Explore the vast range of titles available.

Gout is an auto-inflammatory disease driven by urate deposits with a second co-stimulatory factor evoking an (peri)arthritic fulminant inflammation often with a debute at night; inflammatory signals are enhanced via a NLRP3 pathway. In gout patients, urate metabolism has had a positive balance for a time period of weeks to years before the arthritic syndrome or tophaecous disease becomes manifest. This may be due to katabolism or weight loss, enhanced dietary affluence, and overweight resulting in increased serum urate levels. Also, a decreased urate excretion results in proneness to hyperuricaemia and clinical gout. Pharmacotherapeutically, a negative urate balance should be the aim of clinicians and then the rational choice of treatment with uricosurics seems quite logical and promising, but has not had a thorough attention of pharma, researchers nor of clinicians, though most gout patients were and still are low excretors. Here, an overview on the 70-year-old journey mankind has made in a search for uricosurics resulting so far in only 1 registered uricosuric per continent.

ObjectivesWe explored the effects of B-cell directed therapy in subjects at risk of developing autoantibodypositive rheumatoid arthritis (RA), who never experienced inflammatory arthritis before, and explored biomarkers predictive of arthritis development.MethodsIndividuals positive for both anti-citrullinated peptide antibodies and rheumatoid factor but without arthritis were included in a randomised, double-blind, placebo-controlled study to receive a single infusion of 1000 mg rituximab or placebo.ResultsEighty-one individuals received treatment and were followed up for a mean of 29.0 (0–54) months, during which 30/81 (37%) individuals developed arthritis. The observed risk of developing arthritis in the placebo-treated group was 40%, which was decreased by 55% (HR 0.45, 95% CI 0.154 to 1.322) in the rituximab-treated group at 12 months. Rituximab treatment caused a delay in arthritis development of 12 months compared with placebo treatment at the point when 25% of the subjects had developed arthritis (p<0.0001). Erythrocyte sedimentation rate and the presence of anti-citrullinated α-enolase peptide 1 at baseline were significant predictors of arthritis development.ConclusionsA single infusion of 1000 mg rituximab significantly delays the development of arthritis in subjects at risk of developing RA, providing evidence for the pathogenetic role of B cells in the earliest, prearthritis stage of autoantibody positive RA.

Here, we demonstrate conservative treatment, using only antibiotics, oxygen, and analgesics, as a viable option for barotrauma‐induced tracheal laceration when a broncho‐esophageal fistula is not present.

Innovation systems and transitions thinking have become increasingly pervasive in what has been labelled a third generation of challenge-led innovation and transitions policy programmes. Although this upsurge is cause for celebration, we argue that the challenge now lies in developing the evaluation methods that allow for the assessment of strong and weak programmes, to foster a culture of learning and to maintain momentum. Therefore, in this brief review, we take stock of existing approaches and identify 6 tentative categories of evaluations, which we map out on the axis of formative and summative evaluation. Combining summative evaluations with more frequent formative evaluations may create the environment for rapid learning and policy adaptation necessary to prevent the current rise of systemic innovation and transition programmes from being short lived.

Gout is the most common type of arthritis and is evoked by arousal of the inflammasome in the presence of urate crystals superponed on a dysmetabolism with urate accumulation. Gout can be cured in most patients but still treatment is suboptimal in the majority of patients. Quality guidelines for management from experts such as from American College of Rheumatology aim to give guidance to US physicians and their own rheumatologists but have a value worldwide. We should know about the updates that were recently made publicly, with their strong and conditional recommendations, as we may learn and improve from their updated guideline.

Background High-flow nasal oxygen (HFNO) is frequently used to treat patients with acute hypoxemic respiratory failure (AHRF) due to viral pneumonia, including COVID-19. However, its clinical effect compared to conventional oxygen therapy (COT) remains largely unexplored in patients with a do not intubate (DNI) order. We aimed to assess whether HFNO compared to COT is associated with improved clinical outcomes in hospitalized patients with AHRF due to COVID-19 and a DNI order. Methods This analysis included patients with a DNI order and SARS-CoV-2 infection, selected from three observational studies, who were treated with COT only or HFNO. The primary endpoint was in-hospital mortality, the secondary endpoint was hospital length of stay (LOS). The effect of HFNO vs. COT was assessed using multivariable regression, accounting for pre-selected confounders. Results Between March 2020 and September 2021, 116 patients received HFNO and 110 patients received COT. Median age was 78 [72–83], and 78% of the patients had a Clinical Frailty Scale score of 4 to 9. In-hospital mortality was 64% for HFNO and 71% for COT ( p  = 0.29), with an adjusted odds ratio of 0.72 (95% confidence interval [0.34–1.54], p  = 0.40). Hospital LOS was 11 [6–18] days for HFNO, and 7 [4–12] days for COT ( p  < 0.001), with a remaining difference after adjusting for confounders ( p  < 0.01). Conclusion The lack of survival benefit and increased hospital LOS should be taken into account when considering HFNO for patients with a DNI order, suffering from AHRF due to viral pneumonia, like COVID-19. Clinical trial registration HFNO-COVID-19 study: DTR, NL9067 (Dutch Trial Registry), registration date: 27-11-2020.

Background The ABCG2 Q141K ( rs2231142 ) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is ~ 60% that of SLC2A9 , yet the effect size on gout is greater . We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls. Methods We analysed 1699 European gout cases and 14,350 normouricemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables. Results In Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR = 1.85, P  = 3.8E − 21 and OR meta  = 1.85, P  = 1.3E − 03 , respectively). There was evidence for an effect of 141K in determining HU in European (OR = 1.56, P  = 1.7E − 18 ) but not in Polynesian (OR meta  = 1.49, P  = 0.057). For SLC2A9 rs11942223 , the T allele associated with gout in the presence of HU in European (OR = 1.37, P  = 4.7E − 06 ), however significantly weaker than ABCG2 rs2231142 141K ( P Het  = 0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and rs10011796 . Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian ( P  = 0.009) and 2.6-fold in European ( P  = 9.9E − 06 ). The 141K allele of ABCG2 associated with increased gout flare frequency in Polynesian ( P meta   =  2.5E − 03 ). Conclusion These data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

To assess the cost-effectiveness of various combinations of urate lowering therapy (ULT) and anti-inflammatory treatment in the management of newly diagnosed gout patients, from the Dutch societal perspective. A probabilistic patient-level simulation estimating costs and quality-adjusted life years (QALYs) comparing gout and hyperuricemia treatment strategies was performed. ULT options febuxostat, allopurinol and no ULT were considered. Flare treatments naproxen, colchicine, prednisone, and anakinra were considered. A Markov Model was constructed to simulate gout disease. Health states were no flare, and severe pain, mild pain, moderate pain, or no pain in the presence of a flare. Model input was derived from patient level clinical trial data, meta-analyses or from previously published health-economic evaluations. The results of probabilistic sensitivity analyses were presented using incremental cost-effectiveness ratios (ICERs), and summarized using cost-effectiveness acceptability curves (CEACs). Scenario analyses were performed. The ICER for allopurinol versus no ULT was €1,381, when combined with naproxen. Febuxostat yielded the highest utility, but also the highest costs (€4,385 vs. €4,063 for allopurinol), resulting in an ICER of €25,173 when compared to allopurinol. No ULT was not cost-effective, yielding the lowest utility. For the gout flare medications, comparable effects on utility were achieved. Combined with febuxostat, naproxen was the cheapest option (€4,404), and anakinra the most expensive (€4,651). The ICER of anakinra compared to naproxen was €818,504. Colchicine and prednisone were dominated by naproxen. Allopurinol and febuxostat were both cost-effective compared to No ULT. Febuxostat was cost-effective in comparison with allopurinol at higher willingness-to-pay thresholds. For treating gout flares, colchicine, naproxen and prednisone offered comparable health economic implications, although naproxen was the favoured option.

Abstract Sensing customer needs capabilities generally help firms to utilize customer feedback. Yet, as research linking micro-economics to industrial dynamics has shown, a strong focus on such feedback may prevent an adequate response to more promising market developments. We analyse this tension for firms providing customized services, whose innovativeness heavily depends on customer input. By drawing upon an NK search model, we simulate various interactive search strategies. Our simulations result in hypotheses concerning the strategies’ relation to innovation-based turnover. We use survey data from 292 firms to substantiate our expectations empirically. Both our simulation and regression results point to a positive influence on turnover of sensing customer needs and of customer feedback. While the interaction effect is positive for non-customizing service providers, it is negative for their customizing counterparts. The latter group may fail to exploit their inventiveness, as they concentrate on tuning new services to the specific needs of existing customers rather than turning them into more widely marketable innovations.

BackgroundIncreased titers of autoantibodies targeting the G-protein-coupled receptors angiotensin II type 1 receptor (AT1R) and endotelin-1 type A receptor (ETAR) are associated with severe coronavirus disease 2019 (COVID-19) infection. The aim of this study was to determine whether 1) these antibodies are specifically related to COVID-19 disease pathogenesis or increased during any severe respiratory illness, 2) if they are formed during illness, and 3) if they correlate with inflammatory markers or long-term symptoms.MethodsAntibodies against AT1R, ETAR, and antinuclear antibodies (ANAs) were measured in n=40 prospectively enrolled COVID-19 patients and n=207 COVID-19 patients included in a biobank. Clinical and laboratory findings were prospectively and retrospectively assessed in both cohorts, and results were combined for analysis. The presence of auto-antibodies against AT1R or ETAR in peripheral blood was compared between hospitalized patients with COVID-19 and controls (n=39). Additionally, AT1R and ETAR titers were compared between patients with an unfavorable disease course, defined as intensive care admission and/or death during hospital admission (n=121), to those with a favorable disease course (n=126). A subset of intubated patients with severe COVID-19 were compared to intubated patients with acute respiratory distress syndrome (ARDS) due to any other cause.ResultsSignificantly increased AT1R and ETAR antibody titers were found in COVID-19 patients compared to controls, while titers were equal between favorable and unfavorable COVID-19 disease course groups. On ICU, intubated patients with COVID-19 had significantly increased AT1R and ETAR titers compared to patients with ARDS due to any other cause. The titers did not correlate with baseline inflammatory markers during admission or with diffusion capacity, cognitive impairment, or fatigue measured at 3 months follow-up.ConclusionsIn patients hospitalized for COVID-19, antibodies against AT1R and ETAR are increased compared to controls and patients with ARDS due to other causes than COVID-19. The baseline antibody titers do not correlate with inflammatory markers or long-term symptoms in this study.