Background: Antibodies directed against acetylcholine receptor (AChR) are absent in approximately 15% of patients with gMG. Approved treatment options represent an unmet need in the AChR-antibody (Ab)- gMG population. Efgartigimod is an immunoglobulin G1 (IgG1) antibody Fc fragment that selectively reduces IgG levels by blocking neonatal Fc receptor (FcRn)-mediated IgG recycling. Here, we describe efgartigimod efficacy in AChR-Ab- participants with gMG receiving either efgartigimod IV or subcutaneous (SC) efgartigimod PH20 (coformulated with recombinant human hyaluronidase PH20) across clinical studies. Methods: Post hoc analyses were conducted to examine efficacy and safety of efgartigimod IV and/or efgartigimod PH20 SC in AChR-Ab- participants in ADAPT/ADAPT+ and ADAPT-SC/ADAPT-SC+ trials. Results: Among pooled AChR-Ab- participants (n=56), mean (SE) MG-ADL total score improvement from baseline to Week 3 was -3.7 (Cycle 1: 0.44 [n=55]). Consistent MG-ADL improvements occurred with repeated cycles. Clinically meaningful improvements (CMI; ≥2-point MG-ADL decrease) occurred in 76.4% (n=42/55) of participants (Cycle 1, Week 3). In Cycle 1, 23.2% (n=13/56) of participants achieved minimal symptom expression (MG-ADL 0-1). Similar efficacy results occurred across all cycles. Overall safety profile was similar between AChR-Ab+ and AChR-Ab- participants. Conclusions: Both efgartigimod IV and efgartigimod PH20 SC were well tolerated and led to CMI in participants with AChR-Ab- gMG.

Do ideologically extreme candidates enjoy fundraising advantages over more moderate candidates? Extant work documents a relationship between candidates’ positions and campaign contributions subnationally and in donor surveys, yet identification challenges have hampered investigation in the congressional context. I employ a close primaries regression discontinuity design to examine how “as-if random” nominations of extreme versus moderate House candidates influence general election contributions from individual donors and corporate political action committees (PACs) from 1980 to 2020. Results at both the nominee and contributor levels demonstrate that corporate PACs financially penalize extremists, while individual donors respond similarly to extreme and moderate candidates. These findings contribute to ongoing debates regarding the extent and nature of campaign contributors’ role in congressional polarization.

In Colombia, there has been very little discussion about the epidemiological transition in the 20th century, therefore, there are few empirical studies, and this mainly focus on the second half of the 20th century, and on the factors associated with improvements in mortality indicators. In this paper, we define three stages of the epidemiological transition in the country during the period 1918–1998, with special emphasis on changes in mortality rates, causes of death and the contribution of different age groups. Likewise, a co-integration analysis is carried out to model the long-term relationship between the mortality rate and the variables of nutrition, public health, education and economic growth. Finally, we show the results of the structural change tests of the mortality rates for pneumonia and tuberculosis to examine the impact of the arrival of sulphonamides and penicillin in Colombia.

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.

How does candidate ideology affect donors' contribution decisions in U.S. House elections? Studies of donor motivations have struggled with confounding of candidate, donor, and district characteristics in observational data and the difficulty of assessing trade-offs in surveys. We investigate how these factors affect contribution decisions using experimental vignettes administered to 7,000 verified midterm donors. While ideological congruence influences donors' likelihood of contributing to a candidate, district competitiveness and opponent extremity are equally important. Moreover, the response to ideology is asymmetric and heterogeneous: donors penalize more moderate candidates five times more heavily than more extreme candidates, with the most extreme donors exhibiting the greatest preference for candidates even more extreme than themselves. Republicans also exhibit a greater relative preference for extremism than Democrats, although partisan differences are smaller than differences by donor extremism. Our findings suggest that strategic considerations matter, and donors incentivize candidate extremism even more than previously thought.

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.

To evaluate the diagnostic accuracy of three types of antigenic preparations from Strongyloides venezuelensis infective larvae for detection of serum IgG anti-Strongyloides antibodies by enzyme-linked immunosorbent assay (ELISA). Soluble somatic fractions (SSF) and membrane somatic fractions (MSF) and excretory−secretory (E/S) products from S. venezuelensis infective larvae were evaluated against 71 sera from individuals with strongyloidiasis, 105 sera from healthy individuals, and 84 sera from individuals with other helminth infections. Using an ELISA cut-off for 100% sensitivity, E/S products were 97.88% specific followed by MSF (93.12%) and then by SSF (85.2%). The occurrence of cross-reactivity with other helminths was 4.76% (4/84) with E/S products, 8.33% (7/84) with MSF, and 17.86% (15/84) with SSF. For a cut-off for 100% specificity, E/S products showed a sensitivity of 88.73% whereas MSF and SSF showed sensitivities of 59.15% and 53.52%, respectively. In conclusion, E/S products were the best antigenic option for the serodiagnosis of human strongyloidiasis.

The current study examined how parenting and adolescent interpersonal styles jointly influence youths’ abilities to form close relationships – a central developmental milestone – yet avoid substance use, which predominantly occurs in the presence of peers. Nine annual waves from an adolescent sample (N = 387) were used to assess (a) combinations of interpersonal and parenting styles from early to middle adolescence using longitudinal latent profile analysis, (b) the validity of these profiles on indicators of adjustment, and (c) the relationships between the profiles and growth in substance use across adolescence as well as substance-related consequences in late adolescence. The results supported five distinct combinations of interpersonal and parenting styles, and validity analyses identified both risk and protective profiles. The protective profile submissive–communal interpersonal style + high-warmth–authoritative parenting style was associated with indicators of positive social adjustment (e.g., friendship quality, resistance to peer influence) as well as lower levels of substance use. Significant differences also emerged with respect to substance-related consequences. The findings of this study highlight how combinations of adolescent interpersonal style and parenting render adolescents more or less successful at navigating peer relationships while avoiding substance use behaviors.

Early adolescence is thought to represent a window of vulnerability when exposure to substances is particularly harmful, partly because the neurotoxic effects of adolescent substance use may derail self-regulation development. However, previous studies fail to account for externalizing symptoms, such as aggression and delinquency, that accompany adolescent substance use and may also derail the development of self-regulation. The current study aims to clarify whether the neurotoxic effects of adolescent substance use are associated with deficits in effortful control (EC) after accounting for externalizing symptoms and to examine reciprocal relationships between EC, externalizing symptoms, and substance use. A longitudinal sample of adolescents (N = 387) was used to estimate bifactor models of externalizing symptoms across five assessments (Mage = 11.6 to 19.9). The broad general externalizing factors were prospectively associated with declines in EC across adolescence and emerging adulthood. However, the narrow substance use specific factors were not prospectively associated with EC. Findings suggest that the broader externalizing context, but not the specific neurotoxic effects of substance use, may hamper self-regulation development. It is critical to account for the hierarchical structure of psychopathology, namely externalizing symptoms, when considering development of EC.

The current study examined a bifactor model of affective dimensions of withdrawal. Specifically, a model which specified a general factor of anxious-avoidant withdrawal (i.e., withdrawal with negative affect), a specific factor of unsociability (i.e., withdrawal without negative affect), and a specific factor of negative affect without withdrawal was specified in the primary sample (n = 238, 56.3% boys, M age = 44.92 months, SD = 5.32 months) and a validation sample (n = 332, 52.6% boys, M age = 47.11 months, SD = 7.32 months). The model provided a good fit to the data in both samples. In the primary sample, longitudinal relations between the bifactor model and peer victimization were examined across three time points (Time 1 in the spring, Time 2 in the fall, and Time 3 in the spring). Results showed that negative affect without withdrawal was concurrently associated with higher levels of relational and physical victimization at T1, unsociability predicted reductions in relational victimization from T1 to T2 as children entered a new classroom, and anxious-avoidant withdrawal predicted reductions in relational and physical victimization from T2 to T3 as children acclimated to the new classroom. Developmental considerations and clinical implications are discussed.

As an Israeli writing at the turn of the twenty-first Century, I have become accustomed to hearing the word ‘settlement’ used by liberals almost invariably as a derogatory term. The Jewish settlements to the west of the Jordan river, now populated by close to a quarter of a million Jews, are often said to be a central obstacle to peace in the Middle East, as well as being immoral in and of themselves. Consistent liberals realize that this attitude poses a problem for the endorsement of the Zionist effort altogether, since settlement has been a central tenet of this doctrine from the start and the main practical tool for achieving its goals within contested territories. It was also the primary apparatus for achieving Western control over North America, Australia, and New Zealand, wholly at the expense of the aboriginal inhabitants of those places. This, too, is the source of a great deal of contemporary liberal breast-beating.