Corrosion fatigue of engineering alloys in aqueous environments

A comparative study of the fatigue crack growth rate (FCGR) behaviour of five alloys in air and in aqueous environments has been performed. The alloys tested include: mild steel as a reference material, a corrosion resistant dual phase steel, 3CR12, a proprietary martensitic stainless steel, AISI 431, a newly developed 8% Cr martensitic steel, Alloy 825, and a newly developed corrosion-abrasion resistant metastable austenitic alloy, 1210. Tests were conducted in laboratory air, distilled water at rest potential, 500 ppm chloride solution at rest potential, 1000 ppm chloride solution at rest potential, and 1000 ppm chloride solution at -1200 m V see; solution temperatures were maintained at 25⁰ C. Crack growth rate tests were performed using sinusoidal loading at a load ratio R = 0.1, a frequency of 3Hz in the laboratory air, and a frequency of 1 Hz in the aqueous environments. At the completion of testing, fracture surfaces were studied using a scanning electron microscope. In air, the mild steel and 3CR12 display comparable rates of cracking and exhibit a greater resistance to fatigue crack propagation than the martensitic AISI 431 and Alloy 825; Alloy 825 shows the least resistance to fatigue crack propagation. The deformation induced transformation in 1210 gives this alloy the greatest resistance to fatigue crack propagation in air. Fatigue crack growth rates were all enhanced in the aqueous environments. The greatest overall rate of environmentally assisted cracking was shown by alloy 825 while the lowest was shown by the mild steel. Although the rate of cracking of 1210 in the aqueous environments was less than that of Alloy 825, 1210 was influenced the most by the aqueous environments. An environmentally assisted cracking index shows that the rate of fatigue crack propagation in 1210 is increased by 32 times in the 500 ppm chloride solution at low stress intensities. The fatigue crack growth rates of mild steel and AISI 431 were significantly influenced by the cathodically polarised conditions in the 1000 ppm chloride solution, compared to the rest potential conditions. In these cases hydrogen was seen to be evolved from the specimen surfaces. Changes in the fatigue crack growth rate behaviour were accompanied by changes in the fracture surface morphologies. The observed changes varied for each alloy and for each environment, and were manifest by the degree of intergranular cracking, cleavage, quasi cleavage, and increased coarseness of the transgranular cracking. The fracture surface morphologies are reported and discussed in detail. In general, the fracture surface morphologies could be directly related to the relative degrees of environmental influence on the rate of cracking; results are explained in terms of existing hypotheses. It is suggested that the environmentally assisted cracking of mild steel and AISI 431 at cathodic potentials in the 1000 ppm chloride solution could only be attributed to hydrogen assisted cracking. Similarly, it is suggested that the large crack growth rate acceleration of 1210 in the aqueous environments could also be attributed to hydrogen. The similar fracture surface morphologies observed on the other specimens after tests in the aqueous environments suggests-that hydrogen could be responsible for the environmentally assisted cracking of all the steels in aqueous environments

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the \u3ci\u3eSalmonella\u3c/i\u3e Type III Secretion Antigen Delivery System

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ∆phoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01+ macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag181-189-specific CD8+ T-cell responses in peripheral blood. A significant percentage of the Gag181-189- specific T-cell population in each animal also expressed the intestinal homing receptor α4β7. Additionally, Gag181-189-specific CD8+ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model

Spironolactone for heart failure with preserved ejection fraction

BACKGROUND: Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. METHODS: In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. RESULTS: With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spironolactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. CONCLUSIONS: In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure

A comparison of clinical- and patient-reported outcomes of the cemented ATTUNE and PFC sigma fixed bearing cruciate sacrificing knee systems in patients who underwent total knee replacement with both prostheses in opposite knees

Abstract Background The ATTUNE Knee by DePuy Synthes was introduced in 2013. It is designed to provide better range of motion and address patient-reported instability. The PFC Sigma Knee, an earlier prosthesis by DePuy Synthes, is a common knee replacement with a strong clinical track record. Our aim is to compare the outcomes after primary total knee replacement for end-stage knee osteoarthritis of the PFC and ATTUNE knee systems in 21 patients who each have prosthesis in opposite knees using WOMAC, Oxford Knee and SF-12 scores and evaluation of range of motion. Methods A review was carried out on 21 patients who underwent primary total knee replacement with both the ATTUNE and PFC knee systems. These were staged operations performed in the same institution and by the same surgeon. All cases were followed up for a minimum of 6 months. WOMAC, Oxford Knee and SF-12 scores, as well as knee range of motion were recorded preoperatively and at 6 months postoperatively. Results There was a significant difference in pre- to 6-month post-operative outcomes in PFC and ATTUNE groups with regard to improvement in range of motion (10° ± 8 and 13° ± 11, respectively). There was also a significant improvement in WOMAC scores (PFC group) and Oxford Knee Scores (ATTUNE group) (8.9 ± 7.7 and 12.1 ± 8.4, respectively). There was a significant improvement in SF-12 Score in both groups (10.1 ± 9.3 for PFC and 15.8 ± 13.3 for ATTUNE). The minimum clinically important difference (MCID) in scoring systems at 6 months was reached by 6 patients in the PFC group and 12 in the ATTUNE group. Conclusion A significant difference was demonstrated in clinical outcome at 6 months postoperatively between PFC and ATTUNE knee systems in patients who underwent total knee arthroplasty with both prostheses. Superior results were recorded for the ATTUNE knee system

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the \u3ci\u3eSalmonella\u3c/i\u3e Type III Secretion Antigen Delivery System

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ∆phoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01+ macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag181-189-specific CD8+ T-cell responses in peripheral blood. A significant percentage of the Gag181-189- specific T-cell population in each animal also expressed the intestinal homing receptor α4β7. Additionally, Gag181-189-specific CD8+ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model

Study design and baseline profile for adults with type 2 diabetes in the once-weekly subcutaneous SEmaglutide randomized PRAgmatic (SEPRA) trial

Introduction Once-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve glycemic control and reduce the risk of major adverse cardiovascular events in people with T2D and established cardiovascular disease. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase III clinical trial program demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide; however, determining its effectiveness in a real-world setting could support decision-making by clinicians, payers and policy makers in routine clinical practice.Research design and methods SEmaglutide PRAgmatic (SEPRA) is an ongoing open-label, randomized, pragmatic clinical trial designed to compare the effects of once-weekly subcutaneous semaglutide versus standard of care in US health-insured adults with T2D and physician-determined inadequate glycemic control. The primary end point is the proportion of participants achieving glycated hemoglobin (HbA1c) <7.0% at year 1; other key outcomes include glycemic control, weight loss, healthcare utilization, and patient-reported outcomes. Individual-level data will be collected from routine clinical practice and health insurance claims. The last patient last visit is expected by June 2023.Results Between July 2018 and March 2021, 1278 participants were enrolled from 138 study sites across the USA. At baseline, 54% were male with mean±SD age 57.4±11.1 years and body mass index 35.7±8.0 kg/m2. Mean diabetes duration was 7.4±6.0 years and mean HbA1c was 8.5±1.6%. At baseline, concomitant antidiabetes medications included metformin, sulfonylureas, sodium-glucose co-transporter-2 inhibitors, and dipeptidyl peptidase-4 inhibitors. The majority of participants had hypertension and dyslipidemia. The trial design was self-assessed using the PRagmatic Explanatory Continuum Indicator Summary-2 tool by the study steering group and was scored 4–5 in all domains suggesting a highly pragmatic study.Conclusions SEPRA, a highly pragmatic ongoing study, will provide data on the effects of once-weekly subcutaneous semaglutide in a real-world setting when used during routine management of T2D.Trial registration number NCT03596450.Trial registration numbe

Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the Salmonella Type III Secretion Antigen Delivery System

Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ΔphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01(+) macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag(181-189) epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag(181-189)-specific CD8(+) T-cell responses in peripheral blood. A significant percentage of the Gag(181-189)-specific T-cell population in each animal also expressed the intestinal homing receptor α4β7. Additionally, Gag(181-189)-specific CD8(+) T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model