Successful treatment of bifenthrin toxicosis using therapeutic plasma exchange.

OBJECTIVE: To describe a case of bifenthrin toxicosis in a dog with a successful outcome following the use of therapeutic plasma exchange (TPE) and intralipid therapy. CASE SUMMARY: An 8-month-old female neutered poodle mix dog ingested an unknown amount of powered bifenthrin, which resulted in acutely altered mentation, cranial nerve deficits, and intractable tremors that persisted in severity despite aggressive medical management to include intravenous fluids, intravenous lipid emulsion, anticonvulsant medications, and methocarbamol. TPE was initiated after lack of significant clinical improvement 12 hours after initial presentation. The dog underwent cardiopulmonary arrest (CPA) following approximately 1 plasma volume equivalent exchange. The dog was successfully resuscitated and showed marked improvement 12 hours postarrest and post-TPE treatment. Serum bifenthrin concentrations were analyzed prior to TPE (445.38 ng/mL) and ∼10 hours after TPE (51.18 ng/mL), which resulted in an 89% reduction in serum bifenthrin concentration. NEW INFORMATION: TPE may be a promising adjunctive therapeutic modality for bifenthrin toxicosis in dogs.

Star Formation Shut Down by Multiphase Gas Outflow in a Galaxy at a Redshift of 2.45.

Large-scale outflows driven by supermassive black holes are thought to play a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star formation quenching is remarkably rapid1-3, thus requiring effective removal of gas4 as opposed to slow gas heating5,6. While outflows of ionized gas are commonly detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at redshift z = 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray or radio activity are detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.

Supporting each other: Older adults' experiences empowering food security and social inclusion in rural and food desert communities.

Older adults vulnerable to food insecurity are at risk of poor psychological and physical health. Poor public infrastructure or proximity to food sources can exacerbate risk of food insecurity. Reduced statutory services for social care has heightened the responsibility on third sector organisations and community-led volunteering, essential to supporting healthy ageing in place and reducing the inequalities of ageing. The aim of this qualitative study was to explore how older adults' volunteering with a third sector organisation focused on food access supports food security and builds social capital for socially or economically marginalised older adults within rural and food desert communities. The study aims to bridge the knowledge gap of how volunteering in vulnerable geographies affects food insecurity and community. Semi-structured interviews were conducted with seven older (55+) volunteer 'meal makers' working with the third sector organisation Food Train and its 'Meal Makers' project. Interview recordings were transcribed and thematically analysed. Ecomap methodology was used to illustrate the lived experiences of older adult volunteers as told through the interviews. Two themes were identified by Thematic Analysis: (1) Networks, connectedness, and exposure to social capital, and (2) Supplementary support. This study finds that older adult volunteers are well placed within community interventions supporting food insecure older adults in rural or food desert communities. Ecomaps demonstrated that high social capital volunteers can mediate food access barriers and highlighted points of local knowledge and social connection. Volunteer engagement provides opportunities for food secure older adults to share local knowledge and build networks of food support and social inclusion for food insecure older adults. Older age volunteering should be advocated as a multi-faceted intervention promoting mutual health and wellbeing in volunteer and beneficiary.

High phase resolution: Probing interactions in complex interfaces with sum frequency generation.

An often-quoted statement attributed to Wolfgang Pauli is that God made the bulk, but the surface was invented by the devil. Although humorous, the statement really reflects frustration in developing a detailed picture of a surface. In the last several decades, that frustration has begun to abate with numerous techniques providing clues to interactions and reactions at surfaces. Often these techniques require considerable prior knowledge. Complex mixtures on irregular or soft surfaces-complex interfaces-thus represent the last frontier. Two optical techniques: sum frequency generation (SFG) and second harmonic generation (SHG) are beginning to lift the veil on complex interfaces. Of these techniques, SFG with one excitation in the infrared has the potential to provide exquisite molecular- and moiety-specific vibrational data. This Perspective is intended both to aid newcomers in gaining traction in this field and to demonstrate the impact of high-phase resolution. It starts with a basic description of light-induced surface polarization that is at the heart of SFG. The sum frequency is generated when the input fields are sufficiently intense that the interaction is nonlinear. This nonlinearity represents a challenge for disentangling data to reveal the molecular-level picture. Three, high-phase-resolution methods that reveal interactions at the surface are described.

ST2-Conditioned Medium Fosters Dorsal Horn Cell Excitability and Synaptic Transmission in Cultured Mouse Spinal Cord.

Conditioned medium obtained from bone marrow-derived stem cells has been proposed as a novel cell-free therapy in spinal cord injury and neuropathic pain, yet the direct effect on spinal neuron function has never been investigated. Here, we adopted spinal cord organotypic cultures (SCOCs) as an experimental model to probe the effect of ST2 murine mesenchymal stem cells-conditioned medium (ST2-CM) on dorsal horn (DH) neuron functional properties. Three days of SCOC exposure to ST2-CM increased neuronal activity measured by Fos expression, as well as spontaneous or induced firing. We showed that the increase in neuronal excitability was associated with changes in both intrinsic membrane properties and an enhanced excitatory drive. The increased excitability at the single-cell level was substantiated at the network level by detecting synchronous bursts of calcium waves across DH neurons. Altogether, SCOCs represent a viable tool to probe mesenchymal cells' effect on intact neuronal networks. Our findings indicate that ST2-CM enhances neuronal activity and synaptic wiring in the spinal dorsal horn. Our data also support the trophic role of mesenchymal cells CM in maintaining network activity in spinal circuits.

Extracellular vesicles derived from umbilical cord mesenchymal stromal cells show enhanced anti-inflammatory properties via upregulation of miRNAs after pro-inflammatory priming.

Autoimmune conditions, such as rheumatoid arthritis, are characterised by a loss of immune tolerance, whereby the immune cells attack self-antigens causing pain and inflammation. These conditions can be brought into remission using pharmaceutical treatments, but often have adverse side effects and some patients do not respond favourably to them. Human umbilical cord mesenchymal stromal cells (UCMSCs) present a promising alternative therapeutic due to their innate anti-inflammatory properties which can be strengthened using pro-inflammatory conditions. Their therapeutic mechanism of action has been attributed to paracrine signalling, by which nanosized acellular particles called 'extracellular vesicles' (EVs) are one of the essential components. Therefore, this research analysed the anti-inflammatory properties of UCMSC-EVs 'primed' with pro-inflammatory cytokines and at baseline with no inflammatory cytokines (control). Both control and primed EVs were co-cultured with un-pooled peripheral blood mononuclear cells (PBMCs; n = 6) from healthy donors. Neither control nor primed EVs exerted a pro-inflammatory effect on PBMCs. Instead, the primed EVs showed the immunosuppressive potential by increasing the expression of the anti-inflammatory protein FoxP3 in PBMCs. This may be attributed to the upregulated miRNAs identified in primed EVs in comparison to control EVs (miR-139-5p, miR-140-5p, miR-214-5p). These findings aid in understanding how UCMSC-EVs mediate immunosuppression and support their potential use in treating autoimmune conditions.

Extracellular Vesicle Depletion Protocols of Foetal Bovine Serum Influence Umbilical Cord Mesenchymal Stromal Cell Phenotype, Immunomodulation, and Particle Release.

The immunomodulatory properties of MSCs can be recreated using their extracellular vesicles (EVs). Yet, the true capabilities of the MSC EVs cannot be distinguished from contaminating bovine EVs and protein derived from supplemental foetal bovine serum (FBS). FBS EV depletion protocols can minimise this, but vary in terms of depletion efficiency, which can negatively impact the cell phenotype. We explore the impact of FBS EV depletion strategies, including ultracentrifugation, ultrafiltration, and serum-free, on umbilical cord MSC characteristics. Whilst a greater depletion efficiency, seen in the ultrafiltration and serum-free strategies, did not impact the MSC markers or viability, the MSCs did become more fibroblastic, had slower proliferation, and showed inferior immunomodulatory capabilities. Upon MSC EV enrichment, more particles, with a greater particle/protein ratio, were isolated upon increasing the FBS depletion efficiency, except for serum-free, which showed a decreased particle number. Whilst all conditions showed the presence of EV-associated markers (CD9, CD63, and CD81), serum-free was shown to represent a higher proportion of these markers when normalised by total protein. Thus, we caution MSC EV researchers on the use of highly efficient EV depletion protocols, showing that it can impact the MSC phenotype, including their immunomodulatory properties, and stress the importance of testing in consideration to downstream objectives.

A comprehensive review of quantum bioreactor cell manufacture: Research and clinical applications.

The Quantum cell expansion system manufactured by Terumo-BCT is perhaps the most widely reported Good Manufacturing Practice-compliant bioreactor used for the expansion of adherent cell populations, both for research purposes and clinical cell-based therapies/trials. Although the system was originally designed for adherent cell expansion, more recently suspension cultures and extracellular vesicle manufacturing protocols have been published using the Quantum system. Cell therapy research and regenerative medicine in general is a rapidly expanding field and as such it is likely that the use of this system will become even more widespread and perhaps mandatory, for both research and development and in the clinic. The purpose of this review is to describe, compare and discuss the diverse range of research and clinical applications currently using the Quantum system, which to our knowledge has not previously been reviewed. In addition, current and future challenges will also be discussed.

Pericardial effusion secondary to epicardial undifferentiated pleomorphic sarcoma in a young cat.

Case summary: A 6.4 kg 3-year-old male neutered indoor-outdoor domestic shorthair cat was referred for further evaluation of non-resolving lethargy and hyporexia of 4 days' duration. Physical examination identified tachypnea with mild respiratory effort and muffled lung sounds bilaterally. Point-of-care ultrasound revealed a large volume of pleural and pericardial effusion (PCE), which was confirmed by thoracic radiography. Echocardiogram indicated normal cardiac function but revealed a mass-like structure along the left epicardium within the pericardial space. After 72 hours in hospital, re-evaluation via echocardiogram showed the epicardial mass lesion to have doubled in size and with apparent extension to involve the pericardium. The patient was hospitalized for 72 h of supportive care and intervention, including therapeutic pericardiocentesis, bilateral thoracocentesis, thoracic and cardiac imaging and infectious disease testing. On the third day of hospitalization, the patient developed cardiac tamponade. Further workup was discussed, including CT and subtotal pericardiectomy with biopsy, but the cat was euthanized due to clinical decline and rapid re-accumulation of effusion. Post-mortem histopathologic evaluation diagnosed an epicardial pleomorphic sarcoma, exclusive of mesothelioma or histiocytic sarcoma on immunohistochemistry (IHC). Relevance and novel information: This report describes a case of epicardial undifferentiated pleomorphic sarcoma (UPS) in a young cat presenting with pleural and PCE. Pleomorphic sarcoma is a rarely reported mesenchymal neoplasia in the feline patient and has thus far primarily been identified in peripheral soft tissue structures. IHC is key to the correct histopathologic diagnosis. To our knowledge, epicardial UPS has not been previously reported in a cat.

Impact of Celiac Disease on Dating.

BACKGROUND/AIMS: When seeking a romantic partner, individuals with celiac disease (CD) must navigate challenging social situations. We aimed to investigate dating-related behaviors in adults with CD. METHODS: A total of 11,884 affiliates of the Celiac Disease Center at Columbia University were invited to participate in an online survey. Adults (≥ 18 years) with biopsy-diagnosed CD were included. Among the 5,249 who opened the email, 538 fully completed the survey (10.2%). The survey included a CD-specific dating attitudes/behaviors questionnaire, a Social Anxiety Questionnaire (SAQ), a CD-specific quality of life instrument (CD-QOL), and a CD Food Attitudes and Behaviors scale (CD-FAB). RESULTS: Respondents were primarily female (86.8%) and the plurality (24.4%) was in the 23-35 year age range. 44.3% had dated with CD, and among them, 68.4% reported that CD had a major/moderate impact on their dating life. A major/moderate impact was more commonly reported among females (69.3%, p < 0.001), 23-35-year-olds (77.7%, p = 0.015), those with a household income < $50 K (81.7%, p = 0.019), and those with a lower CD-QOL score (50.5 vs. 73.4, p = 0.002). While on dates, 39.3% were uncomfortable explaining precautions to waiters, 28.2% engaged in riskier eating behaviors, and 7.5% intentionally consumed gluten. 39.0% of all participants were hesitant to kiss their partner because of CD; females more so than males (41.1% vs. 22.7%, p = 0.005). CONCLUSIONS: The majority of participants felt that CD had a major/moderate impact on their dating life. This impact may result in hesitation toward dating and kissing, decreased QOL, greater social anxiety, and less adaptive eating attitudes and behaviors. CD and the need to adhere to a gluten free diet have a major impact on dating and intimacy.

Microvillous tip vesicles may be an origin of placental extracellular vesicles.

INTRODUCTION: Extracellular vesicles are now believed to be important mediators of placental-maternal communication. However, little is known about the formation of extracellular vesicles by human placenta. This study uses nanoscale three-dimensional imaging to investigate how and where placental extracellular vesicles form. METHODS: Term and first trimester human placental villi were imaged by serial block face scanning electron microscopy. These images were analysed to quantify vesicle surface density. Segmentation was performed to reconstruct three-dimensional images of extracellular vesicles. Live imaging light microscopy of first trimester villous explants was performed. RESULTS: Vesicles were observed on the tips of placental microvilli in term and first trimester placenta. In term placenta these microvillous tip vesicles had a median size of 0.55 µm and their surface area density exceeded 22000 per mm2. Microvillous tip vesicle membranes had a lower electron density than the microvillous plasma membrane. Thirty seven percent of vesicles had a complex membrane structure including double membranes, internal vesicles and vesicle chains. Budding of smaller secondary vesicles from microvillous tip vesicle membranes was observed. Live imaging of a first trimester villus explant observed formation of vesicles which were larger but visually similar to the secondary vesicles observed by electron microscopy. DISCUSSION: These observations suggest that extracellular vesicles are forming on the tips of placental microvilli prior to release into maternal blood. However, it cannot be discounted that there are maternal extracellular vesicles that have bound to microvilli. In either case, the high surface area density of microvillous tip vesicles is consistent with an important role in placental-maternal signalling.

Fertility preserving management for postpartum haemorrhage secondary to subinvolution of the placental implantation site.

A 40-year-old woman presents with recurrent secondary postpartum haemorrhage (PPH) following her third normal vaginal delivery. Histology from subsequent evacuation of the uterus confirmed that she had subinvolution of the placental implantation site. Hysterectomy is the most common method of managing this condition and recurrent PPH, most often due to significant vaginal bleeding. We present a case of subinvolution of the placental implantation site with recurrent PPH managed with medical treatment alone, to offer a fertility-sparing treatment option.

A Systematic Review and Meta-Analysis Examining Whether Changing Ovarian Sex Steroid Hormone Levels Influence Cerebrovascular Function.

Sex differences in cerebrovascular disease rates indicate a possible role for ovarian sex steroid hormones in cerebrovascular function. To synthesise and identify knowledge gaps, a systematic review and meta-analysis was conducted to assess how ovarian sex steroid hormone changes across the lifespan affect cerebrovascular function in women. Three databases (EMBASE, MEDLINE and Web of Science) were systematically searched for studies on adult cerebrovascular function and ovarian sex steroid hormones. Forty-five studies met pre-defined inclusion criteria. Studied hormone groups included hormone replacement therapy (HRT; n = 17), pregnancy (n = 12), menstrual cycle (n = 7), menopause (n = 5), oral contraception (n = 2), and ovarian hyperstimulation (n = 2). Outcome measures included pulsatility index (PI), cerebral blood flow/velocity (CBF), resistance index (RI), cerebral autoregulation, and cerebrovascular reactivity. Meta-analysis was carried out on HRT studies. PI significantly decreased [-0.05, 95% CI: (-0.10, -0.01); p = 0.01] in post-menopausal women undergoing HRT compared to post-menopausal women who were not, though there was considerable heterogeneity (I 2 = 96.8%). No effects of HRT were seen in CBF (p = 0.24) or RI (p = 0.77). This review indicates that HRT improves PI in post-menopausal women. However, there remains insufficient evidence to determine how changing ovarian sex steroid hormone levels affects cerebrovascular function in women during other hormonal phases (e.g., pregnancy, oral contraception).

Public Attitudes towards Medicinal Waste and Medicines Reuse in a 'Free Prescription' Healthcare System.

This study investigates public attitudes towards medicinal waste and medicines reuse within a 'free prescription' healthcare system. A quantitative online survey was employed in a sample drawn from the population of Wales, where prescription medicines have been 'free' since 2007. Qualitative interviews informed the content of the attitude statements with categorical or ordinal response options assigned. The questionnaire was hosted on the HealthWise Wales platform for 1 year from October 2017. Of the 5584 respondents, 67.2% had at least one medicine on repeat prescription. Overall, 89.1% held strong concerns about medicinal waste. High acceptance for the reuse of prescription medicines which have been returned unused by patients to pharmacies was reported for tablets (78.7%) and capsules (75.1%) if the medicine is checked by a pharmacist first (92.4% rated essential). Concerns identified related to tampering of packs (69.2%) and the need for hygienic storage (65.4%). However, those working in healthcare had less concern about the safety of reusing medicines. The level of public acceptance for the reuse of medication was higher than previously reported. This is the largest survey to capture these views to date, which has implications for the future design of medicines reuse schemes.

Demyelinating Events Following Initiation of Anti-TNFα Therapy in the British Society for Rheumatology Biologics Registry in Rheumatoid Arthritis.

OBJECTIVE: To establish the incidence of demyelination in patients who have received anti-tumor necrosis factor alpha (anti-TNFα) therapy, through analysis of adverse events reported in a prospective cohort of patients receiving biological therapies. METHODS: A cohort study was performed on prospectively acquired data via the British Society for Rheumatology Biologics Register in Rheumatoid Arthritis. All potential demyelinating events during follow-up were extracted and classified as definite, probable, or possible blinded to treatment data. The point of starting an anti-TNF therapy in individuals with no prior reported demyelination was the time of exposure. Crude rates of demyelination and standardized incident rates (SIRs) compared with the general UK population were calculated. RESULTS: Thirty-five individuals with demyelinating events were identified from a total pool of 13,489. The median age at study entry was 44 years, and the median disease duration was 8 years; 71% were female. Events occurred a median of 3 (interquartile range 1-5) years from the start of the first anti-TNF therapy. Twenty-six events occurred in individuals still taking anti-TNFα therapy; of the other 9, 6 were within 90 days of drug withdrawal. The raw incidence of demyelination was 19.7/100,000 patient-years (95% CI 13.7-27.3). The SIR in the whole population was 1.38 (95% CI 0.96-1.92) and 0.83 (0.51-1.26) limited to definite/probable cases. CONCLUSIONS: Demyelination following anti-TNF therapy is uncommon. Patients receiving anti-TNFα therapy show a marginally increased SIR; this is lost in sensitivity analyses. Patients concerned about anti-TNFα-associated demyelination can be relatively reassured by these data.

Successful treatment of severe COVID-19 pneumonia and hyperinflammatory syndrome with tocilizumab.

As of 28 October 2020, there are over 44 000 000 confirmed COVID-19 infections and over 1 000 000 deaths worldwide, including 945 367 infections and 45 765 deaths in the UK. Acute respiratory distress syndrome occurs in 50% of patients with secondary haemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome characterised by a surge of cytokines, including interleukin 6 (IL-6). Here we describe the case of the first patient with severe COVID-19 pneumonia successfully treated with tocilizumab, a humanised monoclonal antibody against the IL-6 receptor, in the UK. Early treatment (after 7-10 days from the onset of symptoms) with tocilizumab could (1) reduce the risk of requiring non-invasive or invasive ventilation; (2) offer a chance of survival to people who are not fit for escalation or have refused to be ventilated; and (3) potentially increase the chance of survival in some patients who are already ventilated but fail to improve with supportive treatment.

Serum cytokine profiles in healthy nonhuman primates are blunted by sedation and demonstrate sexual dimorphism as detected by a validated multiplex immunoassay.

Cytokine profiling is a valuable tool for monitoring immune responses associated with disease and treatment. This study assessed the impact of sex and sedation on serum cytokines in healthy nonhuman primates (NHPs). Twenty-three cytokines were measured from serum using a bead-based multiplex assay. Assay validation for precision, sensitivity, recovery, linearity, and stability was performed. Samples from male and female cynomolgus and rhesus macaques either cooperating or sedated were compared. All cytokines except TNFα demonstrated acceptable sensitivity and precision, with variable recovery and linearity. IFNγ, IL-2, IL-5, IL-6, IL-8, IL-12/23 (p40), IL-13, IL-15, MCP-1, TGFα, VEGF met acceptance criteria; G-CSF, IL-4, IL-10, MIP1α, sCD40L were marginal. Higher cytokine levels were observed in females and cytokine levels were blunted in sedated NHPs when compared to awake cooperating NHPs. Significant differences observed in cytokines related to sex, species, or imposed by handling highlight the importance of model design on translational relevance for clinical settings.

CRISPRi enables isoform-specific loss-of-function screens and identification of gastric cancer-specific isoform dependencies.

INTRODUCTION: Genes contain multiple promoters that can drive the expression of various transcript isoforms. Although transcript isoforms from the same gene could have diverse and non-overlapping functions, current loss-of-function methodologies are not able to differentiate between isoform-specific phenotypes. RESULTS: Here, we show that CRISPR interference (CRISPRi) can be adopted for targeting specific promoters within a gene, enabling isoform-specific loss-of-function genetic screens. We use this strategy to test functional dependencies of 820 transcript isoforms that are gained in gastric cancer (GC). We identify a subset of GC-gained transcript isoform dependencies, and of these, we validate CIT kinase as a novel GC dependency. We further show that some genes express isoforms with opposite functions. Specifically, we find that the tumour suppressor ZFHX3 expresses an isoform that has a paradoxical oncogenic role that correlates with poor patient outcome. CONCLUSIONS: Our work finds isoform-specific phenotypes that would not be identified using current loss-of-function approaches that are not designed to target specific transcript isoforms.