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In this paper, we study the global clock synchronization problem for wireless sensor networks. Based on belief propagation, we propose a fully distributed algorithm which has low overhead and can achieve scalable synchronization. It is also shown analytically that the proposed algorithm always converges for strongly connected networks. Simulation results show that the proposed algorithm achieves better accuracy than consensus algorithms. Furthermore, the belief obtained at each sensor provides an accurate prediction on the algorithm's performance in terms of MSE. [ABSTRACT FROM AUTHOR]

Energy level alignments are crucial for designing high-performance semiconductor devices. However, the reported energy levels, especially the lowest unoccupied energy levels (LUMOs), exhibit significant variability for a given molecular compound. This variability often leads to misunderstanding of device working mechanisms. In this study, single-carrier devices with organic/interlayer/organic structures are proposed to probe the energy level alignments at organic–organic heterojunctions. It is observed that carrier transport characteristics deviate significantly depending on charge scattering or trapping. Five organic molecules, including 1, 3, 5-tri(m-pyrid-3-ylphenyl)benzene (TmPyPB), 4, 4′-bis(arbazole-9-y1)biphenyl (CBP), 2, 2′, 2″-(1,3,5-benzinetriyl)-tris(1-phenyl-1-H-benzimidazole) (TPBi), bis[2-(2-hydroxyphenyl)-pyridine] beryllium (Bepp2), and tris(8-hydroxyquinolinato)aluminum (Alq3), are utilized to test the method. The deduced LUMO level order for these materials is found to deviate significantly from reported values. Furthermore, the effect of differences in the energy level arrangement on the performance of electroluminescent devices is investigated. This work suggests that determining LUMO energy alignments via single-carrier analysis is a valuable method for understanding device working mechanisms. [ABSTRACT FROM AUTHOR]

The phase and crystal morphology transitions of two typical types of mold fluxes were investigated fundamentally using differential scanning calorimetry (DSC) and confocal scanning laser microscopy (CSLM) techniques. For the traditional CaO–SiO2–CaF2-based mold flux, different cooling rates can change the phases and the crystal morphologies. Faceted cuspidine and CaSiO3 are co-precipitated when the cooling rate is less than 50 °C·min−1. The phases transform from Ca4Si2O7F2 and CaSiO3 to Ca4Si2O7F2 at the cooling rate of 50 °C·min−1. Cuspidine shows four different morphologies: faceted shape, fine stripe, fine stripe dendrite, and flocculent dendrite. The crystalline phases of CaAl2O4 and Ca3B2O6 are co-precipitated in the CaO–Al2O3-based mold flux. Neither the phases nor the crystal morphologies change in the low cooling rate range (5 °C·min−1 to 50 °C·min−1). With decreasing temperature, the morphology of CaAl2O4 firstly becomes dendritic, and then the dendritic quality gradually changes to a large-mesh blocky shape at the cooling rates of 100 °C·min−1, 200 °C·min−1, and 500 °C·min−1. Different cooling rates do not show an obvious impact on the morphology transition of CaAl2O4. The strong crystallization ability and large rate of crystallization affect the control of the heat transfer of the CaO–Al2O3-based mold flux during casting. The big morphology difference between primary crystals of the CaO–SiO2–CaF2-based mold flux and the CaO–Al2O3-based mold flux is probably one of the biggest factors limiting lubrication between the CaO–Al2O3-based mold flux and high-Al steel during casting. [ABSTRACT FROM AUTHOR]

Background: Porto Alegre, Brazil, has the highest rates of congenital syphilis and HIV in the country. Other treatable sexually transmitted infections (STIs) are associated with poor pregnancy and neonatal outcomes, but are only diagnosed by syndromic algorithms.Methods: Between September 2018 and November 2019, we offered all pregnant women clinic-based STI testing for HIV antibody and treponemal antibody (via lateral flow assay rapid tests provided by the Brazilian Government) and for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis (via polymerase chain reaction-based testing provided by Gene Xpert, Sunnyvale, CA) in 10 public prenatal health clinics in Porto Alegre. Participating women answered a brief survey via audio computer-assisted survey instrument regarding demographics, partnerships, and sexual behaviors. All infected individuals received appropriate treatment and referrals.Results: Of 400 pregnant women recruited, 94 (24%) were diagnosed with an STI, including 2% with HIV, 11% with syphilis, 9% with chlamydia, 1% with gonorrhea, 5% with trichomoniasis, and 3% with more than 1 STI. In our multivariate analysis, younger age (adjusted odds ratio [AOR], 1.1; 95% confidence interval [CI], 1-1.2), being non-White (AOR, 1.8; 95% CI, 1.1-3.1), having less education (AOR, 2; 95% CI, 1.2-3.4), and having a relationship <1 year (AOR, 2; 95% CI, 1.1-3.6) were all independent predictors of women having an STI. Endorsing symptoms of an STI (e.g., vaginal ulcers/lesions and vaginal discharge) was not predictive of having a laboratory-diagnosed STI (OR, 1.1; 95% CI, 0.7-1.7).Conclusions: Etiologic-based screening for STIs was uniformly accepted by women attending both hospital-based and primary health clinics in the south of Brazil and can result in appropriate treatment of pregnant women. [ABSTRACT FROM AUTHOR]

The quest for a non-hormonal male contraceptive pill for men still exists. Serine protease 37 (PRSS37) is a sperm-specific protein that when ablated in mice renders them sterile. In this study we sought to examine the molecular sequelae of PRSS37 loss to better understand its molecular function, and to determine whether human PRSS37 could rescue the sterility phenotype of knockout (KO) mice, allowing for a more appropriate model for drug molecule testing. To this end, we used CRISPR-EZ to create mice lacking the entire coding region of Prss37, used pronuclear injection to create transgenic mice expressing human PRSS37, intercrossed these lines to generate humanized mice, and performed LC–MS/MS of KO and control tissues to identify proteomic perturbances that could attribute a molecular function to PRSS37. We found that our newly generated Prss37 KO mouse line is sterile, our human transgene rescues the sterility phenotype of KO mice, and our proteomics data not only yields novel insight into the proteome as it evolves along the male reproductive tract, but also demonstrates the proteins significantly influenced by PRSS37 loss. In summary, we report vast biological insight including insight into PRSS37 function and the generation of a novel tool for contraceptive evaluation. [ABSTRACT FROM AUTHOR]

Background: Many smartphone applications (apps) for weight loss are available, but little is known about their effectiveness.Objective: To evaluate the effect of introducing primary care patients to a free smartphone app for weight loss.Design: Randomized, controlled trial. (ClinicalTrials.gov: NCT01650337).Setting: 2 academic primary care clinics.Patients: 212 primary care patients with body mass index of 25 kg/m2 or greater.Intervention: 6 months of usual care without (n = 107) or with (n = 105) assistance in downloading the MyFitnessPal app (MyFitnessPal).Measurements: Weight loss at 6 months (primary outcome) and changes in systolic blood pressure and behaviors, frequency of app use, and satisfaction (secondary outcomes).Results: After 6 months, weight change was minimal, with no difference between groups (mean between-group difference, -0.30 kg [95% CI, -1.50 to 0.95 kg]; P = 0.63). Change in systolic blood pressure also did not differ between groups (mean between-group difference, -1.7 mm Hg [CI, -7.1 to 3.8 mm Hg]; P = 0.55). Compared with patients in the control group, those in the intervention group increased use of a personal calorie goal (mean between-group difference, 2.0 d/wk [CI, 1.1 to 2.9 d/wk]; P < 0.001), although other self-reported behaviors did not differ between groups. Most users reported high satisfaction with MyFitnessPal, but logins decreased sharply after the first month.Limitations: Despite being blinded to the name of the app, 14 control group participants (13%) used MyFitnessPal. In addition, 32% of intervention group participants and 19% of control group participants were lost to follow-up at 6 months. The app was given to patients by research assistants, not by physicians.Conclusion: Smartphone apps for weight loss may be useful for persons who are ready to self-monitor calories, but introducing a smartphone app is unlikely to produce substantial weight change for most patients.Primary Funding Source: Robert Wood Johnson Foundation Clinical Scholars Program, National Institutes of Health/National Center for Advancing Translational Sciences for the UCLA Clinical and Translational Science Institute, and the Resource Centers for Minority Aging Research Center for Health Improvement of Minority Elderly under the National Institutes of Health/National Institute on Aging. [ABSTRACT FROM AUTHOR]

Background: Care coordination tools and toolkits can be challenging to implement. Practice facilitation, an active but expensive strategy, may facilitate toolkit implementation. We evaluated the comparative effectiveness of distance coaching, a form of practice facilitation, for improving the implementation of care coordination quality improvement (QI) projects.Methods: We conducted a mixed methods evaluation of the Coordination Toolkit and Coaching (CTAC) initiative. Twelve matched US Veterans Health Administration primary care clinics were randomized to receive coaching and an online care coordination toolkit ("coached"; n = 6) or access to the toolkit only ("non-coached"; n = 6). We did interviews at six, 12, and 18 months. For coached sites, we'ly collected site visit fieldnotes, prospective coach logs, retrospective coach team debriefs, and project reports. We employed matrix analysis using constructs from the Consolidated Framework for Implementation Research and a taxonomy of outcomes. We assessed each site's project(s) using an adapted Complexity Assessment Tool for Systematic Reviews.Results: Eleven sites implemented a local CTAC project. Eight sites (5 coached, 3 non-coached) used at least one tool from the toolkit. Coached sites implemented significantly more complex projects than non-coached sites (11.5 vs 7.5, 95% confidence interval 1.75-6.25, p < 0.001); engaged in more formal implementation processes (planning, engaging, reflecting and evaluating); and generally had larger, more multidisciplinary QI teams. Regardless of coaching status, sites focused on internal organizational improvement and low-intensity educational projects rather than the full suite of care coordination tools. At 12 months, half the coached and non-coached sites had clinic-wide project implementation; the remaining coached sites had implemented most of their project(s), while the remaining non-coached sites had either not implemented anything or conducted limited pilots. At 18 months, coached sites reported ongoing effort to monitor, adapt, and spread their CTAC projects, while non-coached sites did not report much continuing work. Coached sites accrued benefits like improved clinic relationships and team QI skill building that non-coached sites did not describe.Conclusions: Coaching had a positive influence on QI skills of (and relationships among) coached sites' team members, and the scope and rigor of projects. However, a 12-month project period was potentially too short to ensure full project implementation or to address cross-setting or patient-partnered initiatives.Trial Registration: NCT03063294 . [ABSTRACT FROM AUTHOR]

While fluid replacement therapy is a primary treatment modality used in vaso-occlusive crises for sickle cell disease, data is limited on its safety, efficacy, and variability. We performed a retrospective analysis on 157 unique patient encounters from 49 sickle cell patients hospitalized with a vaso-occlusive episode at our institution from 2013 to 2017. The median length of hospital stay was 4 days (IQR 2-7). The mean total amount of intravenous fluid administered during the hospitalization was 7.4 L (Std 9.6). The mean total amount of fluid intake including intravenous fluids, blood transfusions, and oral fluids was 14.2 L (Std 18.2). Multivariate analyses revealed significant associations between the development of any adverse event (including a new oxygen requirement, acute chest syndrome, aspiration event, other hospital-acquired infection, acute kidney injury, and intensive care unit transfer) and the following variables: intravenous fluid administered in the first 24 h (p = 0.001, OR 1.899, 95% CI 1.319-2.733), total amount of intravenous fluid administered (p = 0.005, OR 1.081, 95% CI 1.023-1.141), and total amount of fluid intake including oral fluids, blood transfusions, and intravenous fluids (p = 0.009, OR 1.046, 95% CI 1.011-1.081). Other factors found to be significantly associated with any adverse event were dialysis dependence prior to admission (p < 0.001, OR 12.984, 95% CI 3.660-46.056) and admission to an inpatient service versus an emergency room or observation unit (p = 0.008, OR 3.201, 95% CI 1.346-7.612). While fluid administration may theoretically slow the sickling process, this data suggests that fluid administration during a vaso-occlusive episode, and especially total volume given in the first 24 h, may also lead to adverse events. [ABSTRACT FROM AUTHOR]

Chronic systemic sterile inflammation is implicated in the pathogenesis of cerebrovascular disease and white matter injury. Non-invasive blood markers for risk stratification and dissection of inflammatory molecular substrates in vivo are lacking. We sought to identify whether an interconnected network of inflammatory biomarkers centered on IL-18 and all previously associated with white matter lesions could detect overt and antecedent white matter changes in two populations at risk for cerebral small vessel disease. In a cohort of 167 older adults (mean age: 76, SD 7.1, 83 females) that completed a cognitive battery, physical examination, and blood draw in parallel with MR imaging including DTI, we measured cerebral white matter hyperintensities (WMH) and free water (FW). Concurrently, serum levels of a biologic network of inflammation molecules including MPO, GDF-15, RAGE, ST2, IL-18, and MCP-1 were measured. The ability of a log-transformed population mean-adjusted inflammatory composite score (ICS) to associate with MR variables was demonstrated in an age and total intracranial volume adjusted model. In this cohort, ICS was significantly associated with WMH (β = 0.222, p = 0.013), FW (β = 0.3, p = 0.01), and with the number of vascular risk factor diagnoses (r = 0.36, p<0.001). In a second cohort of 131 subjects presenting for the evaluation of acute neurologic deficits concerning for stroke, we used serum levels of 11 inflammatory biomarkers in an unbiased principal component analysis which identified a single factor significantly associated with WMH. This single factor was strongly correlated with the six component ICS identified in the first cohort and was associated with WMH in a generalized linear regression model adjusted for age and gender (p = 0.027) but not acute stroke. A network of inflammatory molecules driven by IL-18 is associated with overt and antecedent white matter injury resulting from cerebrovascular disease and may be a promising peripheral biomarker for vascular white matter injury. [ABSTRACT FROM AUTHOR]

Purpose This paper aims to report the tribological behavior of Ag nanoparticles/reduced graphene oxide nanocomposites (Ag/RGO NCs) and Ag nanoparticles (Ag NPs) as a green additive in oil with different concentration and under different friction conditions.Design/methodology/approach The Ag/RGO NCs and Ag NPs were both synthesized in a chemical reduction method. The diameter of silver nanoparticles implanted between RGO sheets was about 25 nm and that of silver sol was 70 nm. The morphology and structure of Ag/RGO NC were characterized by TEM, XRD and FTIR. The tribological properties of Ag/RGO NCs and Ag NPs as lubricant oil additive were evaluated by measuring the friction coefficients and wear of the surface in different condition which were tested on UMT-II.Findings The results indicated that both the additives improved the friction-reduced and anti-wear properties of paraffin oil, and Ag/RGO NCs has better tribological performance than Ag NPs. The excellent tribological properties were attributed to the special structure of Ag/RGO NC and the formation of tribofilm reducing the friction and wear on the shearing surfaces.Research limitations/implications It is relatively difficult to observe the morphology of the lubricant film formed on the friction surface and to analyze the chemical composition at different depths of the lubricant film.Originality/value It is the first time for Ag/RGO NCs to be applied to improve the friction-reduced and anti-wear properties of lubricant oil as additive. [ABSTRACT FROM AUTHOR]

Low-dimension metal halide perovskites are attractive for bandgap tunable optoelectronic materials. Among them, 1-D CsPbBr 3 quantum wires (QWs) are emerging as promising deep-blue luminescent material. However, the growth dynamics of 1-D perovskite QWs are intricate, making the study and control of 1-D QWs highly challenging. In this study, a strategy for controlling both the length and width of the CsPbBr 3 QWs was realized. The temperature-dependent isotropic growth mechanism was revealed and employed as the main tool for the oriented growth of 1-D CsPbBr 3 QWs for various aspect ratios. Our results pave the way for the controlled synthesis of ultrasmall perovskite nanocrystals.

Infectious bursal disease virus (IBDV) caused an acute and highly contagious infectious disease characterized by severe immunosuppression, causing considerable economic losses to the poultry industry globally. Although this disease was well-controlled under the widely use of commercial vaccines in the past decades, the novel variant IBDV strains emerged recently because of the highly immunized-selection pressure in the field, posting new threats to poultry industry. Here, we reported novel variant IBDV is responsible for a disease outbreak, and assessed the epidemic and pathogenicity of IBDV in this study. Moreover, we constructed a challenge model using Fowl adenovirus serotype 4 (FAdV-4) to study on the immunosuppressive effect. Our findings underscore the importance of IBDV surveillance, and provide evidence for understanding the pathogenicity of IBDV., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Lipid metabolism plays a central role in prostate cancer. To date, the major focus has centered on de novo lipogenesis and lipid uptake in prostate cancer, but inhibitors of these processes have not benefited patients. A better understanding of how cancer cells access lipids once they are created or taken up and stored could uncover more effective strategies to perturb lipid metabolism and treat patients. Here, we identified that expression of adipose triglyceride lipase (ATGL), an enzyme that controls lipid droplet homeostasis and a previously suspected tumor suppressor, correlates with worse overall survival in men with advanced, castration-resistant prostate cancer (CRPC). Molecular, genetic, or pharmacologic inhibition of ATGL impaired human and murine prostate cancer growth in vivo and in cell culture or organoids under conditions mimicking the tumor microenvironment. Mass spectrometry imaging demonstrated that ATGL profoundly regulates lipid metabolism in vivo, remodeling membrane composition. ATGL inhibition induced metabolic plasticity, causing a glycolytic shift that could be exploited therapeutically by cotargeting both metabolic pathways. Patient-derived phosphoproteomics identified ATGL serine 404 as a target of CAMKK2-AMPK signaling in CRPC cells. Mutation of serine 404 did not alter the lipolytic activity of ATGL but did decrease CRPC growth, migration, and invasion, indicating that noncanonical ATGL activity also contributes to disease progression. Unbiased immunoprecipitation/mass spectrometry suggested that mutation of serine 404 not only disrupts existing ATGL protein interactions but also leads to new protein-protein interactions. Together, these data nominate ATGL as a therapeutic target for CRPC and provide insights for future drug development and combination therapies., Significance: ATGL promotes prostate cancer metabolic plasticity and progression through both lipase-dependent and lipase-independent activity, informing strategies to target ATGL and lipid metabolism for cancer treatment., (©2023 American Association for Cancer Research.)

Avian leukemia virus subgroup J (ALV-J) causes various diseases associated with tumor formation and decreased fertility and induced immunosuppressive disease, resulting in significant economic losses in the poultry industry globally. Virus usually exploits the host cellular machinery for their replication. Although there are increasing evidences for the cellular proteins involving viral replication, the interaction between ALV-J and host proteins leading to the pivotal steps of viral life cycle are still unclear. Here, we reported that ribonucleoside-diphosphate reductase subunit M2 (RRM2) plays a critical role during ALV-J infection by interacting with capsid protein P27 and activating Wnt/β-catenin signaling. We found that the expression of RRM2 is effectively increased during ALV-J infection, and that RRM2 facilitates ALV-J replication by interacting with viral capsid protein P27. Furthermore, ALV-J P27 activated Wnt/β-catenin signaling by promoting β-catenin entry into the nucleus, and RRM2 activated Wnt/β-catenin signaling by enhancing its phosphorylation at Ser18 during ALV-J infection. These data suggest that the upregulation of RRM2 expression by ALV-J infection favors viral replication in host cells via activating Wnt/β-catenin signaling. IMPORTANCE Our results revealed a novel mechanism by which RRM2 facilitates ALV-J growth. That is, the upregulation of RRM2 expression by ALV-J infection favors viral replication by interacting with capsid protein P27 and activating Wnt/β-catenin pathway in host cells. Furthermore, the phosphorylation of serine at position 18 of RRM2 was verified to be the important factor regulating the activation of Wnt/β-catenin signaling. This study provides insights for further studies of the molecular mechanism of ALV-J infection., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate whether symptoms of gastroesophageal reflux disease and radiographic measures of esophageal dilation are associated with radiographic progression of systemic sclerosis-related interstitial lung disease (SSc-ILD)., Methods: Participants of the Scleroderma Lung Study II, which compared mycophenolate versus cyclophosphamide for SSc-ILD, completed the reflux domain of the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 at baseline. The diameter and area of the esophagus in the region of maximum dilation was measured by quantitative image analysis. Univariate and multivariable linear regression analyses were created to evaluate the relationship between these measures of esophageal involvement and progression of SSc-ILD over 2 years, based on the radiologic quantitative interstitial lung disease (QILD) and quantitative lung fibrosis (QLF) in the lobe of maximum involvement (LM). All multivariable models controlled for the treatment arm, baseline ILD severity, and proton-pump inhibitor use., Results: The baseline mean patient-reported reflux score was 0.57, indicating moderate reflux (n = 141). Baseline mean maximal esophageal diameter and area were 22 mm and 242 mm 2 , respectively. Baseline reflux scores were significantly associated with the change in QLF-LM and QILD-LM in the univariate and multivariable models. Neither radiographic measure of esophageal dilation was associated with the change in radiographic measures of lung involvement., Conclusion: Severity of reflux symptoms as measured by an SSc-specific questionnaire was independently associated with the change in the radiographic extent of ILD and fibrosis over 2 years in patients with SSc-ILD. Two objective measures of esophageal dilation were not associated with radiographic progression of ILD, highlighting the need for improved objective measures of esophageal dysfunction in SSc., (© 2022 American College of Rheumatology.)

Infectious bursal disease virus (IBDV) causes an acute and highly contagious infectious disease characterized by severe immunosuppression, causing great economic losses to the poultry industry globally. Over the past 30 years, this disease has been well controlled through vaccination and strict biosafety measures. However, novel variant IBDV strains have emerged in recent years, posing a new threat to the poultry industry. Our previous epidemiological survey showed that few novel variant IBDV strains had been isolated from chickens immunized with the attenuated live vaccine W2512-, suggesting that this vaccine is efficacious against novel variant strains. Here, we report the protective effect of the W2512 vaccine against novel variant strains in SPF chickens and commercial yellow-feathered broilers. We found that W2512 causes severe atrophy of the bursa of Fabricius in SPF chickens and commercial yellow-feathered broilers, induces high levels of antibodies against IBDV, and protects chickens from infection with the novel variant strains via a placeholder effect. This study highlights the protective effect of commercial attenuated live vaccines against the novel IBDV variant and provides guidance for the prevention and control of this disease., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: Observational studies have shown that men with systemic sclerosis have an increased risk of interstitial lung disease (ILD) and mortality compared with women. However, previous studies have not controlled for treatment effect or evaluated the biological mechanism or mechanisms underlying this sex difference. We aimed to compare ILD progression and long-term morbidity and mortality outcomes in male and female participants of two randomised controlled trials for systemic sclerosis-associated ILD., Methods: For this post-hoc analysis, data from all participants in the Scleroderma Lung Study (SLS) I and SLS II were analysed. The primary objective was to explore the effect of sex on the course of the percentage predicted forced vital capacity (FVC) during and after active treatment over the 24-month study periods. In SLS I, 158 participants (111 women, 47 men) were randomly assigned to receive oral cyclophosphamide (cyclophosphamide; ≤2 mg/kg daily) or placebo; in SLS II, 142 participants (105 women, 37 men) were randomly assigned to receive oral mycophenolate mofetil (1500 mg twice daily) or oral cyclophosphamide (≤2 mg/kg daily). Sex (ie, male or female) was self-reported in both studies by the participants. Changes in radiographic fibrosis and time to death and respiratory failure were secondary outcomes of the present analysis. Baseline levels of biomarkers implicated in the pathobiology of systemic sclerosis-associated ILD were measured in bronchoalveolar lavage fluid in SLS I., Findings: In the SLS I placebo group, the rate of decline in percentage predicted FVC from 3 months to 12 months was greater in men than in women, but the difference was not significant (estimated effect -0·29 [95% CI -0·67 to 0·10]; p=0·14). In SLS II, the rate of decline in percentage predicted FVC from 3 months to 12 months was significantly worse in men treated with either cyclophosphamide (estimated effect -0·72; [95% CI -1·14 to -0·31]; p=0·00060) or mycophenolate mofetil (estimated effect -0·34 [-0·58 to -0·10]; p=0·0051) than in women. A greater proportion of men had a decline in percentage predicted FVC of 10% or greater compared with women for the pooled active treatment groups from SLS I and SLS II and the placebo group of SLS I. Men had worse radiographic outcomes at 2 years than women in SLS II, even after adjusting for baseline disease severity and treatment arm assignment. Long-term survival was worse in men in SLS I (log-rank test p=0·080) and SLS II (log-rank test p=0·030). In SLS II, male sex was independently associated with increased mortality (hazard ratio 2·42 [95% CI 1·16 to 5·04]; p=0·018). In bronchoalveolar lavage fluid, men had increased concentrations of pro-fibrotic mediators (eg, matrix metalloproteinase-13 and tissue inhibitor of metallopeptidase 1), whereas women had increased pro-inflammatory mediators (eg, interleukin [IL]-12, IL-7, and granulocyte-colony stimulating factor)., Interpretation: In two randomised controlled trials, men with systemic sclerosis-associated ILD had a less favourable course of ILD both with and without active treatment, as well as worse long-term survival. Sex differences in pro-fibrotic or inflammatory mediators of disease might account for these differences and warrant future study., Funding: US National Institutes of Health; US National Heart, Lung, and Blood Institute; US National Institute of Arthritis and Musculoskeletal and Skin Diseases; Bristol Myers Squibb; and Hoffmann-LaRoche., Competing Interests: We report no financial or personal relationships related to the submitted work. ERV reports the following financial relationships outside of the submitted work on SLS I and SLS II outcomes: consulting and speaking fees (Boehringer Ingelheim); and institutional support received for performing systemic sclerosis studies for Kadmon, Forbius, Boehringer Ingelheim, and Horizon. DPT reports receiving modest financial support from Genentech for participation in an investigator-initiated trial outside of the submitted work. RS reports institutional support received for performing systemic sclerosis studies for Boehringer Ingelheim outside of the submitted work. SA reports the following financial relationships outside of the submitted work on SLS I and SLS II outcomes: consulting (Boehringer Ingelheim, Corbus, Novartis, CSL Behring, AbbVie, and AstraZeneca); payment or honoraria for lectures or presentations (Integrity CE and the North Carolina Rheumatology Association); institutional support received for doing systemic sclerosis studies for Momenta, Boehringer Ingelhim, Janssen, Scleroderma Research Foundation, the US Department of Defense and the NIH; and a leadership role (unpaid volunteer) for the Scleroderma Clinical Trial Consortium and the Scleroderma Foundation Medical Advisory Board. GHK reports being a research consultant for MedQIA and has a patent issued on the radiographic quantification of ILD (UC-2015-0324982-A1). JG is the founder of MedQIA. MDR reports receiving institutional support from Genentech for leading an investigator-initiated clinical trial in systemic sclerosis-associated ILD outside of the SLS I and SLS II studies reported here. All other authors declare no competing interests outside of the submitted work.

Introduction: Results from several clinical trials suggest there is a dose-response effect for beta interferon-1a (INFβ1a) in multiple sclerosis (MS)., Methods: Our objective was to confirm these results through a retrospective analysis of patients with MS who had breakthrough disease (BD) on intramuscular (IM) INFβ1a (Avonex®) once per week (QW), who were switched to twice per week (BIW) IM INFβ1a between 1995 and 2015. The primary outcome measure was no further BD for at least 24 months. A secondary outcome measure was decrease in mean percentage of disease activity over time. BD was defined as continued relapses, new T2 or enhanced lesions on magnetic resonance imaging (MRI) of the brain, or worsening of the Expanded Disability Status Scale (EDSS) or the neurological examination., Results: Among 92 patients on QW IM INFβ1a, 53 patients with BD were switched to BIW IM INFβ1a. Of these 53 patients, 44 had adequate follow-up for at least 2 years. Twenty-three of these had no further BD for 24 months or more (range 24-192 months). Beta interferon neutralizing antibody testing was negative in 19 patients. An intent-to-treat analysis of the uncensored data from 52 switched patients also supported a treatment benefit., Conclusion: For patients with MS having breakthrough disease on QW INFβ1a, switching to more frequently administered INFβ may be an option. Advantages to using IM INFβ1a for this include no skin reactions and a lower incidence of neutralizing antibodies. Further pragmatic, observational, larger-group studies comparing treatment with Avonex® and higher dosed IM INFβ1a, such as the recently FDA-approved IM peginterferon beta-1a, may be indicated., (© 2022. The Author(s).)