Dayanand Medical College & Hospital

Abstract Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes 1 . Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel 2 ) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

BACKGROUND: The hepatitis C pandemic has been systematically studied and characterized in North America and Europe, but this important public health problem has not received equivalent attention in other regions. AIM: The objective of this systematic review was to characterize hepatitis C virus (HCV) epidemiology in selected countries of Asia, Australia and Egypt, i.e. in a geographical area inhabited by over 40% of the global population. METHODOLOGY: Data references were identified through indexed journals and non-indexed sources. In this work, 7770 articles were reviewed and 690 were selected based on their relevance. RESULTS: We estimated that 49.3-64.0 million adults in Asia, Australia and Egypt are anti-HCV positive. China alone has more HCV infections than all of Europe or the Americas. While most countries had prevalence rates from 1 to 2% we documented several with relatively high prevalence rates, including Egypt (15%), Pakistan (4.7%) and Taiwan (4.4%). Nosocomial infection, blood transfusion (before screening) and injection drug use were identified as common risk factors in the region. Genotype 1 was common in Australia, China, Taiwan and other countries in North Asia, while genotype 6 was found in Vietnam and other Southeast Asian countries. In India and Pakistan genotype 3 was predominant, while genotype 4 was found in Middle Eastern countries such as Egypt, Saudi Arabia and Syria. CONCLUSION: We recommend implementation of surveillance systems to guide effective public health policy that may lead to the eventual curtailment of the spread of this pandemic infection.

OBJECTIVE: To report the clinical, radiological, and immunological association of demyelinating disorders with anti–Nmethyl- D-aspartate receptor (NMDAR) encephalitis. METHODS: Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. RESULTS: Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p50.011). INTERPRETATION: Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis.

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohn's disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

Objectives: To identify the risk factors associated with Candida auris candidaemia, as this fungus now poses a global threat.

BACKGROUND: A unified set of criteria for neurocysticercosis (NCC) has helped to standardize its diagnosis in different settings. METHODS: Cysticercosis experts were convened to update current diagnostic criteria for NCC according to two principles: neuroimaging studies are essential for diagnosis, and all other information provides indirect evidence favoring the diagnosis. Recent diagnostic advances were incorporated to this revised set. RESULTS: This revised set is structured in absolute, neuroimaging and clinical/exposure criteria. Absolute criteria include: histological confirmation of parasites, evidence of subretinal cysts, and demonstration of the scolex within a cyst. Neuroimaging criteria are categorized as major (cystic lesions without scolex, enhancing lesions, multilobulated cysts, and calcifications), confirmative (resolution of cysts after cysticidal drug therapy, spontaneous resolution of single enhancing lesions, and migrating ventricular cysts on sequential neuroimaging studies) and minor (hydrocephalus and leptomeningeal enhancement). Clinical/exposure criteria include: detection of anticysticercal antibodies or cysticercal antigens by well-standardized tests, systemic cysticercosis, evidence of a household Taenia carrier, suggestive clinical manifestations, and residency in endemic areas. Besides patients having absolute criteria, definitive diagnosis can be made in those having two major neuroimaging criteria (or one major plus one confirmative criteria) plus exposure. For patients presenting with one major and one minor neuroimaging criteria plus exposure, definitive diagnosis of NCC requires the exclusion of confounding pathologies. Probable diagnosis is reserved for individuals presenting with one neuroimaging criteria plus strong evidence of exposure. CONCLUSIONS: This revised set of diagnostic criteria provides simpler definitions and may facilitate its more uniform and widespread applicability in different scenarios.

INTRODUCTION: Ulcerative colitis occurs worldwide. It is considered common in most of Europe and North America and uncommon in most of the developing Asian countries. The incidence/prevalence of ulcerative colitis varies not only according to geographical region but also with race and ethnicity. There are no reported data from India on the incidence of the disease and its prevalence. MATERIAL AND METHODS: A house to house survey was conducted by questionnaire, formulated to enquire about symptoms that are suggestive of ulcerative colitis. Those with prolonged diarrhoea with or without rectal bleeding were considered as suspected cases. These suspected cases were subjected to video sigmoidoscopy/colonoscopy and rectal biopsy. In addition, patients already diagnosed and receiving treatment for ulcerative colitis, encountered during the survey, were reviewed. Resurvey of the same areas was conducted after a one year interval to detect new cases. Using direct methods, standardised rates were calculated using world standard population weights 22, 18, 16, 12, 12, 9, 7, 3, and 1 for each 10 year age group. Standardised rates were also obtained separately for males, females, and combined populations, using the Punjab state 1991 population census data. Rates were also estimated according to UK 2000 population data. Ninety five per cent confidence intervals (95% CI) of prevalence and incidence rates of ulcerative colitis were estimated under the assumption that the distribution of cases followed a Poisson probability model. RESULTS: A total population of 51 910 were screened from January to March 1999. We identified 147 suspected cases and of these 23 were finally established as ulcerative colitis cases, giving a crude prevalence rate of 44.3 per 100 000 inhabitants (95% CI 29.4-66.6). A second visit to the same areas after one year identified 10 suspected cases in a population of 49 834. Of these, three were confirmed as "definite" ulcerative colitis giving a crude incidence rate of 6.02 cases per 100 000 inhabitants (95% CI 1.2-17.6). CONCLUSIONS: This is the first population based study from India reporting on the incidence and prevalence of ulcerative colitis. The disease frequency is not much less than that reported from Europe and North America.

Recommendation 4.

Human cadaveric donors are essential for research in the anatomical sciences. However, many research papers in the anatomical sciences often omit a statement regarding the ethical use of the donor cadavers or, as no current standardized versions exist, use language that is extremely varied. To rectify this issue, 22 editors-in-chief of anatomical journals, representing 17 different countries, developed standardized and simplified language that can be used by authors of studies that use human cadaveric tissues. The goal of these editor recommendations is to standardize the writing approach by which the ethical use of cadaveric donors is acknowledged in anatomical studies that use donor human cadavers. Such sections in anatomical papers will help elevate our discipline and promote standardized language use in others non anatomy journals and also other media outlets that use cadaveric tissues.

Abstract AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca 2+ -impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are co-expressed with GluA1, most GRIA2 mutations cause a decreased current amplitude and some also affect voltage rectification. Our results show that de-novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD and DEE also disrupt glutamatergic synaptic transmission.

OBJECTIVES: Cirrhotics with minimal hepatic encephalopathy (MHE) have a poor health-related quality of life (HRQOL). Treatment of MHE is still evolving. The aim of this double-blind randomized pilot study was to assess the efficacy of rifaximin in improving neuropsychometric (NP) test performance and HRQOL in patients with MHE. METHODS: MHE was diagnosed if any two NP tests (number and figure connection tests, picture completion, digit symbol, and block design tests) were deranged beyond 2 s.d. of normal. HRQOL was assessed using the sickness impact profile (SIP) questionnaire. RESULTS: A total of 486 patients with cirrhosis were screened and 284 were found eligible. Out of these 115 (40.9%) had MHE, of which 21 refused consent and 94 were randomized to receive placebo (n=45) and rifaximin (n=49; 1200 mg/day) for 8 weeks. At the end of treatment, significantly more number of patients in rifaximin group showed reversal of MHE (75.5% (37/49) vs. 20% (9/45) in placebo group; P<0.0001). Rifaximin group also showed significant reduction in mean number of abnormal NP tests (baseline, 2.35 (95% confidence interval (CI), 2.17-2.53); 2 weeks, 1.29 (95% CI, 1.02-1.56), P=0.002; 8 weeks, 0.81 (95% CI, 0.61-1.02), P=0.000), compared with placebo group (baseline, 2.31 (95% CI, 2.03-2.59); 2 weeks, 2.03 (95% CI, 1.74-2.31); 8 weeks, 1.97 (95% CI, 1.69-2.25), P>0.05). The mean total SIP score also improved significantly in rifaximin group (baseline, 11.67 (95% CI, 10.31-13.03); 8 weeks, 6.45 (95% CI, 5.59-7.30); P=0.000) compared with placebo group (baseline, 9.86 (95% CI, 8.66-11.06); 8 weeks, 8.51 (95% CI, 7.35-9.67); P=0.82). Improvement in HRQOL correlated with improvement in NP tests. Rifaximin was well tolerated. CONCLUSIONS: Rifaximin significantly improves both cognitive functions and HRQOL in patients with MHE.

Alpha (α)-2-Adrenergic receptor (AR) agonists have been the focus of interest for their sedative, analgesic, perioperative sympatholytic, anesthetic-sparing, and hemodynamic-stabilizing properties.[1] Dexmedetomidine, a highly selective a2-AR agonist with a relatively high ratio of α2/ α 1-activity (1620:1 as compared to 220:1 for clonidine), possesses all these properties but lacks respiratory depression,[23] making it a useful and safe adjunct in diverse clinical applications.[4] Numerous investigations into its uses have featured in various issues of this journal. This editorial aims to provide an overview of its current clinical status and new therapeutic avenues under investigation. Mechanism of action The hypnotic and supraspinal analgesic effects of dexmedetomidine are mediated by the hyperpolarization of noradrenergic neurons, which suppresses neuronal firing in the locus ceruleus along with inhibition of norepinephrine release and activity in the descending medullospinal noradrenergic pathway, secondary to activation of central α2-ARs.[256] This suppression of inhibitory control triggers neurotransmitters that decrease histamine secretion producing hypnosis similar to normal sleep, without ventilatory depression, making dexmedetomidine a near ideal sedative.[127] Suppression of activity in the descending noradrenergic pathway, which modulates nociceptive neurotransmission, terminates propagation of pain signals leading to analgesia.[6] In the spinal cord, activation of both α2-C and α2-ARs, situated in the neurons of superficial dorsal horn especially lamina II,[589] directly reduces pain transmission by reducing the release of pro-nociceptive transmitter, substance P and glutamate from primary afferent terminals and by hyperpolarizing spinal interneurons via G-protein-mediated activation of potassium channels.[5] Postsynaptic activation of central α2-ARs results in sympatholytic effect leading to hypotension and bradycardia, an effect judiciously used to attenuate the stress response of surgery.[1011] Other useful effects of activation of α2-ARs include decreased salivation, increased glomerular filtration, decreased intraocular pressure, and decreased shivering threshold.[12] Majority of the above effects of dexmedetomidine can be utilized beneficially in the intensive care and in the conduct of anesthesia. Intensive Care Sedation In 1999, Food and Drug Administration (FDA) approved dexmedetomidine as a sedative and supplement to sedation in the intensive care units (ICU) for patients undergoing mechanical ventilation of less than 24 hours duration. It has a short elimination half life of 2 h and a linear pharmacokinetic behavior, in continuous infusion for 24 h, with a short α- half-life of 6 min.[1213] These pharmacokinetic properties and the availability of an antagonistic agent Atipamezole,[1214] make it an ideal drug for intravenous titration both as a sole agent and for continuous infusion in the ICU, operating room, and other areas. Its unique sedative action mimics normal sleep, which translates into an advantage during weaning from mechanical ventilation. Dexmedetomidine need not be discontinued and the ongoing sedation can be maintained following tracheal extubation, preventing emergence delirium and agitation.[215] With a large body of recent research supporting its favorable profile in improving outcome and long-term brain function in the critically ill, studies are now focusing on the safety and efficacy of dexmedetomidine beyond 24 h.[216–18] In a Phase IV study, dexmedetomidine was safe in dosages up to 1.4 mcg/kg/hour for greater than 24 h and did not produce rebound tachycardia or hypertension when abruptly discontinued.[1819] The Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS) randomized trial[20] reported an earlier return to a delirium-free cognitive state and more ventilator-free days with dexmedetomidine when used for 24 to 120 h.[220] The above studies indicate that it can be used long-term (>24 h) in critically ill patients. Recent work has shown that omitting or halving the loading dose eliminates adverse cardiovascular effects like hypotension and bradycardia but preserves dexmedetomidine's sedative action.[2–42122] Caution should be exercised in patients who are volume depleted, vasoconstricted, or have severe heart block.[2421] Publication of few cases of asystole after its use warrants intense vigilance with its use and the need for a large-scale study on its safety.[2324] Sole agent for Procedural Sedation A new role as a sole agent for procedural sedation is fast emerging mainly due to its faster onset of action, faster recovery and discharge times. The Federal Drug Administration (FDA) has approved the use of dexmedetomidine as a sedative–analgesic and/or total anesthetic in adults and pediatric patients undergoing small minimally invasive procedures, with or without the need for tracheal intubation.[4] It is a safe sedative alternative to benzodiazepine / opioid combinations in patients undergoing monitored anesthesia care for a multitude of procedures because of its analgesic, “cooperative sedation,” and lack of respiratory depression properties.[41125–28] For the same reason, it has been used in the pediatric population and its use has even been reported in a 24-week gestation neonate treated for refractory agitation while on mechanical ventilation.[2930] An novel therapeutic role of dexmedetomidine is its use for opioid/benzodiazepine withdrawal in sedated pediatric patients during mechanical ventilation in critical care areas.[31] It counters the physiologic effects of withdrawal secondary to decrease in sympathetic outflow and noradrenergic activity, mediated mainly through postsynaptic α2-AR subtype in the locus ceruleus.[3233] It has potential for treatment of agitation and alcohol withdrawal in alcoholic patients after brain trauma, who require reliable, serial neurological testing to monitor the course of their traumatic brain injury.[34] This neuroprotective property is attributed to its preservation of sleep architecture and ventilatory drive with decreased sympathetic tone and inflammatory responses.[3536] Dexmedetomidine has shown neuroprotective effects in animal models of perinatal excitotoxic injury and hypoxic-ischemic injury,[37] making it a therapeutic option for prevention and treatment of post-anesthesia emergence, shivering, or delirium.[353839] Perioperative use Perioperative applications of dexmedetomidine include premedication, as part of multimodal anesthetic regimen, prevention of emergence delirium, and pain in the postoperative period.[212] Premedication with dexmedetomidine not only offers anxiolysis, sedation and analgesia, but also helps in attenuating the stress responses to tracheal intubation/extubation and emergence from anesthesia. Dexmedetomidine has high bioavailability when administered by the relatively noninvasive buccal or nasal route.[40] The buccal route ensures more compliance and better absorption (up to 82%) in younger children than intravenous administration.[240] Studies evaluating the efficacy, safety, optimal dosage of buccal dexmedetomidine in children have found a dose of 3–4 mcg/kg, one hour before surgery to be safe and effective.[41] Preliminary studies[4042] report better sedation at parental separation and induction of anesthesia with 1 mcg/kg intranasal dexmedetomidine when given 30-45 minutes prior to surgical procedure as compared to oral midazolam.[4344] The technique causes no discomfort during administration,[42] is relatively quick, simple, and may have benefits over transmucosal routes and rectal administration. The nasal route is effective and well tolerated for sedation and postoperative analgesia in adults in the dose of 1 μg/ kg given 45 min before surgery.[45] More studies are needed to evaluate the effect of premedication routes on various outcome measures like preoperative anxiety levels, induction time, emergence excitation, postoperative analgesic requirements, and postoperative behaviordisturbances.[4445] As an adjunct to general anesthesia it has minimum alveolar concentration (MAC) and opiate sparing properties, which helps in decreasing the inhalational anesthetic and opioid requirements by up to 90%,[24647] which can be used to advantage in situations where high anesthetic concentration is either undesirable or not tolerated. Certain neurosurgical procedures require a hemodynamically stable, comfortable, sedated patient who is awake and co-operative enough to perform neuromotor and neurocognitive tests on demand. Dexmedetomidine achieves this desired neurophysiologic profile, in dose of 0.2 to 0.5 mcg/kg/h, for procedures like awake craniotomies, deep brain stimulation, surgery near speech areas, minimally invasive endoscopic procedures, stereotactic interventions, interoperative imaging etc.[23748–50] Dexmedetomidine reduces rocuronium requirements during sevoflurane anesthesia, by altering the pharmacokinetic profile of rocuronium.[51] This effect may decrease muscle relaxant requirements during surgery, thereby potentially reducing the risk of residual muscle weakness during emergence. Dexmedetomidine significantly attenuates postoperative pain and reduces opioid and volatile anesthetic requirements in morbidly obese patients, without causing any cardio-respiratory depression and ensuring faster, neuromuscular recovery and smooth emergence.[52] Successful use of dexmedetomidine for sedation during vascular and cardiac surgery has been reported due to its cardio-protective modulation of sympathetic tone and maintenance of myocardial oxygen supply/demand ratio with consequent less perioperative ischemia.[2453] An emerging application, is its role in facilitating awake fiber-optic intubation (AFOI) in difficult airway situations.-[5455] Successful AFOI in patients with a difficult airway necessitates maintenance of a clear dry airway, with spontaneous ventilation, such that the airway is secured without any discomfort to the patient and complications like upper airway obstruction, respiratory depression, and aspiration are avoided. Dexmedetomidine provides an ideal solution to this problem especially in critical airways compromised due to anatomical distortions and infections.[56] Series of case reports document efficacy of dexmedetomidine as a sole sedative for awake intubations in managing a critical airway, as a bolus ranging from 0.5 to 1 mcg/kg followed by infusion of 0.2 to 0.7 mcg/kg/hr, with no evidence of respiratory depression.[5758] An unique attempt in this field has been the use of dexmedetomidine without any topicalization for AFOI in a patient with a critical airway who had a true documented allergy to local anesthetics.[59] For acute/chronic pain - The greater α2-AR selectivity of dexmedetomidine enhances the therapeutic window of dexmedetomidine in the treatment of pain.[60] Its opiate sparing effects has important implications for the management of acute postoperative pain and chronic pain states, including disorders involving spasticity or myofascial pain, neuropathic pain, sympathetically maintained pain such as complex regional pain syndrome (CRPS) and chronic daily headaches. It is evolving as an adjuvant analgesic, both as intravenous and intrathecal infusion, in cancer pain refractory to multiple treatment modalities.[6162] Pre- and intra-operative intravenous dexmedetomidine prolongs the duration of sensory block of local anesthetics during spinal anesthesia[63] and peripheral nerve block.[64] Postoperatively, intravenous dexmedetomidine infusion is associated with a reduction in nausea and vomiting, reducing postoperative morbidity.[60] Its use in obstetric analgesia is being explored in view of the high lipophilicity. It is retained in the placental tissue, thereby resulting in less fetal transfer and a decreased incidence of fetal bradycardia. Continuous intravenous dexmedetomidine infusion has been successfully used as an adjunct to systemic opioids in laboring parturients who could not benefit from epidural analgesia.[6566] As a neuraxial adjuvant - α2-AR agonists can activate a number of antinociceptive mechanisms depending on the dose and the route of administration; however, the main site for their antinociceptive effect in physiological pain conditions seems to be the spinal dorsal horn.[67] Evidence indicates that neuraxial administration of dexmedetomidine produces spinal analgesia as efficiently as clonidine.[56869] Epidural dexmedetomidine exhibits synergism with local anesthetics prolonging the sensory/motor block duration time, postoperative analgesia, and results in intense motor block,[70] without any additional morbidity. Clinical studies exhibit potentiation of neuraxial local anesthetics, decrease in intraoperative anesthetic requirements with prevention of intraoperative awareness, improved intraoperative oxygenation, and improved postoperative analgesia when epidural dexmedetomidine was used in conjunction with general anesthesia.[71] Experimental animal and human studies of intrathecal dexmedetomidine as an additive to local anesthetics, have observed a dose dependent prolongation of sensory block, increase in motor block, along with prolongation of the postoperative analgesia, thus allowing for a decrease in the local anesthetic dose in high risk group of patients.[568697273] In a few dose finding studies, investigators have used 3, 5, and 10 mcg of intrathecal dexmedetomidine in human subjects with favorable results,[72–74] along with preserved hemodynamic stability and lack of sedation. A drawback of dexmedetomidine supplemented spinal block characteristics may be an increase in the duration of motor block, which may not suit ambulatory procedures.[74] More clinical studies are needed to validate the efficacy and safety of the optimum intrathecal dose of dexmedetomidine for supplementation with spinal local anesthetics. No neurological deficits have been reported till date in studies on both humans and animals during intrathecal/epidural use.[5687275] However, there is some evidence of demyelinization of the oligodendrocytes in the white matter, suggesting harmful effects on the myelin sheath when administered via the epidural route in animal studies.-[76] Advanced pathologic investigations are required to establish its safety. As an adjuvant in peripheral nerve block and intravenous regional anesthesia - Few clinical studies have evaluated the effect of adding dexmedetomidine to local anesthetics in peripheral nerve blocks. In a randomized double blind trial, dexmedetomidine shortened the onset time and prolonged the duration of the block and postoperative analgesia, when added to levobupivacaine for axillary brachial plexus block.[77] Animal studies have not shown any evidence of neurotoxicity even at higher doses, when applied directly to sciatic nerve models.[78] Furthermore, addition of dexmedetomidine in clinically relevant doses to ropivacaine results in a dose dependent increase in the duration of sensory and motor block.-[7980] Dexmedetomidine has also been reported to improve block quality, prolong post-deflation analgesia, and decrease tourniquet pain when used as an additive to lignocaine in intravenous regional anesthesia.[81] The peripheral analgesic effects of dexmedetomidine that potentiate local anesthetics are mediated by α2A-AR binding[6082] and have been utilized to enhance postoperative analgesia after intra-articular administration and direct infiltration of dexmedetomidine in a dose of 1 mcg/kg as an adjunct to local anesthetics.[82–84] Dexmedetomidine has evolved as a panacea for various applications/procedures with multiple promising delivery routes. Its clinical applications in adults and children include premedication, as part of multimodal anesthetic regimen, regional anesthesia, sedation, monitored anesthesia care, procedural sedation, prevention / treatment of emergence delirium, alcohol withdrawal & shivering, and the list continues to grow. Dexmedetomidine appears to have promising future applications in the field of neuroprotection, cardioprotection, and renoprotection, especially in children.[4445] The novel therapeutic uses of this α2-AR agonist can be put safely into practice after thorough evaluation by Randomized Controlled Trials .

Wnt/beta-catenin signaling plays an important role in normal development. However, its aberrant activation is associated with several cancers. The aim of this study is to examine the Wnt/beta-catenin pathway in patients with advanced pancreatic adenocarcinoma (n = 31). Paraffin sections from tumors (n = 16) and normal pancreata (n = 3) were used to determine the localization of beta-catenin. An additional 15 frozen tumors, adjacent normal pancreata (n = 5), or normal pancreata (n = 4) were utilized for protein isolation. Tumors were also examined for mutations in exon 3 of the CTNNB1 gene. More than 65% of the tumors showed an increase in total beta-catenin, consistent with its enhanced membranous, cytoplasmic, and nuclear localization, but only two showed mutations in CTNNB1. The majority of the remaining tumors demonstrated concurrent increases in Wnt-1 and frizzled-2 (positive regulators) and a decrease in Ser45/Thr41-phospho-beta-catenin. Electrophoretic mobility shift assay demonstrated beta-catenin-T-cell factor binding in tumors only. Adenomatous polyposis coli and axin, which are both negative regulators, remained unchanged. Unexpectedly, total glycogen synthase kinase-3beta protein was elevated in these tumors. Elevated levels of E-cadherin were also observed, although E-cadherin-beta-catenin association in tumors remained unaffected. Thus, Wnt/beta-catenin activation was observed in 65% of pancreatic adenocarcinomas, independently of beta-catenin gene mutations in most tumors.

1 Disclaimer. It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to the guidelines listed below to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances. While IDSA makes every effort to present accurate and reliable information, the information provided in these guidelines is "as is" without any warranty of accuracy, reliability, or otherwise, either express or implied. Neither IDSA nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented.

➤ Short bone-conserving femoral stems in total hip arthroplasty were designed to preserve proximal bone stock.➤ Given the distinct fixation principles and location of loading among these bone-conserving stems, a classification system is essential to compare clinical outcomes.➤ Due to the low quality of currently available evidence, only a weak recommendation can be provided for clinical usage of certain stem designs, while some other designs cannot be recommended at this time.➤ A high prevalence of stem malalignment, incorrect sizing, subsidence, and intraoperative fractures has been reported in a subset of these short stem designs.➤ Stronger evidence, including prospective multicenter randomized trials comparing standard stems with these newer designs, is necessary before widespread use can be recommended.

BACKGROUND: Increasing trend of hypertension is a worldwide phenomenon. The data on sustained hypertension in school going children is scanty in India. The present study was conducted to evaluate the prevalence of sustained hypertension and obesity in apparently healthy school children in rural and urban areas of Ludhiana using standard criteria. METHODS AND RESULTS: A total of 2467 apparently healthy adolescent school children aged between 11-17 years from urban area and 859 students from rural area were taken as subjects. Out of total 3326 students, 189 were found to have sustained hypertension; in urban areas prevalence of sustained hypertension was 6.69% (n=165) and in rural area it was 2.56% (n=24). Males outnumbered females in both rural and urban areas. The mean systolic and diastolic blood pressure of hypertensive population in both urban and rural population was significantly higher than systolic and diastolic blood pressure in their normotensive counterparts (urban normotensive systolic blood pressure:115.48+/-22.74 mmHg, urban hypertensive systolic blood pressure: 137.59+/-11.91 mmHg, rural normotensive systolic blood pressure: 106.31+/-19.86 mmHg, rural hypertensive systolic blood pressure: 131.63+/-10.13 mmHg, urban normotensive diastolic blood pressure: 74.18+/-17.41 mmHg, urban hypertensive diastolic blood pressure: 84.58+/-8.14 mmHg, rural normotensive diastolic blood pressure: 68.84+/-16.96 mmHg, rural hypertensive diastolic blood pressure: 79.15+/-7.41 mmHg). Overweight populationwas significantly higher in urban area. There were 287 (11.63%) overweight students and 58 (2.35%) were obese. In rural population overweight and obese students were 44 (4.7%) and 34 (3.63%) respectively. There was significant increase in prevalence of hypertension in both rural and urban population with increased body mass index in urban students; those with normal body mass index had prevalence of hypertension of 4.52% (n=96), in overweight it was 15.33% (n=44) and in obese it was 43.10% (n=25). In rural area, the overweight students showed prevalence of sustained hypertension in 6.82% (n=3) and in obese group it was 61.76% (n=21). None of the student with normal body mass index in rural area was found to be hypertensive. The mean body mass index of hypertensive population in both rural and urban areas was significantly higher than respective normotensive population (mean body mass index in urban normotensive group: 20.34+/-3.72 kg/m2, hypertensive group: 24.91+/-4.92 kg/m2; mean body mass index in rural normotensive group: 18.41+/-3.41 kg/m2, hypertensive group: 21.37+/-3.71 kg/m2, p<0.01). CONCLUSIONS: Prevalence of sustained hypertension is on the rise in urban area even in younger age groups. Blood pressure is frequently elevated in obese children as compared to lean subjects. This is possibly related to their sedentary lifestyle, altered eating habits, increased fat content of diet and decreased physical activities.

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), β blockers, and mineralocorticoid receptor antagonists (MRAs) are of proven benefit and are recommended by guidelines for management of patients with heart failure and reduced ejection fraction (HFrEF). We aimed to examine the first prospective multinational data from Asia on prescribing patterns of guideline-directed medical therapies and analyse its effect on outcomes. METHODS: In the prospective multinational ASIAN-HF registry (with enrolment from 46 centres in 11 countries in Asia), we enrolled patients aged 18 years or older, with symptomatic heart failure (stage C, with at least one episode of decompensated heart failure in the past 6 months that resulted in admission to hospital or was treated in an outpatient clinic) and left ventricular systolic dysfunction (ejection fraction ≤40% on baseline echocardiography, consistent with 2016 European Society of Cardiology guidelines). We excluded patients with heart failure caused by severe valvular heart disease, life-threatening comorbidity with a life expectancy of less than 1 year, who were unable or unwilling to give consent, or who had concurrent participation in a clinical trial. Patients were followed up for 3 years for the outcomes of death and cause-specific admittance to hospital. Primary outcomes were uptake of guideline-directed medical therapies (as proportions) by therapeutic class, achieved doses as proportions of guideline-recommended doses, and their association with 1-year composite outcome of all-cause death or admittance to hospital because of heart failure. This study is registered with ClinicalTrials.gov, number NCT01633398. FINDINGS: [5·1], 33% New York Heart Association class III or IV). Follow-up data were available for 4544 (90%) of 5061 eligible patients taking medication for heart failure, with median follow-up of 417 days (IQR 214-735). ACE inhibitors or ARBs were prescribed to 3868 (77%) of 5005 patients, β blockers to 3975 (79%) of 5061, and MRAs to 2998 (58%) of 5205, with substantial regional variation. Guideline-recommended dose was achieved in only 17% of cases for ACE inhibitors or ARB, 13% for β blockers, and 29% for MRAs. Country (all three drug classes), increasing body-mass index (ACE inhibitors or ARBs and MRAs), and in-patient recruitment (ACE inhibitors or ARBs and β blockers) were associated with attainment of guideline-recommended dose (all p<0·05). When adjusted for indication bias, increasing drug doses, from low dose (1-<25% of guideline-recommended dose) upwards were associated with lower hazards of a 1-year composite outcome for ACE inhibitors or ARBs and β blockers compared with non-users. The lowest adjusted hazards were in the group that attained guideline-recommended doses above 50% (hazard ratio [HR] 0·54, 95% CI 0·50-0·58 for ACE inhibitors or ARBs [50-99·9%]; HR 0·47, 0·46-0·50 for β blockers, and HR 0·77, 0·72-0·81 for MRAs [≥100%]). INTERPRETATION: Guideline-directed medical therapies at recommended doses are underutilised in patients with HFrEF. Improved uptake and uptitration of guideline-directed medical therapies are needed for better patient outcomes. FUNDING: National Medical Research Council (Singapore), A*STAR Biomedical Research Council ATTRaCT program, Boston Scientific Investigator Sponsored Research program, and Bayer.

We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻⁴) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10⁻⁸) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⁻³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10⁻⁴) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10⁻⁵ to < 10⁻⁷), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.

Abstract In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients ( F ROH ) for &gt;1.4 million individuals, we show that F ROH is significantly associated ( p &lt; 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44–66%] in the odds of having children. Finally, the effects of F ROH are confirmed within full-sibling pairs, where the variation in F ROH is independent of all environmental confounding.