Confirming Pathogenicity of the F386L PSEN1 Variant in a South Asian Family With Early-Onset Alzheimer Disease

ObjectivesThe F386L PSEN1 variant has been reported in 1 Japanese family with limited clinical information. We aimed to prove that F386L is pathogenic by demonstrating that it segregates with early-onset Alzheimer disease (AD).MethodsEight individuals in a South Asian family provided DNA for genetic testing and underwent a neurologic examination.ResultsThe female proband was diagnosed with AD at age 45 years and died at age 49 years. She had a CSF biomarker profile consistent with AD, and her florbetaben PET scan was amyloid positive with high uptake in the striatum. Her MRI showed no prominent white matter disease. Her affected relatives had an age at onset range of 38–57 years and had imaging and biomarker profiles similar to hers.DiscussionThe results presented here, in conjunction with the prior report, confirm the pathogenicity of F386L. Furthermore, our study highlights the importance of studying families from underrepresented populations to identify or confirm the pathogenicity of rare variants that may be specific to certain genetic ancestries.

Water cluster in hydrophobic crystalline porous covalent organic frameworks

Progress over the past decades in water confinement has generated a variety of polymers and porous materials. However, most studies are based on a preconception that small hydrophobic pores eventually repulse water molecules, which precludes the exploration of hydrophobic microporous materials for water confinement. Here, we demonstrate water confinement across hydrophobic microporous channels in crystalline covalent organic frameworks. The frameworks are designed to constitute dense, aligned and one-dimensional polygonal channels that are open and accessible to water molecules. The hydrophobic microporous frameworks achieve full occupation of pores by water via synergistic nucleation and capillary condensation and deliver quick water exchange at low pressures. Water confinement experiments with large-pore frameworks pinpoint thresholds of pore size where confinement becomes dominated by high uptake pressure and large exchange hysteresis. Our results reveal a platform based on microporous hydrophobic covalent organic frameworks for water confinement.

Radioiodinated esomeprazole as a model for peptic ulcer localization

This work focuses on tracking stomach ulcer localized in mice. High labeling yield and radiochemical purity were achieved for the formation of a [125I]esomeprazole radiotracer at optimum conditions of oxidizing agent content (chloramines-T (Ch-T), 100 μg), substrate amount (Esom, 100 μg), pH of reaction mixture (6), reaction time (30 min) and temperature (37 °C), using radioactive iodine-125 (200–450 MBq). The radiolabeled compound, [125I]esom, was stable in serum and saline solution during 24 h. Esom is acting as a histamine-2-receptor antagonist (H2RA). Biodistribution studies were carried in normal and ulcerated mice. High uptake of 78.12 ± 0.80% injected dose/g organ (ID/g) observed in ulcerated mice confirmed the suitability of [125I]esomeprazole as a novel radiotracer for stomach imaging.

First-in-human DR5 PET reveals insufficient DR5 expression in patients with gastrointestinal cancer

BackgroundDeath receptor 5 (DR5) is a promising therapeutic target for cancer therapy. However, many clinical trials of DR5 agonists failed to show significant therapeutic efficacy in patients with cancer. The study aimed to investigate the feasibility of using 89Zr-CTB006 positron emission tomography (PET) for noninvasive imaging of DR5 expression in preclinical models and patients with gastrointestinal (GI) cancers.MethodsBalb/c, Sp2/0 xenograft and patient-derived tumor xenograft were employed for micro-PET/CT imaging in vivo. In the clinical study, patients with GI cancers planning to undergo surgical operation were enrolled and underwent 18F-FDG and 89Zr-CTB006 PET/CT. The tumor tissues were obtained through surgical operation and DR5 expression levels were confirmed by RNAscope.ResultsPreclinical studies showed that 89Zr-CTB006 PET could specifically detect DR5 expression levels in vivo. Twenty-one patients, including nine gastric cancers and 12 colorectal cancers, were enrolled. The biodistribution showed high uptake in the liver and spleen and low uptake in the brain, lung and muscle with an acceptable whole-body dosimetry of 0.349 mSv/MBq. Strikingly, the adrenal glands maintained stable high uptake over the entire examination in all patients. The tumor lesions showed different levels of uptake of 89Zr-CTB006 with a mean maximum standardized uptake value (SUVmax) of 6.63±3.29 (range 1.8–13.8). Tumor tissue was obtained from 18 patients, and 89Zr-CTB006 uptake in patients with RNAscope scores of 3–4 was significantly higher than that in patients with scores of 0–2. An SUVmax of 9.3 at 48 hours and 6.3 at 72 hours could be used to discriminate the DR5 expression status of tumors both with a sensitivity and specificity of 100% and 92.9%, respectively.Conclusions89Zr-CTB006 PET/CT is capable of detecting DR5 expression in cancer patients and is a promising approach to screen patients with DR5 overexpression.

Application of Consolidated Framework for Implementation Research to Improve Clostridioides difficile Infection Management in South African District Hospitals

Background Clostridioides difficile infection (CDI) is a global health threat. Measurable gaps exist in CDI quality of care and CDI knowledge in South Africa. This study describes the development of a CDI intervention informed by the local context within South African public district level hospitals, and analyzes the CDI intervention development, implementation process and adaptations to understand acceptance, uptake, successes, and failures of the CDI intervention. Methods A CDI checklist intervention was designed and implemented at three district level hospitals in the Western Cape, South Africa. The Consolidated Framework for Implementation Research (CFIR) was used as a framework to contextualize study findings, including a description of the implementation process and adaptations for each hospital. A mixed-methods approach was applied with quantitative outcomes data and qualitative interview and focus group data with front-line and administrative healthcare personnel. Transcripts were coded to a priori workflow steps as well as to aspects of the CDI checklist intervention and emerging themes. The CFIR framework was applied to results from the qualitative interviews, observations by research team members, and quantitative patient outcomes data in order to identify drivers and barriers to implementation and to understand differences in uptake at the three sites. Highly relevant and moderately relevant constructs for the Intervention, Inner Setting, and Implementation Process domains were identified. Results Each hospital adapted the implementation process based on available resources, while maintaining the intervention core elements. One hospital displayed high uptake of the intervention compared to the two other hospitals. Highly relevant CFIR constructs linked to intervention uptake included tension for change, strong peer intervention champions, champions in influential leadership positions, and intervention complexity, among others. Tension of change at the high uptake hospital was also supported by an academic partnership for antimicrobial stewardship. Conclusion We provide a straight-forward health systems strengthening intervention for CDI that is both needed and uncomplicated, in an understudied LMIC setting. Intervention uptake was highest in the hospital with tension for change, influential champions, and existing academic partnerships. Further research is needed in reaching and involving understudied settings with fewer academic connections and to examine impact on patient outcomes.