We present transverse electron focusing measurements in the two dimensional electrons gas formed at the interface of a GaAs/AlGaAs heterostructure. The experimental arrangement consists of two ...orthogonal quantum point contacts (QPCs), one acting as injector and the other as detector of the collimated 1D electrons as a function of transverse magnetic field. The focusing spectrum shows anomalous behaviour, the first and third focusing peaks split into two sub-peaks while second peak remains as a single peak. The observed splitting, a signature of spin states, arises from the spin-orbit interaction when the 1D electrons are injected into the 2D regime, thus allowing us to manipulate the spin states within the 1D channel.
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•11/464 (2.4%) patients presenting with non-traumatic neurological injury had evidence of current/recent HEV infection.•In 7/11 cases HEV RNA was found in the serum.•Three cases were ...neuralgic amyotrophy with bilateral symptoms, which is the HEV-associated phenotype.•The relationship between HEV and neuralgic amyotrophy is causal.•The relationship between HEV and other neurological syndromes requires further study.
Hepatitis E virus (HEV) has been associated with a number of neurological syndromes, but causality has not yet been established. The aim of this study was to explore the relationship between HEV and neurological illness by prospective HEV testing of patients presenting with acute non-traumatic neurological injury.
Four hundred and sixty-four consecutive patients presenting to hospital with acute non-traumatic neurological illnesses were tested for HEV by serology and PCR from four centres in the UK, France and the Netherlands.
Eleven of 464 patients (2.4%) had evidence of current/recent HEV infection. Seven had HEV RNA identified in serum and four were diagnosed serologically. Neurological cases in which HEV infection was found included neuralgic amyotrophy (n=3, all PCR positive); cerebral ischemia or infarction (n=4); seizure (n=2); encephalitis (n=1); and an acute combined facial and vestibular neuropathy (n=1). None of these cases were clinically jaundiced and median ALT at presentation was 24IU/L (range 8–145). Cases of HEV-associated neuralgic amyotrophy were found in each of the participating countries: all were middle-aged males with bilateral involvement of the brachial plexus.
In this cohort of patients with non-traumatic neurological injury, 2.4% had evidence of HEV infection. Symptoms of hepatitis were mild or absent and no patients were jaundiced. The cases of HEV-associated neuralgic amyotrophy had similarities with other HEV-associated cases described in a large retrospective study. This observation supports a causal relationship between HEV and neuralgic amyotrophy. To further understand the relevance of HEV infection in patients with acute neurological illnesses, case-control studies are warranted.
Lay summary: Hepatitis E virus (HEV), as its name suggests, is a hepatotropic virus, i.e. it causes damage to the liver (hepatitis). Our findings show that HEV can also be associated with a range of injury to the nervous system.
Soil organic carbon (SOC) is a soil health indicator and understanding dynamics changing SOC stocks will help achieving net zero goals. Here we present four datasets featuring 11,750 data points ...covering co-located aboveground and below-ground metrics for exploring ecosystem SOC dynamics. Five sites across England with an established land use contrast, grassland and woodland next to each other, were rigorously sampled for aboveground (n = 109), surface (n = 33 soil water release curves), topsoil, and subsoil metrics. Commonly measured soil metrics were analysed in five soil increments for 0-1 metre (n = 4550). Less commonly measured soil metrics which were assumed to change across the soil profile were measured on a subset of samples only (n = 3762). Additionally, we developed a simple method for soil organic matter fractionation using density fractionation which is part of the less common metrics. Finally, soil metrics which may impact SOC dynamics, but with less confidence as to their importance across the soil profile were only measured on topsoil (~5-15 cm = mineral soil) and subsoil (below 50 cm) samples (n = 2567).
The constitutional t(11;22)(q23;q11) translocation is the only recurrent non‐Robertsonian translocation known in humans. Carriers are phenotypically normal and are usually referred for cytogenetic ...testing because of multiple miscarriages, infertility, or having aneuploidy in offspring. A breast cancer predisposition has been suggested, but previous studies have been small and had methodological shortcomings. We therefore conducted a long‐term prospective study of cancer and mortality risk in carriers. We followed 65 male and 101 female carriers of t(11;22)(q23;q11) diagnosed in cytogenetic laboratories in Britain during 1976–2005 for cancer and deaths for an average of 21.4 years per subject. Standardised mortality (SMR) and incidence (SIR) ratios were calculated comparing the numbers of observed events with those expected from national age‐, sex‐, country‐ and calendar‐period‐specific population rates. Cancer incidence was borderline significantly raised for cancer overall (SIR = 1.56, 95% CI: 0.98–2.36, n = 22), and significantly raised for invasive breast cancer (SIR = 2.74, 95% CI: 1.18–5.40, n = 8) and in situ breast cancer (SIR = 13.0, 95% CI: 3.55–33.4, n = 4). Breast cancer risks were particularly increased at ages <50 (SIR = 4.37, 95% CI: 1.42–10.2 for invasive, SIR = 22.8, 95% CI: 2.76–82.5 for in situ). Mortality was borderline significantly raised for breast cancer (SMR = 4.82, 95% CI: 0.99–14.1) but not significantly raised for other cancers or causes. Individuals diagnosed with t(11;22)(q23;q11) appear to be at several‐fold increased breast cancer risk, with the greatest risks at premenopausal ages. Further research is required to understand the genetic mechanism involving 11q23 and 22q11 and there may be a need for enhanced breast cancer surveillance among female carriers.
What's new?
The constitutional translocation between chromosome bands 11q23 and 22q11 is recurrent in human populations, with highly consistent breakpoints. A breast cancer predisposition among carriers has been suggested, but previous studies have been small and had methodological shortcomings. In this first long‐term follow‐up study of site‐specific cancer and mortality risks among carriers, an increased risk of breast cancer was observed compared to the general population, with greatest risks in younger women. The results suggest that carriers of t(11;22)(q23;q11) may require enhanced surveillance for breast cancer and point to the importance of the chromosomal regions 11q23 and 22q11 in breast cancer development.
Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap.
The GO2 randomized clinical trial sought to optimize chemotherapy ...dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making.
This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty.
There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care.
First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival.
A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 95% CI, 0.89-1.32) and C vs A (HR = 1.10 95% CI, 0.90-1.33). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 95% CI, 0.32-1.48, P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes.
This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment.
isrctn.org Identifier: ISRCTN44687907.
Background:
Many of the painful, disabling features of early diffuse cutaneous systemic sclerosis have an inflammatory component and are potentially treatable with corticosteroid therapy. These ...features include painful and itchy skin, fatigue and musculoskeletal involvement. Yet many clinicians are understandably reluctant to prescribe corticosteroids because of the concern that these are a risk factor for scleroderma renal crisis. The aim of PRedSS (PRednisolone in early diffuse cutaneous Systemic Sclerosis) is to evaluate the efficacy and safety of moderate dose prednisolone in patients with early diffuse cutaneous systemic sclerosis, specifically whether moderate dose prednisolone is (a) effective in terms of reducing pain and disability, and improving skin score and (b) safe, with particular reference to renal function.
Methods:
PRedSS is a Phase II, multicentre, double-blind randomised controlled trial which aims to recruit 72 patients with early diffuse cutaneous systemic sclerosis. Patients are randomised to receive either prednisolone (dosage approximately 0.3 mg/kg) or placebo therapy for 6 months. The two co-primary outcome measures are the difference in mean Health Assessment Questionnaire Disability Index at 3 months and the difference in modified Rodnan skin score at 3 months. Secondary outcome measures include patient reported outcome measures of itch, hand function, anxiety and depression, and helplessness.
Results:
Recruitment commenced in December 2017 and after a slow start (due to delays in opening centres) 25 patients have now been recruited.
Conclusion:
PRedSS should help to answer the question as to whether clinicians should or should not prescribe prednisolone in early diffuse cutaneous systemic sclerosis.
The KEAP1–NRF2-mediated cytoprotective response plays a key role in cellular homoeostasis. Insufficient NRF2 signaling during chronic oxidative stress may be associated with the pathophysiology of ...several diseases with an inflammatory component, and pathway activation through direct modulation of the KEAP1–NRF2 protein–protein interaction is being increasingly explored as a potential therapeutic strategy. Nevertheless, the physicochemical nature of the KEAP1–NRF2 interface suggests that achieving high affinity for a cell-penetrant druglike inhibitor might be challenging. We recently reported the discovery of a highly potent tool compound which was used to probe the biology associated with directly disrupting the interaction of NRF2 with the KEAP1 Kelch domain. We now present a detailed account of the medicinal chemistry campaign leading to this molecule, which included exploration and optimization of protein–ligand interactions in three energetic “hot spots” identified by fragment screening. In particular, we also discuss how consideration of ligand conformational stabilization was important to its development and present evidence for preorganization of the lead compound which may contribute to its high affinity and cellular activity.
The existence of Wigner crystallization, one of the most significant hallmarks of strong electron correlations, has to date only been definitively observed in two-dimensional systems. In ...one-dimensional (1D) quantum wires Wigner crystals correspond to regularly spaced electrons; however, weakening the confinement and allowing the electrons to relax in a second dimension is predicted to lead to the formation of a new ground state constituting a zigzag chain with nontrivial spin phases and properties. Here we report the observation of such zigzag Wigner crystals by use of on-chip charge and spin detectors employing electron focusing to image the charge density distribution and probe their spin properties. This experiment demonstrates both the structural and spin phase diagrams of the 1D Wigner crystallization. The existence of zigzag spin chains and phases which can be electrically controlled in semiconductor systems may open avenues for experimental studies of Wigner crystals and their technological applications in spintronics and quantum information.
Molecular and structural consequences of early renal allograft injury.
Chronic allograft nephropathy is an important cause of graft failure. Many donor and recipient factors contribute to its ...development. Prospective analysis of these factors has been hindered by the lack of sensitive and specific indicators of renal injury. As a consequence protocol biopsies have been increasingly used in the assessment of renal allograft injury. We performed protocol renal allograft biopsies to prospectively examine the role of important determinants and mediators of chronic allograft nephropathy.
A total of 51 consecutive cadaveric renal transplant recipients entered a randomized prospective study of tacrolimus (Tac) versus cyclosporine (CsA) microemulsion based immunosuppression. Study patients underwent protocol renal allograft biopsies at the time of engraftment and at 3, 6 and 12 months post-transplantation. Biopsies were analyzed by quantitative polymerase chain reaction (PCR) for mRNA for transforming growth factor-β (TGF-β), thrombospondin, and fibronectin. Measurements of renal structural injury were estimated by quantitative assessment of interstitial fibrosis and glomerulosclerosis. Changes in profibrotic growth factors and renal structural injury were related to donor and recipient determinants by stepwise regression analysis.
Longitudinal assessment of renal injury demonstrated an early and progressive increase in mRNA for TGF-β, thrombospondin (TSP) and fibronectin (FBN): TGF-β baseline, 1.9 ± 0.2 log copies; TGF-β 6 months, 2.5 ± 0.2 log copies, P < 0.05 6 months vs. baseline; TSP baseline, 1.9 ± 0.2 log copies; TSP 6 months, 2.4 ± 0.2 log copies, P < 0.05 6 months vs. baseline; FBN baseline, 2.0 ± 0.2 log copies; FBN 12 months, 2.3 ± 0.2 log copies, P < 0.05 12 months vs. baseline. This increase in profibrotic growth factors within the allograft was associated with a significant increase in interstitial fibrosis (Vvi) on renal biopsies: Vvi baseline, 13 ± 1%; Vvi 3 months, 18 ± 1%; Vvi 6 months, 28 ± 2%; Vvi 12 months, 34 ± 2%; P < 0.05 3, 6, and 12 months vs. baseline. Histological analysis demonstrated chronic allograft nephropathy in 4% biopsies at 3 months, 12% at 6 months and in 49% at 12 months. These changes in renal structure were not associated with any change in creatinine clearance (CCr): CCr 3 months, 56 ± 2mL/min, CCr 24 months, 56 ± 2mL/min; P = NS. Stepwise regression analysis of key donor and recipient determinants of chronic renal injury identified calcineurin inhibitors and acute rejection episodes as important factors involved in the development of chronic renal injury. In particular, the use of cyclosporine compared to tacrolimus was associated with a tenfold increase in TGF-β mRNA (TGF-β mRNA at 6 months, CsA vs. Tac, 3 ± 0.3 vs. 2 ± 0.3 log copies, P < 0.05), interstitial fibrosis (Vvi at 6 months, CsA vs. Tac, 33 ± 4% vs. 24 ± 2%, P < 0.05). Changes in growth factors and renal structure predicted impaired renal function (CCr at 12 months, CsA vs. Tac, 53 ± 4mL/min vs. 62 ± 2mL/min, P < 0.05). Similarly, acute rejection episodes were associated with an accelerated development of interstitial fibrosis (Vvi at 6 months, acute rejection vs. no rejection, 34 ± 3% vs. 25 ± 2%; P < 0.05), but not with changes in TGF-β, thrombospondin or fibronectin expression.
Our results suggest that structural injury develops early in the natural history of the renal allograft and is mediated, in part, by the early up-regulation of profibrotic growth factors. We have determined that calcineurin inhibitors, in particular cyclosporine, and acute rejection episodes are key factors in the development of renal structural injury.
Background
In the UK, it is recommended that hospital patients have their nutritional status assessed within 24 h of admission using the Malnutrition Universal Screening Tool (MUST). The present ...study aimed to examine the association between nurse staffing levels and missed nutritional status assessments.
Methods
A single‐centre, retrospective, observational study was employed using routinely collected MUST assessments from 32 general adult hospital wards over 2 years, matched to ward nurse staffing levels. We used mixed‐effects logistic regression to control for ward characteristics and patient factors.
Results
Of 43 451 instances where staffing levels could be linked to a patient for whom an assessment was due, 21.4% had no MUST score recorded within 24 h of admission. Missed assessments varied between wards (8–100%). There was no overall association between registered nurse staffing levels and missed assessments; although higher admissions per registered nurse were associated with more missed assessments odds ratio (OR) = 1.09, P = 0.005. Higher healthcare assistant staffing was associated with lower rates of missed assessments (OR = 0.80, P < 0.001). There was a significant interaction between registered nurses and healthcare assistants staffing levels (OR = 0.97, P = 0.011).
Conclusions
Despite a written hospital policy requiring a nutritional assessment within 24 h of admission, missed assessments were common. The observed results show that compliance with the policy for routine MUST assessments within 24 h of hospital admission is sensitive to staffing levels and workload. This has implications for planning nurse staffing.
Negative patient outcomes associated with malnutrition in hospital patients can be avoided by ensuring that every patient has a nutritional assessment completed and recorded, leading to appropriate interventions aimed at avoiding preventable deterioration. However, research shows missed nutritional assessments with lower levels of nurses in hospital wards. The findings from an observational study using administrative routinely collected data on the prevalence of missed nutritional assessments in a hospital in England show that compliance with the policy for routine Malnutrition Universal Screening Tool (MUST) assessment within 24 h of hospital admission is sensitive to staffing levels and workload. This has implications for planning nurse staffing.
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