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Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials.

Porous nanosilica (PNS) has been attracting much attention in fabrication of nanocarriers for a drug delivery system (DDS). However, the unmodified PNS-based carriers exhibited a significant initial burst release of drug, which may limit their potential clinical application. In this study, PNS was surface conjugated with cyclodextrin (CD) which was functionalized with adamantylamine-polyethylene glycol (APEG) for 5-fluorouracil (5-FU) delivery, in which case CD was used due to its ability to form a stable inclusion complex with 5-FU and APEG. The conjugated PNS (PNSC@APEG) was successfully prepared with spherical shape and diameter around 50 nm, determined by transmission electron microscopy (TEM). In addition, 5-FU was efficiently trapped in PNSC@APEG particles, which were around 63.4%±3.8% and was slowly released up to 3 days in phosphate buffer saline (PBS). Furthermore, the cell proliferation kit I (MTT) assay data showed that PNSC@APEG was a biocompatible nanocarrier. These results indicated that PNSC@APEG nanoparticles have a great potential as novel carriers for anticancer drug delivery.

Iatrogenic arterial injuries are rare but well-recognised complications of spinal surgery. This paper presents a case of an iatrogenic arterial injury during a total en bloc spondylectomy resulting in significant haemorrhage and the patient's haemodynamic instability. The devastating complication was successfully treated with an emergency thoracic endovascular aortic repair via a percutaneous popliteal approach, while the patient remained in prone position. The patient had an uneventful recovery with no subsequent arterial injury or pseudoaneurysm to the access vessel. [ABSTRACT FROM AUTHOR]

This paper sheds some light on the impact of regional trade agreements (RTAs) on international tourism demand in Vietnam. They are using gravity model with data from 29 countries with the highest number of tourists to Vietnam from 2007–2019. The empirical findings indicate a relevant degree of heterogeneity in the results. While the the free trade agreement enhances the international tourism demand in Vietnam, ASEAN community it. These results emphasize the importance of solid integration in promoting Vietnam's tourism flows. [ABSTRACT FROM AUTHOR]

In addition to routine anticoagulation and compression therapy, we propose a holistic approach to the patient considering the whole spectrum of serious adverse events and challenges that patients with DVT may encounter. Even though there was heterogeneity in the trial designs, the main outcomes suggest that intervention should not be the standard of care in all patients with proximal DVT. Keywords: Thrombosis; Thromboembolism; Embolism and thrombosis; Venous insufficiency EN Thrombosis Thromboembolism Embolism and thrombosis Venous insufficiency 61 64 4 02/07/23 20230201 NES 230201 Future studies should focus on patient selection for interventional therapy, best practices for stent surveillance, and long term anticoagulation Deep vein thrombosis (DVT) is a common condition affecting one in 1000 patients in the Western world.[1] Patients normally present acutely with symptoms of a hot, painful, swollen leg. The CaVenT[15] trial assessed CDT in 209 patients, from 20 centres in Norway, with symptomatic (< 21 days) DVT located higher than the proximal half of the femoral vein. [Extracted from the article]

Aim: Perioperative anaemia is common and is associated with increased postoperative complications, delayed recovery and increased morbidity and mortality. However, current management of anaemia after surgery is variable. This student‐ and trainee‐led collaborative study aims to audit the postoperative variations in anaemia treatment and transfusions (POSTVenTT) and quantify its impact on patient outcomes after major abdominal surgery. Method: This is the first Australian and Aotearoa New Zealand multicentre study in surgical patients conducted by networks of trainees, students and consultants. Data will be prospectively collected on consecutive adult patients undergoing elective and emergency major abdominal surgery with follow‐up to 30 days after hospital discharge. The primary endpoint will be adherence to anaemia management guidelines. Secondary outcomes will include postoperative anaemia, blood transfusion, postoperative complications as per the Clavien–Dindo classification, length of stay and hospital readmission at 30 days. Discussion: This protocol describes the first Australian and Aotearoa New Zealand collaborative study by medical students and surgical trainees. The collaboration will aim to provide a clear understanding of current practices regarding the management and risk factors for anaemia and association with patient outcomes after major abdominal surgery. [ABSTRACT FROM AUTHOR]

Esophageal foreign bodies are common conditions that may lead to serious complications, such as esophageal perforation, neck abscess, mediastinitis, arterial injury, and lung damage. We report a rare case of esophageal fish bone impingement on the aorta that was managed without complication by endoscopic removal. [ABSTRACT FROM AUTHOR]

Porous nanosilica (PNS) has been receiving wider attention in the fabrication of nanocarriers for drug delivery. However, unmodified PNS nanoparticles have shown an initial rapid release of encapsulated drugs, which may limit their potential applications in the clinical setting. In this report, in order to improve the efficiency of drug delivery, PNS nanoparticles were first synthesized and then surface conjugated with gelatin-poly (ethylene glycol) methyl ether (GEL-mPEG) to form PNS-GEL-mPEG nanocarriers for doxorubicin (DOX) delivery. The co-polymer structure and morphology of the obtained nanocarriers were analyzed using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), transmission electron microscopy (TEM) and dynamic light scattering (DLS). The loading capacity, encapsulation efficiency and DOX release behavior of DOX@PNS-GEL-mPEG nanocarriers were also evaluated. Results showed that the conjugated PNS nanocarriers were spherical shape with an average diameter of 69.60 ± 3.27 nm, as compared to 58.93 ± 2.42 nm of PNS nanocarriers. Also, the PNS-GEL-mPEG nanoparticles showed their ability to effectively encapsulate DOX. In detail, DOX was significantly encapsulated into PNS-GEL-mPEG nanocarriers to form DOX@PNS-GEL-mPEG nanocarriers with high loading efficiency of 85.88 ± 0.15%. Moreover, the synthesized DOX@PNS-GEL-mPEG nanoparticles exhibited a sustainable release of DOX up to 96 h, without a burst release, as compared with less than 2 h from unconjugated PNS nanocarriers, and exhibited a pH-dependent drug release behavior of DOX in acidic media. These results indicated that DOX@PNS-GEL-mPEG nanocarriers have high potential applications for efficient DOX loading and release in cancer therapy. [ABSTRACT FROM AUTHOR]