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Background and purpose: Minimally invasive surgery for ICH has shown a significantly improved functional outcome for selected ICH patients. This study aimed to evaluate the factors influencing the outcome of supratentorial ICH patients treated with stereotactic computed tomographic (CT) guided recombinant tissue plasminogen activator (rt-PA). Methods: We retrospectively evaluated data from 80 consecutive supratentorial ICH patients between December 2017 and July 2020, analyzing their 180-day outcomes, and identifying clinical, radiological factors for good prognosis within 180 days. Results: The mean age was 55.6 years (SD 11.4). The median preoperative Glasgow Coma Scale (GCS) score was 9 (interquartile range - IQR 6–12). The mean final ICH volume was 26.5 ml (SD 27.5), with ICH volume reduction by an average of 66.7 %. Six months after the procedure, 40 patients (50 %) had favorable outcomes (modified Rankin Scale [mRS]) score 0–3). In multivariate analysis, age (odds ratio [OR] = 0.939, 95 % confidence interval (CI) = 0.894 – 0.986; p = 0.012), the GCS score before operation (OR = 1.525, 95 % CI = 1.008 – 2.309; p = 0.046), the initial midline shift (OR = 0.808, 95 % CI = 0.661 – 0.988; p = 0.038), and the residual volume hematoma (OR = 0.949, 95 % CI = 0.908 – 0.992, p = 0.020) were the significant predictors of a favorable 180-day outcome. Receiver operating characteristic curve analysis confirmed that the best cut-off point for predicting the good functional 180-day outcome was a GCS score of 9 before the procedure [area under the curve: 0.721, 95 % CI = 0.608 – 0.833, p = 0.001]. Conclusion: CT-guided thrombolysis and aspiration can be safe and effective in reducing ICH volume. A preoperation GCS score above or equal to 9 and younger age were associated with improved long-term outcomes in patients with supratentorial ICH.

Objective: This study aimed to assess the impact of preoperative chronic kidney disease (CKD) on the oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who underwent standard radical nephroureterectomy (RNU). Methods: A total of 1172 UTUC patients who received RNU at a single center in Taiwan between February 2005 and August 2019 were included. The patients were categorized into two groups based on their preoperative CKD stage: CKD stage ≤3 (811 patients) and CKD stage >3 (361 patients). The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) formula. The study investigated the oncological outcomes, including intravesical recurrence, non-urothelial recurrence, and cancer-specific mortality, stratified by preoperative CKD status. Results: The main findings indicated that UTUC patients with CKD stage >3 in Taiwan exhibited a higher proportion of females (p 3 and CKD stage ≤3 groups. The study also demonstrated that patients with concurrent bladder cancer and variant histology had higher rates of intravesical recurrence, non-urothelial recurrence, and cancer-specific mortality. The CKD stage >3 group exhibited lower rates of intravesical recurrence (p = 0.0014), higher rates of non-urothelial recurrence (p 3 exhibit distinct characteristics compared to the general population with urothelial carcinoma. They are associated with a non-smoking status, a higher proportion of females, and less aggressive pathological features. Additionally, CKD stage >3 can serve as a clinical indicator for intravesical and non-urothelial recurrence. Further investigation into molecular aspects and treatment modifications for these patients is warranted.

Objectives: To determine the associated pathogen during the 2023 conjunctivitis outbreak in Vietnam Methods: RNA-sequencing was used to identify pathogens before and during the outbreak. Results: 24 patients with infectious conjunctivitis between March and October 2023 from Hai Yen Vision Institute in Vietnam were swabbed. Coxsackievirus A24v was the most common pathogen identified. Phylogenetic analysis of these strains demonstrates similarities to the Coxsackievirus identified in the 2022 India outbreak. Human adenovirus D was also circulating. Ocular findings of tearing, purulence, and itching were common in this outbreak. Conclusions: Multiple viruses can co-circulate during conjunctivitis outbreaks. Hemorrhagic conjunctivitis, commonly associated with coxsackievirus conjunctivitis, was not a common clinical sign in this outbreak. Repeat genetic surveillance, with the notable inclusion of RNA virus detection strategies, is important for outbreak detection.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

The optimal treatment of acute chemical pneumonitis remains controversial. Here we report a healthy man with severe chemical pneumonitis caused by accidental inhalation of vanadium pentoxide. He presented with acute respiratory distress and received aggressive steroid therapy on arrival. Pulmonary symptoms and chest X-ray were improved dramatically the next day. The beneficial effect of steroid therapy for such a critical patient may outweigh the infection risk following inhalation of relative sterile material. We suggest early and aggressive steroid therapy may help shorten the disease course.

The initial contagiousness of a communicable disease within a given population is quantified by the basic reproduction number, R0. This number depends on both pathogen and population properties. On the basis of compartmental models that reproduce Coronavirus Disease 2019 (COVID-19) surveillance data, we used Bayesian inference and the next-generation matrix approach to estimate region-specific R0 values for 280 of 384 metropolitan statistical areas (MSAs) in the United States (US), which account for 95% of the US population living in urban areas and 82% of the total population. We focused on MSA populations after finding that these populations were more uniformly impacted by COVID-19 than state populations. Our maximum a posteriori (MAP) estimates for R0 range from 1.9 to 7.7 and quantify the relative susceptibilities of regional populations to spread of respiratory diseases. One-Sentence Summary: Initial contagiousness of Coronavirus Disease 2019 varied over a 4-fold range across urban areas of the United States.

Summary: Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Summary: Background: Diarrhoeal disease is a leading cause of childhood illness and death globally, and Shigella is a major aetiological contributor for which a vaccine might soon be available. The primary objective of this study was to model the spatiotemporal variation in paediatric Shigella infection and map its predicted prevalence across low-income and middle-income countries (LMICs). Methods: Individual participant data for Shigella positivity in stool samples were sourced from multiple LMIC-based studies of children aged 59 months or younger. Covariates included household-level and participant-level factors ascertained by study investigators and environmental and hydrometeorological variables extracted from various data products at georeferenced child locations. Multivariate models were fitted and prevalence predictions obtained by syndrome and age stratum. Findings: 20 studies from 23 countries (including locations in Central America and South America, sub-Saharan Africa, and south and southeast Asia) contributed 66 563 sample results. Age, symptom status, and study design contributed most to model performance followed by temperature, wind speed, relative humidity, and soil moisture. Probability of Shigella infection exceeded 20% when both precipitation and soil moisture were above average and had a 43% peak in uncomplicated diarrhoea cases at 33°C temperatures, above which it decreased. Compared with unimproved sanitation, improved sanitation decreased the odds of Shigella infection by 19% (odds ratio [OR]=0·81 [95% CI 0·76–0·86]) and open defecation decreased them by 18% (OR=0·82 [0·76–0·88]). Interpretation: The distribution of Shigella is more sensitive to climatological factors, such as temperature, than previously recognised. Conditions in much of sub-Saharan Africa are particularly propitious for Shigella transmission, although hotspots also occur in South America and Central America, the Ganges–Brahmaputra Delta, and the island of New Guinea. These findings can inform prioritisation of populations for future vaccine trials and campaigns. Funding: NASA, National Institutes of Health–The National Institute of Allergy and Infectious Diseases, and Bill & Melinda Gates Foundation.

With the concepts of Industry 4.0 and smart manufacturing gaining popularity, there is a growing notion that conventional manufacturing will witness a transition toward a new paradigm, targeting innovation, automation, better response to customer needs, and intelligent systems. Within this context, this review focuses on the concept of cyber–physical production system (CPPS) and presents a holistic perspective on the role of the CPPS in three key and essential drivers of this transformation: data-driven manufacturing, decentralized manufacturing, and integrated blockchains for data security. The paper aims to connect these three aspects of smart manufacturing and proposes that through the application of data-driven modeling, CPPS will aid in transforming manufacturing to become more intuitive and automated. In turn, automated manufacturing will pave the way for the decentralization of manufacturing. Layering blockchain technologies on top of CPPS will ensure the reliability and security of data sharing and integration across decentralized systems. Each of these claims is supported by relevant case studies recently published in the literature and from the industry; a brief on existing challenges and the way forward is also provided.

This study examines the effect of people's attitudes toward physical activity on their bus use intentions in rural areas in Japan. We utilized the theory of planned behavior and designated three variables—attitude toward bus use, subjective norms, and perceived behavioral control—as mediators for the hypothesized effect. Analysis results showed that attitude toward physical activity had a significant effect on bus use intention. For transport policy, this implies that improving attitudes toward physical activity can increase bus use and reduce physical inactivity, partly caused by car dependence. Results from a multiple-group analysis, for the hypothesized model, revealed that this finding is particularly valid for young people, car drivers, and people living within five minutes of the nearest bus stop. Finally, the effect of attitude toward physical activity on bus use intention is higher with the presence of mediators; these mediators help to increase the model's predictability for the variance of bus use intention from 8.6% to 64.4%.

Introduction: Streptococcus suis is a zoonotic pathogen found in swine that may cause systemic infection in humans. S. suis is endemic in Southeast Asia and is the leading cause of adult meningitis in Vietnam. Given Vietnam's increasing centralization of the swine industry, we sought to estimate the prevalence of S. suis on large swine farms in Northern Vietnam. Methods: A cross-sectional, one-health-oriented, surveillance study for S. suis was conducted between October 2019–March 2020. Swine oral, swine worker nasal, and bioaerosol samples were collected from four large-scale swine farms (>500 swine) in three provinces in Northern Vietnam: Lao Cai, Bac Giang, and Quang Ninh. Samples were evaluated for presence of S. suis growth on blood agar plates and confirmed with conventional polymerase chain reaction. Results: The authors found that 4/174 (2.3%, 95% CI: 0.6–5.8%) of swine oral samples and 1/58 (1.7%, 95% CI: 0–9.2%) bioaerosol samples were positive for S. suis by bacterial culture and conventional PCR. S. suis was not detected in any swine worker nasal wash samples. There was no significant relationship between sampling location and month of sample collection with results of swine oral or bioaerosol samples. Conclusion: Compared to previous reports from slaughterhouses in Vietnam, the lower than expected prevalence of S. suis, supports the notion that that recent efforts to centralize Vietnam's pork industry through establishment of large-scale farms with better biosecurity may have been effective in limiting S. suis prevalence on these large farms.

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HTT gene that codes for an elongated polyglutamine tract in the huntingtin (HTT) protein. HTT is subject to multiple post-translational modifications (PTMs) that regulate its cellular function. Mutating specific PTM sites within mutant HTT (mHTT) in HD mouse models can modulate disease phenotypes, highlighting the key role of HTT PTMs in the pathogenesis of HD. These findings have led to increased interest in developing small molecules to modulate HTT PTMs in order to decrease mHTT toxicity. However, the therapeutic efficacy of pharmacological modulation of HTT PTMs in preclinical HD models remains largely unknown. HTT is palmitoylated at cysteine 214 by the huntingtin-interacting protein 14 (HIP14 or ZDHHC17) and 14-like (HIP14L or ZDHHC13) acyltransferases. Here, we assessed if HTT palmitoylation should be regarded as a therapeutic target to treat HD by (1) investigating palmitoylation dysregulation in rodent and human HD model systems, (2) measuring the impact of mHTT-lowering therapy on brain palmitoylation, and (3) evaluating if HTT palmitoylation can be pharmacologically modulated. We show that palmitoylation of mHTT and some HIP14/HIP14L-substrates is decreased early in multiple HD mouse models, and that mHTT palmitoylation decreases further with aging. Lowering mHTT in the brain of YAC128 mice is not sufficient to rescue aberrant palmitoylation. However, we demonstrate that mHTT palmitoylation can be normalized in COS-7 cells, in YAC128 cortico-striatal primary neurons and HD patient-derived lymphoblasts using an acyl-protein thioesterase (APT) inhibitor. Moreover, we show that modulating palmitoylation reduces mHTT aggregation and mHTT-induced cytotoxicity in COS-7 cells and YAC128 neurons.

Transgene-free induced pluripotent stem cells (iPSCs) are valuable for both basic research and potential clinical applications. We previously reported that a replication-defective and persistent Sendai virus (SeVdp) vector harboring four reprogramming factors (SeVdp-iPS) can efficiently induce generation of transgene-free iPSCs. This vector can express all four factors stably and simultaneously without chromosomal integration and can be eliminated completely from reprogrammed cells by suppressing vector-derived RNA-dependent RNA polymerase. Here, we describe an improved SeVdp-iPS vector (SeVdp(KOSM)302L) that is automatically erased in response to microRNA-302 (miR-302), uniquely expressed in pluripotent stem cells (PSCs). Gene expression and genome replication of the SeVdp-302L vector, which contains miRNA-302a target sequences at the 3′ untranslated region of L mRNA, are strongly suppressed in PSCs. Consequently, SeVdp(KOSM)302L induces expression of reprogramming factors in somatic cells, while it is automatically erased from cells successfully reprogrammed to express miR-302. As this vector can reprogram somatic cells into transgene-free iPSCs without the aid of exogenous short interfering RNA (siRNA), the results we present here demonstrate that this vector may become an invaluable tool for the generation of human iPSCs for future clinical applications.

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is accompanied by morphological, functional, and metabolic alterations before acquisition of full pluripotency. Although the genome-wide effects of the reprogramming factors on gene expression are well documented, precise mechanisms by which gene expression changes evoke phenotypic responses remain to be determined. We used a Sendai virus-based system that permits reprogramming to progress in a strictly KLF4-dependent manner to screen for KLF4 target genes that are critical for the progression of reprogramming. The screening identified Tcl1 as a critical target gene that directs the metabolic shift from oxidative phosphorylation to glycolysis. KLF4-induced TCL1 employs a two-pronged mechanism, whereby TCL1 activates AKT to enhance glycolysis and counteracts PnPase to diminish oxidative phosphorylation. These regulatory mechanisms described here highlight a central role for a reprogramming factor in orchestrating the metabolic shift toward the acquisition of pluripotency during iPSC generation.

Rickettsia felis is an emerging zoonosis, causing flea-borne spotted fever (FBSF). Serological diagnosis is typically confounded by cross-reactivity with typhus group rickettsiae and prior to the development of specific serological methods, cases of FBSF in Australia were misdiagnosed. Patient sera tested between August 2010 and December 2013 and known to be seropositive to R. typhi by immunofluorescence antibody testing (IFAT) were subsequently retested against R. felis using an R. felis-specific IFAT. Sera of 49 patients were of a sufficient quality to be included in re-analysis. A classification of FBSF and murine typhus (MT) was attributed to fourteen and seven patients respectively, based on a minimum four-fold higher antibody titre to R. felis than to R. typhi and vice versa. Twenty-eight patients were classified as indeterminate for either R. felis or R. typhi (antibody titres within two-fold of one another). Historically, it is likely that Australian patients clinically ill with FBSF were misdiagnosed. It is important that medical practitioners consider FBSF as part of their differential diagnoses, and obtain relevant history with regard to patient's exposure to domestic pets and their fleas. Australian microbiology diagnostic laboratories should include serological testing for R. felis as part of the diagnostic panel for febrile diseases. Veterinarians are encouraged to increase their awareness of this emerging zoonosis and advocate flea control in pets.

Summary: Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters and enhancers of activity-regulated genes. Exactly how histone acetylation modulates transcription of these genes has remained unknown. We used single-cell in situ transcriptional analysis to show that Fos and Npas4 are transcribed in stochastic bursts in mouse neurons and that membrane depolarization increases mRNA expression by increasing burst frequency. We then expressed dCas9-p300 or dCas9-HDAC8 fusion proteins to mimic or block activity-induced histone acetylation locally at enhancers. Adding histone acetylation increased Fos transcription by prolonging burst duration and resulted in higher Fos protein levels and an elevation of resting membrane potential. Inhibiting histone acetylation reduced Fos transcription by reducing burst frequency and impaired experience-dependent Fos protein induction in the hippocampus in vivo. Thus, activity-inducible histone acetylation tunes the transcriptional dynamics of experience-regulated genes to affect selective changes in neuronal gene expression and cellular function. : Using CRISPR-mediated epigenome editing, Chen et al. show that enhancer histone acetylation fine-tunes the activity-dependent transcription of Fos in neurons. Keywords: neuronal activity-inducible transcription, enhancer, histone acetylation, CRISPR, epigenome editing, transcriptional bursting

We have recently reported that CYB5D2 plays a role in suppression of cervical cancer tumorigenesis, “CYB5D2 displays tumor suppression activities towards cervical cancer” [1]. We provide the accompany data here describing the effects of CYB5D2 overexpression and addition of recombinant CYB5D2 on HeLa cell cycle distribution. Furthermore, we will present the conditions used to specifically determine CYB5D2 expression in primary cervical and cervical cancer tissues using immunohistochemistry (IHC) and the patient cohort involved in assessing the CYB5D2 protein levels in primary cervical and cervical cancer tissues.

Pediatric glioblastoma is a malignant disease with an extremely poor clinical outcome. Patients usually suffer from resistance to radiation therapy, so targeted drug treatment may be a new possibility for glioblastoma therapy. Survivin is also overexpressed in glioblastoma. YM155, a novel small-molecule survivin inhibitor, has not been examined for its use in glioblastoma therapy. Methods: The human glioblastoma cell line M059K, which expresses normal DNA-dependent protein kinase (DNA-PK) activity and is radiation-resistant, and M059J, which is deficient in DNA-PK activity and radiation-sensitive, were used in the study. Cell viability, DNA fragmentation, and the expression of survivin and securin following YM155 treatment were examined using MTT (methylthiazolyldiphenyl-tetrazolium) assay, ELISA assay, and Western blot analysis, respectively. Results: YM155 caused a concentration-dependent cytotoxic effect, inhibiting the cell viability of both M059K and M059J cells by 70% after 48 hours of treatment with 50 nM YM155. The half-maximal inhibitory concentration (IC50) was around 30–35 nM for both cell lines. Apoptosis was determined to have occurred in both cell lines because immunoreactive signals from the DNA fragments in the cytoplasm were increased 24 hours after treatment with 30 nM YM155. The expression of survivin and securin in the M059K cells was greater than that measured in the M059J cells. Treatment with 30 nM YM155, for both 24 and 48 hours, significantly suppressed the expression of survivin and securin in both cell lines. Conclusion: The novel survivin inhibitor YM155 elicits potent cytotoxicity in glioblastoma cells in vitro via DNA-PK-independent mechanisms. YM155 could be used as a new therapeutic agent for the treatment of human glioblastomas.

For the first time, ultrasonic emulsification was studied for cinnamon essential oil (CEO) Pickering emulsion, stabilized by cellulose nanocrystal (CNC) from rice straw. Sonication proved to be an effective method for emulsifying CEO, creating small emulsion droplets around 700 nm in size, with an even dispersion characterized through a low polydispersity index. The biomass-derived CNC exhibits high encapsulation efficiency (> 95 %) with varying CEO concentration (5-25 vol%), creating droplets with negative surface charge with limited aggregation of emulsions. Optimization through the Box Behnken design using response surface methodology provides a model for the interaction and effects of variables towards the formulation. Optimal condition was concluded to be at 11.47 vol% CEO, 0.84 wt/vol% CNC and at 6 sonication cycles. The optimized Pickering emulsions retain the antimicrobial properties of CEO, with a large inhibition zone and low MIC value of around 0.048 vol% CEO. DPPH inhibition assay indicates that the emulsification process enhances the antioxidation properties of cinnamon essential oil, expressed through a lower IC 50 of 0.90 vol% CEO, in comparison to pure essential oil at 1.33 vol% CEO. Overall, this research proposes a novel approach towards using nanocellulose as carriers for essential oil with potential in a large variety of applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Antiretroviral therapy may alter susceptibility to nonkeratinocyte skin cancers (NKSCs) by improving immunity in people living with HIV. Using linked data from HIV and cancer registries in 12 states/regions in the United States during the antiretroviral therapy era (1996‒2018), we calculated standardized incidence ratios for 27 NKSCs, comparing incidence with that of the general population. Risk factors for NKSCs were evaluated using Poisson regression. There were 2,743 NKSCs diagnosed in 585,706 people living with HIV followed for 4,575,794 person-years. Kaposi sarcoma was the most common cancer (82%), followed by melanoma (12%) and cutaneous lymphoma (2.6%). Incidence was elevated for virus-related NKSCs: Kaposi sarcoma (standardized incidence ratio = 147, 95% confidence interval = 141‒153), diffuse large B-cell lymphoma (standardized incidence ratio = 5.19, 95% confidence interval = 3.13‒8.11), and Merkel cell carcinoma (standardized incidence ratio = 3.15, 95% confidence interval = 1.93‒4.87); elevated incidence for diffuse large B-cell lymphoma and Merkel cell carcinoma was observed only among people living with HIV with a previously acquired immunodeficiency syndrome diagnosis. Kaposi sarcoma risk was highest among men who have sex with men. Incidence was not increased for melanoma, adnexal carcinomas, and sarcomas. Melanoma and Merkel cell carcinoma arose disproportionately on sun-exposed skin, supporting a role for UVR in their development. In conclusion, risk for most NKSCs was similar to that of the general population during the antiretroviral therapy era, suggesting that people living with HIV without NKSC risk factors may not require intensive skin surveillance., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Angioimmunoblastic T-cell lymphoma (AITL) is proposed to be initiated by age-related clonal hematopoiesis (ACH) with TET2 mutations, whereas the G17V RHOA mutation in immature cells with TET2 mutations promotes the development of T follicular helper (TFH)-like tumor cells. Here, we investigated the mechanism by which TET2-mutant immune cells enable AITL development using mouse models and human samples. Among the 2 mouse models, mice lacking Tet2 in all the blood cells (Mx-Cre × Tet2flox/flox × G17V RHOA transgenic mice) spontaneously developed AITL for approximately up to a year, while mice lacking Tet2 only in the T cells (Cd4-Cre × Tet2flox/flox × G17V RHOA transgenic mice) did not. Therefore, Tet2-deficient immune cells function as a niche for AITL development. Single-cell RNA-sequencing (scRNA-seq) of >50 000 cells from mouse and human AITL samples revealed significant expansion of aberrant B cells, exhibiting properties of activating light zone (LZ)-like and proliferative dark zone (DZ)-like germinal center B (GCB) cells. The GCB cells in AITL clonally evolved with recurrent mutations in genes related to core histones. In silico network analysis using scRNA-seq data identified Cd40-Cd40lg as a possible mediator of GCB and tumor cell cluster interactions. Treatment of AITL model mice with anti-Cd40lg inhibitory antibody prolonged survival. The genes expressed in aberrantly expanded GCB cells in murine tumors were also broadly expressed in the B-lineage cells of TET2-mutant human AITL. Therefore, ACH-derived GCB cells could undergo independent clonal evolution and support the tumorigenesis in AITL via the CD40-CD40LG axis., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: The purpose of this study was to evaluate health care provider awareness and perceptions of the 2 types of advanced practice pharmacists (APPhs) in New Mexico: pharmacist clinicians (PhCs) and community pharmacists with independent prescriptive authority (iRPhs)., Methods: A cross-sectional electronic survey was administered to health care providers in New Mexico to describe awareness and perceptions of APPhs and benefits and barriers to collaborative practice with APPhs., Results: A total of 5905 providers received the emailed survey, and 634 (11%) completed the survey, with 68% of the respondents indicating that they were not aware of the 2 types of APPhs in New Mexico. The top benefits of working with a PhC identified by the respondents were access to medication knowledge, enhanced clinical outcomes, and increased access to patient care. The barriers to employing a PhC at their practice included cost, difficulty in billing for services, and limited reimbursement. Importantly, 80% of the respondents felt that PhCs should be recognized as providers for insurance reimbursement. Awareness of iRPhs varied by prescriptive authority service, ranging from 34% for tuberculin skin testing to 84% for adult vaccinations. Overall, 80%-92% indicated that iRPhs should be reimbursed, depending on the prescriptive authority service., Conclusion: Provider awareness of APPhs in New Mexico was low; however, the willingness to refer patients to APPhs for clinical services was high. Cost, difficulty in billing for services, and reimbursement for PhC services were the primary identified barriers to adding a PhC into practice. Most of the respondents indicated that both types of APPhs should be granted provider status and reimbursed by third-party payers for their services., (Copyright © 2021 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

For the first time, the pigment composition of basidiocarps from the Chilean mushroom Cortinarius pyromyxa was studied under various aspects like phylogeny, chemistry and antibiotic activity. A molecular biological study supports the monotypic position of C. pyromyxa in subgenus Myxacium, genus Cortinarius. Four undescribed diterpenoids, named pyromyxones A-D, were isolated from fruiting bodies of C. pyromyxa. Their chemical structures were elucidated based on comprehensive one- and two-dimensional NMR spectroscopic analysis, ESI-HRMS measurements, as well as X-ray crystallography. In addition, the absolute configurations of pyromyxones A-D were established with the aid of J H,H , NOESY spectra and quantum chemical CD calculation. The pyromyxones A-D possess the undescribed nor-guanacastane skeleton. Tested pyromyxones A, B, and D exhibit only weak activity against gram-positive Bacillus subtilis and gram-negative Aliivibrio fischeri as well as the phytopathogenic fungi Botrytis cinerea, Septoria tritici and Phytophthora infestans., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Species of the Culex vishnui subgroup, Cx. fuscocephala and Cx. gelidus, which are known Japanese encephalitis (JE) vectors, are distributed in rice agroecosystems in Asian countries. Hence, although ecological studies of rice agroecosystems in northern Vietnam are necessary, very few integrated studies of breeding habitats of mosquitoes, including JE vectors, have been conducted. We carried out a field study and investigated the mosquito fauna in six rice production areas in northern Vietnam during the rainy and dry seasons of 2009. Mosquitoes and potential mosquito predators were collected from aquatic habitats by using larval dippers. We collected 1780 Culex individuals (including 254 Cx. tritaeniorhynchus; 113 Cx. vishnui, 58 Cx. vishnui complex, consisting of Cx. vishnui and Cx. pseudovishnui; 12 Cx. gelidus; 1 Cx. bitaeniorhynchus; and 1 Cx. fuscocephala), 148 Anopheles individuals (including 5 An. vagus), 1 Mansonia annulifera, and 1 Mimomyia chamberlaini during the rainy season. During the dry season, we collected 176 Culex individuals (including 33 Cx. vishnui, 24 Cx. tritaeniorhynchus, 8 Cx. vishnui complex, and 1 Cx. gelidus) and 186 Anopheles individuals (including 9 An. tessellatus, 2 An. kochi, and 2 An. barbumbrosus). We found mosquitoes in all aquatic habitats, namely, rice fields, ditches, ponds, wetlands, irrigation canals, and rice nurseries, and Cx. tritaeniorhynchus and Cx. vishnui complex were found in all the above six areas. Heteroptera such as Micronecta, Veliidae, and Pleidae were abundant and widely distributed in both the seasons. The abundance of mosquito larvae was higher in the rice fields, ditches, and ponds during the rainy season than during the dry season. Cx. tritaeniorhynchus, Cx. vishnui complex, Cx. fuscocephala, and Cx. gelidus were abundant in rice agroecosystems (rice fields, ditches, ponds, and wetlands) in northern Vietnam, and their abundance was high during the rainy season. These findings deepen our understanding of mosquito ecology and strengthen mosquito control strategies to be applied in rice ecosystems Vietnam in the future., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Introduction: Cost-utility analyses are useful to study conditions without a widely accepted treatment algorithm; in pediatric urology, one such condition is vesicoureteral reflux (VUR). A necessary component of cost-utility analyses is to accurately calculate the "utility", a numerical surrogate of quality of life, for various health states. Our aims were to determine utility values for representative VUR health states and to verify the feasibility of a novel online platform for utility elicitation in order to reduce the time and expense of such analyses., Methods: A cross-sectional survey of American adults was conducted using the time-trade-off (TTO) method. Respondents were recruited from an online work interface, Amazon's Mechanical Turk (MTurk). Four annualized VUR health states were assessed: VUR treated with/without continuous antibiotic prophylaxis (CAP) and with/without associated febrile urinary tract infection (UTI). A 6-week post-operative scenario following open ureteroneocystostomy was also assessed., Results: We received 278 survey responses (70% response rate). The respondents were largely between the ages of 25 and 44 (59%), female (60%), and Caucasian (76%). Thirty-seven percent had a college degree, and 44% were parents. Compared with a perfect health state of 1.0, we found mean utilities of 0.87 for VUR, regardless of whether CAP was used or whether UTI was present (p=0.9). The immediate post-operative period following ureteroneocystostomy garnered an annualized utility of 0.94., Conclusions: Our data suggest that MTurk-based utility assessment is feasible, and that subjects view the VUR health state as only slightly inferior to perfect health. This includes VUR health states incorporating CAP and febrile UTI., (Copyright © 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

CRLX101 is a nanopharmaceutical consisting of cyclodextrin-based polymer molecule and camptothecin. The CRLX101 nanoparticle is designed to concentrate and slowly release camptothecin in tumors over an extended period of time. Tumor biopsy and blood samples collected from patients with advanced solid malignancies before and after CRLX101 treatment are subjected to immunohistochemistry and pharmacogenomics. The expression of Topoisomerase-1, Ki-67, CaIX, CD31 and VEGF decreased after CRLX101 treatment. The expressions of these proteins are inversely proportional with survival duration of the patients. The Drug Metabolism Enzymes and Transporters (DMET) array shows an allele frequency in patients similar to global populations with none of the SNPs associated with toxicity. The results suggest that the observed lower toxicity is not likely to be due to different genotypes in SNPs. CRLX101 demonstrates a promising anti-tumor activity in heavily pre-treated or treatment-refractory solid tumor malignancies presumably by inhibition of proliferation and angiogenesis correlating with tumor growth inhibition. From the clinical editor: In this cancer treatment study clinical samples collected from patients were subjected to immunohistochemistry and pharmacogenomics. The expressions of key proteins that are inversely proportional with survival duration of the patients decreased after treatment with CRLX101, a camptothecin slow-release nanoparticle conjugate. This anti-tumor activity in heavily pre-treated and treatment resistant solid tumors, promises a novel therapeutic approach., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The objectives of this study were to quantify Salmonella counts on retail raw poultry meat in Vietnam and to phenotypically characterize (serovars and antibiotic resistance) the isolates. A total of 300 chicken carcasses were collected from two cities and two provinces in Vietnam. Salmonella counts on the samples were determined according to the most-probable-number (MPN) method of the U.S. Department of Agriculture, Food Safety and Inspection Service (USDA-FSIS). A total of 457 isolates were serotyped and tested for antibiotic susceptibility. Overall, 48.7% of chicken samples were Salmonella positive with a count of 2.0 log MPN per carcass. There were no significant differences (P > 0.05) in log MPN per carcass by the study variables (market type, storage condition, and chicken production system). There was a significant difference (P < 0.05) in Salmonella-positive prevalence by chicken production system. Among the 22 Salmonella serovars identified, Albany was the most frequent (34.1%), followed by Agona (15.5%) and Dabou (8.8%). Resistance to at least one antibiotic was common (i.e., 73.3%), with high resistance to tetracycline (59.1%) and ampicillin (41.6%). Resistance to three antibiotics was the most frequently found multidrug resistance profile (17.7%, n = 81); the profile that was resistant to the highest number of drugs was resistant to nine antibiotics (0.7%, n = 3). Only Salmonella Albany posed phenotypic resistance to ceftriaxone (a drug of choice to treat severe cases of salmonellosis). The data revealed that, whereas Salmonella prevalence on raw poultry was high (48.7%), counts were low, which suggests that the exposure risk to Salmonella is low. However, improper storage of raw chicken meat and cross-contamination may increase Salmonella cell counts and pose a greater risk for infection. These data may be helpful in developing risk assessment models and preventing the transmission of foodborne Salmonella from poultry to humans in Vietnam.

Cultures of the sulfate reducing bacteria Desulfovibrio desulfuricans were grown under anoxic conditions to study the effect of added sulfide, selenite and mercuric ions. A chemical trap consisting in a CuSO4 solution was used to control the poisoning effect induced by the bacterial production of hydrogen sulfide via the precipitation of CuS. Following the addition of Hg(2+), the formation of methylmercury (MeHg) was correlated to bacterial proliferation with most of MeHg found in the culture medium. A large fraction (50-80%) of added Hg(2+) to a culture ended up in a solid phase (Hg(0) and likely HgS) limiting its bioavailability to cells with elemental Hg representing ~40% of the solid. Following the addition of selenite, a small fraction was converted into Se(0) inside the cells and, even though the conversion to this selenium species increased with the increase of added selenite, it never reached more than 49% of the added amount. The formation of volatile dimethylselenide is suggested as another detoxification mechanism. In cultures containing both added selenite and mercuric ions, elemental forms of the two compounds were still produced and the increase of selenium in the residual fraction of the culture suggests the formation of mercuric selenite limiting the bioavailability of both elements to cells., (Copyright © 2013 Elsevier B.V. All rights reserved.)

This study was conducted to estimate the prevalence of Salmonella on chicken carcasses collected from six regions in Vietnam. A total of 1,000 whole, dressed chicken carcasses were collected from five cities and seven provinces across the six regions in Vietnam. Of these, 900 samples were collected from wet markets and 100 from supermarkets. All samples were analyzed for the presence of Salmonella according to a method recommended by the U. S. Department of Agriculture, Food Safety and Inspection Service. The overall Salmonella prevalence was 45.9%. There was no significant difference (P > 0.05) in Salmonella prevalence by (i) location (Ha Noi city, 51.1%; Hai Phong city, 45.6%; Da Nang and Can Tho cities, 45.5%; Bac Ninh province and Ho Chi Minh city, 44.7%; Dong Nai province, 44.6%; Ha Tinh province, 44.4%; Phu Tho province, 43.8%; Lao Cai province, 43.5%; Kien Giang province, 41.9%; and Lam Dong province, 40.9%), (ii) market type (wet market, 46.2%; supermarket samples, 43.0%), and (iii) storage temperature at retail (ambient storage, 46.4%; chilled storage, 45.1%). Hence, Salmonella presence on poultry meat in Vietnam was not associated with a specific city or province, market type, or storage temperature at retail. Strategies to reduce Salmonella levels on raw poultry in Vietnam should be undertaken to improve the safety of poultry products and reduce the incidence of human salmonellosis from poultry consumption.

Camptothecin showed remarkable anticancer activity in animal models of cancer but was restricted in clinical use for its adverse toxicity in patients. The preclinical efficacy of CRLX101, a nanoparticle (NP) assembly containing cyclodextrin-based polymer and camptothecin was evaluated by in vitro cytotoxicity in gastric cancer cell lines and in vivo antitumor effects in human gastric cancer cell line BGC823 xenografts. Treated tumor sections were analyzed for presence of NPs and compared with vehicle control tumors for hypoxia and angiogenesis. Gastric cancer cell lines showed high in vitro cytotoxicity for CRLX101 and also showed strong antitumor activity in vivo. Electron micrographs revealed the intracellular presence of NPs in close proximity to vesicles. A significant decrease in expressions of carbonic anhydrase, VEGF, and CD31 proteins in treated tumors indicated an inhibition of hypoxia and angiogenesis. The results provide preclinical data for gastric adenocarcinoma., From the Clinical Editor: This study describes a nanoparticle assembly containing cyclodextrin-based polymer and camptothecin, resulting in increased bioavailability of camptothecin, an effective but toxic anti-cancer agent. The antitumor effects and safety profile were demonstrated in a gastric carcinoma cell line., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A gas chromatography-mass spectrometry (GC-MS) method was developed to simultaneously separate cholesterol, eight cholesterol oxidation products (COPs), and two conjugated linoleic acids (9-cis,11-trans-CLA and 10-trans,12-cis-CLA) and to evaluate their stability in a model system during heating. Among four capillary columns tested, an Equity-5 column with low-polar stationary phase provided better resolution within 30 min. A high-performance liquid chromatography method was also developed to determine cholesterol hydroperoxides by using a YMC C30 column with diphenyl-1-pyrenylphosphine as fluorescence reagent. No formation of COPs or degradation of cholesterol and CLAs occurred at 100 degrees C, but the levels of COPs rose drastically at 150 degrees C. The first-order rate of cholesterol degradation declined following a rise in CLA concentration. For 0-, 100-, and 500-microg/ml CLA levels, the formation profiles of 7-hydroxycholesterol, 7-ketocholesterol, and 5,6-epoxycholesterol at 150 degrees C were fitted as multiple first-order curves, whereas a single first-order model could adequately describe 7-hydroperoxycholesterol and cholestane-3beta,5alpha,6beta-triol formation. A CLA-to-cholesterol mole ratio of 0.49 was required to prevent cholesterol oxidation at 150 degrees C., (2010 Elsevier Inc. All rights reserved.)

The hepatitis B virus X protein (HBX) plays key regulatory roles in viral replication and the development of hepatocellular carcinoma. HBX is an unstable protein; its instability is attributed to rapid degradation through the ubiquitin-proteasome pathway. Here, we show that the middle and carboxyl-terminal domains of HBX, independently fused to GFP, render the recombinant proteins susceptible to proteasomal degradation, while the amino-terminal domain has little effect on the ubiquitination or stability of HBX. Mutation of any single or combination of up to five of six lysine residues, all located in the middle and carboxyl-terminal domain, did not prevent HBX from being ubiquitinated, ruling out any specific lysine as the sole site of ubiquitination. Surprisingly, HBX in which all six lysines were mutated and showed no evidence of ubiquitination, was still susceptible to proteasomal degradation. These results suggest that both ubiquitin-dependent and -independent proteasomal degradation processes are operative in HBX turnover.

Major constituents of the amyloid plaques found in the brain of Alzheimer's patients are the 39-43 residue beta-amyloid (Abeta) peptides. Extensive in vitro as well as in vivo biochemical studies have shown that the 40- and 42-residue Abeta peptides play major roles in the neurodegenerative pathology of Alzheimer's disease. Although the two Abeta peptides share common aggregation properties, the 42-residue peptide is more amyloidogenic and more strongly associated with amyloid pathology. Thus, characterizations of the two Abeta peptides are of critical importance in understanding the molecular mechanism of Abeta amyloid formation. In this report, we present combined CD and NMR studies of the monomeric states of the two peptides under both non-amyloidogenic (<5 degrees C) and amyloid-forming conditions (>5 degrees C) at physiological pH. Our CD studies of the Abeta peptides showed that initially unfolded Abeta peptides at low temperature (<5 degrees C) gradually underwent conformational changes to more beta-sheet-like monomeric intermediate states at stronger amyloidogenic conditions (higher temperatures). Detailed residue-specific information on the structural transition was obtained by using NMR spectroscopy. Residues in the N-terminal (3-12) and 20-22 regions underwent conformational changes to more extended structures at the stronger amyloidogenic conditions. Almost identical structural transitions of those residues were observed in the two Abeta peptides, suggesting a similar amyloidogenic intermediate for the two peptides. The 42-residue Abeta (1-42) peptide was, however, more significantly structured at the C-terminal region (39-42), which may lead to the different aggregation propensity of the two peptides.

Aims: To evaluate the utility of multidetector computed tomography (MCT) in assessing tumor size and nodal status in patients with advanced breast cancers before and after the neoadjuvant chemotherapy., Methods: Twenty-eight proven locally advanced breast cancer patients with 30 tumors were enrolled in this study. MCT was used to assess tumor size and axillary lymph nodes before and after the neoadjuvant chemotherapy. The correlation between tumor size on MCT and gross tumor size was tested., Results: The MCT measurements documented complete response in 3, partial response in 18, non-response in 8 and progressed in 1. The mean tumor diameters on pathology and post-chemotherapy MCT were 3.6cm (S.D.=+/-2.9cm) and 3.1cm (S.D.=+/-2.6cm), respectively. The Pearson correlation coefficient was 0.76 (p<0.001). The sensitivity, specificity, positive predictive valve, negative predictive valve and accuracy of MCT in diagnosing the axillary lymph node metastases after pre-operative neoadjuvant chemotherapy were counted, respectively, to 72%, 40%, 85.7%, 22.2% and 66.7%. All the 5 downstaged axillary nodal statuses from node-positive to node-negative on MCT had micrometastases., Conclusion: MCT can be used to evaluate tumor size and nodal status in patients with advanced breast cancer. As there is a baseline MCT before chemotherapy for comparison, we are potentially aware of the possibility of false negative nodal micrometastases on the post-chemotherapy MCT.

The human kinetochore is a highly complex macromolecular structure that connects chromosomes to spindle microtubules (MTs) in order to facilitate accurate chromosome segregation. Centromere-associated protein E (CENP-E), a member of the kinesin superfamily, is an essential component of the kinetochore, since it is required to stabilize the attachment of chromosomes to spindle MTs, to develop tension across aligned chromosomes, to stabilize spindle poles and to satisfy the mitotic checkpoint. Here we report the 2.5A resolution crystal structure of the motor domain and linker region of human CENP-E with MgADP bound in the active site. This structure displays subtle but important differences compared to the structures of human Eg5 and conventional kinesin. Our structure reveals that the CENP-E linker region is in a "docked" position identical to that in the human plus-end directed conventional kinesin. CENP-E has many advantages as a potential anti-mitotic drug target and this crystal structure of human CENP-E will provide a starting point for high throughput virtual screening of potential inhibitors.

Pericarditis complicating cardiac trauma and resulting in tamponade is uncommon. Possible causes include an autoimmune reaction or an inflammatory response to blood entering the pericardium. We present two patients, one with effusive and one with constrictive pericarditis occurring within 2 weeks of a penetrating trauma close to but not directly involving the heart. These cases illustrate the importance of clinical suspicion and aggressive management in the diagnosis and management of such patients.