Diabetic macular ischaemia- a new therapeutic target?

Diabetic macular ischaemia (DMI) is traditionally defined and graded based on the angiographic evidence of an enlarged and irregular foveal avascular zone. However, these anatomical changes are not surrogate markers for visual impairment. We postulate that there are vascular phenotypes of DMI based on the relative perfusion deficits of various retinal capillary plexuses and choriocapillaris. This review highlights several mechanistic pathways, including the role of hypoxia and the complex relation between neurons, glia, and microvasculature. The current animal models are reviewed, with shortcomings noted. Therefore, utilising the advancing technology of optical coherence tomography angiography (OCTA) to identify the reversible DMI phenotypes may be the key to successful therapeutic interventions for DMI. However, there is a need to standardise the nomenclature of OCTA perfusion status. Visual acuity is not an ideal endpoint for DMI clinical trials. New trial endpoints that represent disease progression need to be developed before irreversible vision loss in patients with DMI. Natural history studies are required to determine the course of each vascular and neuronal parameter to define the DMI phenotypes. These DMI phenotypes may also partly explain the development and recurrence of diabetic macular oedema. It is also currently unclear where and how DMI fits into the diabetic retinopathy severity scales, further highlighting the need to better define the progression of diabetic retinopathy and DMI based on both multimodal imaging and visual function. Finally, we discuss a complete set of proposed therapeutic pathways for DMI, including cell-based therapies that may provide restorative potential.     

Vasovagal reactions after COVID-19 vaccination in Japan

Coronavirus disease 2019 (COVID-19) vaccine administration started in February 2021 in Japan. As of December 2021, approximately 75% of the population aged ≥12 years had received two doses of vaccine. We conducted a study to investigate vasovagal reactions (VVR) after COVID-19 vaccination using data on adverse events following immunization. The crude reporting rate of VVR (cases/1,000,000 doses) after vaccination was 9.6 in all age groups combined, and was more frequent in the younger age groups: 28.6 and 37.2 in individuals aged 10–19 years and 20–29 years, respectively. In individuals aged 10–29 years, the rate was similar in males and females (33.0 and 34.2, respectively, p = 0.53); but was higher after dose 1 than after dose 2 (57.4 and 8.8, respectively, p < 0.001). Based on these results, caution needs to be exercised when vaccinating adolescents and young adults, especially with dose 1 of COVID-19 vaccines.     

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.     

Outcomes of Irreversible Electroporation for Perihilar Cholangiocarcinoma: A Prospective Pilot Study

PurposeTo investigate the safety and efficacy of percutaneous or open irreversible electroporation (IRE) in a prospective cohort of patients with locally advanced, unresectable perihilar cholangiocarcinoma (PHC).Materials and MethodsIn a multicenter Phase I/II study, patients with unresectable PHC due to extensive vascular involvement or N2 lymph node metastases or local recurrence after resection for PHC were included and treated by open or percutaneous IRE combined with palliative chemotherapy (current standard of care). The primary outcome was the number of major adverse events occurring within 90 d after IRE (grade ≥3), and the upper limit was predefined at 60%. Secondary outcomes included technical success rate, hospital stay, and overall survival (OS).ResultsTwelve patients (mean age, 63 y ± 12) were treated with IRE. The major adverse event rate was 50% (6 of 12 patients), and no 90-d mortality was observed. All procedures were technically successful, with no intraprocedural adverse events requiring additional interventions. The median OS from diagnosis was 21 mos (95% confidence interval, 15–27 mos), with a 1-y survival rate of 75% after IRE.ConclusionsPercutaneous IRE in selected patients with locally advanced PHC seems feasible, with a major adverse event rate of 50%, which was below the predefined upper safety limit in this prospective study. Future comparative research exploring the efficacy of IRE is warranted.     

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。     

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.