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Background:Antinuclear antibodies (ANA) to intranuclear particles are found in the blood of people with and without autoimmune diseases. To our knowledge, only 1 past genome-wide association study (GWAS) has sought to identify genetic factors related to ANA positivity, reporting association with HLA-DR in a Japanese population (Terao C, Arthritis Rheum, 2014). Dissecting the genetic basis for ANA positivity would allow new insights into autoimmunity susceptibility.Objectives:We conducted a genome-wide association study for ANA positivity.Methods:We used data from the Mass General Brigham Biobank, containing linked electronic health records and genotyping (Illumina’s Multi-Ethnic Genotyping Array or Global Screening Array chips) for >65,000 consented patients. We identified subjects with genotyping and results for either hep2 or ML immunofluorescence ANA assays (1989-2022). ANA+, those with ≥1 result of ≥ 1:40 titer, were compared to ANA-, those with no positive ANA results. After quality control, we imputed using the Haplotype Reference Consortium, excluding variants with imputation score <0.5. Classical HLA alleles and amino acids for HLA genes were imputed with SNP2HLA using TopMed HLA data as reference. We restricted analyses to those with predicted European ancestry (1000 Genomes EUR group; 82% of biobank subjects). Diagnostic codes identified 8 autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma (SSc), Sjögren’s syndrome, mixed connective tissue disease (MCTD), multiple sclerosis (MS), primary biliary cirrhosis (PBC), and autoimmune thyroid disease (ATD). GWAS for ANA + vs – was done in PLINK2, with logistic regression adjusted for age, sex and 4 genetic principal components. Linkage disequilibrium (LD) block was defined as r2>0.5 using EUR information. We also tested for associations with ANA ≥ 1:80, excluding anti-nucleolar or anti-centromere patterns, excluding those with autoimmune diseases vs. ANA-, and HLA alleles and amino acids.Results:We studied 12,875 subjects with ANA and genotyping results: 7,035 ANA + (≥ 1:40) vs. 5,840 ANA -. The female/male ratio was similar in both groups: 62.9% female in ANA+ vs. 62.1% in ANA- (p 0.39). Patients who were ANA+ were older than the ANA- (56.1 ± 15.8 vs. 52.1 ± 15.2 years, p<0.0001). Of ANA+ patients, 33% had ≥1 of the 8 autoimmune diseases, as did 19% of ANA- patients. Overall, SLE, RA, SSc, Sjogren’s syndrome, MCTD, MS, PBC and ATD were present in 538, 1425, 159, 370, 65, 354, 63 and 408 subjects (with ANA+ proportions 71%, 55%, 78%, 74%, 82%, 55%, 63%, and 62% respectively). 8,073,314 SNPs with MAF>=0.01 were included. The strongest GWAS association with ANA+ ≥1:40 (vs. ANA -) was for rs3134951 on chromosome 6 in the HLA region (OR 1.2, 95% CI 1.1-1.3, p 1.6×10-9) (Figure 1). Within the HLA region, HLA-DQB1:0201 allele had the strongest association (OR 1.3, 95% CI 1.2-1.3, p 9.2×10-11). We identified two suggestive novel loci for ANA +, one in LOC105373419 (rs60343674) on chromosome 2 and the other in ABHD5 (rs12489159) on chromosome 3. (Figure 1) HLA-DRB1:03 and HLA-B:08 alleles, not in strong LD, each had significant associations (Figure 2). Repeated GWAS for ≥1:80 titer and ≥ 1:80 excluding anti-centromere and anti-nucleolar patterns vs. ANA - showed similar, but stronger signals for rs3134951 on chromosome 6 (p=5.6×10-13 and p=2.3×10-14, respectively). GWAS excluding those with known autoimmune diseases had weaker signal for rs3134951 (p=2.6×10-7). This SNP, rs3134951 at 6p.21.32, is intergenic and associated with 2 genes, FKBPL and PRRT1, previously associated with SLE (Yin X, Annals Rheum Dis, 2020).Conclusion:HLA-DRB, HLA-DQB1 and HLA-B, and newly identified rs3134951 at 6p.21.32 are genetic factors predisposing to ANA positivity in this European ancestry population. We are pursuing stratified analyses by ANA pattern and titer, sex, and autoimmune disease.REFERENCES: NIL.Acknowledgements:NIL.Disclosure of Interests:Jing Cui: None declared, Jeong Yee: None declared, Emily G. Oakes: None declared, Hongshu Guan: None declared, Liming Liang: None declared, Karen Costenbader Bristol Myers Squibb, Glaxo Smith Kline, Cabaletta Bio, Merck, Gilead,

Estimates of design floods are required for the design of hydraulic structures and to quantify the risk of failure of the structures. Many international studies have shown that design floods estimated using a regionalised method result in more reliable estimates of design floods than values computed from a single site or from other methods. A number of regional flood frequency analysis (RFFA) methods have been developed, which cover all or parts of South Africa. These include methods developed by Van Bladeren (1993), Mkhandi et al. (2000), Görgens (2007) and Haile (2011). The performance of these methods has been assessed at selected flow-gauging sites in the province of KwaZulu-Natal (KZN), South Africa. It is recommended that the limitations of available flow records to estimate extreme flow events need to be urgently addressed. From the results for KZN the JPV method, with a regionalised GEV distribution with the veld zone regionalisation, generally gave the best performance when compared to design floods estimated from the annual maximum series extracted from the observed data. It is recommended that the performance of the various RFFA methods needs to be assessed at a national scale and that a more detailed regionalisation be used in the development of an updated RFFA method for South Africa.

•In a subsample within VITAL, a double-blind randomized controlled trial of adults randomized to n-3 fatty acids or placebo, we identified reductions in proinflammatory n-3 fatty acid-derived lipid mediators and increases in n-3 fatty acid-derived lipid proresolving mediators in those receiving n-3 fatty acids after 1 y.•Larger 1-y lipid biomarker changes were seen in patients with reported low (<1 serving/mo) vs. high (≥3.9 servings/wk) fish intake at baseline.•Analyses did not reveal significant multiplicative interactions between low vs. high baseline fish intake and randomization to n-3 fatty acids for 1 y upon the change in concentration of lipid mediators. We assessed the joint effects of omega (n)-3 fatty acid supplementation and dietary fish intake on systemic lipid mediators of inflammation among adults. Within VITAL, a double-blind randomized controlled trial, adults were randomized to ω-3 fatty acids (460 mg EPA + 380 mg DHA/d) or placebo. We selected participants who reported low (<1 serving/mo) baseline dietary fish intake and matched them by age, sex, race, and trial arm to participants with self-reported highest fish intake (≥3.9 servings/wk). Baseline and 1-y plasma samples were tested for 9 ω-3 fatty acid-derived lipid mediators. Multivariable linear models assessed lipid mediator changes and joint effects of ω-3 fatty acid supplementation and dietary fish intake. Forty-eight participants with low baseline fish intake were matched to 48 with high fish intake. Mean age was 64.6 (±7.26), 50% were female, and 85% non-Hispanic white. One-year lipid mediator changes in expected directions were observed in those receiving ω-3 fatty acids versus placebo: reductions in proinflammatory mediators, PGD2, 5-HETE, and 12-HETE; increases in proresolving mediators, EPA and DHA. Larger 1-y lipid biomarker changes were seen in those with low baseline fish intake randomized to active ω-3 fatty acids for DHA, EPA, PGD2, Resolvin D1, and Resolvin D4 were observed, although no significant multiplicative interactions were detected. Beneficial changes in circulating proresolving and proinflammatory mediators were found with 1-y of ω-3 fatty acid supplementation versus placebo for all participants, with a trend toward larger effects among those with low baseline fish intake, although interactions were not significant.

Schedule control and supervisor support for family and personal life may help employees manage the work-family interface. Existing data and research designs, however, have made it difficult to conclusively identify the effects of these work resources. This analysis utilizes a group-randomized trial in which some units in an information technology workplace were randomly assigned to participate in an initiative, called STAR, that targeted work practices, interactions, and expectations by (1) training supervisors on the value of demonstrating support for employees' personal lives and (2) prompting employees to reconsider when and where they work. We find statistically significant, although modest, improvements in employees' work-family conflict and family time adequacy, and larger changes in schedule control and supervisor support for family and personal life. We find no evidence that this intervention increased work hours or perceived job demands, as might have happened with increased permeability of work across time and space. Subgroup analyses suggest the intervention brought greater benefits to employees more vulnerable to work-family conflict. This study uses a rigorous design to investigate deliberate organizational changes and their effects on work resources and the work-family interface, advancing our understanding of the impact of social structures on individual lives.

The American chestnut (Castanea dentata) was a dominant, foundational forest canopy tree in eastern North America until an imported chestnut blight (caused by Cryphonectria parasitica) rendered it functionally extinct across its native range. Biotechnological approaches have the potential to help restore the species, but field‐based breeding advances are hampered by long generation times, ≤ 50% transgene inheritance, and regulatory restrictions on outdoor breeding of transgenic trees. Self‐incompatibility and flowering phenology further limit generational advances and field testing of chestnuts. Our work here demonstrates that long generational times and field constraints can be circumvented by producing both male and receptive female flowers in controlled indoor environments. Additionally, we developed an embryo rescue protocol for both indoor and field conditions, in which developing embryos can be extracted and micropropagated from immature seeds collected between 6 and 8 weeks post‐pollination. These advances have enabled production of the first homozygous transgenic American chestnuts, which have produced pollen that was used for outdoor controlled pollinations and yielded nearly 100% transgene inheritance by offspring. This work also provides event‐specific DNA markers to differentiate transgenic chestnut lines and identify homozygous individuals. We demonstrate that an obligate outcrossing forest tree can reach sexual maturity rapidly in controlled, indoor environments. When coupled with genomic analyses and other biotechnological advances, this procedure could facilitate the reintroduction of this iconic species.

Background Galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days in phase 2 and 3 trials. In these analyses, we aimed to evaluate the safety and tolerability of galcanezumab compared with placebo for prevention of episodic or chronic migraine. Methods Data were integrated from three double-blind clinical studies for the up to 6-month galcanezumab exposure group ( N  = 1435), and from five clinical studies for the up to 1-year all-galcanezumab exposure group ( N  = 2276). Patients received a monthly 120 mg subcutaneous injection of galcanezumab (with a 240 mg loading dose in month 1), 240 mg galcanezumab, or placebo. Outcomes measured were treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and discontinuation due to AEs (DCAEs). Laboratory results, vital signs, electrocardiogram (ECG), suicidal ideation and behavior results were evaluated. Results TEAEs that occurred more frequently in galcanezumab-treated patients included injection site pain, injection site reactions excluding pain, constipation, vertigo, and pruritus. The proportion of DCAEs among galcanezumab-treated patients ranged between 1.8 and 3.0%, and differed from placebo group for galcanezumab 240 mg ( P  < 0.05). Fewer than 2.0% of patients in either galcanezumab dose-group compared with 1.0% of placebo-treated patients reported a SAE. There were no clinically meaningful differences between galcanezumab and placebo in laboratory measures, vital signs including blood pressure, ECGs, cardiovascular-related AEs, or suicidal ideation and behavior. Conclusions Galcanezumab demonstrated a favorable safety and tolerability profile for up to 1 year of treatment for the prevention of migraine. Trial registration Clinical Trials CGAB =  NCT02163993 , EVOLVE-1 =  NCT02614183 , EVOLVE-2 =  NCT02614196 , REGAIN =  NCT02614261 , and CGAJ =  NCT02614287 . All were first posted on 25 November 2015, except CGAB posted on 16 June 2014, and before enrolling the first patient.

Within mammalian systems, there exists enormous opportunity to use synthetic gene circuits to enhance phenotype-based drug discovery, to map the molecular origins of disease, and to validate therapeutics in complex cellular systems. While drug discovery has relied on marker staining and high-content imaging in cell-based assays, synthetic gene circuits expand the potential for precision and speed. Here we present a vision of how circuits can improve the speed and accuracy of drug discovery by enhancing the efficiency of hit triage, capturing disease-relevant dynamics in cell-based assays, and simplifying validation and readouts from organoids and microphysiological systems (MPS). By tracking events and cellular states across multiple length and time scales, circuits will transform how we decipher the causal link between molecular events and phenotypes to improve the selectivity and sensitivity of cell-based assays. Synthetic gene circuits enable real-time monitoring of diverse molecular events in live cells.Synthetic circuits provide internal controls to expedite hit validation and facilitate hit prioritization.Synthetic circuits enable on-line validation of induced pluripotent stem cell (iPSC)-derived cells.Synthetic circuits potentiate longitudinal tracking of neurodegenerative-associated phenotypes.

Context:Previous studies have shown a relationship between glycemic control and posttransplant morbidity.Objective:We conducted a prospective randomized controlled trial in postliver transplant patients to evaluate intensive inpatient glycemic control and effects on outcomes to 1 year.Research Design and Intervention:A total of 164 patients [blood glucose (BG) >180 mg/dL] were randomized into 2 target groups: 82 with a BG of 140 mg/dL and 82 with a BG of 180 mg/dL. Continuous insulin infusions were initiated and then converted to subcutaneous basal bolus insulin therapy by our glucose management service.Results:The inpatient mean BG level was significantly different (140 group, 151.4 ± 19.5 mg/dL vs 180 group, 172.6 ± 27.9 mg/dL; P < 0.001). Any infection within 1 year occurred in 35 of the 82 patients (42.7%) in the 140 group and 54 of 82 (65.9%) in the 180 group (P = 0.0046). In a time-to-first infection analysis, being in the 140 group resulted in a hazard ratio of 0.54 (95% confidence interval, 0.35 to 0.83; P = 0.004); the difference between the 2 groups was statistically significant at 1 month (P = 0.008). The number with adjudicated transplant rejection was similar between the 2 groups [17 of 82 (20.7%) and 20 of 82 (24.3%) in the 140 and 180 groups, respectively; P = not significant]. Severe hypoglycemia (BG ≤40 mg/dL) occurred in 3 patients (2 in the 140 group and 1 in the 180 group). However, more patients had moderate hypoglycemia (BG, 41 to 70 mg/dL) in the 140 group [27 of 82 (32.9%) vs 10 of 82 (12.2%) in the 180 group; P = 0.003]. Insulin-related hypoglycemia was not associated with the incidence of severe adverse outcomes.Conclusions:Glycemic control of 140 mg/dL safely resulted in a reduced incidence of infection after transplantation compared with 180 mg/dL, but with an increase in moderate hypoglycemia.Randomized post–liver transplant patients received intensive vs moderate glycemic control. Outcomes were measured up to 1 year, and infections were reduced in the those on intensive treatment.

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eukaryotic translation initiation factor-2α (eIF2α). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α kinase PKR-like ER kinase (PERK), a common component of the UPR and ISR, reversed the mRNA translation block in stressed human islets and delayed the onset of diabetes, reduced islet inflammation, and preserved β cell mass in T1D-susceptible mice. Single-cell RNA-Seq of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen-processing and presentation pathways in β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein programmed death-ligand 1 (PD-L1) in β cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-βH1 human β cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity and that inhibition of PERK may offer a strategy for preventing or delaying the development of T1D.

The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV) is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA) poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4-9.9 Log10TCID50/ml) on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature) anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the highly productive PER.C6 cell culture platform, the stably attenuated CAVA strains may serve as an attractive low-cost and (bio)safe option for the production of a novel next generation IPV.