Clinical Characteristics and Prognosis of Older Patients with Coronavirus Disease 2019 Requiring Mechanical Ventilation.

An older age is associated with severe progression and poor prognosis in coronavirus disease 2019 (COVID-19), and mechanical ventilation is often required. The specific characteristics of older patients undergoing mechanical ventilation and their prognostic factors are largely unknown. We aimed to identify potential prognostic factors in this group to inform treatment decisions. This retrospective cohort study collected data from patients with COVID-19 at 22 medical centers. Univariate and multivariate Cox regression analyses were performed to assess factors that influence mortality. We allocated 434 patients in geriatric (≥80 years) and elderly (65-79 years) groups. The former group scored significantly higher than the elderly group in the clinical frailty scale and sequential organ failure assessment, indicating more severe organ dysfunction. Significantly lower administration rates of tocilizumab and extracorporeal membrane oxygenation and higher intensive care unit (ICU) and in-hospital mortality were noted in the geriatric group. The factors associated with ICU and in-hospital mortality included high creatinine levels, the use of continuous renal replacement therapy, prone positioning, and the administration of life-sustaining treatments. These results highlight significant age-related differences in the management and prognosis of critically ill older patients with COVID-19. Increased mortality rates and organ dysfunction in geriatric patients undergoing mechanical ventilation necessitate age-appropriate treatment strategies to improve their prognoses.

Retinoic acid modulation of granule cell activity and spatial discrimination in the adult hippocampus.

Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARß) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.

Conversion surgery for initially unresectable locally advanced biliary tract cancer: A multicenter collaborative study conducted in Japan and Korea.

BACKGROUND: Although surgical resection is the only curative treatment for biliary tract cancer, in some cases, the disease is diagnosed as unresectable at initial presentation. There are few reports of conversion surgery after the initial treatment for unresectable locally advanced biliary tract cancer. This study aimed to evaluate the efficacy and safety of conversion surgery in patients with initially unresectable locally advanced biliary tract cancer. METHODS: We retrospectively collected clinical data from groups of patients in multiple centers belonging to the Japanese Society of Hepato-Biliary-Pancreatic Surgery and Korean Association of Hepato-Biliary-Pancreatic Surgery. We analyzed two groups of prognostic factors (pretreatment and surgical factors) and their relation to the treatment outcomes. RESULTS: A total of 56 patients with initially unresectable locally advanced biliary tract cancer were enrolled in this study of which 55 (98.2%) patients received chemotherapy, and 16 (28.6%) patients received additional radiation therapy. The median time from the start of the initial treatment to resection was 6.4 months. Severe postoperative complications of Clavien-Dindo grade III or higher occurred in 34 patients (60.7%), and postoperative mortality occurred in five patients (8.9%). Postoperative histological results revealed CR in eight patients (14.3%). The median survival time from the start of the initial treatment in all 56 patients who underwent conversion surgery was 37.7 months, the 3-year survival rate was 53.9%, and the 5-year survival rate was 39.1%. CONCLUSIONS: Conversion surgery for initially unresectable locally advanced biliary tract cancer may lead to longer survival in selected patients. However, more precise preoperative safety evaluation and careful postoperative management are required.

Comparative Anatomy of the Dentate Mossy Cells in Nonhuman Primates: Their Spatial Distributions and Axonal Projections Compared With Mouse Mossy Cells.

Glutamatergic mossy cells (MCs) mediate associational and commissural connectivity, exhibiting significant heterogeneity along the septotemporal axis of the mouse dentate gyrus (DG). However, it remains unclear whether the neuronal features of MCs are conserved across mammals. This study compares the neuroanatomy of MCs in the DG of mice and monkeys. The MC marker, calretinin, distinguishes two subpopulations: septal and temporal. Dual-colored fluorescence labeling is utilized to compare the axonal projection patterns of these subpopulations. In both mice and monkeys, septal and temporal MCs project axons across the longitudinal axis of the ipsilateral DG, indicating conserved associational projections. However, unlike in mice, no MC subpopulations in monkeys make commissural projections to the contralateral DG. In monkeys, temporal MCs send associational fibers exclusively to the inner molecular layer, while septal MCs give rise to wide axonal projections spanning multiple molecular layers, akin to equivalent MC subpopulations in mice. Despite conserved septotemporal heterogeneity, interspecies differences are observed in the topological organization of septal MCs, particularly in the relative axonal density in each molecular layer along the septotemporal axis of the DG. In summary, this comparative analysis sheds light on both conserved and divergent features of MCs in the DG of mice and monkeys. These findings have implications for understanding functional differentiation along the septotemporal axis of the DG and contribute to our knowledge of the anatomical evolution of the DG circuit in mammals.

CORRIGENDUM: Correction of the ethical statements. Training efficacy of robotic duct-to-mucosa pancreaticojejunostomy simulation using silicone models for surgical fellows.

[This corrects the article on p. 45 in vol. 106, PMID: 38205096.].

Clinical characteristics and prognosis of patients with COVID-19 on mechanical ventilation undergoing continuous renal replacement therapy.

BACKGROUND: The coronavirus disease (COVID-19) pandemic has significantly strained global healthcare, particularly in the management of patients requiring mechanical ventilation (MV) and continuous renal replacement therapy (CRRT). This study investigated the characteristics and prognoses of these patients. METHODS: This multicenter retrospective cohort study gathered data from patients with COVID-19 across 26 medical centers. Logistic analysis was used to identify the factors associated with CRRT implementation. RESULTS: Of the 640 patients with COVID-19 who required MV, 123 (19.2%) underwent CRRT. Compared to the non-CRRT group, the CRRT group was older and exhibited higher sequential organ failure assessment scores. The incidence of hypertension, diabetes, cardiovascular disease, chronic neurological disease, and chronic kidney disease was also higher in the CRRT group. Moreover, the CRRT group had higher intensive care unit (ICU) (75.6% vs. 26.9%, p < 0.001) and in-hospital (79.7% vs. 29.6%, p < 0.001) mortality rates. CRRT implementation was identified as an independent risk factor for both ICU mortality (hazard ratio [HR]:1.833, 95% confidence interval [CI]:1.342-2.505, p < 0.001) and in-hospital mortality (HR: 2.228, 95% CI: 1.648-3.014, p < 0.001). Refractory respiratory failure (n = 99, 19.1%) was the most common cause of death in the non-CRRT death group, and shock with multi-organ failure (n = 50, 40.7%) was the most common cause of death in the CRRT death group. Shock with multi-organ failure and cardiac death were significantly more common in the CRRT death group, compared to non-CRRT death group. CONCLUSION: This study indicates that CRRT is associated with higher ICU and in-hospital mortality rates in patients with COVID-19 who require MV. Notably, the primary cause of death in the CRRT group was shock with multi-organ failure, emphasizing the severe clinical course for these patients, while refractory respiratory failure was most common in non-CRRT patients.

Multifunctional hydrogel dressing based on fish gelatin/oxidized hyaluronate for promoting diabetic wound healing.

Non-healing chronic diabetic wound treatment remains an unsolved healthcare challenge and still threatens patients' lives. Recently, hydrogel dressings based on natural biomaterials have been widely investigated to accelerate the healing of diabetic wounds. In this study, we introduce a bioactive hydrogel based on fish gelatin (FG) as a candidate for diabetic wound treatments, which is a recently emerged substitute for mammalian derived gelatin. The composite hydrogel simply fabricated with FG and oxidized hyaluronate (OHy) through Schiff base reaction could successfully accelerate wound healing due to their adequate mechanical stability and self-healing ability. In vitro studies showed that the fabricated hydrogels exhibited cytocompatibility and could reduce pro-inflammatory cytokine expression such as NO, IL-1ß, TNF-α, and PGE2 in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In addition, the production of reactive oxygen species (ROS), a key marker of free radicals producing oxidative stress, was also reduced by fabricated hydrogels. Furthermore, in vivo experiments demonstrated that the hydrogel could promote wound closure, re-epithelialization, collagen deposition, and protein expression of CD31, CD206, and Arg1 in diabetic mice models. Our study highlights the advanced potential of FG as a promising alternative material and indicates that FOHI can be successfully used for diabetic wound healing applications.

A Methodological Approach for Motor Selection in Dental Impression Material Dispensers Using Experimental and Image Analysis Techniques.

This study presents a methodology to prevent the overdesign of electric dispensers for dental impression materials by analyzing the necessary load and determining the appropriate pressurization speed and drive motor capacity. We derived an equation to calculate the required torque and rotational speed of the motor based on the extrusion load and the speed of the impression material. A specialized load measurement system was developed to measure the load necessary to extrude the impression material. Through experiments and image processing, we measured the radius of curvature of the trajectory of the impression material and correlated it with the pressurization speed. Techniques such as position coordinate plotting, curve fitting, and circle fitting were employed to determine the pressurization speed that aligns with the manufacturer's recommended curvature radius. These findings led to a substantial decrease in the necessary motor torque and rotational speed compared with the current standards. This research provides a systematic approach to sizing drive motors using extrusion load and pressurization speed, aiming to reduce overdesign, power consumption, and the weight and size of the motor and battery, thereby contributing to the development of more efficient and compact dental impression material dispensers.

Establishment, characterization, and biobanking of 36 pancreatic cancer organoids: prediction of metastasis in resectable pancreatic cancer.

PURPOSE: Early dissemination of primary pancreatic ductal adenocarcinoma (PDAC) is the main cause of dismal prognosis as it highly limits possible treatment options. A number of PDAC patients experience distant metastasis even after treatment due to the metastatic clones. We aimed to demonstrate the molecular architecture of borderline resectable PDAC manifests cancer dissemination of PDAC. METHODS: Here, 36 organoids isolated from primary tumor masses of PDAC patients with diverse metastatic statues are presented. Whole-exome sequencing and RNA sequencing were performed and drug responses to clinically relevant 18 compounds were assessed. RESULTS: Our results revealed that borderline resectable PDAC organoids exhibited distinct patterns according to their metastatic potency highlighted by multiple genetic and transcriptional factors and strong variances in drug responses. CONCLUSIONS: These data suggest that the presence of metastatic PDAC can be identified by integrating molecular compositions and drug responses of borderline resectable PDAC.

Perioperative textbook outcomes of minimally invasive pancreatoduodenectomy: a multicenter retrospective cohort analysis in a Korean minimally invasive pancreatic surgery registry.

BACKGROUND: The aim of this study is to investigate the perioperative composite textbook outcomes of pancreatic surgery after minimally invasive pancreatoduodenectomy (MIPD). MATERIALS AND METHODS: The cohort study was conducted across 10 institutions and included 1552 patients who underwent MIPD registered with the Korean Study Group on Minimally Invasive Pancreatic Surgery between May 2007 and April 2020. We analyzed perioperative textbook outcomes of pancreatic surgery after MIPD. Subgroup analyses were performed to assess outcomes based on the hospital volume of MIPD. RESULTS: Among all patients, 21.8% underwent robotic pancreatoduodenectomy. High-volume centers (performing >20 MIPD/year) performed 88.1% of the procedures. The incidence of clinically relevant postoperative pancreatic fistula was 11.5%. Severe complications (Clavien-Dindo grade ≥IIIa) occurred in 15.1% of the cases. The 90-day mortality rate was 0.8%. The mean hospital stay was 13.7 days. Textbook outcomes of pancreatic surgery success were achieved in 60.4% of patients, with higher rates observed in high-volume centers than in low-volume centers (62.2% vs. 44.7%, P<0.001). High-volume centers exhibited significantly lower conversion rates (5.4% vs. 12.5%, P=0.001), lower 90-day mortality (0.5% vs. 2.7%, P=0.001), and lower 90-day readmission rates (4.5% vs. 9.6%, P=0.006) than those low-volume centers. CONCLUSION: MIPD could be performed safely with permissible perioperative outcomes, including textbook outcomes of pancreatic surgery, particularly in experienced centers. The findings of this study provided valuable insights for guiding surgical treatment decisions in periampullary disease.

Association between hypotension during pancreatectomy and development of postoperative diabetes.

CONTEXT: With advancements in long-term survival after pancreatectomy, post-pancreatectomy diabetes has become a concern, and the risk factors are not established yet. Pancreatic islets are susceptible to ischemic damage, though there is a lack of clinical evidence regarding glycemic deterioration. OBJECTIVE: To investigate association between hypotension during pancreatectomy and development of post-pancreatectomy diabetes. DESIGN: In this retrospective, longitudinal cohort study, we enrolled patients without diabetes who underwent distal pancreatectomy or pancreaticoduodenectomy between January 2005 and December 2018, from two referral hospitals in Korea. MAIN OUTCOME MEASURES: Intraoperative hypotension [IOH] was defined as a 20% or greater reduction in systolic blood-pressure. The primary and secondary outcomes were incident diabetes and postoperative Homeostatic Model Assessment [HOMA] indices. RESULTS: We enrolled 1,129 patients (average age, 59 years; 49% men; 35% distal pancreatectomy). IOH occurred in 83% (median duration, 25 minutes; interquartile range [IQR], 5-65). During a median follow-up of 3.9 years, diabetes developed in 284 patients (25%). The cumulative incidence of diabetes was proportional to increases in the duration and depth of IOH (P < 0.001). For the median duration in an IOH when compared to a reference time of 0 minute, the hazard ratio [HR] was 1.48 (95% CI, 1.14-1.92). The effect was pronounced with distal pancreatectomy compared to pancreaticoduodenectomy. Furthermore, the duration of IOH was inversely correlated with 1-year HOMA beta-cell function (P < 0.002), but not with HOMA insulin resistance. CONCLUSIONS: These results support the hypothesis that IOH during pancreatectomy may elevate risk of diabetes by inducing beta cell insufficiency.

The Value of Textbook Outcome in Benchmarking Pancreatoduodenectomy for Nonfunctioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Textbook outcome (TO) is a composite variable that can define the quality of pancreatic surgery. The aim of this study is to evaluate TO after pancreatoduodenectomy (PD) for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). PATIENTS AND METHODS: All patients who underwent PD for NF-PanNETs (2007-2016) in different centers were included in this retrospective study. TO was defined as the absence of severe postoperative complications and mortality, length of hospital stay ≤ 19 days, R0 resection, and at least 12 lymph nodes harvested. RESULTS: Overall, 477 patients were included. The TO rate was 32%. Tumor size [odds ratio (OR) 1.696; p = 0.013], a minimally invasive approach (OR 12.896; p = 0.001), and surgical volume (OR 2.062; p = 0.023) were independent predictors of TO. The annual frequency of PDs increased over time as well as the overall rate of TO. At a median follow-up of 44 months, patients who achieved TO had similar disease-free (p = 0.487) and overall survival (p = 0.433) rates compared with patients who did not achieve TO. TO rate in patients with NF-PanNET > 2 cm was 35% versus 27% in patients with NF-PanNET ≤ 2 cm (p = 0.044). Considering only NF-PanNETs > 2 cm, patients with TO and those without TO had comparable 5-year overall survival rates (p = 0.766) CONCLUSIONS: TO is achieved in one-third of patients after PD for NF-PanNETs and is not associated with a benefit in terms of long-term survival.

Multi-proteomic analyses of 5xFAD mice reveal new molecular signatures of early-stage Alzheimer's disease.

An early diagnosis of Alzheimer's disease is crucial as treatment efficacy is limited to the early stages. However, the current diagnostic methods are limited to mid or later stages of disease development owing to the limitations of clinical examinations and amyloid plaque imaging. Therefore, this study aimed to identify molecular signatures including blood plasma extracellular vesicle biomarker proteins associated with Alzheimer's disease to aid early-stage diagnosis. The hippocampus, cortex, and blood plasma extracellular vesicles of 3- and 6-month-old 5xFAD mice were analyzed using quantitative proteomics. Subsequent bioinformatics and biochemical analyses were performed to compare the molecular signatures between wild type and 5xFAD mice across different brain regions and age groups to elucidate disease pathology. There was a unique signature of significantly altered proteins in the hippocampal and cortical proteomes of 3- and 6-month-old mice. The plasma extracellular vesicle proteomes exhibited distinct informatic features compared with the other proteomes. Furthermore, the regulation of several canonical pathways (including phosphatidylinositol 3-kinase/protein kinase B signaling) differed between the hippocampus and cortex. Twelve potential biomarkers for the detection of early-stage Alzheimer's disease were identified and validated using plasma extracellular vesicles from stage-divided patients. Finally, integrin α-IIb, creatine kinase M-type, filamin C, glutamine γ-glutamyltransferase 2, and lysosomal α-mannosidase were selected as distinguishing biomarkers for healthy individuals and early-stage Alzheimer's disease patients using machine learning modeling with approximately 79% accuracy. Our study identified novel early-stage molecular signatures associated with the progression of Alzheimer's disease, thereby providing novel insights into its pathogenesis.

Maladaptation of dentate gyrus mossy cells mediates contextual discrimination deficit after traumatic stress.

Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.

Risk Factors for the Mortality of Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation in a Non-Centralized Setting: A Nationwide Study.

BACKGROUND: Limited data are available on the mortality rates of patients receiving extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19). We aimed to analyze the relationship between COVID-19 and clinical outcomes for patients receiving ECMO. METHODS: We retrospectively investigated patients with COVID-19 pneumonia requiring ECMO in 19 hospitals across Korea from January 1, 2020 to August 31, 2021. The primary outcome was the 90-day mortality after ECMO initiation. We performed multivariate analysis using a logistic regression model to estimate the odds ratio (OR) of 90-day mortality. Survival differences were analyzed using the Kaplan-Meier (KM) method. RESULTS: Of 127 patients with COVID-19 pneumonia who received ECMO, 70 patients (55.1%) died within 90 days of ECMO initiation. The median age was 64 years, and 63% of patients were male. The incidence of ECMO was increased with age but was decreased after 70 years of age. However, the survival rate was decreased linearly with age. In multivariate analysis, age (OR, 1.048; 95% confidence interval [CI], 1.010-1.089; P = 0.014) and receipt of continuous renal replacement therapy (CRRT) (OR, 3.069; 95% CI, 1.312-7.180; P = 0.010) were significantly associated with an increased risk of 90-day mortality. KM curves showed significant differences in survival between groups according to age (65 years) (log-rank P = 0.021) and receipt of CRRT (log-rank P = 0.004). CONCLUSION: Older age and receipt of CRRT were associated with higher mortality rates among patients with COVID-19 who received ECMO.

Systematic review on surveillance for non-resected branch-duct intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: The management of branch-duct type intraductal papillary mucinous neoplasms (BD-IPMN) varies in existing guidelines. This study investigated the optimal surveillance protocol and safe discontinuation of surveillance considering natural history in non-resected IPMN, by systematically reviewing the published literature. METHODS: This review was guided by PRISMA. Research questions were framed in PICO format "CQ1-1: Is size criteria helpful to determine surveillance period? CQ1-2: How often should surveillance be carried out? CQ1-3: When should surveillance be discontinued? CQ1-4: Is nomogram predicting malignancy useful during surveillance?". PubMed was searched from January-April 2022. RESULTS: The search generated 2373 citations. After screening, 83 articles were included. Among them, 33 studies were identified for CQ1-1, 19 for CQ1-2, 26 for CQ1-3 and 12 for CQ1-4. Cysts <1.5 or 2 cm without worrisome features (WF) were described as more indolent, and most studies advised an initial period of surveillance. The median growth rate of cysts <2 cm ranged from 0.23 to 0.6 mm/year. Patients with cysts <2 cm showing no morphological changes and no WF after 5-years of surveillance have minimal malignancy risk of 0-2%. Two nomograms created with over 1000 patients had AUCs of around 0.8 and appear to be feasible in a real-world practice. CONCLUSIONS: For patients with suspected BD-IPMN <2 cm and no other WF, less frequent surveillance is recommended. Surveillance may be discontinued for cysts that remain stable during 5-year surveillance, with consideration of patient condition and life expectancy. With this updated surveillance strategy, patients with non-worrisome BD-IPMN should expect more streamlined management and decreased healthcare utilization.

Whole-genome bisulfite sequencing identifies stage- and subtype-specific DNA methylation signatures in pancreatic cancer.

In pancreatic ductal adenocarcinoma (PDAC), no recurrent metastasis-specific mutation has been found, suggesting that epigenetic mechanisms, such as DNA methylation, are the major contributors of late-stage disease progression. Here, we performed the first whole-genome bisulfite sequencing (WGBS) on mouse and human PDAC organoid models to identify stage-specific and molecular subtype-specific DNA methylation signatures. With this approach, we identified thousands of differentially methylated regions (DMRs) that can distinguish between the stages and molecular subtypes of PDAC. Stage-specific DMRs are associated with genes related to nervous system development and cell-cell adhesions, and are enriched in promoters and bivalent enhancers. Subtype-specific DMRs showed hypermethylation of GATA6 foregut endoderm transcriptional networks in the squamous subtype and hypermethylation of EMT transcriptional networks in the progenitor subtype. These results indicate that aberrant DNA methylation contributes to both PDAC progression and subtype differentiation, resulting in significant and reoccurring DNA methylation patterns with diagnostic and prognostic potential.