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The response of objects engulfed in, and adjacent to, large-scale pool fires is of interest in accident and safety assessments. In this study, Fuego, a low-Mach turbulent reacting flow code was used to study conjugate heat transfer in a 7.9 m diameter JP-8 pool fire. Simulations were designed to replicate past experimental measurements (Blanchat et al., 2006) of incident heat flux to three cylindrical calorimeters in and around the pool fire. Two turbulent combustion models were compared directly - the eddy dissipation concept and a more recently developed unsteady flamelet model. First and second order spatial and temporal discretization schemes were also compared to assess the performance of low-dissipation numerical operators. Heat flux predictions to the transportation size calorimeter outside the fire were within experimental uncertainties. Inside the fire, experimental measurements were higher than predicted values and may have been a consequence of soot deposition and augmented participating media radiation from soot and fuel vapor. Simulation predictions improved in cases where turbulent kinetic energy and mixing were more resolved. This work, and others referenced herein, suggest that spatial resolution on the order of 0.5–1.0 cm may be required to fully resolve fluid instabilities, vortex production between fire plumes and crosswind, soot production, and fuel-air mixing. This presents a substantial computational challenge for safety assessments of engulfed objects in fully turbulent pool fires.

Background: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer. Patient and methods: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen's Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after a washout period. Results: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Inter-observer agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. Similarly, consensus-observer agreement was substantial to almost perfect in the whole cohort and moderate to substantial in the HER2-low group. Conclusion: HER2-low breast cancer suffers from lower concordance among expert pathologists. While most cases can reproducibly be classified, a small proportion (10%) remained challenging. Refining the criteria for reporting and consensus scoring will help select appropriate patients for targeted therapy.

This commentary is a critical reflection by early career researchers (ECRs) working in qualitative health research (QHR) during the COVID-19 pandemic. The consequences of the pandemic have been acutely felt by ECRs working in QHR. Many studies stopped, almost overnight, as healthcare institutions restricted access and redeployed staff, forcing researchers to redesign or even abandon projects. We reflect on the burden of these challenges for insecurely employed QHR ECRs and discuss the approaches adopted to retain scientific integrity and redesign studies. We also highlight the impact of COVID-19 on career development and relationship building – both during the emergency pandemic period and in the reshaped context of academia that continues to operate under the long shadow of COVID-19. We conclude by outlining a programme of change for how the practice and organisation of QHR could be reshaped, identifying opportunities for learning from the pandemic. Embracing these learnings will benefit not only the careers and wellbeing of QHR ECRs, but also universities, funders and the overall health and future of QHR.

Background & Aims: AXL and MERTK expression on circulating monocytes modulated immune responses in patients with cirrhosis (CD14+HLA-DR+AXL+) and acute-on-chronic liver failure (CD14+MERTK+). AXL expression involved enhanced efferocytosis, sustained phagocytosis, but reduced tumor necrosis factor-α/interleukin-6 production and T-cell activation, suggesting a homeostatic function. Axl was expressed on murine airway in tissues contacting the external environment, but not interstitial lung- and tissue-resident synovial lining macrophages. Here, we assessed AXL expression on tissue macrophages in patients with cirrhosis. Methods: Using multiplexed immunofluorescence we compared AXL expression in liver biopsies in cirrhosis (n = 22), chronic liver disease (n = 8), non-cirrhotic portal hypertension (n = 4), and healthy controls (n = 4). Phenotype and function of isolated primary human liver macrophages were characterized by flow cytometry (cirrhosis, n = 11; control, n = 14) ex vivo. Also, AXL expression was assessed on peritoneal (n = 29) and gut macrophages (n = 16) from cirrhotic patients. Regulation of AXL expression was analyzed in vitro and ex vivo using primary hepatic stellate cells (HSCs), LX-2 cells, and GAS6 in co-culture experiments. Results: AXL was expressed on resident (CD68+) but not tissue-infiltrating (MAC387+) liver macrophages, hepatocytes, HSCs, or sinusoidal endothelial cells. Prevalence of hepatic CD68+AXL+ cells significantly decreased with cirrhosis progression: (healthy, 90.2%; Child-Pugh A, 76.1%; Child-Pugh B, 64.5%; and Child-Pugh C, 18.7%; all P < .05) and negatively correlated with Model for End-Stage Liver Disease and C-reactive protein (all P < .05). AXL-expressing hepatic macrophages were CD68highHLA-DRhighCD16highCD206high. AXL expression also decreased on gut and peritoneal macrophages from cirrhotic patients but increased in regional lymph nodes. GAS6, enriched in the cirrhotic liver, appeared to be secreted by HSCs and down-regulate AXL in vitro. Conclusions: Decreased AXL expression on resident liver macrophages in advanced cirrhosis, potentially in response to activated HSC-secreted GAS6, suggests a role for AXL in the regulation of hepatic immune homeostasis.

Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF. Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed. Results: In ALF, baseline cortisol concentrations

For the first time, purple corn pericarp (PCP) was converted to polyphenol-rich extract using two-pot ultrasound extraction technique. According to Plackett-Burman design (PBD), the significant extraction factors were ethanol concentration, extraction time, temperature, and ultrasonic amplitude that affected total anthocyanins (TAC), total phenolic content (TPC), and condensed tannins (CT). These parameters were further optimized using the Box-Behnken design (BBD) method for response surface methodology (RSM). The RSM showed a linear curvature for TAC and a quadratic curvature for TPC and CT with a lack of fit > 0.05. Under the optimum conditions (ethanol (50%, v/v), time (21 min), temperature (28 °C), and ultrasonic amplitude (50%)), a maximum TAC, TPC, and CT of 34.99 g cyanidin/kg, 121.26 g GAE/kg, and 260.59 of EE/kg, respectively were obtained with a desirability value 0.952. Comparing UAE to microwave extraction (MAE), it was found that although UAE had a lower extraction yield, TAC, TPC, and CT, the UAE gave a higher individual anthocyanin, flavonoid, phenolic acid profile, and antioxidant activity. The UAE took 21 min, whereas MAE took 30 min for maximum extraction. Regarding product qualities, UAE extract was superior, with a lower total color change (ΔE) and a higher chromaticity. Structural characterization using SEM showed that MAE extract had severe creases and ruptures, whereas UAE extract had less noticeable alterations and was attested by an optical profilometer. This shows that ultrasound, might be used to extract phenolics from PCP as it requires lesser time and improves phenolics, structure, and product qualities.

In November 2022, the findings of the Avoiding Late Diagnosis of Ovarian cancer (ALDO) study were published. Subsequent media coverage suggested that investigators had found a safe alternative to risk-reducing bilateral salpingoophorectomy (rrBSO) in patients with pathogenic BRCA1 and BRCA2 germline mutations who chose to decline or defer risk-reducing surgery. Unfortunately, this media coverage was largely misleading. Specifically, in the ALDO trial, 4 of 6 patients found to have ovarian cancer by the ALDO screening methodology were diagnosed with advanced-stage disease. The primary endpoint of the ALDO study was the rate of complete surgical cytoreduction, rather than stage at diagnosis or overall survival, which is an inappropriate surrogate for benefit in a population at risk of ovarian cancer.The ALDO trial again demonstrates that screening women at high-risk of ovarian cancer should not be considered a safe alternative to risk-reducing surgery, and can lead to false reassurance and the development of preventable cases of ovarian cancer. While we should continue to investigate new screening options, future efforts should largely focus on why patients decline rrBSO in the first place and how we can pivot our efforts to better address concerns related to rrBSO, including sequelae of surgical menopause. Furthermore, as we continue to understand the role of the fallopian tube in the epithelial ovarian cancer (EOC) disease process, we must identify the role of salpingectomy alone in prevention of EOC.

Summary: Background: Research has demonstrated that healthcare professionals are not immune to weight stigma attitudes, with evidence showing that people living with overweight or obesity may experience direct and indirect stigma and discrimination. This can impact the quality of care provided and impact patients' engagement in healthcare. Despite this, there is a paucity of research examining patient attitudes towards healthcare professionals living with overweight or obesity, which can also hold implications for the patient–practitioner relationship. Thus, this study examined whether healthcare professionals’ weight status impacts patient satisfaction and recalled advice. Methods: In this prospective cohort study, using an experimental design, 237 participants (113 women, 125 men) aged 32 ± 8.92 with a body mass index of 25.87 ± 6.79 kg m2 were recruited through a participant pooling service (ProlificTM), word of mouth, and social media. The majority of participants were from the UK: 119, followed by participants from the USA: 65, Czechia: 16, Canada: 11, and other countries (N = 26). Participants completed an online experiment consisting of questionnaires assessing satisfaction with healthcare professionals and recalled advice after exposure to one of eight conditions assessing the impact of healthcare professional weight status (lower weight or obesity), gender (woman or man) and profession (psychologist or dietitian). A novel approach to creating the stimuli was used to exposure participants to healthcare professionals of different weight status. All of the participants responded to the experiment hosted on Qualtrics™ in the period from June 8, 2016 to July 5, 2017. Study hypotheses were examined using linear regression with dummy variables and follow up post-hoc analysis to estimate marginal means with adjustment for planned comparisons. Findings: The only statistically significant result was a difference with a small effect in patient satisfaction, where satisfaction was significantly higher in healthcare professional who was a women living with obesity compared to healthcare professional who was a man living with obesity (estimate = −0.30; SE = 0.08; df = 229; ωₚ2 = 0.05; CI = −0.49 to −0.11; p

The application of high energy density photonic sources to the surface of metallic substrates causes localised topological evolution as the interface deforms due to hydrodynamic forces through fusion and vapourisation state transitions. Understanding how this laser energy is deposited, which may involve multiple reflection events, coupled with a thermal-fluid-dynamics framework capable of describing the heat and mass transfer in the system, permits accurate predictions of many important processes, including Laser Powder Bed Fusion, selective laser melting and laser welding among many others. In this work, we present laserbeamFoam: a multi-phase thermal-fluid-dynamics solver incorporating a ray-tracing algorithm and associated Fresnel equation implementation to determine the absorptivity of the discretised laser rays as a function of incidence angle through multiple reflections. laserbeamFoam is released under the GNU general public license with source code available on GitHub.

Summary: Background: People living with overweight or obesity (PLwO) can be stigmatised by healthcare professionals (HCPs). Reducing focus on weight is a proposed strategy to provide less threatening healthcare experiences. Given the lack of research on weight bias within obesity services, this study aimed to explore implicit bias among obesity specialist HCPs and explore views on non-weight focused approaches. Methods: Obesity specialist HCPs were invited to a webinar, “An exploration of non-weight focused approaches within bariatric services”, held in October 2021. Implicit weight bias was examined using the BiasProof mobile device test, based on the Implicit Association Test. Poll data was analysed descriptively, and qualitative data was analysed using framework analysis. Findings: 82 of the 113 HCPs who attended the webinar consented to contribute data to the study. Over half (51%) had an implicit weight bias against PLwO. Most (90%) agreed/strongly agreed that obesity services are too weight focused and that patients should not be weighed at every appointment (86%). Perceived benefits of taking a non-weight focused approach included patient-led care, reducing stigma and supporting patient wellbeing, while perceived barriers included loss of objectivity, inducing risk and difficulty demonstrating effectiveness. Interpretation: Our findings indicate that half of obesity specialists HCPs in our sample of 82 providers, who are primarily dieticians and psychologists, have an implicit weight bias against PLwO. HCPs feel that a weight-focused approach within services was a barrier to patient care, but that there is a lack of alternative non-weight focused measures. Further research is needed into substitute outcome measures for clinical practice, also seeking the views of PLwO, and into interventions to address implicit weight bias. Funding: Johnson & Johnson funded the BiasProof licence and publication open access charge.

Objectives: A country’s immunization system's effectiveness depends on its supply chain's efficacy. To assess the challenges of maintaining an efficient vaccine supply chain, Malawi conducted its assessment using The EVM2.0 tool (Effective Vaccine Management). Methods: It is a cross-sectional study in which all EVM requirements were assessed between September and October 2021. Data were collected from eighty-two randomly selected sites using the site selection tool of the EVM. Data were entered into the EVM assessment tool 2.0 version 1.12 for analysis. This tool generates performance indicators and criteria scores for assessed sites, compared with a WHO minimum score of 80%. Results: Overall criteria scores across all levels of the immunization supply chain showed a statistically significant mean difference of 5.92 (t = 2.58, P = 0.02). Comparative overall mean criteria scores across different levels of the immunization supply chain showed no statistically significant difference for primary (p = 0.76), sub-national (p = 0.69), and lowest distribution stores (p = 0.12). However, a substantial gap was found in the overall mean scores of the health facility’s service point (SP) (t = 4.12, P = 0.001). The overall category scores across all immunization supply chain levels did not show a statistically significant difference. However, among individual category scores, Infrastructure (76 %), Equipment (67 %), Policies and procedures (62 %), Financial (47 %), and Resources (64 %) were found to be below the WHO minimum score. Conclusion: Though the 2021 Malawi EVM assessment findings are promising, they still identified the gaps to be improved to ensure the vaccine availability in the right amount, at the right time, and at the right cost.

The National Petroleum Reserve in Alaska (NPR-A) encompasses more than 9.5 million hectares of federally managed land on the Arctic Coastal Plain of northern Alaska, where it supports a diversity of wildlife, including millions of migratory birds. Within the NPR-A, Teshekpuk Lake and the surrounding area provide important habitat for migratory birds and this area has been designated by the Bureau of Land Management as the Teshekpuk Lake Special Area (TLSA) because numerous waterfowl species use the area for breeding and molting. Our goal was to provide a mechanism for land managers to assess relative value of areas for molting waterfowl. This approach was based on the population densities of Pacific black brant (Branta bernicla nigricans) and cackling geese (Branta hutchinsii) and pre-defined thresholds for the minimum fraction of the population contained within selected areas. Prioritizations were based on long-term records of population density combined with global-positioning system data to reveal small-scale patterns of habitat use. The highest population density of the Pacific black brant was found along the Beaufort Sea coast on the eastern edge of the study area, whereas cackling geese were somewhat more widely distributed. Depending on the criteria used for prioritization and width of protective buffers placed around selected units, 52–85% of the Goose Molting Area was identified as high-priority area. The effectiveness of this approach to protection of molting birds assumes that buffers around high value units are wide enough to provide adequate protection from disturbance related to oil and gas development.

High energy density advanced manufacturing processes, such as power beam welding and additive manufacturing, are notoriously difficult to simulate. Such processes initiate fusion, and vapourisation, state transitions in their respective (normally metallic) substrates generating complex metallic flows over incredibly short time scales. To mathematically model such processes, equations describing the conservation of momentum, conservation of energy, and an equation that describes the evolution of the metallic substrate interface must be considered. In this work, we present beamWeldFoam, an OpenFOAM solver capable of simulating these high energy density advanced manufacturing processes. In beamWeldFoam, the metallic substrate, and shielding gas phase, are treated as incompressible. The volumetric dilation due to the vapourisation state transition is neglected, instead, a phenomenological recoil pressure term is used to capture the contribution to the momentum and energy fields due to vaporisation events. beamWeldFoam is released under the GNU general public license, and its source code is available on Github.

Summary: Evidence has accumulated to demonstrate the pervasiveness, impact and implications of weight stigma. As such, there is a need for concerted efforts to address weight stigma and discrimination that is evident within, policy, healthcare, media, workplaces, and education. The continuation of weight stigma, which is known to have a negative impact on mental and physical health, threatens the societal values of equality, diversity, and inclusion. This health policy review provides an analysis of the research evidence highlighting the widespread nature of weight stigma, its impact on health policy and the need for action at a policy level. We propose short- and medium-term recommendations to address weight stigma and in doing so, highlight the need change across society to be part of efforts to end weight stigma and discrimination. Funding: None.

Coronary artery fistula (CAF) is an abnormal connection between a coronary artery and a heart chamber resulting in left-to-right shunt. A large CAF was an unexpected cause of heart failure in a 58-year-old woman who underwent transcatheter closure of the CAF with improvement in symptoms but complicated by myocardial infarction. (Level of Difficulty: Beginner.)

Background: Ensuring that patients have high quality, equitable experiences in healthcare is a high priority in the UK. As such, identifying and addressing areas where patient experiences are unsatisfactory and inequitable is of high priority, and has been included as part of the National Health Service (NHS) England equity objectives. Methods: The healthcare experiences of people who identified as living with overweight or obesity were gathered from freely available websites using the Patient Experience Platform (PEP). PEP was used to gather and analyse all comments from NHS UK, Google, Facebook and Twitter that related to care experiences of people who identified as living with overweight or obesity across all NHS Acute and Specialist Trusts and all general practitioners (GPs) in England from 01/01/2018 to 31/12/2020. These healthcare experiences were analysed to provide care quality metrics, a comparison of care across regions of England, and to explore associations between behavioural clusters of personality attributes, values and sentiment with care quality metrics. Findings: Perceptions of the quality of care were significantly lower for people who identified as living with overweight or obesity compared to people who didn't identify as living with overweight or obesity across all regions for ‘Effective Treatment’ and ‘Emotional Support’. The perceived quality of care metrics can be predicted by the behavioral clusters, where for instance, the experiences of people who identified as living with overweight or obesity in the negative behavioral cluster have a lower overall perceived quality of care score. Themes arising from the data also highlighted that barriers quality care experienced by people who identified as living with obesity include the speed of access, effective treatment, and emotional support, with stigmatising healthcare experiences are reported. Interpretation: The findings of this study provide insights into the experiences reported via freely available websites, of people who self-identified as living with overweight or obesity in healthcare in England. These insights demonstrate that the perceived quality of care was lower for people who identified as living with overweight or obesity compared to the general population, and that there is regional variation in care quality. The study has also shown that patient experiences differ based on personality attributes, values and sentiment, highlighting the need for patient-centred care and personalised approaches. These findings hold important considerations for healthcare and policy makers aiming to address healthcare inequity.

Summary: Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properties of DMF were examined following paracetamol exposure. Transcriptomic and biochemical analysis revealed that DMF rescue was underpinned by reduced Nf-kB and TGF-β signaling and cell senescence. Following on from these studies, we employed a Zebrafish model to study paracetamol exposure in vivo. We combined a genetically modified Zebrafish model, expressing green fluorescent protein exclusively in the liver, with automated microscopy. Pre-treatment with DMF, prior to paracetamol exposure, led to reduced liver damage in Zebrafish demonstrating protective properties.

Background: Coronavirus disease 2019 (COVID-19) has led to unprecedented changes in the way we live, particularly for people at higher risk of severe illness from COVID-19. People with pre-existing health conditions have been markedly impacted and, in some instances, left unsupported due to reduced provision of routine healthcare services. People living with obesity (PLWO) are identified as at higher risk of severe illness from COVID-19 infection. Currently, there is a paucity of evidence about the impact of the first COVID-19 lockdown on PLWO, including those accessing weight management and bariatric surgery services (WMS). Methods: 543 adults (16–80 years) with obesity (BMI ≥ 30 kg/m2) were recruited between 14th May and 9th July 2020 through social media advertisements, professional and patient obesity organisations and WMS. Participants completed an online survey regarding the impact of the first COVID-19 lockdown upon, mental health, well-being, health-related behaviours, risk mitigating behaviours, access to WMS and weight stigma. Findings: During the first COVID-19 lockdown, the majority of PLWO reported deterioration of their mental health and health-related behaviours such as diet, physical activity (PA) and sleep. With 55% reporting an unhealthier diet, 61% reduced PA and 80% worsening of their sleep. Higher depression and lower wellbeing scores were found to associate with the greatest adverse impact upon health-related behaviours. PLWO who were attending WMS prior to the first lockdown reported a greater deterioration of their diet, with nearly 50% reporting worsening of their diet and PA worsening compared to PLWO who were not attending WMS. Most participants took two or more risk mitigating actions (73%). PLWO attending WMS reported reduced access (44%) with insufficient information (49%) from their clinical service providers. The majority of participants reported no change in perceived weight stigma. Interpretation: This study shows the detrimental impact of the first COVID-19 lockdown on PLWO in relation to health-related behaviours, mental health and access to WMS. Our findings show that PLWO with poor mental health and those attending WMS were most adversely impacted and highlights the need for greater mental health support and continued provision of support from WMS for PLWO during future lockdowns. Funding: This research was funded through National Institute for Health Research University College London Hospitals Biomedical Research Centre funding.

Background: The incidence of acute cardiac injury in COVID-19 patients is very often subclinical and can be detected by cardiac magnetic resonance imaging. The aim of this study was to assess if subclinical myocardial dysfunction could be identified using left ventricular global longitudinal strain (LV-GLS) in patients hospitalized with COVID-19. Methods: We performed a search of COVID-19 patients admitted to our institution from January 1st, 2020 to June 8th, 2020, which revealed 589 patients (mean age = 66 ± 18, male = 56%). All available 60 transthoracic echocardiograms (TTE) were reviewed and off-line assessment of LV-GLS was performed in 40 studies that had sufficient quality images and the views required to calculate LV-GLS. We also analyzed electrocardiograms and laboratory findings including inflammatory markers, Troponin-I, and B-type natriuretic peptide (BNP). Results: Of 589 patients admitted with COVID-19 during our study period, 60 (10.1%) underwent TTE during hospitalization. Findings consistent with overt myocardial involvement included reduced ejection fraction (23%), wall motion abnormalities (22%), low stroke volume (82%) and increased LV wall thickness (45%). LV-GLS analysis was available for 40 patients and was abnormal in 32 patients (80%). All patients with LV dysfunction had elevated cardiac enzymes and positive inflammatory biomarkers. Conclusions: Subclinical myocardial dysfunction as measured via reduced LV-GLS is frequent, occurring in 80% of patients hospitalized with COVID-19, while prevalent LV function parameters such as reduced EF and wall motion abnormalities were less frequent findings. The mechanism of cardiac injury in COVID-19 infection is the subject of ongoing research.

The spatial variations of photosynthetic picoplankton abundance and biomass and the picoplankton's contribution to chlorophyll a concentration along the transect from Khatanga Bay to the continental slope in the western part of the Laptev Sea were studied in September 2017. Picoeukaryotes dominated in the picophytoplankton communities. Picophytoplankton in Khatanga Bay showed more variability than those over the Laptev shelf and continental slope: abundance and biomass were the highest in the southern part of the bay and markedly decreased with increasing salinity in its northern part. Picocyanobacteria were found over the shelf and slope at temperatures of +2.4 to -1.6°С and salinity from 22 to 34. Picophytoplankton contribution to total chlorophyll a on the shelf was higher than in Khatanga Bay. The study of picophytoplankton of Khatanga Bay and in the western Laptev Sea can serve as a baseline for future assessment of the Laptev Sea ecosystem response to interannual and climate changes.

Background: Case reports, case series and cohort studies have been published describing the clinical course and outcomes of people living with human immunodeficiency virus (PLWH) who contract coronavirus disease 2019 (COVID-19) pneumonia. However, the majority of the published work focuses on patients with well-controlled human immunodeficiency virus (HIV) on antiretroviral therapy (ART). Case presentation: We present a case of a new diagnosis of HIV with Acquired Immune Deficiency Syndrome (AIDS) made simultaneously to diagnosis of COVID-19, with co-infection with pneumocystis jirovecii pneumonia (PJP) and possible cytomegalovirus (CMV) pneumonitis. The patient decompensated following initiation of ART, suggestive of possible immune reconstitution inflammatory syndrome (IRIS). Conclusions: This case illustrates the importance of maintaining a high suspicion for HIV/AIDS in patients with risk factors. Additionally, this case raises the possibility that IRIS may develop in the setting of ART initiation in patients with COVID-19.

Despite substantial research, the early diagnosis of preeclampsia remains elusive. Lipids are now recognized to be involved in regulation and pathophysiology of some disease. Shotgun lipidomic studies were undertaken to determine whether serum lipid biomarkers exist that predict preeclampsia later in the same in pregnancy. A discovery study was performed using sera collected at 12–14 weeks pregnancy from 27 controls with uncomplicated pregnancies and 29 cases that later developed preeclampsia. Lipids were extracted and analyzed by direct infusion into a TOF mass spectrometer. MS signals, demonstrating apparent differences were selected, their abundances determined, and statistical differences tested. Statistically significant lipid markers were reevaluated in a second confirmatory study having 43 controls and 37 preeclampsia cases. Multi-marker combinations were developed using those lipid biomarkers confirmed in the second study. The initial study detected 45 potential preeclampsia markers. Of these, 23 markers continued to be statistically significant in the second confirmatory set. Most of these markers, representing several lipid classes, were chemically characterized, typically providing lipid class and potential molecular components using MS2. Several multi-marker panels with areas under the curve >0.85 and high predictive values were developed. Developed panels of serum lipidomic biomarkers appear to be able to identify most women at risk for preeclampsia in a given pregnancy at 12–14 weeks gestation.

Parkinson's disease (PD), caused by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta, is the most common movement disorder. While its etiology remains unknown, mitochondrial dysfunction is recognized as one of the major cellular defects contributing to PD pathogenesis. Mitochondrial uncoupling protein 2 (UCP2) has been implicated in neuroprotection in several neuronal injury models. Here we show that hucp2 expression in Drosophila DA neurons under the control of the tyrosine hydroxylase (TH) promoter protects those flies against the mitochondrial toxin rotenone-induced DA neuron death, head dopamine depletion, impaired locomotor activity and energy deficiency. Under normal conditions, hUCP2 flies maintain an enhanced locomotor activity and have higher steady-state ATP levels suggesting improved energy homeostasis. We show that while no increased mitochondrial DNA content or volume fraction is measured in hUCP2 flies, augmented mitochondrial complex I activity is detected. Those results suggest that it is increased mitochondrial function but not mitochondrial biogenesis that appears responsible for higher ATP levels in hUCP2 flies. Consistent with this notion, an up-regulation of Spargel, the Drosophila peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) homologue is detected in hUCP2 flies. Furthermore, a Spargel target gene Tfam, the mitochondrial transcription factor A is up-regulated in hUCP2 flies. Taken together, our results demonstrate a neuroprotective effect of hUCP2 in DA neurons in a Drosophila sporadic PD model. Moreover, as the TH promoter activity is present in both DA neurons and epidermis, our results reveal that hucp2 expression in those tissues may act as a stress signal to trigger Spargel activation resulting in enhanced mitochondrial function and increased energy metabolism.

The activity of a key mitochondrial tricarboxylic acid cycle enzyme, α-ketoglutarate dehydrogenase complex (KGDHC), declines in many neurodegenerative diseases. KGDHC consists of three subunits. The dihydrolipoyl succinyl transferase (DLST) component is unique to KGDHC. DLST+/− mice showed reduced mRNA and protein levels and decreased brain mitochondrial KGDHC activity. Neurotoxic effects of mitochondrial toxins were exacerbated in DLST+/− mice. MPTP produced a significantly greater reduction of striatal dopamine and tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta of DLST+/− mice. DLST deficiency enhanced the severity of lipid peroxidation in the substantia nigra after MPTP treatment. Striatal lesions induced by either malonate or 3-nitropropionic acid (3-NP) were significantly larger in DLST+/− mice than in wildtype controls. DLST deficiency enhanced the 3-NP inhibition of mitochondria enzymes, and 3-NP induced protein and DNA oxidations. These observations support the hypothesis that reductions in KGDHC may impair the adaptability of the brain and contribute to the pathogenesis of neurodegenerative diseases.

Mutations in the parkin gene cause autosomal recessive familial Parkinson's disease (PD). Parkin-deficient mouse models fail to recapitulate nigrostriatal dopaminergic neurodegeneration as seen in PD, but produce deficits in dopaminergic neurotransmission and noradrenergic-dependent behavior. Since sporadic PD is thought to be caused by a combination of genetic susceptibilities and environmental factors, we hypothesized that neurotoxic insults from catecholaminergic toxins would render parkin knockout mice more vulnerable to neurodegeneration. Accordingly, we investigated the susceptibility of catecholaminergic neurons in parkin knockout mice to the potent dopaminergic and noradrenergic neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) respectively. We report that nigrostriatal dopaminergic neurons in parkin knockout mice do not show increased susceptibility to the parkinsonian neurotoxin, MPTP, in acute, subacute and chronic dose regimens of the neurotoxin. Additionally, parkin knockout mice do not show increased vulnerability to the noradrenergic neurotoxin, DSP-4, regarding levels of norepinephrine in cortex, brain stem and spinal cord. These findings suggest that absence of parkin in mice does not increase susceptibility to the loss of catecholaminergic neurons upon exposure to both dopaminergic and noradrenergic neurotoxins.

Previously, uridine pro-drug 2′,3′,5′-tri-O-acetyluridine (PN401) was shown to be protective in the mitochondrial complex II inhibitor 3-nitropropionic acid model of Huntington's disease (HD). In this study, PN401 increased survival and improved motor function on the rotarod in both R6/2 and N171-82Q polyglutamine repeat mouse models of HD. PN401 significantly decreased neurodegeneration in both the piriform cortex and striatum although PN401 decreased huntingtin protein aggregates only in the striatum. Cortical and striatal brain-derived neurotrophic factor (BDNF) protein levels were reduced in the +/− compared to the −/− N171-82Q mice and PN401 treatment significantly increased cortical BDNF in both +/− and −/− mice, but PN401 did not affect striatal BDNF. These results suggest that PN401 may have beneficial effects in the treatment of neurodegenerative diseases such as HD.

Multiple cell death pathways are implicated in the etiology of amyotrophic lateral sclerosis (ALS), but the cause of the characteristic motor neuron degeneration remains unknown. To determine whether CNS metabolic defects are critical for ALS pathogenesis, we examined the temporal evolution of energetic defects in the G93A SOD1 mouse model of familial ALS. [14C]-2-deoxyglucose in vivo autoradiography in G93A mice showed that glucose utilization is impaired in components of the corticospinal and bulbospinal motor tracts prior to either pathologic or bioenergetic changes in the spinal cord. This was accompanied by significant depletions in cortical ATP content in presymptomatic mice, which was partially ameliorated by creatine administration. Findings suggest that bioenergetic defects are involved in the initial stages of mSOD1-induced toxicity in G93A mice and imply that the selective dysfunction and degeneration of spinal cord motor neurons in this model may be secondary to dysfunction within cerebral motor pathways.

ALS is a devastating neurodegenerative disorder for which no effective treatment exists. Multiple molecular mechanisms are involved in the pathogenesis. We tested the catalytic antioxidant AEOL 10150, the histone deacetylase inhibitor phenylbutyrate (PBA), and the combination of PBA and AEOL 10150 in the G93A transgenic mouse model, administered from disease onset. AEOL 10150 alone improved motor function and extended survival by 11%, PBA alone significantly improved motor function and extended survival by 13%. PBA and AEOL 10150 together increased survival by 19%. Increased histone acetylation was confirmed by Western blot. Quantitative real-time RT-PCR analysis revealed upregulation of compounds capable of protecting cells against oxidative stress and apoptosis. Markers of oxidative damage were reduced in the lumbar spinal cord as compared to vehicle administration. These results suggest that agents inhibiting apoptosis and blocking oxidative stress show efficacy in treating mutant-SOD1-associated ALS and that a combination of agents targeting different disease mechanisms may exert additive therapeutic effects.

Abnormalities in the function of α-synuclein are implicated in the pathogenesis of Parkinson's disease (PD). We found that α-synuclein-deficient mice are resistant to MPTP-induced degeneration of dopaminergic neurons. There was dose-dependent protection against loss of both dopamine in the striatum and dopamine transporter (DAT) immunoreactive neurons in the substantia nigra. These effects were not due to alterations in MPTP processing. We found that α-synuclein-deficient mice are also resistant to both malonate and 3-nitropropionic acid (3-NP) neurotoxicity. There was reduced generation of reactive oxygen species in α-synuclein-deficient mice following administration of 3-NP. These findings implicate α-synuclein as a modulator of oxidative damage, which has been implicated in neuronal death produced by MPTP and other mitochondrial toxins.

Promethazine (PMZ) is an FDA-approved antihistaminergic drug that was identified as a potentially neuroprotective compound in the NINDS screening program. PMZ accumulates in brain mitochondria in vivo and inhibits Ca2+-induced mitochondrial permeability transition pore (PTP) in rat liver mitochondria in vitro. We hypothesized that PMZ may have a protective effect in a mitochondrial toxin model of Parkinson's disease (PD). Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) sustained a significant loss of dopaminergic neurons within the SNpc that was strongly attenuated by PMZ treatment. However, neither striatal MPP+ concentrations nor MPTP-induced inhibition of mitochondrial complex I were affected by PMZ treatment. In isolated mouse brain mitochondria, PMZ partially prevented and reversed MPP+-induced depolarization of membrane potential and inhibited the Ca2+-induced PTP in brain mitochondria. The sum of data indicates that PMZ is a strong neuroprotective agent capable of protecting dopaminergic neurons against MPTP toxicity in vivo.

Amyotrophic lateral sclerosis (ALS) is characterized by a progressive loss of large motor neurons in the brain and spinal cord. Amyloid precursor protein (APP), the transmembrane precursor of β-amyloid (Aβ), accumulates in the anterior horn motor neurons of ALS patients with mild lesions. APP undergoes an alternative proteolysis mediated by caspase-3, which is activated in motor neurons in a mouse model of ALS. The ALS spinal cord motor neurons also show evidence of increased oxidative damage, which is thought to alter APP processing. We sought to determine whether Aβ42, the more pathogenic Aβ species, accumulates in the postmortem lumbar spinal cord of ALS patients. While there was little or no Aβ42 labeling in control spinal cord tissues, elevated Aβ42 immunoreactivity occurred in ALS motor neuronal perikarya and axonal swellings in the anterior horn. A few Aβ42-positive neurons exhibited thioflavine S staining. No extracellular Aβ42 deposits were found. Aβ42 coexisted with the oxidative damage markers malondialdehyde, 8-hydroxydeoxyguanosine, heme oxygenase-1, and nitrotyrosine in abnormal neurons. The neurons with intracellular Aβ42 accumulation also displayed robust cleaved caspase-3 immunoreactivity. Very little Aβ40 immunoreactivity occurred in motor neurons of both control and ALS. These results suggest that aberrant accumulation of Aβ42 in ALS spinal cord motor neurons is associated with oxidative stress, and may play a role in the pathogenesis of neurodegeneration in ALS.

Molecular machinery involved in apoptosis plays a role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD) and Huntington's disease (HD). Several caspase inhibitors, such as the well-known peptidyl inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone (zVADfmk), can protect neurons from apoptotic death caused by mitochondrial toxins. However, the poor penetrability of zVADfmk into brain and toxicity limits its use therapeutically. In the present study, a novel peptidyl broad-spectrum caspase inhibitor, Q-VD-OPH, which offers improvements in potency, stability, and toxicity over zVADfmk, showed significant protection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 3-nitropropionic acid (3NP), and malonate toxicities. Q-VD-OPH significantly reduced dopamine depletion in striatum produced by MPTP administration and prevented MPTP-induced loss of dopaminergic neurons in the substantia nigra. It significantly reduced the size of striatal lesions produced by intrastriatal malonate injections and systemic administration of 3NP. Western blots performed on tissues from the midbrain following administration of MPTP or the striatum in 3NP-treated animals showed increases of the active forms of caspase-9 and caspase-8, as well as the caspase-8-mediated proapoptotic protein Bid, which were inhibited Q-VD-OPH treatment. These findings suggest that systematically active broad-spectrum caspase inhibitors maybe useful in the treatment of neurodegenerative diseases such as PD and HD.

Surveillance and monitoring of foods for the presence of antimicrobial-resistant (AMR) bacteria are required to assess the risks these bacteria pose to human health. Frequently consumed raw or lightly cooked, live bivalve shellfish such as mussels and oysters can be a source of exposure to AMR bacteria. This study sought to determine the prevalence of third-generation cephalosporin (3GC) and carbapenem-resistant bacteria in live mussel and oyster shellstock available for retail purchase through the course of one calendar year. Just over half of the 180 samples (52%) tested positive for the presence of 3GC-resistant bacteria belonging to thirty distinct bacterial species. Speciation of the isolates was carried out using the Bruker MALDI Biotyper. Serratia spp., Aeromonas spp., and Rahnella spp. were the most frequently isolated groups of bacteria. Antibiotic resistance testing confirmed reduced susceptibility for 3GCs and/or carbapenems in 15 of the 29 Aeromonas isolates. Based on AMR patterns, and species identity, a subset of ten Aeromonas strains was chosen for further characterization by whole genome sequence analysis. Genomic analysis revealed the presence of multiple antibiotic resistance and virulence genes. A number of mobile genetic elements were also identified indicating the potential for horizontal gene transfer. Differences in gene detection by the bioinformatic tools and databases used (ResFinder. CARD RGI, PlasmidFinder, and MobSuite) are discussed. This study highlights the strengths and limitations of using genomics tools to perform hazard characterization of diverse foodborne bacterial species.

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Place-based socio-economic and biophysical context has been viewed as an essential driver in shaping perceptions of forest risks and land management. Growing evidence of the importance of diverse community context in forested landscapes sets the stage to further consider how people's understandings of their local environment influence natural resource management preferences. However, research to date largely lacks considerations of how community context informs social responses to long-term environmental change over time. Using the mountain pine beetle (MPB) outbreak in Colorado, we analyze and compare longitudinal interview and survey data collected from nine north-central Colorado communities to understand the relationships between community context and changing perceptions of forest disturbance and engagement with land management. Both qualitative and quantitative findings show that community context framed and continues to inform variations in local perceptions of the MPB outbreak and forest management. Interviews with key informants provided rich narratives on different context-based trajectories in local residents' perceptional responses, while survey data allowed for general patterns of evolving community variations (e.g., stable or clearer community clustering, reduced community differences) to be uncovered. We explore methodological implications for community indication and future directions for understanding differing community responses to slow-moving environmental change. Incorporating knowledge of changing local contexts and variations can also help practitioners advance toward more dynamic and effective management strategies.

Water Quality Indices (WQIs) are increasingly being applied for reporting on the suitability of water for a variety of human uses including agriculture. This systematic review identified and compared 42 examples of Agricultural use Water Quality Indices (AgWQIs) for surface waters in published literature. The review confirmed the growing popularity in AgWQI reporting, particularly in the last six years. All studies incorporated the suitability of water for irrigated cropping into their AgWQI with three also addressing stock watering. The review confirmed that all parameter thresholds adopted by AgWQI studies originated from either the Food and Agriculture Organisation of the United Nations publication Water quality for agriculture publication or National Standards. An AgWQI common key was developed to overcome interstudy method variability and facilitate comparative assessment. This assessment determined that all study methods originated from two sources, the Canadian Council of Ministers of the Environment Water Quality Index, and the National Sanitation Foundation Water Quality Index. For studies adopting the latter method, a further three strategies for parameter weightings and eight functions for developing water quality ratings were identified. Our assessment also identified and explored limitations with some equations, including a method known as the proportionality constant. Significant variation in parameters, classes, thresholds, subindices, and weightings between studies was found, but also some areas of agreement. Based on the review findings, a guide has been developed to assist in future AgWQI development.

Background: In many conditions characterised by septal hypertrophy, females have been shown to have worse outcomes compared to males. In clinical practice and research, similar cutoff points for septal hypertrophy are still used for both sexes. Here, we explore the association between different cutoff points for septal hypertrophy and survival in relation to sex. Methods and results: We performed a retrospective analysis of consecutive patients undergoing echocardiography between March 2010 and February 2021 in a large tertiary referral centre. A total of 70,965 individuals were included. Over a mean follow-up period of 59.1 ± 37 months, 9631 (25 %) males and 8429 (26 %) females died. When the same cutoff point for septal hypertrophy was used for both sexes, females had worse prognosis than males. The impact of septal hypotrophy on survival became statistically significant at a lower threshold in females compared to males: 11.1 mm (HR 1.13, CI 95 %:1.03–1.23, p = 0.01) vs 13.1 mm (HR 1.21, CI 95 %: 1.12–1.32, p

Background: For mismatch repair protein deficient (dMMR) endometrial cancer (EC), first line therapy remains platinum-based chemotherapy. For dMMR EC that has progressed on standard first line platinum containing chemotherapy, treatment with programmed death ligand-1 (PD-1) inhibitors such as pembrolizumab have become integral to second line therapy. The challenging question remains, however, what the next best step is when these treatments fail. Case: Here we report the case of a 71-year-old female who developed disease recurrence more than 20 years after surgical treatment for early stage dMMR endometrioid EC, with subsequent progression of disease on second line pembrolizumab therapy; however displayed excellent response to third line treatment with lenvatinib and pembrolizumab. Conclusion: Consensus regarding third line treatment for patients with dMMR EC who progress on single agent PD-1 inhibitors after platinum-based chemotherapy failure remains unclear. While single agent pembrolizumab has demonstrated the greatest efficacy for dMMR disease, this case demonstrates a patient who had progression of disease on single agent pembrolizumab, however had excellent response with combination pembrolizumab and lenvatinib. Further study is warranted to assess the efficacy of this regimen for advanced or recurrent dMMR EC.

Summary: Background: Obesity is highly stigmatized, with negative obesity-related stereotypes widespread across society. Internalized weight stigma (IWS) is linked to negative outcomes including poor mental health and disordered eating. Previous evidence examining population groups at higher risk of experiencing IWS comes from small, nonrepresentative samples. Here, we re-assess previously reported associations of IWS with demographic, socioeconomic, and wider social factors in a large general population birth cohort study for the first time. Methods: In the Avon Longitudinal Study of Parents and Children (ALSPAC), we explored differences in IWS at age 31 years by sex, ethnicity, socioeconomic factors, sexual orientation, and family and wider social influences, using confounder-adjusted multivariable regression. Findings: In models adjusted for potential confounders and BMI in childhood, adolescence, and adulthood (N = 4060), IWS was higher for females (standardized beta: 0.56, 95% CI: 0.50, 0.61), sexual minorities (0.17 S.D. higher, 95% CI: 0.09, 0.24), and less socioeconomically advantaged individuals (e.g., 0.16 S.D. higher (95% CI: 0.08, 0.24) for participants whose mothers had minimum or no qualifications, compared to a university degree). The social environment during adolescence and young adulthood was important: IWS was higher for people who at age 13 years felt pressure to lose weight from family (by 0.13 S.D., 95% CI: 0.03, 0.23), and the media (by 0.17, 95% CI: 0.10, 0.25), or had experienced bullying (e.g., 0.25 S.D., 95% CI: 0.17, 0.33 for bullying at age 23 years). Interpretation: Internalized weight stigma differs substantially between demographic groups. Risk is elevated for females, sexual minorities, and socioeconomically disadvantaged adults, and this is not explained by differences in BMI. Pressure to lose weight from family and the media in adolescence may have long-lasting effects on IWS. Funding: The ESRC, MRC, NIHR, and Wellcome Trust.

Introduction: This study aimed to identify social, psychological, and contextual factors that influenced attendance at routine oral health visits in a cohort of 189 preschool children who were followed over a 2-year period. Methods: Generalized estimating equation was used to examine the association between clinic attendance and the predictors. ORs and 95% CIs were reported in the multiple logistic regression models. The study was conducted in Rochester, New York, between February 2016 and February 2021. Results: Prior to the COVID-19 pandemic declaration, the rate of canceled and no-show appointments was greater for routine clinic visits (20% and 24%, respectively) than for research visits (14% and 9%, respectively) for the same participants; these rates increased during the pandemic. After adjusting for sociodemographic factors, the likelihood of a canceled or no-show appointment was associated with parental depression (OR=1.06, CI=1.03, 1.09), regardless of the type or occurrence of the visit. Conclusions: Findings from this study demonstrate that attendance to oral health care in young children is reliably reduced with parental depression and that this may provide one mechanism for early emerging health inequalities of oral health.

In this update to the laserbeamFoam toolbox, a multi-component version of the solver is included with pair-wise Fickian Diffusion between selected component pairs. This new solver, multiComponentlaserbeamFoam, captures the multi-component nature of mixing between alloys, and as-such could be used to simulate dissimilar laser joining processes, and dissimilar laser-powder-bed additive manufacturing, among others. Additionally a multi-laser version of the original laserbeamFoam solver is included (arraylaserbeamFoam) that can simulate N incident laser sources on a metallic substrate, where the direction, velocity, and other laser characteristics can be specified independently. In both these solvers, as in the original laserbeamFoam solver, the phenomenological recoil pressure treatment is used, as opposed to the full volumetric dilation treatment, for computational tractability.

Purpose: We present the case of a 48-year-old patient with recurrent World Health Organization grade II meningioma in the left occipital region who underwent a subtotal resection, followed by postoperative proton therapy to residual disease and the resection cavity. Fourteen months after radiation treatment completion, surveillance imaging revealed numerous ring-enhancing infratentorial lesions, both within and outside of the high-dose field, of concern for viable tumor. We describe the use of advanced imaging and proton biologic effectiveness analyses to enable the diagnosis of radiation necrosis (RN) and ascertain intrinsic physical factors contributing to the development of RN in this patient. Methods and Materials: Multiparametric magnetic resonance imaging (MRI) and Monte Carlo predictions of linear energy transfer (LET) and variable relative biologic effectiveness dose were performed. Results: The dosimetric analysis revealed that of the 10 lesions, 9 were located outside of the clinical treatment volume and 6 received a dose of