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Abstract This paper, which presents highlights of the World Energy Employment report 2023 published by the International Energy Agency with the support and analytical contribution of Enel Foundation, provides an overview of the impacts of decarbonization process on the energy workforce at a global level. Data collected and estimated with deep granularity across the entire value chain shows that increasing investments in the power sector, electric vehicles and other clean technologies are fuelling workforce growth in the energy sector: nearly 67 million people were employed in the energy sector worldwide in 2022, an increase of 3.4 million jobs compared to 2019. Projections under several energy transition scenarios demonstrate that the energy transition will have a net positive effect on jobs through 2030, with job additions in clean energy sectors far outweighing declines in sectors associated with fossil fuels. However, a more detailed analysis of the most in-demand skills within the energy sector reveals that skills shortages in some sectors are preventing the workforce from growing as quickly as needed. Across the energy industry, employers are reporting difficulty hiring and retaining workers with the skills needed to deploy clean energy technologies. To relieve this bottleneck, the paper identifies key intervention areas to build a pipeline of skilled labour (e.g., through reskilling and upskilling initiatives, along with energy transition-focused education) and thus minimize employment-related delays in the decarbonization process.

Abstract Boston Children’s Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children’s Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools. Since its launch, 66 investigators representing 26 divisions and 45 phenotype-based cohorts have joined the CRDC. These studies enrolled 4653 families, with 35% of analyzed cases having a finding either confirmed or under further investigation. This accessible and harmonized genomics platform also supports additional institutional data collections, research and clinical, and now encompasses 13,800+ patients and their families. This has fostered new research projects and collaborations, increased genetic diagnoses and accelerated innovative research via integration of genomics research with clinical care.

Change theory has increasingly become an area of scholarship in STEM education. While this area has traditionally been a topic for organizational psychology, business management, communication studies, and higher education, STEM education researchers are increasingly aware of the need to use formal theories to guide change efforts and research. Formal change theory encompasses our current research-based knowledge about how and why change occurs, and therefore, can guide the selection and design of promising interventions. Yet learning about and using theory is challenging because many of us have no formal training in this area and relevant scholarship comes from many different disciplines. Inconsistent terminology creates an additional barrier. Thus, this essay aims to contribute to a common lexicon in STEM higher educational change efforts by clearly distinguishing between formalized change theory, which emerges from research, and a theory of change, which guides the logic of a specific project. We also briefly review the current state of the field regarding the use of formal change theory and provide examples of how change theory has been used in biology education. Lastly, we offer practical guidance for researchers and change agents who wish to more intentionally and effectively use change theory in their work.

IntroductionEggs can mediate foodborne disease resulting in salmonellosis outbreaks that are most commonly caused by Salmonella enterica serovar Enteritidis. Ovotransferrin is a prominent egg-white antimicrobial glycoprotein belonging to the transferrin family, members of which exhibit powerful iron-chelating activity. However, several studies have also described the ability of transferrin proteins to disrupt bacterial membranes. This study aimed to investigate the antimicrobial activity of ovotransferrin toward S. Enteritidis membranes at 30°C under egg-white conditions.Materials and methodsThis aim was supported by the deployment of a synthetic medium designed to mimic egg-white (matching the ionic composition and pH). The ability of ovotransferrin to induce bacterial membrane permeabilization in S. Enteritidis was investigated by measuring substrate accessibility to periplasmic β-lactamase and cytosolic β-galactosidase.ResultsThe depolarization of the inner membrane of S. Enteritidis was measured using a fluorescence probe [DiSC3(5)]. The results show that ovotransferrin induces permeabilization of the outer membrane but not the inner membrane whereas egg white permeabilizes both membranes. In addition, the dissipation of the proton motive force by egg white was found to involve a contribution by ovotransferrin since this protein provoked inner-membrane depolarization.DiscussionIt can thus be concluded that ovotransferrin exerts a membranes perturbation activity on S. Enteritidis under egg-white conditions, in addition to its well-known iron-chelation activity.

Recent evidence suggests that the development of gut microbiota during infancy affects several metabolic, immune, and endocrine pathways in humans. An imbalance in gut microbiota diversity or function, also known as dysbiosis, not only affects early child growth and development, but is also linked with the development of chronic, non-communicable diseases in later life. The Child Health And Microbiome Development Study – Pakistan (CHAMP) study aimed to longitudinally assess gut microbiota development and associated factors (maternal, child, and demographic) during early childhood in populations residing in malnutrition-endemic communities in Pakistan. A prospective cohort of mother-infant pairs (n=70) will be recruited from District Swat, Pakistan, and followed for two years. Complete information about demographic characteristics, anti-natal and post-natal care, dietary intake, feeding practices, and child health will be collected at baseline and 3, 6, 12, 18, and 24 months. Anthropometric measurements (height, weight, mid-upper arm circumference, and head circumference), dry blood spots, and fecal samples were also collected. Ethical approval for the study was obtained from Khyber Medical University, Pakistan. The study is also registered on clincaltrial.gov (Ref no: NCT05793294). The study findings will help researchers understand gut microbiota development, associated factors, and their impact on longitudinal growth in infants during the first two years of life.

ABSTRACT: This study aimed to assess the milk production data for New Zealand dairy goats in either a standard lactation (SL; ≤305 d in milk [DIM]) or extended lactation (EL; >305 and ≤670 DIM) using a random regression (RR) with third- and fifth-order Legendre polynomials, respectively. Persistency of EL was defined as (B/A) × 100, where A was the accumulated yield from d 1 to 305, and B was the accumulated yield from d 366 to 670. On average, goats in SL produced 1,183 kg of milk, 37 kg of fat, 37 kg of protein, and 54 kg of lactose. The average production of milk, fat, protein, and lactose in EL were 2,473 kg, 78 kg, 79 kg, and 112 kg, respectively. The average persistences for milk, fat, protein, and lactose yields during EL were 98%, 98%, 102%, and 96%, respectively. The relative prediction errors were close to 10% and the concordance correlation coefficients >0.92, indicating that the RR model with Legendre polynomials is adequate for modeling lactation curves for both SL and EL. Total yields and persistency were analyzed with a mixed model that included the fixed effects (year, month of kidding, parity, and proportion of Saanen) as covariates and the random effects of animal and residual errors. Effects of year, month of kidding, and parity were significant on the total yields of milk, fat, protein, and lactose for both SL and EL. The total milk yield of first-parity goats with SL was 946 kg and the total milk yield of second-parity goats with SL was 1,284 kg, making a total of 2,230 kg over 2 years. The total milk yield of a first-parity goat with EL was 2,140 kg. Thus, on average, a goat with SL for the first and second parity produced 90 kg more milk than a first-parity goat subjected to EL. However, a second-parity goat subjected to EL produced 43 kg more milk (2,639 kg) than a goat with SL following the second and third parity (1,284 kg + 1,312 kg). These data, along with the various other benefits of EL (e.g., fewer offspring born and reduced risk of mastitis, lameness, and metabolic problems in early lactation), indicate that EL as a management strategy holds the potential to improve dairy goat longevity and lifetime efficiency without compromising milk production.

The gut microbiota residing in the distal ileum and colon is the most complex, diverse, and densest microbial ecosystem in the human body. Despite its known role in human health and disease, gut microbiome diversity and function are rarely explored in vulnerable populations such as refugees. The current study aimed to explore gut microbiota diversity and sources of variation among adolescent Afghan refugees residing in Peshawar, Pakistan. Stool samples were collected from 10 – 18 years old, healthy adolescents (n=205) for 16S rRNA gene sequence (V4-V5 hypervariable region) analysis on isolated faecal DNA. Bioinformatics analyses were performed using Kraken2, Bracken and Phyloseq. The data presented here will allow researchers to profile the gut microbiota of this rarely explored, vulnerable population who are at high risk of food insecurity and malnutrition. The data can be used to provide insight on the impact of demographic characteristics, dietary intake, nutritional status, and health on gut microbiome diversity, and enables a comparative analysis with similar data sets from other population groups of relevance. The amplicon sequencing data are deposited in the NCBI Sequence Read Archive as BioProject PRJNA1105775.

Digital adherence technologies are increasingly used to support tuberculosis (TB) treatment adherence. Using microcosting, we estimated healthcare system costs (in 2022 US dollars) of 2 digital adherence technologies, 99DOTS medication sleeves and video-observed therapy (VOT), implemented in demonstration projects during 2018–2021. We also obtained cost estimates for standard directly observed therapy (DOT). Estimated per-person costs of 99DOTS for drug-sensitive TB were $98 in Bangladesh (n = 719), $119 in the Philippines (n = 396), and $174 in Tanzania (n = 976). Estimated per-person costs of VOT were $1,154 in Haiti (87 drug-sensitive), $304 in Moldova (173 drug-sensitive), $452 in Moldova (135 drug-resistant), and $661 in the Philippines (110 drug-resistant). 99DOTS costs may be similar to or less expensive than standard DOT. VOT is more expensive, although in some settings, labor cost offsets or economies of scale may yield savings. 99DOTS and VOT may yield savings to local programs if donors cover infrastructure costs.

Abstract The incretin hormones glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP), are thought to be the main drivers of insulin secretion in individuals with sulfonylurea (SU)‐treated KCNJ11 permanent neonatal diabetes. The aim of this study was to assess for the first time the incretin hormone response to carbohydrate and protein/fat in adults with sulfonylurea‐treated KCNJ11 permanent neonatal diabetes compared with that of controls without diabetes. Participants were given a breakfast high in carbohydrate and an isocaloric breakfast high in protein/fat on two different mornings. Incremental area under the curve and total area under the curve (0‐240 minutes) for total GLP‐1 and GIP were compared between groups, using non‐parametric statistical methods. Post‐meal GLP‐1 and GIP secretion were similar in cases and controls, suggesting this process is adenosine triphosphate‐sensitive potassium channel‐independent. Future research will investigate whether treatments targeting the incretin pathway are effective in individuals with KCNJ11 permanent neonatal diabetes who do not have good glycemic control on sulfonylurea alone.

Abstract Background Neonatal near-miss (NNM) can be considered as an end of a spectrum that includes stillbirths and neonatal deaths. Clinical audits of NNM might reduce perinatal adverse outcomes. The aim of this review is to evaluate the effectiveness of NNM audits for reducing perinatal mortality and morbidity and explore related contextual factors. Methods PubMed, Embase, Scopus, CINAHL, LILACS and SciELO were searched in February/2023. Randomized and observational studies of NNM clinical audits were included without restrictions on setting, publication date or language. Primary outcomes: perinatal mortality, morbidity and NNM. Secondary outcomes: factors contributing to NNM and measures of quality of care. Study characteristics, methodological quality and outcome were extracted and assessed by two independent reviewers. Narrative synthesis was performed. Results Of 3081 titles and abstracts screened, 36 articles had full-text review. Two studies identified, rated, and classified contributing care factors and generated recommendations to improve the quality of care. No study reported the primary outcomes for the review (change in perinatal mortality, morbidity and NNM rates resulting from an audit process), thus precluding meta-analysis. Three studies were multidisciplinary NNM audits and were assessed for additional contextual factors. Conclusion There was little data available to determine the effectiveness of clinical audits of NNM. While trials randomised at patient level to test our research question would be difficult or unethical for both NNM and perinatal death audits, other strategies such as large, well-designed before-and-after studies within services or comparisons between services could contribute evidence. This review supports a Call to Action for NNM audits. Adoption of formal audit methodology, standardised NNM definitions, evaluation of parent’s engagement and measurement of the effectiveness of quality improvement cycles for improving outcomes are needed.

In the ablation zone of land-terminating areas of the Greenland Ice Sheet, water pressures at the bed control seasonal and daily ice motion variability. During the melt season, large amounts of surface meltwater access the bed through moulins, which sustain an efficient channelized subglacial system. Water pressure within these subglacial channels can be inferred by measuring the hydraulic head within moulins. However, moulin head data are rare, and subglacial hydrology models that simulate water pressure fluctuations require water storage in moulins or subglacial channels. Neither the volume nor the location of such water storage is currently well constrained. Here, we use the Moulin Shape (MouSh) model, which quantifies time-evolving englacial storage, coupled with a subglacial channel model to simulate head measurements from a small moulin in Pâkitosq, western Greenland. We force the model with surface meltwater input calculated using field-acquired weather data. Our first-order simulations of moulin hydraulic head either overpredict the diurnal range of oscillation of the moulin head or require an unrealistically large moulin size to reproduce observed head oscillation ranges. We find that to accurately match field observations of moulin head, additional subglacial water must be added to the system. This subglacial baseflow is likely sourced from basal melt and nonlocal surface water inputs upstream. We hypothesize that the additional baseflow represents strong subglacial network connectivity throughout the channelized system and is consistent with our small moulin likely connecting to a higher-order subglacial channel.

Background: Malignancy is a long-term complication of lung transplantation (LTx); however, contemporary Australian data and detailed evaluation of nonreportable cancers are lacking. Methods: Retrospective review of LTx recipients’ medical records and registry data linkage were performed to identify histologically proven malignancies. Baseline clinico-demographic variables were collected, and cancer incidence was compared with reported data for the general Australian population. Results: There were 1,715 LTx in 1,631 patients between 1989 and 2021, with a follow-up of 9,696 person-years. Eight hundred and ninety-three (54.8%) patients were male, and the median age at first LTx was 54.7 years. There were 886 deaths with a median overall survival of 7.5 years (95% confidence intervals (CI) 6.8-8.3 years). One thousand seven hundred and seventy-four separate invasive cancer events occurred across 407 patients, of which, 1,588 (89.5%) were nonmelanoma skin cancers (NMSCs). This translated to a 9-fold increased incidence of NMSCs and a 4-fold increased incidence of other cancers compared with the general population. Cancer mortality reached parity with chronic lung allograft dysfunction 10 years postfirst transplant and was independently associated with age (hazard ratios (HR) per year increase in age 1.02 [95% CI 1.01-1.03], p = 0.001), Epstein-Barr virus primary mismatch (HR 3.24 [95% CI 1.68-6.25], vs nonmismatch, p = 0.002), and cancer count (HR per cancer event 1.19 [95% CI 1.13-1.24], p

Objectives Bariatric surgery is an effective treatment for severe obesity that leads to significant physical health improvements. Few studies have prospectively described the short-term impact of surgery on mental health using standardised case-finding measures for anxiety or depressive disorders. This study describes the prevalence and short-term course of these conditions following surgery.Design Prospective observational cohort study.Setting 12 National Health Service centres in England.Participants Participants studied took part in the By-Band-Sleeve study, a multicentre randomised controlled trial evaluating the surgical management of severe obesity. We included participants who had undergone surgery (gastric bypass, gastric band or sleeve gastrectomy) within 6 months of randomisation.Primary and secondary outcome measures Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS) at baseline and 12 months post-randomisation. Sociodemographic variables collected at prerandomisation included body mass index, age, sex, ethnicity, marital status, tobacco use, employment status and income band.Results In our sample of 758 participants, 94.5% (n 716) and 93.9% (n 712) had completed baseline anxiety (HADS-A) and depression (HADS-D) subscales. At pre-randomisation 46.1% (n 330/716, 95% CI 42.4% to 49.7%) met clinical case criteria for anxiety and 48.2% (n 343/712, 95% CI 44.5% to 51.8%) for depression. Among participants returning completed 12 months post-randomisation questionnaires (HADS-A n 503/716, HADS-D n 498/712), there was a significant reduction in the proportion of clinical cases with anxiety (−9.5%, 95% CI −14.3% to -4.8% p

Background: Research efforts can produce practice-changing results with widespread implications for patient care. While critical to the advancement of the field, such efforts do not often provide direct compensation. However, a researcher’s academic productivity may facilitate industry relationships, either as the impetus for the affiliation or a result of collaboration. Methods: Queries of the Centers for Medicaid and Medicare Services publicly available Open Payments System allowed for extraction of industry compensation data for orthopedic surgeons in 7 categories, including royalties and licensing fees, consulting fees, gifts, honoria, and 3 unique speaking fees delineations. This system identifies physicians by taxonomy identifications; however, Centers for Medicaid and Medicare Services does not have a unique code for shoulder and elbow surgeons. Therefore, identification of shoulder and elbow surgeons proceeded utilizing the American Shoulder and Elbow Surgeons (ASES) society 2019 membership directory. Cross-referencing this membership list with extracted Open Payments data provided industry funding information for all ASES members. Physicians then underwent an academic productivity assessment. Queries of Web of Science, Scopus, and Google Scholar User Profile databases provided the Hirsch index (h-index) and m-index for each surgeon. Bivariate and multivariate analyses produced statistical results. Results: From 2016 to 2020, 631,130, 158, and 72 ASES members earned mean annual industry compensation $100,000, respectively. Royalties (91.5%) predominated in the top earning group, compared with consulting fees (58.0%, 55.0%) in the 2 middle-tier groups. H-index and m-index correlated positively with total compensation (h-index: r = 0.18, P $100,000) had higher h-index and m-index scores than either intermediate ($1001-$10,000, $10,001-$100,000) or lowest (

Abstract Background Type 2 diabetes mellitus (T2DM) and its associated complications puts considerable strain on healthcare systems. With the global incidence of T2DM increasing, effective disease management is essential. Physical activity (PA) is a key component of T2DM management; however, rates of PA engagement are low in this population. Developing effective and sustainable interventions that encourage PA is a high priority. Electrically assisted bicycles are becoming increasingly popular and may increase PA in healthy adults. This study aimed to provide evidence of the feasibility of conducting a randomized controlled trial to evaluate the efficacy of an e-cycling intervention to increase PA and improve health in individuals with T2DM. Methods A parallel-group two-arm randomized, waitlist-controlled pilot study was conducted. Individuals were randomized to either an e-bike intervention or standard care. The intervention incorporated two one-to-one e-bike skills training and behavioural counselling sessions delivered by a community-based cycling charity, followed by a 12-week e-bike loan with two further sessions with the instructors. Feasibility was assessed via measures related to recruitment, retention and intervention implementation. Post-intervention interviews with instructors and participants explored the acceptability of the study procedures and intervention. Clinical, physiological and behavioural outcomes were collected at baseline and post-intervention to evaluate the intervention’s potential. Results Forty participants (M age = 57) were randomized, of which 34 were recruited from primary care practices. Thirty-five participants were retained in the trial. The intervention was conducted with high fidelity (> 80% content delivered). E-bike training provided participants with the skills, knowledge and confidence needed to e-bike independently. Instructors reported being more confident delivering the skills training than behavioural counselling, despite acknowledging its importance. The study procedures were found to be acceptable to participants. Between-group differences in change during the intervention were indicative of the interventions potential for improving glucose control, health-related quality of life and cardiorespiratory fitness. Increases in overall device measured moderate-to-vigorous PA behaviour following the intervention were found, and there was evidence that this population self-selected to e-cycle at a moderate intensity. Conclusions The study’s recruitment, retention, acceptability and potential efficacy support the development of a definitive trial subject to identified refinements. Trial registration ISRCTN, ISRCTN67421464 . Registered 17/12/2018.

Abstract Background Many children and adolescents with Type 1 Diabetes Mellitus (T1DM) don’t meet the recommended levels of physical activity. Healthcare professionals (HCPs) have a key role in supporting and encouraging children and adolescents with T1DM to be physically active. This study aims to understand the perspectives of HCPs in relation to supporting physical activity and implementing guidelines relating to physical activity. Methods An online mixed methods survey was circulated to HCPs in pediatric diabetes units in England and Wales. Participants were asked about how they support physical activity in their clinic and their perceptions of barriers/enablers of providing physical activity support to children and adolescents with T1DM. Quantitative data were analysed descriptively. An deductive thematic approach was applied to the free text responses using the Capability Opportunity Motivation model of Behaviour (COM-B) as a framework. Results Responses were received from 114 individuals at 77 different pediatric diabetes units (45% of pediatric diabetes units in England and Wales). HCPs surveyed felt that the promotion of physical activity is important (90%) and advised patients to increase levels of physical activity (88%). 19% of the respondents felt they did not have sufficient knowledge to provide support. HCPs reported limited knowledge and confidence, time and resources as barriers to providing support. They also felt the current guidance was too complicated with few practical solutions. Conclusion Pediatric HCPs need training and support to be able to encourage and support children and adolescents with T1D to be a physical activity. In addition, resources that provide simple and practical advice to manage glucose around exercise are needed.

Abstract Background Immune checkpoint inhibitors (ICI) are associated with immune-mediated adverse effects, potentially involving any organ. ICI has also been associated with an increased risk of cardiovascular disease in cancer populations. Objective To characterize the incidence and risk of major atherosclerotic cardiovascular events associated with ICI use in a high-risk and advanced melanoma population. Methods We conducted a retrospective cohort study of patients with high-risk or advanced melanoma (AJCC stage II, III or IV) presenting to an academic tertiary hospital between 2015–2020. The main outcome was major atherosclerotic cardiovascular events (MACE) including acute myocardial infarction, ischemic stroke, acute limb ischemia and coronary revascularization. Results The study cohort consisted of 646 patients, including 289 who had been treated with ICI. The incidence of MACE was higher in the ICI treated group (3.6 vs. 0.9 events per 100-person years). After adjusting for age, sex, smoking history and prior BRAF and/or MEK inhibitor use, ICI treatment was associated with an increased risk of MACE (HRadj 2.8, 95% CI 1.1–6.9, p = 0.03). Elevated risk was especially pronounced in patients with a past history of MACE (HR 14.4, 95% CI 1.9–112.3, p = 0.01). Conclusion Patients with high-risk or advanced melanoma are at an increased risk of atherosclerotic cardiovascular events following ICI treatment, particularly those with a history of cardiovascular disease.

Abstract Here, we systematically review research on teaching knowledge in the context of undergraduate STEM education, with particular attention to what this research reveals about knowledge that is important for evidence-based teaching. Evidence-based teaching can improve student outcomes in undergraduate STEM education. However, the enactment of promising evidence-based teaching strategies depends greatly on the instructor and potentially on the teaching knowledge they are able to deploy. The review includes an overview of prevalent teaching knowledge theory, including pedagogical content knowledge, mathematical knowledge for teaching, and pedagogical knowledge. We compare and contrast teaching knowledge theory and terminology across STEM disciplines in order to build bridges for researchers across disciplines. Our search for peer-reviewed investigations of teaching knowledge in undergraduate science, engineering and mathematics yielded 45 papers. We examined the theoretical frameworks used in each study and analyzed study approaches, comparing across disciplines. Importantly, we also synthesized findings from research conducted in the context of evidence-based teaching. Overall, teaching knowledge research is sparse and siloed by discipline, and we call for collaborative work and better bridge-building across STEM disciplines. Though disciplinary divergences are common in discipline-based education research, the effect is magnified in this research area because the theoretical frameworks are themselves siloed by discipline. Investigations of declarative knowledge were common, and we call for increased attention to knowledge used in the practice of teaching. Finally, there are not many studies examining teaching knowledge in the context of evidence-based teaching, but the existing work suggests that components of pedagogical content knowledge, pedagogical knowledge, and content knowledge influence the implementation of evidence-based teaching. We describe implications for future teaching knowledge research. We also call on those who develop and test evidence-based strategies and curriculum to consider, from the beginning, the teaching knowledge needed for effective implementation.

ABSTRACT Instructor discourse, defined as verbal interactions with students in the classroom, can play an important role in student learning. Instructors who use dialogic discourse invite students to develop their own ideas, and both students and the instructor share ideas in back-and-forth exchanges. This type of discourse is well-suited to facilitate deep learning for students but is rare in undergraduate biology classrooms. Understanding the reasoning that underlies the use of dialogic discourse can inform teaching professional development for instructors who are learning to use discourse to support student learning. Through classroom video recordings to identify dialogic discourse and stimulated recall interviews to elicit instructor reasoning, we investigated why undergraduate biology instructors used dialogic discourse in active-learning lessons. Using inductive and deductive qualitative analysis of interview transcripts, we identified and characterized seven reasons that instructors used dialogic discourse, including three aligned with a theoretical framework of student cognitive engagement and four that emerged from our data set. In addition to aiming to prompt generative cognitive engagement in 34% of instances of dialogic discourse, instructors used dialogic discourse to prompt activity, supply information, provide feedback, decipher student thinking, leverage student thinking, and cue students to make connections. Reasoning varied across different types of dialogic discourse. These findings provide valuable insights that can inform research, teaching professional development, and individual instructors’ reflections.

Summary: Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that NSP8 engages in strong genetic interactions with several human candidates, most prominently with the ATE1 arginyltransferase to induce actin arginylation and cytoskeletal disorganization, and that two ATE1 inhibitors can reverse NSP8 phenotypes. The DCR enables parallel global-scale functional analysis of SARS-CoV-2 components in a prime genetic model system.

The regulation of the distinct intrinsic phenotypic states in melanoma remain poorly characterised. Here, multi-omics analysis for a panel of 68 early passage melanoma cell lines reveals that cancer cell intrinsic transcriptomic programs are associated with distinct immune features.

Nearly all meltwater from glaciers and ice sheets is routed englacially through moulins. Therefore, the geometry and evolution of moulins has the potential to influence subglacial water pressure variations, ice motion, and the runoff hydrograph delivered to the ocean. We develop the Moulin Shape (MouSh) model, a time-evolving model of moulin geometry. MouSh models ice deformation around a moulin using both viscous and elastic rheologies and melting within the moulin through heat dissipation from turbulent water flow, both above and below the water line. We force MouSh with idealized and realistic surface melt inputs. Our results show that, under realistic surface melt inputs, variations in surface melt change the geometry of a moulin by approximately 10 % daily and over 100 % seasonally. These size variations cause observable differences in moulin water storage capacity and moulin water levels compared to a static, cylindrical moulin. Our results suggest that moulins are important storage reservoirs for meltwater, with storage capacity and water levels varying over multiple timescales. Implementing realistic moulin geometry within subglacial hydrologic models may therefore improve the representation of subglacial pressures, especially over seasonal periods or in regions where overburden pressures are high.

Oscillations in global modes of variability (MoVs) form global teleconnections that affect regional climate variability and modify the potential for severe and damaging weather conditions. Understanding the link between certain MoVs and regional climate can improve the ability to more accurately predict environmental conditions that impact human life and health. In this study, we explore the connection between different MoVs, including the Arctic oscillation (AO), Eurasian teleconnection, Indian Ocean dipole (IOD), North Atlantic oscillation (NAO), and El Niño southern oscillation (Nino34), with winter and summer climates in the High Mountain Asia (HMA) region, including geopotential height at 250 hPa (z250), 2 m air temperature (T2M), total precipitation (PRECTOT), and fractional snow cover area (fSCA). Relationships are explored for the same monthly period between the MoVs and the climate variables, and a lagged correlation analysis is used to investigate whether any relationship exists at different time lags. We find that T2M has a negative correlation with the Eurasian teleconnection in the Inner Tibetan Plateau and central China in both winter and summer and a positive correlation in western China in summer. PRECTOT has a positive correlation with all MoVs in most regions in winter, especially with the IOD, and a negative correlation in summer, especially with the Eurasian teleconnection. Snow cover in winter is positively correlated with most indices throughout many regions in HMA, likely due to wintertime precipitation also being positively correlated with most indices. Generally, the AO and NAO show similar correlation patterns with all climate variables, especially in the winter, possibly due to their oscillations being so similar. Furthermore, the AO and NAO are shown to be less significant in explaining the variation in HMA climate compared to other MoVs such as the Eurasian teleconnection. Overall, our results identify different time windows and specific regions within HMA that exhibit high correlations between climate and MoVs, which might offer additional predictability of the MoVs as well as of climate and weather patterns in HMA and throughout the globe.

Biofilms that colonize on the surface of microplastics (MPs) in freshwaters may pose a potential health risk. This study examined factors that influence MP-associated biofilm growth, including polymer type, degree of weathering, and source water quality. Weathered MPs produced in-lab were employed in biofilm trials conducted on site using a passive flow-through system with raw water at drinking water treatment facility intakes. Adenosine triphosphate (ATP) was used to quantify biofilm abundance; biofilm composition was assessed via metagenomic sequencing. Biofilm growth was observed on all polymer types examined and most prevalent on polyvinyl chloride (PVC), where ATP levels were 6 to 12 times higher when compared to other polymers. Pathogen-containing species including Salmonella enterica and Escherichia coli were present on all polymers with relative abundance up to 13.7%. S. enterica was selectively enriched on weathered MPs in specific water matrices. These findings support the need to research the potential accumulation of pathogenic organisms on microplastic surfaces.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA (P

Abstract Background It is unclear whether diet affects glycaemic control in type 2 diabetes (T2D), over and above its effects on bodyweight. We aimed to assess whether changes in dietary patterns altered glycaemic control independently of effects on bodyweight in newly diagnosed T2D. Methods We used data from 4-day food diaries, HbA1c and potential confounders in participants of the Early-ACTivity-In-Diabetes trial measured at 0, 6 and 12 months. At baseline, a ‘carb/fat balance’ dietary pattern and an ‘obesogenic’ dietary pattern were derived using reduced-rank regression, based on hypothesised nutrient-mediated mechanisms linking dietary intake to glycaemia directly or via obesity. Relationships between 0 and 6 month change in dietary pattern scores and baseline-adjusted HbA1c at 6 months (n = 242; primary outcome) were assessed using multivariable linear regression. Models were repeated for periods 6–12 months and 0–12 months (n = 194 and n = 214 respectively; secondary outcomes). Results Reductions over 0–6 months were observed in mean bodyweight (− 2.3 (95% CI: − 2.7, − 1.8) kg), body mass index (− 0.8 (− 0.9, − 0.6) kg/m2), energy intake (− 788 (− 953, − 624) kJ/day), and HbA1c (− 1.6 (− 2.6, -0.6) mmol/mol). Weight loss strongly associated with lower HbA1c at 0–6 months (β = − 0.70 [95% CI − 0.95, − 0.45] mmol/mol/kg lost). Average fat and carbohydrate intakes changed to be more in-line with UK healthy eating guidelines between 0 and 6 months. Dietary patterns shifting carbohydrate intakes higher and fat intakes lower were characterised by greater consumption of fresh fruit, low-fat milk and boiled/baked potatoes and eating less of higher-fat processed meats, butter/animal fats and red meat. Increases in standardised ‘carb/fat balance’ dietary pattern score associated with improvements in HbA1c at 6 months independent of weight loss (β = − 1.54 [− 2.96, − 0.13] mmol/mol/SD). No evidence of association with HbA1c was found for this dietary pattern at other time-periods. Decreases in ‘obesogenic’ dietary pattern score were associated with weight loss (β = − 0.77 [− 1.31, − 0.23] kg/SD) but not independently with HbA1c during any period. Conclusions Promoting weight loss should remain the primary nutritional strategy for improving glycaemic control in early T2D. However, improving dietary patterns to bring carbohydrate and fat intakes closer to UK guidelines may provide small, additional improvements in glycaemic control. Trial registration ISRCTN92162869 . Retrospectively registered on 25 July 2005

IntroductionCardiorespiratory exercise has emerged as a promising candidate to modify disease progression in Huntington’s disease (HD). In animal models, exercise has been found to alter biomarkers of neuroplasticity and delay evidence of disease, and some interventions–including exercise–have shown benefits in human HD patients. In healthy human populations, increasing evidence suggests that even a single bout of exercise can improve motor learning. In this pilot study, we investigated the effect of a single bout of moderate intensity aerobic exercise on motor skill learning in presymptomatic and early manifest HD patients.MethodsParticipants were allocated to either an exercise (n = 10) or control (n = 10) group. They performed either 20 min of moderate intensity cycling or rest before practicing a novel motor task, the sequential visual isometric pinch force task (SVIPT). After 1 week, the retention of the SVIPT was measured in both groups.ResultsWe found that the exercise group performed significantly better during initial task acquisition. There were no significant differences in offline memory consolidation between groups, but total skill gain across both acquisition and retention sessions was greater in the group who exercised. The better performance of the exercise group was driven by improvements in accuracy, rather than speed.DiscussionWe have shown that a single bout of moderate intensity aerobic exercise can facilitate motor skill learning in people with HD gene-expansion. More research is needed to investigate the underlying neural mechanisms and to further explore the potential for neurocognitive and functional benefits of exercise for people with HD.

Abstract Background STEM instructors who leverage student thinking can positively influence student outcomes and build their own teaching expertise. Leveraging student thinking involves using the substance of student thinking to inform instruction. The ways in which instructors leverage student thinking in undergraduate STEM contexts, and what enables them to do so effectively, remains largely unexplored. We investigated how undergraduate STEM faculty leverage student thinking in their teaching, focusing on faculty who engage students in work during class. Results From analyzing interviews and video of a class lesson for eight undergraduate STEM instructors, we identified a group of instructors who exhibited high levels of leveraging student thinking (high-leveragers) and a group of instructors who exhibited low levels of leveraging student thinking (low-leveragers). High-leveragers behaved as if student thinking was central to their instruction. We saw this in how they accessed student thinking, worked to interpret it, and responded in the moment and after class. High-leveragers spent about twice as much class time getting access to detailed information about student thinking compared to low-leveragers. High-leveragers then altered instructional plans from lesson to lesson and during a lesson based on their interpretation of student thinking. Critically, high-leveragers also drew on much more extensive knowledge of student thinking, a component of pedagogical content knowledge, than did low-leveragers. High-leveragers used knowledge of student thinking to create access to more substantive student thinking, shape real-time interpretations, and inform how and when to respond. In contrast, low-leveragers accessed student thinking less frequently, interpreted student thinking superficially or not at all, and never discussed adjusting the content or problems for the following lesson. Conclusions This study revealed that not all undergraduate STEM instructors who actively engage students in work during class are also leveraging student thinking. In other words, not all student-centered instruction is student-thinking-centered instruction. We discuss possible explanations for why some STEM instructors are leveraging student thinking and others are not. In order to realize the benefits of student-centered instruction for undergraduates, we may need to support undergraduate STEM instructors in learning how to learn from their teaching experiences by leveraging student thinking.

Abstract Huntington’s disease (HD) mouse models suggest that cardiovascular exercise may enhance neuroplasticity and delay disease signs, however, the effects of exercise on neuroplasticity in people with HD are unknown. Using a repeated-measures experimental design, we compared the effects of a single bout of high-intensity exercise, moderate-intensity exercise, or rest, on motor cortex synaptic plasticity in 14 HD CAG-expanded participants (9 premanifest and 5 early manifest) and 20 CAG-healthy control participants, using transcranial magnetic stimulation. Measures of cortico-motor excitability, short-interval intracortical inhibition and intracortical facilitation were obtained before and after a 20-min bout of either high-intensity interval exercise, moderate-intensity continuous exercise, or rest, and again after intermittent theta burst stimulation (iTBS). HD participants showed less inhibition at baseline compared to controls. Whereas the control group showed increased excitability and facilitation following high-intensity exercise and iTBS, the HD group showed no differences in neuroplasticity responses following either exercise intensity or rest, with follow-up Bayesian analyses providing consistent evidence that these effects were absent in the HD group. These findings indicate that exercise-induced synaptic plasticity mechanisms in response to acute exercise may be attenuated in HD, and demonstrate the need for future research to further investigate exercise and plasticity mechanisms in people with HD.

Unprecedented economic growth in China has created a new market potential for high-quality foods in the global food industry. This has led several studies to investigate consumer preferences for food safety and quality attributes in the retail market. However, there are limited studies related to the food service sector, specifically to combine these two concepts. Therefore, this study was conducted to investigate these preferences from the perspectives of both the customers and restaurant managers in relation to ducks in the Chinese food service sector. This involved estimating the willingness-to-pays for quality and safety attributes such as branding, premium quality, safety certification, and the biotech country of origin, including the United States, the European Union, and China using regression analysis. The empirical results showed that Chinese consumers and restaurant owners/managers have a similar preference for branded, high quality, and safe domestic products. However, their relative preferences for these attributes are not identical, as indicated by the consumers' highest preference for safety certification, while managers mostly focus on the quality. These findings are expected to provide more information on the market preferences for food produced in emerging Asian economies with special diet cultures and traditions.

Although iron is an essential nutrient for humans, as well as for almost all other organisms, it is poorly absorbed (~15%) from the diet such that most passes through the upper gut into the large intestine. The colonic microbiota is thus exposed to, and potentially influenced by, such residual iron which could have an impact on human health. The aim of the research described here is to determine how the major forms of dietary iron (inorganic iron and haem) influence metabolic activity and composition of the human gut microbiota by utilizing an in vitro parallel, pH-controlled anaerobic batch culture approach. Controlled iron provision was enabled by the design of a ‘modified’ low-iron gut-model medium whereby background iron content was reduced from 28 to 5 μM. Thus, the impact of both low and high levels of inorganic and haem iron (18–180 μM and 7.7–77 μM, respectively) could be explored. Gut-microbiota composition was determined using next generation sequencing (NGS) based community profiling (16S rRNA gene sequencing) and flow-fluorescent in situ hybridization (FISH). Metabolic-end products (organic acids) were quantified using gas chromatography (GC) and iron incorporation was estimated by inductively coupled plasma optical emission spectroscopy (ICP-OES). Results showed that differences in iron regime induced significant changes in microbiota composition when low (0.1% w/v) fecal inoculation levels were employed. An increase in haem levels from 7.7 to 77 μM (standard levels employed in gut culture studies) resulted in reduced microbial diversity, a significant increase in Enterobacteriaceae and lower short chain fatty acid (SCFA) production. These effects were countered when 18 μM inorganic iron was also included into the growth medium. The results therefore suggest that high-dietary haem may have a detrimental effect on health since the resulting changes in microbiota composition and SCFA production are indicators of an unhealthy gut. The results also demonstrate that employing a low inoculum together with a low-iron gut-model medium facilitated in vitro investigation of the relationship between iron and the gut microbiota.

Abstract Objectives Despite the success of immune checkpoint blockade, most metastatic melanoma patients fail to respond to therapy or experience severe toxicity. Assessment of biomarkers and immunophenotypes before or early into treatment will help to understand favourable responses and improve therapeutic outcomes. Methods We present a high‐dimensional approach for blood T‐cell profiling using three multi‐parameter cytometry panels: (1) a TruCount panel for absolute cell counts, (2) a 27‐colour spectral panel assessing T‐cell markers and (3) a 20‐colour spectral panel evaluating intracellular cytokine expression. Pre‐treatment blood mononuclear cells from patients and healthy controls were cryopreserved before staining across 11 batches. Batch effects were tracked using a single‐donor control and the suitability of normalisation was assessed. The data were analysed using manual gating and high‐dimensional strategies. Results Batch‐to‐batch variation was minimal, as demonstrated by the dimensionality reduction of batch‐control samples, and normalisation did not improve manual or high‐dimensional analysis. Application of the workflow demonstrated the capacity of the panels and showed that patients had fewer lymphocytes than controls (P = 0.0027), due to lower naive CD4+ (P = 0.015) and CD8+ (P = 0.011) T cells and follicular helper T cells (P = 0.00076). Patients showed trends for higher proportions of Ki67 and IL‐2‐expressing cells within CD4+ and CD8+ memory subsets, and increased CD57 and EOMES expression within TCRγδ+ T cells. Conclusion Our optimised high‐parameter spectral cytometry approach provided in‐depth profiling of blood T cells and found differences in patient immunophenotype at baseline. The robustness of our workflow, as demonstrated by minimal batch effects, makes this approach highly suitable for the longitudinal evaluation of immunotherapy effects.

Iron deficiency is the most prevalent human micronutrient deficiency, disrupting the physiological development of millions of infants and children. Oral iron supplementation is used to address iron-deficiency anemia and reduce associated stunting but can promote infection risk since restriction of iron availability serves as an innate immune mechanism against invading pathogens. Raised iron availability is associated with an increase in enteric pathogens, especially Enterobacteriaceae species, accompanied by reductions in beneficial bacteria such as Bifidobacteria and lactobacilli and may skew the pattern of gut microbiota development. Since the gut microbiota is the primary driver of immune development, deviations from normal patterns of bacterial succession in early life can have long-term implications for immune functionality. There is a paucity of knowledge regarding how both iron deficiency and luminal iron availability affect gut microbiota development, or the subsequent impact on immunity, which are likely to be contributors to the increased risk of infection. Piglets are naturally iron deficient. This is largely due to their low iron endowments at birth (primarily due to large litter sizes), and their rapid growth combined with the low iron levels in sow milk. Thus, piglets consistently become iron deficient within days of birth which rapidly progresses to anemia in the absence of iron supplementation. Moreover, like humans, pigs are omnivorous and share many characteristics of human gut physiology, microbiota and immunity. In addition, their precocial nature permits early maternal separation, individual housing, and tight control of nutritional intake. Here, we highlight the advantages of piglets as valuable and highly relevant models for human infants in promoting understanding of how early iron status impacts physiological development. We also indicate how piglets offer potential to unravel the complexities of microbiota-immune responses during iron deficiency and in response to iron supplementation, and the link between these and increased risk of infectious disease.

Abstract Background Type 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the ‘intermediate’ range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D. Methods We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model. Results The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified ‘high-risk’ with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44–47 mmol/mol [6.2–6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39–41 mmol/mol (5.7–5.9%) and 7.0% (5.4, 8.6%) for 42–43 mmol/mol (6.0–6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7–6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%). Conclusions A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D.

ABSTRACT: Objectives: ST11 is a high-risk sequence type associated with carbapenem-resistant Klebsiella pneumoniae strains. Carbapenemase-producing hypervirulent K. pneumoniae (hvKp) are a major concern as they harbour a diverse range of pathogenicity traits. Here we describe the characteristics of K. pneumoniae strain KP75w isolated from a tertiary-care hospital in Pakistan. Methods: Antimicrobial susceptibility testing was performed by the Kirby–Bauer disk diffusion test and broth microdilution assay. The virulence phenotype was determined by string test as well as biofilm and cell adhesion assays. Genome sequencing was performed using MiSeq and HiSeq 2500 platforms with 30 × coverage. Results: Antimicrobial resistance profiling characterised strain KP75w as a multidrug-resistant carbapenemase-producing strain with a meropenem minimum inhibitory concentration (MIC) of 4 μg/mL, which is above the CLSI susceptible breakpoint (≤1 μg/mL). The annotated contigs indicated a genome size of 5 644 609 bp with 5679 coding regions. KP75w (ST11) was designated as a carbapenemase-producing hvKp strain on the basis of the presence of a carbapenemase gene (blaNDM-1) and hypervirulence genes (rmpA2, iucABCD–iutA, fyuA, irp, mrk, ybt, fep and virB2). KP75w was found to contain a 163-kb virulence region showing 58.8% identity to the large virulence plasmid pLVPK, supporting the hypervirulence of KP75w. Conclusion: KP75w is a novel non-hypermucoviscous carbapenemase-producing hvKp ST11 strain that appears to represent the convergence of multidrug resistance with hypervirulence traits in clinical K. pneumoniae strains from the Southeast Asian region.

A leading hypothesis for the mechanism of fast supraglacial lake drainages is that transient extensional stresses briefly allow crevassing in otherwise compressional ice flow regimes. Lake water can then hydrofracture a crevasse to the base of the ice sheet, and river inputs can maintain this connection as a moulin. If future ice sheet models are to accurately represent moulins, we must understand their formation processes, timescales, and locations. Here, we use remote-sensing velocity products to constrain the relationship between strain rates and lake drainages across ∼ 1600 km2 in Pâkitsoq, western Greenland, between 2002–2019. We find significantly more extensional background strain rates at moulins associated with fast-draining lakes than at slow-draining or non-draining lake moulins. We test whether moulins in more extensional background settings drain their lakes earlier, but we find insignificant correlation. To investigate the frequency at which strain-rate transients are associated with fast lake drainage, we examined Landsat-derived strain rates over 16 and 32 d periods at moulins associated with 240 fast-lake-drainage events over 18 years. A low signal-to-noise ratio, the presence of water, and the multi-week repeat cycle obscured any resolution of the hypothesized transient strain rates. Our results support the hypothesis that transient strain rates drive fast lake drainages. However, the current generation of ice sheet velocity products, even when stacked across hundreds of fast lake drainages, cannot resolve these transients. Thus, observational progress in understanding lake drainage initiation will rely on field-based tools such as GPS networks and photogrammetry.

Abstract Abnormal postprandial suppression of glucagon in Type 2 diabetes (T2DM) has been attributed to impaired insulin secretion. Prior work suggests that insulin and glucagon show an inverse coordinated relationship. However, dysregulation of α‐cell function in prediabetes occurs early and independently of changes in β‐cells, which suggests insulin having a less significant role on glucagon control. We therefore, sought to examine whether hepatic vein hormone concentrations provide evidence to further support the modulation of glucagon secretion by insulin. As part of a series of experiments to measure the effect of diabetes‐associated genetic variation in TCF7L2 on islet cell function, hepatic vein insulin and glucagon concentrations were measured at 2‐minute intervals during fasting and a hyperglycemic clamp. The experiment was performed on 29 nondiabetic subjects (age = 46 ± 2 years, BMI 28 ± 1 Kg/m2) and enabled post‐hoc analysis, using Cross‐Correlation and Cross‐Approximate Entropy (Cross‐ApEn) to evaluate the interaction of insulin and glucose. Mean insulin concentrations rose from fasting (33 ± 4 vs. 146 ± 12 pmol/L, p

Partial tetrasomy of distal 13q has a reported association with a variable phenotype including microphthalmia, ear abnormalities, hypotelorism, facial dysmorphisms, urogenital defects, pigmentation and skin defects, and severe learning difficulties. A wide range of mosaicism has been reported, which may, to some extent, account for the variable spectrum of observed phenotypes. We report here a pregnancy conceived using intrauterine insemination in a 32-year-old female with a history of infertility. Non-invasive prenatal screening (NIPS) was performed in the first trimester which reported an increased risk for trisomy 13. Follow-up cytogenetic workup using chorionic villus sampling (CVS) and amniotic fluid samples showed a mosaic karyotype with a small supernumerary marker chromosome (sSMC). Chromosomal microarray analysis (CMA) identified a mosaic 31.34 Mb terminal gain on chr13q31.1q34 showing the likely origin of the sSMC to distal chromosome 13q. Follow-up metaphase FISH testing suggested an inverted duplication rearrangement involving 13q31q34 in the marker chromosome and the presence of a neocentromere. At 21 months of age, the proband has a history of gross motor delay, hypotonia, left microphthalmia, strabismus, congenital anomaly of the right optic nerve, hemangiomas, and a tethered spinal cord. Postnatal chromosome analyses in buccal, peripheral blood, and spinal cord ligament tissues were consistent with the previous amniocentesis and CVS findings, and the degree of mosaicism varied from 25 to 80%. It is often challenging to pinpoint the chromosomal identity of sSMCs using banding cytogenetics. A combination of low-pass genome sequencing of cell-free DNA, chromosomal microarray, and FISH enabled the identification of the precise chromosomal rearrangement in this patient. This study adds to the growing list of clinically identified neocentric marker chromosomes and is the first described instance of partial tetrasomy 13q31q34 identified in a mosaic state prenatally. Since NIPS is now being routinely performed along with invasive testing for advanced maternal age, an increased prenatal detection rate for mosaic sSMCs in otherwise normal pregnancies is expected. Future studies investigating how neocentromeres mediate gene expression changes could help identify potential epigenetic targets as treatment options to rescue or reverse the phenotypes seen in patients with congenital neocentromeres.

Introduction Tuberculosis (TB) caused by Mycobacterium tuberculosis is a common infectious disease associated with significant morbidity and mortality, especially in low-income and middle-income countries. Successful treatment of the disease requires prolonged intake (6–8 months) of multiple antibiotics with potentially detrimental consequences on the composition and functional potential of the human microbiome. The protocol described in the current study aims to identify microbiome (oral and gut) signatures associated with TB pathogenesis, treatment response and outcome in humans.Methods and analysis Four hundred and fifty, newly diagnosed patients with TB from three district levels (Peshawar, Mardan and Swat) TB diagnosis and treatment centres, will be recruited in this non-interventional, prospective cohort study and will be followed and monitored until treatment completion. Demographic and dietary intake data, anthropometric measurement and blood, stool and salivary rinse samples will be collected at baseline, day 15, month-2 and end of the treatment. Additionally, we will recruit age (±3 years) and sex-matched healthy controls (n=30). Blood sampling will allow monitoring of the immune response during the treatment, while salivary rinse and faecal samples will allow monitoring of dynamic changes in oral and gut microbiome diversity. Within this prospective cohort study, a nested case–control study design will be conducted to assess perturbations in oral and gut microbiome diversity (microbial dysbiosis) and immune response and compare between the patients groups (treatment success vs failure).Ethics and dissemination The study has received ethics approval from the Ethic Board of Khyber Medical University Peshawar, and administrative approval from Provincial TB Control Programme of Khyber Pakhtunkhwa, Pakistan. The study results will be presented in national and international conferences and published in peer-reviewed journals.Trial registration number NCT04985994.

Fully understanding how glaciers respond to environmental change will require new methods to help us identify the onset of ice acceleration events and observe how dynamic signals propagate within glaciers. In particular, observations of ice dynamics on seasonal timescales may offer insights into how a glacier interacts with various forcing mechanisms throughout the year. The task of generating continuous ice velocity time series that resolve seasonal variability is made difficult by a spotty satellite record that contains no optical observations during dark, polar winters. Furthermore, velocities obtained by feature tracking are marked by high noise when image pairs are separated by short time intervals and contain no direct insights into variability that occurs between images separated by long time intervals. In this paper, we describe a method of analyzing optical- or radar-derived feature-tracked velocities to characterize the magnitude and timing of seasonal ice dynamic variability. Our method is agnostic to data gaps and is able to recover decadal average winter velocities regardless of the availability of direct observations during winter. Using characteristic image acquisition times and error distributions from Antarctic image pairs in the ITS_LIVE dataset, we generate synthetic ice velocity time series, then apply our method to recover imposed magnitudes of seasonal variability within ±1.4 m yr−1. We then validate the techniques by comparing our results to GPS data collected on Russell Glacier in Greenland. The methods presented here may be applied to better understand how ice dynamic signals propagate on seasonal timescales and what mechanisms control the flow of the world’s ice.

Background: Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) and globus pallidus interna (GPi) is an effective treatment for cardinal motor symptoms and motor complications in Parkinson’s Disease (PD). However, malpositioned DBS electrodes can result in suboptimal therapeutic response. Objective: We explored whether recovery of the H-reflex—an easily measured electrophysiological analogue of the stretch reflex, known to be altered in PD—could serve as an adjunct biomarker of suboptimal versus optimal electrode position during STN- or GPi-DBS implantation. Methods: Changes in soleus H-reflex recovery were investigated intraoperatively throughout awake DBS target refinement across 26 nuclei (14 STN). H-reflex recovery was evaluated during microelectrode recording (MER) and macrostimulation at multiple locations within and outside target nuclei, at varying stimulus intensities. Results: Following MER, H-reflex recovery normalized (i.e., became less Parkinsonian) in 21/26 nuclei, and correlated with on-table motor improvement consistent with an insertional effect. During macrostimulation, H-reflex recovery was maximally normalized in 23/26 nuclei when current was applied at the location within the nucleus producing optimal motor benefit. At these optimal sites, H-reflex normalization was greatest at stimulation intensities generating maximum motor benefit free of stimulation-induced side effects, with subthreshold or suprathreshold intensities generating less dramatic normalization. Conclusion: H-reflex recovery is modulated by stimulation of the STN or GPi in patients with PD and varies depending on the location and intensity of stimulation within the target nucleus. H-reflex recovery shows potential as an easily-measured, objective, patient-specific, adjunct biomarker of suboptimal versus optimal electrode position during DBS surgery for PD.

Purpose – The purpose of this paper is to examine the effects of procedural justice, training opportunities and innovation on job satisfaction and affiliation commitment via the mediating effect of organizational identification. The authors also explored the moderating role of satisfaction with supervisor on the relationship between the antecedents and organizational identification as well as its moderating effect on the mediational chain. Design/methodology/approach – The authors used structural equation modeling techniques, using MPLUS 7.4, to analyze data collected from 247 full-time employees who were recruited by undergraduate students attending a private university in the Southeast region of the USA. Findings – Results demonstrated that the indirect effects for procedural justice and training opportunities as predictors were significant, while none of the paths for innovation as a predictor were significant. Satisfaction with supervisor moderated the relationships between procedural justice and organizational identification and innovation and organizational identification. Originality/value – This research expands the nomological network concerning antecedents and consequences of organizational identification. It also explores the role of satisfaction with one’s supervisor, as this can affect identification with the organization. This research provides support for the notion that stronger employee–organization relationships lead to positive individual and organizational outcomes.

Each summer, large volumes of surface meltwater drain off the Greenland ice sheet (GrIS) surface through moulins to the bed, impacting subglacial hydrology and ice flow dynamics. Supraglacial surface routing delays may propagate to englacial and subglacial hydrologic systems, requiring accurate assessment to correctly estimate subglacial effective pressures. We compare hourly supraglacial moulin discharge simulations from three surface meltwater routing models – the synthetic unit hydrograph (SUH), the bare-ice component of surface routing and lake filling (SRLF), and the rescaled width function (RWF) – for four internally drained catchments on the southwestern Greenland ice sheet surface. The routing models are forced identically using surface runoff from the Modèle Atmosphérique Régionale regional climate model (RCM). For each catchment, simulated moulin hydrographs are input to the SHAKTI subglacial hydrologic model to simulate diurnally varying subglacial effective-pressure variations in the vicinity of a single moulin. Overall, all three routing models produce more realistic moulin discharges than simply using RCM runoff outputs without surface routing but produce significant differences in peak moulin discharge and time to peak. In particular, the RWF yields later, smaller peak moulin discharges than the SUH or SRLF due to its representation of slow interfluve flow between supraglacial meltwater channels, and it can readily accommodate the seasonal evolution of supraglacial stream and river networks. Differences among the three routing models are reflected in a series of simple idealized subglacial hydrology simulations that yield different diurnal effective-pressure amplitudes; however, the supraglacial hydrologic system acts as short-term storage for surface meltwater, and the temporal mean effective pressure is relatively consistent across routing models.

Immunotherapies now dominate the treatment landscape for melanoma, but why they only work in a subset of patients remains unclear. Here, the authors perform an immunogenomic analysis on 67 intratumor sub-regions of a PD-1 inhibitor resistant melanoma, and 2 additional metastases from a single patient, mapping the spatial relationships between genomic and immune heterogeneity at high resolution.