Enhancing readmission prediction models by integrating insights from home healthcare notes: Retrospective cohort study.

BACKGROUND: Hospital readmission is an important indicator of inpatient care quality and a significant driver of increasing medical costs. Therefore, it is important to explore the effects of postdischarge information, particularly from home healthcare notes, on enhancing readmission prediction models. Despite the use of Natural Language Processing (NLP) and machine learning in prediction model development, current studies often overlook insights from home healthcare notes. OBJECTIVE: This study aimed to develop prediction models for 30-day readmissions using home healthcare notes and structured data. In addition, it explored the development of 14- and 180-day prediction models using variables in the 30-day model. DESIGN: A retrospective observational cohort study. SETTING(S): This study was conducted at Ajou University School of Medicine in South Korea. PARTICIPANTS: Data from electronic health records, encompassing demographic characteristics of 1819 participants, along with information on conditions, drug, and home healthcare, were utilized. METHODS: Two distinct models were developed for each prediction window (30-, 14-, 180-day): the traditional model, which utilized structured variables alone, and the common data model (CDM)-NLP model, which incorporated structured and topic variables extracted from home healthcare notes. BERTopic facilitated topic generation and risk probability, representing the likelihood of documents being assigned to specific topics. Feature selection involved experimenting with various algorithms. The best-performing algorithm, determined using the area under the receiver operating characteristic curve (AUROC), was used for model development. Model performance was assessed using various learning metrics including AUROC. RESULTS: Among 1819 patients, 251 (13.80 %) experienced 30-day readmission. The least absolute shrinkage and selection operator was used for feature extraction and model development. The 15 structured features were used in the traditional model. Moreover, five additional topic variables from the home healthcare notes were applied in the CDM-NLP model. The AUROC of the traditional model was 0.739 (95 % CI: 0.672-0.807). The AUROC of the CDM-NLP model was high at 0.824 (95 % CI: 0.768-0.880), which indicated an outstanding performance. The topics in the CDM-NLP model included emotional distress, daily living functions, nutrition, postoperative status, and cardiorespiratory issues. In extended prediction model development for 14- and 180-day readmissions, the CDM-NLP consistently outperformed the traditional model. CONCLUSIONS: This study developed effective prediction models using both structured and unstructured data, thereby emphasizing the significance of postdischarge information from home healthcare notes in readmission prediction.

Diagnostic ability of [18F]FDG PET/CT for distinguishing benign from malignant spleen lesions.

OBJECTIVES: [18F]Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is a non-invasive imaging modality used in the differential diagnosis of splenic lesions, although ideal parameters and thresholds remain unclear. The present study evaluated the ability of [18F]FDG PET/CT, including its visual and quantitative parameters, to differentiate between benign and malignant splenic lesions. METHODS: Patients who underwent [18F]FDG PET/CT following the detection of splenic lesions on contrast-enhanced CT were retrospectively analysed. Visual parameters assessed on [18F]FDG PET/CT included whole spleen uptake intensity, lesion multiplicity, and lesion uptake, and quantitative parameters included maximum standardised uptake value (SUVmax), lesion-to-background ratio (LBR), metabolic tumour volume (MTV), total lesion glycolysis (TLG), and lesion size. Parameters differentiating between benign and malignant lesions were evaluated by Pearson's chi-square test, Mann-Whitney U-test, and receiver operating characteristics (ROC) curve analysis. RESULTS: Splenic lesion uptake (p = 0.001) was the only visual parameter significantly distinguishing between benign and malignant lesions. ROC curve analysis demonstrated that SUVmax had the largest area under the ROC, 0.91 (p < 0.001), with an optimal cut-off > 5.3 having a sensitivity of 90.3% and a specificity of 80.6%. Subgroup analysis of malignant lesions showed that SUVmax (p = 0.013), LBR (p = 0.012), and TLG (p = 0.034) were significantly higher in splenic lymphomas than in splenic metastases. CONCLUSION: Of the [18F]FDG PET/CT parameters investigated, SUVmax had the highest accuracy in diagnosing malignant splenic lesions and was significantly higher in splenic lymphomas than in splenic metastases. Visual determination of [18F]FDG uptake by splenic lesions may be an easily evaluated parameter. CLINICAL RELEVANCE STATEMENT: SUVmax and visual grade of [18F]FDG PET/CT help to differentiate spleen lesions. [18F]FDG PET/CT is useful for discriminating between benign and malignant spleen lesions. KEY POINTS: Many splenic lesions are difficult to diagnose on anatomical imaging, with histopathologic analyses are required. SUVmax of PET/CT provided the diagnostic ability to differentiate between benign and malignant splenic lesions. More than normal spleen uptake can be a convenient parameter to diagnose malignant spleen lesions.

Scutellarin inhibits inflammatory PANoptosis by diminishing mitochondrial ROS generation and blocking PANoptosome formation.

PANoptosis is manifested with simultaneous activation of biomarkers for both pyroptotic, apoptotic and necroptotic signaling via the molecular platform PANoptosome and it is involved in pathologies of various inflammatory diseases including hemophagocytic lymphohistiocytosis (HLH). Scutellarin is a flavonoid isolated from herbal Erigeron breviscapus (Vant.) Hand.-Mazz. and has been shown to possess multiple pharmacological effects, but it is unknown whether scutellarin has any effects on PANoptosis and related inflammatory diseases. In this study, we found that scutellarin inhibited cell death in bone marrow-derived macrophages (BMDMs) and J774A.1 cells treated with TGF-ß-activated kinase 1 (TAK1) inhibitor 5Z-7-oxozeaenol (OXO) plus lipopolysaccharide (LPS), which has been commonly used to induce PANoptosis. Western blotting showed that scutellarin dose-dependently inhibited the activation biomarkers for pyroptotic (Caspase-1p10 and GSDMD-NT), apoptotic (cleaved Casp3/8/9 and GSDME-NT), and necroptotic (phosphorylated MLKL) signaling. The inhibitory effect of scutellarin was unaffected by NLRP3 or Caspase-1 deletion. Interestingly, scutellarin blocked the assembly of PANoptosome that encompasses ASC, RIPK3, Caspase-8 and ZBP1, suggesting its action on upstream signaling. Consistent with this, scutellarin inhibited mitochondrial damage and mitochondrial reactive oxygen species (mtROS) generation in cells treated with OXO+LPS. Further, mito-TEMPO that can scavenge mtROS significantly inhibited OXO+LPS-induced PANoptotic cell death. In line with the in vitro results, scutellarin markedly alleviated systemic inflammation, multiple organ injury, and activation of PANoptotic biomarkers in mice with HLH. Collectively, our data suggest that scutellarin can inhibit PANoptosis by suppressing mitochondrial damage and mtROS generation and thereby mitigating multiple organ injury in mice with inflammatory disorders.

Hsp47 promotes biogenesis of multi-subunit neuroreceptors in the endoplasmic reticulum.

Protein homeostasis (proteostasis) deficiency is an important contributing factor to neurological and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is poorly understood. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched interacting chaperone for gamma-aminobutyric acid type A (GABAA) receptors. Here, we show that Hsp47 enhances the functional surface expression of GABAA receptors in rat neurons and human HEK293T cells. Furthermore, molecular mechanism study demonstrates that Hsp47 acts after BiP (Gene: HSPA5) and preferentially binds the folded conformation of GABAA receptors without inducing the unfolded protein response in HEK293T cells. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. Overexpressing Hsp47 is sufficient to correct the surface expression and function of epilepsy-associated GABAA receptor variants in HEK293T cells. Hsp47 also promotes the surface trafficking of other Cys-loop receptors, including nicotinic acetylcholine receptors and serotonin type 3 receptors in HEK293T cells. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 plays a critical and general role in the maturation of multi-subunit Cys-loop neuroreceptors.

A probiotic NVP1704 alleviates stress-induced sleeplessness/depression-like symptoms in mice by upregulating serotonergic and GABAergic systems and downregulating NF-κB activation.

Sleeplessness (insomnia) is a potential symptom of depression. A probiotic NVP1704 alleviates depression-like behavior and neuroinflammation in mice. Therefore, to understand whether NVP1704 could be effective against sleeplessness in vivo, we exposed immobilization stress (IS) in mice, then orally administered NVP1704 for 5 days, and assayed depression/anxiety-like behavior in the open field, elevated plus maze, and tail suspension tests, sleeping latency time, and sleep duration, euthanized then by exposure to CO2, and analyzed their related biomarkers. Oral administration of NVP1704 decreased IS-induced depression/anxiety-like behavior and sleeping latency time and increased IS-suppressed sleeping duration. NVP1704 increased IS-suppressed expression of γ-aminobutyric acid (GABA), GABAA receptor α1 (GABAARα1) and α2 subunits (GABAARα2), serotonin, 5-HT receptors (5-HT1AR and 5-HT1BR), and melatonin receptors (MT1R and MT2R) in the prefrontal cortex and thalamus. NVP1704 also increased the IS-suppressed GABAARα1-positive cell population in the prefrontal cortex and decreased IS-induced corticosterone, TNF-α, and IL-6 expression and the NF-κB+Iba1+ cell population in the brain and myeloperoxidase, TNF-α, and IL-6 expression and the NF-κB+CD11c+ cell population in the colon. Based on these findings, NVP1704 may alleviate depression/anxiety/sleeplessness-like behaviors through the upregulation of serotonergic and GABAergic systems and downregulation of NF-κB activation.

Biocompatible and nondegradable microcapsules using an ethylamine-bridged EGCG dimer for successful therapeutic cell transplantation.

Conventional alginate microcapsules are widely used for encapsulating therapeutic cells to reduce the host immune response. However, the exchange of monovalent cations with divalent cations for crosslinking can lead to a sol-gel phase transition, resulting in gradual degradation and swelling of the microcapsules in the body. To address this limitation, we present a biocompatible and nondegradable epigallocatechin-3-gallate (EGCG)-based microencapsulation with ethylamine-bridged EGCG dimers (EGCG(d)), denoted as 'Epi-Capsules'. These Epi-Capsules showed increased physical properties and Ca2+ chelating resistance compared to conventional alginate microcapsules. Horseradish peroxidase (HRP) treatment is very effective in increasing the stability of Epi-Capsule((+)HRP) due to the crosslinking between EGCG(d) molecules. Interestingly, the Epi-Capsules(oxi) using a pre-oxidized EGCG(d) can support long-term survival (>90 days) of xenotransplanted insulin-secreting islets in diabetic mice in vivo, which is attributed to its structural stability and reactive oxygen species (ROS) scavenging for lower fibrotic activity. Collectively, this EGCG-based microencapsulation can create Ca2+ chelating-resistance and anti-oxidant activity, which could be a promising strategy for cell therapies for diabetes and other diseases.

The relationship between depression, anxiety and lower urinary tract symptoms in men.

Purpose: Patients with lower urinary tract symptoms (LUTS) often experience comorbid depression and anxiety, yet the mechanisms underlying this association remain incompletely understood. This prospective study aimed to investigate the relationship between depression, anxiety, and LUTS in men. Materials and methods: A prospective study was conducted with 350 male patients who underwent urologic examinations at our institution from January 2021 to December 2021. Of these, 131 patients meeting the inclusion criteria were included. Various questionnaires, including the International Prostate Symptom Score (IPSS) and the Hospital Anxiety and Depression Scale (HADS), as well as LUTS examinations (prostate-specific antigen test, transrectal ultrasonography, and urine flowmetry), were administered. Results: Among the 350 patients, 131 were included in the analysis, with an average age of 58.0 ± 13.69 years. The total IPSS was 18.0 ± 8.69, with the average voiding symptom score at 8.7 ± 5.19 and the average storage symptom score at 6.0 ± 3.27. Both anxiety and depression were found to be correlated with LUTS (P < 0.05). After adjusting for age, hypertension, and diabetes, anxiety (but not depression) was significantly associated with LUTS based on regression analysis. Conclusion: Men with LUTS are more likely to experience anxiety. Therefore, it is essential to assess and address anxiety when managing men with LUTS.

Sex-Specific Risk Factors and Clinical Dementia Outcomes for White Matter Hyperintensities in a large South Korean Cohort.

Objective: White matter hyperintensities (WMH) on brain MRI images are the most common feature of cerebral small vessel disease (CSVD). Studies have yielded divergent findings on the modifiable risk factors for WMH and WMH's impact on cognitive decline. Mounting evidence suggests sex differences in WMH burden and subsequent effects on cognition. Thus, we aimed to identify sex-specific modifiable risk factors for WMH. We then explored whether there were sex-specific associations of WMH to longitudinal clinical dementia outcomes. Methods: Participants aged 49-89 years were recruited at memory clinics and underwent a T2-weighted fluid-attenuated inversion recovery (FLAIR) 3T MRI scan to measure WMH volume. Participants were then recruited for two additional follow-up visits, 1-2 years apart, where clinical dementia rating sum of boxes (CDR-SB) scores were measured. We first explored which known modifiable risk factors for WMH were significant when tested for a sex-interaction effect. We additionally tested which risk factors were significant when stratified by sex. We then tested to see whether WMH is longitudinally associated with clinical dementia that is sex-specific. Results: The study utilized data from 713 participants (241 males, 472 females) with a mean age of 72.3 years and 72.8 years for males and females, respectively. 57.3% and 59.5% of participants were diagnosed with mild cognitive impairment (MCI) for males and females, respectively. 40.7% and 39.4% were diagnosed with dementia for males and females, respectively. Of the 713 participants, 181 participants had CDR-SB scores available for three longitudinal time points. Compared to males, females showed stronger association of age to WMH volume. Type 2 Diabetes was associated with greater WMH burden in females but not males. Finally, baseline WMH burden was associated with worse clinical dementia outcomes longitudinally in females but not in males. Discussion: Elderly females have an accelerated increase in cerebrovascular burden as they age, and subsequently are more vulnerable to clinical dementia decline due to CSVD. Additionally, females are more susceptible to the cerebrovascular consequences of diabetes. These findings emphasize the importance of considering sex when examining the consequences of CSVD. Future research should explore the underlying mechanisms driving these sex differences and personalized prevention and treatment strategies. Clinical trial registration: The BICWALZS is registered in the Korean National Clinical Trial Registry (Clinical Research Information Service; identifier, KCT0003391). Registration Date 2018/12/14.

Neuroimaging and natural language processing-based classification of suicidal thoughts in major depressive disorder.

Suicide is a growing public health problem around the world. The most important risk factor for suicide is underlying psychiatric illness, especially depression. Detailed classification of suicide in patients with depression can greatly enhance personalized suicide control efforts. This study used unstructured psychiatric charts and brain magnetic resonance imaging (MRI) records from a psychiatric outpatient clinic to develop a machine learning-based suicidal thought classification model. The study included 152 patients with new depressive episodes for development and 58 patients from a geographically different hospital for validation. We developed an eXtreme Gradient Boosting (XGBoost)-based classification models according to the combined types of data: independent components-map weightings from brain T1-weighted MRI and topic probabilities from clinical notes. Specifically, we used 5 psychiatric symptom topics and 5 brain networks for models. Anxiety and somatic symptoms topics were significantly more common in the suicidal group, and there were group differences in the default mode and cortical midline networks. The clinical symptoms plus structural brain patterns model had the highest area under the receiver operating characteristic curve (0.794) versus the clinical notes only and brain MRI only models (0.748 and 0.738, respectively). The results were consistent across performance metrics and external validation. Our findings suggest that focusing on personalized neuroimaging and natural language processing variables improves evaluation of suicidal thoughts.

Comparison of digital and analog [68Ga]Ga-PSMA-11 PET/CT for detecting post-prostatectomy biochemical recurrence in prostate cancer patients: a prospective study.

Digital positron emission tomography/computed tomography (PET/CT) has shown enhanced sensitivity and spatial resolution compared with analog PET/CT. The present study compared the diagnostic performance of digital and analog PET/CT with [68Ga]Ga-PSMA-11 in prostate cancer patients who experienced biochemical recurrence (BCR) after prostatectomy. Forty prostate cancer patients who experienced BCR, defined as serum prostate-specific antigen (PSA) concentrations exceeding 0.2 ng/mL after prostatectomy, were prospectively recruited. These patients were stratified into three groups based on their serum PSA levels. [68Ga]Ga-PSMA-11 was injected into each patient, and images were acquired using both analog and digital PET/CT scanners. Analog and digital PET/CT showed comparable lesion detection rate (71.8% vs. 74.4%), sensitivity (85.0% vs. 90.0%), and positive predictive value (PPV, 100.0% vs. 100.0%). However, digital PET/CT detected more lesions (139 vs. 111) and had higher maximum standardized uptake values (SUVmax, 14.3 vs. 10.3) and higher kappa index (0.657 vs. 0.502) than analog PET/CT, regardless of serum PSA levels. On both analog and digital PET/CT, lesion detection rates and interrater agreement increased with increasing serum PSA levels. Compared with analog PET/CT, digital PET/CT detected more lesions with a higher SUVmax and better interrater agreement in prostate cancer patients who experienced BCR after prostatectomy.

Ameliorative effects of the mixed aqueous extract of Aurantii Fructus Immaturus and Magnoliae Officinalis Cortex on loperamide-induced STC mice.

Aurantii fructus immaturus (AFI) and Magnoliae Officinalis Cortex (MOC) have been used to treat constipation in China for thousands of years. In this study, a mouse model of slow transit constipation (STC) was established by gavage of loperamide at a dose of 10 mg/kg bw/day for seven days. Seventy-two mice were randomly allocated to six groups (control, STC model, 3 g/kg AFI + MOC, 6 g/kg AFI + MOC, 12 g/kg AFI + MOC, and mosapride). A mixed aqueous extract of AFI and MOC was administered to the STC mice at the corresponding doses from the first day of modelling. Body weight, faecal water content, gastrointestinal transit time, and intestinal propulsion rate were evaluated. Serum levels of neurotransmitters and gastrointestinal hormones, colonic expression of aquaporins (AQP), and interstitial cells of Cajal (ICC) were assessed using ELISA, immunohistochemistry, and Western blot analysis. The abundance and diversity of the gut microbiota were analysed by 16S rRNA gene sequencing. The mixed aqueous extract significantly increased faecal water content and intestinal propulsion rate and shortened gastrointestinal transit time in STC mice. Furthermore, the administration of AFI and MOC significantly decreased serum vasoactive intestinal peptide (VIP), nitric oxide (NO), and somatostatin (SS) levels and increased serum motilin (MTL) levels in STC mice. The protein expression levels of AQP3 and AQP4 in the colon tissue of STC mice significantly decreased following AFI + MOC treatment, whereas those of AQP9 significantly increased. Moreover, the AFI + MOC treatment led to an increase in the number and functionality of ICCs. In addition, the relative abundances of Ruminococcus and Oscillospira increased in response to the administration of AFI + MOC in STC mice. In conclusion, the mixed aqueous extract of AFI and MOC promoted defaecation and increased intestinal mobility in STC mice. Its mechanisms of action involve modulatory effects on neurotransmitters, gastrointestinal hormones, AQPs, and ICCs. AFI + MOC treatment also improved the diversity and abundance of the gut microbiota in STC mice, particularly short-chain fatty acid-producing bacteria, which may play an important role in its beneficial effect on constipation.

UBTF mediates activation of L3MBTL2 to suppress NISCH expression through histone H2AK119 monoubiquitination modification in breast cancer.

Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2) has been related to transcriptional inhibition and chromatin compaction. Nevertheless, the biological functions and mechanisms of L3MBTL2 are undefined in breast cancer (BRCA). Here, we revealed that L3MBTL2 is responsible for the decline of Nischarin (NISCH), a well-known tumor suppressor, in BRCA, and explored the detailed mechanism. Knockdown of L3MBTL2 reduced monoubiquitination of histone H2A at lysine-119 (H2AK119ub), leading to reduced binding to the NISCH promoter and increased expression of NISCH. Meanwhile, the knockdown of L3MBTL2 decreased proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of BRCA cells, and increased apoptosis, which were abated by NISCH knockdown. Nucleolar transcription factor 1 (UBTF) induced the transcription of L3MBTL2 in BRCA, and the suppressing effects of UBTF silencing on EMT in BRCA cells were also reversed by NISCH knockdown. Knockdown of UBTF slowed tumor progression and attenuated lung tumor infiltration, whereas simultaneous knockdown of NISCH accelerated EMT and increased tumor lung metastasis. Taken together, our results show that L3MBTL2, transcriptionally activated by UBTF, exerts oncogenic functions in BRCA, by catalyzing H2AK119Ub and reducing expression of NISCH.

Precisely targeted drug delivery by mesenchymal stem cells-based biomimetic liposomes to cerebral ischemia-reperfusion injured hemisphere.

The precise and targeted delivery of therapeutic agents to the lesion sites remains a major challenge in treating brain diseases represented by ischemic stroke. Herein, we modified liposomes with mesenchymal stem cells (MSC) membrane to construct biomimetic liposomes, termed MSCsome. MSCsome (115.99 ± 4.03 nm) exhibited concentrated accumulation in the cerebral infarcted hemisphere of mice with cerebral ischemia-reperfusion injury, while showing uniform distribution in the two cerebral hemispheres of normal mice. Moreover, MSCsome exhibited high colocalization with damaged nerve cells in the infarcted hemisphere, highlighting its advantageous precise targeting capabilities over liposomes at both the tissue and cellular levels. Leveraging its superior targeting properties, MSCsome effectively delivered Dl-3-n-butylphthalide (NBP) to the injured hemisphere, making a single-dose (15 mg/kg) intravenous injection of NBP-encapsulated MSCsome facilitate the recovery of motor functions in model mice by improving the damaged microenvironment and suppressing neuroinflammation. This study underscores that the modification of the MSC membrane notably enhances the capacity of liposomes for precisely targeting the injured hemisphere, which is particularly crucial in treating cerebral ischemia-reperfusion injury.

Evaluation of machine learning approach for surgical results of Ahmed valve implantation in patients with glaucoma.

BACKGROUND: Ahmed valve implantation demonstrated an increasing proportion in glaucoma surgery, but predicting the successful maintenance of target intraocular pressure remains a challenging task. This study aimed to evaluate the performance of machine learning (ML) in predicting surgical outcomes after Ahmed valve implantation and to assess potential risk factors associated with surgical failure to contribute to improving the success rate. METHODS: This study used preoperative data of patients who underwent Ahmed valve implantation from 2017 to 2021 at Ajou University Hospital. These datasets included demographic and ophthalmic parameters (dataset A), systemic medical records excluding psychiatric records (dataset B), and psychiatric medications (dataset C). Logistic regression, extreme gradient boosting (XGBoost), and support vector machines were first evaluated using only dataset A. The algorithm with the best performance was selected based on the area under the receiver operating characteristics curve (AUROC). Finally, three additional prediction models were developed using the best performance algorithm, incorporating combinations of multiple datasets to predict surgical outcomes at 1 year. RESULTS: Among 153 eyes of 133 patients, 131 (85.6%) and 22 (14.4%) eyes were categorized as the success and failure groups, respectively. The XGBoost was shown as the best-performance model with an AUROC value of 0.684, using only dataset A. The final three further prediction models were developed based on the combination of multiple datasets using the XGBoost model. All datasets combinations demonstrated the best performances in terms of AUROC (dataset A + B: 0.782; A + C: 0.773; A + B + C: 0.801). Furthermore, advancing age was a risk factor associated with a higher surgical failure incidence. CONCLUSIONS: ML provides some predictive value in predicting the outcomes of Ahmed valve implantation at 1 year. ML evaluation revealed advancing age as a common risk factor for surgical failure.

Flight or fight: different strategies of intertidal periwinkle Littoraria sinensis coping with high temperature across populations.

Intertidal organisms usually live near their upper thermal limits, and are vulnerable to future global warming. As a vital response to thermal stress, thermoregulatory strategy in physiological and behavioral performance is essential for organisms coping with thermal stress and surviving the changing world. To investigate the relationship between the thermoregulatory strategy and habitat temperature, in the present study, we comparatively investigated the thermal responsive strategy among different geographic populations of the supralittoral snail Littoraria sinensis by determining snails' cardiac function and behavioral performance. Our results indicated that populations inhabiting high ambient temperatures had higher sublethal temperatures (i.e. Arrhenius breakpoint temperatures, ABTs, the temperature at which the heart rate shapely decreases with further heating) and lethal temperatures (i.e. Flatline temperatures, FLTs, the temperature at which heart rate ceases), and behaved less actively (e.g. shorter moving distances and shorter moving time) in the face of high and rising temperatures-a physiological fight strategy. On the other hand, populations at relatively low ambient temperatures had relatively lower physiological upper thermal limits with lower ABTs and FLTs and moved more actively in the face of high and rising temperatures-a behavioral flight strategy. These results demonstrate that the thermoregulatory strategies of the snails are closely related to their habitat temperatures and are different among populations surviving divergent thermal environments.

Facile Fabrication of Multifunctional Hydrogel Nanoweb Coating Using Carboxymethyl Chitosan-Based Short Nanofibers for Blood-Contacting Medical Devices.

Blood-contacting medical devices (BCDs) require antithrombotic, antibacterial, and low-friction surfaces. Incorporating a nanostructured surface with the functional hydrogel onto BCD surfaces can enhance the performances; however, their fabrication remains challenging. Here, we introduce a straightforward method to fabricate a multifunctional hydrogel-based nanostructure on BCD surfaces using O-carboxymethyl chitosan-based short nanofibers (CMC-SNFs). CMC-SNFs, fabricated via electrospinning and cutting processes, are easily sprayed and entangled onto the BCD surface. The deposited CMC-SNFs form a robust nanoweb layer via fusion at the contact area of the nanofiber interfaces. The superhydrophilic CMC-SNF nanoweb surface creates a water-bound layer that effectively prevents the nonspecific adhesion of bacteria and blood cells, thereby enhancing both antimicrobial and antithrombotic performances. Furthermore, the CMC-SNF nanoweb exhibits excellent lubricity and durability on the bovine aorta. The demonstration results of the CMC-SNF coating on catheters and sheaths provide evidence of its capability to apply multifunctional surfaces simply for diverse BCDs.

Enhancing the Therapeutic Efficacy of GLP-1 for Hyperglycemia Treatment: Overcoming Barriers of Oral Gene Therapy with Taurocholic Acid-Conjugated Protamine Sulfate and Calcium Phosphate.

Activating the glucagon-like peptide-1 (GLP-1) receptor by oral nucleic acid delivery would be a promising treatment strategy against hyperglycemia due to its various therapeutic actions. However, GLP-1 receptor agonists are effective only in subcutaneous injections because they face multiple barriers due to harsh gastrointestinal tract (GIT) conditions before reaching the site of action. The apical sodium bile acid transporter (ASBT) pathway at the intestinal site could be an attractive target to overcome the problem. Herein, we used our previously established multimodal carrier system utilizing bile salt, protamine sulfate, and calcium phosphate as excipients (PTCA) and the GLP-1 gene as an active ingredient (GENE) to test the effects of different formulation doses against diabetes and obesity. The carrier system demonstrated the ability to protect the GLP-1 model gene encoded within the plasmid at the GIT and transport it via ASBT at the target site. A single oral dose, regardless of quantity, showed the generation of GLP-1 and insulin from the body and maintained the normoglycemic condition by improving insulin sensitivity and blood sugar tolerance for a prolonged period. This oral gene therapy approach shows significantly higher therapeutic efficacy in preclinical studies than currently available US Food and Drug Administration-approved GLP-1 receptor agonists such as semaglutide and liraglutide. Also, a single oral dose of GENE/PTCA is more effective than 20 insulin injections. Our study suggests that oral GENE/PTCA formulation could be a promising alternative to injection-based therapeutics for diabetics, which is effective in long-term treatment and has been found to be highly safe in all aspects of toxicology.

Noninvasive ROS imaging and drug delivery monitoring in the tumor microenvironment.

Reactive oxygen species (ROS) that are overproduced in certain tumors can be considered an indicator of oxidative stress levels in the tissue. Here, we report a magnetic resonance imaging (MRI)-based probe capable of detecting ROS levels in the tumor microenvironment (TME) using ROS-responsive manganese ion (Mn2+)-chelated, biotinylated bilirubin nanoparticles (Mn@bt-BRNPs). These nanoparticles are disrupted in the presence of ROS, resulting in the release of free Mn2+, which induces T1-weighted MRI signal enhancement. Mn@BRNPs show more rapid and greater MRI signal enhancement in high ROS-producing A549 lung carcinoma cells compared with low ROS-producing DU145 prostate cancer cells. A pseudo three-compartment model devised for the ROS-reactive MRI probe enables mapping of the distribution and concentration of ROS within the tumor. Furthermore, doxorubicin-loaded, cancer-targeting ligand biotin-conjugated Dox/Mn@bt-BRNPs show considerable accumulation in A549 tumors and also effectively inhibit tumor growth without causing body weight loss, suggesting their usefulness as a new theranostic agent. Collectively, these findings suggest that Mn@bt-BRNPs could be used as an imaging probe capable of detecting ROS levels and monitoring drug delivery in the TME with potential applicability to other inflammatory diseases.

RECOVER-NEURO: study protocol for a multi-center, multi-arm, phase 2, randomized, active comparator trial evaluating three interventions for cognitive dysfunction in post-acute sequelae of SARS-CoV-2 infection (PASC).

BACKGROUND: Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as "brain fog" and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work. METHODS: RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English. DISCUSSION: This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.