Late Failure Research Articles

Preparation and Load-Bearing Capacity of Lattice Cell Warren Truss Slot Resin-Stiffener-Reinforced Foam Sandwich Material

This study optimized and proposed a Warren truss slot-hole structure with a double-sided, square shallow slot and vertical and horizontal corrugated symmetry, achieved with inclined holes based on the stability and a good bearing capacity of an inclined strut truss structure. The tetrahedral truss lattice cells were obverse and reverse-staggered in the central core of the structure. Compared with the double-sided, square shallow groove cylindrical straight hole, the resin consumption of the Warren truss slot holes was similar to that of a vacuum-assisted resin infusion; however, the external flat compression force of the Warren truss slot holes on the resin stiffener structure doubled, and its bending contact force increased by approximately 1.5 times. Furthermore, the resulting Warren truss-slotted resin structure exhibited a late failure time. Compared with the double-sided, square shallow groove cylindrical straight hole foam-core sandwich composite, the Warren truss slot resin-stiffener-reinforced sandwich composite exhibited an increase of 4.7 kN in the flat compression load, an improvement of ~40% in flat compressive strength performance, an increase of ~0.58 kN in the bending load, and an improvement of ~60% in the bending strength, demonstrating its better bearing strength performance.

Differential expression of epigenetic modifiers in early and late cardiotoxic heart failure reveals DNA methylation as a key regulator of cardiotoxicity.

Anthracycline-induced cardiotoxicity is a well-known serious clinical entity. However, detailed mechanistic insights on how short-term administration leads to late and long-lasting cardiotoxicity, are still largely undiscovered. We hypothesize that chemotherapy provokes a memory effect at the level of epigenomic DNA modifications which subsequently lead to cardiotoxicity even years after cessation of chemotherapy. We explored the temporal evolution of epigenetic modifiers in early and late cardiotoxicity due to anthracyclines by means of RNA-sequencing of human endomyocardial left ventricular biopsies and mass spectrometry of genomic DNA. Based on these findings, validation of differentially regulated genes was obtained by performing RT-qPCR. Finally, a proof-of-concept in vitro mechanistic study was performed to dissect some of the mechanistic aspects of epigenetic memory in anthracycline-induced cardiotoxicity. Correlation of gene expression between late and early onset cardiotoxicity revealed an R 2 value of 0.98, demonstrating a total of 369 differentially expressed genes (DEGs, FDR < 0.05). of which 72% (n = 266) were upregulated, and 28% of genes, (n = 103) downregulated in later as compared to earlier onset cardiotoxicity. Gene ontology analysis showed significant enrichment of genes involved in methyl-CpG DNA binding, chromatin remodeling and regulation of transcription and positive regulation of apoptosis. Differential mRNA expression of genes involved in DNA methylation metabolism were confirmed by RT-qPCR in endomyocardial biopsies. In a larger biopsy cohort, it was shown that Tet2 was more abundantly expressed in cardiotoxicity biopsies vs. control biopsies and vs. non-ischemic cardiomyopathy patients. Moreover, an in vitro study was performed: following short-term doxorubicin treatment, H9c2 cells were cultured and passaged once they reached a confluency of 70%-80%. When compared to vehicle-only treated cells, in doxorubicin-treated cells, three weeks after short term treatment, Nppa, Nppb, Tet1/2 and other genes involved in active DNA demethylation were markedly upregulated. These alterations coincided with a loss of DNA methylation and a gain in hydroxymethylation, reflecting the epigenetic changes seen in the endomyocardial biopsies. Short-term administration of anthracyclines provokes long-lasting epigenetic modifications in cardiomyocytes both in vivo and in vitro, which explain in part the time lapse between the use of chemotherapy and the development of cardiotoxicity and, eventually, heart failure.

Understanding Passive Membrane Permeation of Peptides: Physical Models and Sampling Methods Compared.

The early characterization of drug membrane permeability is an important step in pharmaceutical developments to limit possible late failures in preclinical studies. This is particularly crucial for therapeutic peptides whose size generally prevents them from passively entering cells. However, a sequence-structure-dynamics-permeability relationship for peptides still needs further insight to help efficient therapeutic peptide design. In this perspective, we conducted here a computational study for estimating the permeability coefficient of a benchmark peptide by considering and comparing two different physical models: on the one hand, the inhomogeneous solubility-diffusion model, which requires umbrella-sampling simulations, and on the other hand, a chemical kinetics model which necessitates multiple unconstrained simulations. Notably, we assessed the accuracy of the two approaches in relation to their computational cost.

Young patients undergoing carotid endarterectomy have increased rates of recurrent disease and late neurological events

ObjectivesThere are few data regarding outcomes of patients with premature cerebrovascular disease (age ≤55 years) who undergo carotid endarterectomy (CEA). The objective of this study was to analyze the demographics, presentation, perioperative and later outcomes of younger patients undergoing CEA. MethodsThe Society for Vascular Surgery Vascular Quality Initiative was queried for CEA cases between 2012 and 2022. Patients were stratified based on age of less than 55 or age greater than 55 years. Primary end points were periprocedural stroke, death, myocardial infarction, and composite outcomes. Secondary end points included restenosis (≥80%) or occlusion, late neurological events and reintervention. ResultsOf 120,549 patients undergoing CEA, 7009 (5.5%) were 55 years old or younger (mean age, 51.3 years). Younger patients were more likely to be African American (7.7% vs 4.5%; P < .001), female (45.2% vs 38.9%; P < .001), and active smokers (57.3% vs 24.1%; P < .001). They were less likely than older patients to have hypertension (82.5% vs 89.7%; P < .001), coronary artery disease (25.0% vs 27.3%; P < .001), and congestive heart failure (7.8% vs 11.4%; P < .001). Younger patients were significantly less likely than older patients to be on aspirin, anticoagulation, statins, or beta-blockers, but were more likely to be taking P2Y12 inhibitors (37.2 vs 33.7%; P < .001). Younger patients were more likely to present with symptomatic disease (35.1% vs 27.6%; P < .001) and were more likely to undergo nonelective CEA (19.2% vs 12.8%; P < .001). Younger and older patients had similar rates of perioperative stroke/death (2% vs 2%; P = NS) and postoperative neurological events (1.9% vs 1.8%; P = NS). However, younger patients had lower rates of overall postoperative complications compared with their older counterparts (3.7% vs 4.7%; P < .001). Of these patients, 72.6% had recorded follow-up (mean, 13 months). During follow-up, younger patients were significantly more likely than older patients to experience a late failure, defined as significant restenosis (≥80%) or complete occlusion of the operated artery (2.4% vs 1.5%; P < .001) and were more likely to experience any neurological event (3.1% vs 2.3%; P < .001). Reintervention rates did not significantly differ between the two cohorts. After controlling for covariates using a logistic regression model, age 55 years or younger was independently associated with increased odds of late restenosis or occlusion (odds ratio, 1.591; 95% confidence interval, 1.221-2.073; P < .001) as well as late neurological events (odds ratio, 1.304; 95% confidence interval, 1.079-1.576; P = .006). ConclusionsYoung patients undergoing CEA are more likely to be African American, female, and active smokers. They are more likely to present symptomatically and undergo nonelective CEA. Although perioperative outcomes are similar, younger patients are more likely to experience carotid occlusion or restenosis as well as subsequent neurological events, during a relatively short follow-up period. These data suggest that younger CEA patients may require more diligent follow-up, as well as a continued aggressive approach to medical management of atherosclerosis to prevent future events related to the operated artery, given the particularly aggressive nature of premature atherosclerosis.

Artemether-lumefantrine, mefloquine and atovaquone-proguanil in the treatment of uncomplicated Plasmodium falciparum malaria in travellers: A retrospective comparative study of efficacy and treatment failures.

The aim of this study was to evaluate the rates of parasitaemia clearance and the prevalence of treatment failure in patients with uncomplicated Plasmodium falciparum malaria treated with artemether-lumefantrine (AL), mefloquine (MQ), and atovaquone-proguanil (AP). The retrospective descriptive study included adult patients with uncomplicated P. falciparum malaria treated at the University Hospital Bulovka in Prague from 2006 to 2019. Parasitaemia clearance was estimated using a linear regression model. The study included 72 patients with a median age of 33 years (IQR 27-45) and a male to female ratio of 3.2:1. Thirty-six patients (50.0%) were treated with AL, 27 (37.5%) with MQ and 9 (12.5%) with AP. The proportion of VFR and migrants was 22.2% with no significant differences among the three groups. The median time to the parasitaemia clearance was two days (IQR 2-3) in patients treated with AL versus four days in the MQ (IQR 3-4) and AP (IQR 3-4) groups, p<0.001. The clearance rate constant was 3.3/hour (IQR 2.5-4.0) for AL, 1.6/hour (IQR 1.3-1.9) for MQ, and 1.9/hour (IQR 1.3-2.4) for AP, p<0.001. Malaria recrudescence occurred in 5/36 (13.9%) patients treated with AL and in no patients treated with MQ or AP. The findings demonstrate the superior efficacy of AL compared to other oral antimalarials in early malaria treatment. However, we observed a higher rate of late treatment failure in patients treated with AL than previously reported. This issue warrants further investigation of possible dose adjustments, extended regimens, or alternative artemisinin-based combinations.

Descemet's Membrane Endothelial Keratoplasty for Corneal Endothelial Failure Secondary to Three Types of Phakic Intraocular Lens - Retrospective Study.

To analyze the outcomes of Descemet's membrane endothelial keratoplasty (DMEK) for corneal endothelial failure secondary to phakic intraocular lens implantation (PIOL) at a reference center for corneal transplantation in Spain. Retrospective, single-surgeon case series. Single-center analysis of patients who underwent DMEK for PIOL-related corneal decompensation between July 2011 and July 2020 with at least 6 months of follow-up postoperatively. Primary outcome was final best-corrected visual acuity (BCVA, logMAR) compared to pre-DMEK BCVA. Secondary outcomes analyzed included post-DMEK refractive spherical equivalent, endothelial cell loss (%ECL), and graft failure. Sixteen eyes (14 patients) underwent DMEK for PIOL-related corneal decompensation. Mean (SD) time to PIOL explantation was 9.3 (5.0) years, and median (P25-P75) time between PIOL explantation and DMEK surgery was 3 (2-4) months. Median pre-DMEK BCVA was 0.80 (1.08-0.60) logMAR. A statistically significant improvement in BCVA was observed 1 month after DMEK (p = 0.001), and median final BCVA was 0.15 (0.0-0.35) logMAR (p = 0.002). Mean %ECL was 55.6 (18.7) % at 2-year follow-up and 61.7 (11.7) % in eyes with over 4 years of follow-up. Two eyes required re-bubbling (12.5%), one of which ended in primary graft failure (6.2%) and one eye had late endothelial graft failure (LEGF) at 4-year follow-up (1/15 grafts, 6.7%). In patients with PIOL-related corneal decompensation, DMEK leads to good and clinically significant refractive and visual outcomes in the medium-long term, with a good safety profile. Prospective studies are encouraged to ascertain whether these cases are at increased risk of accelerated endothelial cell loss and LEGF.

Covid-19 Pandemic Strategy for Treatment of Acute Uncomplicated Appendicitis with Antibiotics- Risk Categorization and Shared Decision-Making

BackgroundDuring the Coronavirus disease 2019 (COVID-19) pandemic, a protocol was adopted by our department on antibiotics treatment for Acute Uncomplicated Appendicitis (AUA). Our study aimed to determine the feasibility and safety of non-operative treatment (NOT), compared to upfront laparoscopic appendectomy (LA), for AUA in children during the pandemic. MethodOur prospective comparative study was conducted from May 1, 2020 to January 31, 2021. Patient selection criteria included: age ≥5 years, abdominal pain duration ≤48 h, ultrasound (US)/Computered Tomography scan confirmation of AUA, US appendiceal diameter 6–11 mm with no features of perforation/abscess collection and no faecolith. For NOT patients, intravenous antibiotics were administered for 24–48 h followed by oral for 10-day course. Comparison was performed between patients whose parents preferred NOT to those who opted for up-front appendectomy. Primary outcomes were NOT success at index admission, early and late NOT failure rates till 27 months. Secondary outcomes were differences in complication rate, hospital length of stay (LOS) and cost between groups. Results77 patients were recruited: 43 (55.8%) underwent NOT while 34 (44.2%) patients opted for LA. Success of NOT at index admission was 90.7% (39/43). Overall, NOT failure rate at 27 months’ follow-up was 37.2% (16/43). Of the NOT failures, 1 appendix was normal on histology while only 1 was perforated. There were no significant differences in secondary outcomes between both groups except for LOS of late NOT failure. Cost for upfront LA was nearly thrice that of NOT. ConclusionOur stringent COVID protocol together with shared decision-making with parents is a safe and feasible treatment option during a crisis situation. Level of EvidenceTreatment study, Level II.

VEST III trial - should we support the vein grafts?

VEST III trial is the largest randomized controlled trial to date to evaluate the role of external stents on late graft failure. In this study, an external stent was applied to vein grafts and compared with another unsupported vein graft in the same patient. The groups were compared for overall graft patency and intimal hyperplasia. Patent vein grafts were further assessed and graded based on the Fitzgibbon patency scale. This review discusses the strengths and weaknesses of the trial.

Implant survival rate of patients in Dental Hospital Hasanuddin University: 8 years evaluation

Data on dental implant treatment's success and survival rate are still limited. Meanwhile, the data on the success and survival after implant placement and restoration can be used to evaluate materials, improve the dental implant treatment, and enhance the service quality at Hasanuddin University Dental Hospital. The purpose of this study is to analyze the dental implant survival rate, the contributing factors that enhance the survival rate, and the factors causing the failure of the dental implants at the Prosthodontic Clinic of Dental and Oral Hospital, Hasanuddin Uni-versity. The final study group consisted of 11 patients with 20 implants. Implant failure was categorized based on implant loss, mobility, or removal due to severe peri-implant infection or implant fracture. Implant survival rates were grouped based on sex, age, smoking habit, placement location, diameter, length, and placement time. The value of implant survival rate was assessed based on the presentation of successful implants. Of all 20 cases, five implants failed, indicating a cumulative implant survival rate of 75%. Based on the failure period, there are initial failure cases before loading and late failure cases after loading. One implant failed within the first six months, and two implants failed 2 years after insertion of the superstructure. The leading cause of implant failure before loading is osseointe-gration failure. In the case of implants that failed after installing the superstructure, peri-implantitis occurs continous-ly. It was concluded that the implant survival rate for patients at the Hasanuddin University Dental Hospital is 75%. Dental implant survival rates include gender, age, implant placement location, smoking habits, implant diameter, length, and immediate or delayed implant placement. The factors causing the failure of the implant in this study were osseointegration failure and peri-implantitis

Development and Validation of a Prediction Model for Kidney Failure in Long-Term Survivors of Childhood Cancer.

Kidney failure is a rare but serious late effect following treatment for childhood cancer. We developed a model using demographic and treatment characteristics to predict individual risk of kidney failure among 5-year survivors of childhood cancer. Five-year survivors from the Childhood Cancer Survivor Study (CCSS) without history of kidney failure (n = 25,483) were assessed for subsequent kidney failure (ie, dialysis, kidney transplantation, or kidney-related death) by age 40 years. Outcomes were identified by self-report and linkage with the Organ Procurement and Transplantation Network and the National Death Index. A sibling cohort (n = 5,045) served as a comparator. Piecewise exponential models accounting for race/ethnicity, age at diagnosis, nephrectomy, chemotherapy, radiotherapy, congenital genitourinary anomalies, and early-onset hypertension estimated the relationships between potential predictors and kidney failure, using area under the curve (AUC) and concordance (C) statistic to evaluate predictive power. Regression coefficient estimates were converted to integer risk scores. The St Jude Lifetime Cohort Study and the National Wilms Tumor Study served as validation cohorts. Among CCSS survivors, 204 developed late kidney failure. Prediction models achieved an AUC of 0.65-0.67 and a C-statistic of 0.68-0.69 for kidney failure by age 40 years. Validation cohort AUC and C-statistics were 0.88/0.88 for the St Jude Lifetime Cohort Study (n = 8) and 0.67/0.64 for the National Wilms Tumor Study (n = 91). Risk scores were collapsed to form statistically distinct low- (n = 17,762), moderate- (n = 3,784), and high-risk (n = 716) groups, corresponding to cumulative incidences in CCSS of kidney failure by age 40 years of 0.6% (95% CI, 0.4 to 0.7), 2.1% (95% CI, 1.5 to 2.9), and 7.5% (95% CI, 4.3 to 11.6), respectively, compared with 0.2% (95% CI, 0.1 to 0.5) among siblings. Prediction models accurately identify childhood cancer survivors at low, moderate, and high risk for late kidney failure and may inform screening and interventional strategies.

Guided Dental Implant Surgery: Systematic Review.

Among the common procedures in clinical practice in the field of dentistry is prosthetic rehabilitation through the insertion of dental implants. In order to obtain the best aesthetic and functional results, the oral surgeon who deals with implantology must be able to position the dental implants correctly; a crucial role is therefore played by the diagnostic and treatment planning phases, where attention must be paid to anatomical constraints and prosthetic constraints in the alveolar bone site. The parameters, such as bone quality, bone volume, and anatomical restrictions, can be processed and simulated using implant planning software. The simulation of the virtual positioning of the implant can lead to the construction of a three-dimensional model of the implant positioning guide, which can be used during the implant surgery. The aim of this systematic review is to evaluate survival rates, early and late failure rates, peri-implant bone remodeling, and possible implant-prosthetic complications related to implants placed using digitally designed surgical guides. This systematic review was written following the indications of PRISMA and envisaged the use of 3 databases: Scopus, PubMed, and Cochrane Library. Results: Only 9 of the 2001 records were included, including 2 retrospective studies and 7 prospective studies. Conclusion: On the basis of the studies selected in this review, it can be seen that the implant survival obtained with the use of guided implant surgery shows high percentages. Many recorded failures occurred early, due to a lack of osseointegration, and the variables that come into play in the survival of the implants are many.

Predictive value of HACOR score on the clinical outcome of non-invasive positive pressure ventilation in the treatment of chronic obstructive pulmonary disease with pulmonary encephalopathy

To explore the predictive value of HACOR score [heart rate (H), acidosis (A), consciousness (C), oxygenation (O), and respiratory rate (R)] on the clinical outcome of non-invasive positive pressure ventilation in patients with pulmonary encephalopathy due to chronic obstructive pulmonary disease (COPD). A prospective study was conducted. The patients with COPD combined with pulmonary encephalopathy who were admitted to Henan Provincial People's Hospital from January 1, 2017 to June 1, 2021 and initially received non-invasive positive pressure ventilation were enrolled. Besides non-invasive positive pressure ventilation, standard medical treatments were delivered to these patients according to guidelines. The need for endotracheal intubation was judged as failure of non-invasive ventilation treatment. Early failure was defined as the need for endotracheal intubation within 48 hours of treatment, and late failure was defined as the need for endotracheal intubation 48 hours and later. The HACOR score at different time points after non-invasive ventilation, the length of intensive care unit (ICU) stay, the total length of hospital stay, and the clinical outcome were recorded. The above indexes of patients with non-invasive ventilation were compared between successful and failed groups. The receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive effect of HACOR score on the failure of non-invasive positive pressure ventilation in the treatment of COPD with pulmonary encephalopathy. A total of 630 patients were evaluated, and 51 patients were enrolled, including 42 males (82.35%) and 9 females (17.65%), with a median age of 70.0 (62.0, 78.0) years old. Among the 51 patients, 36 patients (70.59%) were successfully treated with non-invasive ventilation and discharged from the hospital eventually, and 15 patients (29.41%) failed and switched to invasive ventilation, of which 10 patients (19.61%) were defined early failure, 5 patients (9.80%) were late failure. The length of ICU and the total length of hospital stay of the non-invasive ventilation successful group were significantly longer than those of the non-invasive ventilation failure group [length of ICU stay (days): 13.0 (10.0, 16.0) vs. 5.0 (3.0, 8.0), total length of hospital stay (days): 23.0 (12.0, 28.0) vs. 12.0 (9.0, 15.0), both P < 0.01]. The HACOR score of patients at 1-2 hours in the non-invasive ventilation failure group was significantly higher than that in the successful group [10.47 (6.00, 16.00) vs. 6.00 (3.25, 8.00), P < 0.05]. However, there was no significant difference in HACOR score before non-invasive ventilation and at 3-6 hours between the two groups. The ROC curve showed that the area under the ROC curve (AUC) of 1-2 hour HACOR score after non-invasive ventilation for predicting non-invasive ventilation failure in COPD patients with pulmonary encephalopathy was 0.686, and the 95% confidence interval (95%CI) was 0.504-0.868. When the best cut-off value was 10.50, the sensitivity was 60.03%, the specificity was 86.10%, positive predictive value was 91.23%, and negative predictive value was 47.21%. Non-invasive positive pressure ventilation could prevent 70.59% of COPD patients with pulmonary encephalopathy from intubation. HACOR score was valuable to predict non-invasive positive pressure ventilation failure in pulmonary encephalopathy patients due to COPD.

Emergency, ABO-Incompatible Living Donor Liver Re-Transplantation for Graft Failure Complicated by Pneumonia-Associated Sepsis.

Although liver re-transplantation is the only therapeutic option for acute and chronic graft failure, few studies have addressed the use of ABO-incompatible living donors in the emergency setting. Here, based on our experience, we report a successful case of emergency, ABO-incompatible, adult-to-adult, living donor liver re-transplantation (LDLT) for late graft failure from chronic rejection complicated by pneumonia-related sepsis. A fifty-five-year-old man had undergone LDLT for hepatocellular carcinoma accompanied by hepatitis C virus (HCV)-related cirrhosis in 30 September 2013. The voluntary donor was his 56-year-old wife, who was also a carrier of HCV. The donor and recipient blood types were the same: O and Rh positive. She underwent a right hepatectomy and was discharged on postoperative day (POD) seven. The patient was also discharged without complications on POD eleven and was followed up with on an outpatient basis. Abdominal distension and jaundice were developed at 6 months after LDLT, when the serum total bilirubin level was 2.7 mg/dL. The serum total bilirubin levels increased rapidly to 22.9 mg/dL over the next 4 months. Chronic rejection was diagnosed via liver biopsy. On 3 October 2014, he developed pneumonia-related sepsis and showed the progressive deterioration of liver function. Liver re-transplantation using the right liver from his ABO-incompatible, 20-year-old nephew was performed as an emergency in 15 October 2014. The donor blood type was A and Rh positive. The resection of the failed graft and the implantation of a new graft was performed by the intragraft dissection technique to re-use previously transplanted graft vessels in order to cope with severe adhesions. The recipient went through a gradual recovery process and was finally discharged on POD 50 with normal liver function, while the donor had an uneventful recovery and was discharged on POD 7. Biloma due to bile leak was detected three months after re-transplantation and was cured by percutaneous interventional procedures. Since then, the postoperative course has been event-free at regular outpatient follow-ups. The patient has so far had normal laboratory findings and no signs of complications. It has been 98 months since the re-transplantation, and the recipient and two donors are still in good condition with normal liver function, having complete satisfaction with the results obtained from this re-transplantation. In conclusion, long-term, satisfactory outcomes can be achieved in emergency, ABO-incompatible, adult-to-adult, living donor liver re-transplantation for graft failure complicated by pneumonia-related sepsis in selected patients.

Inhibition of Intimal Thickening By PRH (Proline-Rich Homeodomain) in Mice.

Late vein graft failure is caused by intimal thickening resulting from endothelial cell (EC) damage and inflammation which promotes vascular smooth muscle cell (VSMC) dedifferentiation, migration, and proliferation. Nonphosphorylatable PRH (proline-rich homeodomain) S163C:S177C offers enhanced stability and sustained antimitotic effect. Therefore, we investigated whether adenovirus-delivered PRH S163C:S177C protein attenuates intimal thickening via VSMC phenotype modification without detrimental effects on ECs. PRH S163C:S177C was expressed in vitro (human saphenous vein-VSMCs and human saphenous vein-ECs) and in vivo (ligated mouse carotid arteries) by adenoviruses. Proliferation, migration, and apoptosis were quantified and phenotype was assessed using Western blotting for contractile filament proteins and collagen gel contraction. EC inflammation was quantified using VCAM (vascular cell adhesion protein)-1, ICAM (intercellular adhesion molecule)-1, interleukin-6, and monocyte chemotactic factor-1 measurement and monocyte adhesion. Next Generation Sequencing was utilized to identify novel downstream mediators of PRH action and these and intimal thickening were investigated in vivo. PRH S163C:S177C inhibited proliferation, migration, and apoptosis and promoted contractile phenotype (enhanced contractile filament proteins and collagen gel contraction) compared with virus control in human saphenous vein-VSMCs. PRH S163C:S177C expression in human saphenous vein-ECs significantly reduced apoptosis, without affecting cell proliferation and migration, while reducing TNF (tumor necrosis factor)-α-induced VCAM-1 and ICAM-1 and monocyte adhesion and suppressing interleukin-6 and monocyte chemotactic factor-1 protein levels. PRH S163C:S177C expression in ligated murine carotid arteries significantly impaired carotid artery ligation-induced neointimal proliferation and thickening without reducing endothelial coverage. Next Generation Sequencing revealed STAT-1 (signal transducer and activator of transcription 1) and HDAC-9 (histone deacetylase 9) as mediators of PRH action and was supported by in vitro and in vivo analyses. We observed PRH S163C:S177C attenuated VSMC proliferation, and migration and enhanced VSMC differentiation at least in part via STAT-1 and HDAC-9 signaling while promoting endothelial repair and anti-inflammatory properties. These findings highlight the potential for PRH S163C:S177C to preserve endothelial function whilst suppressing intimal thickening, and reducing late vein graft failure.

Allograft Ocular Surface Stem Cell Transplantation Outcomes With Decreased or No Systemic Immunosuppression in the Elderly.

The aim of this study was to report outcomes after allograft ocular surface stem cell transplantation (OSST) for limbal stem cell deficiency in the setting of decreased or no systemic immunosuppression (SI) in the elderly. A retrospective chart review was performed of all eyes that underwent OSST for limbal stem cell deficiency between 2005 and 2020 at CVP Physicians. Inclusion criteria included patients who were (1) at least 70 years at the time of (2) allograft OSST. Postoperative SI regimens were assessed. Outcome measures included improvement in visual acuity, ocular surface stability, and adverse effects. There were 14 eyes of 14 patients that met the inclusion criteria with mean follow-up of 3.0 (range 0.4-7.0) years. SI was run at a lower level for 6 patients, and 8 patients did not receive any SI. Nine eyes underwent keratolimbal allograft, 1 had a living-related conjunctival limbal allograft, and 4 had combined OSST. Most eyes (85.7%) attained improvement in visual acuity during their follow-up. At the last follow-up, 57.1% maintained a stable ocular surface. Six eyes developed acute rejection or late failure. Minimal adverse events were noted. Elderly patients administered less or no SI exhibit overall favorable outcomes after allograft OSST. Although not significantly different, surface stability and duration of improved vision was greater with low SI. No SI may be an option that still achieves improved vision in a high proportion for at least part of their follow-up. Decreasing SI after OSST in this population can improve quality of life while minimizing adverse effects.

Revealing the artemisinin and piperaquine treatment failure: a systematic review

Background: Artemisinin-based combination therapy (ACT) consists of a potent artemisinin component. Since the dihydroartemisinin performance effectiveness depends on piperaquine interaction still challenging, further research needs to establish the current status of artemisinin resistance relative to its geography and recognize any drug resistance interaction between dihydroartemisinin and piperaquine. Aim: This systematic review was aimed to find out the effect of dihydroartemisinin and piperaquine interaction concerning resistance, recurrence, parasitological failure, clinical failure, parasite clearance time, parasite reduction ratio, cure rate, which may affect treatment failure of patients with uncomplicated P. falciparum. Method: The article was not limited to year and country. This study analyzed any effect of interaction. Pubmed and Scopus were used as electronic databases, and MeSH terms and keywords were used to find specific studies. A total of 2131 studies were initially identified; however, 20 were eligible for qualitative synthesis. Result: The dihydroartemisinin piperaquine cure rate reported in Asia and Africa was above 98%. Eight RCTs, eleven prospective cohort studies, and one retrospective and prospective cohort study were included in this review. Design studies did not compare the same anti-malarial drug pattern, so it was difficult to do a pooled analysis. Even though this drug combination did not show a clear description of piperaquine resistance can affect artemisinin resistance, the adequate clinical and parasitological failure (ACPR) from this research reached above 93%, and for early treatment failure (ETF), late clinical failure (LCF), and late parasitological failure (LPF), were almost 0 %. Conclusion: The dihydroartemisinin-piperaquine combination still has highly efficacious therapy to fight malaria in some areas based on these multiple factors and reviews.

Causes, risk factors and complications of dental implant failure

Osseointegration, which refers to the direct attachment of dental implants (DIs) to the neighboring host bone, is a great predictor of the therapeutic efficacy of DIs. The factors that determine whether DIs are successful have been evolving over time. Presently, these factors comprise the lack of mobility at the beginning of the prosthetic stage. DIs have a high chance of success; however, they occasionally fail. The failure of properly implanted DIs has been attributed to inappropriate patient identification; inadequate dental hygiene associated with microbial plaque buildup. The three most significant factors that lead to early implant failure appear to be a paucity of basic stability, surgical injury, and infection. Due to disruption of the basic bone recovery process, initial symptoms of infection may portend a far more serious outcome than if similar issues arise later. It appears that peri-implantitis and occlusal overloading are the main causes of late failure. Among the predisposing variables for implant problems and failure include poor prosthesis fabrication and subpar implant design.

Discordant Clinical and Microbiological Outcomes Are Associated With Late Clinical Relapse in Clinical Trials for Complicated Urinary Tract Infections.

Current US Food and Drug Administration guidance recommends that the primary endpoint for complicated urinary tract infection clinical trials be a composite of the clinical and microbiological responses, assessed at a fixed point after therapy. Although some participants meet the criteria for clinical success, they do not meet the criteria for microbiological eradication and are classified as treatment failures. These discordant outcomes have raised questions about the utility of the microbiological endpoint. We analyzed participant data from 13 phase 3 clinical trials submitted to the US Food and Drug Administration (N = 4842). Outcomes were determined at the test of cure (TOC) visit, recommended to occur at least 5 days after therapy and at the late follow-up visit, recommended to occur 21 to 28 days after randomization. Clinical and microbiological success were defined as the resolution of complicated urinary tract infection symptoms present at study entry, with no new symptoms (clinical cure), and a reduction in density of the original pathogen to <103 CFU/mL on urine culture (microbiological eradication). Among included participants, 70.7% were concordant successes at the TOC visit, 18.0% were discordant failures (clinical cure/microbiological persistence), and 6.7% were concordant failures (clinical failure/microbiological persistence). Discordant participants were at an increased risk for clinical failure at the late follow-up visit, and the risk of late clinical failure increased with time. Discordant clinical and microbiological outcomes at the TOC visit were associated with an increased risk of late clinical failure. Microbiological outcomes appear to be an important component of the endpoint.

Safety and therapeutic efficacy of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria at Shecha health centre, Arba Minch, Ethiopia

BackgroundIn 2004, Ethiopia adopted artemether-lumefantrine (AL, Coartem®) as first-line treatment for the management of uncomplicated Plasmodium falciparum malaria. Continuous monitoring of AL therapeutic efficacy is crucial in Ethiopia, as per the World Health Organization (WHO) recommendation. This study aimed to assess the therapeutic efficacy of AL in the treatment of uncomplicated P. falciparum infection.MethodsA 28 day onearm, prospective evaluation of the clinical and parasitological response to AL was conducted at Shecha Health Centre, Arba Minch town, Southern Ethiopia. Patients were treated with six-dose regimen of AL over three days and monitored for 28 days with clinical and laboratory assessments. Participant recruitment and outcome classification was done in accordance with the 2009 WHO methods for surveillance of anti-malarial drug efficacy guidelines.ResultsA total of 88 study participants were enrolled and 69 of them completed the study with adequate clinical and parasitological response. Two late parasitological failures were observed, of which one was classified as a recrudescence by polymerase chain reaction (PCR). The PCRcorrected cure rate was 98.6% (95% CI 92.3–100). AL demonstrated a rapid parasite and fever clearance with no parasitaemia on day 2 and febrile cases on day 3. Gametocyte clearance was complete by day three. No serious adverse events were reported during the 28 days follow-up.ConclusionThe study demonstrated high therapeutic efficacy and good safety profile of AL. This suggests the continuation of AL as the first-line drug for the treatment of uncomplicated P. falciparum malaria in Ethiopia. Periodic therapeutic efficacy studies and monitoring of markers of resistance are recommended for early detection of resistant parasites.

MELCOR 2.2-ASTEC V2.2 crosswalk study reproducing SBLOCA and CSBO scenarios in a PWR1000-like reactor part II: Analysis of containment thermal-hydraulics and ex-vessel phenomena

The Accident Source Term Evaluation Code (ASTEC) and Methods of Estimation of Leakages and Consequences of Releases (MELCOR) system codes are both used by Tractebel to perform Severe Accident (SA) analyses for the Belgian Nuclear Power Plants (NPPs).This paper contains the second part of the comparative study between these two integral software focused on the SA progression in the containment after the Vessel Failure (VF).The main phenomena characterize this phase of the accident usually called ex-vessel phase are the Molten Corium Concrete Interaction (MCCI) and ex-vessel corium/debris coolability, which determine the containment Thermal-Hydraulics (TH) response and can cause its late failure. Despite their importance from a safety point of view, chemical and physical processes behind these phenomena are not yet well understood, partly because of their extreme complexity and partly because of the limitations of current experimental capabilities in reproducing them. As result, models developed and implemented in the codes to describe the MCCI and debris coolability are extremely simplified because based on limited data availability.The benchmark study consists of a comparison of the results calculated by the ASTEC and MELCOR codes during the ex-vessel phase following two different scenarios a Complete Station Blackout (CSBO) and a Small Break Loss Of Coolant Accident (SBLOCA).For each scenario, two different Severe Accident Management Strategies (SAMS) are adopted, the first one is to ensure that the corium, once fully relocated in the cavity, has top-flooding conditions throughout the transient, while the second one is to keep the reactor cavity completely dry. Furthermore, for every case reproduced the reference and best-practice models are investigated.The results show that in case of dry cavity conditions, despite the different VF timing calculated by the two codes, the final results provide very similar indications even though some dissimilarity is observed regarding the amount of fission product (FP) released through the Containment Filtering Venting System (CFVS).In contrast, in the case of wet cavity conditions, the accident progression predicted is significantly different regarding number of venting operations, TH containment conditions, and amount of concrete ablated.The discrepancies observed, should be sought in the corium and debris coolability models, which given their parametric nature and oversimplification can lead to these results.