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Abstract The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.

Abstract Microglia are important players in surveillance and repair of the brain. Implanting an electrode into the cortex activates microglia, produces an inflammatory cascade, triggers the foreign body response, and opens the blood-brain barrier. These changes can impede intracortical brain-computer interfaces performance. Using two-photon imaging of implanted microelectrodes, we test the hypothesis that low-intensity pulsed ultrasound stimulation can reduce microglia-mediated neuroinflammation following the implantation of microelectrodes. In the first week of treatment, we found that low-intensity pulsed ultrasound stimulation increased microglia migration speed by 128%, enhanced microglia expansion area by 109%, and a reduction in microglial activation by 17%, indicating improved tissue healing and surveillance. Microglial coverage of the microelectrode was reduced by 50% and astrocytic scarring by 36% resulting in an increase in recording performance at chronic time. The data indicate that low-intensity pulsed ultrasound stimulation helps reduce the foreign body response around chronic intracortical microelectrodes.

Abstract Population-representative estimates of SARS-CoV-2 infection prevalence and antibody levels in specific geographic areas at different time points are needed to optimise policy responses. However, even population-wide surveys are potentially impacted by biases arising from differences in participation rates across key groups. Here, we used spatio-temporal regression and post-stratification models to UK’s national COVID-19 Infection Survey (CIS) to obtain representative estimates of PCR positivity (6,496,052 tests) and antibody prevalence (1,941,333 tests) for different regions, ages and ethnicities (7-December-2020 to 4-May-2022). Not accounting for vaccination status through post-stratification led to small underestimation of PCR positivity, but more substantial overestimations of antibody levels in the population (up to 21 percentage points), particularly in groups with low vaccine uptake in the general population. There was marked variation in the relative contribution of different areas and age-groups to each wave. Future analyses of infectious disease surveys should take into account major drivers of outcomes of interest that may also influence participation, with vaccination being an important factor to consider.

Abstract Background Patients who have benefited from specialist intervention during periods of acute/complex palliative care needs often transition from specialist-to-primary care once such needs have been controlled. Effective communication between services is central to co-ordination of care to avoid the potential consequences of unmet needs, fragmented care, and poor patient and family experience. Discharge communications are a key component of care transitions. However, little is known about the experiences of those primarily receiving these communications, to include patients’, carers’ and primary care healthcare professionals. This study aims to have a better understanding of how the discharge communications from specialist palliative care services to primary care are experienced by patients, carers, and healthcare professionals, and how these communications might be improved to support effective patient-centred care. Methods This is a 15-month qualitative study. We will interview 30 adult patients and carers and 15 healthcare professionals (n = 45). We will seek a range of experiences of discharge communication by using a maximum variation approach to sampling, including purposively recruiting people from a range of demographic backgrounds from 4–6 specialist palliative care services (hospitals and hospices) as well as 5–7 general practices. Interview data will be analysed using a reflexive thematic approach and will involve input from the research and advisory team. Working with clinicians, commissioners, and PPI representatives we will co-produce a list of recommendations for discharge communication from specialist palliative care. Discussion Data collection may be limited by the need to be sensitive to participants’ wellbeing needs. Study findings will be shared through academic publications and presentations. We will draft principles for how specialist palliative care clinicians can best communicate discharge with patients, carers, and primary care clinicians. These will be shared with clinicians, policy makers, commissioners, and PPI representatives and key stakeholders and organisations (e.g. Hospice UK) and on social media. Key outputs will be recommendations for a specialist palliative care discharge proforma. Trial registration Registered in ISRCTN Registry on 29.12.2023 ref: ISRCTN18098027.

Human visual function depends on the biological lens, a biconvex optical element formed by coordinated, synchronous generation of growth shells produced from ordered cells at the lens equator, the distal edge of the epithelium. Growth shells are comprised of straight (St) and S-shaped (SSh) lens fibers organized in highly symmetric, sinusoidal pattern which optimizes both the refractile, transparent structure and the unique microcirculation that regulates hydration and nutrition over the lifetime of an individual. The fiber cells are characterized by diversity in composition and age. All fiber cells remain interconnected in their growth shells throughout the life of the adult lens. As an optical element, cellular differentiation is constrained by the physical properties of light and its special development accounts for its characteristic symmetry, gradient of refractive index (GRIN), short range transparent order (SRO), and functional longevity. The complex sinusoidal structure is the basis for the lens microcirculation required for the establishment and maintenance of image formation.

Background: Hospice palliative care aims to provide timely interventions and holistic care that focusses on quality of life for people who are terminally ill. In the first two years of the Covid-19 pandemic the national political and healthcare contexts changed significantly. Throughout this time hospices had to repeatedly adjust their approach to supporting terminally ill people, many of whom were especially vulnerable to Covid-19. Aim: The aim of this paper was to explore hospice patients, carers, staff and senior managers stories to identify how changing pandemic narratives affected their understanding of hospice palliative care as timely, holistic and supporting quality of life. Methods: Narrative analysis of in-depth interviews with patients, carers, staff and senior managers (n = 70) recruited from hospices across the West-Midlands, UK, in 2020–22. Findings: We identified four ‘pandemic narratives’ (reaction; revision; resilience; (re)normalisation) in the participants' accounts of hospice palliative care support in the first two years of the pandemic. In each narrative we explore how Covid-19 and the associated pandemic guidance affected what quality of life was understood to be; how what was considered to be timely care could change during the palliative care journey; and, how different ideas of holistic care were emphasised as the hospice and wider healthcare context changed. Conclusion: This is the first-time stories about the first two-years of the Covid-19 pandemic from hospice patients, carers, staff and senior managers have been analysed together. We identified how the pandemic brought an existential challenge to ideas of what hospice palliative care is and could be. Our findings suggest that ‘living with covid’ will continue to affect hospice palliative care's ideals of timeliness of care, holistic support, and quality of life left.

Cloning and transfer of long-stranded DNA in the size of a bacterial whole genome has become possible by recent advancements in synthetic biology. For the whole genome cloning and whole genome transplantation, bacteria with small genomes have been mainly used, such as mycoplasmas and related species. The key benefits of whole genome cloning include the effective maintenance and preservation of an organism's complete genome within a yeast host, the capability to modify these genome sequences through yeast-based genetic engineering systems, and the subsequent use of these cloned genomes for further experiments. This approach provides a versatile platform for in-depth genomic studies and applications in synthetic biology. Here, we cloned an entire genome of an insect-associated bacterium, Spiroplasma chrysopicola, in yeast. The 1.12 Mbp whole genome was successfully cloned in yeast, and sequences of several clones were confirmed by Illumina sequencing. The cloning efficiency was high, and the clones contained only a few mutations, averaging 1.2 nucleotides per clone with a mutation rate of 4 × 10−6. The cloned genomes could be distributed and used for further research. This study serves as an initial step in the synthetic biology approach to Spiroplasma.

Background: The need for palliative care is rising globally with 76% of those who are in need living in low- and middle-income countries (LMICs). Digital health interventions (DHIs) have been identified as a means of making palliative care more widely accessible. This review summarizes the range and characteristics of DHIs used to deliver palliative care in LMICs and sought to identify factors that influence their implementation and utilization. Objectives: This review aims to summarize the range and characteristics of DHIs used to deliver palliative care in LMICs and identify factors that influence their implementation and utilization. Design: Mixed-method systematic review incorporating both quantitative and qualitative data. Data sources and methods: All studies focusing on DHIs for patients who need palliative care (adults/children) and their caregivers (patient and caregiver centred) in LMICs and published in English were identified through a systematic search of MEDLINE, EMBASE, PsycINFO and CINAHL databases. Data synthesis and analysis were carried out following the convergent integrated approach based on the Joanna Briggs Institute (JBI) methodology for mixed-methods systematic reviews. Results: Fifteen studies were included (three qualitative, four mixed-methods and eight quantitative studies). Telemedicine/mHealth was the most reported DHI utilized in LMICs in delivering palliative care. Patients and caregivers benefited from using DHIs in many ways including increased access to care with reduced discomfort, travel time and risk of health care-associated infections. Health care providers also reported that using DHI such as telemedicine enables them to provide care in a more effective and efficient way. Four factors were identified as the main barriers to implementation: resource constraints; literacy, training and skills; governance, operational and communication issues and technical issues. Conclusion: DHIs, such as telemedicine, have the potential to enhance accessibility to palliative care in LMICs, particularly in rural areas. Comprehensive strategies for their use are required to address the identified barriers.

ABSTRACT Cyanobacteria are photosynthetic organisms that have garnered significant recognition as potential hosts for sustainable bioproduction. However, their complex regulatory networks pose significant challenges to major metabolic engineering efforts, thereby limiting their feasibility as production hosts. Genome streamlining has been demonstrated to be a successful approach for improving productivity and fitness in heterotrophs but is yet to be explored to its full potential in phototrophs. Here, we present the systematic reduction of the genome of the cyanobacterium exhibiting the fastest exponential growth, Synechococcus elongatus UTEX 2973. This work, the first of its kind in a photoautotroph, involved an iterative process using state-of-the-art genome-editing technology guided by experimental analysis and computational tools. CRISPR-Cas3 enabled large, progressive deletions of predicted dispensable regions and aided in the identification of essential genes. The large deletions were combined to obtain a strain with 55-kb genome reduction. The strains with streamlined genome showed improvement in growth (up to 23%) and productivity (by 22.7%) as compared to the wild type (WT). This streamlining strategy not only has the potential to develop cyanobacterial strains with improved growth and productivity traits but can also facilitate a better understanding of their genome-to-phenome relationships.IMPORTANCEGenome streamlining is an evolutionary strategy used by natural living systems to dispense unnecessary genes from their genome as a mechanism to adapt and evolve. While this strategy has been successfully borrowed to develop synthetic heterotrophic microbial systems with desired phenotype, it has not been extensively explored in photoautotrophs. Genome streamlining strategy incorporates both computational predictions to identify the dispensable regions and experimental validation using genome-editing tool, and in this study, we have employed a modified strategy with the goal to minimize the genome size to an extent that allows optimal cellular fitness under specified conditions. Our strategy has explored a novel genome-editing tool in photoautotrophs, which, unlike other existing tools, enables large, spontaneous optimal deletions from the genome. Our findings demonstrate the effectiveness of this modified strategy in obtaining strains with streamlined genome, exhibiting improved fitness and productivity.

Rats can condition cephalic-phase insulin responses (CPIRs) to specific sounds or times of the day that predict food availability. The present study asked whether mice can condition a CPIR to the flavor of sapid solutions that produce postoral glucose stimulation. To this end, we subjected C57BL/6 mice to one of six experimental protocols. We varied both the duration of the five training sessions (i.e., 23 h or 1 h) and the nature of the training solution. In Experiment 1, consumption of a 0.61% saccharin solution was paired with IG co-infusion of a 16% glucose solution. In Experiments 2–6, the mice consumed a training solution containing a mixture of 0.61% saccharin + 16% glucose, 32% sucrose, 32% maltodextrin, flavored 32% maltodextrin, or 16% maltodextrin. We subsequently asked whether consumption of any of these fluids conditioned a CPIR to a test solution that produced a similar flavor, but which did not elicit a CPIR in naïve mice. The mice did condition a CPIR, but only to the solutions containing 32% maltodextrin. We attribute this conditioning to postoral actions of the concentrated maltodextrin solutions.

The successful 2020 launch and 2021 landing of the National Aeronautics and Space Administration’s (NASA) Perseverance Mars rover initiated the first phase of the NASA and European Space Agency (ESA) Mars Sample Return (MSR) campaign. The goal of the MSR campaign is to collect scientifically interesting samples from the Martian surface and return them to Earth for further study in terrestrial laboratories. The MSR campaign consists of three major spacecraft components to accomplish this objective: the Perseverance Mars rover, the Sample Retrieval Lander (SRL) and the Earth Return Orbiter (ERO). Onboard the ERO spacecraft is the Capture, Containment and Return System (CCRS). CCRS will capture, process and return to Earth the samples that have been collected after they are launched into Mars orbit by the Mars Ascent Vehicle (MAV), which is delivered to Mars onboard the SRL. To facilitate the processing of the orbiting sample (OS) via the CCRS, we have designed and developed a vision system to determine the OS capture orientation. The vision system is composed of two cameras sensitive to the visible portion of the electromagnetic spectrum and two illumination modules constructed from broadband light emitting diodes (LED). Vision system laboratory tests and physics-based optical simulations predict CCRS ground processing will be able to correctly identify the OS post-capture orientation using only a single vision system image that is transmitted to Earth from Mars orbit.

The growing exposure to occupational chemicals and the spread of human immunodeficiency virus (HIV) infection are major global health issues. However, there is little data on the carcinogenic risk profile of HIV-infected individuals who have been occupationally exposed to chemical mixtures. This study therefore investigated the levels of cancer risk biomarkers in HIV-infected individuals exposed to occupational chemicals, exploring the relationship between apoptotic regulatory and oxidative response markers as a measure of cancer risk. Study participants (mean age 38.35±0.72 years) were divided into four groups according to their HIV status and occupational chemical exposure: 62 HIV-positive exposed (HPE), 66 HIV-positive unexposed (HPU), 60 HIV-negative exposed (HNE), and 60 HIV-negative unexposed (HNU). Serum p53, β-cell lymphoma-2 (bcl2), 8-hydroxydeoxyguanosine (8-OHdG), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured using standard methods. Clusters of differentiation 4 (CD4+) T-lymphocytes were enumerated using flow cytometry. Serum p53 and bcl2 levels in HPE (0.91±0.11ng/ml and 122.37±15.77ng/ml) were significantly lower than HNU (1.49±0.15ng/ml and 225.52±33.67ng/ml) (p < 0.05), respectively. Wildtype p53 and bcl2 were positively and significantly correlated with 8-OHdG (r = 0.35, p

AbstractEntrepreneurship has evolved into a valuable tool for facilitating job creation in response to Nigeria’s youth bulge and declining job opportunities in the formal sector. This study assessed the impact of entrepreneurship on youths’ livelihood, focusing on the National Directorate of Employment (NDE) program in Kano state. The study employed both qualitative and quantitative methods. A total of 266 respondents, including 148 young entrepreneurs and 118 non-entrepreneurs, were sampled using a multi-stage sampling technique, with Focused Group Discussions (FGDs) used to collect qualitative data from 25 youths. Data were analyzed using descriptive statistics and an Endogenous Switching Treatment Effect Regression (ESTER) model. The descriptive analysis showed that engagement in entrepreneurship was determined by age, having consistent income source, credit access, number of entrepreneurs in the household, access to entrepreneurship training, household size, and asset ownership. Even though entrepreneurs earned higher monthly income than non-entrepreneurs, their income was just slightly above the Nigerian minimum wage. Furthermore, asset ownership, access to credit, group membership, and access to training, all of which are strong predictors of entrepreneurship, were higher among entrepreneurs compared to non-entrepreneurs. The findings also revealed that entrepreneurs had better livelihood outcomes, as measured by income and self-assessed living condition, than non-entrepreneurs. Even though these outcomes could have resulted from other externalities, the empirical analysis helped to address such endogeneity, thereby attributing the outcome estimates solely to entrepreneurship. These results, therefore, show the relevance of entrepreneurship in alleviating poverty and generating better livelihood outcomes for young Nigerians.

Abstract Background Docetaxel (DTX) has been used to treat numerous types of cancers. Poor solubility, lower bioavailability, and serious side effects limit its use in cancer treatment. The objective of the present research work was to develop DTX-loaded niosomes to overcome these issues and investigate the anticancer effect on breast cancer. Niosomes of DTX were prepared and evaluated to estimate particle size, surface potential, morphology by TEM, %EE, in vitro drug release, %hemolysis, in vitro cytotoxicity, and stability. The cytotoxicity effect of plain DTX and DTX-loaded niosomes was performed on MCF-7 cell lines. Results The mean particle size, zeta potential, and %EE of DTX-loaded niosomes were 244.9 nm, − 7.1 mV, and 97.43%, respectively. Besides, combining the DTX with polymers enhanced drug loading capacity. The TEM images confirmed spherical-shaped niosomes. The IR, DSC, and P-XRD studies indicate no chemical interaction between drug and excipients. The developed DTX niosomes showed a sustained release behavior and lower in vitro cytotoxicity when compared to plain DTX. Conclusion The current research work demonstrates the suitability of co-loading of DTX in niosomes as a promising approach to enhance the efficiency of DTX. Graphical Abstract

Abstract Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.

This longitudinal study aimed to quantify the effects of dietary supplementation of a direct-fed microbial (DFM) consisting of three lactobacilli isolates on milk yield, milk fat and protein yields, somatic cell count (SCC), and liveweight in a single dairy herd in Australia. A total of 150 dairy cows were randomly selected based on parity and days in milk and divided into two groups: control (n = 75) and DFM treatment (n = 75). Throughout the study, the two groups of cows were housed separately in a dry lot yard, and each group had their own feeding area. For the DFM treatment group, selected cows in mid-lactation were supplemented with 10 mL/cow/day of the DFM via top dressing of the feed for the remainder of the lactation and through the dry period, extending into subsequent lactation. The control group had no supplementation. The milk yield and liveweight were recorded daily. Milk samples were collected every two months for milk component analysis (fat, protein, and somatic cell count [SCC]). The DFM-treated cows gained more liveweight across the study (19.40 kg, 95% CI 0.44 kg; 38.30 kg, p = 0.05) compared to the control cows. In the second production year, the DFM-treated cows mobilized more liveweight (−6.06 kg, 95% CI −10.49 kg; −1.61 kg, p = 0.01) and produced more milk (0.39 L/d 95% CI 0.10; 0.89, p = 0.05). Over a full lactation, DFM cows yielded at least 258 L (95% CI 252 L; 265 L) more milk than controls. No significant differences were found in fat and protein yield or SCC. This study suggests that consistent and ongoing supplementation with a Lacticaseibacillus- and Lentilactobacillus-based DFM could have a positive effect on milk production, but further research is needed to understand the underlying mechanism.

Understanding the links between development and evolution is one of the major challenges of biology. ‘Heterochronies’, evolutionary alterations in the timings of development are posited as a key mechanism of evolutionary change, but their quantification requires gross simplification of organismal development. Consequently, how changes in event timings influence development more broadly is poorly understood. Here, we measure organismal development as spectra of energy in pixel values of video, creating high-dimensional landscapes integrating development of all visible form and function. This approach we termed ‘Energy proxy traits’ (EPTs) is applied alongside previously identified heterochronies in three freshwater pulmonate molluscs (Lymnaea stagnalis, Radix balthica and Physella acuta). EPTs were calculated from time-lapse video of embryonic development to construct a continuous functional time series. High-dimensional transitions in phenotype aligned with major sequence heterochronies between species. Furthermore, differences in event timings between conspecifics were associated with changes in high-dimensional phenotypic space. We reveal EPTs as a powerful approach to considering the evolutionary importance of alterations to developmental event timings. Reimagining the phenotype as energy spectra enabled continuous quantification of developmental changes in high-dimensional phenotypic space, rather than measurement of timings of discrete events. This approach has the possibility to transform how we study heterochrony and development more generally.

Some types of collagens, including transmembrane MACIT collagens and C. elegans cuticle collagens, are N-terminally cleaved at a dibasic site that resembles the consensus for furin or other proprotein convertases of the subtilisin/kexin (PCSK) family. Such cleavage may release transmembrane collagens from the plasma membrane and affect extracellular matrix assembly or structure. However, the functional consequences of such cleavage are unclear and evidence for the role of specific PCSKs is lacking. Here, we used endogenous collagen fusions to fluorescent proteins to visualize the secretion and assembly of the first collagen-based cuticle in C. elegans and then tested the role of the PCSK BLI-4 in these processes. Unexpectedly, we found that cuticle collagens SQT-3 and DPY-17 are secreted into the extraembryonic space several hours before cuticle matrix assembly. Furthermore, this early secretion depends on BLI-4/PCSK; in bli-4 and cleavage-site mutants, SQT-3 and DPY-17 are not efficiently secreted and instead form large intracellular puncta. Their later assembly into cuticle matrix is reduced but not entirely blocked. These data reveal a role for collagen N-terminal processing in intracellular trafficking and the control of matrix assembly in vivo. Our observations also prompt a revision of the classic model for C. elegans cuticle matrix assembly and the pre-cuticle-to-cuticle transition, suggesting that cuticle layer assembly proceeds via a series of regulated steps and not simply by sequential secretion and deposition.

Summary: The bacterial strain JCVI-syn3.0 stands as the first example of a living organism with a minimized synthetic genome, derived from the Mycoplasma mycoides genome and chemically synthesized in vitro. Here, we report the experimental evolution of a syn3.0- derived strain. Ten independent replicates were evolved for several hundred generations, leading to growth rate improvements of > 15%. Endpoint strains possessed an average of 8 mutations composed of indels and SNPs, with a pronounced C/G- > A/T transversion bias. Multiple genes were repeated mutational targets across the independent lineages, including phase variable lipoprotein activation, 5 distinct; nonsynonymous substitutions in the same membrane transporter protein, and inactivation of an uncharacterized gene. Transcriptomic analysis revealed an overall tradeoff reflected in upregulated ribosomal proteins and downregulated DNA and RNA related proteins during adaptation. This work establishes the suitability of synthetic, minimal strains for laboratory evolution, providing a means to optimize strain growth characteristics and elucidate gene functionality.

For plants, distinguishing between mutualistic and pathogenic microbes is a matter of survival. All microbes contain microbe-associated molecular patterns (MAMPs) that are perceived by plant pattern recognition receptors (PRRs). Lysin motif receptor-like kinases (LysM-RLKs) are PRRs attuned for binding and triggering a response to specific MAMPs, including chitin oligomers (COs) in fungi, lipo-chitooligosaccharides (LCOs), which are produced by mycorrhizal fungi and nitrogen-fixing rhizobial bacteria, and peptidoglycan in bacteria. The identification and characterization of LysM-RLKs in candidate bioenergy crops including Populus are limited compared to other model plant species, thus inhibiting our ability to both understand and engineer microbe-mediated gains in plant productivity. As such, we performed a sequence analysis of LysM-RLKs in the Populus genome and predicted their function based on phylogenetic analysis with known LysM-RLKs. Then, using predictive models, molecular dynamics simulations, and comparative structural analysis with previously characterized CO and LCO plant receptors, we identified probable ligand-binding sites in Populus LysM-RLKs. Using several machine learning models, we predicted remarkably consistent binding affinity rankings of Populus proteins to CO. In addition, we used a modified Random Walk with Restart network-topology based approach to identify a subset of Populus LysM-RLKs that are functionally related and propose a corresponding signal transduction cascade. Our findings provide the first look into the role of LysM-RLKs in Populus-microbe interactions and establish a crucial jumping-off point for future research efforts to understand specificity and redundancy in microbial perception mechanisms.

Idiomatics--the scientific study of idiomatic language and figurative language--is a pervasive theme in global literature, yet its precise terminology often lacks clear definition. This article addresses this challenge directly by delving into the etymology, significance, and universality of idiomatics. It emphasizes the pivotal role of idiomatics in understanding human behavior and language development, stressing its interdisciplinary relevance. Advocating for idiomatics to gain recognition as a distinct academic discipline, the article calls for the establishment of clear boundaries and methodologies within academia. It concludes with a compelling appeal for collective action, urging idiomatists worldwide to unite under the imperative "Make it happen!" To this end, it presents ten strategic priorities that transcend geographical and linguistic divides, uniting researchers and language professionals in a common mission to advance idiomatics. These priorities underscore the urgency of addressing the current state of idiomatics and shaping its future trajectory, emphasizing the need for decisive action and collaboration. Through concerted efforts, the article seeks to propel idiomatics into new heights of understanding and application across diverse linguistic and cultural contexts, one priority at a time.

Abstract Objective To characterize normative adult ranges for cochlear promontory thickness relevant to the development of subendosteal and transpromontory electrodes to rehabilitate various neurotologic disorders. Patients Adults (≥18 years). Intervention In vivo radiologic assessment using a 192‐slice CT scanner (Force‐192; Siemens Healthcare) with ultrahigh‐resolution scan mode combined and iterative reconstruction. Main Outcome Measure Cochlear promontory thickness. Results Among 48 included patients (96 ears), the mean (SD) age was 56 (18) years (range 25–94) and included 25 (52%) women. Of that 12 patients (25%) had osteopenia (n = 6) or osteoporosis (n = 6). The mean (SD) body mass index was 28 (5) kg/m2. The mean (SD) promontory thickness for the 96 temporal bones under study was 1.22 (0.24) mm (range 0.55–1.85). There was not a statistically significant association between age and promontory thickness (correlation coefficient .08; p = .44). Promontory thickness was significantly greater for men than women (mean 1.28 vs. 1.17 mm; p = .03) and increased with increasing body mass index (correlation coefficient .30; p = .004). Last, promontory thickness was significantly less for patients with osteopenia or osteoporosis compared with those without these conditions (mean 1.09 vs. 1.27 mm; p = .002). Conclusions Cochlear promontory thickness can vary by almost 1.5 mm across patients and is significantly associated with patient sex, body mass index, and comorbid osteopenia/osteoporosis. Subendosteal and transpromontory electrode placement techniques must account for this degree of variability. Level of Evidence IV

Abstract Background The provision of palliative care is increasing, with many people dying in community-based settings. It is essential that communication is effective if and when patients transition from hospice to community palliative care. Past research has indicated that communication issues are prevalent during hospital discharges, but little is known about hospice discharges. Methods An explanatory sequential mixed methods study consisting of a retrospective review of hospice discharge letters, followed by hospice focus groups, to explore patterns in communication of palliative care needs of discharged patients and describe why these patients were being discharged. Discharge letters were extracted for key content information using a standardised form. Letters were then examined for language patterns using a linguistic methodology termed corpus linguistics. Thematic analysis was used to analyse the focus group transcripts. Findings were triangulated to develop an explanatory understanding of discharge communication from hospice care. Results We sampled 250 discharge letters from five UK hospices whereby patients had been discharged to primary care. Twenty-five staff took part in focus groups. The main reasons for discharge extracted from the letters were symptoms “managed/resolved” (75.2%), and/or the “patient wishes to die/for care at home” (37.2%). Most patients had some form of physical needs documented on the letters (98.4%) but spiritual needs were rarely documented (2.4%). Psychological/emotional needs and social needs were documented in 46.4 and 35.6% of letters respectively. There was sometimes ambiguity in “who” will be following up “what” in the discharge letters, and whether described patients’ needs were resolved or ongoing for managing in the community setting. The extent to which patients received a copy of their discharge letter varied. Focus groups conveyed a lack of consensus on what constitutes “complexity” and “complex pain”. Conclusions The content and structure of discharge letters varied between hospices, although generally focused on physical needs. Our study provides insights into patterns associated with those discharged from hospice, and how policy and guidance in this area may be improved, such as greater consistency of sharing letters with patients. A patient-centred set of hospice-specific discharge letter principles could help improve future practice.

The dynamic nature of developing organisms and how they function presents both opportunity and challenge to researchers, with significant advances in understanding possible by adopting innovative approaches to their empirical study. The information content of the phenotype during organismal development is arguably greater than at any other life stage, incorporating change at a broad range of temporal, spatial and functional scales and is of broad relevance to a plethora of research questions. Yet, effectively measuring organismal development, and the ontogeny of physiological regulations and functions, and their responses to the environment, remains a significant challenge. “Phenomics”, a global approach to the acquisition of phenotypic data at the scale of the whole organism, is uniquely suited as an approach. In this perspective, we explore the synergies between phenomics and Comparative Developmental Physiology (CDP), a discipline of increasing relevance to understanding sensitivity to drivers of global change. We then identify how organismal development itself provides an excellent model for pushing the boundaries of phenomics, given its inherent complexity, comparably smaller size, relative to adult stages, and the applicability of embryonic development to a broad suite of research questions using a diversity of species. Collection, analysis and interpretation of whole organismal phenotypic data are the largest obstacle to capitalising on phenomics for advancing our understanding of biological systems. We suggest that phenomics within the context of developing organismal form and function could provide an effective scaffold for addressing grand challenges in CDP and phenomics.

Abstract Background The interaction of polygenic risk (PRS) and environmental effects on development of bipolar disorder (BD) is understudied, as are high‐risk offspring perceptions of their family environment (FE). We tested the association of offspring‐perceived FE in interaction with BD‐PRS on liability for BD in offspring at high or low familial risk for BD. Methods Offspring of a parent with BD (oBD; n = 266) or no psychiatric disorders (n = 174), aged 12–21 at recruitment, participated in the US and Australia. Empirically‐derived profiles of FE classified offspring by their perceived levels of familial cohesion, flexibility, and conflict. Offspring BD‐PRS were derived from Psychiatric Genomics Consortium BD‐GWAS. Lifetime DSM‐IV bipolar disorders were derived from the Schedule for Affective Disorders and Schizophrenia for School‐Aged Children. We used a novel stepwise approach for latent class modeling with predictors and distal outcomes. Results Fifty‐two offspring were diagnosed with BD. For those with well‐functioning FE (two‐thirds of the sample), higher BD‐PRS tracked positively with liability for BD. However, for those with high‐conflict FEs, the relationship between BD‐PRS and liability to BD was negative, with highest risk for BD observed with lower BD‐PRS. In exploratory analyses, European‐ancestry offspring with BD had elevated history of suicidal ideation in high‐conflict FE compared to well‐functioning‐FE, and of suicide attempt with low‐BD‐PRS and high‐conflict FE. Conclusions The data suggest that the relationship of BD‐PRS and offspring liability for BD differed between well‐functioning versus high‐conflict FE, potentially in line with a multifactorial liability threshold model and supporting future study of and interventions improving family dynamics.

The calf’s gastrointestinal tract (GIT) microbiome undergoes rapid shifts during early post-natal life, which can directly affect calf performance. The objectives of this study were to characterise and compare differences in the establishment and succession of GIT microbiota, GIT morphological changes, and the growth of dairy calves from birth until weaned. Forty-four newborn Holstein-Friesian calves were randomly selected and assigned to Treatment (TRT) and Control (CON) groups. The TRT group calves received a once-daily dose of a direct-fed microbial (DFM) liquid product containing Lacticaseibacillus paracasei, Lentilactobacillus buchneri, and Lacticaseibacillus casei, all formerly known as Lactobacillus. Fresh faecal samples were manually taken from the rectum of all calves, and gross necropsy was performed on the forestomachs and gastrointestinal tracts. Bacterial DNA was extracted from frozen faecal samples for 16S rRNA gene amplicon sequencing. Calves in the TRT group had greater live weights (p = 0.02) at weaning compared with calves in the CON group (mean = 69.18 kg, SD = 13.37 kg). The average daily live weight gain (ADG) and total feed intake were similar between the two groups. Calves in the TRT group had greater duodenum, abomasum, and reticulum weights (p = 0.05). Rumen and intestinal development (p < 0.05) and faecal microbial diversity (p < 0.05) were more pronounced in the TRT group. The relative abundances of eight genera differed (p < 0.001) between the groups. Supplementing calves with the LAB-based DFM increased live weight at weaning and had a more pronounced effect on the development of rumen and the gastrointestinal tract and on microbiota diversity and evenness. Future work is needed to better understand the potential association of LAB-DFM products on gut mucosa-associated microbiota.

We present an analysis of high-resolution optical spectra recorded for 30 stars of the split extended main-sequence turnoff of the young (∼40 Myr) Small Magellanic Cloud globular cluster NGC 330. Spectra were obtained with the Michigan/Magellan Fiber System and Magellan Inamori Kyocera Echelle spectrographs located on the Magellan-Clay 6.5 m telescope. These spectra revealed the presence of Be stars, occupying primarily the cool side of the split main sequence. Rotational velocity ( $v\sin i$ ) measurements for most of the targets are consistent with the presence of two populations of stars in the cluster: one made up of rapidly rotating Be stars ( $\langle v\sin i\rangle \approx 200$ km s ^−1 ) and the other consisting of warmer stars with slower rotation ( $\langle v\sin i\rangle \approx 50$ km s ^−1 ). Core emission in the H δ photospheric lines was observed for most of the H α emitters. The shell parameter computed for the targets in our sample indicates that most of the observed stars should have inclinations below 75°. These results confirm the detection of Be stars obtained through photometry but also reveal the presence of narrow H α and H δ features for some targets that cannot be detected with low-resolution spectroscopy or photometry. Asymmetry variability of H α line profiles on the timescales of a few years is also observed and could provide information on the geometry of the decretion disks. Observations revealed the presence of nebular H α emission, strong enough in faint targets to compromise the extraction of spectra and to impact narrow-band photometry used to assess the presence of H α emission.

M15 is a globular cluster with a known spread in neutron-capture elements. This paper presents abundances of neutron-capture elements for 62 stars in M15. Spectra were obtained with the Michigan/Magellan Fiber System spectrograph, covering a wavelength range from ∼4430 to 4630 Å. Spectral lines from Fe i , Fe ii , Sr i , Zr ii , Ba ii , La ii , Ce ii , Nd ii , Sm ii , Eu ii , and Dy ii were measured, enabling classifications and neutron-capture abundance patterns for the stars. Of the 62 targets, 44 are found to be highly Eu-enhanced r -II stars, another 17 are moderately Eu-enhanced r -I stars, and one star is found to have an s -process signature. The neutron-capture patterns indicate that the majority of the stars are consistent with enrichment by the r -process. The 62 target stars are found to show significant star-to-star spreads in Sr, Zr, Ba, La, Ce, Nd, Sm, Eu, and Dy, but no significant spread in Fe. The neutron-capture abundances are further found to have slight correlations with sodium abundances from the literature, unlike what has been previously found; follow-up studies are needed to verify this result. The findings in this paper suggest that the Eu-enhanced stars in M15 were enhanced by the same process, that the nucleosynthetic source of this Eu pollution was the r -process, and that the r -process source occurred as the first generation of cluster stars was forming.

The Huanggang depression in eastern China is a significant Cenozoic salt-bearing basin that formed during the alternating dry and wet climate periods from the Eocene to the Oligocene. Despite the economic importance of the Huanggang depression, its saliferous model remains controversial. To address this issue, we conducted comprehensive analyses of the sedimentology and elemental geochemistry on the YZR1 borehole core, which hosts a relatively complete sedimentary record of the Huanggang depression, consisting of five lithofacies’ assemblages. The combined lithofacies and geochemical ratios, including B/Ga, Sr/Ba, and V/(V + Ni), provide insights into the paleolake’s evolution in the Huanggang depression. Our analyses indicated that the paleolake underwent a transition from a freshwater lake to a brackish water/saline lake, subsequently transforming into a salt lake, reverting back to a brackish water/saline lake, and ultimately returning to its original state as a freshwater lake. These changes are reflected in the sedimentary record and inform the six stages of evolution of the paleolake of the Dawenkou Formation. We propose two metallogenic models to explain the accumulation of the thick halite (LA1) and thin halite layers (LA2), respectively. LA1 is primarily dominated by halite deposition, forming in an extremely shallow water environment under arid climate conditions. In contrast, LA2 records the alternating deposition of halite, anhydrite, and mudstone, and formed in a shallow water environment under arid to semi-arid climatic conditions. LA1 has a much drier climate and higher salinity than LA2. Our results suggest that the salt-forming period in the Huanggang depression occurred from the late Eocene to the early Oligocene. The halite in the Huanggang depression formed in a shallow water environment, providing the basis for the halite deposition model of the depression. This study sheds light on the formation mechanism of halite in the Paleogene in eastern China.

Abstract Environmental factors contribute to risk of bipolar disorder (BD), but how environmental factors impact the development of psychopathology within the context of elevated genetic risk is unknown. We herein sought to identify epigenetic signatures operating in the context of polygenic risk for BD in young people at high familial risk (HR) of BD. Peripheral blood-derived DNA was assayed using Illumina PsychArray, and Methylation-450K or -EPIC BeadChips. Polygenic risk scores (PRS) were calculated using summary statistics from recent genome-wide association studies for BD, major depressive disorder (MDD) and cross-disorder (meta-analysis of eight psychiatric disorders). Unrelated HR participants of European ancestry (n = 103) were stratified based on their BD-PRS score within the HR-population distribution, and the top two quintiles (High-BD-PRS; n = 41) compared against the bottom two quintiles (Low-BD-PRS; n = 41). The High-BD-PRS stratum also had higher mean cross-disorder-PRS and MDD-PRS (ANCOVA p = 0.035 and p = 0.024, respectively). We evaluated DNA methylation differences between High-BD-PRS and Low-BD-PRS strata using linear models. One differentially methylated probe (DMP) (cg00933603; p = 3.54 × 10−7) in VARS2, a mitochondrial aminoacyl-tRNA synthetase, remained significantly hypomethylated after multiple-testing correction. Overall, BD-PRS appeared to broadly impact epigenetic processes, with 1,183 genes mapped to nominal DMPs (p

Abstract Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E−05 to 6.27E−03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E−03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32–2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.

The impact of prior infection on the immune response to COVID-19 vaccination has not been fully characterised. Here, the authors use data from ~100,000 adults in the UK and find that a single vaccine dose in those with prior infection produces a comparable or stronger response to two doses in those without infection.

Inborn errors of metabolism (IEM) are a group of genetically derived diseases that are individually rare but collectively common and can be very severe. While high-income countries usually employ modern scientific technologies like tandem mass spectrometry for IEM investigation, these disorders are, in contrast, only rarely screened for in developing countries due to misconceptions that the required facilities are beyond the reach of these countries. This paper attempts to educate scientists and clinicians in developing countries on low-technology IEM screening methods that only require moderate facilities. Although a definitive diagnosis of IEM may require specialised laboratory investigations and attendant interpretation, in most cases, the basic facilities available in the average clinical chemistry laboratory in developing countries can allow the early detection of IEM. This early detection would facilitate critical early decision making, thus leading to better management, optimised treatment, and reduced morbidity and or mortality of IEM in these resource-limited countries. With this approach, a few referral centres for confirmatory investigation, comparable to those existing in developed countries, could be established. This can be integrated into creative health education for healthcare professionals and families who have individuals with IEM. What this study adds: IEMs are important enough that every country, developed or developing, should have screening plans and basic laboratory facilities that are adequate for initial IEM diagnosis. No country should therefore give up on testing for IEMs on the excuse of a paucity of advanced facilities.

NADPH oxidases (NOX's), and the reactive oxygen species (ROS) they produce, play an important role in host defense, thyroid hormone synthesis, apoptosis, gene regulation, angiogenesis and other processes. However, overproduction of ROS by these enzymes is associated with cardiovascular disease, fibrosis, traumatic brain injury (TBI) and other diseases. Structural similarities between NOX's have complicated development of specific inhibitors. Here, we report development of NCATS-SM7270, a small molecule optimized from GSK2795039, that inhibited NOX2 in primary human and mouse granulocytes. NCATS-SM7270 specifically inhibited NOX2 and had reduced inhibitory activity against xanthine oxidase in vitro. We also studied the role of several NOX isoforms during mild TBI (mTBI) and demonstrated that NOX2 and, to a lesser extent, NOX1 deficient mice are protected from mTBI pathology, whereas injury is exacerbated in NOX4 knockouts. Given the pathogenic role played by NOX2 in mTBI, we treated mice transcranially with NCATS-SM7270 after injury and revealed a dose-dependent reduction in mTBI induced cortical cell death. This inhibitor also partially reversed cortical damage observed in NOX4 deficient mice following mTBI. These data demonstrate that NCATS-SM7270 is an improved and specific inhibitor of NOX2 capable of protecting mice from NOX2-dependent cell death associated with mTBI.

Abstract Background Diffuse intrinsic pontine glioma (DIPG) is a notoriously difficult tumor to treat, with an overall survival of DIPG patients being only 11 months. One of the major obstacles for the effective treatment of DIPG is the blood–brain barrier (BBB). In order to circumvent the BBB, drug delivery methods are needed that target the pontine area. One such approach is microbubble-mediated focused ultrasound (FUS)—a non-invasive method that can temporarily and locally open the BBB. Previously, it was shown that FUS is safe with minimal side effects and rapid recovery times in preclinical animal models with different DIPG tumors. However, recent studies have shown that combining FUS with a single treatment of the chemotherapeutic drug doxorubicin did not improve survival in a DIPG xenograft model. As the duration of doxorubicin exposure might play a role in tumor response, we hypothesized that the use of a long-circulation (PEGylated) liposomal formulation of doxorubicin could lead to improved overall survival through a longer exposure time to the tumor. Method DIPG xenograft models were established with orthotopic injections of HSJD-DIPG-07 tumor cells into the pontine area of female athymic nude-foxn1nu mice. Tumor engraftment was confirmed with bioluminescence imaging (BLI) 40 days post-inoculation. Mice were randomized into groups receiving either liposomal formulations of doxorubicin (2B3-101 or Caelyx®) or free doxorubicin in combination with or without FUS treatment. Treatment groups received 5 mg/kg 2B3-101 or Caelyx® 1 h before FUS treatment or 5 mg/kg free doxorubicin immediately after FUS. Results Histological analysis, however, revealed liposome extravasation in healthy controls but not in HSJD-DIPG-07 xenograft 24 h after treatment. Furthermore, BLI monitoring did not show reduced signal after treatment, which was further illustrated with a survival analysis, showing no significant difference between treated and control animals (p = 0.3). Conclusion We did not observe a treatment effect after a single dose of free doxorubicin or the liposomal formulations 2B3-101 or Caelyx® in combination with FUS in DIPG-bearing mice.

Abstract We investigated gene–environment effects on structural brain endophenotype in bipolar disorder (BD) using a novel method of combining polygenic risk scores with epigenetic signatures since traditional methods of examining the family history and trauma effects have significant limitations. The study enrolled 119 subjects, including 55 BD spectrum (BDS) subjects diagnosed with BD or major depressive disorder (MDD) with subthreshold BD symptoms and 64 non-BDS subjects comprising 32 MDD subjects without BD symptoms and 32 healthy subjects. The blood samples underwent genome-wide genotyping and methylation quantification. We derived polygenic risk score (PRS) and methylation profile score (MPS) as weighted summations of risk single nucleotide polymorphisms and methylation probes, respectively, which were considered as molecular measures of genetic and environmental risks for BD. Linear regression was used to relate PRS, MPS, and their interaction to 44 brain structure measures quantified from magnetic resonance imaging (MRI) on 47 BDS subjects, and the results were compared with those based on family history and childhood trauma. After multiplicity corrections using false discovery rate (FDR), MPS was found to be negatively associated with the volume of the medial geniculate thalamus (FDR = 0.059, partial R 2 = 0.208). Family history, trauma scale, and PRS were not associated with any brain measures. PRS and MPS show significant interactions on whole putamen (FDR = 0.09, partial R 2 = 0.337). No significant gene–environment interactions were identified for the family history and trauma scale. PRS and MPS generally explained greater proportions of variances of the brain measures (range of partial R 2 = [0.008, 0.337]) than the clinical risk factors (range = [0.004, 0.228]).

Abstract Objective Describe the presentation and management strategy for patients with symptomatic foramen of Huschke (FH). Patients Adults with persistent FH confirmed on imaging. Interventions Diagnosis and management of symptomatic persistent FH. Main outcome measure Resolution of otologic symptoms. Results A total of four patients with symptomatic, radiographically‐confirmed persistent FH were included. The majority of patients endorsed otalgia (n = 4) and otorrhea (n = 3), and only one patient was noted to have a conductive hearing loss. All patients were noted to have dynamic movement of an external auditory canal mass with mandible manipulation on examination, and all patients had an identifiable fistula on imaging. Patients underwent surgical intervention, including both preauricular (n = 2) and transcanal (n = 2) approaches, and all endorsed symptomatic resolution after convalescence. Conclusions Persistent FH remains an uncommon and potentially underrecognized cause of otologic symptoms. Diagnosis requires a high index of suspicion, and one must rely on both key examination findings and imaging to confirm this diagnosis. In appropriately selected patients, surgical intervention can provide durable symptomatic resolution. Level of evidence IV

Background Large datasets of detailed anthropometric measurements are scarce in children. The Japanese Standard Association 1978–1981 survey provides a rare opportunity to use high quality data from Japanese children. Aim To construct inside leg length (ILL) and inside leg length to stature ratio (ILL/S) reference centile curves for Japanese children. Subjects and methods The study sample consisted of 14,825 boys and 14,577 girls age 0–18 years for stature and weight measurements, and 9064 boys and 8796 girls age 0–12 years for ILL measurements, who participated in the 1978–1981 national survey on body sizes. LMS method was used to construct the reference centile curves. The reference centile curves for stature, weight, ILL, and ILL/S were compared to those of British children. Results The L, M, and S reference values for Japanese children are presented for stature, weight, ILL, and ILL/S. Compared with British children of 0–12 years of age, Japanese children of 0–12 years of age had shorter median stature, shorter median ILL, and shorter median ILL/S. Conclusion We present the first reference values for ILL and ILL/S in Japanese children. Japanese children had relatively shorter legs compared to British children from infancy.

Studying the effects of temperature on cookies are necessary especially if the impact on quality attributes are to be deduced. More so, blending wheat flour, date flour, and pineapple juice could improve the nutrient quality required in modern-day cookies. This current study investigated the quality attributes of date and wheat flour pineapple juice blended cookies as affected by different baking temperatures. With pineapple juice serving as water substitute, the formulated date, and wheat flour blends adhered to the following ratios: 100:0, 90:10, 80:20, and 70:30. Baking cookies involved two different temperatures (160 °C and 180 °C) with constant time (30 min). Quality attributes determined proximate composition, micronutrients, physical and functional properties, and microbial and sensory qualities. Cookies proximate results showed moisture (6.89–7.40%), protein (8.73–10.22%), fat (14.37–15.99%), fiber (1.02–1.11%), ash (0.77–1.20%) and carbohydrate (64.85–67.71%). Various ranges appeared, from energy values (434.90–444.10 kcal), minerals (calcium = 33.18–62.45 mg/100 g; iron = 3.47–5.75 mg/100 g; potassium = 100.07–358.63 mg/100 g), vitamins (vitamin A =1.99–4.89 mg/100 g; vitamin C = 0.04–0.15 mg/100 g), physical (weight = 7.4–7.75 g; diameter = 3.50–4.01 cm; thickness = 0.99–1.20 cm; volume = 3.11–3.77 cm3; density = 2.06–2.41 g/cm3; spread ratio = 2.92–4.05 cm3), to functional (water absorption = 1.14–1.18 g/g; oil absorption capacity = 1.31–1.33 g/g; bulk density = 0.74–0.76 g/mL) properties. The microbial loads seemed somewhat acceptable as overall acceptability favoured sample WDFb (90% wheat, 10% date flour). The acceptability of cookies baked at 160 °C over those baked at 180 °C suggests the need for further studies to determine the energy requirements, and long-term environmental implications such (baking) temperatures would pose.

Triclosan (TCS), a synthesized chlorinated phenolic compound, is commonly utilized in consumable products as an antimicrobial agent. TCS has sparked widespread awareness because of its toxicity and possible negative effect on public health in recent years. In this study, a highly sensitive, fast, and cost-effective isocratic reversed-phase high-performance liquid chromatography (RP-HPLC) method coupled with solid-phase extraction for analysis of triclosan in human urine samples was developed. The method utilized methanol and water in a ratio of 90 : 10 as the mobile phase on a Phenomenex Luna 3 µm C18(2) 100 Å, 150 × 4.60 mm stationary phase, with a runtime of 5 minutes. The method showed good resolution of triclosan in the presence of the sample matrix. Validation of the method was performed according to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH). Linearity was tested over a range of 0.00625 µg/mL to 6.4 µg/mL, as accuracy recorded a recovery of 89.25%, 91.0%, and 92.75%. Limits of detection (LOD) and quantification (LOQ) were obtained to be 0.0173 µg/mL and 0.0525 µg/mL, respectively. The method proved to be robust over a temperature range of 26°C, 30°C, and 35°C and a flow rate of 0.5 ml, 1.0 ml, and 1.5 ml. The developed method was employed to detect and quantify triclosan in 153 urine samples, comprising 60 samples from Ibadan, Nigeria, and 93 samples from Kumasi, Ghana. Triclosan was detected in a total of 52 samples with an average content of 0.054588 µg/ml. This method can therefore be used for the routine analysis of triclosan in urine samples.

The hippocampus is responsible for encoding behavioral episodes into short-term and long-term memory. The circuits that mediate these processes are subject to neuromodulation, which involves regulation of synaptic plasticity and local neuronal excitability. In this review, we present evidence to demonstrate the influence of dopaminergic neuromodulation on hippocampus-dependent memory, and we address the controversy surrounding the source of dopamine innervation. First, we summarize historical and recent retrograde and anterograde anatomical tracing studies of direct dopaminergic projections from the ventral tegmental area and discuss dopamine release from the adrenergic locus coeruleus. Then, we present evidence of dopaminergic modulation of synaptic plasticity in the hippocampus. Plasticity mechanisms are examined in brain slices and in recordings from in vivo neuronal populations in freely moving rodents. Finally, we review pharmacological, genetic, and circuitry research that demonstrates the importance of dopamine release for learning and memory tasks while dissociating anatomically distinct populations of direct dopaminergic inputs.

Background: The Covid-19 pandemic resulted in the development of numerous recommendations for practice and policy for specialist palliative care provided by hospices in United Kingdom (UK), as hospices were significantly affected by the pandemic and protections put in place. The aim of this review is to identify and synthesise recommendations or implications for policy and practice that have been generated for adult hospice specialist palliative care during the first 24 months of the Covid-19 pandemic. Methods: AMED, BNI, CINAHL, EMBASE, EMCARE, HMIC, Medline, PsycINFO, PubMed databases were searched for peer-reviewed papers, as well as hand searches for grey literature. Literature relating to hospices and Covid-19 in the UK were included and a thematic synthesis of recommendations for hospice policy and practice was undertaken. Results: 858 articles were identified with 12 meeting the inclusion criteria. Fifty-eight recommendations or implications were identified: 31 for policy, 27 for practice, and 10 covering both. Recommendations were organised under ten themes. There were several recommendations seeking to secure hospice resources to mitigate the short-term impact of the pandemic, as well as those focused on longer-term implications such as core funding. The impact of the pandemic on the quality of hospice care was the focus for numerous recommendations around improving integration of hospice care in the community, provision of bereavement support and better use of Advance Care Plans (ACP). However, there were significant gaps related to carer visitation in hospices, inequities of palliative care, or hospice-at-home services. Conclusion: The Covid-19 pandemic and protections exposed several ongoing policy and practice needs, especially around hospice resources, while generating novel issues for hospices to address. Significant policy gaps remain to be addressed to mitigate the impact of the pandemic on the quality of hospice specialist palliative care.

Most people who are infected with SARS-CoV-2 seroconvert within a few weeks, but the determinants and duration of the antibody response are not known. Here, the authors characterise these features of the immune response using data from a large representative community sample of the UK population.

Abstract The role of calcium in blood pressure has been widely studied among hypertensive patients; however, no study has explored the role of calcium in hypertensive crises. The primary objective of this study is to evaluate the differences in serum calcium levels between hypertensive crises patients and a 1:1 random matched controls (age‐, sex‐, race‐, diabetes, and body mass index matched). This study is a single‐center, retrospective, chart review, case‐control study of patients with hypertensive crises (case group) and patients without hypertensive crises (control group). Patients were included in the case group if they were 18 years of age or older with hypertensive crises and have a documented calcium level. The control group patients were required to be 18 years of age or older, have a documented calcium level, and have no diagnosis of hypertensive crises. The primary outcome of the study was to compare the mean serum calcium in patients with hypertensive crises vs patients without hypertensive crises. Five hundred and sixty‐six patients were included in the study: 283 patients in both the case group and control group. The primary outcome results showed that serum calcium concentration was not significantly different between the case group (8.99 ± 0.78 mg/dL) and control group (8.96 ± 0.75 mg/dL) (P = .606). This study found no significant difference in serum calcium levels in patients with hypertensive crises compared to a random matched control group. Larger observational or experimental studies may be useful to evaluate the effect of calcium on blood pressure in hypertensive crises.

Docetaxel (DTX) has poor solubility, serious side effects, and multi-drug resistance (MDR) limiting its use in cancer treatment. Hence, the present study aimed to formulate and develop docetaxel mixed micelles (DTX MMs) for breast cancer treatment. DTX MMs were prepared from a mixture of docetaxel, TPGS, and Poloxamer 188 by using the solvent evaporation method. A 32 factorial design was applied to examine the combined effect of two formulation variables, each at 3 levels, and the 9 possible combinations of DTX MMs. The concentration of TPGS (X1) and concentration of Poloxamer 188 (X2) were independent variables. Whereas, particle size (Y1), and % entrapment efficiency (%EE) (Y2) were dependent variables. DTX MMs were evaluated for particle size analysis, TEM, %EE, in vitro drug release, %hemolysis, and stability study. DTX MMs composition (F6) was optimized based on particle size (143.2 nm), zeta potential (-7.5 mV) and %EE (81%). The TEM images showed spherical-shaped MMs. DTX MMs showed moderately higher IC50 value, indicating lower cytotoxicity when compared to plain DTX against MCF-7 cells. Docetaxel's sustained release from MMs decreased its exposure to normal tissue. Studies using IR, DSC, and P-XRD showed no significant incompatibility. DTX MMs would be a potential therapy for chemotherapy against breast cancer

Background: The Covid-19 pandemic resulted in the development of numerous recommendations for practice and policy for specialist palliative care provided by hospices in United Kingdom (UK), as hospices were significantly affected by the pandemic and protections put in place. The aim of this review is to identify and synthesise recommendations or implications for policy and practice that have been generated for adult hospice specialist palliative care during the first 24 months of the Covid-19 pandemic. Methods: AMED, BNI, CINAHL, EMBASE, EMCARE, HMIC, Medline, PsycINFO, PubMed databases were searched for peer-reviewed papers, as well as hand searchers for grey literature. Literature relating to hospices and Covid-19 in the UK were included and a thematic synthesis of recommendations for hospice policy and practice was undertaken. Results: 858 articles were identified with 12 meeting the inclusion criteria. Fifty-eight recommendations or implications were identified: 31 for policy, 27 for practice, and 10 covering both. Recommendations were organised under ten themes. There were several recommendations seeking to secure hospice resources to mitigate the short-term impact of the pandemic, as well as those focused on longer-term implications such as core funding. The impact of the pandemic on the quality of hospice care was the focus for numerous recommendations around improving integration of hospice care in the community, provision of bereavement support and better use of Advance Care Plans (ACP). However, there were significant gaps related to carer visitation in hospices, inequities of palliative care, or hospice-at-home services. Conclusion: The Covid-19 pandemic and protections exposed several ongoing policy and practice needs, especially around hospice resources, while generating novel issues for hospices to address. Significant policy gaps remain to be addressed to mitigate the impact of the pandemic on the quality of hospice specialist palliative care.

Alcohol use disorder and drinks per week both have been studied genetically and have different correlations with psychiatric diseases. Here the authors integrate multi-omics data to identify unique and shared variants, genes and pathways for alcohol use disorder and drinks per week.