Warm-Sensitive Neurons that Control Body Temperature.

Thermoregulation is one of the most vital functions of the brain, but how temperature information is converted into homeostatic responses remains unknown. Here, we use an unbiased approach for activity-dependent RNA sequencing to identify warm-sensitive neurons (WSNs) within the preoptic hypothalamus that orchestrate the homeostatic response to heat. We show that these WSNs are molecularly defined by co-expression of the neuropeptides BDNF and PACAP. Optical recordings in awake, behaving mice reveal that these neurons are selectively activated by environmental warmth. Optogenetic excitation of WSNs triggers rapid hypothermia, mediated by reciprocal changes in heat production and loss, as well as dramatic cold-seeking behavior. Projection-specific manipulations demonstrate that these distinct effectors are controlled by anatomically segregated pathways. These findings reveal a molecularly defined cell type that coordinates the diverse behavioral and autonomic responses to heat. Identification of these warm-sensitive cells provides genetic access to the core neural circuit regulating the body temperature of mammals. PAPERCLIP.

Pan-European study of genotypes and phenotypes in the Arabidopsis relative Cardamine hirsuta reveals how adaptation, demography, and development shape diversity patterns.

We study natural DNA polymorphisms and associated phenotypes in the Arabidopsis relative Cardamine hirsuta. We observed strong genetic differentiation among several ancestry groups and broader distribution of Iberian relict strains in European C. hirsuta compared to Arabidopsis. We found synchronization between vegetative and reproductive development and a pervasive role for heterochronic pathways in shaping C. hirsuta natural variation. A single, fast-cycling ChFRIGIDA allele evolved adaptively allowing range expansion from glacial refugia, unlike Arabidopsis where multiple FRIGIDA haplotypes were involved. The Azores islands, where Arabidopsis is scarce, are a hotspot for C. hirsuta diversity. We identified a quantitative trait locus (QTL) in the heterochronic SPL9 transcription factor as a determinant of an Azorean morphotype. This QTL shows evidence for positive selection, and its distribution mirrors a climate gradient that broadly shaped the Azorean flora. Overall, we establish a framework to explore how the interplay of adaptation, demography, and development shaped diversity patterns of 2 related plant species.

Cardamine hirsuta: a versatile genetic system for comparative studies.

A major goal in biology is to identify the genetic basis for phenotypic diversity. This goal underpins research in areas as diverse as evolutionary biology, plant breeding and human genetics. A limitation for this research is no longer the availability of sequence information but the development of functional genetic tools to understand the link between changes in sequence and phenotype. Here we describe Cardamine hirsuta, a close relative of the reference plant Arabidopsis thaliana, as an experimental system in which genetic and transgenic approaches can be deployed effectively for comparative studies. We present high-resolution genetic and cytogenetic maps for C. hirsuta and show that the genome structure of C. hirsuta closely resembles the eight chromosomes of the ancestral crucifer karyotype and provides a good reference point for comparative genome studies across the Brassicaceae. We compared morphological and physiological traits between C. hirsuta and A. thaliana and analysed natural variation in stamen number in which lateral stamen loss is a species characteristic of C. hirsuta. We constructed a set of recombinant inbred lines and detected eight quantitative trait loci that can explain stamen number variation in this population. We found clear phylogeographic structure to the genetic variation in C. hirsuta, thus providing a context within which to address questions about evolutionary changes that link genotype with phenotype and the environment.

Detection of COVID-19 by quantitative analysis of carbonyl compounds in exhaled breath.

COVID-19 has caused a worldwide pandemic, creating an urgent need for early detection methods. Breath analysis has shown great potential as a non-invasive and rapid means for COVID-19 detection. The objective of this study is to detect patients infected with SARS-CoV-2 and even the possibility to screen between different SARS-CoV-2 variants by analysis of carbonyl compounds in breath. Carbonyl compounds in exhaled breath are metabolites related to inflammation and oxidative stress induced by diseases. This study included a cohort of COVID-19 positive and negative subjects confirmed by reverse transcription polymerase chain reaction between March and December 2021. Carbonyl compounds in exhaled breath were captured using a microfabricated silicon microreactor and analyzed by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). A total of 321 subjects were enrolled in this study. Of these, 141 (85 males, 60.3%) (mean ± SD age: 52 ± 15 years) were COVID-19 (55 during the alpha wave and 86 during the delta wave) positive and 180 (90 males, 50%) (mean ± SD age: 45 ± 15 years) were negative. Panels of a total of 34 ketones and aldehydes in all breath samples were identified for detection of COVID-19 positive patients. Logistic regression models indicated high accuracy/sensitivity/specificity for alpha wave (98.4%/96.4%/100%), for delta wave (88.3%/93.0%/84.6%) and for all COVID-19 positive patients (94.7%/90.1%/98.3%). The results indicate that COVID-19 positive patients can be detected by analysis of carbonyl compounds in exhaled breath. The technology for analysis of carbonyl compounds in exhaled breath has great potential for rapid screening and detection of COVID-19 and for other infectious respiratory diseases in future pandemics.

Determining the feasibility of calculating pancreatic cancer risk scores for people with new-onset diabetes in primary care (DEFEND PRIME): study protocol.

INTRODUCTION: Worldwide, pancreatic cancer has a poor prognosis. Early diagnosis may improve survival by enabling curative treatment. Statistical and machine learning diagnostic prediction models using risk factors such as patient demographics and blood tests are being developed for clinical use to improve early diagnosis. One example is the Enriching New-onset Diabetes for Pancreatic Cancer (ENDPAC) model, which employs patients' age, blood glucose and weight changes to provide pancreatic cancer risk scores. These values are routinely collected in primary care in the UK. Primary care's central role in cancer diagnosis makes it an ideal setting to implement ENDPAC but it has yet to be used in clinical settings. This study aims to determine the feasibility of applying ENDPAC to data held by UK primary care practices. METHODS AND ANALYSIS: This will be a multicentre observational study with a cohort design, determining the feasibility of applying ENDPAC in UK primary care. We will develop software to search, extract and process anonymised data from 20 primary care providers' electronic patient record management systems on participants aged 50+ years, with a glycated haemoglobin (HbA1c) test result of ≥48 mmol/mol (6.5%) and no previous abnormal HbA1c results. Software to calculate ENDPAC scores will be developed, and descriptive statistics used to summarise the cohort's demographics and assess data quality. Findings will inform the development of a future UK clinical trial to test ENDPAC's effectiveness for the early detection of pancreatic cancer. ETHICS AND DISSEMINATION: This project has been reviewed by the University of Surrey University Ethics Committee and received a favourable ethical opinion (FHMS 22-23151 EGA). Study findings will be presented at scientific meetings and published in international peer-reviewed journals. Participating primary care practices, clinical leads and policy makers will be provided with summaries of the findings.

Decreasing Admissions but Increasing Readmissions for Mental Health in-Patient Treatment in Scotland, UK.

We have analysed mental health data for in-patient admissions from 1997 to 2021 in Scotland. The number of patient admissions for mental health patients is declining despite population numbers increasing. This is driven by the adult population; child and adolescent numbers are consistent. We find that mental health in-patients are more likely to be from deprived areas: 33 % of patients are from the most deprived areas, compared to only 11 % from the least deprived. The average length of stay for a mental health in-patient is decreasing, with a rise in stays lasting less than a day. The number of mental health patients who have been readmitted within a month fell from 1997 to 2011, then increased to 2021. Despite the average stay length decreasing, the number of overall readmissions is increasing, suggesting patients are having more, shorter stays.

A feasibility study on exhaled breath analysis using UV spectroscopy to detect COVID-19.

A 23-subject feasibility study is reported to assess how UV absorbance measurements on exhaled breath samples collected from silicon microreactors can be used to detect COVID-19. The silicon microreactor technology chemoselectively preconcentrates exhaled carbonyl volatile organic compounds and subsequent methanol elution provides samples for analysis. The underlying scientific rationale that viral infection will induce an increase in exhaled carbonyls appears to be supported by the results of the feasibility study. The data indicate statistically significant differences in measured UV absorbance values between healthy and symptomatic COVID-19 positive subjects in the wavelength range from 235 nm to 305 nm. Factors such as subject age were noted as potential confounding variables.

The Impact of COVID-19 on Mental Health Services in Scotland, UK.

There is a global emergency in relation to mental health (MH) and healthcare. In the UK each year, 1 in 4 people will experience MH problems. Healthcare services are increasingly oversubscribed, and COVID-19 has deepened the healthcare gap. We investigated the effect of COVID-19 on waiting times for MH services in Scotland. We used national registers of MH services provided by Public Health Scotland. The results show that waiting times for adults and children increased drastically during the pandemic. This was seen nationally and across most of the administrative regions of Scotland. We find, however, that child and adolescent services were comparatively less impacted by the pandemic than adult services. This is potentially due to prioritisation of paediatric patients, or due to an increasing demand on adult services triggered by the pandemic itself.

Differential Functional Responses of Neutrophil Subsets in Severe COVID-19 Patients.

Neutrophils play a significant role in determining disease severity following SARS-CoV-2 infection. Gene and protein expression defines several neutrophil clusters in COVID-19, including the emergence of low density neutrophils (LDN) that are associated with severe disease. The functional capabilities of these neutrophil clusters and correlation with gene and protein expression are unknown. To define host defense and immunosuppressive functions of normal density neutrophils (NDN) and LDN from COVID-19 patients, we recruited 64 patients with severe COVID-19 and 26 healthy donors (HD). Phagocytosis, respiratory burst activity, degranulation, neutrophil extracellular trap (NET) formation, and T-cell suppression in those neutrophil subsets were measured. NDN from severe/critical COVID-19 patients showed evidence of priming with enhanced phagocytosis, respiratory burst activity, and degranulation of secretory vesicles and gelatinase and specific granules, while NET formation was similar to HD NDN. COVID LDN response was impaired except for enhanced NET formation. A subset of COVID LDN with intermediate CD16 expression (CD16Int LDN) promoted T cell proliferation to a level similar to HD NDN, while COVID NDN and the CD16Hi LDN failed to stimulate T-cell activation. All 3 COVID-19 neutrophil populations suppressed stimulation of IFN-γ production, compared to HD NDN. We conclude that NDN and LDN from COVID-19 patients possess complementary functional capabilities that may act cooperatively to determine disease severity. We predict that global neutrophil responses that induce COVID-19 ARDS will vary depending on the proportion of neutrophil subsets.

A specific low-density neutrophil population correlates with hypercoagulation and disease severity in hospitalized COVID-19 patients.

SARS coronavirus 2 (SARS-CoV-2) is a novel viral pathogen that causes a clinical disease called coronavirus disease 2019 (COVID-19). Although most COVID-19 cases are asymptomatic or involve mild upper respiratory tract symptoms, a significant number of patients develop severe or critical disease. Patients with severe COVID-19 commonly present with viral pneumonia that may progress to life-threatening acute respiratory distress syndrome (ARDS). Patients with COVID-19 are also predisposed to venous and arterial thromboses that are associated with a poorer prognosis. The present study identified the emergence of a low-density inflammatory neutrophil (LDN) population expressing intermediate levels of CD16 (CD16Int) in patients with COVID-19. These cells demonstrated proinflammatory gene signatures, activated platelets, spontaneously formed neutrophil extracellular traps, and enhanced phagocytic capacity and cytokine production. Strikingly, CD16Int neutrophils were also the major immune cells within the bronchoalveolar lavage fluid, exhibiting increased CXCR3 but loss of CD44 and CD38 expression. The percentage of circulating CD16Int LDNs was associated with D-dimer, ferritin, and systemic IL-6 and TNF-α levels and changed over time with altered disease status. Our data suggest that the CD16Int LDN subset contributes to COVID-19-associated coagulopathy, systemic inflammation, and ARDS. The frequency of that LDN subset in the circulation could serve as an adjunct clinical marker to monitor disease status and progression.

Atypical fibroxanthoma with keloidal collagen.

Atypical fibroxanthoma (AFX) is a lesion that typically occurs on actinically damaged skin of the head and neck. Histopathology of these neoplasms reveals atypical cells, which often demonstrate positive staining for immunohistochemical markers such as vimentin and CD10. In the case reported, keloidal collagen was discovered on histopathology. To our knowledge, only rare reports in the literature describe an AFX with similar histopathologic findings, suggesting that this is a distinctive presentation of AFX.

Effects of chronic inhibition of GABA synthesis on attention and impulse control.

BACKGROUND: Cortical GABA regulates a number of cognitive functions including attention and working memory and is dysregulated in a number of psychiatric conditions. In schizophrenia for example, changes in GABA neurons [reduced expression of glutamic acid decarboxylase (GAD), parvalbumin (PV) and the GABA reuptake transporter (GAT1)] suggest reduced cortical GABA synthesis and release; these changes are hypothesized to cause the cognitive deficits observed in this disorder. The goals of this experiment were to determine whether chronically reducing GAD function within the rat PFC causes attention deficits and alterations in PV and GAT1 expression. METHODS: Male Sprague Dawley rats were trained on the 5-choice serial reaction time task (5CSRTT, a task of attention) until they reached criterion performance and then were implanted with a bilateral cannula aimed at the medial PFC. Cannulae were connected to osmotic minipumps that infused the GAD inhibitor l-allylglycine (LAG, 3.2µg/0.5µl/h) for 13days. Following a 5-day recovery from surgery rats were tested on the standard 5CSRTT for 5 consecutive days and then tested on two modifications of the 5CSRTT. Finally, locomotor activity was assessed and the rats sacrificed. Brains were rapidly extracted and flash frozen and analyzed for the expression of GAD67, PV, GAT1 and the obligatory NMDA receptor subunit NR1. RESULTS: Chronic LAG infusions transiently impaired attention, persistently impaired impulse control and increased locomotor activity. Behavioral changes were associated with an upregulation of GAD67, but no change in PV, GAT1 or NR1 expression. SUMMARY: Chronic inhibition of GABA synthesis within the medial PFC, increased impulsive behavior and locomotion, but did not impair attention; results consistent with previous research following acute inhibition of GABA synthesis. Moreover, our data do not support the hypothesis that decreasing GABA synthesis and release is sufficient to cause changes in other GABA-related proteins.

Pre-morbid Conduct Disorder symptoms are associated with cannabis use among individuals with a first episode of psychosis.

BACKGROUND: Early cannabis use has consistently been associated with an increased risk for the later development of psychosis. Studies suggest that Conduct Disorder (CD) is more common amongst young people who later go on to develop psychosis. CD has been associated with greater and earlier cannabis use in general population samples. Based on this evidence, we hypothesised that among patients experiencing their first episode of psychosis, the presence of CD symptoms prior to age 15 would be associated with cannabis use. METHOD: 102 patients experiencing a first episode of psychosis were interviewed to assess CD symptoms prior to age 15 and use of cannabis and other substances. RESULTS: The number of CD symptoms was significantly associated with lifetime cannabis use (odds ratio=5.41 (1.76-16.57), p=0.03) and with first use of cannabis before age 14 (odds ratio=1.46 (1.12-1.92), p=0.006), after controlling for stimulant/hallucinogen use and level of education. CONCLUSIONS: Among patients experiencing a first episode of psychosis, CD symptoms were significantly associated with use of cannabis and with use by age 14. Among individuals vulnerable for psychosis, CD symptoms may independently increase the likelihood of cannabis use which in turn increases the risk of psychosis.

Dialogue among survivors of hematopoietic cell transplantation support-group themes.

Many survivors of hematopoietic cell transplantation (HCT) are challenged by physical, psychological, and social complications throughout the months and years post-transplant, as uncovered by many researchers during the past few years. The literature on the use of support groups for improving quality of life has mostly included studies of participants with solid tumor cancers. There is a paucity of literature describing the use of support groups with HCT survivors. The purpose of the present study is to describe the various issues that are discussed by participants in a monthly post-HCT support group. These issues have been described and grouped into themes by the authors. The results can provide a foundation about long-term effects of HCT that future research can investigate more closely, followed by research that can study interventions to assist in improving quality of life of HCT survivors. Recommendations for applying findings to current clinical practice using support groups are identified.

On the possibility of a pragmatic discourse bioethics: Putnam, Habermas, and the normative logic of bioethical inquiry.

Pragmatic bioethics represents a novel approach to the discipline of bioethics, yet has met with criticisms which have beset the discipline of bioethics in the past. In particular, pragmatic bioethics has been criticized for its excessively fuzzy approach to fundamental questions of normativity, which are crucial to a field like bioethics. Normative questions need answers, and consensus is not always enough. The approach here is to apply elements of the discourse ethics of Habermas and Putnam to the sphere of bioethics, in order to develop a normative structure out of the framework of bioethical inquiry as it stands. The idea here is that the process of inquiry contains its own normative structure as it aims to discover norms. Such an approach, which fuses pragmatic bioethics with discourse ethics (which equally draws on pragmatism), may rightly be called a "Pragmatic Discourse Bioethics."

Germ-line engineering, freedom, and future generations.

New technologies in germ-line engineering have raised many questions about obligations to future generations. In this article, I focus on the importance of increasing freedom and the equality of freedom for present and future generations, because these two ideals are necessary for a just society and because they are most threatened by the wide-scale privatisation of GLE technologies. However, there are ambiguities in applying these ideals to the issue of genetic technologies. I argue that Amartya Sen's capability theory can be used as a framework to ensure freedom and equality in the use of GLE technology. Capability theory articulates the goal of equalising real freedom by bringing all people up to a threshold of basic human capabilities. Sen's capability theory can clarify the proper moral goal of GLE insofar as this technology could be used to bring people up to certain basic human capabilities, thereby increasing their real freedom. And by increasing the freedom of those who lack basic human capabilities, GLE can aid in decreasing the inequalities of freedom among classes of people.