Human germline heterozygous gain-of-function STAT6 variants cause severe allergic disease

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder

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)

Mycoplasma pneumoniae as a cofactor in severe respiratory infections. Clin. Infect. Dis

We report the clinical events associated with severe bacterial or viral infections in four patients whose illnesses followed or coincided with acute Mycoplasma pneumoniae respiratory infection. We propose that M. pneumoniae has the ability to act as a cofactor in severe respiratory disease by facilitating alterations in local respiratory immunity or structure and function. Mycoplasma pneumoniae is recognized as an important and frequent cause of community-acquired respiratory illness in children The role of M. pneumoniae as a cofactor in severe pulmonary infections is not well understood; neither are the details of the pulmonary immunologic events that occur during the course and after the resolution of M. pneumoniae infection in humans. We report the clinical events that occurred in four patients who had severe bacterial or viral infections that appear to have either followed or coincided with M. pneumoniae respiratory infection. Case Reports Clinical and laboratory data for our patients are summarized in table 1. Patient I. A 14-year-old male with respiratory failure was transferred to our hospital. He had previously been well except for recurrent ear infections in early childhood. His respiratory illness began 5 weeks earlier with the onset of a sore throat and an earache. A primary care practitioner found evidence of suppurative pharyngitis and bilateral otitis, and oral penicillin was prescribed. The patient's illness progressed to include a persistent cough that did not abate despite courses of co-trimoxazole and cefaclor. Four days before his transfer, the patient became nauseated and anorexic. The severity of his cough increased, and he was noted to be febrile. He complained of left-upper-quadrant pain, and his cough precipitated both frontal chest pain and back pain. Two days before transfer, he was admitted to another hospital with the diagnosis of left-lower-lobe pneumonia. Intravenous ampicillin was administered. Over the next 24 hours, he became grossly dyspneic and was found to have a Po e of 30 mm Hg while breathing room air. The patient underwent bronchoscopy, and he was intubated and transferred to our hospital, where clinical and radiological evidence of bilateral lower-lobe bronchopneumonia was found. He was ventilated. Vital signs included the following: temperature, 38.2°C; pulse, 120/min; and blood pressure, 120/60 mm Hg. There were no other signs of infection in areas other than the respiratory tract. Radiographs of the chest also revealed small bilateral pleural effusions. The patient's WBC cell count was 9.3 X 109/L (74% polymorphonuclear cells). Blood cultures were negative. Routine cultures of bronchial washings did not yield pathogenic bacteria. Special studies for legionellae and chlamydiae were unrevealing. Respiratory syncytial virus was evident in these washings on both direct immunofluorescence staining and tissue culture. An IgM anti-P1 M. pneumoniae immunoblot assay was strongly positive Intravenous erythromicin and cefuroxime were administered, as was aerosolized ribavirin. The patient was ventilated for 7 days, and although his high fever (temperature, 38°-40°C) started to remit by day 4 after admission, he had mild pyrexia for 12 days. He was transferred back to his referring hospital in considerably improved clinical condition. Patient 2. A 10-year-old male was admitted to the hospital with fever and cough. He had been well until 3 weeks before admission, when he developed a nonproductive cough, fever, and night sweats. Within the first week of his illness, his cough became productive and he complained of mild exercise intolerance. The patient defervesced after 2 weeks, but he experienced episodic right shoulder and subscapular pain during episodes of cough. Three days before admission, he became febrile again and his cough became more productive. The patient was admitted to our hospital. Vital signs included the following: temperature, 38.7°C; pulse, 100/min; respiraat Penn State Universit

Future stories: co-designing virtual reality (VR) experiences with young people with a serious illness in hospital

Hospitalisation can be a challenging experience for young people, including higher levels of anxiety, social isolation, and depression. In this paper we identify the possibilities of an applied theatre pilot that aimed to combine co-designed virtual reality (VR) approaches with intermedial work with young people in hospital. Within the pilot study we worked with three participants in individualised bedside workshops over a four-week period. Analysis from the pilot demonstrated the significance of the co-design process leading to greater degrees of agency for young people, and opportunities for the participants to share experiences with medical staff, carers, and siblings.</p

Effects of simulated light regimes on gene expression in Antarctic krill (Euphausia superba Dana)

A change in photoperiod has been implicated in triggering a transition from an active to a quiescent state in Antarctic krill. We examined this process at the molecular level, to identify processes that are affected when passing a photoperiodic threshold. Antarctic krill captured in the austral autumn were divided into two groups and immediately incubated either under a photoperiod of 12 h light:12 h darkness (LD), simulating the natural light cycle, or in continuous darkness (DD), simulating winter. All other conditions were kept identical between incubations. After 7 days of adaptation, krill were sampled every 4 h over a 24 h period and frozen. Total RNA was extracted from the heads and pooled to construct a suppression subtractive hybridisation library. Differentially expressed sequences were identified and annotated into functional categories through database sequence matching. We found a difference in gene expression between LD and DD krill, with LD krill expressing more genes involved in functions such as metabolism, motor activity, protein binding and various other cellular activities. Eleven of these genes were examined further with quantitative polymerase chain reaction analyses, which revealed that expression levels were significantly higher in LD krill. The genes affected by simulated photoperiodic change are consistent with known features of quiescence, such as a slowing of moult rate, a lowering of activity levels and a reduction in metabolic rate. The expression of proteases involved in apolysis, where the old cuticle separates from the epidermis, showed particular sensitivity to photoperiod and point to the mechanism by which moult rate is adjusted seasonally. Our results show that key processes are already responding at the molecular level after just 7 days of exposure to a changed photoperiodic cycle. We propose that krill switch rapidly between active and quiescent states and that the photoperiodic cycle plays a key role in this process