The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.

Peri-operative SARS-CoV-2 infection increases postoperative mortality. The aim of this study was to determine the optimal duration of planned delay before surgery in patients who have had SARS-CoV-2 infection. This international, multicentre, prospective cohort study included patients undergoing elective or emergency surgery during October 2020. Surgical patients with pre-operative SARS-CoV-2 infection were compared with those without previous SARS-CoV-2 infection. The primary outcome measure was 30-day postoperative mortality. Logistic regression models were used to calculate adjusted 30-day mortality rates stratified by time from diagnosis of SARS-CoV-2 infection to surgery. Among 140,231 patients (116 countries), 3127 patients (2.2%) had a pre-operative SARS-CoV-2 diagnosis. Adjusted 30-day mortality in patients without SARS-CoV-2 infection was 1.5% (95%CI 1.4-1.5). In patients with a pre-operative SARS-CoV-2 diagnosis, mortality was increased in patients having surgery within 0-2 weeks, 3-4 weeks and 5-6 weeks of the diagnosis (odds ratio (95%CI) 4.1 (3.3-4.8), 3.9 (2.6-5.1) and 3.6 (2.0-5.2), respectively). Surgery performed ≥ 7 weeks after SARS-CoV-2 diagnosis was associated with a similar mortality risk to baseline (odds ratio (95%CI) 1.5 (0.9-2.1)). After a ≥ 7 week delay in undertaking surgery following SARS-CoV-2 infection, patients with ongoing symptoms had a higher mortality than patients whose symptoms had resolved or who had been asymptomatic (6.0% (95%CI 3.2-8.7) vs. 2.4% (95%CI 1.4-3.4) vs. 1.3% (95%CI 0.6-2.0), respectively). Where possible, surgery should be delayed for at least 7 weeks following SARS-CoV-2 infection. Patients with ongoing symptoms ≥ 7 weeks from diagnosis may benefit from further delay.

The emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) substantially challenges TB control, especially in the European Region of the World Health Organization, where the highest prevalence of MDR/XDR cases is reported. The current management of patients with MDR/XDR-TB is extremely complex for medical, social and public health systems. The treatment with currently available anti-TB therapies to achieve relapse-free cure is long and undermined by a high frequency of adverse drug events, suboptimal treatment adherence, high costs and low treatment success rates. Availability of optimal management for patients with MDR/XDR-TB is limited even in the European Region. In the absence of a preventive vaccine, more effective diagnostic tools and novel therapeutic interventions the control of MDR/XDR-TB will be extremely difficult. Despite recent scientific advances in MDR/XDR-TB care, decisions for the management of patients with MDR/XDR-TB and their contacts often rely on expert opinions, rather than on clinical evidence.This document summarises the current knowledge on the prevention, diagnosis and treatment of adults and children with MDR/XDR-TB and their contacts, and provides expert consensus recommendations on questions where scientific evidence is still lacking.

Although tuberculosis (TB) has its highest burden among young adults, especially since the advent of HIV infection, two other groups with low immunity, the very young (<1 year) with immature immunity and the elderly (>65 years) with waning immunity, are vulnerable groups not to be forgotten. This review describes the epidemiology,clinical aspects,public health aspects and outcome of TB in patients at the extremes of age. The epidemiology differs therein that TB in infants occurs in developing countries with high incidences of TB and HIV, while TB in the elderly occurs in developed countries with ageing populations. The clinical presentation may be non-specific, history of contact with TB is often not known and TB is often not considered at these age extremes, and when the diagnosis is considered, disease progression may already be advanced. Anti-TB treatment regimens are the same as in other age groups, but drug dosages may need adjustment according to weight, renal function, liver function and other potentially complicating factors. Adverse events are more difficult to observe and both the young and the elderly are reliant on others for adherence to treatment. Mortality at both age extremes is higher than in the general TB population. For all the above reasons, public health measures to: prevent transmission of infection; identify those infected and providing preventive therapy; high index of suspicion in order to make an early diagnosis; and timely initiation of treatment are important in both the very young and the elderly.

An Arg present in the third transmembrane domain of all rhodopsin-like G-protein-coupled receptors is required for efficient signal transduction. Mutation of this Arg in the gonadotropin-releasing hormone receptor to Gln, His, or Lys abolished or severely impaired agoniststimulated inositol phosphate generation, consistent with Arg having a role in receptor activation. To investigate the contribution of the surrounding structural domain in the actions of the conserved Arg, an integrated microdomain modeling and mutagenesis approach has been utilized. The gonadotropin-releasing hormone (GnRH) 1 receptor is a member of the rhodopsin-like G-protein-coupled receptor (GPCR) family (1, 2). These heptahelical proteins include the visual opsins and various receptors for neurotransmitters, peptides, and glycoproteins. Activation of these receptors by their diverse agonists is associated with conformational changes in the receptor that facilitate a signal-propagating interaction with G-proteins (3). These conformational changes can involve relative movement of helices, as reported for rhodopsin (4, 5) and/or rotation of the helices as found in a constitutively active adrenergic receptor (6).Sequence alignment of GPCRs shows that certain amino acids are highly conserved at corresponding positions within the putative transmembrane domains (TMD) (7). Transitions among receptor conformations may reflect dynamic changes in side chain interactions within the receptor. Two of these conserved residues have been studied by reciprocal mutation in the GnRH and serotonin receptors, and the results suggest that the TMD 2 and 7 side chains have an interdependent role in receptor activation (8, 9). Most likely several other conserved side chains also interact to form the skeleton required for the conformational rearrangements that accompany the transition between inactive and active receptor states.The elucidation of the intramolecular interactions and conformational changes underlying receptor activation is hindered by the absence of high resolution structural data for any GPCR. The available low resolution projection maps of rhodopsin do not allow inferences about specific side chain interactions (10, 11). A prevalent approach to investigate structure-function relations of GPCRs is to introduce structural perturbations via site-directed mutagenesis and to evaluate their effect on receptor phenotype in binding and signal transduction assays (12). However, determining the phenotype of mutant receptors does not lead to an unequivocal interpretation concerning the structural basis of that phenotype (13).Molecular modeling has facilitated the integration of experimental observations and biophysical data into a mechanistic scheme for receptor structure and function (12,14). Structural and functional details of ligand binding (15,16) and receptor activation by agonist complexing (8,17) and by constitutively activating mutations (18) have been simulated in such models. The receptor models can thus provide a rationalization of current experime...