Prevention and partial reversion of the lupus phenotype in ABIN1[D485N] mice by an IRAK4 inhibitor

OBJECTIVE: We have reported previously that the IRAK4 inhibitor PF06426779 given to ubiquitin-binding-defective ABIN1[D485N] mice at 6 weeks of age prevents the major facets of lupus that develop 10 weeks later. The present study was undertaken to investigate whether PF06426779 could reverse the lupus phenotype when administered to 13-week-old ABIN1[D485N] mice that had already developed symptoms of lupus. METHODS: Splenomegaly, the number of splenic neutrophils, T(FH) and Germinal Centre B (GCB) cells, serum levels of immunoglobulins, the extent of kidney, liver and lung pathology, and glomerular IgA and IgM were measured after feeding 13-week-old ABIN1[D485N] and wild-type mice for another 10 weeks with R&M3 diet with and without PF06426779 (4 g/kg). RESULTS: Following drug treatment, spleen size and weight, splenic neutrophil numbers, and serum IgA and glomerular IgA levels of ABIN1[D485N] mice returned to those seen in wild-type mice. The rise in splenic T(FH) and GCB numbers, the increase in kidney and liver pathology, and the concentrations of serum IgG1, IgG2A and IgE between 13 and 23 weeks were suppressed. There was no reduction in the level of anti-self double-stranded DNA, anti-self nuclear antigens or IgM during the drug treatment. CONCLUSIONS: The results demonstrate the therapeutic potential of IRAK4 inhibitors for the treatment of lupus and raise the possibility of monitoring efficacy by measuring decreases in the serum levels of IgA. Our results support the view that there may be a closer connection between lupus and IgA nephropathy than realised previously

ICAR: endoscopic skull‐base surgery

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Nations within a nation: variations in epidemiological transition across the states of India, 1990–2016 in the Global Burden of Disease Study

18% of the world's population lives in India, and many states of India have populations similar to those of large countries. Action to effectively improve population health in India requires availability of reliable and comprehensive state-level estimates of disease burden and risk factors over time. Such comprehensive estimates have not been available so far for all major diseases and risk factors. Thus, we aimed to estimate the disease burden and risk factors in every state of India as part of the Global Burden of Disease (GBD) Study 2016

Enterocutaneous Fistulae: Etiology, Treatment, and Outcome – A Study from South India

Background/Aim: Enterocutaneous fistula (ECF) is a difficult condition managed in the surgical wards and is associated with significant morbidity and mortality. Sepsis, malnutrition, and electrolyte abnormality is the classical triad of complications of ECF. Sepsis with malnutrition is the leading cause of death in cases of ECF. Although it is a common condition, no recent report in literature on the profile of patients with ECF has been documented from the southern part of India. Materials and Methods: All consecutive patients who developed or presented with ECF during the study period were included in the study. The etiology, anatomic distribution, fistula output, clinical course, complications, predictive factors for spontaneous closure, and outcomes for patients with ECF were studied. Results: A total of 41 patients were included in this prospective observational study, of which 34 were males and 7 were females. About 95% of ECF were postoperative. Ileum was found to be the most common site of ECF. Also, 49% of fistulas were high output and 51% were low output. Serum albumin levels correlated significantly with fistula healing and mortality. Surgical intervention was required in 41% of patients. Conclusion: Most of the ECF are encountered in the postoperative period. Serum albumin levels can predict fistula healing and mortality. Conservative management should be the first line of treatment. Mortality in patients with ECF continues to be significant and is commonly related to malnutrition and sepsis

Institutional Investment and Intermediation in the Hedge Fund Industry

Using new data on the hedge fund investments of institutional investors, this paper is the first to examine the determinants and consequences of intermediation in the hedge fund industry. Our empirical analysis reveals several findings consistent with predictions from the theoretical literature. First, larger investors are more likely to invest directly with hedge funds instead of using intermediated channels. Second, institutions investing directly tend to outperform their intermediary-using counterparts. The inferior performance of institutions using intermediaries reflects: (i) worse performance on their few direct hedge fund investments and (ii) their larger allocation to funds of hedge funds that are known to perform worse than direct hedge fund investments. Taken together, these findings suggest an equilibrium in which larger institutions enjoy economies of scale, enabling direct investment into relatively better performing hedge funds. As institutional size and the number of hedge fund investments increase, the returns from direct investment do exhibit a decline, suggesting eventual scale diseconomies

CEO Power and Firm Performance under Pressure

Are powerful chief executive officers (CEOs) more effective in responding to pressure from the economic environment? Concentrating decision-making power may facilitate rapid decision making; however, the quality of decision making may be compromised, with severe consequences for the firm if a powerful CEO is less likely to receive independent advice or to have her decisions scrutinized. We empirically investigate the performance of firms with powerful CEOs when industry conditions deteriorate. We focus on industry downturns as these represent an exogenous shock to a firm\u27s environment and on settings in which CEO power and access to quality information is likely more consequential: innovative firms, firms with relatively little related-industry board expertise, firms operating in competitive industries, and firms operating in industries characterized by relatively greater managerial discretion. In each of these settings we find powerful CEOs perform significantly worse than other CEOs, suggesting contexts in which centralized decision making is potentially of greater concern