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Abstract Context Early inflammatory thyroid eye disease (TED) can lead to symptomatic chronic disease, including disabling proptosis. Teprotumumab, an insulin-like growth factor-1 receptor (IGF-1R) inhibitor, previously demonstrated efficacy in acute, high-inflammation TED trials. Objective We present data from the first placebo-controlled trial with teprotumumab in chronic/low disease activity TED. Methods This randomized double-masked, placebo-controlled trial, conducted at 11 US centers, enrolled adult participants with TED duration of 2 to 10 years, Clinical Activity Score (CAS) ≤ 1 or no additional inflammation or progression in proptosis/diplopia for ≥1 year, proptosis ≥3 mm from before TED and/or from normal, euthyroid/mildly hypo/hyperthyroid, no prior teprotumumab, and no steroids within 3 weeks of baseline. Patients received (2:1) intravenous teprotumumab or placebo once every 3 weeks (total 8 infusions). The primary endpoint was proptosis (mm) improvement at Week 24. Adverse events (AEs) were assessed. Results A total of 62 (42 teprotumumab and 20 placebo) patients were randomized. At Week 24, least squares mean (SE) proptosis improvement was greater with teprotumumab (−2.41 [0.228]) than with placebo (−0.92 [0.323]), difference −1.48 (95% CI −2.28, −0.69; P = .0004). Proportions of patients with AEs were similar between groups. Hyperglycemia was reported in 6 (15%) vs 2 (10%) and hearing impairment in 9 (22%) vs 2 (10%) with teprotumumab and placebo, respectively. AEs led to discontinuation in 1 teprotumumab (left ear conductive hearing loss with congenital anomaly) and 1 placebo patient (infusion-related). There were no deaths. Conclusion Teprotumumab significantly improved proptosis vs placebo in longstanding/low inflammation TED, demonstrating efficacy regardless of disease duration/activity. The safety profile was comparable to that previously reported.

Thyroid eye disease (TED) is a complex disease associated with myriad clinical presentations, including facial disfigurement, vision loss, and decreased quality of life. Traditionally, steroid therapy and/or radiation therapy were commonly used in the treatment of active TED. While these therapies can help reduce inflammation, they often do not have a sustainable, significant long-term effect on disease outcomes, including proptosis and diplopia. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment toward targeted biologic therapies. Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches. For instance, the insulin-like growth factor-1 receptor (IGF-1R) has been found to be upregulated in TED patients and to colocalize with the thyroid-stimulating hormone receptor (TSHR), forming a signaling complex. Teprotumumab is an antibody targeted against IGF-1R. By inhibiting the IGF-1R/TSHR signaling pathway, teprotumumab may reduce the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED. Due to promising phase II and III clinical trial results, teprotumumab has become the first biologic US Food and Drug Administration (FDA)-approved for the treatment of TED. In addition, there are currently ongoing studies looking at the use of antibodies targeting the neonatal Fc receptor (FcRn) in various autoimmune diseases, including TED. FcRn functions to transport immunoglobulin G (IgG) and prevent their lysosomal degradation. By blocking the recycling of IgG, this approach may dampen the body’s immune response, in particular the pathogenic IgG implicated in some autoimmune diseases. Advances in our understanding of the pathophysiology of TED, therefore, are leading to more targeted therapeutic options, and we are entering an exciting new phase in the management of TED. This review will cover recent insights into the understanding of TED pathophysiology and novel treatment options as well as ongoing studies of new potential treatment options for TED.

Support for the treatment of uncomplicated appendicitis with non-operative management rather than surgery has been increasing in the literature. We aimed to investigate whether treatment of uncomplicated appendicitis with antibiotics in children is inferior to appendicectomy by comparing failure rates for the two treatments. In this pragmatic, multicentre, parallel-group, unmasked, randomised, non-inferiority trial, children aged 5–16 years with suspected non-perforated appendicitis (based on clinical diagnosis with or without radiological diagnosis) were recruited from 11 children's hospitals in Canada, the USA, Finland, Sweden, and Singapore. Patients were randomly assigned (1:1) to the antibiotic or the appendicectomy group with an online stratified randomisation tool, with stratification by sex, institution, and duration of symptoms (≥48 h vs <48 h). The primary outcome was treatment failure within 1 year of random assignment. In the antibiotic group, failure was defined as removal of the appendix, and in the appendicectomy group, failure was defined as a normal appendix based on pathology. In both groups, failure was also defined as additional procedures related to appendicitis requiring general anaesthesia. Interim analysis was done to determine whether inferiority was to be declared at the halfway point. We used a non-inferiority design with a margin of 20%. All outcomes were assessed in participants with 12-month follow-up data. The trial was registered at ClinicalTrials.gov (NCT02687464). Between Jan 20, 2016, and Dec 3, 2021, 936 patients were enrolled and randomly assigned to appendicectomy (n=459) or antibiotics (n=477). At 12-month follow-up, primary outcome data were available for 846 (90%) patients. Treatment failure occurred in 153 (34%) of 452 patients in the antibiotic group, compared with 28 (7%) of 394 in the appendicectomy group (difference 26·7%, 90% CI 22·4–30·9). All but one patient meeting the definition for treatment failure with appendicectomy were those with negative appendicectomies. Of those who underwent appendicectomy in the antibiotic group, 13 (8%) had normal pathology. There were no deaths or serious adverse events in either group. The relative risk of having a mild-to-moderate adverse event in the antibiotic group compared with the appendicectomy group was 4·3 (95% CI 2·1–8·7; p<0·0001). Based on cumulative failure rates and a 20% non-inferiority margin, antibiotic management of non-perforated appendicitis was inferior to appendicectomy. None.

Thyroid eye disease (TED) is a rare disease that can lead to decreased quality of life, permanent disfigurement, and vision loss. Clinically, TED presents with exophthalmos, periorbital edema, extraocular muscle dysfunction, and eyelid retraction, and can lead to vision-threatening complications such as exposure to keratopathy and dysthyroid optic neuropathy (DON). Over the last several years, significant advancements have been made in the understanding of its pathophysiology as well as optimal management. Ethnic variations in the prevalence, clinical presentation, and risk of vision-threatening complications of TED are summarized, and risk factors associated with TED are discussed. Additionally, significant advances have been made in the management of TED. The management of TED traditionally included anti-inflammatory medications, orbital radiation therapy, orbital surgical decompression, and biologic therapies. Most recently, targeted therapies such as teprotumumab, an insulin-like growth factor-1 receptor antagonist, have been studied in the context of TED, with promising initial data. In this review, updates in the understanding and management of TED are presented with a focus on the international variations in presentation and management.

The design of rotor blades is based on information about aerodynamic phenomena. An important one is fluid-structure interaction (FSI) which describes the interaction between a flexible object (rotor blade) and the surrounding fluid (wind). However, the acquisition of FSI is complex, and only a few practical concepts are known. This paper presents a measurement setup to acquire real information about the FSI of rotating wind turbines in wind tunnel experiments. The setup consists of two optical measurement systems to simultaneously record fluid (PIV system) and deformation (photogrammetry system) information in one global coordinate system. Techniques to combine both systems temporally and spatially are discussed in this paper. Furthermore, the successful application is shown by several experiments. Here, different wind conditions are applied. The experiments show that the new setup can acquire high-quality area-based information about fluid and deformation.

Background Impaired intestinal microcirculation seems to play an important role in the pathogenesis of necrotizing enterocolitis (NEC). A previous study showed that a SrSO 2  < 30% is associated with an increased risk of developing of NEC. We aimed to determine the clinical usefulness of the cut off < 30% for SrSO 2 in predicting NEC in extremely preterm neonates. Methods This is a combined cohort observational study. We added a second cohort from another university hospital to the previous cohort of extremely preterm infants. SrSO 2 was measured for 1–2 h at days 2–6 after birth. To determine clinical usefulness we assessed sensitivity, specificity, positive and negative predictive values for mean SrSO 2  < 30. Odds ratio to develop NEC was assessed with generalized linear model analysis, adjusting for center. Results We included 86 extremely preterm infants, median gestational age 26.3 weeks (range 23.0-27.9). Seventeen infants developed NEC. A mean SrSO 2  < 30% was found in 70.5% of infants who developed NEC compared to 33.3% of those who did not (p = 0.01). Positive and negative predictive values were 0.33 CI (0.24–0.44) and 0.90 CI (0.83–0.96), respectively. The odds of developing NEC were 4.5 (95% CI 1.4–14.3) times higher in infants with SrSO2 < 30% compared to those with SrSO2  ≥  30%. Conclusions A mean SrSO 2 cut off ≥  30% in extremely preterm infants between days 2–6 after birth may be useful in identifying infants who will not develop NEC.

Abstract Context Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). Objective We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. Design Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. Setting Multicenter. Participants Patients with moderate-to-severe, active TED. Intervention In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. Main Outcome Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). Results The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. Conclusions These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

As a fundamental phenomenon of fluid mechanics, recent studies suggested laminar-turbulent transition belonging to the universality class of directed percolation. Here, the onset of a laminar separation bubble on an airfoil is analyzed in terms of the directed percolation model using particle image velocimetry data. Our findings indicate a clear significance of percolation models in a general flow situation beyond fundamental ones. We show that our results are robust against fluctuations of the parameter, namely, the threshold of turbulence intensity, that maps velocimetry data into binary cells (turbulent or laminar). In particular, this percolation approach enables the precise determination of the transition point of the laminar separation bubble, an important problem in aerodynamics.

Wind tunnel experiments with wind turbine models are a promising method for investigating fluid structure interaction (FSI) phenomena. However, the lack of suitable models that feature properly scaled blades and the complexity of aeroelastic and fluid dynamic measurements during turbine operation is challenging. In this paper, the design methodology for aeroelastically scaled blades which are intended for Model Wind Turbine Oldenburg (MoWiTO) 1.8 is presented. The scaling relations are formulated, initiating from the existing turbines’ design. Next, the manufactured blades are equipped on MoWiTO and are subsequently evaluated, during operation under gusty wind fields produced by an active grid. The tip deflection is recorded using an innovative photogrammetry setup. Simulations of an OpenFAST model, which has properties extracted from the scaling formulation, are used as reference. The recorded loads and blade deformations show similar dynamics, compared to the reference. These results prove the design successful, and the capability of measuring FSI phenomena in wind tunnel environment is showcased.

To characterize the effect of prostaglandin analogs (PAs) on tissue specific expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in levator aponeurosis resections (LAR) and conjunctiva-Muller muscle resections (CMMR). Specimens from LAR and CMMR of PA users and non-users were analyzed for tissue specific expression of MMP-3, MMP-7, MMP-9 and TIMP-2 using immunohistochemistry. PA use, marginal reflex distances, levator function and palpebral fissure were documented through chart review. The associations between MMP expression, PA exposure time and ocular characteristics were evaluated with a two-factor analysis of variance and multiple correlation analysis. We observed a tissue specific pattern of expression of MMPs and TIMP-2 in relation to PA exposure between CMMR and LAR specimens. There was increased MMP-7 and TIMP-2 expression in muscle compared to collagen and adipose tissue ( ≤0.005), as well as a statistically significant difference in the relationship of MMP-3, MMP-9 and TIMP-2 levels to PA exposure in the two types of muscles (all ≤0.011). Adipose tissue had a PA-dependent reduced expression of MMP-3 ( <0.022), which was seen in both LAR and CMMR. Decreased expression of MMP-3 in collagen correlated with increased dermatochalasis ( <0.045) and steatoblepharon ( <0.018). PA exposure may affect MMP and TIMP expression in a tissue specific manner, and decreased expression of certain MMPs in collagen correlates to increased clinical measures of prostaglandin associated periorbitopathy (PAP). Further studies with larger samples are needed to ascertain if the changes associated with PAP are due to MMP/TIMP changes or to structural changes.