Background: Zilucoplan, a macrocyclic peptide complement component 5 inhibitor, sustained efficacy for up to 60 weeks of treatment, with a favourable safety profile in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis in an interim analysis of RAISE-XT (NCT04225871). We evaluate the safety and efficacy of zilucoplan up to 96 weeks. Methods: RAISE-XT, a Phase 3, multicentre, open-label extension study, included patients who participated in the double-blind Phase 2 (NCT03315130) and Phase 3 (NCT04115293) zilucoplan studies. Patients self-administered daily subcutaneous zilucoplan 0.3mg/kg injections. Primary outcome was incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. Results: At data cut-off (11 May 2023), median (range) exposure to zilucoplan was 1.8 (0.11–5.1) years (N=200). TEAEs occurred in 191 (95.5%) patients; the most common TEAE was COVID-19 (n=64; 32.0%). At Week 96, mean (standard error) change in MG-ADL score from double-blind study baseline was –6.33 (0.49) and –7.83 (0.60) for patients who received zilucoplan 0.3mg/kg and placebo in the double-blind studies, respectively. Conclusions: Zilucoplan demonstrated a favourable long-term safety profile. Efficacy was sustained for 96 weeks in patients who had previously received zilucoplan and who switched from placebo.

Background: Treatment of generalized myasthenia gravis (gMG) with reduced steroid dosages may minimize steroid-associated AEs. Corticosteroid dosage changes were not permitted during the 26-week, CHAMPION MG study of ravulizumab in adults with anti-acetylcholine receptor antibody-positive (AChRAb+) gMG. Participants who completed the study could receive ravulizumab in the open-label extension (OLE; NCT03920293); corticosteroid adjustments were permitted. Methods: Patients could receive intravenous ravulizumab (blind induction or bridging dose at Week 26 [OLE start] for those previously receiving placebo or ravulizumab, respectively, then 3000–3600 mg at Week 28 and every 8 weeks thereafter) for ≤4 years. Results: Among 161 patients (78 ravulizumab, 83 placebo) who entered the OLE and received ravulizumab for ≤164 weeks, 113 received oral or enteral corticosteroids during the OLE; the proportion treated with >10 mg/day corticosteroids decreased from 58% (n=66) at first OLE dose to 37% (n=42) (35 [31%] received ≤5 mg/day and 71 [63%] received ≤10 mg/day) at last reported dose. Fourteen patients (12%) discontinued corticosteroids. The mean (SD) corticosteroid dosage/patient decreased from 17.5 (11.9) mg/day at first OLE dose to 11.7 (10.9) mg/day at last assessment. Conclusions: Ravulizumab decreased corticosteroid use in patients with AChRAb+ gMG, suggesting a steroid-sparing role for ravulizumab.

Background: Efgartigimod is a human IgG1 antibody Fc-fragment that reduces IgG levels through FcRn blockade. A key efficacy indicator in the treatment of IgG autoantibody-mediated generalized myasthenia gravis (gMG) is improvement in MG-ADL score. Methods: The ADAPT phase 3 trial evaluated safety and efficacy of efgartigimod in patients with gMG, including reaching and maintaining of minimal symptom expression (MSE; defined as an MG-ADL total score of 0 or 1). Results: 167 patients (AChR-Ab+, n=129; AChR-Ab-, n=38) were randomized to receive treatment cycles of 4 weekly infusions of efgartigimod or placebo. Significantly more AChR-Ab+ efgartigimod-treated patients achieved MSE during cycle 1 compared to placebo-treated patients (40.0% [n=26/65] vs 11.1% [n=7/63; P<0.0001]). In cycle 2, 31.4% (n=16/51) of AChR-Ab+ patients in the efgartigimod cohort achieved MSE compared to none in the placebo cohort. MG-ADL score improved by ≥6 points in 56.9% of AChR-Ab+ efgartigimod-treated patients compared to 20.6% of placebo-treated patients in cycle 1. Most patients achieved MSE by week 4 of a cycle, paralleling early reduction in IgG levels, and MSE duration ranged from 1 to ≥10 weeks. Adverse events were predominantly mild to moderate. Conclusions: Efgartigimod treatment resulted in more patients with AChR-Ab+ gMG achieving both MSE and clinically meaningful MG-ADL improvements.

Background: Efgartigimod, a human IgG1 antibody Fc-fragment, reduces IgG levels through neonatal Fc receptor blockade. Patients with anti-acetylcholine receptor antibody–negative (AChR-Ab–) generalized myasthenia gravis (gMG) comprise 15%-20% of the gMG population and have limited approved treatment options. We evaluated long-term safety and efficacy of efgartigimod in AChR-Ab– patients from ADAPT/ADAPT+ (open-label extension). Methods: ADAPT evaluated safety and efficacy of efgartigimod versus placebo in AChR-Ab+ (n=129) and Ab– (n=38) patients with gMG. This integrated analysis includes 37 AChR-Ab– patients who received ≥1 dose of efgartigimod in ADAPT/ADAPT+ through October 2020 (median[range] follow-up: 453[85-721] days). Responder status was defined as ≥2-point (MG-ADL) and ≥3-point (QMG) improvement for ≥4 consecutive weeks (with first improvement 1 week after last infusion). Results: Among AChR-Ab– patients in ADAPT (cycle 1), 68.4% (13/19) efgartigimod-treated were MG-ADL responders (placebo, 63.2% [12/19]), and 52.6% (10/19) were QMG responders (placebo, 36.8% [7/19]). In the integrated ADAPT/ADAPT+ analysis (cycle 1), AChR-Ab– patients improved from baseline in MG-ADL/QMG scores, with consistent improvements across multiple subsequent cycles. No clinically meaningful differences in safety or efficacy outcomes between AChR-Ab+ and Ab– patients occurred. Conclusions: Long-term treatment (median >1 year) with efgartigimod was well tolerated and associated with clinically meaningful improvements in MG-ADL/QMG scores in AChR-Ab– patients.

Background: The 26-week double-blind, randomized, placebo-controlled period (RCP) of the CHAMPION MG study (NCT03920293) demonstrated ravulizumab’s efficacy and tolerability in anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG). Methods: In the ongoing open-label extension (OLE), patients receive intravenous ravulizumab (blind loading dose in placebo-treated patients or bridging dose in ravulizumab-treated patients, then 3000–3600 mg according to body weight every 8 weeks) for ≤4 years. Data from RCP baseline up to Week 60 were analyzed. Results: Ravulizumab’s long-term efficacy (n=161) and safety (n=169) were assessed. Patients who switched from placebo in the RCP to ravulizumab in the OLE (n=83) showed rapid improvement (least squares mean, 95%CI) in Myasthenia Gravis-Activity of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores, which were maintained through 34 weeks (MG-ADL: −1.7, −2.7 to −0.8; QMG: −3.1, −4.2 to −1.9). Improvements achieved by ravulizumab-treated patients (n=78) in the RCP were sustained through 60 weeks (MG-ADL: −4.0, −4.8 to −3.1; QMG: −4.1, −5.4 to −2.9). Ravulizumab was well tolerated; no meningococcal infections were reported. Four deaths unrelated to study treatment occurred. Conclusions: Ravulizumab demonstrated sustained improvements in MG symptoms and was well tolerated for up to 60 weeks in adults with AChR Ab+ gMG.

Background: Efgartigimod is a human IgG1 antibody Fc-fragment that reduces total and pathogenic IgG autoantibody levels through FcRn blockade. ADAPT was a phase 3 trial evaluating efgartigimod in patients with generalized myasthenia gravis (gMG). Patients who completed ADAPT could enroll in ADAPT+ (open-label extension). Methods: Efgartigimod (10 mg/kg intravenous) was administered in cycles of 4 weekly infusions, with subsequent cycles initiated based on clinical evaluation. ADAPT+ evaluated long-term safety and tolerability of efgartigimod in patients with gMG. Efficacy was assessed utilizing MG-ADL and QMG scores. Results: Of 167 patients from ADAPT, 151 (90%) entered ADAPT+, and 145 received ≥1 cycle as of January 2022. Over 217.55 patient-years of follow-up (mean duration per patient, 548 days), incidence of adverse events did not increase with subsequent cycles. AChR-Ab+ patients with ≥1 year of follow-up across ADAPT/ADAPT+ (n=95) received a median (range) 5.0 (0.4–7.6) cycles per year. All AChR-Ab+ patients (n=111) demonstrated consistent improvements (mean change [SE], week 3 of cycle 1) in MG-ADL (-5.0 [0.33]; up to 14 cycles) and QMG (-4.7 [0.41]; up to 7 cycles) scores during each cycle. Conclusions: These ADAPT+ analyses suggest long-term efgartigimod treatment is well tolerated and efficacious. Additional final data cut analyses will be presented at CNSF 2023.

The Survey of Consumer Finances (SCF) indicates that, unlike subprime borrowers, prime borrowers are more likely to own investment homes during recessions than during recoveries. Drawing on this empirical fact, we present and estimate a dynamic stochastic general equilibrium (DSGE) model that distinguishes between borrowers through their credit access. We find that the relative ease of credit access among borrowers explains the divergence in investment homeownership seen in the data. This divergence is amplified when subprime borrowers are subject to lax credit conditions prior to a financial shock or when the nominal interest rate is constrained at the zero lower bound (ZLB). An expansionary monetary policy helps bridge this gap across borrowers.

A slope r is called a left orderable slope of a knot $K \subset S^3$ if the 3-manifold obtained by r-surgery along K has left orderable fundamental group. Consider double twist knots $C(2m, \pm 2n)$ and $C(2m+1, -2n)$ in the Conway notation, where $m \ge 1$ and $n \ge 2$ are integers. By using continuous families of hyperbolic ${\mathrm {SL}}_2(\mathbb {R})$ -representations of knot groups, it was shown in [8, 16] that any slope in $(-4n, 4m)$ (resp. $ [0, \max \{4m, 4n\})$ ) is a left orderable slope of $C(2m, 2n)$ (resp. $C(2m, - 2n)$ ) and in [6] that any slope in $(-4n,0]$ is a left orderable slope of $C(2m+1,-2n)$ . However, the proofs of these results are incomplete, since the continuity of the families of representations was not proved. In this paper, we complete these proofs, and, moreover, we show that any slope in $(-4n, 4m)$ is a left orderable slope of $C(2m+1,-2n)$ detected by hyperbolic ${\mathrm {SL}}_2(\mathbb {R})$ -representations of the knot group.

This paper studies the implications of price flexibility on output volatility under menu costs and finds price flexibility to be output-destabilizing under supply shocks, but not necessarily so under demand shocks. We illustrate that such a result hinges on the extent to which firms can adjust along both the intensive and the extensive margins, the latter of which is often absent in the literature.

The neuro-endoscopy is a surgical technique that allows the neurosurgeon to maintain a visual contact while operating inside the brain of a patient. A special instrument called the neuro-endoscope is inserted in the brain until the neurosurgeon reaches his/her target. Its manipulation requires a high level of training for neurosurgeons. To enforce both quality and safety of neuro-endoscopy, we propose a robotic manipulator based on a Spherical Decoupled Mechanism. This mechanical architecture has been modified from a 5-Bar Spherical Linkages and adapted to this medical application. It is able to generate a Remote Center of Motion of 2 Degrees of Freedom. It merges the advantages of parallel mechanisms with the kinematic and control simplicity of decoupled mechanisms, while having a very simple architecture. Motion capture experiments using a brain simulation model have been performed with a team of neurosurgeons to obtain the kinematic data of the neuro-endoscope during brain exploration. Based on the identified workspace, the mechanism has been optimized using kinematic performance and architectural compactness as criteria. An optimum mechanism has been selected, showing better kinematic performances than the original 5-bar spherical linkage mechanism.

Introduction: Prevalence and incidence of delirium in older patients admitted to acute and long-term care facilities ranges between 9.6% and 89% but little is known in the context of emergency department (ED) incident delirium. Literature regarding the incidence of delirium in the ED and its potential impacts on hospital length of stay (LOS), functional status and unplanned ED readmissions is scant, its consequences have yet to be clearly identified in order to orient modern acute medical care. Methods: This study is part of the multicenter prospective cohort INDEED study. Three Canadian EDs completed the two years prospective study (March-July 2015 and Feb-May 2016). Patients aged 65 years old, initially free of delirium with an ED stay 8hours were followed up to 24h after ward admission. Patients were assessed 2x/day during their entire ED stay and up to 24 hours on hospital ward by research assistants (RA). The primary outcome of this study was incident delirium in the ED or within 24 h of ward admission. Functional and cognitive status were assessed using validated Older Americans’ Resources and Services and the Telephone Interview for Cognitive Status- modified tools. The Confusion Assessment Method (CAM) was used to detect incident delirium. ED and hospital administrative data were collected. Inter-observer agreement was realized among RA. Results: Incident delirium was not different between sites, nor between phases, nor between times from one site to another. All phases confounded, there is between 7 to 11% of ED related incident delirious episodes. Differences were seen in ED LOS between sites in non-delirious patients, but also between some sites for delirious participants (p<0.05). Only one site had a difference in ED LOS between their delirious and non-delirious patients, respectively of 52.1 and 40.1 hours (p<0.05). There is also a difference between sites in the time between arrival to the ED and the incidence of delirium (p=0.003). Kappa statistics were computed to measure inter-rater reliability of the CAM. Based on an alpha of 5%, 138 patients would allow 80% power for an estimated overall incidence proportion of 15 % with 5% precision.. Other predictive delirium variables, such as cognitive status, environmental factors, functional status, comorbidities, physiological status, and ED and hospital length of stay were similar between sites and phases. Conclusion: The fact that incidence of delirium was the same for all sites, despite the differences of ED LOS and different time periods suggest that many other modifiable and non-modifiable factors along LOS influenced the incidence of ED induced delirium. Emergency physician should concentrate on improving senior-friendly environment for the ED.

Introduction: It is documented that physicians and nurses fail to detect delirium in more than half of cases from various clinical settings, which could have serious consequences for seniors and for our health care system. The present study aimed to describe the rate of documented incident delirium in 5 Canadian Emergency departments (ED) by health professionals (HP). Methods: This study is part of the multicenter prospective cohort INDEED study. Patients aged 65 years old, initially free of delirium with an ED stay 8hours were followed up to 24h after ward admission. Delirium status was assessed twice daily using the Confusion Assessment Method (CAM) by trained research assistants (RA). HP reviewed patient charts to assess detection of delirium. HP had no specific routine detection of delirious ED patients. Inter-observer agreement was realized among RA. Comparison of detection between RA and HP was realized with univariate analyses. Results: Among the 652 included patients, 66 developed a delirium as evaluated with the CAM by the RA. Among those 66 patients, only 10 deliriums (15.2%) were documented in the patients medical file by the HP. 54 (81.8%) patients with a CAM positive for delirium by the RA were not recorded by the HP, 2 had incomplete charts. The delirium index was significantly higher in the HP reported group compared to the HP not reported, respectively 7.1 and 4.5 (p<0.05). Other predictive delirium variables, such as cognitive status, functional status, comorbidities, physiological status, and ED and hospital length of stay were similar between groups. Conclusion: It seems that health professionals missed 81.8% of the potential delirious ED patients in comparison to routine structured screening of delirium. HP could identify patients with a greater severity of symptoms. Our study points out the need to better identify elders at risk to develop delirium and the need for fast and reliable tools to improve the screening of this disorder.

Coinfection with human immunodeficiency virus (HIV) and viral hepatitis is associated with high morbidity and mortality in the absence of clinical management, making identification of these cases crucial. We examined characteristics of HIV and viral hepatitis coinfections by using surveillance data from 15 US states and two cities. Each jurisdiction used an automated deterministic matching method to link surveillance data for persons with reported acute and chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infections, to persons reported with HIV infection. Of the 504 398 persons living with diagnosed HIV infection at the end of 2014, 2.0% were coinfected with HBV and 6.7% were coinfected with HCV. Of the 269 884 persons ever reported with HBV, 5.2% were reported with HIV. Of the 1 093 050 persons ever reported with HCV, 4.3% were reported with HIV. A greater proportion of persons coinfected with HIV and HBV were males and blacks/African Americans, compared with those with HIV monoinfection. Persons who inject drugs represented a greater proportion of those coinfected with HIV and HCV, compared with those with HIV monoinfection. Matching HIV and viral hepatitis surveillance data highlights epidemiological characteristics of persons coinfected and can be used to routinely monitor health status and guide state and national public health interventions.

Information about viral acute respiratory infections (ARIs) is essential for prevention, diagnosis and treatment, but it is limited in tropical developing countries. This study described the clinical and epidemiological characteristics of ARIs in children hospitalized in Vietnam. Nasopharyngeal samples were collected from children with ARIs at Ho Chi Minh City Children's Hospital 2 between April 2010 and May 2011 in order to detect respiratory viruses by polymerase chain reaction. Viruses were found in 64% of 1082 patients, with 12% being co-infections. The leading detected viruses were human rhinovirus (HRV; 30%), respiratory syncytial virus (RSV; 23·8%), and human bocavirus (HBoV; 7·2%). HRV was detected all year round, while RSV epidemics occurred mainly in the rainy season. Influenza A (FluA) was found in both seasons. The other viruses were predominant in the dry season. HRV was identified in children of all age groups. RSV, parainfluenza virus (PIV) 1, PIV3 and HBoV, and FluA were detected predominantly in children aged <6 months, 6–12 months, 12–24 months, and >24 months, respectively. Significant associations were found between PIV1 with croup (P < 0·005) and RSV with bronchiolitis (P < 0·005). HBoV and HRV were associated with hypoxia (P < 0·05) and RSV with retraction (P < 0·05). HRV, RSV, and HBoV were detected most frequently and they may increase the severity of ARIs in children.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, is characterized by prolonged maternal stress, undernutrition and dehydration. Maternal stress and malnutrition of pregnancy are linked to poor neonatal outcome and associated with poor adult health, and we recently showed that in utero exposure to HG may lead to increased risks of psychological and behavioral disorders in the offspring. In addition, we have shown familial aggregation of HG, which is strong evidence for a genetic component to the disease. In this study, we compare the rates of psychological and behavioral disorders in 172 adults with and 101 adults without a sibling with HG. The rate of emotional/behavioral disorders is identical (15%) in both groups. The results suggest that the etiology of HG is not likely to include genetic factors associated with emotional and behavioral disorders. In addition, this study provides evidence that the increased incidence of psychological/behavioral disorders among offspring of women with HG is attributable to the HG pregnancy itself, rather than to confounding genetic factors linked to HG.