Redox active or thiol reactive? Optimization of rapid screens to identify less evident nuisance compounds

Compounds that exhibit assay interference or undesirable mechanisms of bioactivity are routinely encountered in assays at various stages of drug discovery. We observed that assays for the investigation of thiol-reactive and redox-active compounds have not been collected in a comprehensive review. Here, we review these assays and subject them to experimental optimization to improve their reliability. We demonstrate the usefulness of our assay cascade by assaying a library of bioactive compounds, chemical probes, and a set of approved drugs. These high-throughput assays should complement the array of wet-lab and in silico assays during the initial stages of hit discovery campaigns to pursue only hit compounds with tractable mechanisms of action.     

Role of site-directed mutagenesis and adjuvants in the stability and potency of anthrax protective antigen

Anthrax is a zoonotic infection caused by the gram-positive, aerobic, spore-forming bacterium Bacillus anthracis. Depending on the origin of the infection, serious health problems or mortality is possible. The virulence of B. anthracis is reliant on three pathogenic factors, which are secreted upon infection: protective antigen (PA), lethal factor (LF), and edema factor (EF). Systemic illness results from LF and EF entering cells through the formation of a complex with the heptameric form of PA, bound to the membrane of infected cells through its receptor. The currently available anthrax vaccines have multiple drawbacks, and recombinant PA is considered a promising second-generation vaccine candidate. However, the inherent chemical instability of PA through Asn deamidation at multiple sites prevents its use after long-term storage owing to loss of potency. Moreover, there is a distinct possibility of B. anthracis being used as a bioweapon; thus, the developed vaccine should remain efficacious and stable over the long-term. Second-generation anthrax vaccines with appropriate adjuvant formulations for enhanced immunogenicity and safety are desired. In this article, using protein engineering approaches, we have reviewed the stabilization of anthrax vaccine candidates that are currently licensed or under preclinical and clinical trials. We have also proposed a formulation to enhance recombinant PA vaccine potency via adjuvant formulation.     

F形空心钉与传统3枚平行钉治疗Pauwels Ⅲ型股骨颈骨折的疗效比较

目的:分析比较"F"形空心钉与传统倒三角3枚平行螺钉内固定治疗青壮年Pauwels Ⅲ型股骨颈骨折的临床疗效。方法：2017年1月至2020年1月收治Pauwels Ⅲ型股骨颈骨折患者38例，根据置入钉方式的不同将其分为两组，其中A组18例，采用"F"形空心钉固定，男12例，女6例，年龄37~55岁，受伤至手术时间1~3 d。B组20例，采用传统倒三角3枚平行拉力螺钉固定，男12例，女8例，年龄35~55岁，受伤至手术时间为1~3 d。比较两组患者骨折不愈合，股骨头坏死，股骨颈短缩，空心螺钉退出情况，髋关节功能Harris评分，疼痛视觉模拟评分（visual analogue scale，VAS）。结果：所有患者获得随访，时间为15~31个月。两组患者在骨折不愈合，股骨颈短缩，股骨头坏死方面差异无统计学意义（P>0.05）；两组患者在螺钉退出方面差异有统计学意义（P<0.05）。两组患者术后12个月时髋关节Harris评分及VAS评分差异均无统计学差异（P>0.05）。结论："F"形与传统倒三角3枚平行空心钉内固定治疗青壮年Pauwels Ⅲ型股骨颈骨折中短期疗效相似，但"F"形空心钉退钉率较低。     

Care of Seniors with Breast Cancer – Treatment Received and Refining Decision Making

AimsTreatment decisions for older patients with breast cancer are complex and evidence is largely extrapolated from younger populations. Frailty and comorbidity need to be considered. We studied the baseline characteristics and treatment decisions in older patients in Christchurch with breast cancer and assessed survival outcomes and prognostic/discriminatory performance of several tools.Materials and methodsWe searched the Canterbury Breast Cancer Registry and identified patients aged 70 years or older at diagnosis with invasive, non-metastatic breast cancer between 1 June 2009 and 30 June 2015. We retrieved demographics, treatment and outcome information. Overall survival and breast cancer-specific survival were estimated. Tools analysing performance status and comorbidity were assessed for their prognostic and discriminatory power.ResultsIn total, 440 patients were identified. Primary surgery was carried out for 362 patients (82.3%): breast-conserving surgery in 114 (of whom 88.6% received radiation therapy); mastectomy in 248 (of whom 24.6% received radiation). Hormone therapy was given for 265 (71.1%) patients with oestrogen receptor-positive cancers. Two hundred and seventy-four (62.3%) patients received full standard treatment, which was associated with significantly improved 5-year survival and 5-year breast cancer-specific survival. The median estimated overall survival was 8.2 years (95% confidence interval 7.3–9.1 years). Of those who died, 71.3% of deaths were due to causes other than breast cancer or unknown causes. The comorbidity-adjusted life expectancy (CALE) showed partial prognostic accuracy. CALE, Charlson and Eastern Cooperative Oncology Group tools all showed discriminatory value.ConclusionIn this population-based series of older patients with breast cancer, showing high levels of primary and adjuvant treatment, patients were more likely to die of causes other than breast cancer. Performance status and comorbidity tools showed prognostic and discriminatory potential in this population supporting their use in treatment decision making. CALE showed the most potential to improve treatment decisions but requires validation in this population to improve prognostic accuracy.     

Moving Knowledge to Action: Aware,Adopt, Adapt (A3)

This article begins with an overview of the knowledge translation (KT) process, introduces commonly used KT terms and the Aware-Adopt-Adapt (A³) KT map. The A³ was created by a nurse practitioner (NP) for practitioners and NP students to provide a map for those who wish to move existing knowledge to practice, yet do not know where to start or do not have the time to take a deeper dive into specific KT theories.     

Update on pediatric corneal diseases and keratoplasty

Managing pediatric corneal disorders is challenging as the prognosis of pediatric keratoplasty depends on several factors. Advancements in the genetic basis of congenital corneal diseases and investigations in congenital corneal conditions provide a better understanding of pediatric corneal conditions. Surgeons performing keratoplasty in children now have a choice of various techniques. Evolving surgical techniques of anterior lamellar and endothelial keratoplasties have expanded the management interventions in these pediatric corneal morbidity conditions; however, considerable concerns still exist in association with corneal transplantation in infants and children. Outcomes in pediatric keratoplasty depend upon the preoperative indications, the timing of surgical intervention, intraoperative and postoperative factors including the patient/care givers’ compliance. Factors such as low scleral rigidity, higher rate of graft failure, need for frequent examinations under anesthesia, and difficulty in optimal visual acuity assessment still remain a considerable challenge in pediatric scenarios. In children, deprivation amblyopia as a result of the corneal opacification can adversely affect visual development, causing dense amblyopia. Outcomes to surgical interventions for management of corneal opacification in children are further compromised by the preexisting amblyopia apart from the concerns of refractive outcome of the graft. Graft rejection, graft infection, amblyopia, and glaucoma continue to be serious concerns. In recent years both anterior and posterior lamellar keratoplasty techniques are being increasingly performed in pediatric eyes, which offer advantages in the form of lower risk of graft rejection. The timing of surgery, careful case selection, cautious intraoperative approach, and optimal postoperative management can improve the anatomical and functional outcome in difficult cases.     

Esophageal Surveillance Practices in Esophageal Atresia Patients: A Survey by the Eastern Pediatric Surgery Network

IntroductionEndoscopic surveillance guidelines for patients with repaired esophageal atresia (EA) rely primarily on expert opinion. Prior to embarking on a prospective EA surveillance registry, we sought to understand EA surveillance practices within the Eastern Pediatric Surgery Network (EPSN).MethodsAn anonymous, 23-question Qualtrics survey was emailed to 181 physicians (surgeons and gastroenterologists) at 19 member institutions. Likert scale questions gauged agreement with international EA surveillance guideline-derived statements. Multiple-choice questions assessed individual and institutional practices.ResultsThe response rate was 77%. Most respondents (80%) strongly agree or agree that EA surveillance endoscopy should follow a set schedule, while only 36% claimed to perform routine upper GI endoscopy regardless of symptoms. Many institutions (77%) have an aerodigestive clinic, even if some lack a multi-disciplinary EA team. Most physicians (72%) expressed strong interest in helping develop evidence-based guidelines.ConclusionsOur survey reveals physician agreement with current guidelines but weak adherence. Surveillance methods vary greatly, underscoring the lack of evidence-based data to guide EA care. Aerodigestive clinics may help implement surveillance schedules. Respondents support evidence-based protocols, which bodes well for care standardization. Results will inform the first multi-institutional EA databases in the United States (US), which will be essential for evidence-based care.Level of EvidenceThis is a prognosis study with level 4 evidence.