Hemophagocytic lymphohistiocytosis (HLH) is an uncommon immunologic disorder associated with high rates of morbidity and mortality characterized by systemic inflammation and multiorgan dysfunction. The standard of care for primary treatment of HLH is chemotherapy (i.e. etoposide), but consideration of alternative therapies is warranted to support treatment goals for critically ill pediatric patients. We present the case of a 7-year-old male with trisomy 21, acute multiorgan failure secondary to infection, and subsequent HLH who was successfully treated with ruxolitinib. This represents the first use of ruxolitinib as a first-line agent for secondary HLH in a critically ill child with trisomy 21.

Background: V enetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more robust data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. Procedure: We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco (UCSF) Benioff Children’s Hospitals from 2016 to 2022. Results: We identified 13 patients (AML , n= 8, B-ALL, n= 3, MDS, n= 2) aged 4 months to 27 years. A median of 3 prior lines of therapy were given (range 0 to 5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved a complete remission (CR); 2 (15%) achieved a partial remission (PR); 3 (23%) had stable disease (SD), and 5 (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5 to 52 months), and 3 months (range 2 weeks to 7.5 months), respectively. Five patients (38%) developed life-threatening infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, encephalitis with bacterial brain abscesses. Conclusions: Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but was frequently associated with severe atypical infections, particularly in combination with cytotoxic chemotherapy.

The fifth-generation communication (5G) requires a highly accurate estimation of the Channel State Information (CSI) to take advantage of the massive Multiple-Input Multiple-Output (MIMO) system. However, traditional channel estimation methods do not always yield reliable estimates. The methodology of this paper consists of Deep Residual Shrinkage Network (DRSN) neural network-based method that is used to solve this problem. Thus, the channel estimation approach, based on DRSN with its learning ability of noise-containing data, is first introduced. Then, the DRSN is used to train the noise reduction process based on the results of the LS channel estimation while applying the pilot frequency subcarriers, where the initially estimated subcarrier channel matrix is considered as a three-dimensional tensor of the DRSN input. Afterward, a mixed-SNR (Signal to Noise Ratio) training data strategy is proposed based on the learning ability of DRSN under different SNRs. Moreover, a joint mixed scenario training strategy is carried out to test the multi scenarios robustness of DRSN. As for the findings, the numerical results indicate that the DRSN method outperforms the Spatial-Frequency-temporal Convolutional Neural Networks (SF-CNN) with similar computational complexity and achieves better advantages in the full SNR range than the Minimum Mean Squared Error (MMSE) estimator with a limited dataset. Moreover, the DRSN approach shows robustness in different propagation environments.

A document by Eriserdi Mollaymeri. Click on the document to view its contents.

A document by Kirolosse M. Girgis. Click on the document to view its contents.

The Electrical network grows in size and complexity every year .The number of fatal and non-fatal accidents is increasing at a disqueting rate every year. Majority of electrical casualty happen to the employees while executing the work. In this paper, we examine this grave problem based on the Indian Grid. We model the grid as a power line communication (PLC) network graph. The capturing of real grid into a graph model is shown. A novel safety algorithm based on the graph model is also proposed.

To perform surgery with a minimally invasive procedure is preferred during daily practices. With the endoscope development in otology, a direct view of ossicles or lesions in the tympanic cavity without disturbing the mastoid becomes possible. Accompanied by a growing number of endoscopic surgeries, the complications were more commonly seen due to certain drawbacks, like single-hand practices and loss of three-dimensional images[1]. Rarely, to our knowledge, dislocated stapes protrudes into the vestibule cavity during endoscopic surgery, which results in profound hearing loss and vertigo.

Key Points: ● The Facial Clinimetric Evaluation (FaCE) scale, consisting of six subscales, measures facial palsy-specific quality of life. ● Each subscale’s weight in the total FaCE score is based on the number of questions but may not reflect the subscale’s true contributions to ‘overall’ facial-palsy specific quality of life. ● In 80 patients, we analyzed the subscales’ correlations with a validated Visual Analogue Scale (VAS) score that quantifies overall facial palsy-related burden. ● Social function and facial comfort had stronger correlations with overall facial palsy-related quality of life than their weights in the FaCE total score suggests. ● Greater importance should be placed on social function and facial comfort when estimating the quality of life of patients with facial palsy.

Streptococcus pneumoniae (S. pneumoniae) is the most important pathogenic bacteria occurred in wide range of habitat, which cause of several diseases, including pneumonia, meningitis, otitis media, bacteremia and other common infections. Every year, approximately 1.6 million people are seriously affected and ultimately die as a result of pneumococcal infections worldwide, affecting people’s lives and health. Relevant studies in recent years have demonstrated the important role of microRNAs (miRNAs) in a variety of diseases. Further research on the mechanism of microRNA and the relationship between microRNA and diseases has shown that microRNA may become a new biological marker for disease diagnosis and may also provide a new approach to disease treatment. The function of microRNA in pneumococcal infections has also been gradually reported, including pneumococcal nasopharyngeal colonization, pneumonia, sepsis, bacteremia, heart invasion, meningitis, acute otitis media, osteoarthritis and other diseases. This article will overview the mechanism and research progress of microRNA in infections caused by S. pneumoniae.

Yinggema lignite (YL) was extracted with isometric acetone/carbon disulfide mixed solvent at room temperature under ultrasonication to remove the soluble organic matter and obtain the extract residue (RYL), and then RYL was separated by density difference with carbon tetrachloride under ultrasonication to obtain the light residue (LRYL). Composition and structure characteristics and pyrolysis products distribution of YL and LRYL were analyzed by Thermogravimetry-Fourier transform infrared spectrometer-Gas chromatography/mass spectrometer (TG-FTIR-GC/MS).

This paper studies the current application and monitoring situation of VR technology. Based on the Unity 3D game engine and VR device HTC Vive, the paper establishes a typical VR interaction scene and propose a VR application runtime monitoring scheme. The main work of this paper includes: (1) VR interactive scene where full-angle observation, movement of the person’s perspective, object touch, object picking, object use and menu interaction are achieved; (2) VR monitoring SDK. The monitoring SDK collects the user device information, runtime performance information, exception information, and user behavior information for the VR application under the user environment, by mounting a monitoring script in the VR application scene; (3) Data analysis center, which is responsible for receiving and storing the data reported by the VR monitoring SDK and helps helps the developer to better understand the situation on operation of the VR application and analyze user behavior through statistics aggregation and algorithm analysis of the data.

The changes and pore structure characteristics of high-temperature granite surface cracks under different heat transfer methods were tested by polarizing microscopy (PM), scanning electron microscopy (SEM), and nuclear magnetic resonance imaging (NMR) to analyze the microstructure changes of geothermal reservoir rocks and quantitatively characterize the effective pore characteristics. A fractal dimension model of granite at different temperatures was established to evaluate the storage performance of geothermal reservoirs based on the fractal geometry theory. The granite at different temperatures had significant changes in the types and morphologies of microcracks under different heat transfer methods. Original microcracks closed to decrease porosity at 150°C. There exist grain boundary microcracks at 300°C, intracrystalline microcracks at 450°C, and transgranular microcracks at 600°C with the increased temperature. Meanwhile, the fractal-dimensional thermal storage performance evaluation method of geothermal reservoirs was applied to find the optimal temperature conditions (450 and 600°C) for the thermal storage performance of macropores and mesopores.

A variational model of pressure-dependent plasticity employing a time-incremental setting is introduced. A novel formulation of the dissipation potential allows one to construct the condensed energy in a variationally consistent manner. For a one-dimensional model problem, an explicit expression for the quasiconvex envelope can be found which turns out to be essentially independent of the original pressure-dependent yield surface. The model problem can be extended to higher dimensions in an empirical manner. Numerical simulation exhibit well-posed behavior showing mesh-independent results.

This case report highlights an incidence of small intestinal DLBCL of the duodenum in an 87-year-old woman presenting with a 2-month history of melena and dysphagia to solid foods and laboratory findings of normocytic anemia. The patient had EGD and biopsies revealed DLBCL.

Interstitial Lung Disease in childhood (chILD) is rare and no longer solely a childhood issue. Many are surviving into adult life. Therefore, many affected with chILD need to transition from paediatric to adult healthcare services. Transition is a significant life event that has the potential to impact on physical and mental health outcomes and across Europe this is a haphazard process for chILD. This qualitative study explores how young people and parents in the United Kingdom experienced transition from paediatric to adult healthcare services for chILD. Participants (n = 7) were recruited from chILD patient organisations and online communities. We focused on the experience of transition and whether there were any information packs or support provided for the transition. The data was analysed by constructivist grounded theory. The study presents a lived experience of transition with themes of lack of transition preparation and planning, challenges of learning how to adapt to adult services and a changing healthcare scene. Due to the complexity of ChILD, parents discussed their need to remain, in part, as an advocate for the young person. Respondents provided recommendations for how transition could be improved along with tips for young people who are new to the transition process, which include educating oneself about the condition and learning medical terminology, being open if there are issues and reaching out for support.

This paper studies, from the point of view of local politicians, the governance of social services in different municipalities and County Councils in Catalonia. The political dimension of local social services has rarely been studied and this article contributes to the understanding of which actors and what kind of relations are developed during the policy process. From a qualitative approach, the study is based on 17 in-depth interviews with local politicians, as well as two focus groups with managers and front-line social workers. The results reveal that local politicians do not have a long-term and strategic perspective, and that they feel more comfortable dealing with management rather than politics. At the local level, social services tend to be a depoliticized issue. Even though local politicians have a positive attitude to talk and work with all the actors, they fail to achieve regular coordination and engagement. Key Practitioner Message

IntroductionWhether one has been infected with SARS-CoV-2 or had the Covid-19 vaccine, a robust innate and adaptive immune response is elicited. Recent studies provide evidence that the adaptive immune response can persist at high levels for over 6 months after vaccination as measured by sera antibody titers (Doria-Rose et al, 2021). Sera antibody titers against the SARS-CoV-2 virus are significantly higher in the vaccinated compared to those who are infected (Assis et al, 2021; Bartsch et al, 2021). For an unknown number of people, either of these events may lead to autoimmune disease (Guimarães et al, 2015); here called SARS-CoV-2 induced autoimmune disease (Ehrenfeld et al, 2020), and Covid-19 vaccine induced autoimmune disease (Toussirot and Bereau, 2015; Segal and Shoenfeld, 2018). While the two conditions may share similar mechanisms of an impaired, hyper immune response, long Covid may have additional mechanisms such as viral persistence (Wang et al 2020; Neurath et al, 2021). Viral persistence, even at low levels, can lead to a number of consequences, including the release of miRNA packaged into exosomes that induces a pro-inflammatory, Warburg-like effect in surrounding cells (Yoshikawa et al, 2019; Proal and VanElzakker, 2021). Common to both conditions, i.e vaccine induced and Covid-19 induced autoimmunity, susceptibility to infection or severe outcomes may include the effects of previous infections or vaccinations. For example, superantigen-mediated T cell activation can trigger broad B cell activation, and production of autoantibodies against a range of tissues has been shown in multi-inflammatory syndrome (Consiglio et al, 2020), and in patients with acute COVID-19. The spike protein, whether a part of the virion or of the Covid-19 vaccine, contains a superantigenic motif known to elicit a hyperinflammatory adaptive immune response (Cheng et al, 2020). Evidence also finds that the spike protein drives NLRP3 inflammasome activation in human microglia (Albornoz et al, 2022), a possible mechanism in developing neurological symptoms following Covid-19 infection or vaccination. One explanation for this happening is that the virus, or vaccine related proteins, can now target vascular endothelial cells and disseminate to the CNS through a hematogenous mechanism. Once at the blood-brain-barrier (BBB), SARS-CoV-2 or vaccine related protein, binds the zonulin receptor and promotes zonulin release. Then zonulin, via PAR2, induces blood-brain-barrier (BBB) disruption allowing the virus or protein to enter. Disruption of barrier function in epithelial and endothelial cells has been found by UC Berkeley scientists to be mediated by the spike protein alone (Biering et al, 2022), meaning that the spike protein made by mRNA vaccines can mediate this disruption of barrier function. Further, PEG has never been used in an approved vaccine until the mRNA vaccines, and its presence in Pfizer-BioNTech and Moderna-1273 vaccines has raised concerns about possible anaphylactic and fusogenic adverse effects (Sfera et al, 2022). Another concern is that PEG promotes temporary permeabilization of the BBB, a property used by the pharmaceutical industry for drug delivery to the CNS (Rabenel et al, 2020). This may account, in part, for the VAERS-reported neuropsychiatric symptoms, including neurodegenerative disorders (Frontera et al, 2022). Many excipients other than PEG are also used in the mRNA vaccines, and they too may be causative for adverse events (Borgsteede et al, 2021).Also, chronic activation of the immune system by viral persistence (or vaccine persistence, depending on how long the spike protein is made) can induce autoimmune responses, and molecular mimicry between components of a pathogen and host tissue can lead to specific post-infectious autoimmunity. Structural similarity between human neuronal antigens and SARS-CoV-2 proteins exists. A particular form of autoimmunity described in long COVID is postural orthostatic tachycardia syndrome, a form of autonomic dysregulation that is possibly induced by functional autoantibodies that target G protein–coupled receptors on neurons (Brodin et al, 2022). Another type of autoimmunity relevant to SARS-CoV-2 infection is the production of neutralizing autoantibodies to type I interferons, explaining a sizeable fraction of cases of hypoxemic COVID-19 pneumonia (Bastard et al, 2021). If such neutralizing autoantibodies are present before SARS-CoV-2 infection, due to prior infections or vaccinations, then a patient is clearly at risk of developing severe acute COVID-19 or vaccine induced autoimmune disease. Neutralizing autoantibodies may also appear after SARS-CoV-2 infection, in which case they might instead enable viral persistence, the formation of a viral reservoir and long COVID.Maguire (2022) has suggested a means to develop vaccines that better prevents the spread of virions and also reduce the probability of vaccine injury. However, current Covid-19 vaccine induced autoimmune disease can be severe in adults (de Brujin et al, 2021; Kaulen et al, 2022) and children (Buckhorn et al, 2021), leading to hospitalization. Life threatening autoimmune disease from Covid-19 vaccination has been successfully treated with a combination of 1. plasma exchange to clear autoantibodies from the blood, 2. Corticosteroids to reduce inflammation, 3. Rituximab to deplete beta cells, and 4. Caplacizumab an anti-von Willebrand factor to clear blood clots (de Bruijn et al, 2021).Autoimmune encephalitidies ((Zlotnik et al, 2021), venous sinus thrombosis (Finisterer and Nics, 2021; Sharifian-Dorche et al, 2021), intracranial hemorrhage with venous sinus thrombosis occurring in the same patient (Purkayastha et al, 2021), and glial fibrillary acidic protein astrocytopathy (GFAP-A) can result following the second dose of an mRNA vaccine (Koh et al, 2022). Autoimmune encephalitis is difficult to diagnose with current clinical diagnostics and therefore often goes untreated (Graus et al, 2016). Autoantibodies can persist for at least 6 months following even mild Covid-19 disease (Liu et al, 2021; Su et al, 2022). Neurological symptoms will result (Patone et al, 2021; Finisterer, 2022), including memory and attention deficits for up to 9 months (Zhao et al, 2022), and brain autoimmunity with attack of myelin in neurons may result (Gupta and Weaver, 2021; Shabani, 2021). Autoantibodies acting on vascular endothelial cells (Bouillet et al, 2013) in the part of the blood supply that feeds the brain, can cause thrombotic thrombocytopenia (Zuo et al, 2020; Gunther et al, 2021), and cerebral venous sinus thrombosis (Finsterer, 2021), and may also underlie the generalized report of “brain fog” in such patients and other forms of encephalopathy (Huang and Huang, 2022). Recent studies have found that spike proteins in SARS-CoV-2 attach to vimentin (Amraei et al, 2022), which is present at the extracellular surface of endothelial cells. This is a possible mechanism underlying the vaccine induced vascular abnormalities. Autoantibodies are also known to attack neutrophils, a key component of the innate immune response, and therefore could be an important reason for severe Covid-19 in those with autoimmune disease, potentially even that induced from vaccination (Weiner and Segelmark, 2016). Douaud et al (2022) found that Covid-19 whether severe or non-severe (not hospitalized), have significant brain damage. Whether this brain damage is the result of a hyperimmune response is not known, and therefore whether a hyperimmune response to vaccination could be resulting in the same brain damage is not known. However, because many of those autopsied after Covid-19 with CNS symptoms have not been found to have virions in their brain tissue, but do have immune cells present, a hyperimmune response is likely causative (Matschke et al, 2020). Concerning too is that mRNA vaccines may introduce DNA into the host genome, thus potentially introducing viral proteins to the host immune system for extended periods. Unlike what physicians in the media have said (Offit, 2021), humans possess robust reverse transcriptase enzymes that can write RNA sequences into DNA (Chandramouly et al, 2021), and the possibility exists that mRNA vaccines may introduce a DNA message into human genomes (Zhang et al, 2021; Alden et al, 2022). More work is required to provide good evidence whether this is happening in vaccinated humans (Doerfler, 2021). While we don’t whether the spike mRNA is inserted into our genomes, and, if so, whether that DNA would be expressed or suppressed, we do have evidence that spike proteins are expressed for at least two months following Covid-19 mRNA vaccination.As Danice Hertz, MD has written in a response to an article about Long Covid, “There are many thousands of people who have suffered a similar neurological syndrome as a result of receiving a Covid vaccine. I am one of those people and have severe neuropathic pain from head to toe as well as tinnitus, dizziness, imbalance, blurred vision, fatigue, headaches for 14 months now. Many of us have been diagnosed with small fiber neuropathy, dysautonomia and mast cell activation syndrome. It is time that these vaccine reactions be acknowledged, and that research be conducted to help understand the mechanism of injury so better treatments can be available to help those like me who have suffered terrible injury from the vaccines” (George, 2022). Recently, Gregory Poland, MD, director of the Mayo Clinic’s Vaccine Research Group in Rochester, Minnesota, reported his severe tinnitus after receiving the second dose of a mRNA covid-19 vaccine. ”It was like someone suddenly blew a dog whistle in my ear,” Poland told MedPage Today. ”It has been pretty much unrelenting.” Since then, Poland said he has been experiencing what he describes as life-altering tinnitus. Commenting on his symptoms, he ”can only begin to estimate the number of times I just want to scream because I can’t get rid of the noise or how many hours of sleep I’ve lost,” (Henderson, 2022).In this analysis and case study of vaccine induced autoimmune disease, I’ll first assume that the vaccine was manufactured correctly, and transported and stored appropriately so that the vaccine itself was normal. This, of course, is a big assumption given recent reports of manufacturing irregularities at the vaccine manufacturing facilities (Kansteiner, 2021). Because the VAERS vaccine adverse event reporting system in the US is voluntary, and few physicians or individuals who have been vaccinated report their injuries (Vaccines and The National Vaccine Injury Compensation Program, https://dash.harvard.edu/handle/1/9453695), the rate of vaccine induced injury is unknown. “The concern of some physicians about potential legal liability for an adverse event following vaccination was cited by some participants as a reason for underreporting in VAERS” (IOM, 1997). According to Ross et al (2010), “less than 0.3% of all adverse drug events and 1-13% of serious events are reported to the Food and Drug Administration (FDA). Likewise, fewer than 1% of vaccine adverse events are reported” (Ross et al, 2010). The underreporting of AEs occurs for many different vaccines that are routinely used (Cunningham, 2010). The problem of underreported AEs is significant (about 85%) for all drugs, not just vaccines (Hazell and Shakir, 2006).Some studies have attempted to capture the true rate, such as that for vaccine induced myocarditis (Barda et al, 2021), but these studies are rare and are usually poorly executed, if only because the data base from which the adverse events are taken is of poor quality. Here’s part of the problem too: if one has been injured by the vaccine, symptomatic for tinnitus, vertigo, and brain fog, there are not ostensible or clinically measurable manifestations of the disease. Not displaying something such as facial paralysis, often errantly called Bell’s Palsey by physicians (Scorza and Finisterer, 2021), leads the clinician to order blood tests and perhaps an nMRI scan. Nothing will be found when the physician orders these tests. Using standard clinical measures without a semi-shotgun approach to assaying the patients exoproteosome, in search of autoantibodies, the clinician will find no problems with their patients and tell the patient, “It’s all in your head” (Boodman, 2018). In terms of doing research on vaccine induced injuries, according to an article in Science, “I’ve talked to a lot of clinicians and researchers at various universities, and they don’t want to touch it” (Couzin-Frankel and Vogel, 2022).According to the CDC, among 71,491 U.S. adults who were hospitalized with COVID-19, 27.8 percent were overweight and 50.2 were obese (Kompaniyets et al, 2021). The analysis included 148,494 patients who received a COVID-19 diagnosis at emergency departments or inpatient visits between April 1 and Dec. 31 across 238 hospitals. Thus, 78% of the people sampled in this study who were hospitalized because of Covid-19, 78% were overweight or obese. Those who were overweight or obese were more likely to require invasive mechanical ventilation. Obesity was also linked to increased risk for hospitalization and death, especially among those under age 65. As BMI rose, so did the risk, the CDC found. Obesity is a major risk factor for autoimmune disease (Versini et al, 2014), and obese patients with Covid-19 produce a majority of SARS-CoV-2-specific antibodies that are autoimmune and not neutralizing (Frasca et al, 2021). Among other problems, autoantibodies can destroy neutrophils (Shastri and Logue, 1993) and leave the patient with a diminished innate immune response to the virus.

The insect cell-baculovirus expression vector system (IC-BEVS) has shown to be a powerful platform to produce complex biopharmaceutical products, such as recombinant proteins and VLPs. More recently IC-BEVS has been also used as an alternative to produce adeno-associated virus (AAV). However, little is known about the variability of insect cell populations and the potential effect of heterogeneity on product titer and/or quality. In this study, transcriptomics analysis of Sf9 insect cells during the production of recombinant AAV using a low multiplicity of infection, dual-baculovirus system was performed via single-cell RNA-seq (scRNA-seq). Before infection, the principal source of variability in Sf9 insect cells was associated to cell cycle. Over the course of infection, an increase in transcriptional heterogeneity was detected, this being linked to the expression of baculovirus genes as well as to differences in AAV transgenes ( rep, cap and gfp) expression. Noteworthy, at 24 hours post-infection (hpi) only 29 % of cells showed to enclose all three necessary AAV transgenes to produce packed AAV particles, indicating limitations of the dual baculovirus system. In addition, the trajectory analysis herein performed highlighted biological processes such as protein folding, metabolic processes, translation and stress response has been significantly altered upon infection. Overall, this work reports the first application of scRNA-seq to the IC-BEVS and highlights significant variations in individual cells within the population, providing insight for rational cell and process engineering towards improved AAV production in IC-BEVS.

Objectives: The CF Foundation sponsored competitive awards for Mental Health Coordinators (MHCs) from 2016-2018 to implement the international guidelines for mental health screening and treatment in US CF centers. Longitudinal surveys evaluated success in implementing these guidelines using the Consolidated Framework for Implementation Research (CFIR). Methods: MHCs completed annual surveys assessing implementation from Preparation/Basic Implementation (e.g., using recommended screeners) to Full Implementation/Sustainability (e.g., providing evidence-based treatments). Points were assigned to questions through consensus, with higher scores assigned to more complex tasks. Linear regression and mixed effects models were used to: 1) examine differences in centers and MHC characteristics, 2) identify predictors of success, 3) model the longitudinal trajectory of implementation scores. Results: 122 MHCs (88.4% responded): Cohort 1 N=80, Cohort 2 N=30, Cohort 3 N=12. No differences in center characteristics were found. Significant improvements in implementation were observed across centers over time. Years of experience on a CF team was the only significant predictor of success; those with 1-5 years or longer reported the highest implementation scores. Change over time was predicted by >5 years of experience. Conclusions: Implementation of the mental health guidelines was highly successful over time. Funding for MHCs with dedicated time was critical. Longitudinal modeling indicated that CF centers with diverse characteristics could implement them, supported by evidence from the CF Patient Registry showing nearly universal uptake of mental health screening in the US. Years of experience predicted better implementation, suggesting that education and training of MHCs and retention of experienced providers are critical to success.

Background and Purpose: This study investigated the reno-protective effects of a highly selective AT2R agonist peptide, β-Pro7Ang III in a mouse model of acute kidney injury (AKI). Experimental Approach: C57BL/6J mice underwent either sham surgery or unilateral kidney ischemia-reperfusion injury (IRI) for 40 minutes. IRI mice were treated with either β-Pro7Ang III or perindopril and at 7 days post-surgery the kidneys analysed for histopathology and the development of fibrosis and matrix metalloproteinase (MMP)-2 and -9 activity. The association of the therapeutic effects of β-Pro7Ang III with macrophage number and phenotype was determined in vivo and in vitro. Key Results: Decreased kidney tubular injury, interstitial matrix expansion and reduced interstitial immune cell infiltration in IRI mice receiving β-Pro7Ang III treatment was observed at day 7, compared to IRI mice without treatment. This correlated to reduced collagen accumulation and MMP-2 activity in IRI mice following β-Pro7Ang III treatment. FACS analysis showed a reduced number and proportion of CD45+CD11b+F4/80+ macrophages in IRI kidneys in response to β-Pro7Ang III, correlating with a significant increase in M2 macrophage markers and decreased M1 markers at day 3 and 7 post-IR injury, respectively. In vitro analysis of cultured THP-1 cells showed that β-Pro7Ang III attenuated lipopolysaccharide (LPS)-induced tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 production but increased IL-10 secretion, compared to LPS alone. Conclusion and Implications: Therapeutic delivery of β-Pro7Ang III was renoprotective via alteration of macrophage phenotype and anti-inflammatory cytokine release, therefore mitigating the downstream progression of ischemic AKI.

Background and Purpose: Emerging studies indicated that Klotho is a marker of renal injury and owns a protective effect on different kinds of kidney diseases. However, the role of Klotho in vancomycin (Van)-induced acute kidney injury (AKI) is largely unclear. Hence this study aimed to explore the regulatory mechanism of Klotho in Van-AKI. Experimental Approach: The mRNA expression of Klotho and the JAK2/STAT3/GPx3 axis was assessed by RNA sequence analysis after the Van challenging; the mechanism action of Klotho was examined in vitro by Klotho small interfering RNA and recombinant Klotho. The expression of reactive oxygen species and antioxidant enzymes was detected by flow cytometry and spectrophotometry. Transmission electron microscopy was performed to scan the structural damage of mitochondria. Western blot, qPCR, and immunofluorescence were applied to further explore the function of the JAK2/STAT3/GPx3 axis in Van-AKI. Key Results: RNA sequence analysis indicated that Van challenging reduced the expression of Klotho and GPx3, but increased JAK2/STAT3. In vitro, Klotho siRNA enhanced the production of reactive oxygen species and the cell apoptosis ratio by regulating the JAK2/STAT3/GPx3 axis, while the decrease of GPx3 was prevented by specific inhibitors of JAK2/STAT3. In contrast, recombinant human Klotho showed the opposite function to Klotho siRNA. In vivo, recombinant mouse Klotho improved the anti-oxidative enzyme level and mitochondria damage as well as renal dysfunction and histological damage via upregulating anti-oxidative ability. Conclusion and Implications: To conclude, the study evidenced that recombinant Klotho ameliorated Van-induced AKI via the JAK2/STAT3/GPx3 signaling axis by upregulating anti-oxidative ability.

Background: EPS8L1, an analog of epidermal growth factor receptor pathway substrate 8 (Eps8), was screened out in our previous work from clinical samples of patients with ovarian cancer. Our studies also indicated that EPS8L1 might involve in various biological activities. In this study, we further investigated the effect and mechanism of EPS8L1 on the migration and metastasis of ovarian cancer. Methods: SKOV-3 cells with EPS8L1 overexpression and knockdown were established to perform in vitro scratch healing, transwell assay and actin-staining studies. Ovarian cancer mice with lung metastasis was established. Bioinformatics assay, qRT-PCR and Western blot were conducted to identify correlated proteins. Also, the Rac1 activity and the expression of MAPK pathway-related proteins were evaluated. Result: The knockdown of EPS8L1 inhibited the cellular migration in vitro and reduced tumors colonization in vivo. Actin-staining and ELISA experiment suggested that EPS8L1 regulated actin formation and cytoskeleton remodeling. Besides, mRNA and protein expression confirmed that EPS8L1 regulated the downstream molecule T-cell lymphoma invasion and metastasis 2 (TIAM2) and stimulated the activation of Rac1. Also, the phosphorylation levels of P38, Erk and Jnk in MAPK pathway decreased after EPS8L1 knockdown. Conclusion: The upregulation of EPS8L1 could promote migration and metastasis of ovarian cancer cells by regulating cytoskeleton remodeling. The mechanism underlying might be EPS8L1 regulates TIAM2 to induce Rac-GDP to Rac-GTP and then activates the downstream MAPK pathway. As a regulatory gene in cell migration and metastasis, EPS8L1 probably provide a new therapeutic target for ovarian cancer treatment.

The Harbour porpoise (Phocoena phocoena) is a highly mobile cetacean species which primarily occurs in coastal and shelf waters across the Northern hemisphere. It inhabits heterogeneous seascapes that vary broadly in salinity and temperature. Here we produced 74 whole genomes at intermediate coverage to study Harbour porpoise’s evolutionary history and investigate the role of local adaptation in the diversification into subspecies and populations. We identified ~6 million high quality SNPs sampled at 8 localities across the North Atlantic and adjacent waters, which we used for population structure, demographic, and genotype-environment association analyses. Our results support a genetic differentiation between three subspecies, and three distinct populations within the subspecies P.p. phocoena: Atlantic, Belt Sea and Proper Baltic Sea. Effective population size and Tajima’s D levels suggest a population contraction in both Black Sea and Iberian porpoises while a population expansion in the P.p. phocoena populations. Phylogenetic trees indicate a post-glacial colonization of Harbour porpoises from a southern refugium. Genotype-environment association analysis identified salinity as a major driver in genomic variation and we identified candidate genes putatively underlying adaptation to different salinity levels. Our study highlights the value of whole genome resequencing to unravel subtle population structure in highly mobile species and shows how strong environmental gradients and local adaptation may lead to population differentiation. The results have great conservation implications as we found major levels of inbreeding and low genetic diversity in the endangered Black Sea subspecies and identified the critically endangered Proper Baltic Sea porpoises as a separate population.

Equine primary hyperparathyroidism is rare compared with the condition in human medicine where it is often encountered and represents the most common explanation for hypercalcemia in the outpatient setting. Primary hyperparathyroidism results from a hyperfunctioning parathyroid gland and surgical treatment (parathyroidectomy) is typically curative. Successful surgical removal of a diseased parathyroid gland can be challenging in horses as both normal and hyperfunctioning glands are difficult to localize. Identification of surgical targets using ultrasonography and/or Technetium-99m sestimibi scintigraphy are useful for this purpose in both the human and equine contexts. However, these localization approaches are not aways effective. Moreover, not all patients are candidates for general anesthesia and surgery and the costs associated with diagnostic localization and parathyroidectomy may be prohibitive for some owners. This commentary presents information about primary hyperparathyroidism in the event that it is not treated and strives to review aspects of the disease when left untreated from the human medical context.