Isoindoline-based fluorogenic probes bearing a self-immolative linker for the sensitive and selective detection of O-GlcNAcase activity.

O-GlcNAcase (OGA) is implicated in several important biological and disease-relevant processes. Here, we synthesized fluorogenic probes for OGA by grafting GlcNAc directly or using a self-immolative linker to the hydroxyl position of 4-hydroxylisoindoline (BHID), a typical excited-state intramolecular proton transfer (ESIPT) probe. The probe was used for a fluorogenic assay to determine the half maximal inhibitory concentration of a known OGA inhibitor and differentiate between OGA and hexosaminidase when GlcNAc is replaced by GlcNPr, where a propionyl group is used instead of an acetyl group.

Timing of follow-up visits after hospital discharge for COPD: Application of a new method.

RATIONALE: A common strategy to reduce COPD readmissions is to encourage patient follow-up with a physician within 1 to 2 weeks of discharge, yet evidence confirming its benefit is lacking. We used a new study design called target randomized trial emulation to determine the impact of follow-up visit timing on patient outcomes. METHODS: All Ontario residents aged 35 or older discharged from a COPD hospitalization were identified using health administrative data and randomly assigned to those who received and did not receive physician visit follow-up by within seven days. They were followed to all-cause emergency department visits, readmissions or death. Targeted randomized trial emulation was used to adjust for differences between the groups. COPD emergency department visits, readmissions or death was also considered. RESULTS: There were 94,034 patients hospitalized with COPD, of whom 73.5% had a physician visit within 30 days of discharge. Adjusted hazard ratio for all-cause readmission, emergency department visits or death for people with a visit within seven days post discharge was 1.03 (95% Confidence Interval [CI]: 1.01-1.05) and remained around 1 for subsequent days; adjusted hazard ratio for the composite COPD events was 0.97 (95% CI 0.95-1.00) and remained significantly lower than 1 for subsequent days. CONCLUSION: While a physician visit after discharge was found to reduce COPD events, a specific time period when a physician visit was most beneficial was not found. This suggests that follow-up visits should not occur at a predetermined time but be based on factors such as anticipated medical need.

Self-Driven, Monopolar Electrohydrodynamic Printing via Dielectric Nanoparticle Layer.

Electrohydrodynamic printing holds both ultrahigh-resolution fabrication capability and unmatched ink-viscosity compatibility yet fails on highly insulating thick/irregular substrates. Herein, we proposed a single-potential driven electrohydrodynamic printing process with submicrometer resolution on arbitrary nonconductive targets, regardless of their geometric shape or sizes, via precoating with an ultrathin dielectric nanoparticle layer. Benefiting from the favorable Maxwell-Wagner polarization, the reversely polarized spot brought about a significant drop (∼57% for ceramics) in the operation voltage as its induced electric field and a negligible residual charge accumulation. Thus, ordered micro/nanostructures with line widths down to 300 nm were directly written at a stage speed as low as 5 mm/s, and silver features with width of ∼2 µm or interval of ∼4 µm were achieved on insulating substrates separately. Flexible sensors and curved heaters were then high-precision printed and demonstrated successfully, presenting this technique with huge potential for fabricating flexible/conformal electronics on arbitrary 3D structures.

High Healthcare Costs in Childhood Inflammatory Bowel Disease: Development of a Prediction Model Using Linked Clinical and Health Administrative Data.

BACKGROUND: The incidence of pediatric-onset inflammatory bowel disease (IBD) and the costs of caring for individuals with IBD are both increasing. We calculated the direct healthcare costs of pediatric IBD in the first year after diagnosis and developed a model to predict children who would have high costs (top 25th percentile). METHODS: Using data from the Canadian Children IBD Network inception cohort (≤16 years of age, diagnosed between 2013 and 2019) deterministically linked to health administrative data from Ontario, Canada, we estimated direct healthcare and medication costs accrued between 31 and 365 days after diagnosis. Candidate predictors included age at diagnosis, sex, rural/urban residence location, distance to pediatric center, neighborhood income quintile, IBD type, initial therapy, disease activity, diagnostic delay, health services utilization or surgery around diagnosis, regular primary care provider, and receipt of mental health care. Logistic regression with stepwise elimination was used for model building; 5-fold nested cross-validation optimized and improved model accuracy while limiting overfitting. RESULTS: The mean cost among 487 children with IBD was CA$15 168 ± 15 305. Initial treatment (anti-tumor necrosis factor therapy, aminosalicylates, or systemic steroids), having a mental health care encounter, undergoing surgery, emergency department visit at diagnosis, sex, and age were predictors of increased costs, while having a regular primary care provider was a predictor of decreased costs. The C-statistic for our model was 0.71. CONCLUSIONS: The cost of caring for children with IBD in the first year after diagnosis is immense and can be predicted based on characteristics at diagnosis. Efforts that mitigate rising costs without compromising quality of care are needed.

Cost of caring for children with IBD is high­CA$15 168 between 31 and 365 days from diagnosis in 487 Canadian children. Predictors of high costs included anti-tumor necrosis factor therapy and mental health care, with lower costs in those with a primary-care provider.

Single-operator single-balloon enteroscopy is safe and effective: A 6-year retrospective study.

OBJECTIVES: Single-balloon enteroscopy (SBE) is an effective tool for the detection of small intestine lesions. Because it is conventionally performed by two operators, the efficacy of single-operator SBE method has not yet been elucidated. We aimed to evaluate the diagnostic yield, total enteroscopy rate, procedure time, and complications of single-operator SBE for small intestinal disease. METHODS: This was a single-center, retrospective study including consecutive patients who underwent single-operator SBE for suspicious small intestinal disorders or required therapeutic interventions between December 2014 and January 2019. The SBE procedures were performed by four endoscopists. Diagnostic yield, total enteroscopy rate, procedure time, incubation depth, and complications were analyzed, and stratification analysis was performed. RESULTS: Altogether 922 patients with 1422 SBE procedures were included for analysis, among whom 250, 172, and 500 patients underwent SBE via the oral route, the anal route and a combined route, respectively. The overall diagnostic yield was 78.52% (724/922). And 253 patients achieved total enteroscopy, with a total enteroscopy rate of 56.10%. The average procedure time for the oral and anal routes were 69.28 ± 14.72 min and 64.95 ± 13.87 min, respectively. While the incubation depth was 389.95 ± 131.42 cm and 191.81 ± 83.67 cm, respectively. Jejunal perforation was observed in one patient, which was managed by endoclips. Stratification analysis showed that the diagnostic yield and total enteroscopy rate significantly increased with operation experience together with decreased procedure time. CONCLUSION: Single-operator SBE is effective and safe for the detection of small intestinal lesions, and is easy to master.

Elevated basophil count is associated with increased risk of endometriosis.

Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date. We analysed two targeted study cohorts: a tertiary centre cohort (Endometriosis at Oxford University [ENDOX] study, 325 cases/177 controls) and a large-scale population study (UK Biobank [UKBB], 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils and basophils analysed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 x10^9/L: OR 1.65 [95%CI:1.06-2.57], P trend = 0.025) and replicated in the UKBB dataset (basophils >0.04 x10^9/L: OR 1.26 [95%CI:1.09-1.45], P trend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI [1.25 to 4.22], P trend = 0.007; UKBB study (OR = 1.40, 95% CI [1.07 to 1.85], P trend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal.

Cultivating the uncultured: Harnessing the "sandwich agar plate" approach to isolate heme-dependent bacteria from marine sediment.

In the classical microbial isolation technique, the isolation process inevitably destroys all microbial interactions and thus makes it difficult to culture the many microorganisms that rely on these interactions for survival. In this study, we designed a simple coculture technique named the "sandwich agar plate method," which maintains microbial interactions throughout the isolation and pure culture processes. The total yield of uncultured species in sandwich agar plates based on eight helper strains was almost 10-fold that of the control group. Many uncultured species displayed commensal lifestyles. Further study found that heme was the growth-promoting factor of some marine commensal bacteria. Subsequent genomic analysis revealed that heme auxotrophies were common in various biotopes and prevalent in many uncultured microbial taxa. Moreover, our study supported that the survival strategies of heme auxotrophy in different habitats varied considerably. These findings highlight that cocultivation based on the "sandwich agar plate method" could be developed and used to isolate more uncultured bacteria.

The State-of-the-Art Antibacterial Activities of Glycyrrhizin: A Comprehensive Review.

Licorice (Glycyrrhiza glabra) is a plant of the genus Glycyrrhiza in the family Fabaceae/Leguminosae and is a renowned natural herb with a long history of medicinal use dating back to ancient times. Glycyrrhizin (GLY), the main active component of licorice, serves as a widely utilized therapeutic agent in clinical practice. GLY exhibits diverse medicinal properties, including anti-inflammatory, antibacterial, antiviral, antitumor, immunomodulatory, intestinal environment maintenance, and liver protection effects. However, current research primarily emphasizes GLY's antiviral activity, while providing limited insight into its antibacterial properties. GLY demonstrates a broad spectrum of antibacterial activity via inhibiting the growth of bacteria by targeting bacterial enzymes, impacting cell membrane formation, and altering membrane permeability. Moreover, GLY can also bolster host immunity by activating pertinent immune pathways, thereby enhancing pathogen clearance. This paper reviews GLY's inhibitory mechanisms against various pathogenic bacteria-induced pathological changes, its role as a high-mobility group box 1 inhibitor in immune regulation, and its efficacy in combating diseases caused by pathogenic bacteria. Furthermore, combining GLY with other antibiotics reduces the minimum inhibitory concentration, potentially aiding in the clinical development of combination therapies against drug-resistant bacteria. Sources of information were searched using PubMed, Web of Science, Science Direct, and GreenMedical for the keywords "licorice", "Glycyrrhizin", "antibacterial", "anti-inflammatory", "HMGB1", and combinations thereof, mainly from articles published from 1979 to 2024, with no language restrictions. Screening was carried out by one author and supplemented by others. Papers with experimental flaws in their experimental design and papers that did not meet expectations (antifungal papers, etc.) were excluded.

Prolonged Complete Remission Using Tislelizumab for Hepatocellular Carcinoma After Adjuvant Chemotherapy Failure: A Case Report.

In recent years, there have been limited reports on the efficacy of later-line anti-programmed cell death -1 (PD-1) therapy in achieving prolonged and complete remission in patients with hepatocellular carcinoma (HCC). Tislelizumab, a humanized anti-PD-1 monoclonal IgG4 antibody, has shown promising results in the treatment of HCC. This report highlights the case of a patient with HCC who experienced the development of lung metastatic lesions following HCC resection and chemotherapy, but achieved a prolonged complete response (CR) after receiving tislelizumab treatment. In April 2017, a 56-year-old male diagnosed with primary HCC underwent hepatectomy and hepatic arterial infusion pump placement. Following the surgery, the patient received adjuvant hepatic arterial infusion chemotherapy (HAIC) with 4 cycles of cisplatin+5-fluorouracil (PF) regimen starting in June 2017. In May 2018, lung metastatic lesions were detected, and the patient underwent 4 cycles of oxaliplatin+leucovorin+5-fluorouracil (FOLFOX) chemotherapy. However, the disease progressed in August 2018, leading to the administration of arsenic trioxide treatment. Despite this, further progression was observed in October 2018, prompting the patient's enrollment in a clinical trial for tislelizumab therapy. Initially, the patient achieved a partial response (PR) to tislelizumab, which was followed by a CR that lasted for almost 4 years. Unfortunately, tislelizumab treatment had to be discontinued due to immune-related adverse events (AE). Subsequently, the patient received lenvatinib and maintained a CR until July 2023. Tislelizumab monotherapy, when used as a third-line treatment, has demonstrated remarkable efficacy in facilitating patients with advanced HCC to attain a durable CR.

Enhanced dispersion of prussian blue via intercalation into layered double hydroxides for efficient solar seawater evaporation.

Prussian blue (PB) is favored for its photothermal absorption capability in solar vapor generation applications. However, the photothermal conversion efficiency of current PB-based devices is limited by the material's poor dispersion. Herein, we report a method of incorporating PB in the interlayers of layered double hydroxides (LDHs) to prevent its aggregation. The dispersion is further enhanced and stabilized by the addition of sodium dodecyl sulfate (SDS). The thermal and water stability of PB is improved due to the rigid structure of LDHs and interactions between layers and anions. Elemental analysis confirms that with the increase of molar ratio of Mg/Al and the introduction of SDS, concentrations of PB are decreased accordingly. As a result, the rate of solar vapor generation is increased by 35.9% for powders containing 50 mg of equivalent PB. Of note, converting this material into a three-dimensional structure of high rebound foam further enhances solar water evaporation rate, from 0.79 kg m-2 h-1 to 0.98 kg m-2 h-1, with only 20 mg of equivalent PB, increasing the corresponding photothermal conversion efficiency from 53.8% to 66.3%.

Staphylococcal enterotoxin B exposed to pregnant rats inhibits the hedgehog signaling pathway in thymic T lymphocytes of the offspring.

The Hedgehog (Hh) signaling pathway is involved in T cell differentiation and development and plays a major regulatory part in different stages of T cell development. A previous study by us suggested that prenatal exposure to staphylococcal enterotoxin B (SEB) changed the percentages of T cell subpopulation in the offspring thymus. However, it is unclear whether prenatal SEB exposure impacts the Hh signaling pathway in thymic T cells. In the present study, pregnant rats at gestational day 16 were intravenously injected once with 15 µg SEB, and the thymi of both neonatal and adult offspring rats were aseptically acquired to scrutinize the effects of SEB on the Hh signaling pathway. It firstly found that prenatal SEB exposure clearly caused the increased expression of Shh and Dhh ligands of the Hh signaling pathway in thymus tissue of both neonatal and adult offspring rats, but significantly decreased the expression levels of membrane receptors of Ptch1 and Smo, transcription factor Gli1, as well as target genes of CyclinD1, C-myc, and N-myc in Hh signaling pathway of thymic T cells. These data suggest that prenatal SEB exposure inhibits the Hh signaling pathway in thymic T lymphocytes of the neonatal offspring, and this effect can be maintained in adult offspring via the imprinting effect.

Antipsychotic Discontinuation and New Trazodone Use in Ontario Nursing Homes: Evidence of Medication Substitution.

OBJECTIVES: An unintended consequence of efforts to reduce antipsychotic medications in nursing homes is the increase in use of other psychotropic medications; however, evidence of substitution remains limited. Our objective was to measure individual-level prescribing patterns consistent with substitution of trazodone for antipsychotics. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Residents of Ontario nursing homes aged 66-105 years with an admission assessment between April 1, 2010, and March 31, 2019, who were receiving an antipsychotic and had no antidepressant medication use at admission to the nursing home. METHODS: We used linked health administrative data to examine changes in medication use over three quarterly assessments following admission. Antipsychotic and trazodone use were measured at each assessment. The rate of trazodone initiation was compared between residents no longer dispensed an antipsychotic (discontinued) and those with an ongoing antipsychotic (continued) using discrete time survival analysis, controlling for baseline resident characteristics. RESULTS: We identified 13,306 residents dispensed an antipsychotic with no antidepressant use at admission (mean age 84 years, 61.5% women, 82.8% with dementia). As of the first quarterly assessment, nearly 20% of residents no longer received an antipsychotic and 9% received a new trazodone medication. Over time, residents who discontinued antipsychotics had a rate of trazodone initiation that was 82% higher compared to residents who continued (adjusted hazard ratio 1.82, 95% CI 1.66-2.00). CONCLUSIONS AND IMPLICATIONS: Residents admitted to a nursing home with antipsychotic use had a higher rate of trazodone initiation if they discontinued (vs continued) an antipsychotic. These findings suggest antipsychotic substitution with trazodone after entering a nursing home.

Risk factors of pneumothorax in computed tomography guided lung nodule marking using autologous blood: a retrospective study.

BACKGROUND: To investigate the risk factors of pneumothorax of using computed tomography (CT) guidance to inject autologous blood to locate isolated lung nodules. METHODS: In the First Hospital of Putian City, 92 cases of single small pulmonary nodules were retrospectively analyzed between November 2019 and March 2023. Before each surgery, autologous blood was injected, and the complications of each case, such as pneumothorax and pulmonary hemorrhage, were recorded. Patient sex, age, position at positioning, and nodule type, size, location, and distance from the visceral pleura were considered. Similarly, the thickness of the chest wall, the depth and duration of the needle-lung contact, the length of the positioning procedure, and complications connected to the patient's positioning were noted. Logistics single-factor and multi-factor variable analyses were used to identify the risk factors for pneumothorax. The multi-factor logistics analysis was incorporated into the final nomogram prediction model for modeling, and a nomogram was established. RESULTS: Logistics analysis suggested that the nodule size and the contact depth between the needle and lung tissue were independent risk factors for pneumothorax. CONCLUSION: The factors associated with pneumothorax after localization are smaller nodules and deeper contact between the needle and lung tissue.

The Emerging Role of Ubiquitin-Specific Protease 36 (USP36) in Cancer and Beyond.

The balance between ubiquitination and deubiquitination is instrumental in the regulation of protein stability and maintenance of cellular homeostasis. The deubiquitinating enzyme, ubiquitin-specific protease 36 (USP36), a member of the USP family, plays a crucial role in this dynamic equilibrium by hydrolyzing and removing ubiquitin chains from target proteins and facilitating their proteasome-dependent degradation. The multifaceted functions of USP36 have been implicated in various disease processes, including cancer, infections, and inflammation, via the modulation of numerous cellular events, including gene transcription regulation, cell cycle regulation, immune responses, signal transduction, tumor growth, and inflammatory processes. The objective of this review is to provide a comprehensive summary of the current state of research on the roles of USP36 in different pathological conditions. By synthesizing the findings from previous studies, we have aimed to increase our understanding of the mechanisms underlying these diseases and identify potential therapeutic targets for their treatment.

VAMP2 controls murine epidermal differentiation and carcinogenesis by regulation of nucleophagy.

Differentiation of murine epidermal stem/progenitor cells involves the permanent withdrawal from the cell cycle, the synthesis of various protein and lipid components for the cornified envelope, and the controlled dissolution of cellular organelles and nuclei. Deregulated epidermal differentiation contributes to the development of various skin diseases, including skin cancers. With a genome-wide shRNA screen, we identified vesicle-associated membrane protein 2 (VAMP2) as a critical factor involved in skin differentiation. Deletion of VAMP2 leads to aberrant skin stratification and enucleation in vivo. With quantitative proteomics, we further identified an autophagy protein, focal adhesion kinase family interacting protein of 200 kDa (FIP200), as a binding partner of VAMP2. Additionally, we showed that both VAMP2 and FIP200 are critical for murine keratinocyte enucleation and epidermal differentiation. Loss of VAMP2 or FIP200 enhances cutaneous carcinogenesis in vivo. Together, our findings identify important molecular mechanisms underlying epidermal differentiation and skin tumorigenesis.

Direct Degradation of Fresh and Dried Macroalgae by Agarivorans albus B2Z047.

Marine macroalgae are increasingly recognized for their significant biological and economic potential. The key to unlocking this potential lies in the efficient degradation of all carbohydrates from the macroalgae biomass. However, a variety of polysaccharides (alginate, cellulose, fucoidan, and laminarin), are difficult to degrade simultaneously in a short time. In this study, the brown alga Saccharina japonica was found to be rapidly and thoroughly degraded by the marine bacterium Agarivorans albus B2Z047. This strain harbors a broad spectrum of carbohydrate-active enzymes capable of degrading various polysaccharides, making it uniquely equipped to efficiently break down both fresh and dried kelp, achieving a hydrolysis rate of up to 52%. A transcriptomic analysis elucidated the presence of pivotal enzyme genes implicated in the degradation pathways of alginate, cellulose, fucoidan, and laminarin. This discovery highlights the bacterium's capability for the efficient and comprehensive conversion of kelp biomass, indicating its significant potential in biotechnological applications for macroalgae resource utilization.

KDM5 family as therapeutic targets in breast cancer: Pathogenesis and therapeutic opportunities and challenges.

Breast cancer (BC) is the most frequent malignant cancer diagnosis and is a primary factor for cancer deaths in women. The clinical subtypes of BC include estrogen receptor (ER) positive, progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) positive, and triple-negative BC (TNBC). Based on the stages and subtypes of BC, various treatment methods are available with variations in the rates of progression-free disease and overall survival of patients. However, the treatment of BC still faces challenges, particularly in terms of drug resistance and recurrence. The study of epigenetics has provided new ideas for treating BC. Targeting aberrant epigenetic factors with inhibitors represents a promising anticancer strategy. The KDM5 family includes four members, KDM5A, KDM5B, KDM5C, and KDMD, all of which are Jumonji C domain-containing histone H3K4me2/3 demethylases. KDM5 proteins have been extensively studied in BC, where they are involved in suppressing or promoting BC depending on their specific upstream and downstream pathways. Several KDM5 inhibitors have shown potent BC inhibitory activity in vitro and in vivo, but challenges still exist in developing KDM5 inhibitors. In this review, we introduce the subtypes of BC and their current therapeutic options, summarize KDM5 family context-specific functions in the pathobiology of BC, and discuss the outlook and pitfalls of KDM5 inhibitors in this disease.

Crohn's disease treatment and memory T-cell subset changes: insights from a case series.

Background: Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics. Methods: A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student t-test. Results: Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8+ T cells in PBMCs (P=0.0005), and altered frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8+ stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients. Conclusions: The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings.

Hyponatremia-associated hospital visits are not reduced by early electrolyte testing in older adults starting antidepressants.

BACKGROUND: Clinical practice guidelines recommend early serum electrolyte monitoring when starting antidepressants in older adults due to the increased risk of hyponatremia. It is unclear whether this monitoring improves outcomes. METHODS: Population-based, retrospective cohort study of Ontario adults aged ≥66 years who initiated therapy with a selective serotonin reuptake inhibitor (SSRI) or selective norepinephrine reuptake inhibitor (SNRI) between April 1, 2013, and January 31, 2020. The index date was the date of the first such prescription, and the exposure of interest was serum electrolyte measurement during the subsequent 7 days. The primary outcome was any emergency department or hospital admission with hyponatremia within 8-60 days of antidepressant initiation. Poisson regression models compared individuals who had versus did not have their serum electrolytes tested in the week following SSRI/SNRI initiation, weighting by propensity score-based overlap weights. RESULTS: Among the 420,085 patients aged ≥66 years initiating treatment with an SSRI/SNRI, 26,808 (6.4%) had serum electrolytes measured in the subsequent 7 days and 6109 (1.5%) subsequently presented to hospital with hyponatremia. The time from drug initiation to hospitalization varied (median 29, interquartile range [IQR] 17-44 days), and the median sodium concentration measured in the community (136, IQR 133-138 mmol/L) was marginally higher than those at the time of hospitalization (132, IQR 130-134 mmol/L). Patients who underwent electrolyte testing in the week following SSRI/SNRI treatment were more likely to attend an emergency department (ED) or hospital with hyponatremia within 8-60 days relative to those who did not (relative risk = 2.31, 95% confidence interval: 2.16-2.46). CONCLUSIONS: Testing serum electrolytes in the week after starting an SSRI/SNRI is not associated with a reduced risk of a hospital visit with hyponatremia. These findings do not support current guidelines recommending routine electrolyte monitoring.

Individual Atg8 paralogs and a bacterial metabolite sequentially promote hierarchical CASM-xenophagy induction and transition.

Atg8 paralogs, consisting of LC3A/B/C and GBRP/GBRPL1/GATE16, function in canonical autophagy; however, their function is controversial because of functional redundancy. In innate immunity, xenophagy and non-canonical single membranous autophagy called "conjugation of Atg8s to single membranes" (CASM) eliminate bacteria in various cells. Previously, we reported that intracellular Streptococcus pneumoniae can induce unique hierarchical autophagy comprised of CASM induction, shedding, and subsequent xenophagy. However, the molecular mechanisms underlying these processes and the biological significance of transient CASM induction remain unknown. Herein, we profile the relationship between Atg8s, autophagy receptors, poly-ubiquitin, and Atg4 paralogs during pneumococcal infection to understand the driving principles of hierarchical autophagy and find that GATE16 and GBRP sequentially play a pivotal role in CASM shedding and subsequent xenophagy induction, respectively, and LC3A and GBRPL1 are involved in CASM/xenophagy induction. Moreover, we reveal ingenious bacterial tactics to gain intracellular survival niches by manipulating CASM-xenophagy progression by generating intracellular pneumococci-derived H2O2.