Quality of Life in Patients Undergoing Revisional Bariatric Surgery: From Sleeve Gastrectomy to Roux-en-Y Gastric Bypass.

Sleeve gastrectomy (SG) is the most performed bariatric surgery worldwide. However, this surgery may be associated with long-term weight regain and severe gastroesophageal reflux disease (GERD), sometimes necessitating conversion to Roux-en-Y gastric bypass (RYGB) to improve quality of life (QoL). We conducted a systematic review on QoL measures following the conversion of SG to RYGB. We searched various databases for studies conducted between January 2005 and September 2023. Four studies, involving 196 participants in total, met the inclusion criteria. Different assessment methods were used to evaluate QoL following the conversion. In the included studies, we observed that GERD symptoms and proton pump inhibitor (PPI) use both decreased following conversion to RYGB. Excess weight loss (EWL) was also observed in all studies.

Implementation of an Interdisciplinary Transfer Huddle Intervention for Prolonged Wait Times During Inter-ICU Transfer.

BACKGROUND: ICU transfers from a regional to a tertiary-level hospital are initiated typically for a higher level of care. Extended transfer wait times can negatively affect survival, length of stay (LOS), and cost. METHODS: In this prospective single-center study, the subjects were adult ICU patients admitted to regional hospitals between January and October 2022, for whom a request was made to transfer to a tertiary-level medical ICU. The authors developed and implemented an interdisciplinary transfer huddle intervention (THI) with the goal of reducing wait times by providing a consistent channel of communication between key stakeholders. The primary outcome was the number of hours elapsed between transfer request and the time of transfer to the tertiary hospital. Secondary outcomes included in-hospital mortality, discharge to home, ICU LOS, and hospital LOS. Data were abstracted from electronic health records and periods before (January to June 2022) and after (June to October 2022) the intervention were compared. Data were analyzed using logistic regression or negative binomial regression, adjusting for patient demographic and clinical characteristics. ICU fellows also completed a daily survey about barriers they perceived to the THI application. RESULTS: During the study period, 76 patients were transferred. The THI was completed 75.0% of the time. There were no statistically significant differences in the primary and secondary outcomes before and after the intervention. The top perceived barriers to transfer were lack of physical beds (50.0%) and staffing limitations (37.5%). CONCLUSION: The authors successfully developed and implemented a transfer huddle to ensure consistent interdisciplinary communication for patients being transferred between ICUs and identified barriers to such transfer. However, transfer times and patient outcomes were not significantly different after the change. Future studies should consider staffing challenges, hospital capacity, and the role of dedicated transfer teams in in decreasing inter-ICU transfer wait times.

Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy.

PURPOSE: Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody-drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody. EXPERIMENTAL DESIGN: [225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity. RESULTS: Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line-derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 µCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi. CONCLUSIONS: [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen-positive and prostate-specific membrane antigen-deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.

Organ-Specific Glucose Uptake: Does Sex Matter?

Glucose uptake by peripheral organs is essential for maintaining blood glucose levels within normal range. Impaired glucose uptake is a hallmark of type 2 diabetes (T2D) and metabolic syndrome and is characterized by insulin resistance. Male sex is an independent risk factor for the development of T2D. We tested whether sex and diet are independent variables for differential glucose uptake by various organs. Here, in a longitudinal study, we used 18F-fluorodeoxyglucose (FDG) and positron emission tomography (PET) to determine baseline differences in whole-body glucose uptake in young male and female mice on chow and high-fat diets. We report that sex and diet are important independent variables that account for differential glucose uptake in brown fat, skeletal muscle, liver, heart, kidney, and the stomach, but not the brain, lungs, pancreas, small intestine, or perigonadal adipose. Of the seven organs analyzed, two organs, namely brown fat, and the heart had the highest concentrations of FDG, followed by the brain, kidneys, and skeletal muscle on chow diet. Young female mice had 47% greater FDG uptake in the brown fat compared to male mice, whereas skeletal muscle FDG uptake was 49% greater in male mice. The high-fat diet inhibited FDG uptake in brown fat, skeletal muscle, and the heart, three major organs involved in uptake, whereas brain uptake was enhanced in both sexes. These foundational and groundbreaking findings suggest that mechanisms of glucose homeostasis are context- and organ-dependent and highlight the need to study sex-specific outcomes and mechanisms for diseases such as T2D, obesity, and metabolic syndrome.

Longitudinal Imaging of T Cells and Inflammatory Demyelination in a Preclinical Model of Multiple Sclerosis Using 18F-FAraG PET and MRI.

Lymphocytes and innate immune cells are key drivers of multiple sclerosis (MS) and are the main target of MS disease-modifying therapies (DMT). Ex vivo analyses of MS lesions have revealed cellular heterogeneity and variable T cell levels, which may have important implications for patient stratification and choice of DMT. Although MRI has proven valuable to monitor DMT efficacy, its lack of specificity for cellular subtypes highlights the need for complementary methods to improve lesion characterization. Here, we evaluated the potential of 2'-deoxy-2'-18F-fluoro-9-ß-d-arabinofuranosylguanine (18F-FAraG) PET imaging to noninvasively assess infiltrating T cells and to provide, in combination with MRI, a novel tool to determine lesion types. Methods: We used a novel MS mouse model that combines cuprizone and experimental autoimmune encephalomyelitis to reproducibly induce 2 brain inflammatory lesion types, differentiated by their T cell content. 18F-FAraG PET imaging, T2-weighted MRI, and T1-weighted contrast-enhanced MRI were performed before disease induction, during demyelination with high levels of innate immune cells, and after T cell infiltration. Fingolimod immunotherapy was used to evaluate the ability of PET and MRI to detect therapy response. Ex vivo immunofluorescence analyses for T cells, microglia/macrophages, myelin, and blood-brain barrier (BBB) integrity were performed to validate the in vivo findings. Results:18F-FAraG signal was significantly increased in the brain and spinal cord at the time point of T cell infiltration. 18F-FAraG signal from white matter (corpus callosum) and gray matter (cortex, hippocampus) further correlated with T cell density. T2-weighted MRI detected white matter lesions independently of T cells. T1-weighted contrast-enhanced MRI indicated BBB disruption at the time point of T cell infiltration. Fingolimod treatment prevented motor deficits and decreased T cell and microglia/macrophage levels. In agreement, 18F-FAraG signal was decreased in the brain and spinal cord of fingolimod-treated mice; T1-weighted contrast-enhanced MRI revealed intact BBB, whereas T2-weighted MRI findings remained unchanged. Conclusion: The combination of MRI and 18F-FAraG PET enables detection of inflammatory demyelination and T cell infiltration in an MS mouse model, providing a new way to evaluate lesion heterogeneity during disease progression and after DMT. On clinical translation, these methods hold great potential for stratifying patients, monitoring MS progression, and determining therapy responses.

Synthesis and Preliminary Biological Assessment of Carborane-Loaded Theranostic Nanoparticles to Target Prostate-Specific Membrane Antigen.

Boron neutron capture therapy (BNCT) is an encouraging therapeutic modality for cancer treatment. Prostate-specific membrane antigen (PSMA) is a cell membrane protein that is abundantly overexpressed in prostate cancer and can be targeted with radioligand therapies to stimulate clinical responses in patients. In principle, a spatially targeted neutron beam together with specifically targeted PSMA ligands could enable prostate cancer-targeted BNCT. Thus, we developed and tested PSMA-targeted poly(lactide-co-glycolide)-block-poly(ethylene glycol) (PLGA-b-PEG) nanoparticles (NPs) loaded with carborane and tethered to the radiometal chelator deferoxamine B (DFB) for simultaneous positron emission tomography (PET) imaging and selective delivery of boron to prostate cancer. Monomeric PLGA-b-PEGs were covalently functionalized with either DFB or the PSMA ligand ACUPA. Different nanoparticle formulations were generated by nanoemulsification of the corresponding unmodified and DFB- or ACUPA-modified monomers in varying percent fractions. The nanoparticles were efficiently labeled with 89Zr and were subjected to in vitro and in vivo evaluation. The optimized DFB(25)ACUPA(75) NPs exhibited strong in vitro binding to PSMA in direct binding and competition radioligand binding assays in PSMA(+) PC3-Pip cells. [89Zr]DFB(25) NPs and [89Zr]DFB(25)ACUPA(75) NPs were injected to mice with bilateral PSMA(-) PC3-Flu and PSMA(+) PC3-Pip dual xenografts. The NPs demonstrated twofold superior accumulation in PC3-Pip tumors to that of PC3-Flu tumors with a tumor/blood ratio of 25; however, no substantial effect of the ACUPA ligands was detected. Moreover, fast release of carborane from the NPs was observed, resulting in a low boron delivery to tumors in vivo. In summary, these data demonstrate the synthesis, characterization, and initial biological assessment of PSMA-targeted, carborane-loaded PLGA-b-PEG nanoparticles and establish the foundation for future efforts to enable their best use in vivo.

High Genetic Heterogeneity in Chinese Patients With Waardenburg Syndrome Revealed by Next-Generation Sequencing.

OBJECTIVE: This study aimed to explore the genetic causes of probands who were diagnosed with Waardenburg syndrome (WS) or congenital sensorineural hearing loss. METHODS: A detailed physical and audiological examinations were carried out to make an accurate diagnosis of 14 patients from seven unrelated families. We performed whole-exome sequencing in probands to detect the potential genetic causes and further validated them by Sanger sequencing in the probands and their family members. RESULTS: The genetic causes for all 14 patients with WS or congenital sensorineural hearing loss were identified. A total of seven heterozygous variants including c.1459C > T, c.123del, and c.959-409_1173+3402del of PAX3 gene (NM_181459.4), c.198_262del and c.529_556del of SOX10 gene (NM_006941.4), and c.731G > A and c.970dup of MITF gene (NM_000248.3) were found for the first time. Of these mutations, we had confirmed two (c.1459C > T and c.970dup) are de novo by Sanger sequencing of variants in the probands and their parents. CONCLUSION: We revealed a total of seven novel mutations in PAX3, SOX10, and MITF, which underlie the pathogenesis of WS. The clinical and genetic characterization of these families with WS elucidated high heterogeneity in Chinese patients with WS. This study expands the database of PAX3, SOX10, and MITF mutations and improves our understanding of the causes of WS.

Ionically Crosslinked Complex Gels Loaded with Oleic Acid-Containing Vesicles for Transdermal Drug Delivery.

Skin is an attractive site for drug administration partly because of its easy accessibility and favorable properties (e.g., less invasiveness and high patient compliance) over some other common routes of administration. Despite this, the efficiency in transdermal drug delivery has been largely limited by poor skin permeation. To address this problem, this study reports the generation of oleic acid-containing vesicles, which can enhance the drug delivery efficiency while showing good stability and limited skin disruption. Upon being loaded into a complex gel, along with the incorporation of the polymer blending technique, a delivery system exhibiting tunable transdermal flux of 2,3,5,4'-tetrahydroxystilbene 2-O-ß-D-glucoside is reported. Taking the good biocompatibility and tunable delivery performance into account, our system warrants further development and optimization for future applications in the treatment of skin diseases.