O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases

Commentary: Lessons from the COVID-19 global health response to inform TB case finding

The coronavirus disease 2019 (COVID-19) has emerged as a serious threat to global public health, demanding urgent action and causing unprecedented worldwide change in a short space of time. This disease has devastated economies, infringed on individual freedoms, and taken an unprecedented toll on healthcare systems worldwide. As of 1 April 2020, over a million cases of COVID-19 have been reported in 204 countries and territories, resulting in more than 51,000 deaths. Yet, against the backdrop of the COVID-19 pandemic, lies an older, insidious disease with a much greater mortality. Tuberculosis (TB) is the leading cause of death by a single infectious agent and remains a potent threat to millions of people around the world. We discuss the differences between the two pandemics at present, consider the potential impact of COVID-19 on TB case management, and explore the opportunities that the COVID-19 response presents for advancing TB prevention and control now and in future

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

New Australian guidelines for the treatment of alcohol problems: an overview of recommendations

Summary of recommendations and levels of evidence Chapter 2: Screening and assessment for unhealthy alcohol use Screening Screening for unhealthy alcohol use and appropriate interventions should be implemented in general practice (Level A), hospitals (Level B), emergency departments and community health and welfare settings (Level C). Quantity–frequency measures can detect consumption that exceeds levels in the current Australian guidelines (Level B). The Alcohol Use Disorders Identification Test (AUDIT) is the most effective screening tool and is recommended for use in primary care and hospital settings. For screening in the general community, the AUDIT-C is a suitable alternative (Level A). Indirect biological markers should be used as an adjunct to screening (Level A), and direct measures of alcohol in breath and/or blood can be useful markers of recent use (Level B). Assessment Assessment should include evaluation of alcohol use and its effects, physical examination, clinical investigations and collateral history taking (Level C). Assessment for alcohol-related physical problems, mental health problems and social support should be undertaken routinely (GPP). Where there are concerns regarding the safety of the patient or others, specialist consultation is recommended (Level C). Assessment should lead to a clear, mutually acceptable treatment plan which specifies interventions to meet the patient’s needs (Level D). Sustained abstinence is the optimal outcome for most patients with alcohol dependence (Level C). Chapter 3: Caring for and managing patients with alcohol problems: interventions, treatments, relapse prevention, aftercare, and long term follow-up Brief interventions Brief motivational interviewing interventions are more effective than no treatment for people who consume alcohol at risky levels (Level A). Their effectiveness compared with standard care or alternative psychosocial interventions varies by treatment setting. They are most effective in primary care settings (Level A). Psychosocial interventions Cognitive behaviour therapy should be a first-line psychosocial intervention for alcohol dependence. Its clinical benefit is enhanced when it is combined with pharmacotherapy for alcohol dependence or an additional psychosocial intervention (eg, motivational interviewing) (Level A). Motivational interviewing is effective in the short term and in patients with less severe alcohol dependence (Level A). Residential rehabilitation may be of benefit to patients who have moderate-to-severe alcohol dependence and require a structured residential treatment setting (Level D). Alcohol withdrawal management Most cases of withdrawal can be managed in an ambulatory setting with appropriate support (Level B). Tapering diazepam regimens (Level A) with daily staged supply from a pharmacy or clinic are recommended (GPP). Pharmacotherapies for alcohol dependence Acamprosate is recommended to help maintain abstinence from alcohol (Level A). Naltrexone is recommended for prevention of relapse to heavy drinking (Level A). Disulfiram is only recommended in close supervision settings where patients are motivated for abstinence (Level A). Some evidence for off-label therapies baclofen and topiramate exists, but their side effect profiles are complex and neither should be a first-line medication (Level B). Peer support programs Peer-led support programs such as Alcoholics Anonymous and SMART Recovery are effective at maintaining abstinence or reductions in drinking (Level A). Relapse prevention, aftercare and long-term follow-up Return to problematic drinking is common and aftercare should focus on addressing factors that contribute to relapse (GPP). A harm-minimisation approach should be considered for patients who are unable to reduce their drinking (GPP). Chapter 4: Providing appropriate treatment and care to people with alcohol problems: a summary for key specific populations Gender-specific issues Screen women and men for domestic abuse (Level C). Consider child protection assessments for caregivers with alcohol use disorder (GPP). Explore contraceptive options with women of reproductive age who regularly consume alcohol (Level B). Pregnant and breastfeeding women Advise pregnant and breastfeeding women that there is no safe level of alcohol consumption (Level B). Pregnant women who are alcohol dependent should be admitted to hospital for treatment in an appropriate maternity unit that has an addiction specialist (GPP). Young people Perform a comprehensive HEEADSSS assessment for young people with alcohol problems (Level B). Treatment should focus on tangible benefits of reducing drinking through psychotherapy and engagement of family and peer networks (Level B). Aboriginal and Torres Strait Islander peoples Collaborate with Aboriginal or Torres Strait Islander health workers, organisations and communities, and seek guidance on patient engagement approaches (GPP). Use validated screening tools and consider integrated mainstream and Aboriginal or Torres Strait Islander-specific approaches to care (Level B). Culturally and linguistically diverse groups Use an appropriate method, such as the “teach-back” technique, to assess the need for language and health literacy support (Level C). Engage with culture-specific agencies as this can improve treatment access and success (Level C). Sexually diverse and gender diverse populations Be mindful that sexually diverse and gender diverse populations experience lower levels of satisfaction, connection and treatment completion (Level C). Seek to incorporate LGBTQ-specific treatment and agencies (Level C). Older people All new patients aged over 50 years should be screened for harmful alcohol use (Level D). Consider alcohol as a possible cause for older patients presenting with unexplained physical or psychological symptoms (Level D). Consider shorter acting benzodiazepines for withdrawal management (Level D). Cognitive impairment Cognitive impairment may impair engagement with treatment (Level A). Perform cognitive screening for patients who have alcohol problems and refer them for neuropsychological assessment if significant impairment is suspected (Level A). Summary of key recommendations and levels of evidence Chapter 5: Understanding and managing comorbidities for people with alcohol problems: polydrug use and dependence, co-occurring mental disorders, and physical comorbidities Polydrug use and dependence Active alcohol use disorder, including dependence, significantly increases the risk of overdose associated with the administration of opioid drugs. Specialist advice is recommended before treatment of people dependent on both alcohol and opioid drugs (GPP). Older patients requiring management of alcohol withdrawal should have their use of pharmaceutical medications reviewed, given the prevalence of polypharmacy in this age group (GPP). Smoking cessation can be undertaken in patients with alcohol dependence and/or polydrug use problems; some evidence suggests varenicline may help support reduction of both tobacco and alcohol consumption (Level C). Co-occurring mental disorders More intensive interventions are needed for people with comorbid conditions, as this population tends to have more severe problems and carries a worse prognosis than those with single pathology (GPP). The Kessler Psychological Distress Scale (K10 or K6) is recommended for screening for comorbid mental disorders in people presenting for alcohol use disorders (Level A). People with alcohol use disorder and comorbid mental disorders should be offered treatment for both disorders; care should be taken to coordinate intervention (Level C). Physical comorbidities Patients should be advised that alcohol use has no beneficial health effects. There is no clear risk-free threshold for alcohol intake. The safe dose for alcohol intake is dependent on many factors such as underlying liver disease, comorbidities, age and sex (Level A). In patients with alcohol use disorder, early recognition of the risk for liver cirrhosis is critical. Patients with cirrhosis should abstain from alcohol and should be offered referral to a hepatologist for liver disease management and to an addiction physician for management of alcohol use disorder (Level A). Alcohol abstinence reduces the risk of cancer and improves outcomes after a diagnosis of cancer (Level A)

Field dependence of the microwave resistivity in SmBa2Cu3O7 thin films

We report measurements of the microwave complex resistivity at 48 GHz in SmBa2 Cu3 O7−δ thin films. Measurements are performed with a moderate magnetic field, μ0H < 0.8T, applied along the c-axis. We find that the complex resistivity presents clear sublinear field dependences, and that the imaginary part is remarkably sensitive to the moderate magnetic field. Interpretation considering an unusually strong pinning leads to very anomalous field dependences of the single-vortex viscosity and of the pinning constant. By contrast, allowing for a significant effect of the magnetic field on the depletion of the condensate, the data are quantitatively described by the simple free-flow-like expression, supplemented with two-fluid conductivity. In this frame, we obtain the vortex viscosity from the data. We compare vortex viscosity in SmBa2Cu3 O7−δ and in YBa 2 Cu3 O7−δ

Vortex state microwave resistivity in cuprates

The microwave response of high-Tc superconductors yielded information, among the others, on the symmetry of the order parameter and on the temperature dependence of the superfluid fraction (via the measurement of the temperature dependence of the London penetration depth [1]). In the mixed state, most of the attention focussed on the motion of flux lines, with estimates of vortex parameters such as the vortex viscosity and depinning frequency [2]. While the determination of the field dependences of the superfluid and normal fluid could give important information on the electronic structure of the superconducting state, a very few reports dealt with them [3] due to the unavoidable vortex motion contribution. Aim of this work is to determine the field dependent superfluid fraction ns(T,B) from the data of the microwave complex resistivity. With the preliminary identification of the vortex motion contribution, we find that in various cuprate superconductors ns(T,B)=ns(T,0)-AB1/2 up to temperatures T ¡Ö 0.98 Tc. This finding is common to YBa2Cu3O7-d, SmBa2Cu3O7-d and Bi2Sr2CaCu2O8+x, and it can be interpreted by a d-wave pairing (or, at least, a pairing with lines of nodes in the gap) persisting up to high temperatures. We have measured the complex resistivity at 48 GHz in several highly oriented cuprate superconducting thin films, grown by different sputtering techniques [4] on substrates suitable for microwave measurements. Qfactor and frequency shift measurements of a resonant cavity with the superconducting film placed in the end-wall configuration yielded the (a,b) plane complex resitivity r(T,B)=r1(T,B)+ir2(T,B)$, for temperatures from 65 K to Tc and magnetic fields up to 0.8 T (applied along the c axis). The field dependence of r is found to comprise a substantial {sublinear} contribution in almost the full temperature range explored (in the Figure we report a typical measurement taken in SmBa2Cu3O7-d at a single temperature). This is at odds with simple flux motion [5], where r1(T,B)-r1(T,B=0) is proportional to B with no flux creep, while flux creep would change the field dependence to a superlinear one[6]. We identify the vortex motion contribution with the linear term alone: this yields absolute values of vortex viscosities that compare well with published data. We then evaluate the superfluid field dependent conductivity ssf = ns(T,B)/ m0wl02 by subtracting the vortex motion contribution from the measured complex resistivity and inverting the data. The resulting field dependence of ssf is linear with B1/2 in all samples investigated, as reported in the Figure. This is in agreement with the predictions for a superconductor with lines of nodes in the gap[7]. Moreover, the extension of the B1/2 dependence in nearly the full temperature range explored (T> 65 K) and up to temperatures close to Tc indicates that such pairing is not smeared out by the high operating temperatures

Models of Nondeterministic Regular Expressions

Nondeterminism is a direct outcome of interactions and is, therefore a central ingredient for modelling concurrent systems. Trees are very useful for modelling nondeterministic behaviour. We aim at a tree-based interpretation of regular expressions and study the effect of removing the idempotence law X+X=X and the distribution law X•(Y+Z)=X•Y+X•Z from Kleene algebras. We show that the free model of the new set of axioms is a class of trees labelled over A. We also equip regular expressions with a two-level behavioural semantics. The basic level is described in terms of a class of labelled transition systems that are detailed enough to describe the number of equal actions a system can perform from a given state. The abstract level is based on a so-called resource bisimulation preorder that permits ignoring uninteresting details of transition systems. The three proposed interpretations of regular expressions (algebraic, denotational, and behavioural) are proven to coincide. When dealing with infinite behaviours, we rely on a simple version of the ω-induction and obtain a complete proof system also for the full language of nondeterministic regular expressions

Mixed state microwave resistivity of cuprate superconductors

We present a compared experimental investigation of the (a, b) plane vortex-state complex resistivity at 48 GHz in YBa2Cu3O7-delta, SmBa2Cu3O7-delta and Bi2Sr2CaCu2O8+x, In YBa2Cu3O7-delta and SmBa2Cu3O7-delta the field dependence of the response can be consistently by contrast, described by a combination of flux flow and strong pair breaking due to the presence of lines of nodes in the gap. In Bi2Sr2CaCu2O8+x the data might be described by the pair breaking alone. (c) 2005 Elsevier Ltd. All rights reserved