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Severe disease from SARS-CoV-2 infection often progresses to multi-organ failure and results in an increased mortality rate amongst these patients. However, underlying mechanisms of SARS- CoV-2-induced multi-organ failure and subsequent death are still largely unknown. Cytokine storm, increased levels of inflammatory mediators, endothelial dysfunction, coagulation abnormalities, and infiltration of inflammatory cells into the organs contribute to the pathogenesis of COVID-19. One potential consequence of immune/inflammatory events is the acute progression of generalized edema, which may lead to death. We, therefore, examined the involvement of water channels in the development of edema in multiple organs and their contribution to organ dysfunction in a Murine Hepatitis Virus-1 (MHV-1) mouse model of COVID-19. Using this model, we recently reported multi-organ pathological abnormalities and animal death similar to that reported in humans with SARS-CoV-2 infection. We now identified an alteration in protein levels of AQPs 1, 4, 5, and 8 and associated oxidative stress, along with various degrees of tissue edema in multiple organs, which correlate well with animal survival post-MHV-1 infection. Furthermore, our newly created drug (a 15 amino acid synthetic peptide, known as SPIKENET) that was designed to prevent the binding of spike glycoproteins with their receptor(s), angiotensin- converting enzyme 2 (ACE2), and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) (SARS-CoV-2 and MHV-1, respectively), ameliorated animal death and reversed altered levels of AQPs and oxidative stress post-MHV-1 infection. Collectively, our findings suggest the possible involvement of altered aquaporins and the subsequent edema, likely mediated by the virus-induced inflammatory and oxidative stress response, in the pathogenesis of COVID- 19 and the potential of SPIKENET as a therapeutic option.

Background Obesity is associated with an increased breast cancer risk in postmenopausal women and may contribute to worse outcomes. Black women experience higher obesity and breast cancer mortality rates than non-Black women. We examined associations between race, obesity, and clinical tumor stage with breast cancer prognosis. Methods We conducted a prospective cohort study in 1,110 breast cancer patients, using univariable and multivariable Cox regression analyses to evaluate the effects of obesity, race/ethnicity, and clinical tumor stage on progression-free and overall survival (PFS and OS). Results 22% of participants were Black, 64% were Hispanic White, and 14% were non-Hispanic White or another race. 39% of participants were obese (body mass index [BMI] ≥ 30 kg/m 2 ). In univariable analyses, tumor stage III-IV was associated with worse PFS and OS compared to tumor stage 0-II (hazard ratio [HR] = 4.68, 95% confidence interval [CI] = 3.52–6.22 for PFS and HR = 5.92, 95% CI = 4.00-8.77 for OS). Multivariable analysis revealed an association between Black race and worse PFS in obese (HR = 2.19, 95% CI = 1.06–4.51) and non-obese (HR = 2.11, 95% CI = 1.05–4.21) women with tumors staged 0-II. Obesity alone was not associated with worse PFS or OS. Conclusions Results suggest a complex interrelationship between obesity and race in breast cancer prognosis. The association between the Black race and worse PFS in tumor stages 0-II underscores the importance of early intervention in this group. Future studies are warranted to evaluate whether alternative measures of body composition and biomarkers are better prognostic indicators than BMI among Black breast cancer survivors.

Alzheimer's disease involves a drastic departure from the cognitive, functional, and behavioural trajectory of normal ageing, and is both a dreaded and highly prevalent cause of disability to individuals, and a leading source of health and social care expenditure for society. Before the advent of biomarkers, post-mortem examination was the only method available to establish a definitive diagnosis. In this first paper of the Series, we review state-of-the-art diagnostic practices and the typical patient journey in specialist settings, where clinicians engage in a differential diagnosis to establish whether Alzheimer's pathology (cerebral deposition of β-amyloid and hyperphosphorylated tau) is a contributor to cognitive impairment. Biomarkers indicating dysregulation of β-amyloid and tau homeostasis, measured with PET and cerebrospinal fluid analysis, allow a molecular-level diagnosis—a mandatory step in defining eligibility for the recently approved anti-amyloid treatments. We anticipate that easily accessible blood biomarkers, already available in some countries, will lead to a new diagnostic revolution and bring about major changes in health-care systems worldwide.

BackgroundUrinary Tract Infections (UTIs) are common in the paediatric population and can cause life-threatening illness and significant morbidity. Clinical diagnosis remains a challenge owing to non-specific symptoms and clinical overlap with other common paediatric conditions. Prolonged jaundice may be the only clinical manifestation of an underlying UTI, and the National Institute for Health and Care Excellence (NICE) recommends that all neonates with prolonged jaundice should have a mid-stream urine (MSU) sample sent for culture. However, the evidence base behind this guidance remains unclear and has been challenged in recent literature.ObjectivesTo assess the local incidence of positive urine cultures in neonates with isolated prolonged jaundice.To compare the local incidence of positive urine cultures in neonates with isolated prolonged jaundice to published literature.To review how asymptomatic neonates with a positive culture were managed by our service.MethodsThe clinical records of all neonates seen in our prolonged jaundice clinic over an 8-month period in 2020 were retrospectively analysed. MSU samples were reviewed for significant pyuria (≥10 white blood cells per cubic millimetre) or significant organism growth (>100,000 colony-forming units). Patient records were reviewed to assess for symptoms of UTI at the time of, and shortly after, MSU sampling. Clinic notes, discharge summaries, electronic prescribing interfaces and radiology reports were analysed to establish the subsequent management and any significant sequelae.ResultsFifty-nine neonates met the inclusion criteria, of whom 57 (96.6%) had an MSU sample collected. Of these, 10 (17.5%) had single organism growth, 5 (8.8%) had mixed growth, and 42 (73.7%) had no growth. No patients with mixed growth met the criteria for diagnosis of a UTI as defined by NICE guidelines. The incidence of significant growth in neonates attending the prolonged jaundice clinic was 17.5% locally, compared to 0.21% reported in the literature.All 10 samples that cultured an isolated organism had growth >100,000 colony-forming units. Organisms included Coliform Species (40%), E. Coli (20%), Enterobacter Cloacae (20%), Enterococcus (10%), and Group B Streptococcus (10%). Two (20%) also had significant pyuria. Records showed that 4 (40%) of the patients with isolated organism growth were treated with antibiotics.Of the 6 patients (60%) with single organism growth that did not receive antibiotics, none developed symptoms of a UTI or required admission. Three (30%) had a repeat MSU sample, all of which showed no growth.ConclusionsWithin our sampled population there was a significantly higher number of positive urine cultures in neonates attending the prolonged jaundice clinic compared to published rates. The management of patients with significant single organism growth was variable, and in most instances was not in line with current NICE guidance. Despite this, we found no significant illness or admission to hospital in patients with positive MSUs who were not treated with antibiotics.It remains unclear if a proportion of neonates with single organism growth may represent contamination or asymptomatic bacteriuria. Further research is required to establish the risk of significant single organism growth in neonates presenting with isolated prolonged jaundice.

Cardiac catheterisation is crucial for diagnosing and treating paediatric heart diseases, but it is poorly tolerated by small children, infants, and newborns without sedation. This study investigated whether maternal voice during sedation could lower stress and pain in children undergoing cardiac catheterisation and also assessed mothers' stress levels before and after the procedure. This was a prospective, monocentric, randomised, controlled interventional study at the University Hospital Bonn. Children aged 4 years or younger scheduled for elective cardiac catheterisation under procedural sedation and American Society of Anaesthesiologists class between 1 and 3 were eligible. At the end of cardiac catheterisation, the intervention group showed a higher Newborn Infant Parasympathetic Evaluation index with an adjusted mean difference of 9.5 (± 4.2) ( = 0.026) and a lower median Children's and Infants Postoperative Pain Scale score of 2.0 (IQR: 0.0-5.0) versus 4.5 (IQR: 3.0-6.0) than the control group ( = 0.027). No difference in the children's cortisol level was found ( = 0.424). The mothers in the intervention group had a lower cortisol level than those in the control group before cardiac catheterisation (adjusted mean difference: -4.5 nmol/l (± 1.8 nmol/l), = 0.011). Listening to the maternal voice during cardiac catheterisation could lead to less postoperative pain and significantly lower stress and discomfort level in children. Less pain could reduce the incidence of postoperative delirium.Additionally, mothers perceived involvement as positive. A reduced stress level of mothers can positively influence children and possibly reduce pain and anxiety.

Blast exposure ( via detonation of high explosives) represents a major potential trauma source for Servicemembers and Veterans, often resulting in mild traumatic brain injury (mTBI). Executive dysfunction (e.g., alterations in memory, deficits in mental flexibility, difficulty with adaptability) is commonly reported by Veterans with a history of blast-related mTBI, leading to impaired daily functioning and decreased quality of life, but underlying mechanisms are not fully understood and have not been well studied in animal models of blast. To investigate potential underlying behavioral mechanisms contributing to deficits in executive functioning post-blast mTBI, here we examined how a history of repetitive blast exposure in male mice affects anxiety/compulsivity-like outcomes and appetitive goal-directed behavior using an established mouse model of blast mTBI. We hypothesized that repetitive blast exposure in male mice would result in anxiety/compulsivity-like outcomes and corresponding performance deficits in operant-based reward learning and behavioral flexibility paradigms. Instead, results demonstrate an increase in reward-seeking and goal-directed behavior and a congruent decrease in behavioral flexibility. We also report chronic adverse behavioral changes related to anxiety, compulsivity, and hyperarousal. In combination, these data suggest that potential deficits in executive function following blast mTBI are at least in part related to enhanced compulsivity/hyperreactivity and behavioral inflexibility and not simply due to a lack of motivation or inability to acquire task parameters, with important implications for subsequent diagnosis and treatment management.

Over the last 10 years the prevalence of obesity across the European continent has in general been rising. With the exception of a few countries where a levelling-off can be perceived, albeit at a high level, this upward trend seems likely to continue. However, considerable country to country variation is noticeable, with the proportion of people with obesity varying by 10% or more. This variation is intriguing and suggests the existence of different profiles of risk or protection factors operating in different countries. The identification of such protection factors could indicate suitable targets for interventions to help manage the obesity epidemic in Europe. This report is the output of a 2-day workshop on the ‘Diversity of Obesity in Europe'. The workshop included 14 delegates from 12 different European countries. This report contains the contributions and discussions of the materials and viewpoints provided by these 14 experts; it is not the output of a single mind. However, such is the nature of scientific analysis regarding obesity that it is possible that a different set of 14 experts may have come to a different set of conclusions. Therefore the report should not be seen as a definitive statement of a stable situation. Rather it is a focus for discussion and comment, and a vehicle to drive forward further understanding and management of obesity in Europe.

This article explores alternative food initiatives (AFI) and their performances of benign transgression. Through collaborative activist-and-academic-storytelling we tease apart the divergent practices of AFIs to question what mediates these performances in the grey area between conventional and alternative practice. Grounded examples of AFIs performing alternative economy and related acts of 'irritant' civil disobedience show how subverting normative practices of power and authority can catalyse social reproduction of difference, and tangibly alter the conventional food system.

Polysubstance use is prevalent in the population but remains understudied in preclinical models. Alcohol and opioid polysubstance use is associated with negative outcomes, worse treatment prognosis, and higher overdose risk; but underlying mechanisms are still being uncovered. Examining factors that motivate use of one substance over another in different contexts in preclinical models will better our understanding of polysubstance use and improve translational value. Here we assessed baseline anxiety-like and locomotive behavior and then measured voluntary consumption of multiple doses of alcohol and fentanyl in group housed male and female mice using our novel Socially Integrated Polysubstance (SIP) system. Fifty-six male (n=32) and female (n=24) adult mice were housed in groups of 4 for one week with continuous access to food, water, two doses of ethanol (5% and 10%) and two doses of fentanyl (5 ug/ml and 20 ug/ml). Our analyses revealed sex differences across multiple domains - female mice consumed more liquid in the dark cycle, had higher activity, a higher preference for both ethanol and fentanyl over water, and their fentanyl preference increased over the seven days. Furthermore, both male and female mice displayed polysubstance consumption patterns, with female mice displaying more prolonged polysubstance use across days in the SIP chambers. We then used machine-learning techniques to reveal underlying relationships between baseline behavioral phenotypes and subsequent polysubstance consumption patterns, where anxiety- and risk-taking-like behavioral phenotypes mapped onto discrete patterns of polysubstance use, preference, and escalation. By simulating more translationally relevant substance use and improving our understanding of the motivations for different patterns of consumption, this study contributes to the developing preclinical literature on polysubstance use with the goal of facilitating better treatment outcomes and novel therapeutic strategies.