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BACKGROUND AND OBJECTIVES: Neonatal sepsis is a significant contributor to mortality and morbidity; however, the uncontrolled use of antimicrobials is associated with significant adverse effects. Our objective with this article is to review the components of neonatal antimicrobial stewardship programs (ASP) and their effects on clinical outcomes, cost-effectiveness, and antimicrobial resistance. METHODS: We selected randomized and nonrandomized trials and observational and quality improvement studies evaluating the impact of ASP with a cutoff date of May 22, 2023. The data sources for these studies included PubMed, Medline, Embase, Cochrane CENTRAL, Web of Science, and SCOPUS. Details of the ASP components and clinical outcomes were extracted into a predefined form. RESULTS: Of the 4048 studies retrieved, 70 studies (44 cohort and 26 observational studies) of >350 000 neonates met the inclusion criteria. Moderate-certainty evidence reveals a significant reduction in antimicrobial initiation in NICU (pooled risk difference [RD] 19%; 95% confidence interval [CI] 14% to 24%; 21 studies, 27 075 infants) and combined NICU and postnatal ward settings (pooled RD 8%; 95% CI 6% to 10%; 12 studies, 358 317 infants), duration of antimicrobial agents therapy (pooled RD 20%; 95% CI 10% to 30%; 9 studies, 303 604 infants), length of therapy (pooled RD 1.82 days; 95% CI 1.09 to 2.56 days; 10 studies, 157 553 infants), and use of antimicrobial agents >5 days (pooled RD 9%; 95% CI 3% to 15%; 5 studies, 9412 infants). Low-certainty evidence reveals a reduction in economic burden and drug resistance, favorable sustainability metrices, without an increase in sepsis-related mortality or the reinitiation of antimicrobial agents. Studies had heterogeneity with significant variations in ASP interventions, population settings, and outcome definitions. CONCLUSIONS: Moderate- to low-certainty evidence reveals that neonatal ASP interventions are associated with reduction in the initiation and duration of antimicrobial use, without an increase in adverse events. [ABSTRACT FROM AUTHOR]

The success of chimeric antigen receptor T‐cell (CAR‐T) therapy in hematologic malignancies has realized a longstanding effort toward harnessing the immune system to fight cancer in a truly personalized fashion. Second generation chimeric antigen receptors (CAR) incorporating co‐stimulatory molecules like 4‐1BB or CD28 were able to overcome some of the hindrances with initial CAR constructs resulting in efficacious products. Many second‐generation CAR‐T products have been approved in the treatment of relapsed/refractory hematologic malignancies including multiple myeloma (MM), non‐Hodgkin lymphoma (NHL), and acute lymphoblastic leukemia. However, challenges remain in optimizing the manufacturing, timely access, limiting the toxicity from CAR‐T infusions and improving sustainability of responses derived with CAR‐T therapy. Here, we summarize the clinical trial data leading to approval CAR‐T therapies in MM and NHL, discuss the limitations with current CAR‐T therapy strategies and review emerging strategies for overcoming these limitations. [ABSTRACT FROM AUTHOR]

Reconstructing the initial conditions of the universe is a key problem in cosmology. Methods based on simulating the forward evolution of the universe have provided a way to infer initial conditions consistent with present-day observations. However, due to the high complexity of the inference problem, these methods either fail to sample a distribution of possible initial density fields or require significant approximations in the simulation model to be tractable, potentially leading to biased results. In this work, we propose the use of score-based generative models to sample realizations of the early universe given present-day observations. We infer the initial density field of full high-resolution dark matter N -body simulations from the present-day density field and verify the quality of produced samples compared to the ground truth based on summary statistics. The proposed method is capable of providing plausible realizations of the early universe density field from the initial conditions posterior distribution marginalized over cosmological parameters and can sample orders of magnitude faster than current state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Human mobility networks can reveal insights into resilience phenomena, such as population response to, impacts on, and recovery from crises. The majority of human mobility network resilience characterizations, however, focus mainly on macroscopic network properties; little is known about variation in measured resilience characteristics (i.e., the extent of impact and recovery duration) across macroscopic, substructure (motif), and microscopic mobility scales. To address this gap, in this study, we examine the human mobility network in eight parishes in Louisiana (USA) impacted by the 2021 Hurricane Ida. We constructed human mobility networks using location-based data and examined three sets of measures: (1) macroscopic measures, such as network density, giant component size, and modularity; (2) substructure measures, such as motif distribution; and (3) microscopic mobility measures, such as the radius of gyration and average travel distance. To determine the extent of impact and duration of recovery, for each measure, we established the baseline values and examined the fluctuation of measures during the perturbation caused by Hurricane Ida. The results reveal the variation of impact extent and recovery duration obtained from different sets of measures at different scales. Macroscopic measures, such as giant components, tend to recover more quickly than substructure and microscopic measures. In fact, microscopic measures tend to recover more slowly than measures in other scales. These findings suggest that resilience characteristics in human mobility networks are scale-variant, and thus, a single measure at a particular scale may not be representative of the perturbation impacts and recovery duration in the network as a whole. These results spotlight the need to use measures at different scales to properly characterize resilience in human mobility networks. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC) undergoing radical cystectomy (RC). Cisplatin, however, can induce renal toxicity. Furthermore, RC is an independent risk factor for renal injury, with decreases in estimated glomerular filtration rate (eGFR) of up to 6 mL/min/1.73 m2 reported at one year postoperatively. Our objective was to evaluate the effect of cisplatin-based NAC and RC on the renal function of patients undergoing both. METHODS: We analyzed a multicenter database of patients with MIBC, all of whom received cisplatin-based NAC prior to RC. eGFR values were collected at time points T1 (before NAC), T2 (after NAC but before RC), and T3 (one year post-RC). eGFR and proportion of patients with eGFR <60 ml/min/1.73m² (chronic kidney disease [CKD] stage ≥3) were compared between these time points. As all patients in this dataset had received NAC, we identified a retrospective cohort of patients from one institution who had undergone RC during the same time period without NAC for context. RESULTS: We identified 234 patients with available renal function data. From T1 to T3, there was a mean decline in eGFR of 17% (13 mL/min/1.73 m²) in the NAC cohort and an increase in proportion of patients with stage ≥3 CKD from 27% to 50%. The parallel cohort of patients who did not receive NAC was comprised of 236 patients. The mean baseline eGFR in this cohort was lower than in the NAC cohort (66 vs. 75 mL/min/1.73 m²). The mean eGFR decline in this non-NAC cohort from T1 to T3 was 6% (4 mL/min/1.73 m2), and the proportion of those with stage ≥3 CKD increased from 37% to 51%. CONCLUSIONS: Administration of NAC prior to RC was associated with a 17% decline in eGFR and a nearly doubled incidence of stage ≥3 CKD at one year after RC. Patients who underwent RC without NAC had a higher rate of stage ≥3 CKD at baseline but appeared to have less renal function loss at one year. [ABSTRACT FROM AUTHOR]

We evaluate the effectiveness of deep learning (DL) models for reconstructing the masses of galaxy clusters using X-ray photometry data from next-generation surveys. We establish these constraints using a catalogue of realistic mock eROSITA X-ray observations which use hydrodynamical simulations to model realistic cluster morphology, background emission, telescope response, and active galactic nucleus (AGN) sources. Using bolometric X-ray photon maps as input, DL models achieve a predictive mass scatter of |$\sigma _{\ln M_\mathrm{500c}} = 17.8~{{\ \rm per\ cent}}$|⁠ , a factor of two improvements on scalar observables such as richness N gal, 1D velocity dispersion σv,1D, and photon count N phot as well as a 32  per cent improvement upon idealized, volume-integrated measurements of the bolometric X-ray luminosity L X. We then show that extending this model to handle multichannel X-ray photon maps, separated in low, medium, and high energy bands, further reduces the mass scatter to 16.2  per cent. We also tested a multimodal DL model incorporating both dynamical and X-ray cluster probes and achieved marginal gains at a mass scatter of 15.9  per cent. Finally, we conduct a quantitative interpretability study of our DL models and find that they greatly down-weight the importance of pixels in the centres of clusters and at the location of AGN sources, validating previous claims of DL modelling improvements and suggesting practical and theoretical benefits for using DL in X-ray mass inference. [ABSTRACT FROM AUTHOR]

This article discusses the use of percentage of free prostate-specific antigen (%fPSA) as a biomarker for prostate cancer (PCa) risk. While %fPSA has been widely used in the diagnosis and management of PCa, the article argues that reporting risk estimates for unselected PCa based on %fPSA can be misleading and potentially harmful. The authors suggest that the focus should be on minimizing the diagnosis of low-risk PCa while maintaining sensitivity for higher-grade cancers. They recommend removing risk estimates for unselected PCa from laboratory reports and encourage other institutions to consider doing the same. [Extracted from the article]

Background. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has impacted healthcare services and outcomes. We aimed to investigate healthcare resource utilization and early health outcomes of infants born to mothers with perinatal SARS-CoV-2 infection. Methods. The study included all infants born alive between February 1, 2020, and April 30, 2021, in British Columbia. We used linked provincial population-based databases including data on COVID-19 testing, birth, and health information for up to one year from birth. Perinatal COVID-19 exposure for infants was defined being born to mothers with a positive test for SARS-CoV-2 infection during pregnancy or at delivery. Cases of COVID-19-exposed infants were matched with up to four non‐exposed infants by birth month, sex, birthplace, and gestational age in weeks. Outcomes included hospitalizations, emergency department visits, and in-/outpatient diagnoses. Outcomes were compared between groups using conditional logistic regression and linear mixed effects models including effect modification by maternal residence. Results. Among 52,711 live births, 484 infants had perinatal exposure to SARS-CoV-2, an incidence rate of 9.18 per 1000 live births. Exposed infants (54.6% male) had a mean gestational age of 38.5 weeks, and 99% were born in hospital. Proportions of infants requiring at least one hospitalization (8.1% vs. 5.1%) and at least one emergency department visit (16.9% vs. 12.9%) were higher among the exposed vs. unexposed infants, respectively. Among infants from the urban area, those with exposure were more likely to have respiratory infectious diseases (odds ratio: 1.74; 95% confidence intervals: 1.07, 2.84), compared with those without exposure. Interpretation. In our cohort, infants born to mothers with SARS-CoV-2 infection have increased healthcare demands in their early infancy, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Orthostatic hypotension (OH) is a well-recognized phenomenon occurring in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), and is associated with significant morbidity and mortality. A retrospective analysis of patients admitted for first ASCT between June 2012 and April 2014 found that 161/222 (73%) patients were diagnosed with OH during the course of ASCT, including 51 patients who were found to have OH on the day of first orthostatic vitals check. Excluding these 51 patients, 110/171 (64%) patients developed OH during the peri-transplant period, at a median of 7 days post ASCT (95% CI: 6.5–8.5). OH did not significantly impact length of hospitalization, progression free and overall survival. Multivariable analysis revealed four risk factors (i.e. ≥0.5% weight loss/day, white race, gabapentin, antihypertensives) and two protective factors (i.e. antihistamine, proton pump inhibitor) associated with the development of peri-transplant OH. [ABSTRACT FROM AUTHOR]

A recent consensus guideline recommends migrating the therapeutic drug monitoring practice for intravenous vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infection from the traditional trough-based approach to the Bayesian approach based on area under curve to improve clinical outcomes. To support the implementation of the new strategy for hospitals under Hospital Authority, Hong Kong, this study is being proposed to (1) estimate and validate a population pharmacokinetic model of intravenous vancomycin for local adults, (2) develop a web-based individual dose optimization application for clinical use, and (3) evaluate the performance of the application by comparing the treatment outcomes and clinical satisfaction against the traditional approach. 300 adult subjects prescribed with intravenous vancomycin and not on renal replacement therapy will be recruited for population pharmacokinetic model development and validation. Sex, age, body weight, serum creatinine level, intravenous vancomycin dosing records, serum vancomycin concentrations etc. will be collected from several electronic health record systems maintained by Hospital Authority. Parameter estimation will be performed using non-linear mixed-effect modeling techniques. The web-based individual dose optimization application is based on a previously reported application and is built using R and the package shiny. Data from another 50 subjects will be collected during the last three months of the study period and treated as informed by the developed application and compared against historical control for clinical outcomes. Since the study will incur extra blood-taking procedures from patients, informed consent is required. Other than that, recruited subjects should receive medical treatments as usual. Identifiable patient data will be available only to site investigators and clinicians in each hospital. The study protocol and informed consent forms have been approved by the Joint Chinese University of Hong Kong–New Territories East Cluster Clinical Research Ethics Committee (reference number: NTEC-2021-0215) and registered at the Chinese Clinical Trial Registry (registration number: ChiCTR2100048714). [ABSTRACT FROM AUTHOR]

We determine the exact value of the optimal symmetric rate point $(r, r)$ in the Dueck zero-error capacity region of the binary adder channel with complete feedback. We proved that the average zero-error capacity $r = h(1/2-\delta) \approx 0.78974$ , where $h(\cdot)$ is the binary entropy function and $\delta = 1/(2\log _{2}(2 + \sqrt {3}))$. Our motivation is a problem in quantitative group testing. Given a set of $n$ elements two of which are defective, the quantitative group testing problem asks for the identification of these two defectives through a series of tests. Each test gives the number of defectives contained in the tested subset, and the outcomes of previous tests are assumed known at the time of designing the current test. We establish that the minimum number of tests is asymptotic to $(\log _{2} n) / r$ as $n \to \infty $. [ABSTRACT FROM AUTHOR]

Background: There is evidence that food industry actors try to shape science on nutrition and physical activity. But they are also involved in influencing the principles of scientific integrity. Our research objective was to study the extent of that involvement, with a case study of ILSI as a key actor in that space. We conducted a qualitative document analysis, triangulating data from an existing scoping review, publicly available information, internal industry documents, and existing freedom of information requests.Results: Food companies have joined forces through ILSI to shape the development of scientific integrity principles. These activities started in 2007, in direct response to the growing criticism of the food industry's funding of research. ILSI first built a niche literature on COI in food science and nutrition at the individual and study levels. Because the literature was scarce on that topic, these publications were used and cited in ILSI's and others' further work on COI, scientific integrity, and PPP, beyond the fields of nutrition and food science. In the past few years, ILSI started to shape the very principles of scientific integrity then and to propose that government agencies, professional associations, non-for-profits, and others, adopt these principles. In the process, ILSI built a reputation in the scientific integrity space. ILSI's work on scientific integrity ignores the risks of accepting corporate funding and fails to provide guidelines to protect from these risks.Conclusions: The activities developed by ILSI on scientific integrity principles are part of a broader set of political practices of industry actors to influence public health policy, research, and practice. It is important to learn about and counter these practices as they risk shaping scientific standards to suit the industry's interests rather than public health ones. [ABSTRACT FROM AUTHOR]

We study methods for reconstructing Bayesian uncertainties on dynamical mass estimates of galaxy clusters using convolutional neural networks (CNNs). We discuss the statistical background of approximate Bayesian neural networks and demonstrate how variational inference techniques can be used to perform computationally tractable posterior estimation for a variety of deep neural architectures. We explore how various model designs and statistical assumptions impact prediction accuracy and uncertainty reconstruction in the context of cluster mass estimation. We measure the quality of our model posterior recovery using a mock cluster observation catalog derived from the MultiDark simulation and UniverseMachine catalog. We show that approximate Bayesian CNNs produce highly accurate dynamical cluster mass posteriors. These model posteriors are log-normal in cluster mass and recover 68% and 90% confidence intervals to within 1% of their measured value. We note how this rigorous modeling of dynamical mass posteriors is necessary for using cluster abundance measurements to constrain cosmological parameters. [ABSTRACT FROM AUTHOR]

Cold dark matter model predicts that the large-scale structure grows hierarchically. Small dark matter haloes form first. Then, they grow gradually via continuous merger and accretion. These haloes host the majority of baryonic matter in the Universe in the form of hot gas and cold stellar phase. Determining how baryons are partitioned into these phases requires detailed modelling of galaxy formation and their assembly history. It is speculated that formation time of the same mass haloes might be correlated with their baryonic content. To evaluate this hypothesis, we employ haloes of mass above |$10^{14}\, \mathrm{M}_{\odot }$| realized by TNG300 solution of the IllustrisTNG project. Formation time is not directly observable. Hence, we rely on the magnitude gap between the brightest and the fourth brightest halo galaxy member, which is shown that traces formation time of the host halo. We compute the conditional statistics of the stellar and gas content of haloes conditioned on their total mass and magnitude gap. We find a strong correlation between magnitude gap and gas mass, BCG stellar mass, and satellite galaxies stellar mass, but not the total stellar mass of halo. Conditioning on the magnitude gap can reduce the scatter about halo property–halo mass relation and has a significant impact on the conditional covariance. Reduction in the scatter can be as significant as 30 per cent, which implies more accurate halo mass prediction. Incorporating the magnitude gap has a potential to improve cosmological constraints using halo abundance and allows us to gain insight into the baryon evolution within these systems. [ABSTRACT FROM AUTHOR]

In this editorial, the recently published trial examining endoscopic balloon cryoablation after resection of non–muscle‐invasive bladder cancers is discussed. Several issues with the control group, design, and inclusion criteria that limit the application of these data to current urologic practice are identified. [ABSTRACT FROM AUTHOR]

Introduction: regional anesthesia is a safe alternative to general anesthesia. Despite benefits for perioperative morbidity and mortality, this technique is underutilized in low-resource settings. In response to an identified need, a regional anesthesia service was established at the University Teaching Hospital of Kigali (CHUK), Rwanda. This qualitative study investigates the factors influencing implementation of this service in a low-resource tertiary-level teaching hospital. Methods: following service establishment, we recruited 18 local staff at CHUK for in-depth interviews informed by the "Consolidated Framework for Implementation Research" (CFIR). Data were coded using an inductive approach to discover emergent themes. Results: four themes emerged during data analysis. Patient experience and outcomes: where equipment failure is frequent and medications unavailable, regional anesthesia offered clear advantages including avoidance of airway intervention, improved analgesia and recovery and cost-effective care. Professional satisfaction: morale among healthcare providers suffers when outcomes are poor. Participants were motivated to learn techniques that they believe improve patient care. Human and material shortages: clinical services are challenged by high workload and human resource shortages. Advocacy is required to solve procurement issues for regional anesthesia equipment. Local engagement for sustainability: participants emphasized the need for a locally run, sustainable service. This requires broad engagement through education of staff and long-term strategic planning to expand regional anesthesia in Rwanda. Conclusion: while the establishment of regional anesthesia in Rwanda is challenged by human and resource shortages, collaboration with local stakeholders in an academic institution is pivotal to sustainability. [ABSTRACT FROM AUTHOR]

The biopsy of the ulcer revealed positive CMV immunostaining, with negative immunostaining for Herpes simplex virus and fungus. It mainly causes gastrointestinal symptoms, with about 12.9% of patients presenting with esophageal disease.1 Unlike other infectious esophageal ulcers, CMV tends to cause one or more giant (>1 cm) ulcers that may be flat, ovoid, or diamond-shaped.2 AUTHOR CONTRIBUTIONS Delvise Fogwe, first author, wrote and edited the case report. Keywords: cytomegalovirus; esophagitis; immunocompromised; ulcer EN cytomegalovirus esophagitis immunocompromised ulcer 1 2 2 07/29/22 20220701 NES 220701 This report presents a classic case of CMV esophagitis, which may be puzzling to distinguish from other infectious esophageal lesions. [Extracted from the article]

Uterine leiomyosarcoma is a relatively rare malignancy with high mortality due to metastasis and chemoresistance. Leiomyosarcomas share similar morphological characteristics with leiomyomas which are considered to have the potential of transformation into leiomyosarcoma. Accumulated evidence suggests that microRNAs acting as regulators of gene expression at the posttranscriptional level play key roles in diverse biological processes including cellular transformation and tumorigenesis. We hypothesized that miR-200c, whose expression is altered in leiomyomas, equally plays a key role in pathogenesis of leiomyosarcoma. Using SK-LMS-1 leiomyosarcoma cell line as an in vitro model here, we found that the level of expression of miR-200c was significantly lower as compared to isolated leiomyoma smooth muscle cells. Overexpression (gain-of-function) of miR-200c in SK-LMS-1 through direct interaction with 3′-untranslated region of IKBKB, IL8, CDK2, and CCNE2, respectively, resulted in suppression of their expression as determined by quantitative polymerase chain reaction and Western blot analysis. Additionally, gain-of-function of miR-200c through inhibition of IKBKB expression resulted in decreased p65 transcriptional activity in IL8 promoter. Gain-of-function of miR-200c also increased SK-LMS-1 caspase 3/7 activity and inhibited their proliferation and migration. In summary, the results suggest that a progressive decline in miR-200c expression which alters transcriptional regulation of specific target genes that control nuclear factor-κB signaling pathway, inflammation, cell cycle, and migration, in part may promote development and progression of leiomyosarcomas, including their transformation from leiomyomas. [ABSTRACT FROM AUTHOR]

A new, simple and precise ex-situ optical imaging method is developed which allows indirect measurement of the partial pressure of oxygen (as ozone) within fuel cell components. Images of oxygen distribution are recorded with higher spatial (∼20 μm) and time (40 ms) resolutions. This approach is applied to assess oxygen concentration across the face of a pseudo polymer electrolyte fuel cell (PEFC), with a serpentine design flow field. We show that the amount of light produced is directly proportional to the partial pressure of ozone, in the same way as the local current density in a PEFC is proportional to the partial pressure of bimolecular oxygen. Hence the simulated system provides information relevant to a PEFC with the same geometry operating at the same stoichiometric ratio. This new approach allows direct imaging of flow under lands due to pressure gradients between the adjacent channels and non-laminar flow effects due to secondary flow around U -turns. These are major discoveries of fundamental importance in guiding materials development and in validating modelling studies. We find that contrary to many simulation papers, advection is an important mechanism in both the gas diffusion layer (more properly “reactant transport layer”) and the microporous layer. Models which do not include these effects may underestimate reactant transport to the catalyst layer. [ABSTRACT FROM AUTHOR]

A case study of a 64-year-old man presented to a rheumatology clinic with a 1-year history of migratory polyarthralgias. Topics the patient reported having pain, swelling, and redness in his left hip, which had been followed by pain and swelling in his right hip, resulting in limited ability to ambulate without a walker; and Pain in both knees had subsequently developed, with swelling and limited motion, which subsequently migrated to involve both shoulders.

Obstructive sleep apnea (OSA) affects millions of Americans and is estimated to be as prevalent as asthma and diabetes. Given the fact that obesity is a major risk factor for OSA, and given the current global rise in obesity, the prevalence of OSA will increase in the future. Individuals with sleep apnea are often unaware of their sleep disorder. It is usually first recognized as a problem by family members who witness the apneic episodes or is suspected by their primary care doctor because of the individual's risk factors and symptoms. The vast majority remain undiagnosed and untreated, despite the fact that this serious disorder can have significant consequences. Individuals with untreated OSA can stop breathing hundreds of times a night during their sleep. These apneic events can lead to fragmented sleep that is of poor quality, as the brain arouses briefly in order for the body to resume breathing. Untreated, sleep apnea can have dire health consequences and can increase the risk of hypertension, diabetes, heart disease, and heart failure. OSA management has also become important in a number of comorbid neurological conditions, including epilepsy, stroke, multiple sclerosis, and headache. Diagnosis typically involves use of screening questionnaires, physical exam, and an overnight polysomnography or a portable home study. Treatment options include changes in lifestyle, positive airway pressure, surgery, and dental appliances. [ABSTRACT FROM AUTHOR]

The basement membrane (BM) is a specialized form of extracellular matrix (ECM) underlying epithelia and endothelia and surrounding many types of mesenchymal cells. Nidogen, along with collagen IV and laminin, is a major component of BMs. Although certain ECM proteins such as laminin or reelin influence neuronal function via interactions with cell-surface receptors such as integrins, behavioral neurological impairments due to deficits of BM components have been recognized only recently. Here, alterations in neuronal network function underlying these behavioral changes are revealed. Using nidogen-1 knockout mice, with or without additional heterozygous nidogen-2 knockout ( NID1−/−/ NID2+/+ or NID1−/−/ NID2±), we demonstrate that nidogen is essential for normal neuronal network excitability and plasticity. In nidogen-1 knockouts, seizurelike behavior occurs, and epileptiform spiking was seen in hippocampal in vivo EEG recordings. In vitro, hippocampal field potential recordings revealed that lack of nidogen-1, while not causing conspicuous morphological changes, led to the appearance of spontaneous and evoked epileptiform activity, significant increase of the input/output ratio of synaptically evoked responses in CA1 and dentate gyrus, as well as of paired pulse accentuation, and loss of perforant-path long-term synaptic potentiation. Nidogen-1 is thus essential for normal network excitability and plasticity. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The article presents a study on the stimulation of vaginal repair through skeletal muscle-derived stem cells (MDSC) seeded on small intestinal submucosal (SIS) scaffolds with the use of rat model. It uses immunocytochemistry for cell differentiation, stem cell markers screening, and hysterectomy and partial vaginectomy of rats. It notes that MDSC/SIS implants stimulate vaginal tissue repair on the rats thus giving a hint of a promising approach for human vaginal repair.

Background: The skeletal neuromuscular junction is a useful model for elucidating mechanisms that regulate synaptogenesis. Developmentally important intercellular interactions at the neuromuscular junction are mediated by the synaptic portion of a basal lamina that completely ensheaths each muscle fiber. Basal laminas in general are composed of four main types of glycosylated proteins: laminins, collagens IV, heparan sulfate proteoglycans and nidogens (entactins). The portion of the muscle fiber basal lamina that passes between the motor nerve terminal and postsynaptic membrane has been shown to bear distinct isoforms of the first three of these. For laminins and collagens IV, the proteins are deposited by the muscle; a synaptic proteoglycan, z-agrin, is deposited by the nerve. In each case, the synaptic isoform plays key roles in organizing the neuromuscular junction. Here, we analyze the fourth family, composed of nidogen-1 and -2. Results: In adult muscle, nidogen-1 is present throughout muscle fiber basal lamina, while nidogen- 2 is concentrated at synapses. Nidogen-2 is initially present throughout muscle basal lamina, but is lost from extrasynaptic regions during the first three postnatal weeks. Neuromuscular junctions in mutant mice lacking nidogen-2 appear normal at birth, but become topologically abnormal as they mature. Synaptic laminins, collagens IV and heparan sulfate proteoglycans persist in the absence of nidogen-2, suggesting the phenotype is not secondary to a general defect in the integrity of synaptic basal lamina. Further genetic studies suggest that synaptic localization of each of the four families of synaptic basal lamina components is independent of the other three. Conclusion: All four core components of the basal lamina have synaptically enriched isoforms. Together, they form a highly specialized synaptic cleft material. Individually, they play distinct roles in the formation, maturation and maintenance of the neuromuscular junction. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is a breast cancer subtype which is particularly aggressive and invasive. The treatment of TNBC has been limited due to the lack of well-defined molecular targets. Exosomes are nano-sized extracellular vesicles that are released from virtually all cell types into the extracellular space. Due to their endocytic origin, exosomes carry valuable information from their cells of origin. Exosomes were first thought to serve as "garbage disposals" that eliminate unwanted cellular components. Later, they were found to be involved in the pathology of many diseases including cancer. Despite their established roles in multiple diseases, only a small number of studies have focused on the role of exosomes in TNBC. In this review, we outline the roles of exosomes in cancer progression, metastasis and drug resistance in this breast cancer subtype. We then further illustrate the potential roles of exosomes as diagnostic tools, therapeutic targets and delivery systems. [ABSTRACT FROM AUTHOR]

Current guidelines recommend surveillance in metastatic non-seminomatous germ cell tumour patients treated with first-line-chemotherapy and a complete clinical response (normalisation of serum tumour markers and residual masses <1 cm). However, this recommendation is based on a series including patients with good prognosis according to International Germ Cell Cancer Cooperative Group prognostic group (IGCCCG-PG). The aim of this study was to analyse the proportion of residual teratoma and survival among patients with intermediate/poor IGCCCG-PG and a complete clinical response after first-line-chemotherapy. This is a retrospective study of men with intermediate/poor IGCCCG-PG, who had a complete clinical response after first-line chemotherapy. Patients were either followed by surveillance or treated with post-chemotherapy retroperitoneal lymph node dissection (pcRPLND). Between 2009 and 2018, 143 men with intermediate (n = 83) or poor (n = 60) IGCCCG-PG were treated at 11 international centres. Among 33 patients treated with pcRPLND, the specimen showed teratoma and viable cancer in 16 (48%) and 4 (12%). During a median a 7-year follow-up, 20/110 (18%) patients managed with surveillance relapsed, of whom seven (6%) had a retroperitoneal-only relapse versus 2/33 patients managed with pcRPLND relapsed. No difference was observed regarding overall survival (OS) among men treated with pcRPLND or surveillance (5-year OS, 93% and 89%, p -value = 0.35). The median time-to-recurrence among men on surveillance was 1.3 years (range: 0.3–9.1), and the most common sites of relapses included retroperitoneum (11%), chest (5%), and bones (4%). While most men with intermediate/poor IGCCCG-PG harbour teratoma/cancer in the retroperitoneum despite a complete response to first-line-chemotherapy, only 6% managed with surveillance relapsed in the retroperitoneum. There was no significant difference in OS between the two groups. • >95% long-term survival if intermediate/poor risk metastatic NSGCT and remission. • Most men with intermediate/poor IGCCCG have residual cancer in the retroperitoneum. • 6% of those men managed with surveillance relapse in the retroperitoneum only. [ABSTRACT FROM AUTHOR]

B cell lymphoma and multiple myeloma (MM) are the most common hematological malignancies which benefit from therapeutic monoclonal antibodies (mAbs)-based immunotherapies. Despite significant improvement on patient outcome following the use of novel therapies for the past decades, curative treatment is unavailable for the majority of patients. For example, the 5-year survival of MM is currently less than 50%. In the 1980s, interferon-a was used as monotherapy in newly diagnosed or previously treated MM with an overall response rate of 15-20%. Noticeably, a small subset of patients who responded to long-term interferon-a further achieved sustained complete remission. Since 1990, interferon-a-containing regimens have been used as a central maintenance strategy for patients with MM. However, the systemic administration of interferon-a was ultimately limited by its pronounced toxicity. To address this, the selective mAb-mediated delivery of interferon-a has been developed to enhance specific killing of MM and B-cell malignant cells. As such, targeted interferon-a therapy may improve therapeutic window and sustain responses, while further overcoming suppressive microenvironment. This review aims to reinforce the role of interferon-a by consolidating our current understanding of targeting interferon-a with tumor-specific mAbs for B cell lymphoma and myeloma. [ABSTRACT FROM AUTHOR]

We sequenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from nasal and throat swabs of a hospitalized patient during the fifth wave of coronavirus disease 2019 (COVID-19) pandemic in Hong Kong. Genomic characteristics and viral load dynamics of an Omicron BA.2.2 variant before and after molnupiravir treatment were presented. • In vivo impact of molnupiravir on a SARS-CoV-2 Omicron BA.2.2 variant was studied. • Rate of viral load clearance of the treated patient was similar to the untreated. • Quasispecies was observed on day 16 but not on day 10 or earlier. • Nucleotide changes were primarily found in first half of SARS-CoV-2 genome (75%). • 8 extra SNVs found on day 16, C > U transitions were the majority (75%). [ABSTRACT FROM AUTHOR]

Rapid repeat pregnancy (RRP) often occurs in teenage and young mothers. Mothers with a history of RRP are more likely to experience high stress increasing their risk of child maltreatment. Despite these challenges, some mothers can continue to cope adaptively. Social support may play a role in empowering these mothers to overcome the childbearing difficulties. Although the protective effects of social support are well recognized, there has been little evidence on the relative importance of sources of support. For example, whether support from family and friends is equally important in relieving parenting stress remains unanswered. RRP, a social phenomenon encompassing various adverse living and parenting issues, provides an ideal research context to investigate the role of family and friends in preventing child maltreatment. This study examined whether family cohesion and friends' support moderated the association between RRP and child maltreatment in young mothers. We recruited 392 Chinese teenage and young mothers from a population-based integrated young mothers supporting program in Hong Kong. Questionnaires on pregnancy history, family cohesion, social support, and risk of child maltreatment were administered. Moderation analysis was conducted to examine the effect of RRP on child maltreatment as a function of family cohesion or friend support. Results showed that RRP was associated with a higher risk of child neglect (adjusted odds ratio [aOR] = 1.72, p <.05) and physical maltreatment (aOR = 1.91, p <.01), and that family cohesion was more important than friend support in mitigating the risk of child maltreatment for mothers with a history of RRP. Our findings suggest that interventions for young mothers, particularly those with a history of RRP, should be family-based so the whole family can be empowered to tackle the childrearing burden. [ABSTRACT FROM AUTHOR]

There is inconsistent evidence on the association between prenatal substance exposure and child behavioral problems. Children affected by maternal substance misuse are vulnerable to physical abuse and neglect. Few studies have examined factors contributing to internalizing and externalizing problems in these children. This study, with a focus on children with prenatal substance exposure, investigated whether family characteristics (the duration of maternal substance misuse postpartum or the existence of a sibling) moderated the association between adverse exposure (physical abuse or neglect) and behavior (internalizing or externalizing problems). We recruited 54 Hong Kong Chinese mothers with registered records of substance misuse during pregnancy and their children (2-9 years). Mothers completed questionnaires on drug use patterns during pregnancy and postpartum, abusive and neglectful parenting behaviors in the preceding year, and children's current behavioral problems. Moderated regression analyses tested whether abusive and neglectful parenting behavior interacted with family characteristics to affect child behavioral problems. The existence of a sibling moderated the relationship between neglect experience and internalizing problems, with a positive relationship observed only among single children (adjusted B [95% confidence interval] = 3.70 [0.98, 6.41], p =.012). The duration of maternal substance misuse postpartum moderated the relationship between physical abuse experience and externalizing problems, with a positive relationship observed only among children of mothers abusing substances beyond the child's infancy period (adjusted B [95% confidence interval] = 6.86 [2.34, 11.38], p =.008). The results show that the impact of physical abuse and neglect experiences depend on the type of behavior assessed and family and child characteristics. Positive sibling relationship and early detoxification in the mother can foster healthy behavioral development for children exposed prenatally to maternal substance misuse. [ABSTRACT FROM AUTHOR]

Abstract: Impaired glutamatergic activity and synaptic dysfunction contributing to excitotoxicity and neuronal degeneration has been observed in the diabetic retina. Here we analyzed the expression changes and trafficking abnormalities of the AMPA glutamate receptor 2 subunit (GluR2) and its regulators protein kinase Cα (PKCα) and PKC-interacting protein 1 (PICK1) in the rat retina during the early phases of streptozotocin-(STZ-) induced diabetes. Diabetes was induced in Long Evans rats by injection of STZ. Two and six weeks after induction of diabetes, immunohistochemistry and in situ hybridization were performed on retinal paraffin sections to investigate the expression and localization of GluR2 and its regulators PKCα and PICK1. The cellular distribution and trafficking of these proteins in retinae were also investigated by subcellular fractionation and western blotting. While no significant changes were observed for GluR2 transcripts, we observed a strong increase in GluR2 immunoreactivity, predominantly in the ganglion cell layer (GCL) and the inner plexiform layer (IPL), as early as two weeks of diabetes. GluR2/3 immunoreactivity was further increased from the GCL to OPL after 6 weeks of diabetes. Increased expression of a phosphorylated non-synaptic population of GluR2 was detected in the GCL, the IPL and in distinct photoreceptor cells within the outer nuclear layer (ONL) of diabetic animals. Further, the PICK1 retinal distribution was unchanged two and six weeks after onset of diabetes and in both control and diabetic rat retinae the PKCα immunoreactivity remained the same. However, phosphorylated PKCα immunoreactivity was increased in diabetic retina as compared to control and peaked after 6 weeks of diabetes. Activated PKCα was almost completely lost in all membrane fractions and primarily recovered in the cytosolic fraction. These results are consistent with PKCα being re-localized in the diabetic retina. The observations indicate a diabetes-dependent increase in the activation of PKCα and a disturbed GluR2 regulation by altered internalization and recycling. [Copyright &y& Elsevier]

Abstract: Voltage-gated calcium channels (VGCCs) are key regulators of neuronal excitability and important factors in epileptogenesis and neurodegeneration. Recent findings suggest a novel, important proictogenic and proneuroapoptotic role of the Cav2.3 E/R-type VGCCs in convulsive generalized tonic–clonic and hippocampal seizures. Though Cav2.3 is also expressed in key structures of the thalamocortical circuitry, their functional relevance in non-convulsive absence seizure activity remains unknown. To this end, we investigated absence specific spike–wave discharge (SWD) susceptibility in control and Cav2.3-deficient mice by systemic administration of γ-hydroxybutyrolactone (GBL, 70 mg/kg i.p.), followed by electrocorticographic radiotelemetric recordings, behavioral analysis and histomorphological characterization. Based on motoric studies, SWD and power-spectrum density (PSD) analysis, our results demonstrate that Cav2.3−/− mice exhibit increased absence seizure susceptibility and altered absence seizure architecture compared to control animals. This study provides evidence for the first time that Cav2.3 E/R-type Ca2+ channels are important in modulating thalamocortical hyperoscillation exerting anti-epileptogenic effects in non-convulsive absence seizures. [Copyright &y& Elsevier]

Objective: Serotonin reuptake inhibitor (SRI) medications are effective in the treatment of both major depressive disorder and obsessive-compulsive disorder (OCD), but it is unknown whether the neural substrates of treatment response for the two disorders are the same or different. The authors sought to identify pretreatment cerebral glucose metabolic markers of responsiveness to SRI treatment in patients with OCD versus major depressive disorder and to determine whether the pretreatment patterns associated with improvement of OCD symptoms were the same as or different from those associated with improvement of major depressive disorder symptoms. Method: [[sup 18]F]Fluorodeoxyglucose positron emission tomography was used to measure cerebral glucose metabolism in 27 patients with OCD alone, 27 with major depressive disorder alone, and 17 with concurrent OCD and major depressive disorder, who were all then treated with 30-60 mg/day of paroxetine for 8-12 weeks. Correlations were calculated between pretreatment regional metabolism and pre- to post-treatment changes in the severity of OCD symptoms, depressive symptoms, and overall functioning. Results: While improvement of OCD symptoms was significantly correlated with higher pretreatment glucose metabolism in the right caudate nucleus (partial r=-0.53), improvement of major depressire disorder symptoms was significantly correlated with lower pretreatment metabolism in the amygdala (partial r=0.71) and thalamus (partial r=0.34) and with higher pretreatment metabolism in the medial prefrontal cortex and rostral anterior cingulate gyrus (Talairach coordinates: x=0, y=62, z=10) (z=2.91). Conclusions: These findings suggest that, although both OCD and major depressive disorder respond to SRIs, the two syndromes have different neurobiological substrates for response. Elevated activity in the right caudate may be a marker of responsiveness to antiobsessional treatment, while lower right amygdala activity and higher... [ABSTRACT FROM AUTHOR]

Background: Depression prevention among adolescents is crucial for reducing the global disease burden. Internet-based depression prevention approaches are found to be effective but they were mostly evaluated in a Western context. Grasping the Opportunity is a Chinese Internet intervention, which was translated and modified from CATCH-IT developed in the West. We aimed to evaluate the effectiveness of Grasp the Opportunity in reducing depressive symptoms in Chinese adolescents.Methods: In this randomized controlled trial, Chinese adolescents aged 13 to 17 years with mild-to-moderate depressive symptoms were recruited from three secondary schools in Hong Kong. The participants (n = 257) were randomly assigned to receive either intervention or attention control. The primary outcome was the improvement in depressive symptoms according to the revised Center for Epidemiologic Studies Depression Scale (CESD-R) at the 12-month follow-up. Analyses were performed using intention to treat (ITT).Results: The participants were randomly assigned to receive the intervention (n = 130) or attention control (n = 127). Follow-up data were obtained from 250 (97%) participants. Only 26 (10%) participants completed the intervention. Compared to the attention control, Grasp the Opportunity led to reductions in depressive symptoms at the 12-month follow-up with a medium effect size using ITT analysis (mean difference 2.6, 95% CI 0.59-5.55, effect size d = 0.36).Conclusions: Grasp the Opportunity is effective in reducing depressive symptoms in Chinese adolescents over a long follow-up period. Poor completion rate is the major challenge in the study. [ABSTRACT FROM AUTHOR]

Skin punch biopsy demonstrated mixed neutrophilic and mononuclear cell inflammation with hemorrhage and necrosis; Periodic acid-Schiff-diastase and Gram stain were negative for microorganisms. Graph A 72-year-old woman with a medical history of segmental colitis associated with diverticulosis (SCAD) on balsalazide and recent appendiceal orifice sessile serrated adenoma ( B a b ) requiring laparoscopic appendectomy and partial cecectomy presented to clinic with a tender erythematous skin lesion with wet suppurative ulcers, irregular borders, and cribriform purpuric overhanging borders in the subumbilical and left abdominal regions ( B b b ). [Extracted from the article]

Background: This study aims to assess evidence for any socioeconomic gradients in childhood obesity and hypertension in a population-representative sample in Hong Kong, China. Methods: The data of a stratified random sampled growth survey collected in 2005–2006 was matched with a population by-census. Obesity was defined using the International Obesity Task Force standard and hypertension was defined using the Hong Kong norm table. Family socioeconomic status (SES) was measured by maternal education level. Neighbourhood SES was measured by median household income of the neighbourhood. Multilevel Poisson regression models with robust standard error were used to test the association. Body mass indices of children’s parents were included as potential confounders. Intra-school/neighbourhood correlations were adjusted using random factors. Results: Totally 14842 children (age 6–19 years) included in the analysis, in which 16.6% of them were overweight or obese. Children whose mother only completed secondary school or below had higher risk of childhood obesity (RR 1.41, 95% CI 1.13–1.76, p = 0.003) and hypertension (RR 1.18, 95% CI 1.01–1.36, p = 0.03). Meanwhile, children in the lowest neighbourhood SES group had higher risk of childhood underweight (RR 1.61, 95% CI 1.04–2.49, p = 0.03), overweight (RR 1.35, 95% CI 1.05–1.72, p = 0.02), and obesity (RR 2.07, 95% CI 1.11–3.88, p = 0.02). Conclusions: Socioeconomic gradient in childhood obesity and hypertension existed in Hong Kong, one of the most developed cities in China. These results have implications for policymakers and public health experts and highlight the need to monitor trends in other parts of China. [ABSTRACT FROM AUTHOR]

Concise total syntheses of (±)-7-hydroxy debromo agelastatin A (AglA), (±)-AglA, and 11-nitro AglA are presented based on an identified pseudo-symmetry element. This synthetic strategy was developed based on a desire to improve solubility of this potent anticancer agent while also developing a synthetic strategy that would enable late-stage variation of the pyrrole moiety. A stability study of pyrrole-derived carbinolamines revealed critical substituent effects impacting the equilibrium between the cyclic carbinolamine and keto pyrrole forms. 7-Hydroxy AglA existed primarily in the ketopyrrole form however the des-bromo variant existed primarily in the cyclic carbinolamine form. Cytotoxicity assays revealed activity for a 13-nitro AglA derivative (∼14–63 μM) for breast cancer cells (MDA-MB-231 and MCF7) and a glioblastoma cell line (U87) while for 7-hydroxy des-bromo AglA, measurable activity was only observed against the glioblastoma cell line. [Display omitted] [ABSTRACT FROM AUTHOR]

Extracellular matrix (ECM) proteins are thought to subserve structural functions as, for example, tissue barriers as well as guidance structures during cell growth, differentiation and tissue repair. Deletion of basement membrane (BM) components results in malformations of different organs, including the brain. Recent data, however, suggest that interference with cellular membrane-associated proteins interacting with ECM can alter neuronal excitability and synaptic plasticity without obvious underlying structural damage. This does not only apply to classical ECM proteins such as laminin, reelin and tenascin, but also to molecules of a rather specialized ECM, the BM. Here, nidogen (also termed entactin) appears to subserve a function in neuronal plasticity. Nidogen ablation leads to epileptic activity in vivo and the appearance of spontaneous epileptiform activity in vitro. This raises the intriguing question whether the BM protein nidogen may directly influence neuronal function in the CNS, opening the possibility of modulatory mechanisms of synaptic plasticity and excitability reaching beyond classical processes confined to cellular interactions. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Presents information on a study which described the electronics for a high-performance positron emission mammography camera. Components of the camera; System architecture; Individual circuit boards of the camera; Performance measurements of the electronics; Conclusions.