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This paper deals with the details of preparation of three principal routes for bulking of cellulose fibres. One route is dry cross-linking/hornification using aluminium ions and other salts followed by drying/curing. The mechanisms of these reactions still remain unknown. A second route is physical grafting of fibres using carboxymethylcellulose and bringing the acidic groups into their aluminium form before forming a sheet of paper/board. Hence, curing is not necessary, and this constitutes a unique wet bulking methodology. The mechanism behind this method is believed to be an increase in the surface friction of fibres, when the electrostatic double layer is shielded together with electrostatic cross-linking with aluminium ions. The higher friction between fibres partly prevents the sheet consolidation during drying. A third route is physical grafting of fibres using carboxymethyl cellulose and ion-exchanging the acidic groups with aluminium salts before drying and curing of the fibres. A most interesting factor is that all the thermal treatment methods do not form fibre nodules due to interfibre crosslinking during the heat treatment, a commonly observed phenomena when dealing with chemical crosslinking of fibres. All routes investigated are water-based and should be fairly simple to implement in commercial operations. An inherent advantage is that the bulking is associated with lower water retention values, which should be advantageous for a higher solids content after pressing and, hence, beneficial for paper machine productivity. Bulking is, however, also associated with a loss in bond strength, which in most cases must be alleviated using various additives such as starches and microfibrillated cellulose and it has also been demonstrated in the project how the strength properties (such as z-strength) could be restored at a higher bulk., QC 20221028

QC 20230523

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data., Funding Agencies:SciLifeLab United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH)MH077139 MH1095320European Commission 610307 733161 825843European Research Council (ERC)European Commission CoG-2015_681742_NASCENTStrategic Research Area Epidemiology at Karolinska Institutet Vth 80-year Foundation Clinical Research Support (Avtal om Läkarutbildning och Forskning) Swedish government County councils ALF-agreement IMI2 Joint Undertaking 115974European Federation of Pharmaceutical Industries and Associations with JDRF H2020 Program ERA PerMed JTC 2018 Call (VR) 2018-05619

Objective: To analyse the prognosis and outcomes of SARS-CoV-2 infection in patients with primary SS. Methods: We searched for patients with primary SS presenting with SARS-CoV-2 infection (defined following and according to the European Centre for Disease Prevention and Control guidelines) among those included in the Big Data Sjögren Registry, an international, multicentre registry of patients diagnosed according to the 2002/2016 classification criteria. Results: A total of 51 patients were included in the study (46 women, mean age at diagnosis of infection of 60 years). According to the number of patients with primary SS evaluated in the Registry (n = 8211), the estimated frequency of SARS-CoV-2 infection was 0.62% (95% CI 0.44, 0.80). All but two presented with symptoms suggestive of COVID-19, including fever (82%), cough (57%), dyspnoea (39%), fatigue/myalgias (27%) and diarrhoea (24%), and the most frequent abnormalities included raised lactate dehydrogenase (LDH) (88%), CRP (81%) and D-dimer (82%) values, and lymphopenia (70%). Infection was managed at home in 26 (51%) cases and 25 (49%) required hospitalization (five required admission to ICU, four died). Compared with patients managed at home, those requiring hospitalization had higher odds of having lymphopenia as laboratory abnormality (adjusted OR 21.22, 95% CI 2.39, 524.09). Patients with comorbidities had an older age (adjusted OR 1.05, 95% CI 1.00, 1.11) and showed a risk for hospital admission six times higher than those without (adjusted OR 6.01, 95% CI 1.72, 23.51) in the multivariate analysis. Conclusion: Baseline comorbidities were a key risk factor for a more complicated COVID-19 in patients with primary SS, with higher rates of hospitalization and poor outcomes in comparison with patients without co

Objective. To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS). Methods. By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression. Results. There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.

Background: To assess the risk of incident cardiovascular disease in patients with primary Sjögren's syndrome, overall and stratified by Ro/SSA and La/SSB autoantibody status. Methods: A cohort of patients with primary Sjögren's syndrome in Sweden (n = 960) and matched controls from the general population (n = 9035) were included, and data extracted from the National Patient Register to identify events of myocardial infarction, cerebral infarction and venous thromboembolism. Hazard ratios were estimated using cox proportional hazard regressions. Results: During a median follow‐up of 9.5 years, the overall hazard ratio (HR) was 1.6 (95% CI 1.2–2.1) for myocardial infarction, 1.2 (95% CI 0.9–1.7) for cerebral infarction and 2.1 (95% CI 1.6–2.9) for venous thromboembolism. Patients positive for both Ro/SSA and La/SSB autoantibodies had a substantially higher risk of cerebral infarction (HR 1.7, 95% CI 1.0–2.9) and venous thromboembolism (HR 3.1, 95% CI 1.9–4.8) than the general population. These risks were not significantly increased in Ro/SSA‐ and La/SSB‐negative patients. Among autoantibody‐positive patients, the highest HR of cerebral infarction was seen after ≥10 years disease duration (HR 2.8, 95% CI 1.4–5.4), while the HR for venous thromboembolism was highest 0–5 years after disease diagnosis (HR 4.7, 95% CI 2.3–9.3) and remained high throughout disease duration. Conclusions: Primary Sjögren's syndrome is associated with a markedly increased risk of cardiovascular disease and the presence of Ro/SSA and La/SSB autoantibodies identify the subgroup of patients carrying the highest risk. These findings suggest that monitoring and prevention of cardiovascular disease in this patient group should be considered.

Objective: Environmental factors have been suggested in the pathogenesis of rheumatic diseases. We here investigated whether infections increase the risk of developing primary Sjögren's syndrome (pSS). Methods: Patients with pSS in Sweden (n = 945) and matched controls from the general population (n = 9048) were included, and data extracted from the National Patient Register to identify infections occurring before pSS diagnosis during a mean observational time of 16.0 years. Data were analysed using conditional logistic regression models. Sensitivity analyses were performed by varying exposure definition and adjusting for previous health care consumption. Results: A history of infection associated with an increased risk of pSS (OR 1.9, 95% CI 1.6–2.3). Infections were more prominently associated with the development of SSA/SSB autoantibody‐positive pSS (OR 2.7, 95% CI 2.0–3.5). When stratifying the analysis by organ system infected, respiratory infections increased the risk of developing pSS, both in patients with (OR 2.9, 95% CI 1.8–4.7) and without autoantibodies (OR 2.1, 95% CI 1.1–3.8), whilst skin and urogenital infections only significantly associated with the development of autoantibody‐positive pSS (OR 3.2, 95% CI 1.8–5.5 and OR 2.7, 95% CI 1.7–4.2). Furthermore, a dose–response relationship was observed for infections and a risk to develop pSS with Ro/SSA and La/SSB antibodies. Gastrointestinal infections were not significantly associated with a risk of pSS. Conclusions: Infections increase the risk of developing pSS, most prominently SSA/SSB autoantibody‐positive disease, suggesting that microbial triggers of immunity may partake in the pathogenetic process of pSS.

Supplement: 129Meeting Abstract: OP04

The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value = 1.0 x 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio = 0.56; P-value = 6.6 x 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.

The genetic background of primary Sjogrens syndrome (pSS) is partly shared with systemic lupus erythematosus (SLE). Immunoglobulin G Fc receptors are important for clearance of immune complexes. Fcg receptor variants and gene deletion have been found to confer SLE risk. In this study, four Fc gamma receptor single-nucleotide polymorphisms (SNPs) and one copy number variation (CNV) were studied. Swedish and Norwegian pSS patients (N = 527) and controls (N = 528) were genotyped for the Fc gamma receptor gene variant FCGR2A H131R (rs1801274) by the Illumina GoldenGate assay. FCGR3A F158V (rs396991) was analysed in 488 patients and 485 controls, FCGR3B rs447536 was analysed in 471 patients and 467 controls, and FCGR3B rs448740 was analysed in 478 cases and 455 controls, using TaqMan SNP genotyping assays. FCGR3B CNV was analysed in 124 patients and 139 controls using a TaqMan copy number assay. None of the SNPs showed any association with pSS. Also, no FCGR3B CNV association was detected. The lack of association of pSS with Fc gamma receptor gene variants indicates that defective immune complex clearance may not be as important in pSS pathogenesis as in SLE, and may point to important differences between SLE and pSS.

We performed a candidate gene association study in 540 patients with primary Sjögren's Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10(-5), OR 1.68, the family with sequence similarity 167 member A-B-lymphoid tyrosine kinase (FAM167A-BLK) locus, P=4.7 × 10(-4), OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10(-4), OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS

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The mechanical properties, including fracture toughness and fatigue, fatigue-crack growth rates and corrosion characteristics have been determined for a total of 51 lots of 7050-T76 sheet, 7050-T73651 plate, 7050-T73652 hand forgings, 7050-T736 die forgings and 7050-T76511 extruded shapes. Tables of computed design mechanical properties, modulus of elasticity values and individual stress-strain curves are presented. The critical stress-intensity factor, (K sub c), was determined for samples of each lot of sheet and the plane-strain stress-intensity factor, (K sub Ic), was determined for plate, hand and die forgings and extruded shapes. The combination of strength and toughness of all products are generally comparable to or higher than those of conventional 7XXX alloys. Axial-stress fatigue strengths were determined in ambient-air and salt-fog environments. Modified Goodman diagrams were developed from tests made in ambient air., See also report dated Apr 1973, AD-766 335.

The mechanical properties, fracture toughness, fatigue, fatigue-crack growth rates in three environments and corrosion characteristics of 10 lots each of 2048-T851, 7050-T7351 and 7475-T7351 plate and 2219-T852 hand forgings have been evaluated. Data for establishing MIL-HDBK-5 values, including modulus of elasticity and stress-strain are presented.

Manufacturing methods were established for the production of aluminum alloy 7050 aircraft-size rivets. Strength, formability and corrosion tests were conducted on wire to establish the aging practices to be applied to the rivets. The purity level had no noticeable effect on rivet fabrication, strength properties, formability or resistance to stress-corrosion cracking (SCC) of the wires. The rivets, in 3/32, 3/16 and 3/8-in. diameter sizes, were given second step agings of 8 hours at 345, 350 and 355 F. Driving and hole-fill evaluations, static tests of lap-shear joints, fatigue tests of high load-transfer joints and SCC tests were conducted using the 7050 rivets. The driving and hole-fill quality, the static strength and resistance to SCC for 7050 alloy rivets equals or exceeds that of 2024-T31 ('ice-box') rivets. Driven shear strength values were at least 15 per cent greater than that typically found for 2024-T31 rivets. The fatigue strength of joints with 7050 rivets was less than similar joints containing 2024-T31 rivets. A production aging practice is recommended to place the 7050 rivets in the T73 temper. Residual stress around the rivet hole can affect the resistance to stress-corrosion cracking of the material being joined.

The tensile, compressive, shear, bearing, fracture toughness and axial-stress fatigue properties, fatigue-crack propagation rates and corrosion characteristics have been determined for 10 lots of alclad 7050-T76 sheet ranging from 0.025-in. through 0.249-in. thick. Tables of computed design mechanical properties and individual tensile and compressive stress-strain curves are presented. The effect of stretching on the tensile properties was also studied. Axial-stress fatigue strengths and fatigue-crack propagation rates were determined in ambient-air and salt-fog environments.

A large amount of scatter was encountered in the tee fillet weld tests; however, the average fatigue strength of the specimens prepared with the E7016 electrode was about 10 per cent greater than that of the specimens prepared with the E6010 electrode. All of the E7016 joints had fatigue strengths which were significantly greater than the exceptionally low fatigue strengths of some of the E6010 joints. The exceptionally low fatigue strengths of some of the specimens prepared with the E6010 electrode appeared to be caused by an abnormally large amount of porosity in the weld metal. The E7016 welds were relatively free from porosity. The tee fillet joints produced with the low hydrogen electrodes conforming to the Military Specification Mil-E-986A (Mil 180) had an average fatigue strength which was about 10 per cent greater than the average fatigue strength of the E7016 joints and about 25 per cent greater than that of the E6010 joints. Preheating to 300 deg. F. had little effect on the E6010 joints, but increased the average fatigue strength of the E7016 joints about 10 per cent so that they performed about as well as the Mil 180 specimens. Removal of the paper spacers prior to testing decreased the average fatigue strength about 15 per cent. The ultimate strengths of the statically tested tee fillet specimens varied from 58,000 psi to 63,200 psi on the throat of the weld. (Author)

The 'stress-corrosion-fatigue' performance of several high strength- aluminum alloys was investigated by tests of hydraulic cylinders and other types of specimens. Specimens were prepared from forgings and forging stock of alloys 2014-T6, 7075-T6, 7075-T73, 7079-T6, and X7080-T7 and from premium castings of alloy CH70-T7. Alloy 7075-T73 rated best in the corrosion-fatigue tests; no stress-corrosion cracking occurred in this alloy, and the lives of forged cylinders subjected to repeated loadings to 80% of design stress in a corrosive environment were at least 10 times as long for this alloy as for forged cylinders of alloys 2014-T6, 7075-T6, or 7079-T6. Fractographic examination showed that stress-corrosion cracking as well as fatigue cracking occurred in alloys 2014-T6, 7075-T6, and 7079-T6 in the stress-corrosion-fatigue tests. The investigation demonstrated that stress corrosion and fatigue can interact under certain conditions to produce failures in shorter times and fewer cycles than for either phenomenon occurring by itself.

All forty of the hand forgings scheduled for test have been received; chemical analyses have been made and most of the tensile, compressive, shear and bearing properties have been determined. The results of axial-stress fatigue tests of smooth specimens are reported. The results of some tests to determine the effects of notch geometry on the rate of fatigue-crack propagation are presented. Additional tests are being initiated to determine if the uniformity of crack initiation can be improved by using a different notch and crack initiation procedure. Tests are in progress to determine whether it is feasible to change the load during a test to obtain crack-propagation rates at more than one stress level., See also Technical management rept. no. 1, AD-833 230.

Except for a few tests, the tensile, compressive, shear and bearing properties were determined for all but three of a total of forty 2014-T652, 2024-T852, 7075-T7352 and 7079-T652 hand forgings scheduled for test. Ratios among these properties were calculated. Plane-strain fracture-toughness values were determimed for two of the hand forgings. The results of axial-stress fatigue tests (R = 0.0) of smooth specimens are presented. The preparation of specimens for the stress-corrosion and exfoliation tests was initiated. Tests of the 6x24-in. 2014-T652 hand forging are in progress to study the effects of notch geometry, specimen length and stress on the rate of fatigue crack propagation.