Prevention of diabetes by FTY720-mediated stabilization of peri-islet tertiary lymphoid organs.

ObjectiveThe nonobese diabetic (NOD) mouse is a well-established mouse model of spontaneous type 1 diabetes, which is characterized by an autoimmune destruction of the insulin-secreting pancreatic beta-cells. In this study, we address the role of tertiary lymphoid organs (TLOs) that form in the pancreas of NOD mice during disease progression.MethodsWe developed a model designed to "lock" lymphocytes in the pancreatic lymph node (PLN) and pancreas by the use of FTY720, which blocks the exit of lymphocytes from lymph nodes. A combination of flow cytometry, immunofluorescence, and analysis of clinical scores was used to study the effects of long-term FTY720 treatment on TLO development and development of diabetes.ResultsContinuous treatment of NOD mice with FTY720 prevented diabetes development even at a time of significant insulitis. Treatment withdrawal led to accelerated disease independent of the PLN. Interestingly, naive T-cells trafficked to and proliferated in the TLOs. In addition, morphological changes were observed that occurred during the development of the disease. Remarkably, although the infiltrates are not organized into T/B-cell compartments in 8-week-old mice, by 20 weeks of age, and in age-matched mice undergoing FTY720 treatment, the infiltrates showed a high degree of organization. However, in naturally and FTY720-induced diabetic mice, T/B-cell compartmentalization was lost.ConclusionOur data show that TLOs are established during diabetes development and suggest that islet destruction is due to a loss of TLO integrity, which may be prevented by FTY720 treatment

AI Testing Framework for Next-G O-RAN Networks: Requirements, Design, and Research Opportunities

Openness and intelligence are two enabling features to be introduced in next generation wireless networks, e.g. Beyond 5G and 6G, to support service heterogeneity, open hardware, optimal resource utilization, and on-demand service deployment. The open radio access network (O-RAN) is a promising RAN architecture to achieve both openness and intelligence through virtualized network elements and well-defined interfaces. While deploying artificial intelligence (AI) models is becoming easier in O-RAN, one significant challenge that has been long neglected is the comprehensive testing of their performance in realistic environments. This article presents a general automated, distributed and AI-enabled testing framework to test AI models deployed in O-RAN in terms of their decision-making performance, vulnerability and security. This framework adopts a master-actor architecture to manage a number of end devices for distributed testing. More importantly, it leverages AI to automatically and intelligently explore the decision space of AI models in O-RAN. Both software simulation testing and software-defined radio hardware testing are supported, enabling rapid proof of concept research and experimental research on wireless research platforms.Comment: To be published in IEEE Wireless Communications Magazin

Materialized View Selection in XML Databases

Materialized views, a rdbms silver bullet, demonstrate its efficacy in many applications, especially as a data warehousing/decison support system tool. The pivot of playing materialized views efficiently is view selection. Though studied for over thirty years in rdbms, the selection is hard to make in the context of xml databases, where both the semi-structured data and the expressiveness of xml query languages add challenges to the view selection problem. We start our discussion on producing minimal xml views (in terms of size) as candidates for a given workload (a query set). To facilitate intuitionistic view selection, we present a view graph (called vcube) to structurally maintain all generated views. By basing our selection on vcube for materialization, we propose two view selection strategies, targeting at space-optimized and space-time tradeoff, respectively. We built our implementation on top of Berkeley DB XML, demonstrating that significant performance improvement could be obtained using our proposed approaches

Identifying Patients With Vesicovaginal Fistula at High Risk of Urinary Incontinence After Surgery:

To develop a risk score to identify women with vesicovaginal fistula at high risk of residual urinary incontinence after surgical repair

Improvement and retention of emergency obstetrics and neonatal care knowledge and skills in a hospital mentorship program in Lilongwe, Malawi

To evaluate whether a hospital-based mentoring program could significantly increase short- and longer-term emergency obstetrics and neonatal care (EmONC) knowledge and skills among health providers

Association between duration of gonadotrophin-releasing hormone agonist use and cardiovascular risks: A population-based competing-risk analysis

Background Although androgen deprivation therapy has known cardiovascular risks, it is unclear if its duration is related to cardiovascular risks. This study thus aimed to investigate the associations between gonadotrophin-releasing hormone (GnRH) agonist use duration and cardiovascular risks. Methods This retrospective cohort study included adult patients with prostate cancer receiving GnRH agonists in Hong Kong during 1999–2021. Patients who switched to GnRH antagonists, underwent bilateral orchidectomy, had <6 months of GnRH agonist, prior myocardial infarction (MI), or prior stroke was excluded. All patients were followed up until September 2021 for a composite endpoint of MI and stroke. Multivariable competing-risk regression using the Fine-Gray subdistribution model was used, with mortality from any cause as the competing event. Results In total, 4038 patients were analyzed (median age 74.9 years old, interquartile range (IQR) 68.7–80.8 years old). Over a median follow-up of 4.1 years (IQR 2.1–7.5 years), longer GnRH agonists use was associated with higher risk of the endpoint (sub-hazard ratio per year 1.04 [1.01–1.06], p = 0.001), with those using GnRH agonists for ≥2 years having an estimated 23% increase in the sub-hazard of the endpoint (sub-hazard ratio 1.23 [1.04–1.46], p = 0.017). Conclusion Longer GnRH agonist use may be associated with greater cardiovascular risks

Urinary Sodium Profiling in Chronic Heart Failure to Detect Development of Acute Decompensated Heart Failure

OBJECTIVES This study sought to determine the relationship between urinary sodium (U-na) concentration and the pathophysiologic interaction with the development of acute heart failure (AHF) hospitalization. BACKGROUND No data are available on the longitudinal dynamics of U-na concentration in patients with chronic heart failure (HF), including its temporal relationship with AHF hospitalization. METHODS Stable, chronic HF patients with either reduced or preserved ejection fraction were prospectively included to undergo prospective collection of morning spot U-na samples for 30 consecutive weeks. Linear mixed modeling was used to assess the longitudinal changes in U-na concentration. Patients were followed for the development of the clinical endpoint of AHF. RESULTS A total of 80 chronic HF patients (71 +/- 11 years of age; an N-terminal pro-B-type natriuretic peptide [NT-proBNP] concentration of 771 [interquartile range: 221 to 1,906] ng/l; left ventricular ejection fraction [LVEF] 33 +/- 7%) prospectively submitted weekly pre-diuretic first void morning U-na samples for 30 weeks. A total of 1,970 U-na samples were collected, with mean U-na concentration of 81.6 +/- 41 mmol/l. Sodium excretion remained stable over time on a population level (time effect p = 0.663). However, interindividual differences revealed the presence of high (88 mmol/l U-na [n = 39]) and low (73 mmol/l U-na [n = 41]) sodium excreters. Only younger age was an independent predictor of high sodium excretion (odds ratio [OR]: 0.91; 95% confidence interval [CI]: 0.83 to 1.00; p = 0.045 per year). During 587 +/- 54 days of follow-up, 21 patients were admitted for AHF. Patients who developed AHF had significantly lower U-na concentrations (F-[1.80] = 24.063; p <0.001). The discriminating capacity of U-na concentration to detect AHF persisted after inclusion of NT-proBNP and estimated glomerular filtration rate (eGFR) measurements as random effects (p = 0.041). Furthermore, U-na concentration dropped (U-na = 46 +/- 16 mmol/l vs. 70 +/- 32 mmol/l, respectively; p = 0.003) in the week preceding the hospitalization and returned to the individual's baseline (U-na = 71 +/- 22 mmol/l; p = 0.002) following recompensation, while such early longitudinal changes in weight and dyspnea scores were not apparent in the week preceding decompensation. CONCLUSIONS Overall, U-na concentration remained relatively stable over time, but large interindividual differences existed in stable, chronic HF patients. Patients who developed AHF exhibited a chronically lower U-na concentration and exhibited a further drop in U-na concentration during the week preceding hospitalization. Ambulatory U-na sample collection is feasible and may offer additional prognostic and therapeutic information. (C) 2019 by the American College of Cardiology Foundation

Insulin-induced remission in new-onset NOD mice is maintained by the PD-1–PD-L1 pathway

The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)–programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte–associated antigen 4 pathway. Anti–PD-1 and anti–PD-L1, but not anti–PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1–PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1–PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1–PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues