Evaluation of the Genetic Association Between Adult Obesity and Neuropsychiatric Disease

Extreme obesity (EO, BMI>50) is frequently associated with neuropsychiatric disease (NPD). As both EO and NPD are heritable central nervous system disorders, we assessed the prevalence of protein truncating (PTV) and copy number variants (CNV) in genes/regions previously implicated in NPD, in adults with EO (n=149) referred for weight loss/bariatric surgery. We also assessed the prevalence of CNVs in patients referred to University College London Hospital (UCLH) with EO (n=218) and obesity (O, BMI 35-50, n=374) and a Swedish cohort of participants from the community with predominantly O (n=161). The prevalence of variants was compared to controls in ExAC/gnomAd database. In the discovery cohort (high NPD prevalence: 77%), the cumulative PTV/CNV allele frequency (AF) was 7.7 % vs 2.6% in controls (Odds Ratio (OR) 3.1, (95% CI 2-4.1, p<0.0001). In the UCLH EO cohort (intermediate NPD prevalence: 47%), CNV AF (1.8% vs 0.9% in controls, OR 1.95, 95% CI 0.96-3.93, p=0.06) was lower than the discovery cohort. CNV AF was not increased in the UCLH O cohort (0.8%). No CNVs were identified in the Swedish cohort with no NPD. These findings suggest PTV/CNVs, in genes/regions previously associated with NPD, may contribute to NPD in patients with EO

Origin of the Spin-Orbital Liquid State in a Nearly J=0 Iridate Ba3ZnIr2O9

We show using detailed magnetic and thermodynamic studies and theoretical calculations that the ground state of Ba3ZnIr2O9 is a realization of a novel spin-orbital liquid state. Our results reveal that Ba3ZnIr2O9 with Ir5+ (5d(4)) ions and strong spin-orbit coupling (SOC) arrives very close to the elusive J = 0 state but each Ir ion still possesses a weak moment. Ab initio density functional calculations indicate that this moment is developed due to superexchange, mediated by a strong intradimer hopping mechanism. While the Ir spins within the structural Ir2O9 dimer are expected to form a spin-orbit singlet state (SOS) with no resultant moment, substantial frustration arising from interdimer exchange interactions induce quantum fluctuations in these possible SOS states favoring a spin-orbital liquid phase down to at least 100 mK

Exosomes Derived from M. Bovis BCG Infected Macrophages Activate Antigen-Specific CD4+ and CD8+ T Cells In Vitro and In Vivo

Activation of both CD4+ and CD8+ T cells is required for an effective immune response to an M. tuberculosis infection. However, infected macrophages are poor antigen presenting cells and may be spatially separated from recruited T cells, thus limiting antigen presentation within a granuloma. Our previous studies showed that infected macrophages release from cells small membrane-bound vesicles called exosomes which contain mycobacterial lipid components and showed that these exosomes could stimulate a pro-inflammatory response in naïve macrophages. In the present study we demonstrate that exosomes stimulate both CD4+ and CD8+ splenic T cells isolated from mycobacteria-sensitized mice. Although the exosomes contain MHC I and II as well as costimulatory molecules, maximum stimulation of T cells required prior incubation of exosomes with antigen presenting cells. Exosomes isolated from M. bovis and M. tuberculosis infected macrophages also stimulated activation and maturation of mouse bone marrow-derived dendritic cells. Interestingly, intranasal administration of mice with exosomes isolated from M. bovis BCG infected macrophages induce the generation of memory CD4+ and CD8+ T cells. The isolated T cells also produced IFN-γ upon restimulation with BCG antigens. The release of exosomes from infected macrophages may overcome some of the defects in antigen presentation associated with mycobacterial infections and we suggest that exosomes may be a promising M. tuberculosis vaccine candidate

Application of sebomics for the analysis of residual skin surface components to detect potential biomarkers of type-1 diabetes mellitus

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Te images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Metabolic imbalance in chronic diseases such as type-1 diabetes may lead to detectable perturbations in the molecular composition of residual skin surface components (RSSC). This study compared the accumulation rate and the composition of RSSC in type-1 diabetic patients with those in matched controls in order to identify potential biomarkers of the disease. Samples of RSSC were collected from the foreheads of type-1 diabetic (n = 55) and non-diabetic (n = 58) volunteers. Samples were subsequently analysed to identify individual components (sebomic analysis). There was no significant difference in the rate of accumulation of RSSC between type-1 diabetics and controls. In terms of molecular composition, 171 RSSC components were common to both groups, 27 were more common in non-diabetics and 18 were more common in type-1 diabetic patients. Statistically significant (P < 0.05) differences between diabetic and non-diabetic volunteers were observed in the recovered amounts of one diacylglyceride (m/z 594), six triacylglycerides (m/z 726-860) and six free fatty acids (m/z 271-345). These findings indicate that sebomic analysis can identify differences in the molecular composition of RSSC components between type-1 diabetic and non-diabetic individuals. Further work is required to determine the practical utility and identity of these potential biomarkers.Peer reviewedFinal Published versio

Sustainable conversion of agro-wastes into useful adsorbents

Preparation and characterization of raw andactivated carbon derived from three different selectedagricultural wastes: kola nut pod raw and activated (KNPRand KNPA), bean husk raw and activated (BHR and BHA)and coconut husk raw and activated (CHR and CHA) wereinvestigated, respectively. Influences of carbonization andacid activation on the activated carbon were investigatedusing SEM, FTIR, EDX, pHpzcand Boehm titration tech-niques, respectively. Carbonization was done at 350°C for2 h followed by activation with 0.3 M H3PO4(ortho-phosphoric acid). Results obtained from SEM, FTIR, andEDX revealed that, carbonization followed by acid acti-vation had a significant influence on morphology and ele-mental composition of the samples. SEM showed well-developed pores on the surface of the precursors after acidtreatment, FTIR spectra revealed reduction, broadening,disappearance or appearance of new peaks after acid acti-vation. EDX results showed highest percentage of carbonby atom respectively in the order BHA[KNPA[CHArespectively. The pHpzcwas found to be 5.32, 4.57 and 3.69for KNPA, BHA and CHA, respectively. Boehm titrationresult compliments that of pHpzc, indicating that the sur-faces of the prepared adsorbents are predominantly acidic.This study promotes a sustainable innovative use of agro-wastes in the production of cheap and readily availableactivated carbons, thereby ensuring more affordable waterand effluent treatment adsorbents

Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012

OBJECTIVE: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. DESIGN: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. RESULTS: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO (2)/FiO (2) ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO (2)/FI O (2) 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5-10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). CONCLUSIONS: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients

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