Search

Uncorrected refractive errors are a leading cause of visual impairment across the world. In today's society, laser in situ keratomileusis (LASIK) has become the most commonly performed surgical procedure to correct refractive errors. However, regression of the initially achieved refractive correction has been a widely observed phenomenon following LASIK since its inception more than two decades ago. Despite technological advances in laser refractive surgery and various proposed management strategies, post‐LASIK regression is still frequently observed and has significant implications for the long‐term visual performance and quality of life of patients. This review explores the mechanism of refractive regression after both myopic and hyperopic LASIK, predisposing risk factors and its clinical course. In addition, current preventative strategies and therapies are also reviewed. [ABSTRACT FROM AUTHOR]

Alkali antimonide photocathodes have wide applications in free-electron lasers and electron cooling. The short lifetime of alkali antimonide photocathodes necessitates frequent replacement of the photocathodes during a beam operation. Furthermore, exposure to mediocre vacuum causes loss of photocathode quantum efficiency due to the chemical reaction with residual gas molecules. Theoretical analyses have shown that covering an alkali antimonide photocathode with a monolayer graphene or hexagonal boron nitride protects it in a coarse vacuum environment due to the inhibition of chemical reactions with residual gas molecules. Alkali antimonide photocathodes require an ultra-high vacuum environment, and depositing a monolayer 2D material on it poses a serious challenge. In the present work, we have incorporated a novel method known as intercalation, in which alkali atoms pass through the defects of a graphene thin film to create a photocathode material underneath. Initially, Sb was deposited on a Si substrate, and a monolayer graphene was transferred on top of the Sb film. Heat cleaning around 550–600 °C effectively removed the Sb oxides, leaving metallic Sb underneath the graphene layer. Depositing Cs on top of a monolayer graphene enabled the intercalation process. Atomic force microscopy, Raman spectroscopy, x-ray photoelectron spectroscopy, low energy electron microscopy, and x-ray diffraction measurements were performed to evaluate photocathode formation underneath the monolayer graphene. Our analysis shows that Cs penetrated the graphene and reacted with Sb and formed Cs3Sb.

Hamiltonian learning is an important procedure in quantum system identification, calibration, and successful operation of quantum computers. Through queries to the quantum system, this procedure seeks to obtain the parameters of a given Hamiltonian model and description of noise sources. Standard techniques for Hamiltonian learning require careful design of queries and O(ε^{−2}) queries in achieving learning error ε due to the standard quantum limit. With the goal of efficiently and accurately estimating the Hamiltonian parameters within learning error ε through minimal queries, we introduce an active learner that is given an initial set of training examples and the ability to interactively query the quantum system to generate new training data. To ensure applicability on near-term quantum hardware, the active learner operates in batch mode as opposed to sequentially, proposing batches of queries to be made during learning. We formally specify and experimentally assess the performance of this Hamiltonian active learning (HAL) algorithm for learning the six parameters of a two-qubit cross-resonance Hamiltonian on four different superconducting IBM quantum devices. Compared with standard techniques for the same problem and a specified learning error, HAL achieves more than a 95% reduction in queries required, and upwards of 33% reduction over a sequential active learner. Moreover, with access to prior information on a subset of Hamiltonian parameters and given the ability to select queries with linearly (or exponentially) longer system interaction times during learning, HAL can exceed the standard quantum limit and achieve Heisenberg (or super-Heisenberg) limited convergence rates during learning.

Background: In Covid-19, profound systemic inflammatory responses are accompanied by both metabolic risk factors for severity and, separately, metabolic mechanisms have been shown to underly disease progression. It is unknown whether this reflects similar situations in sepsis or is a unique characteristic of Covid-19. Aims: Define the immunometabolic signature of Covid-19. Methods: 65 patients with Covid-19,19 patients with sepsis and 14 healthy controls were recruited and sampled for plasma, serum and peripheral blood mononuclear cells (PBMCs) through 10 days of critical illness. Metabotyping was performed using the Biocrates p180 kit and multiplex cytokine profiling undertaken. PBMCs underwent phenotyping by flow cytometry. Immune and metabolic readouts were integrated and underwent pathway analysis. Results: Phopsphatidylcholines (PC) are reduced in Covid-19 but greater than in sepsis. Compared to controls, tryptophan is reduced in Covid-19 and inversely correlated with the severity of the disease and IFN-ɣ concentrations, conversely the kyneurine and kyneurine/tryptophan ratio increased in the most severe cases. These metabolic changes were consistent through 2 pandemic waves in our centre. PD-L1 expression in CD8+ T cells, Tregs and CD14+ monocytes was increased in Covid-19 compared to controls. Conclusions: In our cohort, Covid-19 is associated with monocytopenia, increased CD14+ and Treg PD-L1 expression correlating with IFN-ɣ plasma concentration and disease severity (SOFA score). The latter is also associated with metabolic derangements of Tryptophan, LPC 16:0 and PCs. Lipid metabolism, in particular phosphatidylcholines and lysophosphatidylcolines, seems strictly linked to immune response in Covid-19. Our results support the hypothesis that IFN-ɣ -PD-L1 axis might be involved in the cytokine release syndrome typical of severe Covid-19 and the phenomenon persisted through multiple pandemic waves despite use of immunomodulation.

Mechanosensitive Piezo1 channels transduce mechanical stimuli into electrochemical signals. Jiang et al. show that due to the bending rigidity of the membrane, the overlap of neighboring Piezo1 footprints produces a flattening of the Piezo1 footprints and a cation-selective conducting pore. This study suggests that the clustering of Piezo1 channels may tune its sensitivity to applied force.

Abstract Background The clinical effectiveness of neurally adjusted ventilatory assist (NAVA) has yet to be demonstrated, and preliminary studies are required. The study aim was to assess the feasibility of a randomized controlled trial (RCT) of NAVA versus pressure support ventilation (PSV) in critically ill adults at risk of prolonged mechanical ventilation (MV). Methods An open-label, parallel, feasibility RCT (n = 78) in four ICUs of one university-affiliated hospital. The primary outcome was mode adherence (percentage of time adherent to assigned mode), and protocol compliance (binary—≥ 65% mode adherence). Secondary exploratory outcomes included ventilator-free days (VFDs), sedation, and mortality. Results In the 72 participants who commenced weaning, median (95% CI) mode adherence was 83.1% (64.0–97.1%) and 100% (100–100%), and protocol compliance was 66.7% (50.3–80.0%) and 100% (89.0–100.0%) in the NAVA and PSV groups respectively. Secondary outcomes indicated more VFDs to D28 (median difference 3.0 days, 95% CI 0.0–11.0; p = 0.04) and fewer in-hospital deaths (relative risk 0.5, 95% CI 0.2–0.9; p = 0.032) for NAVA. Although overall sedation was similar, Richmond Agitation and Sedation Scale (RASS) scores were closer to zero in NAVA compared to PSV (p = 0.020). No significant differences were observed in duration of MV, ICU or hospital stay, or ICU, D28, and D90 mortality. Conclusions This feasibility trial demonstrated good adherence to assigned ventilation mode and the ability to meet a priori protocol compliance criteria. Exploratory outcomes suggest some clinical benefit for NAVA compared to PSV. Clinical effectiveness trials of NAVA are potentially feasible and warranted. Trial registration ClinicalTrials.gov , NCT01826890 . Registered 9 April 2013.

OBJECTIVES/GOALS: Microtubule poisons, like Taxol, are used to treat triple negative breast cancer (TNBC) and may induce lethal aneuploidy in cancer cells. Patients initially respond, but often develop drug resistance. New targeted drugs that cause aneuploidy may be a valuable approach to therapy. One potential target is the Kinesin 13 MCAK, which limits aneuploidy. METHODS/STUDY POPULATION: TCGA and GSE47561 databases were probed for MCAK expression, and data was stratified by subtype and survival statistics. Knockdown studies were performed to test whether MCAK knockdown sensitizes cells to taxanes for cell proliferation and for induction of aneuploidy. FRET and image-based screens were used to identify MCAK inhibitors from small molecule inhibitor libraries. Inhibitors were then tested for functional effects in multiple cell-based assays and for clonal growth in colony formation assays. RESULTS/ANTICIPATED RESULTS: MCAK expression is upregulated in TNBC and associated with reduced overall survival. Knockdown of MCAK caused a two-to-five-fold reduction of the IC50 for Taxol in cancer cell lines, with no change in normal cell lines. Taxol treatment or MCAK knockdown increased aneuploidy induction, with no additive effect between the two. Our small molecule screen identified three putative MCAK inhibitors, which induced aneuploidy in both taxane-sensitive and taxane-resistant cells. These inhibitors also reduced clonogenic growth, and the most potent inhibitor, C4, caused an approximate five-fold reduction in the IC50 for Taxol in cell proliferation assays. DISCUSSION/SIGNIFICANCE: MCAK can serve as a biomarker of breast cancer prognosis. MCAK knockdown or inhibition sensitizes cancer cells to Taxol without affecting normal cells, making it a potential target in combination therapy. MCAK inhibitors also reduce growth as single agents in taxane resistant lines, giving them potential use as therapies in resistant disease.

Background: Placenta accreta spectrum (PAS) disorder refers to pathologic adherence of the placenta and presents multiple perinatal challenges, accounting for between 30–50% of emergency peripartum hysterectomies. Accurate prenatal diagnosis allows multidisciplinary management and delivery at centres with experience and has been shown to improve perinatal outcomes. This study aims to analyse the results of implementing different strategies across the years on the diagnosis and management of PAS in a tertiary Australian hospital (Liverpool Hospital) including: the use of magnetic resonance imaging (MRI) and the benefits of the use of iliac artery balloons and ureteric stents. Secondary objectives include analysis of the risk factors and outcomes. Methods: Retrospective case series of 34 pregnancies complicated by PAS disorders, diagnosed between 2004 and 2020, and delivered at Liverpool Hospital. Descriptive and analytic study (with a significance level of p ≤ 0.05), approved by the Research Ethics and Governance Information System. Results: The incidence of PAS was 0.6 per 1000 deliveries. The typical risk factors (previous uterine surgeries and placenta praevia) were present in 79% of the cases. MRI was used in 39% of the cases (when ultrasound was inconclusive or placenta posterior) and was only inconclusive in 1 case. In total, 32% required emergency delivery due to haemorrhage or preterm labor. The overall complications rate was 32%. Ureteric stents were used in 44% of the cases and there were no ureteric injuries. The use of iliac balloons reduced the total blood loss (2.5 L compared to 2.8 L), however this difference was not statistically significant (p = 0.21). Conclusions: The prenatal diagnosis of PAS is essential to allow optimal perinatal management of these cases. The use of MRI appears helpful when ultrasound is inconclusive. In our study, the use of iliac balloons reduced blood loss, although this was not statistically significant, and ureteric stents appeared useful to avoid ureteric injury in the most complex cases, although the sample is very small. We hope that our study will help us improving our clinical practice.

Background:. A natural aesthetic appearance of the lip and a favorable scar are essential goals of cleft lip repair. Wider clefts intuitively pose a greater technical challenge; however, the relationship between initial width and aesthetic outcome remains controversial. The current study aimed to determine whether lip adhesion can help wider clefts achieve safe, consistent aesthetic outcomes. Methods:. A retrospective cohort study was conducted on unilateral cleft lip patients who underwent lip repair within a 2-year period by the senior author. Subjects were divided into three groups based on cleft severity: (1) wide complete clefts that required lip adhesion before definitive repair, (2) narrower complete clefts that did not require lip adhesion, and (3) incomplete clefts. Aesthetic outcomes related to the vermillion and upper lip scar were rated by 48 blinded observers. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney tests. Nasal outcomes were not assessed. Results:. Seventeen patients were included in the study: five in group 1, six in group 2, and six in group 3. Patients with the widest clefts did not have inferior results compared with the other groups. In fact, they had statistically significantly higher aesthetic scores in all scar-related outcomes compared with those in groups 2 and 3 (P < 0.0001). Conclusions:. This study suggests that a wide cleft does not necessarily foreshadow a poor surgical outcome. In fact, wide clefts may have pleasing results, and the use of a staged lip adhesion approach can be useful for achieving the desired outcome in wider clefts.

This graphic interlude features a selection of pictures and videos illustrating the topic of this issue: “The Torn Object”.

A new species of Eumerus, Eumerus druk Smit sp. nov., is described from Bhutan. This species belongs to the bactrianus subgroup of the strigatus species group. Seven species are currently known within this subgroup: four European, one of which is also found in the Near East, and three more only known from Tajikistan. The new species extends this disjunct distribution to the east by at least 2,000 km, stretching far beyond the reported Turano-Mediterranean region and into the Himalayas. A diagnosis and a key to all Central and Eastern Palaearctic species of the Eumerus bactrianus subgroup are provided.

Eumerus Meigen (Diptera, Syrphidae) is one of the most speciose hoverfly genera in Europe, with several species groups recognized within. As part of the tricolor group of species, a subgroup of long-legged representatives stands out. We name it Eumerus binominatus subgroup and provide descriptions for two new European species which belong to this subgroup: E. grallator sp. nov. from mainland Spain and E. tenuitarsis sp. nov. from Lesvos and Evros, Greece. A key for all five recognized species of the binominatus subgroup is provided.

Bacteria assemble the surface layer (S-layer), a crystalline protein coat surrounding the curved surface, using protein self-assembly. Here authors image native and purified RsaA, the S-layer protein from C. crescentus, and show that protein crystallization alone is sufficient to assemble and maintain the S-layer in vivo.

Abstract Background Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration ClinicalTrials.gov, NCT00878709. Trial registered April 9, 2009.

Rotating (also termed continuous spin) detonation technology is gaining interest in the global research and development community due to the potential for increased performance. Potential performance benefits, thrust chamber design, and thrust chamber cooling loads are analyzed for propellant applications using liquid oxygen or high-concentration hydrogen peroxide oxidizers with kerosene, hydrogen, and methane fuels. Performance results based on a lumped parameter treatment show that theoretical specific impulse gains of 3–14% are achievable with the highest benefit coming from hydrogen-fueled systems. Assessment of thrust chamber designs for notional space missions shows that both thrust chamber length and diameter benefits are achievable given the tiny annular chamber volume associated with the rotating detonation combustion. While the passing detonation front drastically increases local heat fluxes, global energy balances can be achieved if operating pressures are limited to be comparable to existing or prior space engines.

Introduction People living in slums face several challenges to access healthcare. Scarce and low-quality public health facilities are common problems in these communities. Costs and prevalence of catastrophic health expenditures (CHE) have also been reported as high in studies conducted in slums in developing countries and those suffering from chronic conditions and the poorest households seem to be more vulnerable to financial hardship. The COVID-19 pandemic may be aggravating the economic impact on the extremely vulnerable population living in slums due to the long-term consequences of the disease. The objective of this review is to report the economic impact of seeking healthcare on slum-dwellers in terms of costs and CHE. We will compare the economic impact on slum-dwellers with other city residents.Methods and analysis This scoping review adopts the framework suggested by Arksey and O’Malley. The review is part of the accountability and responsiveness of slum-dwellers (ARISE) research consortium, which aims to enhance accountability to improve the health and well-being of marginalised populations living in slums in India, Bangladesh, Sierra Leone and Kenya. Costs of accessing healthcare will be updated to 2020 prices using the inflation rates reported by the International Monetary Fund. Costs will be presented in International Dollars by using purchase power parity. The prevalence of CHE will also be reported.Ethics and dissemination Ethical approval is not required for scoping reviews. We will disseminate our results alongside the events organised by the ARISE consortium and international conferences. The final manuscript will be submitted to an open-access international journal. Registration number at the Research Registry: reviewregistry947.

Background Neurally adjusted ventilatory assist (NAVA) involves an intricate interaction between patient, clinician and technology. To improve our understanding of this complex intervention and to inform future trials, this survey aimed to examine clinician attitudes, beliefs and barriers to NAVA use in critically ill adults within an institution with significant NAVA experience.Methods A survey of nurses, doctors and physiotherapists in four Intensive Care Units (ICUs) of one UK university-affiliated hospital (75 NAVA equipped beds). The survey consisted of 39 mixed open and structured questions. The hospital had 8 years of NAVA experience prior to the survey.Results Of 466 distributed questionnaires, 301 (64.6%) were returned from 236 nurses (78.4%), 53 doctors (17.6%) and 12 physiotherapists (4.0%). Overall, 207/294 (70.4%) reported clinical experience. Most agreed that NAVA was safe (136/177, 76.8%) and clinically effective (99/176, 56.3%) and most perceived ‘improved synchrony’, ‘improved comfort’ and ‘monitoring the diaphragm’ to be key advantages of NAVA. ‘Technical issues’ (129/189, 68.3%) and ‘NAVA signal problems’ (94/180, 52.2%) were the most cited clinical disadvantage and cause of mode cross-over to Pressure Support Ventilation (PSV), respectively. Most perceived NAVA to be more difficult to use than PSV (105/174, 60.3%), although results were mixed when compared across different tasks. More participants preferred PSV to NAVA for initiating ventilator weaning (93/171 (54.4%) vs 29/171 (17.0%)). A key barrier to use and a consistent theme throughout was ‘low confidence’ in relation to NAVA use.Conclusions In addition to broad clinician support for NAVA, this survey describes technical concerns, low confidence and a perception of difficulty above that associated with PSV. In this context, high-quality training and usage algorithms are critically important to the design and of future trials, to clinician acceptance and to the clinical implementation and future success of NAVA.

Experience and anecdotal evidence indicate that first-year students experience challenges in terms of adapting to our university construction management course environment. The purpose of the study is to determine the impact of a team building event on first-year students’ skills, core competencies, ability to manage themselves, work as a team, interface with each other, strategize, plan, evolve tactics, and take action.. A quantitative approach using a questionnaire survey in a South African university post completion of the event determined the perceptions of the students. Findings include that the team building activities contributed to enhancing participants’ skills, their understanding and appreciation of core competencies and the development thereof, and their ability to communicate with first-year colleagues; built confidence in their abilities including that of completing a task, and enhanced participants’ alternative thought processes, ability to be creative, strategize, evolve tactics, take action, and plan. The students benefited from, enjoyed the team building activities and believed that it contributed to improving their time management skills. Based upon the findings, conclusions are that the one-day first-year orientation team-building event had the desired impact in terms of the development of the first-year students’ abilities. Recommendations are that the one-day first-year orientation team-building event is staged annually, and a study pertaining to the impact of the intervention on student performance be determined following the completion of a full academic year and again post-graduation.

The Proline, Glutamate, Valine and Lysine-rich (PEVK) region of titin constitutes an entropic spring that provides passive tension to striated muscle. To study the functional and structural repercussions of a small reduction in the size of the PEVK region, we investigated skeletal muscles of a mouse with the constitutively expressed C-terminal PEVK exons 219–225 deleted, the TtnΔ219–225 model (MGI: TtnTM 2.1Mgot). Based on this deletion, passive tension in skeletal muscle was predicted to be increased by ∼17% (sarcomere length 3.0 μm). In contrast, measured passive tension (sarcomere length 3.0 μm) in both soleus and EDL muscles was increased 53 ± 11% and 62 ± 4%, respectively. This unexpected increase was due to changes in titin, not to alterations in the extracellular matrix, and is likely caused by co-expression of two titin isoforms in TtnΔ219–225 muscles: a larger isoform that represents the TtnΔ219–225 N2A titin and a smaller isoform, referred to as N2A2. N2A2 represents a splicing adaption with reduced expression of spring element exons, as determined by titin exon microarray analysis. Maximal tetanic tension was increased in TtnΔ219–225 soleus muscle (WT 240 ± 9; TtnΔ219–225 276 ± 17 mN/mm2), but was reduced in EDL muscle (WT 315 ± 9; TtnΔ219–225 280 ± 14 mN/mm2). The changes in active tension coincided with a switch toward slow fiber types and, unexpectedly, faster kinetics of tension generation and relaxation. Functional overload (FO; ablation) and hindlimb suspension (HS; unloading) experiments were also conducted. TtnΔ219–225 mice showed increases in both longitudinal hypertrophy (increased number of sarcomeres in series) and cross-sectional hypertrophy (increased number of sarcomeres in parallel) in response to FO and attenuated cross-sectional atrophy in response to HS. In summary, slow- and fast-twitch muscles in a mouse model devoid of titin’s PEVK exons 219–225 have high passive tension, due in part to alterations elsewhere in splicing of titin’s spring region, increased kinetics of tension generation and relaxation, and altered trophic responses to both functional overload and unloading. This implicates titin’s C-terminal PEVK region in regulating passive and active muscle mechanics and muscle plasticity.

Premise Over 3000 species of plants and animals release toxic hydrogen cyanide (HCN) gas when their tissues are crushed. To investigate the role of cyanogenesis in Passiflora–herbivore interactions, we developed an inexpensive, rapid, sensitive method for measuring HCN emissions from crushed tissues. Methods The method includes crushed tissue confinement in a closed chamber, where cyanogenesis reactions occur, followed by evacuation of gas to a portable HCN meter. Parts per million readings are repeated at 5‐min intervals until HCN is depleted. Three versions of the closed reaction chamber apparatus were tested: plastic cup, airtight combination mortar‐pestle, and glass desiccator jar. Results We calibrated the method by comparing with a closed chamber measurement apparatus. The procedure's repeatability was demonstrated with a standard curve using known quantities of cyanogenic glycoside standard. Data collected with this method were also compared with the conventional colorimetric procedure. We processed over 2000 samples using this technique, revealing diverse elements of cyanogenic variation. Conclusions These methods produced well‐defined data with minimal error. Results illustrated a one to four order‐of‐magnitude variation at organizational levels ranging from individual leaves to the entire Passiflora community. We now have a promising tool for uncovering the HCN phytochemical landscape in unprecedented detail.

The construction industry plays a major role in South Africa’s economic development. Despite its importance, the poor health and safety (H&S) performance and associated costs to the industry are a concern. The literature review indicates that improved H&S performance can be achieved on a project where there is a collaborative approach among all stakeholders during the six project stages. This study focuses on the impact of the Construction Regulations 2014 on a water utility’s projects’ H&S performance. It determines the H&S involvement of client representatives and internal project stakeholders during the six project stages. It also addresses their commitment towards H&S, measures taken by them during planning and design, in contracts to improve H&S, and to select conscious contractors, and the extent of their H&S participation in construction H&S. Mixed methods research (a questionnaire survey and four case study projects) was used to collect the data required for the study. A total of 67 responses were obtained from the five stakeholder groups from the water utility, namely client representatives, designers, quantity surveyors (QSs), project managers (PMs), and construction H&S (CHS) professionals to obtain information regarding their H&S involvement during the six project stages. Four case study projects (three pre- Construction Regulations 2014 and one post- Construction Regulations 2014) were obtained, using a stratified random sampling technique and a checklist to obtain information regarding the stakeholder H&S involvement during the six project stages and the overall project performance. The study found that the Construction Regulations 2014 are perceived to have had an impact on the water utility’s H&S performance. There is a direct relationship between stakeholder H&S involvement and project H&S performance. The integration of H&S in the initial project phases; early involvement of CHS professionals, and H&S training for stakeholders are among the recommendations arising from this study.

The South African Construction Regulations realise the contributions by each member of a project team to health and safety (H&S) improvement. These Regulations amplify the roles and contributions of clients to project realisation. The tenets of the Regulations conform with the observation that clients’ H&S leadership and behaviours are an effective means of improving construction H&S performance in the industry. This article reports on a study that examined current clients’ leadership approach and expectations in terms of H&S in South African construction. The review of relevant literature provides the platform for the research survey, which was conducted among selected clients of the industry. The findings show that clients’ H&S leadership roles and behaviours have a significant influence on construction H&S performance in South Africa. Findings reveal that unethical behaviour, in terms of procurement and contract awards, is a serious challenge to the improvement of H&S performance in the industry.

Summary: Succinylation is a post-translational protein acylation modification that converts the cationic lysine side chain to an anion with large potential impacts on protein structure and function. Here we characterize the epigenome-wide distribution of succinyllysine marks in chromatin using chromatin immunoprecipitation sequencing (ChIP-seq). We estimate that more than one-third of all nucleosomes contain lysine succinylation marks and demonstrate a potential role of chromatin succinylation in modulating gene expression. We further demonstrate that defective tricarboxylic acid (TCA) cycle metabolism perturbs the succinyllysine distribution in chromatin, correlating with transcriptional responses. This is consistent with previous observations linking nucleosome succinylation with enhanced in vitro transcription. We additionally demonstrate that defective TCA cycle metabolism results in a DNA repair defect and sensitivity to genotoxic agents, consistent with previously reported chromatin hypersuccinylation effects observed in the context of SIRT7 depletion. Chromatin succinylation may thus represent a mechanism by which metabolism modulates both genome-wide transcription and DNA repair activities. : Cellular Physiology; Molecular Mechanism of Gene Regulation; Proteomics Subject Areas: Cellular Physiology, Molecular Mechanism of Gene Regulation, Proteomics

We present our approach to rapidly establishing a standardized, multi-site, nation-wide COVID-19 screening program in Belgium. Under auspices of a federal government Task Force responsible for upscaling the country’s testing capacity, we were able to set up a national testing initiative with readily available resources, putting in place a robust, validated, high-throughput, and decentralized qPCR molecular testing platform with embedded proficiency testing. We demonstrate how during an acute scarcity of equipment, kits, reagents, personnel, protective equipment, and sterile plastic supplies, we introduced an approach to rapidly build a reliable, validated, high-volume, high-confidence workflow based on heterogeneous instrumentation and diverse assays, assay components, and protocols. The workflow was set up with continuous quality control monitoring, tied together through a clinical-grade information management platform for automated data analysis, real-time result reporting across different participating sites, qc monitoring, and making result data available to the requesting physician and the patient. In this overview, we address challenges in optimizing high-throughput cross-laboratory workflows with minimal manual intervention through software, instrument and assay validation and standardization, and a process for harmonized result reporting and nation-level infection statistics monitoring across the disparate testing methodologies and workflows, necessitated by a rapid scale-up as a response to the pandemic.

To address the decline in biodiversity, international cooperation in monitoring of threatened species is needed. Citizen science can play a crucial role in achieving this challenging goal, but most citizen science projects have been established at national or regional scales. Here we report on the establishment and initial findings of the European Stag Beetle Monitoring Network (ESBMN), an international network of stag beetle (Lucanus cervus) monitoring schemes using the same protocol. The network, started in 2016, currently includes 14 countries (see results) but with a strong variation in output regarding the number of transects (148 successful transects in total) and transect walks (1735). We found differences across European regions in the number of stag beetles recorded, related to phenology and temperature, but not for time of transect start. Furthermore, the initial experiences of the ESBMN regarding international cooperation, citizen science approach, and drop-out of volunteers is discussed. An international standardised protocol that allows some local variation is essential for international collaboration and data management, and analysis is best performed at the international level, whereas recruiting, training, and maintaining volunteers is best organised locally. In conclusion, we appeal for more joint international citizen science-based monitoring initiatives assisting international red-listing and conservation actions.

Abstract Background Optimal breastfeeding has benefits for the mother-infant dyads. This study investigated the prevalence and determinants of cessation of exclusive breastfeeding (EBF) in the early postnatal period in a culturally and linguistically diverse population in Sydney, New South Wales, Australia. Methods The study used routinely collected perinatal data on all live births in 2014 (N = 17,564) in public health facilities in two Local Health Districts in Sydney, Australia. The prevalence of mother’s breastfeeding intention, skin-to-skin contact, EBF at birth, discharge and early postnatal period (1–4 weeks postnatal) were estimated. Multivariate logistic regression models that adjusted for confounders were conducted to determine association between cessation of EBF in the early postnatal period and socio-demographic, psychosocial and health service factors. Results Most mothers intended to breastfeed (92%), practiced skin-to-skin contact (81%), exclusively breastfed at delivery (90%) and discharge (89%). However, the prevalence of EBF declined (by 27%) at the early postnatal period (62%). Younger mothers (

Diamond, a highly radiation-resistant material, is considered a nearly ideal material for radiation detection, particularly in high-energy physics. In this study, radiation damage from high-energy proton beams was induced in diamond crystals to determine exposure lifetime in detectors made from this material; the effects were investigated using non-destructive x-ray techniques and through the FLUKA simulation package. Two diamond detectors were irradiated by an 800 MeV proton beam at different fluence rates, and the real-time current response was recorded to observe degradation in the signal over time. It was determined that the proton fluence rate had a significant effect on the device degradation. The detector performance from the irradiated detectors was characterized using x-ray beam-induced current measurements, and the mechanism of proton radiation damage to diamond sensors, especially the radiation effects on carrier transport, was studied. The vacancies generated from proton irradiation were considered the major source of detector degradation by trapping holes and inducing an internal electric field. Simulation results from the FLUKA package revealed an uneven distribution of the radiation-induced vacancies along the beam path, and the corresponding detector signals calculated from the simulation results displayed a good match to the experimental results.

The search by SKB (Swedish Nuclear Fuel and Waste Management Co.) for a site to locate the deep geological repository for spent nuclear fuel in Sweden has involved geoscientific investigations at several locations since the 1970s. The objectives were to characterise geologically a bedrock volume as well as its hydrogeology and hydrochemistry. To acquire high-quality hydrogeochemical data, a complete system for groundwater sampling and analysis, as well as for interpretation strategies, has been developed through a continuous process of modification and refinement. Since the largest part of the Swedish bedrock is composed of granitoids, the site investigations had to adapt to the special difficulties of fractured crystalline rocks. This paper discusses the problems with groundwater sampling that are specific to fractured crystalline rocks and describes the solutions adopted and methods developed by SKB since the early 2000s during the site investigations. The methodology described in this paper for the characterisation of deep groundwaters in crystalline rocks is not only applicable in the context of radioactive waste disposal but also useful when sampling groundwaters for any purpose in such rocks. Sampling of groundwaters in fractured rocks at depth, often down to approximately 1,000 m, involves special challenges since the natural conditions of the groundwater are easily disturbed, especially by the initial drilling, but also by every subsequent activity performed in the borehole, including the actual groundwater sampling. The sampling strategy presented in this paper shows that planning of the sampling preferably starts already when the drilling procedure is decided. Each following step is described in detail and includes tracing the drilling fluid, selecting the best borehole sections to sample, procedures for the actual sampling, and selection of analytical protocol; all this with the goal of taking representative samples. Although the evaluation of the sampling uncertainties is not a straightforward procedure, an adequate categorisation routine has been established to classify groundwater samples regarding sample quality, representativeness, and suitability for further interpretations and modelling.

Introduction The optimal management of patent ductus arteriosus (PDA) remains contentious. The medications used to treat PDA are often non-steroidal anti-inflammatory drugs, which are associated with a number of unwanted adverse effects. Paracetamol is a medication with an excellent safety profile in infants and has been suggested as a safe alternative medication in situations where other medications have failed or are contraindicated. There are limited data on the use of early, intravenous paracetamol in preterm infants.Methods and analysis This trial aims to address whether early treatment with paracetamol will reduce the number of infants requiring intervention for PDA. This is a randomised, double-blind, placebo-controlled trial in preterm infants 0.9 mm will be randomised to receive either (1) intravenous paracetamol at a dose of 15 mg/kg initially, followed by every 6 hours at a dose of 7.5 mg/kg for 5 days; or (2) intravenous 5% dextrose every 6 hours for 5 days. The primary outcome is the need for any intervention for management of PDA up to 5 days. Secondary outcomes include closure of the ductus arteriosus at 5 days, size of the ductus arteriosus, ductal reopening, systemic blood flow, mortality and significant morbidities. The target sample size of 100 infants yields >80% power, at the two-sided 5% level significance, to detect a 50% reduction in the need for intervention assuming that approximately 60% of infants in this study would otherwise have required intervention for PDA.Ethics and dissemination A report on the results of the planned analyses will be prepared. The results of the primary analysis of all end points will be presented at medical conferences and submitted for publication in peer-reviewed journals. Separate manuscripts pertaining to the second aim of the study may be written, and these will also be submitted for publication in peer-reviewed journals.Trial registration number ACTRN12616001517460.

Transient receptor potential vanilloid 5 (TRPV5) is a highly calcium selective ion channel that acts as the rate-limiting step of calcium reabsorption in the kidney. The lack of potent, specific modulators of TRPV5 has limited the ability to probe the contribution of TRPV5 in disease phenotypes such as hypercalcemia and nephrolithiasis. Here, we performed structure-based virtual screening (SBVS) at a previously identified TRPV5 inhibitor binding site coupled with electrophysiology screening and identified three novel inhibitors of TRPV5, one of which exhibits high affinity, and specificity for TRPV5 over other TRP channels, including its close homologue TRPV6. Cryo-electron microscopy of TRPV5 in the presence of the specific inhibitor and its parent compound revealed novel binding sites for this channel. Structural and functional analysis have allowed us to suggest a mechanism of action for the selective inhibition of TRPV5 and lay the groundwork for rational design of new classes of TRPV5 modulators.

Background: Abnormalities on cardiac imaging (cardiac magnetic resonance imaging [CMR] or positron emission tomography [PET]), left ventricular ejection fraction (LVEF), and electrophysiology study (EPS) all predict ventricular arrhythmias (VA) in patients with cardiac sarcoidosis (CS). We sought to assess the utility of EPS in patients with CS and abnormal cardiac imaging, focusing on those with LVEF >35%. Methods: We identified all patients treated at our institution from 2000 to 2017 who: 1.) had probable or definite CS; 2.) had either late gadolinium enhancement (LGE) on CMR or abnormal 18-flourodeoxyglucose (FDG) uptake on PET, and 3.) had undergone EPS. The primary endpoint was VA during follow up. Results: Twenty five patients were included, of whom 10 (40%) had positive EPS. During a mean follow-up of 4.8 +/− 3.4 years, 11 (44%) patients had VA. The positive predictive value (PPV) of EPS for VA was 100% and the negative predictive value (NPV) of EPS for VA was 93%. Among 12 patients with LVEF >35% and no prior VA, the PPV of EPS for VA was 100% and the NPV of EPS for VA was 90%. Conclusion: EPS may help with risk stratification in patients with CS and abnormal imaging, especially those without conventional indications for ICD placement. Among patients with LVEF >35% and no history of prior VA, a negative EPS has good positive and negative predictive value for future VA events. Keywords: Cardiac sarcoidosis, Ventricular arrhythmia, Sudden cardiac death, Electrophysiology study, Implantable cardioverter defibrillator