 patients with levels 50 ng/ml received replacement therapy. (p=0.86) Median daily dose of Vitamin D replacement was 2800 units/day (IQR 800–2800) in 50 ng/dl group. No significant difference in dosing between these groups (p=0.12). Data on vitamin D levels pre and post 3 months of treatment with Vitamin D therapy were available in 58 patients. Patients received either 400IU/day (n=6), 800–1600IU/day (n=28) or >1600 IU/Day (n=24). Median delta change in vitamins D levels in the 3 groups were −3 ng/ml, −1 ng/ml and 12 ng/ml over the 3 month treatment period. An average daily dose of >1600 IU/day Resulted in a significantly greater increase in Vitamin D levels when compared to doses When those patients with Vitamin D levels of 50 ng/dl and no significant difference was found between dosages of vitamin D administered. Conclusion Vitamin D deficiency is prevalent, affecting over 50% of patients with advanced cirrhosis. Oral vitamin D replacement therapy is ineffective in cirrhotics at repleting stores over a 3 month period irrespective of dose given. Future evaluation of efficacy of IM administration in this unique cohort of patients is urgently needed to evaluate if this allows normalisation of Vitamin D levels.

Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self-administration impacted cognitive flexibility and 5-HT(2C)R localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT(2C) receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT(2C) receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT(2C) receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT(2C)R co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females.

Compared with adults, adolescent behavior is often characterized by reduced behavioral flexibility, increased sensitivity to reward, and increased likelihood to take risks. These traits, which have been hypothesized to confer heightened vulnerability to psychopathologies such as substance use disorders (SUDs), have been the focus of studies in laboratory animal models that seek to understand their neural underpinnings. However, rodent studies to date have typically used only males and have adopted standard methodological practices (e.g., weight loss inducing food restriction) that are likely to have a disparate impact on adolescents compared with adults. Here, we used adolescent and adult Sprague-Dawley rats of both sexes to study instrumental behavior tasks that assess behavioral flexibility (strategy shifting and reversal learning; Experiment 1), sensitivity to reward value (outcome devaluation; Experiment 2), and risky decision making (probability discounting; Experiment 3). In Experiment 1, we found that adolescents were faster to acquire reversal learning than adults but there were no differences in strategy shifting. In Experiments 2 and 3, adolescents and adults were equally sensitive to changes in reward value and exhibited similar reductions in preference for a large reward when reinforcement probability was decreased. However, adolescents responded more efficiently and earned reinforcers at a higher rate than their same-sex, adult counterparts. Together, these findings provide only limited support for the existence of an "adolescent-typical" phenotype in Sprague-Dawley rats and instead suggest that age differences in the expression of these behaviors may depend on conditions such as pubertal status and motivational state. (PsycINFO Database Record

Objective/Background Systematically compare four criteria for Positional Obstructive Sleep Apnea (POSA) based on AASM 2007 and 2012 hypopnea scoring definitions. Patients/Methods 142 records acquired by in-home polysomnography (Sleep Profiler PSG2™) were retrospectively analyzed using AHI based on the American Academy Sleep Medicine 2007 and 2012 criteria (AHI2007 and AHI2012). Positional obstructive sleep apnea (POSA) was characterized using four criteria: Amsterdam Positional OSA Classification (APOC), supine AHI twice the non-supine AHI (Cartwright), Cartwright plus the non-supine AHI Results Correlations between the Cartwright and Overall/NS-AHI criteria increased with the inclusion of a more relaxed definition of hypopneas (AHI2007 = 0.79 and AHI2012 = 0.86, P Conclusions The four criteria used to identify POSA have similarities and differences. While there were similarities between the Cartwright and Overall/NS-AHI criteria in the detection of POSA prevalence across both scoring criteria, the Overall/NS-AHI provided the most consistent detection of those most likely to demonstrate important reductions in sleep disordered breathing severity if supine sleep is avoided.

The elevation of treeline is rising in many areas throughout the world. Encroachment of forest into alpine regions fragments habitats and causes changes in microhabitat potentially altering the density and distribution of species. Our study investigates two species of alpine Crassulaceae, Sedum lanceolatum and Rhodiola integrifolia, as part of a larger project determining the effects of forest encroachment in the front ranges of the Rocky Mountains. Previous studies of S. lanceolatum showed a decrease in its density, but an increase in herbivory by larvae of the butterfly Parnassius smintheus with increasing distance from the treeline. To better understand the potential impact of forest encroachment on these species and the microhabitat associations of the plant species, we counted their abundance and determined soil depth, soil type, and dominant rock type in 8417 quadrats of 1 m2 area spaced at 10 m intervals throughout 17 alpine meadows along Jumpingpound Ridge, AB, Canada. Using a geographic information system we extracted slope, aspect, elevation, and distance from treeline for each quadrat. S. lanceolatum was abundant in these meadows and its density was influenced by all factors examined, predominantly through effects on soil moisture. Its positive association with treeline was primarily at high elevation in meadows with west-facing aspects. R. integrifolia had a more restricted distribution and relatively low density; it was most abundant in gravelly soils with north-facing aspects and little slope. Comparing the distribution of each species to a model predicting future forest encroachment indicates that both will lose habitat to forest encroachment. R. integrifolia is predicted to lose 31 % of its current habitat area. S. lanceolatum, which occurs across a broader range of microhabitats, is predicted to lose 19 % of its current habitat area to forest encroachment. These losses will negatively affect P. smintheus, but the overall impacts of forest encroachment on the butterfly are predicted to be minimal.