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Intervening CIV absorbers are key tracers of metal-enriched gas in galaxy halos over cosmic time. Previous studies suggest that the CIV cosmic mass density ($\Omega_{\rm CIV}$) decreases slowly over 1.5 $\lesssim z\lesssim$ 5 before declining rapidly at $z\gtrsim$ 5, but the cause of this downturn is poorly understood. We characterize the $\Omega_{\rm CIV}$ evolution over 4.3 $\lesssim z\lesssim$ 6.3 using 260 absorbers found in 42 XSHOOTER spectra of $z\sim$ 6 quasars, of which 30 come from the ESO Large Program XQR-30. The large sample enables us to robustly constrain the rate and timing of the downturn. We find that $\Omega_{\rm CIV}$ decreases by a factor of 4.8 $\pm$ 2.0 over the ~300 Myr interval between $z\sim$ 4.7 and $z\sim$ 5.8. The slope of the column density (log N) distribution function does not change, suggesting that CIV absorption is suppressed approximately uniformly across 13.2 $\leq$ log N/cm$^{-2}$ < 15.0. Assuming that the carbon content of galaxy halos evolves as the integral of the cosmic star formation rate density (with some delay due to stellar lifetimes and outflow travel times), we show that chemical evolution alone could plausibly explain the fast decline in $\Omega_{\rm CIV}$ over 4.3 $\lesssim z\lesssim$ 6.3. However, the CIV/CII ratio decreases at the highest redshifts, so the accelerated decline in $\Omega_{\rm CIV}$ at $z\gtrsim$ 5 may be more naturally explained by rapid changes in the gas ionization state driven by evolution of the UV background towards the end of hydrogen reionization., Comment: 20 pages, 8 figures, 4 tables. Published in MNRAS

Fluvial point bar deposits are described from the ca. 1 Ga Diabaig Formation, representing some of the most compelling architectural evidence of planform sinuosity recognized in pre-vegetation sedimentary strata to date. The stratigraphic architecture of the deposits indicates different planform transformations in response to meander-bend expansion and downstream migration. Point bar architectural motifs are locally abundant in the unit and this is attributed to elevated amounts of mud-calibre cohesive sediment. Mud afforded landscape stability that, together with limited stream power, was sufficient to corral sediment into single-thread, sinuous channels. Significant volumes of fine-grained sediment were encouraged to accumulate by the local basin setting of several topographically confined endorheic depressions. These conditions ceased once the hydrologically closed valleys were filled, with the overlying sandstone-dominated Applecross Formation subsequently deposited by low-sinuosity, braided rivers that bypassed fine-grained sediment oceanward. Other endorheic basins conducive to the formation of depositional meanders should be expected to have been relatively widespread on pre-vegetation Earth, though many individually limited in size, confined by their inherited topographies. Depositional architectures representative of sinuous channel planforms remain scarce within more extensive, externally drained basins.

The article presents Smart Urban Governance for More-than-Human Future(s) anthology comprising six speculative creative works. It draws on techniques of futuring as a methodology to explore how creative practice as an act of futuring and exhibitions as sites to ponder environmental governance can empower more-than-human futures. Reporting on participatory observations and semi-structured interviews with the exhibition audience, the article contributes that creative futuring can empower futures by developing awareness that environmental governance can facilitate nonhuman agencies that conserve and repair the ecological world.

Background:The scale of the 2022 global mpox (formerly known as monkeypox) outbreak has been unprecedented. In less than 6 months, non-endemic countries have reported more than 67 000 cases of a disease that had previously been rare outside of Africa. Mortality has been reported as rare but hospital admission has been relatively common. We aimed to describe the clinical and laboratory characteristics and outcomes of individuals admitted to hospital with mpox and associated complications, including tecovirimat recipients. Methods:In this cohort study, we undertook retrospective review of electronic clinical records and pathology data for all individuals admitted between May 6, and Aug 3, 2022, to 16 hospitals from the Specialist and High Consequence Infectious Diseases Network for Monkeypox. The hospitals were located in ten cities in England and Northern Ireland. Inclusion criteria were clinical signs consistent with mpox and MPXV DNA detected from at least one clinical sample by PCR testing. Patients admitted solely for isolation purposes were excluded from the study. Key outcomes included admission indication, complications (including pain, secondary infection, and mortality) and use of antibiotic and anti-viral treatments. Routine biochemistry, haematology, microbiology, and virology data were also collected. Outcomes were assessed in all patients with available data. Findings:156 individuals were admitted to hospital with complicated mpox during the study period. 153 (98%) were male and three (2%) were female, with a median age of 35 years (IQR 30–44). Gender data were collected from electronic patient records, which encompassed full formal review of clincian notes. The prespecified options for data collection for gender were male, female, trans, non-binary, or unknown. 105 (71%) of 148 participants with available ethnicity data were of White ethnicity and 47 (30%) of 155 were living with HIV with a median CD4 count of 510 cells per mm3(IQR 349–828). Rectal or perianal pain (including proctitis) was the most common indication for hospital admission (44 [28%] of 156). Severe pain was reported in 89 (57%) of 156, and secondary bacterial infection in 82 (58%) of 142 individuals with available data. Median admission duration was 5 days (IQR 2–9). Ten individuals required surgery and two cases of encephalitis were reported. 38 (24%) of the 156 individuals received tecovirimat with early cessation in four cases (two owing to hepatic transaminitis, one to rapid treatment response, and one to patient choice). No deaths occurred during the study period. Interpretation:Although life-threatening mpox appears rare in hospitalised populations during the current outbreak, severe mpox and associated complications can occur in immunocompetent individuals. Analgesia and management of superimposed bacterial infection are priorities for patients admitted to hospital.

Longitudinal observational data on patients can be used to investigate causal effects of time-varying treatments on time-to-event outcomes. Several methods have been developed for estimating such effects by controlling for the time-dependent confounding that typically occurs. The most commonly used is marginal structural models (MSM) estimated using inverse probability of treatment weights (IPTW) (MSM-IPTW). An alternative, the sequential trials approach, is increasingly popular, and involves creating a sequence of "trials" from new time origins and comparing treatment initiators and non-initiators. Individuals are censored when they deviate from their treatment assignment at the start of each "trial" (initiator or noninitiator), which is accounted for using inverse probability of censoring weights. The analysis uses data combined across trials. We show that the sequential trials approach can estimate the parameters of a particular MSM. The causal estimand that we focus on is the marginal risk difference between the sustained treatment strategies of "always treat" vs "never treat." We compare how the sequential trials approach and MSM-IPTW estimate this estimand, and discuss their assumptions and how data are used differently. The performance of the two approaches is compared in a simulation study. The sequential trials approach, which tends to involve less extreme weights than MSM-IPTW, results in greater efficiency for estimating the marginal risk difference at most follow-up times, but this can, in certain scenarios, be reversed at later time points and relies on modelling assumptions. We apply the methods to longitudinal observational data from the UK Cystic Fibrosis Registry to estimate the effect of dornase alfa on survival.

Funder: Health and Care Research Wales, Funder: Cystic Fibrosis Trust, Funder: Wellcome Trust, Funder: National Institute for Health Research (NIHR), We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

The final phase of the reionization process can be probed by rest-frame UV absorption spectra of quasars at z>6, shedding light on the properties of the diffuse intergalactic medium within the first Gyr of the Universe. The ESO Large Programme "XQR-30: the ultimate XSHOOTER legacy survey of quasars at z~5.8-6.6" dedicated ~250 hours of observations at the VLT to create a homogeneous and high-quality sample of spectra of 30 luminous quasars at z~6, covering the rest wavelength range from the Lyman limit to beyond the MgII emission. Twelve quasar spectra of similar quality from the XSHOOTER archive were added to form the enlarged XQR-30 sample, corresponding to a total of ~350 hours of on-source exposure time. The median effective resolving power of the 42 spectra is R~11400 and 9800 in the VIS and NIR arm, respectively. The signal-to-noise ratio per 10 km/s pixel ranges from ~11 to 114 at $\lambda \simeq 1285$ \AA rest frame, with a median value of ~29. We describe the observations, data reduction and analysis of the spectra, together with some first results based on the E-XQR-30 sample. New photometry in the H and K bands are provided for the XQR-30 quasars, together with composite spectra whose characteristics reflect the large absolute magnitudes of the sample. The composite and the reduced spectra are released to the community through a public repository, and will enable a range of studies addressing outstanding questions regarding the first Gyr of the Universe., Comment: 21 pages, 10 figures. Final version accepted by MNRAS

To provide insights into glacier-climate dynamics of the South Shetland Islands (SSI), NW Antarctic Peninsula, we present a new deglaciation and readvance model for the Bellingshausen Ice Cap (BIC) on Fildes Peninsula and for King George Island/Isla 25 de Mayo (KGI) ~62°S. Deglaciation on KGI began after c. 15 cal. ka BP and had progressed to within present-day limits on the Fildes Peninsula, its largest ice-free peninsula, by c. 6.6–5.3 cal. ka BP. Probability density phase analysis of chronological data constraining Holocene glacier advances on KGI revealed up to eight 95% probability ‘gaps’ during which readvances could have occurred. These are grouped into four stages – Stage 1: a readvance and marine transgression, well-constrained by field data, between c. 7.4 and 6.6 cal. ka BP; Stage 2: four probability ‘gaps’, less well-constrained by field data, between c. 5.3 and 2.2 cal. ka BP; Stage 3: a well-constrained but restricted ‘readvance’ between c. 1.7 and 1.5 cal. ka BP; Stage 4: two further minor ‘readvances’, one less well-constrained by field data between c. 1.3 and 0.7 cal. ka BP (68% probability), and a ‘final’ well-constrained ‘readvance’ after

Despite the effectiveness of immuno-chemotherapy, 40% of patients with diffuse large B-cell lymphoma (DLBCL) experience relapse or refractory disease. Longitudinal studies have previously focused on the mutational landscape of relapse but fell short of providing a consistent relapse-specific genetic signature. In our study, we have focused attention on the changes in GEP accompanying DLBCL relapse using archival paired diagnostic/relapse specimens from 38 de novo patients with DLBCL. COO remained stable from diagnosis to relapse in 80% of patients, with only a single patient showing COO switching from activated B-cell–like (ABC) to germinal center B-cell–like (GCB). Analysis of the transcriptomic changes that occur following relapse suggest ABC and GCB relapses are mediated via different mechanisms. We developed a 30-gene discriminator for ABC–DLBCLs derived from relapse-associated genes that defined clinically distinct high- and low-risk subgroups in ABC–DLBCLs at diagnosis in datasets comprising both population-based and clinical trial cohorts. This signature also identified a population of

Purpose Degenerative cervical myelopathy is a progressive slow-motion spinal cord injury. Surgery is the mainstay of treatment. Baseline disability predicts surgical recovery; therefore, timely treatment is critical to restoring function. However, current challenges mean most patients present with advanced disease and are instead left with life changing disabilities. While short-term mortality is rarely reported, the long-term effects of this on life expectancy are unknown, including whether function could be modifiable with timely treatment. This article investigates the effect of DCM on life expectancy. Methods The survival of patients from an observational study of patients undergoing surgery from 1994 to 2007 was compared to their expected survival using a gender- and aged -matched cohort. Comparisons were made by one sample log-rank test and standardised mortality ratios. Factors associated with survival were explored using a Cox regression analysis, including disease severity. Results A total of 357 patients were included in the analysis. After a median follow-up of 15.3 years, 135 of 349 patients had died; 114.7 deaths would have been expected. The DCM cohort had an increased risk of death compared to the non-DCM cohort (standardised mortality ratio 1.18 [95% CI: 1.02–1.34]. Age at operation 1.08 (95% CI: 1.07 to 1.1, p p = 0.02) were associated with worse survival (N = 287). In those surviving at least 2 years after surgery, only severe DCM was associated with conditional survival (HR 1.6, 95% CI 1.04 2.4, p = 0.03). Conclusion Life expectancy is reduced in those undergoing surgery for DCM. This is driven by premature mortality among those left with severe disability. As disability can be reduced with timely treatment, these findings reinforce the need for collective and global action to raise awareness of DCM and enable early diagnosis.

Young people form the primary target demographic of new ‘buy now pay later’ (BNPL) and digital credit services. Despite consistent data showing young people as a cohort are particularly vulnerable to unsustainable levels of indebtedness, little is known about how young people define and make sense of the experience of being in debt through consumer credit services. This paper explores how indebtedness is experienced and understood in relation to wellbeing through a qualitative study using interviews alongside arts-based participatory methods of bodymapping and sandboxing with 24 young people in the Hunter region of NSW, Australia. These methods enabled particular attention to the embodied and affective elements related to the experience of indebtedness to understand debt’s significance for wellbeing for young people. The embodied and affective registers of indebtedness are integral for understanding the conditions informing how wellbeing is negotiated and felt in this context. This study considers the role of BNPL services in young people’s economic lives as part of broader processes of financialisation, and the significance of extended and ubiquitous forms of credit for young people’s wellbeing. Refereed/Peer-reviewed

The vast majority of seasonal influenza vaccines administered each year are derived from virus propagated in eggs using technology that has changed little since the 1930s. The immunogenicity, durability, and breadth of response would likely benefit from a recombinant nanoparticle-based approach. Although the E2 protein nanoparticle (NP) platform has been previously shown to promote effective cell-mediated responses to peptide epitopes, it has not yet been reported to deliver whole protein antigens. In this study, we synthesized a novel maleimido tris-nitrilotriacetic acid (NTA) linker to couple protein hemagglutinin (HA) from H1N1 influenza virus to the E2 NP, and we evaluated the HA-specific antibody responses using protein microarrays. We found that recombinant H1 protein alone is immunogenic in mice but requires two boosts for IgG to be detected and is strongly IgG1 (Th2) polarized. When conjugated to E2 NPs, IgG2c is produced leading to a more balanced Th1/Th2 response. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) significantly enhances the immunogenicity of H1-E2 NPs while retaining the Th1/Th2 balance. Interestingly, broader homo- and heterosubtypic cross-reactivity is also observed for conjugated H1-E2 with MPLA, compared to unconjugated H1 with or without MPLA. These results highlight the potential of an NP-based delivery of HA for tuning the immunogenicity, breadth, and Th1/Th2 balance generated by recombinant HA-based vaccination. Furthermore, the modularity of this protein-protein conjugation strategy may have utility for future vaccine development against other human pathogens.

The Eifelian-aged Hangman Sandstone Formation of southwest England is a unit of the ‘Old Red Sandstone’ that has traditionally been considered relatively barren of trace fossils. Following recent investigations, we here show it to contain the most diverse Middle Devonian non-marine ichnofauna known globally. The fluvial-lacustrine facies of its constituent Trentishoe Member contain representatives of 21 ichnogenera including Archaeonassa, Arenicolites, Beaconites, Bifungites, Circulichnis, Cruziana, Diplichnites, ?Gluckstadella, Gordia, ?Halimededes, ?Lockeia, Merostomichnites, Palmichnium, Petalichnus, Planolites, Polarichnus, Rusophycus, Siskemia, Spirophyton, Steinsfjordichnus, and Taenidium, as well as several microbially induced sedimentary structures. The transitional marine-influenced facies of the underlying Hollowbrook Member are less extensively exposed but contain four additional unique ichnogenera in the form of Cochlichnus, Halopoa, Phycodes, and Teichichnus, as well as further examples of Cruziana, Planolites and Taenidium. A revised ichnological assessment of the unit reveals several notable features, including the youngest known example of the arthropod refugia trace, Polarichnus, as well as a transitional trace fossil form of Diplichnites-Beaconites, demonstrating that the latter was produced by arthropods. As the Hangman Sandstone Formation records the culmination of a marine regression, its ichnofauna can be compared with that of the conformably underlying Lynton Formation, which was deposited in a sandy marine shelf setting. The ichnological differences between these units are acute, with 88% of the Hangman Sandstone Formation trace fossils being exclusive to non-marine or transitional facies. This observation sheds light on the terrestrialization process and indicates that the segregation of marine and non-marine trace fossil communities had accelerated by the Middle Devonian. Internal variability in ichnological signatures within the Hangman Sandstone Formation is also pronounced, with greater ichnodiversity and ichnodisparity in distal fluvio-lacustrine facies than in proximal fluvial facies. By viewing the depositional environment of the unit as a regionally extensive distributive fluvial system, this variability can be partly explained by a bias arising from the distribution of true substrates (bedding planes that demonstrably preserve an ancient sediment-air interface) in the unit, with such phenomena being more readily preserved in the lower energy outer reaches of the depositional system.

A comparative study on the water quality of the interstitial water of two creeks in Rivers State was conducted. Temperature, pH, Conductivity, Dissolved oxygen, biochemical oxygen demand, Salinity, and Total dissolved solid were checked with an in-situ hand-held multi-meter (The EZODO Multi-meter). Dissolved oxygen (DO) was measured with a Milwaukee Dissolved oxygen meter while Biochemical Oxygen Demand (BOD) was determined by the 5-day BOD test (APHA, 2005). The temperature ranged between 28.3 to 29.3℃ in the Opro-ama creek and 26.0 -26.8℃ in Buguma creek. The pH value ranged from 6.2 to 6.8 in Opro-ama creek while that of Sa-ama creek was between 6.8 and 6.99. Salinity ranges from 9.1 to 9.5 (ppt) in the Opro-ama creek while Sa-ama creek recorded a range between 11.2 to 12.0 (ppt). The dissolved oxygen was between 1.5 and 2.3 (µS/cm) in Okpoka creek meanwhile Sa-ama creek varied between 4.6 and 4.10 (µS/cm). The biochemical oxygen demand values were between 1.4 to 2.3 (µS/cm) in Opro-ama creek while that of Sa-ama was between 1.9 to 2.4 (µS/cm). The conductivity values for the Opro-ama creek were between 10.3 and 10.6 while Sa-ama creek recorded a value of 12.5 to12.6 (µS/cm). there were significant variations (P

Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC).To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC.HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital.Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min.The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat.A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control).CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment.The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment.

To investigate endothelial cell loss after Descemet's membrane endothelial keratoplasty (DMEK) when surgery is performed with surgeon-loaded tissue versus preloaded tissue.The endothelial cell count over time of patients who underwent the last DMEK surgery by a single surgeon with surgeon-loaded tissue from 2014-2017 was compared to that of patients who underwent the first DMEK surgery by different single surgeon with preloaded tissue from 2017-2020.Baseline characteristics, including age, sex, and baseline endothelial cell count of DMEK grafts, were not statistically different between the groups. Endothelial cell loss both immediately after surgery and continuing over a 4-year period after surgery was greater in the surgeon-loaded DMEK group compared to the preloaded DMEK group based on log-regression curve analysis. Endothelial cell loss was statistically significantly greater at 1 year, 2 years, 3 years, and 4 years after DMEK surgery with surgeon-loaded tissue compared to preloaded tissue on analysis of variance testing.Preloaded DMEK tissue has significantly less endothelial cell loss both initially after surgery and over time compared to surgeon-loaded DMEK tissue, providing support for use of preloaded DMEK tissue for surgery.

As the British Psychological Society establishes a new Division of Coaching Psychology and routes to chartered membership for coaching psychologists, we revisit the ongoing dialogue into the professionalisation of coaching psychology, with a specific focus on practice in the United Kingdom (UK). We attempt to make distinctions between the practice of a coaching psychologist and a professionally qualified coach. First, we offer an overview of the development of coaching psychology over recent years, contemplating the need to regulate it as a profession. Following that, we consider some of the main coaching and coaching psychology definitions in an attempt to delineate the practice of coaching psychologists from that of non-psychologist coaches. Next, we compare approaches to training and some of the differences between coaching and coaching psychology, as well as the need for an ethical framework and supervision for coaching psychologists. Finally, we conclude by offering a final thought about who is a coaching psychologist.

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

Epidemiologic studies detected an inverse relationship between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major risk factor for ASCVD and suggesting atheroprotective functions of HDL. However, the role of HDL-C as a mediator of risk for ASCVD has been called into question by the failure of HDL-C–raising drugs to reduce cardiovascular events in clinical trials. Progress in understanding the heterogeneous nature of HDL particles in terms of their protein, lipid, and small RNA composition has contributed to the realization that HDL-C levels do not necessarily reflect HDL function. The most examined atheroprotective function of HDL is reverse cholesterol transport, whereby HDL removes cholesterol from plaque macrophage foam cells and delivers it to the liver for processing and excretion into bile. Indeed, in several studies, HDL has shown inverse associations between HDL cholesterol efflux capacity and ASCVD in humans. Inflammation plays a key role in the pathogenesis of atherosclerosis and vulnerable plaque formation, and a fundamental function of HDL is suppression of inflammatory signaling in macrophages and other cells. Oxidation is also a critical process to ASCVD in promoting atherogenic oxidative modifications of LDL (low-density lipoprotein) and cellular inflammation. HDL and its proteins including apoAI (apolipoprotein AI) and PON1 (paraoxonase 1) prevent cellular oxidative stress and LDL modifications. Importantly, HDL in humans with ASCVD is oxidatively modified rendering HDL dysfunctional and proinflammatory. Modification of HDL with reactive carbonyl species, such as malondialdehyde and isolevuglandins, dramatically impairs the antiatherogenic functions of HDL. Importantly, treatment of murine models of atherosclerosis with scavengers of reactive dicarbonyls improves HDL function and reduces systemic inflammation, atherosclerosis development, and features of plaque instability. Here, we discuss the HDL antiatherogenic functions in relation to oxidative modifications and the potential of reactive dicarbonyl scavengers as a therapeutic approach for ASCVD.

BACKGROUND: Motorist Disorientation Syndrome (MDS) is a term used to describe patients who primarily experience symptoms of dizziness/disorientation whilst in a motor car [21]. There is uncertainty about the relevance of vestibular dysfunction and whether this disorder could instead be a visually induced dizziness (VV) or part of a functional disorder similar to Persistent postural perceptual dizziness (PPPD). OBJECTIVE: We present the largest case-series to date of patients whose main complaint is of illusions of movement of self/vehicle when driving, characterising features of this group. METHODS: 18 subjects underwent detailed clinical assessment including validated questionnaires. A subset of patients underwent vestibular function testing. RESULTS: Mean onset age was 42 years, with no gender preponderance. Mean symptom duration was 6.39 years and was significantly longer in women. 50% reported moderate or severe handicap. Vestibular abnormalities were found in 60% of subjects tested. There was no significant difference in VSS total score between those with MDS and vestibular migraine (p = 0.154) with both having higher scores than healthy controls (p = 0.002, 0.000 respectively). CONCLUSIONS: MDS represents consistent symptoms, with high symptom burden, comparable to vestibular migraine. Vestibular deficits were not a consistent feature and similarities to VV and PPPD exist.

Objectives To project the prevalence of people receiving dialysis in Australia for 2021–30 to inform service planning and health policy. Methods Estimates were based on data from 2011 to 2020 from the Australia & New Zealand Dialysis & Transplant (ANZDATA) Registry and the Australian Bureau of Statistics. We projected dialysis and functioning kidney transplant recipient populations for the years 2021–30. Discrete-time, non-homogenous Markov models were built on probabilities for transition between three mutually exclusive states (Dialysis, Functioning Transplant, Death), for five age groups. Two scenarios were employed – stable transplant rate vs a continued increase – to assess the impact of these scenarios on the projected prevalences. Results Models projected a 22.5–30.4% growth in the dialysis population from 14 554 in 2020 to 17 829 (‘transplant growth’) – 18 973 (‘transplant stable’) by 2030. An additional 4983–6484 kidney transplant recipients were also projected by 2030. Dialysis incidence per population increased and dialysis prevalence growth exceeded population ageing in 40–59 and 60–69 year age groups. The greatest dialysis prevalence growth was seen among those aged ≥70 years. Conclusion Modelling of the future prevalence of dialysis use highlights the increasing demand on services expected overall and especially by people aged ≥70 years. Appropriate funding and healthcare planning must meet this demand.

Necroptosis is a mode of programmed, lytic cell death that is executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following activation by the upstream kinases, receptor-interacting serine/threonine protein kinase (RIPK)-1 and RIPK3. Dysregulated necroptosis has been implicated in the pathophysiology of many human diseases, including inflammatory and degenerative conditions, infectious diseases and cancers, provoking interest in pharmacological targeting of the pathway. To identify small molecules impacting on the necroptotic machinery, we performed a phenotypic screen using a mouse cell line expressing an MLKL mutant that kills cells in the absence of upstream death or pathogen detector receptor activation. This screen identified the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinase inhibitor, ABT-869 (Linifanib), as a small molecule inhibitor of necroptosis. We applied a suite of cellular, biochemical and biophysical analyses to pinpoint the apical necroptotic kinase, RIPK1, as the target of ABT-869 inhibition. Our study adds to the repertoire of established protein kinase inhibitors that additionally target RIPK1 and raises the prospect that serendipitous targeting of necroptosis signalling may contribute to their clinical efficacy in some settings.

BackgroundRegular daily nebulised antibiotics are widely used in managing bronchiectasis. This patient population typically has severe bronchiectasis requiring multiple other medications. Given that little is known on patients’ views and preferences for such therapies, this was the focus of our study.MethodsTo explore patient lived-experience using nebulised antibiotics, focus groups and semi-structured interviews were conducted with patients and carers; these were audio-recorded and transcribed to enable thematic analysis. QSR NVivo facilitated data management. The themes developed from the qualitative data analysis were then used to co-design a questionnaire to capture attitudes and preferences towards nebulised therapy. Questionnaires were completed by patients and statistical analysis was performed. Ethical approval was obtained (13/WS/0036).ResultsThirteen patients and carers took part in the study's focus groups, and 101 patients completed the questionnaire. Patients described nebulised therapy as an imposition on their daily routine, in turn affecting reported rates of adherence. Results demonstrated that 10% of all patients using nebulised antibiotics found these hard/very hard to administer. Further, 53% of participants strongly agreed/agreed that they would prefer an antibiotic delivered by an inhaler, over a nebuliser, if it was as effective at preventing exacerbations. Notably, only 10% of participants wished to remain on nebulised therapy.ConclusionsInhaled antibiotics, deliveredviadry power devices were deemed quicker and easier to use by patients. Providing they were at least as effective as current nebulised treatments, patients deemed inhaled antibiotics to be a preferable treatment option.

This paper considered the notion of European option which is geared towards solving analytical and numerical solutions. In particular, we examined the Black-Scholes closed form solution and modified Black-Scholes (MBS) partial differential equation using Crank-Nicolson finite difference method. These partial differential equations were approximated to obtain Call and Put option prices. The explicit price of both options is found accordingly. The numerical solutions were compared to the closed form prices of Black-Scholes formula. More so, comparisons of other parameters were discussed for the purpose of investment plans. The computational results shows: increase in stock volatility increases the value of options, when the initial stock price is equal to its strike price the values of call option is higher than the put option. This informs the investor about the behavior of stock prices for the purpose of decision making. Finally, all simulation results presented graphically using MATLAB.

This article maps the contributions project scholars can make in management journals. Research on projects cuts across disciplinary boundaries, with scholars working in institutions with different norms, epistemologies, rewards, and selection environments. But this diversity can make it hard to know where to publish. We hope our map of the publication landscape—the “V diagram”—will help project scholars better understand and respect one another’s diverse contributions and make conversations across the field flourish.

Introduction: Artificial intelligence (AI) encompasses a wide range of algorithms with risks when used to support decisions about diagnosis or treatment, so professional and regulatory bodies are recommending how they should be managed. Areas covered: AI systems may qualify as standalone medical device software (MDSW) or be embedded within a medical device. Within the European Union (EU) AI software must undergo a conformity assessment procedure to be approved as a medical device. The draft EU Regulation on AI proposes rules that will apply across industry sectors, while for devices the Medical Device Regulation also applies. In the CORE-MD project (Coordinating Research and Evidence for Medical Devices), we have surveyed definitions and summarize initiatives made by professional consensus groups, regulators, and standardization bodies. Expert opinion: The level of clinical evidence required should be determined according to each application and to legal and methodological factors that contribute to risk, including accountability, transparency, and interpretability. EU guidance for MDSW based on international recommendations does not yet describe the clinical evidence needed for medical AI software. Regulators, notified bodies, manufacturers, clinicians and patients would all benefit from common standards for the clinical evaluation of high-risk AI applications and transparency of their evidence and performance.

The effect of Fourier series expansion on the solution of Stochastic Differential Equation (SDE) is considered herein. The detailed measures which govern price function of return rate for capital investments are obtained periodically. Sufficient conditions of stating mathematical propositions and proving it by means of Fourier series expansion are given. These price functions were used as drift (return rate) parameter in the solution of proposed model which follow various pattern according to their propositions. This way, the desired complete solutions were obtained. Finally, the effects of the relevant parameters were demonstrated graphically for the purpose of decision making.

Summary Selected strains of Pasteuria species from the endospore-forming Gram-positive bacteria group have the potential to be developed into control agents for plant-parasitic nematodes. If Pasteuria is to be deployed successfully as a control agent, endospores of the bacterium initially have to adhere to the cuticle of the infective juvenile. Studies of the bacteria isolated from root-knot nematodes have suggested that collagen-like fibres on the endospore surface interact with a cuticle receptor on the second-stage juvenile through a host specific ‘Velcro-like’ mechanism. However, very little is known regarding the biochemical nature of the mechanism in Pasteuria strains isolated from cyst nematodes. Here, using several polyclonal antibodies raised to whole endospores and to synthetic collagen-like peptides, we compare two Pasteuria populations, one a strain from a root-knot nematode, Meloidogyne javanica, and another from cowpea cyst nematode, Heterodera cajani. We demonstrate that there is differential adhesion of endospores to the beet cyst nematode H. schachtii and that the sugar moieties on the endospore surface may protect the collagen-like fibres on the endospore from proteolytic digestion and be involved in the endospore’s specificity.

COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19.We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733.Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1·06 [95% CI 0·89-1·27]; n=499; p=0·52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1·35 [1·06-1·72]; n=247; p=0·01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0·87).Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19.LifeArc and CW+.