Visual pigments in a living fossil, the Australian lungfish Neoceratodus forsteri

Background. One of the greatest challenges facing the early land vertebrates was the need to effectively interpret a terrestrial environment. Interpretation was based on ocular adaptations evolved for an aquatic environment millions of years earlier. The Australian lungfish Neoceratodus forsteri is thought to be the closest living relative to the first terrestrial vertebrate, and yet nothing is known about the visual pigments present in lungfish or the early tetrapods. Results. Here we identify and characterise five visual pigments (rh1, rh2, lws, sws1 and sws2) expressed in the retina of N. forsteri. Phylogenetic analysis of the molecular evolution of lungfish and other vertebrate visual pigment genes indicates a closer relationship between lungfish and amphibian pigments than to pigments in teleost fishes. However, the relationship between lungfish, the coelacanth and tetrapods could not be absolutely determined from opsin phylogeny, supporting an unresolved trichotomy between the three groups. Conclusion. The presence of four cone pigments in Australian lungfish suggests that the earliest tetrapods would have had a colorful view of their terrestrial environment

Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity, and perturb Ca2+ homeostasis in human coronary artery endothelial cells

The sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) plays a critical role in Ca2+ homeostasis via sequestration of this ion into the sarco/endoplasmic reticulum. The activity of this pump is inhibited by oxidants and impaired in ageing tissues and cardiovascular disease. We have shown previously that the myeloperoxidase- (MPO) derived oxidants HOCl and HOSCN target thiols and mediate cellular dysfunction. As SERCA contains Cys residues critical to ATPase activity, we hypothesized that HOCl and HOSCN might inhibit SERCA activity, via thiol oxidation, and increase cytosolic Ca2+ levels in human coronary artery endothelial cells (HCAEC). Exposure of sarcoplasmic reticulum vesicles to pre-formed or enzymatically-generated HOCl and HOSCN resulted in a concentration-dependent decrease in ATPase activity; this was also inhibited by the SERCA inhibitor thapsigargin. Decomposed HOSCN and incomplete MPO enzyme systems did not decrease activity. Loss of ATPase activity occurred concurrently with oxidation of SERCA Cys residues and protein modification. Exposure of HCAEC, with or without external Ca2+, to HOSCN or HOCl, resulted in a time- and concentration-dependent increase in intracellular Ca2+ under conditions that did not result in immediate loss of cell viability. Thapsigargin, but not inhibitors of plasma membrane or mitochondrial Ca2+ pumps/channels, completely attenuated the increase in intracellular Ca2+ consistent with a critical role for SERCA in maintaining endothelial cell Ca2+ homeostasis. Angiotensin II pre-treatment potentiated the effect of HOSCN at low concentrations. MPO-mediated modulation of intracellular Ca2+ levels may exacerbate endothelial dysfunction, a key early event in atherosclerosis, and be more marked in smokers due to their higher SCN− levels

Cognitive status and behavioral problems in older hospitalized patients

OBJECTIVES: (a) To determine the quantity and quality of behavioral problems in older hospitalized patients on acute care units; (b) to determine the burden of these behaviors on staff; and (c) to identify predictors of behavioral problems. METHODS: Upon admission, patients performed the Mini-Mental State Exam (MMSE), the Geriatric Depression Scale (GDS), and information was obtained on age, ethnicity, level of education, living arrangement, and psychiatric history. Two days post-admission, a clinical staff member caring for each patient, performed the Neuropsychiatric Inventory-Questionnaire (NPI-Q) to assess patients' behavioral problems and staff distress. PARTICIPANTS AND SETTING: Forty-two patients, over 60 years of age, admitted to medical and surgical units of the Veterans Affairs Hospitals in Palo Alto and San Francisco, participated. RESULTS: Twenty-three of 42 (55%) patients exhibited behavioral problems. Anxiety, depression, irritability, and agitation/aggression were the most frequently observed behaviors. The severity of the behavioral problems was significantly correlated with staff distress. Lower performance on the MMSE at admission was significantly associated with higher NPI-Q ratings. Specifically, of those cases with scores less than or equal to 27 on the MMSE, 66% had behavioral problems during hospitalization, compared to only 31% of those with scores greater than 27. CONCLUSION: Behavioral problems in older hospitalized patients appear to occur frequently, are a significant source of distress to staff, and can result in the need for psychiatric consultation. Assessment of the mental status of older adults at admission to hospital may be valuable in identifying individuals at increased risk for behavioral problems during hospitalization

Optimising the Duration of Adjuvant Trastuzumab in Early Breast Cancer in the UK.

Adjuvant trastuzumab for patients with HER2 positive early breast cancer demonstrated significant improvements in both disease-free and overall survival with 12 months treatment (1, 2), and this was NICE approved in the UK in 2006. When the FinHer trial demonstrated similar results with nine weeks trastuzumab (3), there was significant interest in whether shorter durations might be as effective. Additional benefits for patients could be less toxicity, fewer hospital visits and a more rapid return to normal life, with considerable societal benefits of reduced costs. PERSEPHONE was the pragmatic UK duration trial funded by the NIHR HTA, which showed that 6 months adjuvant trastuzumab was non-inferior to 12 months with 4-year disease-free survival rate of 89.4% compared with 89.8% respectively (non-inferiority p = 0.01) (4). Less toxicity was reported with 6 months particularly cardiac toxicity and there were cost savings over the first 2 years (5), which were maintained over an average patient’s lifetime when extrapolated using an economic model. After the publication of these results in June 2019, the Optimal Duration of Adjuvant Trastuzumab Working Group was convened, comprising a diverse, multi-disciplinary membership. There were representatives from the PERSEPHONE Trial Management Group including patient advocates, the NCRI Breast Group, the Association of Cancer Physicians (ACP), the Royal College of Radiologists (RCR), and the Independent Cancer Patients’ Voice (ICPV). By November 2019, both dual antibody treatment with trastuzumab and pertuzumab (https://www.nice.org.uk/guidance/ta569) and extended neratinib after single agent trastuzumab (https://www.nice.org.uk/guidance/ta612) had been approved by NICE only for those at high risk of recurrence. Therefore, single agent trastuzumab remained standard of care for those at lower risk of recurrence and recommendations were made for these patients.Funded by NIHR HTA

Moderators, Mediators, and Other Predictors of Risperidone Response in Children with Autistic Disorder and Irritability

Objective/Background: The National Institute of Mental Health (NIMH) Research Units on Pediatric Psychopharmacology (RUPP) Autism Network found an effect size of d = 1.2 in favor of risperidone on the main outcome measure in an 8-week double-blind, placebo-controlled trial for irritabilityin autistic disorder. This paper explores moderators and mediators of this effect. Method: Intention-to-treat (ITT) analyses were conducted with suspected moderators and mediators entered into the regression equations. MacArthur Foundation Network subgroup guidelines were followed in the evaluation of the results. Results: Only baseline severity moderated treatment response: Higher severity showed greater improvement for risperidone but not for placebo. Weight gain mediated treatment response negatively: Those who gained more weight improved less with risperidone and more with placebo. Compliance correlated with outcome for risperidone but not placebo. Higher dose correlated with worse outcome for placebo, but not risperidone. Of nonspecific predictors, parent education, family income, and low baseline prolactin positively predicted outcome; anxiety, bipolar symptoms, oppositional-defiant symptoms, stereotypy, and hyperactivity negatively predicted outcome. Risperidone moderated the effect of change in 5'-nucleotidase, a marker of zinc status, for which decrease was associated with improvement only with risperidone, not with placebo. Conclusion: The benefit–risk ratio of risperidone is better with greater symptom severity. Risperidone can be individually titrated to optimal dosage for excellent response in the majority of children. Weight gain is not necessary for risperidone benefit and may even detract from it. Socioeconomic advantage, low prolactin, and absence of co-morbid problems non-specifically predict better outcome. Mineral interactions with risperidone deserve further study

Understanding the evolution of immune genes in jawed vertebrates

Driven by co-evolution with pathogens, host immunity continuously adapts to optimize defence against pathogens within a given environment. Recent advances in genetics, genomics and transcriptomics have enabled a more detailed investigation into how immunogenetic variation shapes the diversity of immune responses seen across domestic and wild animal species. However, a deeper understanding of the diverse molecular mechanisms that shape immunity within and among species is still needed to gain insight into-and generate evolutionary hypotheses on-the ultimate drivers of immunological differences. Here, we discuss current advances in our understanding of molecular evolution underpinning jawed vertebrate immunity. First, we introduce the immunome concept, a framework for characterizing genes involved in immune defence from a comparative perspective, then we outline how immune genes of interest can be identified. Second, we focus on how different selection modes are observed acting across groups of immune genes and propose hypotheses to explain these differences. We then provide an overview of the approaches used so far to study the evolutionary heterogeneity of immune genes on macro and microevolutionary scales. Finally, we discuss some of the current evidence as to how specific pathogens affect the evolution of different groups of immune genes. This review results from the collective discussion on the current key challenges in evolutionary immunology conducted at the ESEB 2021 Online Satellite Symposium: Molecular evolution of the vertebrate immune system, from the lab to natural populations

Pre-pandemic mental health and disruptions to healthcare, economic and housing outcomes during the COVID-19 pandemic: evidence from 12 UK longitudinal studies

Background: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable. Aims: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing. Method: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies. Results: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3–33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20–1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09–1.41) for disruption to procedures to 1.33 (95% CI 1.20–1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06–1.21) and income (OR 1.12, 95% CI 1.06 –1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00–1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18–1.32) or in one domain (OR 1.11, 95% CI 1.07–1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97–1.03). Conclusions: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities