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This post hoc analysis of the randomized, placebo-controlled N-MOmentum study (NCT02200770) of inebilizumab in neuromyelitis optica spectrum disorder (NMOSD) evaluated relationships between circulating B-cell subsets and aquaporin-4 immunoglobulin G (AQP4-lgG) titers and attacks. Among participants receiving placebo, CD20+ and CD27+ B-cell counts were modestly increased from the pre-attack visit to attack; plasmablast/plasma cell gene signature was increased from baseline to the pre-attack visit (p = 0.016) and from baseline to attack (p = 0.009). With inebilizumab treatment, B-cell subset counts decreased and did not increase with attacks. No difference in change of AQP4-IgG titers from baseline to time of attack was observed.

α-Phenylthioaldehydes are readily prepared using a simple multi-step procedure and herein are introduced as a new precursor for the NHC-catalysed generation of acyl azolium and azolium enolate intermediates that are of widespread synthetic interest and utility. Treatment of α-phenylthioaldehydes with an NHC precatalyst and base produces an efficient redox rearrangement via a Breslow intermediate, elimination of thiophenolate, and subsequent rebound addition to the generated acyl azolium to give the corresponding thiol ester. In the presence of an external alcohol, competition between redox rearrangement and redox esterification can be controlled through judicious choice of the N-aryl substituent within the NHC precatalyst and the base used in the reaction. With NEt3 as base, NHCs bearing electron-withdrawing (N-C6F5 or N-C6H2Cl3) substituents favour redox rearrangement, while triazolium precatalysts with electron-rich N-aryl substituents (N-Ph, N-Mes) result in preferential redox esterification. Using DBU, redox esterification is preferred due to transesterification of the initially formed thiol ester product. Additionally, α-phenylthioaldehyde-derived azolium enolates have been used in enantioselective formal [4 + 2]-cycloaddition reactions to access dihydropyridinone heterocycles with high enantioselectivity (up to >95 : 5 dr, 98 : 2 er).

Given the multitude of challenges Earth is facing, sustainability science is of key importance to our continued existence. Evolution is the fundamental biological process underlying the origin of all biodiversity. This phylogenetic diversity fosters the resilience of ecosystems to environmental change, and provides numerous resources to society, and options for the future. Genetic diversity within species is also key to the ability of populations to evolve and adapt to environmental change. Yet, the value of evolutionary processes and the consequences of their impairment have not generally been considered in sustainability research. We argue that biological evolution is important for sustainability and that the concepts, theory, data, and methodological approaches used in evolutionary biology can, in crucial ways, contribute to achieving the UN Sustainable Development Goals (SDGs). We discuss how evolutionary principles are relevant to understanding, maintaining, and improving Nature Contributions to People (NCP) and how they contribute to the SDGs. We highlight specific applications of evolution, evolutionary theory, and evolutionary biologys diverse toolbox, grouped into four major routes through which evolution and evolutionary insights can impact sustainability. We argue that information on both within-species evolutionary potential and among-species phylogenetic diversity is necessary to predict population, community, and ecosystem responses to global change and to make informed decisions on sustainable production, health, and well-being. We provide examples of how evolutionary insights and the tools developed by evolutionary biology can not only inspire and enhance progress on the trajectory to sustainability, but also highlight some obstacles that hitherto seem to have impeded an efficient uptake of evolutionary insights in sustainability research and actions to sustain SDGs. We call for enhanced collaboration between sustainability science and evolutionary biology to understand how integrating these disciplines can help achieve the sustainable future envisioned by the UN SDGs.

ImportanceCurrent measures of alopecia areata (AA) severity, such as the Severity of Alopecia Tool score, do not adequately capture overall disease impact.ObjectiveTo explore factors associated with AA severity beyond scalp hair loss, and to support the development of the Alopecia Areata Severity and Morbidity Index (ASAMI).Evidence reviewA total of 74 hair and scalp disorder specialists from multiple continents were invited to participate in an eDelphi project consisting of 3 survey rounds. The first 2 sessions took place via a text-based web application following the Delphi study design. The final round took place virtually among participants via video conferencing software on April 30, 2022.FindingsOf all invited experts, 64 completed the first survey round (global representation: Africa [4.7%], Asia [9.4%], Australia [14.1%], Europe [43.8%], North America [23.4%], and South America [4.7%]; health care setting: public [20.3%], private [28.1%], and both [51.6%]). A total of 58 specialists completed the second round, and 42 participated in the final video conference meeting. Overall, consensus was achieved in 96 of 107 questions. Several factors, independent of the Severity of Alopecia Tool score, were identified as potentially worsening AA severity outcomes. These factors included a disease duration of 12 months or more, 3 or more relapses, inadequate response to topical or systemic treatments, rapid disease progression, difficulty in cosmetically concealing hair loss, facial hair involvement (eyebrows, eyelashes, and/or beard), nail involvement, impaired quality of life, and a history of anxiety, depression, or suicidal ideation due to or exacerbated by AA. Consensus was reached that the Alopecia Areata Investigator Global Assessment scale adequately classified the severity of scalp hair loss.Conclusions and relevanceThis eDelphi survey study, with consensus among global experts, identified various determinants of AA severity, encompassing not only scalp hair loss but also other outcomes. These findings are expected to facilitate the development of a multicomponent severity tool that endeavors to competently measure disease impact. The findings are also anticipated to aid in identifying candidates for current and emerging systemic treatments. Future research must incorporate the perspectives of patients and the public to assign weight to the domains recognized in this project as associated with AA severity.

We develop an automated high-throughput workflow for calculating lattice dynamical properties from first principles including those dictated by anharmonicity. The pipeline automatically computes interatomic force constants (IFCs) up to 4th order from perturbed training supercells, and uses the IFCs to calculate lattice thermal conductivity, coefficient of thermal expansion, and vibrational free energy and entropy. It performs phonon renormalization for dynamically unstable compounds to obtain real effective phonon spectra at finite temperatures and calculates the associated free energy corrections. The methods and parameters are chosen to balance computational efficiency and result accuracy, assessed through convergence testing and comparisons with experimental measurements. Deployment of this workflow at a large scale would facilitate materials discovery efforts toward functionalities including thermoelectrics, contact materials, ferroelectrics, aerospace components, as well as general phase diagram construction.

BackgroundA major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations.MethodsData from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Most cases are sporadic, but well characterized germline alterations in APC, ELP1, GPR161, PTCH1, SUFU, and TP53 predispose to medulloblastoma. However, knowledge about pathogenic/likely pathogenic (P/LP) variants that predispose to medulloblastoma vary based on genes evaluated, patient demographics, and pathogenicity definitions. METHODS: Germline exome sequencing was conducted on 160 childhood survivors of medulloblastoma. Analyses focused on rare variants in 239 known cancer susceptibility genes (CSGs). P/LP variants were identified using ClinVar and InterVar. Variants of unknown significance in known medulloblastoma predisposing genes (APC, ELP1, GPR161, PTCH1, SUFU, TP53) were further classified for loss of function variants. We compared the frequency of P/LP variants in cases to that in 1,259 cancer-free adult controls. RESULTS: Twenty cases (12.5%) had a P/LP variant in an autosomal dominant CSG versus 5% in controls (p=1.0 x10-3), and 10 (6.3%) of these were P/LP variants in a known medulloblastoma gene, significantly greater than 0.2% observed in controls (p=1.4x10-8). The CSGs with the most P/LP variants in cases, and significantly higher than controls, were ELP1 (p=3.0x10-4) and SUFU (p=1.4x10-3). CONCLUSION: Approximately one in eight pediatric medulloblastoma survivors had an autosomal dominant P/LP CSG variant. We confirm several known associated genes and identify novel genes that may be important in medulloblastoma.

Previous research has found that construal level—how abstractly or concretely people represent events—can impact implicit evaluations. Abstract high-level construal (vs. concrete low-level construal) promotes evaluative responses consistent with global (strongly held, long-term) rather than local (short-term, situational) goals. It remains unclear by what cognitive process(es) this occurs. In this paper, we examine twopossibilities. High-level construal might enhance the unintended influence of activated evaluative associations or facilitate the detection and implementation of intentional responses. To examine these possibilities, the current study applies a multinomial processing tree model to data from Fujita and Han (2009). Results suggest that high-level construal facilitates goal-consistent evaluations by increasing both the unintentional influence of activated goal-consistent positive associations and the intentional detection of and implementation of accurate responding to goal-relevant stimuli. These findings extend our understanding of how construal level promotes goal consistentevaluations.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes.

The burden of cervical cancer is disproportionately distributed globally, with the vast majority of cases occurring in low- and middle-income countries. Women with human immunodeficiency virus (HIV) (WWH) are at increased risk of human papillomavirus (HPV) infection and cervical cancer as compared to HIV-negative individuals. HPV vaccination remains a priority in regions with a high burden of cervical cancer and high HIV prevalence. With HPV vaccines becoming more accessible, optimal use beyond the initial World Health Organization-recommended target population of 9 to 14-year-old girls is an important question. In March 2022, a group of experts in epidemiology, immunology, and vaccinology convened to discuss the state-of-the-science of HPV vaccination in WWH. This report summarizes the proceedings: review of HIV epidemiology and its intersection with cervical cancer burden, immunology, HPV vaccination including reduced-dose schedules and experience with other vaccines in people with HIV (PWH), HPV vaccination strategies and knowledge gaps, and outstanding research questions. Studies of HPV vaccine effectiveness among WWH, including duration of protection, are limited. Until data from ongoing research is available, the current recommendation for WWH remains for a multi-dose HPV vaccination regimen. A focus of the discussion included the potential impact of HIV acquisition following HPV vaccination. With no data currently existing for HPV vaccines and limited information from non-HPV vaccines, this question requires further research. Implementation research on optimal HPV vaccine delivery approaches for WWH and other priority populations is also urgently needed.

OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.

BackgroundThe N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD).ObjectiveEvaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum.MethodsAdults (n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed.ResultsA total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks.ConclusionAC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

We propose the hypothesis that small high-density lipoprotein (HDL) particles reduce the risk of Alzheimers disease (AD) by virtue of their capacity to exchange lipids, affecting neuronal membrane composition and vascular and synaptic functions. Concentrations of small HDLs in cerebrospinal fluid (CSF) and plasma were measured in 180 individuals ≥60 years of age using ion mobility methodology. Small HDL concentrations in CSF were positively associated with performance in three domains of cognitive function independent of apolipoprotein E (APOE) ε4 status, age, sex, and years of education. Moreover, there was a significant correlation between levels of small HDLs in CSF and plasma. Further studies will be aimed at determining whether specific components of small HDL exchange across the blood, brain, and CSF barriers, and developing approaches to exploit small HDLs for therapeutic purposes.

BackgroundGenome-wide studies of gene-environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer.MethodsAnalyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs.ResultsAssuming a 1 × 10-5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability

Conversational partners expect each other to communicate rationally and cooperatively and to contribute relevant and informative utterances. Occasionally, however, speakers produce trivial utterances which may violate our expectations of informativity. These utterances can prompt listeners to draw inferences about a speaker’s goals in producing such an utterance. Here we present two studies investigating how and when listeners derive informativity-based inferences. The results demonstrate that speaker knowledge plays an important role in the computation of inferences. Furthermore, the timecourse of the results suggests that these inferences do not always arise automatically and that their computation is costly.

BackgroundInebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770).MethodsPeripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed.FindingsInebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4 cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p = 0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p

Background and objectivesWhile somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms.MethodsWe performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results.ResultsSomatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway.DiscussionWe propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

Cardiovascular diseases (CVD) including heart attacks, strokes, heart failure, and uncontrolled hypertension are leading causes of death among women of all ages. Despite efforts to increase awareness about CVD among women, over the past decade there has been stagnation in the reduction of CVD in women, and CVD among younger women and women of color has in fact increased. We recommend taking action using policy levers to address CVD in women including: (1) Promoting periodic screening for risk factors including blood pressure, lipids/cholesterol, diabetes for all women starting at 18-21 years, with calculated atherosclerotic CVD (ASCVD) risk score use among women 40 years or older. (2) Considering coronary artery calcium (CAC) screening for those with intermediate risk per current guidelines. (3) Enhancing Obstetrics and Gynecology and primary care physician education on reproductive age CVD risk markers, and that follow-up is needed, including extended postpartum follow-up. (4) Offering Health Coaching/motivational Interviewing to support behavior change. (5) Funding demonstration projects using different care models. (6) Creating a Stop High Blood Pressure consult line (for providers and patients) and providing other support resources with actions consumers can take, modeled after the California tobacco quit line. And (7) Requiring inclusion of adverse pregnancy outcomes in all Electronic Health Records, with reminder systems to follow-up on hypertension post-partum.

BackgroundPretreatment HIV drug resistance (PDR) undermines individual treatment success and threatens the achievement of UNAIDS 95-95-95 targets. In many African countries, limited data are available on PDR as detection of recent HIV infection is uncommon and access to resistance testing is limited. We describe the prevalence of PDR among South African women with recent HIV infection from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial.MethodsHIV-uninfected, sexually active women, aged 18-35 years, and seeking contraception were enrolled in the ECHO Trial at sites in South Africa, from 2015 to 2018. HIV testing was done at trial entry and repeated quarterly. We tested stored plasma samples collected at HIV diagnosis from women who seroconverted during follow-up and had a viral load >1000 copies/mL for antiretroviral resistant mutations using a validated laboratory-developed population genotyping assay, which sequences the full protease and reverse transcriptase regions. Mutation profiles were determined using the Stanford Drug Resistance Database.ResultsWe sequenced 275 samples. The median age was 23 years, and majority (98.9%, n = 272) were infected with HIV-1 subtype C. The prevalence of surveillance drug resistance mutations (SDRMs) was 13.5% (n = 37). Nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations were found in 12.4% of women (n = 34). Few women had NRTI (1.8%, n = 5) and protease inhibitor (1.1%, n = 3) mutations. Five women had multiple NRTI and NNRTI SDRMs.ConclusionsThe high levels of PDR, particularly to NNRTIs, strongly support the recent change to the South African national HIV treatment guidelines to transition to a first-line drug regimen that excludes NNRTIs.

Innovation is a very important concern for both managers and governmental policy makers. There is an important interplay between security and technology innovation that is largely unrecognized in the literature. This research considers the case where technology innovation in the form of additional product features increases demand through greater functionality. However, the likelihood of a security breach increases with the number of product features as the features interact in unintended ways, thereby increasing the attack surface. Using a two-stage game, we demonstrate how potential demand changes (from direct risk or externalities) impact firm technology innovation strategy. The analysis shows that the type and extent of customer demand reaction has a significant impact on innovative feature development. This research identifies two potential impacts on the level of innovation that can be strategically managed - the impact of externalities on demand and industry risk - explaining how these forces alter the level of innovation in the product ecosystem. Additionally, high-security development is disincentivized, and leads to a type of competitive behavior where the opportunity window for high-security development for all firms is small.

BackgroundHIV endpoint-driven clinical trials provide oral pre-exposure prophylaxis (PrEP) as HIV prevention standard of care. We evaluated quantifiable plasma tenofovir among South African women who used oral PrEP during the Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial.MethodsECHO, a randomized trial conducted in 4 African countries between 2015 and 2018, assessed HIV incidence among HIV-uninfected women, aged 16-35 years, randomized to 1 of 3 contraceptives. Oral PrEP was offered onsite as part of the HIV prevention package at the South African trial sites. We measured tenofovir in plasma samples collected at the final trial visit among women reporting ongoing PrEP use. We used bivariate and multivariate logistical regression to assess demographic and sexual risk factors associated with plasma tenofovir quantification.ResultsOf 260 women included, 52% were ≤24 years and 22% had Chlamydia trachomatis at enrollment. At PrEP initiation, 68% reported inconsistent/nonuse of condoms. The median duration of PrEP use was 90 days (IQR: 83-104). Tenofovir was quantified in 36% (n = 94) of samples. Women >24 years had twice the odds of having tenofovir quantified vs younger women (OR = 2.12; 95% confidence interval = 1.27 to 3.56). Women who reported inconsistent/nonuse of condoms had lower odds of tenofovir quantification (age-adjusted OR = 0.47; 95% confidence interval = 0.26 to 0.83).ConclusionsOver a third of women initiating PrEP and reporting ongoing use at the final trial visit had evidence of recent drug exposure. Clinical trials may serve as an entry point for PrEP initiation among women at substantial risk for HIV infection with referral to local facilities for ongoing access at trial end.Clinical trial numberNCT02550067.

People often form impressions of others in contexts where both relatively static demographic cues (e.g., age, race, gender) and situationally flexible, dynamic cues (e.g., emotion expressions) are available. We examined whether and how attending to gender (male, female) versus emotion expression (neutral, smiling) affects threat-based person impressions. In three experiments, we heightened the salience of either gender categories or emotion categories in a sequential priming task. Category salience consistently moderated the use of both categories in threat impressions. The effect of gender (emotion) categories was stronger when attention was directed to gender (emotion) than when attention was directed to emotion (gender); however, category salience did not eliminate the use of either category. Implications for models of person construal and bias in person impressions are discussed.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, but occurs infrequently in infants (

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P

Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the Initiative for the Critical Assessment of Metagenome Interpretation (CAMI). The CAMI II challenge engaged the community to assess methods on realistic and complex datasets with long- and short-read sequences, created computationally from around 1,700 new and known genomes, as well as 600 new plasmids and viruses. Here we analyze 5,002 results by 76 program versions. Substantial improvements were seen in assembly, some due to long-read data. Related strains still were challenging for assembly and genome recovery through binning, as was assembly quality for the latter. Profilers markedly matured, with taxon profilers and binners excelling at higher bacterial ranks, but underperforming for viruses and Archaea. Clinical pathogen detection results revealed a need to improve reproducibility. Runtime and memory usage analyses identified efficient programs, including top performers with other metrics. The results identify challenges and guide researchers in selecting methods for analyses.

The solution-state interactions of plutonium and berkelium with the octadentate chelator 3,4,3-LI(1,2-HOPO) (343-HOPO) were investigated and characterized by X-ray absorption spectroscopy, which revealed in situ reductive decomposition of the tetravalent species of both actinide metals to yield Pu(III) and Bk(III) coordination complexes. X-ray absorption near-edge structure (XANES) measurements were the first indication of in situ synchrotron redox chemistry as the Pu threshold and white-line position energies for Pu-343-HOPO were in good agreement with known diagnostic Pu(III) species, whereas Bk-343-HOPO results were found to mirror the XANES behavior of Bk(III)-DTPA. Extended X-ray absorption fine structure results revealed An-OHOPO bond distances of 2.498 (5) and 2.415 (2) Å for Pu and Bk, respectively, which match well with bond distances obtained for trivalent actinides and 343-HOPO via density functional theory calculations. Pu(III)- and Bk(III)-343-HOPO data also provide initial insight into actinide periodicity as they can be compared with previous results with Am(III)-, Cm(III)-, Cf(III)-, and Es(III)-343-HOPO, which indicate there is likely an increase in 5f covalency and heterogeneity across the actinide series.

Nicotinic partial agonists provide an accepted aid for smoking cessation and thus contribute to decreasing tobacco-related disease. Improved drugs constitute a continued area of study. However, there remains no reductionist method to examine the cellular and subcellular pharmacokinetic properties of these compounds in living cells. Here, we developed new intensity-based drug-sensing fluorescent reporters (iDrugSnFRs) for the nicotinic partial agonists dianicline, cytisine, and two cytisine derivatives - 10-fluorocytisine and 9-bromo-10-ethylcytisine. We report the first atomic-scale structures of liganded periplasmic binding protein-based biosensors, accelerating development of iDrugSnFRs and also explaining the activation mechanism. The nicotinic iDrugSnFRs detect their drug partners in solution, as well as at the plasma membrane (PM) and in the endoplasmic reticulum (ER) of cell lines and mouse hippocampal neurons. At the PM, the speed of solution changes limits the growth and decay rates of the fluorescence response in almost all cases. In contrast, we found that rates of membrane crossing differ among these nicotinic drugs by >30-fold. The new nicotinic iDrugSnFRs provide insight into the real-time pharmacokinetic properties of nicotinic agonists and provide a methodology whereby iDrugSnFRs can inform both pharmaceutical neuroscience and addiction neuroscience.

Language use can be characterised as transparent, stating facts about the world, or non-transparent, requiring additional meaning to be inferred. The challenge faced by addressees is recognizing when language use is transparent or not. The current study investigates two factors that may influence how readily participants interpret utterances as instances of transparent or non-transparent language use; speaker knowledgeability and utterance form. When utterances involved negation participants were more likely to recognize this as non-transparent language use and infer that the situation is usually different. Whereas speaker knowledge did not influence how utterances were understood.

BackgroundSurvival from metastatic cutaneous melanoma is substantially lower than for localized disease. Treatments for metastatic melanoma have been limited, but remarkable clinical improvements have been reported in clinical trials in the last decade. We described the characteristics of US patients diagnosed with cutaneous melanoma during 2001-2013 and assessed trends in short-term survival for distant-stage disease.MethodsTrends in 1-year net survival were estimated using the Pohar Perme estimator, controlling for background mortality with life tables of all-cause mortality rates by county of residence, single year of age, sex, and race for each year 2001-2013. We fitted a flexible parametric survival model on the log-hazard scale to estimate the effect of race on the hazard of death because of melanoma and estimated 1-year net survival by race.ResultsOnly 4.4% of the 425 915 melanomas were diagnosed at a distant stage, cases diagnosed at a distant stage are more commonly men, older patients, and African Americans. Age-standardized, 1-year net survival for distant-stage disease was stable at approximately 43% during 2001-2010. From 2010 onward, survival improved rapidly, reaching 58.9% (95% confidence interval = 56.6% to 61.2%) for patients diagnosed in 2013. Younger patients experienced the largest improvement. Survival for distant-stage disease increased in both Blacks and Whites but was consistently lower in Blacks.ConclusionsOne-year survival for distant-stage melanoma improved during 2001-2013, particularly in younger patients and those diagnosed since 2010. This improvement may be a consequence of the introduction of immune-checkpoint-inhibitors and other targeted treatments for metastatic and unresectable disease. Persistent survival inequalities exist between Blacks and Whites, suggesting differential access to treatment.

Critical assessment of structure prediction (CASP) conducts community experiments to determine the state of the art in computing protein structure from amino acid sequence. The process relies on the experimental community providing information about not yet public or about to be solved structures, for use as targets. For some targets, the experimental structure is not solved in time for use in CASP. Calculated structure accuracy improved dramatically in this round, implying that models should now be much more useful for resolving many sorts of experimental difficulties. To test this, selected models for seven unsolved targets were provided to the experimental groups. These models were from the AlphaFold2 group, who overall submitted the most accurate predictions in CASP14. Four targets were solved with the aid of the models, and, additionally, the structure of an already solved target was improved. An a posteriori analysis showed that, in some cases, models from other groups would also be effective. This paper provides accounts of the successful application of models to structure determination, including molecular replacement for X-ray crystallography, backbone tracing and sequence positioning in a cryo-electron microscopy structure, and correction of local features. The results suggest that, in future, there will be greatly increased synergy between computational and experimental approaches to structure determination.

The development of CRISPR-derived genome editing technologies has enabled the precise manipulation of DNA sequences within the human genome. In this review, we discuss the initial development and cellular mechanism of action of CRISPR nucleases and DNA base editors. We then describe factors that must be taken into consideration when developing these tools into therapeutic agents, including the potential for unintended and off-target edits when using these genome editing tools, and methods to characterize these types of edits. We finish by considering specific challenges associated with bringing a CRISPR-based therapy to the clinic, including manufacturing, regulatory oversight, and considerations for clinical trials that involve genome editing agents.

BackgroundIn the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo.ObjectiveTo demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses.MethodsN-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints.ResultsIn the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends.ConclusionN-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy.The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770.

Despite the fundamental nature of the edge state in topological physics, direct measurement of electronic and optical properties of the Fermi arcs of topological semimetals has posed a significant experimental challenge, as their response is often overwhelmed by the metallic bulk. However, laser-driven currents carried by surface and bulk states can propagate in different directions in nonsymmorphic crystals, allowing for the two components to be easily separated. Motivated by a recent theoretical prediction G. Chang et al., Phys. Rev. Lett. 124, 166404 (2020)PRLTAO0031-900710.1103/PhysRevLett.124.166404, we have measured the linear and circular photogalvanic effect currents deriving from the Fermi arcs of the nonsymmorphic, chiral Weyl semimetal RhSi over the 0.45-1.1 eV incident photon energy range. Our data are in good agreement with the predicted spectral shape of the circular photogalvanic effect as a function of photon energy, although the direction of the surface photocurrent departed from the theoretical expectation over the energy range studied. Surface currents arising from the linear photogalvanic effect were observed as well, with the unexpected result that only two of the six allowed tensor element were required to describe the measurements, suggesting an approximate emergent mirror symmetry inconsistent with the space group of the crystal.

The Welsh Transplantation and Immunogenetics Laboratory (WTAIL) is responsible for managing patient work-up for haematopoietic stem cell transplantation (HSCT), the only potentially curative option for many haematological and non-haematological conditions. Work-up requires regular communication between WTAIL and the transplanting clinicians, facilitated by weekly multidisciplinary team (MDT) meetings, to agree decisions and proceed through each work-up stage. Effective communication and minimising error are critical, as transplanting cells from a suboptimal donor could have severe or fatal consequences for the patient. We reviewed our HSCT patient management and identified issues including staff dissatisfaction with the inefficiency of the current (paper-based) system and concern about the potential for incidents caused by errors in manual transcription of patient information and tracking clinical decisions. Another driver for change was the COVID-19 pandemic, which prevented the usual face-to-face MDT meetings in which staff would show clinicians the paper records and reports; the shift to online MDT required new ways of sharing data. In this project we developed a new central reference point for our patient management data along with electronic patient summary sheets, designed with an eye to improving safety and efficiency. Over several improvement cycles we tested and refined the summary sheets with staff and clinicians and experimented with videoconferencing to facilitate data sharing. We conducted interviews with staff from which we concluded that the new process successfully reduced transcription and duplication and improved communication with the clinicians during the pandemic. Despite an increase in workload due to build-up of active patient work-up cases during the pandemic, staff reported that the new summaries enabled them to cope well. A key initiative was creation of a Task and Finish group that helped establish continual improvement culture and identified additional areas for improvement which have been followed up in further improvement projects.

Marine pollutants bioaccumulate at high trophic levels of marine food webs and are transferred to humans through consumption of apex species. Yellowfin tuna (Thunnus albacares) are marine predators, and one of largest commercial fisheries in the world. Previous studies have shown that yellowfin tuna can accumulate high levels of persistent organic pollutants, including Transporter Interfering Chemicals (TICs), which are chemicals shown to bind to mammalian xenobiotic transporters and interfere with their function. Here, we examined the extent to which these same compounds might interfere with the activity of the yellowfin tuna (Thunnus albacares) ortholog of this transporter. To accomplish this goal we identified, expressed, and functionally assayed tuna ABCB1. The results demonstrated a common mode of vertebrate ABCB1 interaction with TICs that predicts effects across these species, based on high conservation of specific interacting residues. Importantly several TICs showed potent inhibition of Ta-ABCB1, such as the organochlorine pesticides Endrin (EC50 = 1.2 ± 0.2 μM) and Mirex (EC50 = 2.3 ± 0.9 μM). However, unlike the effects observed on mouse ABCB1, low concentrations of the organochlorine pesticide TICs p,p'-DDT and its metabolite p,p'-DDD co-stimulated verapamil-induced Ta-ABCB1 ATPase activity possibly suggesting a low transport activity for these ligands in tuna. These results provide a mechanistic basis for understanding the potential vulnerability of tuna to these ubquitous pollutants.

Marine pollutants bioaccumulate at high trophic levels of marine food webs and are transferred to humans through consumption of apex species. Yellowfin tuna (Thunnus albacares) are marine predators, and one of largest commercial fisheries in the world. Previous studies have shown that yellowfin tuna can accumulate high levels of persistent organic pollutants, including Transporter Interfering Chemicals (TICs), which are chemicals shown to bind to mammalian xenobiotic transporters and interfere with their function. Here, we examined the extent to which these same compounds might interfere with the activity of the yellowfin tuna (Thunnus albacares) ortholog of this transporter. To accomplish this goal we identified, expressed, and functionally assayed tuna ABCB1. The results demonstrated a common mode of vertebrate ABCB1 interaction with TICs that predicts effects across these species, based on high conservation of specific interacting residues. Importantly several TICs showed potent inhibition of Ta-ABCB1, such as the organochlorine pesticides Endrin (EC50 = 1.2 ± 0.2 μM) and Mirex (EC50 = 2.3 ± 0.9 μM). However, unlike the effects observed on mouse ABCB1, low concentrations of the organochlorine pesticide TICs p,p'-DDT and its metabolite p,p'-DDD co-stimulated verapamil-induced Ta-ABCB1 ATPase activity possibly suggesting a low transport activity for these ligands in tuna. These results provide a mechanistic basis for understanding the potential vulnerability of tuna to these ubquitous pollutants.

People with schizophrenia are enriched for rare coding variants in genes associated with neurodevelopmental disorders, particularly autism spectrum disorders and intellectual disability. However, it is unclear if the same changes to gene function that increase risk to neurodevelopmental disorders also do so for schizophrenia. Using data from 3444 schizophrenia trios and 37,488 neurodevelopmental disorder trios, we show that within shared risk genes, de novo variants in schizophrenia and neurodevelopmental disorders are generally of the same functional category, and that specific de novo variants observed in neurodevelopmental disorders are enriched in schizophrenia (P = 5.0 × 10-6). The latter includes variants known to be pathogenic for syndromic disorders, suggesting that schizophrenia be included as a characteristic of those syndromes. Our findings imply that, in part, neurodevelopmental disorders and schizophrenia have shared molecular aetiology, and therefore likely overlapping pathophysiology, and support the hypothesis that at least some forms of schizophrenia lie on a continuum of neurodevelopmental disorders.

Reported herein is the structural, spectroscopic, redox, and reactivity properties of a series of iron complexes containing both a π-donating thiolate, and π-accepting N-heterocycles in the coordination sphere, in which we systematically vary the substituents on the N-heterocycle, the size of the N-heterocycle, and the linker between the imine nitrogen and tertiary amine nitrogen. In contrast to our primary amine/thiolate-ligated Fe(II) complex, [FeII(SMe2N4(tren))]+ (1), the Fe(II) complexes reported herein are intensely colored, allowing us to visually monitor reactivity. Ferrous complexes with R = H substituents in the 6-position of the pyridines, [FeII(SMe2N4(6-H-DPPN)]+ (6) and [FeII(SMe2N4(6-H-DPEN))(MeOH)]+ (8-MeOH) are shown to readily bind neutral ligands, and all of the Fe(II) complexes are shown to bind anionic ligands regardless of steric congestion. This reactivity is in contrast to 1 and is attributed to an increased metal ion Lewis acidity assessed via aniodic redox potentials, Ep,a, caused by the π-acid ligands. Thermodynamic parameters (ΔH, ΔS) for neutral ligand binding were obtained from T-dependent equilibrium constants. All but the most sterically congested complex, [FeII(SMe2N4(6-Me-DPPN)]+ (5), react with O2. In contrast to our Mn(II)-analogues, dioxygen intermediates are not observed. Rates of formation of the final mono oxo-bridged products were assessed via kinetics and shown to be inversely dependent on redox potentials, Ep,a, consistent with a mechanism involving electron transfer.

We report the single crystal XRD and MicroED structure, magnetic susceptibility, and EPR data of a series of CaMn3IV O4 and YMn3IV O4 complexes as structural and spectroscopic models of the cuboidal subunit of the oxygen-evolving complex (OEC). The effect of changes in heterometal identity, cluster geometry, and bridging oxo protonation on the spin-state structure was investigated. In contrast to previous computational models, we show that the spin ground state of CaMn3IV O4 complexes and variants with protonated oxo moieties need not be S=9/2. Desymmetrization of the pseudo-C3 -symmetric Ca(Y)Mn3IV O4 core leads to a lower S=5/2 spin ground state. The magnitude of the magnetic exchange coupling is attenuated upon oxo protonation, and an S=3/2 spin ground state is observed in CaMn3IV O3 (OH). Our studies complement the observation that the interconversion between the low-spin and high-spin forms of the S2 state is pH-dependent, suggesting that the (de)protonation of bridging or terminal oxygen atoms in the OEC may be connected to spin-state changes.

CASP (Critical Assessment of Structure prediction) conducts communityexperiments to determine the state of the art in computing proteinstructure from amino acid sequence. The process relies on theexperimental community providing information about not yet public orabout to be solved structures, for use as targets. For some targets, theexperimental structure is not solved in time for use in CASP. Calculatedstructure accuracy improved dramatically in this round, implying thatmodels should now be much more useful for resolving many sorts ofexperimental difficulty. To test this, selected models for sevenunsolved targets were provided to the experimental groups. These modelswere from the AlphaFold2 group, who overall submitted the most accuratepredictions in CASP14. Four targets were solved with the aid of themodels, and, additionally, the structure of an already solved target wasimproved. An a-posteriori analysis showed that in some cases models fromother groups would also be effective. This paper provides accounts ofthe successful application of models to structure determination,including molecular replacement for X-ray crystallography, backbonetracing and sequence positioning in a Cryo-EM structure, and correctionof local features. The results suggest that in future there will begreatly increased synergy between computational and experimentalapproaches to structure determination.

Thousands of species will be sequenced in the next few years; however, understanding how their genomes work, without an unlimited budget, requires both molecular and novel evolutionary approaches. We developed a sensitive sequence alignment pipeline to identify conserved noncoding sequences (CNSs) in the Andropogoneae tribe (multiple crop species descended from a common ancestor ∼18 million years ago). The Andropogoneae share similar physiology while being tremendously genomically diverse, harboring a broad range of ploidy levels, structural variation, and transposons. These contribute to the potential of Andropogoneae as a powerful system for studying CNSs and are factors we leverage to understand the function of maize CNSs. We found that 86% of CNSs were comprised of annotated features, including introns, UTRs, putative cis-regulatory elements, chromatin loop anchors, noncoding RNA (ncRNA) genes, and several transposable element superfamilies. CNSs were enriched in active regions of DNA replication in the early S phase of the mitotic cell cycle and showed different DNA methylation ratios compared to the genome-wide background. More than half of putative cis-regulatory sequences (identified via other methods) overlapped with CNSs detected in this study. Variants in CNSs were associated with gene expression levels, and CNS absence contributed to loss of gene expression. Furthermore, the evolution of CNSs was associated with the functional diversification of duplicated genes in the context of maize subgenomes. Our results provide a quantitative understanding of the molecular processes governing the evolution of CNSs in maize.

IntroductionSocial determinants of health (SDoH) influence health outcomes and contribute to disparities in chronic disease in vulnerable populations. To inform health system strategies to address SDoH, we conducted a multi-stakeholder qualitative study to capture the multi-level influences on health for those living in socio-economically deprived contexts.MethodsVaried qualitative inquiry methods - in-depth interviews, participant-led neighborhood tours, and clinic visit observations - involving a total of 23 participants (10 patients with chronic illnesses in San Francisco neighborhoods with high chronic disease rates, 10 community leaders serving the same neighborhoods, and 3 providers from San Francisco's public health care delivery system). Qualitative analyses were guided by the Chronic Care Model (CCM).ResultsSeveral key themes emerged from this study. First, we enumerated a large array, neighborhood resources such as food pantries, parks/green spaces, and financial assistance services that interact with patients' self-management. Health service providers leveraged these resources to address patients' social needs but suggested a clear need for expanding this work. Second, analyses uncovered multiple essential mechanisms by which community-based organizations (CBOs) provided and navigated among many neighborhood health resources, including social support and culturally aligned knowledge. Finally, many examples of how structural issues such as institutional racism, transportation, and housing inequities are intertwined with health and social service delivery were elucidated.ConclusionThe results contribute new evidence toward the community domain of the CCM. Health care systems must intentionally partner with CBOs to address SDoH and improve community resources for chronic care management, and directly address structural issues to make progress.

Previous research has found that construal level—how abstractly or concretely people represent events—can impact implicit evaluations. Abstract high-level construal (vs. concrete low-level construal) promotes evaluative responses consistent with global (strongly held, long-term) rather than local (short-term, situational) goals. It remains unclear by what cognitive process(es) this occurs. In this paper, we examine twopossibilities. High-level construal might enhance the unintended influence of activated evaluative associations or facilitate the detection and implementation of intentional responses. To examine these possibilities, the current study applies a multinomial processing tree model to data from Fujita and Han (2009). Results suggest that high-level construal facilitates goal-consistent evaluations by increasing both the unintentional influence of activated goal-consistent positive associations and the intentional detection of and implementation of accurate responding to goal-relevant stimuli. These findings extend our understanding of how construal level promotes goal consistentevaluations.

We recently reported that the risk of sexually acquired HIV-1 infection is increased significantly by variants in the gene encoding CD101, a protein thought to modify inflammatory responses. Using blood samples from individuals with and without these variants, we demonstrate that CD101 variants modify the prevalence of circulating inflammatory cell types and show that CD101 variants are associated with increased proinflammatory cytokine production by circulating T cells. One category of CD101 variants is associated with a reduced capacity of regulatory T cells to suppress T cell cytokine production, resulting in a reduction in the baseline level of immune quiescence. These data are supported by transcriptomics data revealing alterations in the intrinsic regulation of antiviral pathways and HIV resistance genes in individuals with CD101 variants. Our data support the hypothesis that CD101 contributes to homeostatic regulation of bystander inflammation, with CD101 variants altering heterosexual HIV-1 acquisition by facilitating increased prevalence and altered function of T cell subsets.

BackgroundText messaging interventions can be an effective and efficient way to improve health behavioral changes. However, most texting interventions are neither tested nor designed with diverse end users, which could reduce their impact, and there is limited evidence regarding the optimal design methodology of health text messages tailored to low-income, low-health literacy populations and non-English speakers.ObjectiveThis study aims to combine participant feedback, crowdsourced data, and researcher expertise to develop motivational text messages in English and Spanish that will be used in a smartphone app-based texting intervention that seeks to encourage physical activity in low-income minority patients with diabetes diagnoses and depression symptoms.MethodsThe design process consisted of 5 phases and was iterative in nature, given that the findings from each step informed the subsequent steps. First, we designed messages to increase physical activity based on the behavior change theory and knowledge from the available evidence. Second, using user-centered design methods, we refined these messages after a card sorting task and semistructured interviews (N=10) and evaluated their likeability during a usability testing phase of the app prototype (N=8). Third, the messages were tested by English- and Spanish-speaking participants on the Amazon Mechanical Turk (MTurk) crowdsourcing platform (N=134). Participants on MTurk were asked to categorize the messages into overarching theoretical categories based on the capability, opportunity, motivation, and behavior framework. Finally, each coauthor rated the messages for their overall quality from 1 to 5. All messages were written at a sixth-grade or lower reading level and culturally adapted and translated into neutral Spanish by bilingual research staff.ResultsA total of 200 messages were iteratively refined according to the feedback from target users gathered through user-centered design methods, crowdsourced results of a categorization test, and an expert review. User feedback was leveraged to discard unappealing messages and edit the thematic aspects of messages that did not resonate well with the target users. Overall, 54 messages were sorted into the correct theoretical categories at least 50% of the time in the MTurk categorization tasks and were rated 3.5 or higher by the research team members. These were included in the final text message bank, resulting in 18 messages per motivational category.ConclusionsBy using an iterative process of expert opinion, feedback from participants that were reflective of our target study population, crowdsourcing, and feedback from the research team, we were able to acquire valuable inputs for the design of motivational text messages developed in English and Spanish with a low literacy level to increase physical activity. We describe the design considerations and lessons learned for the text messaging development process and provide a novel, integrative framework for future developers of health text messaging interventions.

ObjectiveTo assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD).MethodsAdults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach.ResultsCompared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023).ConclusionsDisability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD.Classification of evidenceThis study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.

To assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD). Adults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach. Compared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023). Disability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD. This study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.