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Laccases from white-rot fungi catalyze lignin depolymerization, a critical first step to upgrading lignin to valuable biodiesel fuels and chemicals. In this study, a wildtype laccase from the basidiomycete Fomitiporia mediterranea (Fom_lac) and a variant engineered to have a carbohydrate-binding module (Fom_CBM) were studied for their ability to catalyze cleavage of β-O-4 ether and C-C bonds in phenolic and non-phenolic lignin dimers using a nanostructure-initiator mass spectrometry-based assay. Fom_lac and Fom_CBM catalyze β-O-4 ether and C-C bond breaking, with higher activity under acidic conditions (pH < 6). The potential of Fom_lac and Fom_CBM to enhance saccharification yields from untreated and ionic liquid pretreated pine was also investigated. Adding Fom_CBM to mixtures of cellulases and hemicellulases improved sugar yields by 140% on untreated pine and 32% on cholinium lysinate pretreated pine when compared to the inclusion of Fom_lac to the same mixtures. Adding either Fom_lac or Fom_CBM to mixtures of cellulases and hemicellulases effectively accelerates enzymatic hydrolysis, demonstrating its potential applications for lignocellulose valorization. We postulate that additional increases in sugar yields for the Fom_CBM enzyme mixtures were due to Fom_CBM being brought more proximal to lignin through binding to either cellulose or lignin itself.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Abstract Perceptual learning refers to any change in discrimination abilities as a result of practice, a fundamental process that improves the organism’s response to the external environment. Visual perceptual learning (vPL) is supposed to rely on functional rearrangements in brain circuity occurring at early stages of sensory processing, with a pivotal role for the primary visual cortex (V1). However, top-down inputs from higher-order visual areas (HVAs) have been suggested to play a key part in vPL, conveying information on attention, expectation and the precise nature of the perceptual task. A direct assessment of the possibility to modulate vPL by manipulating top-down activity in awake subjects is still missing. Here, we used a combination of chemogenetics, behavioral analysis and multichannel electrophysiological assessments to show a critical role in vPL acquisition and retention for neuronal activity in the latero-medial secondary visual cortex (LM), the prime source for top-down feedback projections reentering V1.

Abstract Introduction Three randomised controlled trials (RCTs) have demonstrated that first-line cryoballoon pulmonary vein isolation decreases atrial tachycardia in patients with symptomatic paroxysmal atrial fibrillation (PAF) compared with antiarrhythmic drugs (AADs). The aim of this study was to develop a cost-effectiveness model (CEM) for first-line cryoablation compared with first-line AADs for the treatment of PAF. The model used a Danish healthcare perspective. Methods Individual patient-level data from the Cryo-FIRST, STOP AF and EARLY-AF RCTs were used to parameterise the CEM. The model structure consisted of a hybrid decision tree (one-year time horizon) and a Markov model (40-year time horizon, with a three-month cycle length). Health-related quality of life was expressed in quality-adjusted life years (QALYs). Costs and benefits were discounted at 3% per year. Model outcomes were produced using probabilistic sensitivity analysis. Results First-line cryoablation is dominant, meaning it results in lower costs (-€2,663) and more QALYs (0.18) when compared to first-line AADs. First-line cryoablation also has a 99.96% probability of being cost-effective, at a cost-effectiveness threshold of €23,200 per QALY gained. Regardless of initial treatment, patients were expected to receive ∼ 1.2 ablation procedures over a lifetime horizon. Conclusion First-line cryoablation is both more effective and less costly (i.e. dominant), when compared with AADs for patients with symptomatic PAF in a Danish healthcare system.

Abstract Background Vaccination has been recommended as one of the most potent ways of controlling the mpox (formerly, monkeypox) outbreak, particularly among high-risk groups. Here, we evaluated the prevalence of mpox vaccine acceptance and uptake globally. Methods We searched multiple databases for peer-reviewed studies published in English from May 2022 to 25th November 2023 that evaluated mpox vaccine acceptance and/or uptake. We fit a random-effects model meta-analysis to calculate the pooled mpox vaccine acceptance and uptake rates, with their 95% confidence intervals (CI) across population outcomes. We performed subgroup analyses among the six World Health Organization (WHO) regions (Africa [AFR], Region of the Americas [AMR], South-East Asia Region [SEAR], European Region [EUR], Eastern Mediterranean Region [EMR], and the Western Pacific Region [WPR]), as well as among select population subgroups. Results Of the 2531 studies screened, 61 studies, with a cumulative sample size of 263,857 participants from 87 countries were eligible for inclusion. The overall vaccine acceptance and uptake rates were 59.7% and 30.9% globally. Acceptance and uptake rates among the LGBTQI+ community were 73.6% vs 39.8% globally, 60.9% vs. 37.1% in AMR, 80.9% vs. 50.0% in EUR, and 75.2% vs. 33.5% in WPR. Among PLHIV, vaccine acceptance and uptake rates were 66.4% vs. 35.7% globally, 64.0% vs. 33.9% in AMR, 65.1% vs. 27.0% in EUR, and 69.5% vs. 46.6% in WPR. Among healthcare workers, vaccination intention was 51.0% globally. Conclusions Tailored interventions are needed to bolster confidence in the mpox vaccine, maximize vaccine uptake, and increase vaccine access to close the gaps between acceptance and uptake especially among key populations residing in regions with low rates of acceptance and uptake.

Objectives. The identity of the place has an effect on citizens’ identities. The study presented aims to support the connection between slow violence, environmental injustice, and the use of visual sociology to deepen the experiences and relations of people in the surrounding environment. The target is a neighborhood called Tamburi in the city of Taranto, Apulia. Methods. After an initial focus group useful to know more about the context, 8 people residing in the target area took photos to understand how the environmental damage has slowly settled on every aspect of life in the neighborhood and to explore concepts like social memories, and socio-semiotic category. The contribution of a non-residing photojournalist was analyzed, in order to improve and complete observation techniques. Results. Tamburi, literally incorporated by the industry, is a place with a complex identity to the detriment of social life and the new generations’ well-being, accompanied by a correlated social and cultural unease as well as a feeling of abandonment and vindication. It is identified as a sacrifice area due to the high rate of pollutants in circulation, premature deaths, and contamination of the urban and vegetable elements present. Conclusions. Living in territories vulnerable to sacrifice translates into considering the existences therein underestimated. The visual method offers interesting insights into the possibilities of interpreting some phenomena. The images of the neighborhood are a negative stimulus that communicates feelings of fragility in the individual and collective memory and has an impact on the livability and attractiveness of places.

Abstract Background Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. Methods Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13–18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. Results The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. Conclusion Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

RIT1 is a RAS guanosine triphosphatase (GTPase) that regulates different aspects of signal transduction and is mutated in lung cancer, leukemia, and in the germline of individuals with Noonan syndrome. Pathogenic RIT1 proteins promote mitogen-activated protein kinase (MAPK) hyperactivation; however, this mechanism remains poorly understood. Here, we show that RAF kinases are direct effectors of membrane-bound mutant RIT1 necessary for MAPK activation. We identify critical residues in RIT1 that facilitate interaction with membrane lipids and show that these are necessary for association with RAF kinases and MAPK activation. Although mutant RIT1 binds to RAF kinases directly, it fails to activate MAPK signaling in the absence of classical RAS proteins. Consistent with aberrant RAF/MAPK activation as a driver of disease, we show that pathway inhibition alleviates cardiac hypertrophy in a mouse model of RIT1 mutant Noonan syndrome. These data shed light on the function of pathogenic RIT1 and identify avenues for therapeutic intervention.

Sprouty-related EVH-1 domain-containing (SPRED) proteins are a family of proteins that negatively regulate the RAS-Mitogen-Activated Protein Kinase (MAPK) pathway, which is involved in the regulation of the mitogenic response and cell proliferation. However, the mechanism by which these proteins affect RAS-MAPK signaling has not been elucidated. Patients with mutations in SPRED give rise to unique disease phenotypes; thus, we hypothesized that distinct interactions across SPRED proteins may account for alternative nodes of regulation. To characterize the SPRED interactome and evaluate how members of the SPRED family function through unique binding partners, we performed affinity purification mass spectrometry. We identified 90-kDa ribosomal S6 kinase 2 (RSK2) as a specific interactor of SPRED2 but not SPRED1 or SPRED3. We identified that the N-terminal kinase domain of RSK2 mediates the interaction between amino acids 123 to 201 of SPRED2. Using X-ray crystallography, we determined the structure of the SPRED2-RSK2 complex and identified the SPRED2 motif, F145A, as critical for interaction. We found that the formation of this interaction is regulated by MAPK signaling events. We also find that this interaction between SPRED2 and RSK2 has functional consequences, whereby the knockdown of SPRED2 resulted in increased phosphorylation of RSK substrates, YB1 and CREB. Furthermore, SPRED2 knockdown hindered phospho-RSK membrane and nuclear subcellular localization. We report that disruption of the SPRED2-RSK complex has effects on RAS-MAPK signaling dynamics. Our analysis reveals that members of the SPRED family have unique protein binding partners and describes the molecular and functional determinants of SPRED2-RSK2 complex dynamics.

In response to the increased prevalence of remote learning, and exhortation that educators adopt more experiential pedagogy, a methodology is presented to use a free, commercially available game to teach a variety of resource allocation problems in various disciplines. The use of games to provide experiential learning has been shown to increase student enjoyment and mastery of learning outcomes. The technique is appropriate for students at different levels from secondary school through graduate-level university instruction. The lack of cost to the student or university coupled with the ease of adaptability of the game makes the technique widely available to all instructors in both traditional classrooms and distance education settings.

Assessment of major browse feed resources and determine the chemical composition of selected browse feed resource in Korahay Zone, Somali Regional State, was the aim of this study. Kebeles and the household heads were selected purposively in study area. The samples of fresh leaves (800 g) of selected browse species were collected to determine chemical compositions. SPSS version 20 was used for data analysis. The feed related constraints were ranked and analyzed by the ranking index. The current result indicated that, total of 22 trees, 6 shrub, 4 bush and 6 herbaceous species used as feed for livestock in dry and/or wet season were identified in the study area. DM, OM, CP, NDF, ADF, ADL and Ash of Dobera glabra, Grewia bicolor, Boscia minimfolia, Prosopis juliflora, Acacia Senegal, Unidentified (Alankhayir), Unidentified (Geed chic) were determined in current laboratory analysis. DM, OM, CP, NDF, ADF, ADL and Ash of Dobera glabra was 92.8 %, 94.28 %, 14.4 %, 42.5 %, 26.9 %, 5.22 % and 5.73 % respectively. Finally, feed quality and quantity, drought, invasive species and ecological deterioration were identified as major constraints of feed resources in study area. Due to this, intervention and further study should be conducted to tackle existing feed and feed related issues.

Ensuring data security is an essential priority to be put forward once there will be a digital transmission between any two or more targeted audience. Hence, the objective of this paper was to propose a better data security model for a protective information exchange on the internet with steganographic and cryptographic algorithms. Three cryptographic symmetric key encryption algorithm (RC6, Rijndael and TwoFish) and four steganographic carrier object (Image, audio, text and video) were considered. Data obtained show that Rijndael (AES) takes less encipherment and decipherment time compare to RC6 and TwoFish in cryptographic symmetric key encryption algorithm, while image carrier achieves better Peak-Signal-to-Noise Ratio if related to audio, video and text steganography. This research suggests the use of Advanced Encryption Standard and image steganography for efficient information interchange on the internet.

Objective Cryoballoon ablation for pulmonary vein isolation is a time-efficient procedure that can alleviate stress on electrophysiology lab resources. This analysis modeled the impact of cryoballoon ablation on electrophysiology lab operation using data from Latin America. Methods Data from centers in Argentina, Mexico, Colombia, and Chile of the Cryo Global Registry were used as inputs for an electrophysiology lab efficiency simulation model. The model used the assumption that either two (today’s electrophysiology lab operations) or three (including electrophysiology lab operational changes) cryoballoon ablation procedures could be performed per day. The endpoints were the percentage of days that resulted in 1) overtime and 2) time left for an extra non-ablation electrophysiology procedure. Results Data from a total of 232 procedures from six Latin American centers were included in the analysis. The average electrophysiology lab occupancy time for all procedures in Latin America was 132 ± 62 minutes. In the Current Scenario (two procedures per day), 7.4% of simulated days resulted in overtime, and 81.4% had enough time for an extra electrophysiology procedure. In the Enhanced Productivity Scenario (three procedures per day), 16.4% of days used overtime, while 67.4% allowed time for an extra non-ablation electrophysiology procedure. Conclusions Using real-world, Latin American-specific data, we found that with operational changes, three ablation procedures could feasibly be performed daily, leaving time for an extra electrophysiology procedure on more than half of days. Thus, use of cryoballoon ablation is an effective tool to enhance electrophysiology lab efficiency in resource-constrained regions such as Latin America.

Strategies to mobilise natural killer (NK) cells against cancer include tumour-targeting antibodies, NK cell engagers (NKCEs) and the adoptive transfer of ex vivo expanded healthy donor-derived NK cells. Genetic and functional studies have revealed that expression of the activating killer immunoglobulin-like receptor KIR2DS2 is associated with enhanced function in NK cells from healthy donors and improved outcome in several different malignancies. The optimal strategy to leverage KIR2DS2+ NK cells therapeutically is however currently unclear. In this study, we therefore evaluated the response of KIR2DS2-expressing NK cells to activation against cancer with clinically relevant tumour-targeting antibodies and following ex vivo expansion. We identified that KIR2DS2high NK cells from patients with chronic lymphocytic leukaemia and hepatocellular carcinoma had enhanced activation in response to tumour-targeting antibodies compared to KIR2DS2- NK cells. However, the superior function of healthy donor derived KIR2DS2high NK cells was lost following ex vivo expansion which is required for adoptive transfer-based therapeutic strategies. These data provide evidence that targeting KIR2DS2 directly in cancer patients may allow for the utilisation of their enhanced effector function, however such activity may be lost following their ex vivo expansion.

Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). Here, we show that eight different ERKi (both catERKi or dmERKi) drive the turnover of ERK2, the most abundant ERK isoform, with little or no effect on ERK1. Thermal stability assays show that ERKi do not destabilise ERK2 (or ERK1) in vitro, suggesting that ERK2 turnover is a cellular consequence of ERKi binding. ERK2 turnover is not observed upon treatment with MEKi alone, suggesting it is ERKi binding to ERK2 that drives ERK2 turnover. However, MEKi pre-treatment, which blocks ERK2 pT-E-pY phosphorylation and dissociation from MEK1/2, prevents ERK2 turnover. ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. Our results suggest that ERKi, including current clinical candidates, act as 'kinase degraders', driving the proteasome-dependent turnover of their major target, ERK2. This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi.

A survey of the malaria vectors in an area is a critical component of an effective vector control strategy. This study aimed to investigate the malaria vectors in four communities of Southern Gombe, Northeastern Nigeria. A total of 3200 adult female Anopheles reared from larvae in the four communities from two Local Government Areas (LGAs) in Southern Gombe were identified. Anopheles pretoriensis were dominant 1662 (51.9%) followed by An. gambiae sl 868(27.1%), An. maculipalpis 267(8.3), An. rufipes 252(7.9) and An. coustani 10(0.3%), and the least were An. pharoensis 6(0.2%). The remaining 135(4.3%) were unidentified. Of the 262 An. gambiae sl identified by species-specific PCR method, 135(51.5%) were found to be An. coluzzi, 60(22.9%) An. gambiae and only 1(0.4%) was An. arabiensis whereas hybrid constitutes 16(6.1%). To determine significant differences in species composition, the results from the four study sites were pooled together. Anopheles pretoriensis was significantly different from all the other species identified (p = 0.9999). There was a significant difference between the number of species identified as An. coluzzi and An. arabiensis (p = 0.0025). But there was no significant difference between An. coluzzi and An. gambiae (p = 0.1212). The heterogeneity and sympatry of Anopheles species observed is a threat to malaria control as the secondary vectors have behaviour that evades the current vector control interventions. It is expedient to re-strategize the vector control interventions in the study area.

Livestock plays a significant role in the livelihood enhancement of the people, especially in rural areas. The requirement for dietary protein for people from the animal sources is expected to increase. However, due to problems of feed shortages and high costs of feed the livestock sector and its contribution to the country’s economy are threatened in many countries. To address this problem, exploration of alternative sources of cheap feed resources is imperative. Azolla is one of the cheapest feed resources grown in water bodies, mainly in tropical and sub-tropical countries. There are various species of Azolla used as a feed source for livestock. Azolla filiculoides, Azolla pinnata and Azolla microphylla are the main species of Azolla that contribute to livestock feed. Nutritionally, Azolla is a good source of amino acids, minerals, and vitamins. It is commonly used for feeding poultry, sheep, and goats, and dairy cattle. Azolla is used as a supplementary feed with other feed resources to increase feed intake, growth, egg production, and milk yield, as proven by many researches. Besides animal feeding, Azolla is also used for soil fertility improvement, bioremediation, compost making, and biogas production. Therefore, the production and utilization of Azolla in an appropriate, way particularly in wetland areas will contribute to improving livestock nutrition and productivity.

AbstractThe purpose of this study was to investigate the feeding patten of Labeobarbus intermedius at Ribb Reservoir (Lake Tana Sub-basin, Ethiopia). A total of 498 specimens were collected using gillnets. Of these, 302 (60.6%) fish had different foods, while 196 (39.4%) were empty. The fish were dissected, their stomachs were removed, and stomach contents were preserved in a 5% formalin solution. Frequency of occurrence, volumetric method, index of preponderance, and geometric importance index were used to study the feeding pattern. Detritus was the primary food, accounting for 61.6% of the guts by volume. Mud, zooplankton, and phytoplankton were the second most important food items comprising 24.4%, 3.9%, and 2.8% by volume respectively. Feeding pattern differed with the size classes of fish. The smallest fish (17.0 cm FL) majorly consumed detritus followed by mud. The importance of mud increases when the fish grows more except (>31.5 cm FL) size class. The proportions of food items of L. intermedius significantly varied with respect to the dry and wet seasons. Detritus and mud were mostly consumed in the dry season, contributing to 47.8% and 32.4% by volume, respectively. Detritus was the most preferred food item during the wet season, contributing 97.2% of the total guts and 75.6% by volume. Generally, L. intermedius feeding pattern depending on size classes and seasonal variations this may be linked to food availability in the reservoir.

Ionic liquids (ILs) are seen as a more sustainable alternative to volatile organic solvents that are accelerating innovations in many industries such as energy storage, separations, and bioprocessing. The ability to effectively deconstruct lignocellulosic biomass is a significant hurdle in the biorefining/bioprocessing industry and presents limitations towards the commercial production of bioproducts (such as biofuels, biomaterials, etc.). Certain ILs have been shown to promote effective lignin removal, cellulose recovery, and sugar yields from various biomass feedstocks such as corn stover, wheat straw, sugarcane bagasse, sorghum, switchgrass, miscanthus, poplar, pine, eucalyptus, and certain mixtures of municipal solid waste. However, these improvements are often counteracted by the limited biocompatibility of ILs, which results in an IL-induced reduction in enzyme activity and stability—an important downstream step in the conversion of biomass to biofuels/bioproducts. As a result, significant efforts have been made to discover and engineer compatible enzyme-IL systems and to improve our understanding on the effect that these ILs have on these systems. This review seeks to examine the impact of ionic liquids on enzymes involved in lignocellulosic biomass deconstruction, with a specific focus on their relevance in the context of pretreatment. Beyond presenting an overview of the ionic liquid pretreatment landscape, we outline the main factors that influence enzyme activity and stability in the presence of ILs This data is consolidated and analyzed to apply this body of knowledge towards new innovations that could lead to improvements in the processing of biomass to biofuels and bioproducts.

The majority of pathogenic mutations in the neurofibromatosis type I (NF1) gene reduce total neurofibromin protein expression through premature truncation or microdeletion, but it is less well understood how loss-of-function missense variants drive NF1 disease. We have found that patient variants in codons 844 to 848, which correlate with a severe phenotype, cause protein instability and exert an additional dominant-negative action whereby wild-type neurofibromin also becomes destabilized through protein dimerization. We have used our neurofibromin cryogenic electron microscopy structure to predict and validate other patient variants that act through a similar mechanism. This provides a foundation for understanding genotype-phenotype correlations and has important implications for patient counseling, disease management, and therapeutics.

Phlebia radiata is a widespread white-rot basidiomycete fungus with significance in diverse biotechnological applications due to its ability to degrade aromatic compounds, xenobiotics, and lignin using an assortment of oxidative enzymes including laccase. In this work, a chemical screen with 480 conditions was conducted to identify chemical inducers of laccase expression in P. radiata. Among the chemicals tested, phenothiazines were observed to induce laccase activity in P. radiata, with promethazine being the strongest laccase inducer of the phenothiazine-derived compounds examined. Secretomes produced by promethazine-treated P. radiata exhibited increased laccase protein abundance, increased enzymatic activity, and an enhanced ability to degrade phenolic model lignin compounds. Transcriptomics analyses revealed that promethazine rapidly induced the expression of genes encoding lignin-degrading enzymes, including laccase and various oxidoreductases, showing that the increased laccase activity was due to increased laccase gene expression. Finally, the generality of promethazine as an inducer of laccases in fungi was demonstrated by showing that promethazine treatment also increased laccase activity in other relevant fungal species with known lignin conversion capabilities including Trametes versicolor and Pleurotus ostreatus.

BackgroundDespite notable progress in the control and prevention of malaria in the Horn of Africa, the disease continues to cause significant morbidity and mortality in various regions of Ethiopia, and elsewhere in the region. The transmission of malaria is affected by genetic, sociocultural, and ecological factors. Lare is an Ethiopian district adjacent to the Ethio-South Sudan border, in Gambella region. The region currently has the highest prevalence of malaria in Ethiopia. This study assesses the burden and spatiotemporal patterns of disease transmission, including the effect of climatic factors on the occurrence of malaria, across an international border crossing. This understanding can assist in crafting informed programmatic and policy decisions for interventions.MethodsThis study was conducted in Lare district, Southwest Ethiopia, a temperate zone. A retrospective descriptive analysis was conducted using clinical service data collected between 2011 and 2021 from the 9 health facilities of the district. Both clinically diagnosed patients and those identified using microscopy and rapid diagnostic testing (RDT) were included in the study. Additionally, climate data was incorporated into analyses. Examples of analyses include malaria burden, positivity rate, incidence, species frequency, and an ANOVA to assess inter-annual case number and meteorological factor variation.ResultsBetween 2011 and 2021, a total of 96,616 suspected malaria cases were tested by microscopy or RDT, and 39,428 (40.8%) of these cases were reported as positive. There were 1276 patients admitted with 22 deaths recorded. There were further more significant fluctuations in positivity rates across years, the highest being 74.5% in 2021. Incidence varied from 18.0% in 2011 to 151.6% in 2016. The malaria parasite species most detected was Plasmodium falciparum, followed by a smaller proportion of Plasmodium vivax. The greatest proportions of P. falciparum cases were observed in 2018 and 2019, at 97.4% and 97.0% prevalence, respectively. There was significant seasonal variation in case number, the highest observed in July through September of each year. Climatic conditions of annual rainfall, temperature and humidity favored the increment of malaria cases from June until October.ConclusionThe study shows that the burden, i.e. morbidity and mortality (with fluctuating patterns) of malaria are still significant public health problems and can pose serious consequences in the district. This has implication for cross-border malaria transmission risk due to considerable border crossings. The predominant cause of the disease is P. falciparum, which causes severe complications in patients. The district has to prepare to deal with such complications for better patient care and outcomes.

Lignin, the second most abundant biopolymer found in nature, has emerged as a potential source of sustainable fuels, chemicals, and materials. Finding suitable solvents, as well as technologies for efficient and affordable lignin dissolution and depolymerization, are major obstacles in the conversion of lignin to value-added products. Certain ionic liquids (ILs) are capable of dissolving and depolymerizing lignin but designing and developing an effective IL for lignin dissolution remains quite challenging. To address this issue, the COnductor-like Screening MOdel for Real Solvents (COSMO-RS) model was used to screen 5670 ILs by computing logarithmic activity coefficients (ln(γ)) and excess enthalpies (HE) of lignin, respectively. Based on the COSMO-RS computed thermodynamic properties (ln(γ) and HE) of lignin, anions such as acetate, methyl carbonate, octanoate, glycinate, alaninate, and lysinate in combination with cations like tetraalkylammonium, tetraalkylphosphonium, and pyridinium are predicted to be suitable solvents for lignin dissolution. The dissolution properties such as interaction energy between anion and cation, viscosity, Hansen solubility parameters, dissociation constants, and Kamlet-Taft parameters of selected ILs were evaluated to assess their propensity for lignin dissolution. Furthermore, molecular dynamics (MD) simulations were performed to understand the structural and dynamic properties of tetrabutylammonium [TBA]+-based ILs and lignin mixtures and to shed light on the mechanisms involved in lignin dissolution. MD simulation results suggested [TBA]+-based ILs have the potential to dissolve lignin because of their higher contact probability and interaction energies with lignin when compared to cholinium lysinate.

Objectives The primary objective of this study was to describe the self-reported reproductive health of retired elite women’s footballers with specific reference to menstrual function, pregnancy and motherhood, contraceptive use and pelvic floor function.Methods An electronic survey was disseminated to women’s footballers (18 years or older) who had retired from elite football within 10 years of completing the survey.Results 69 respondents completed the survey (mean age 35.8 years, mean age at retirement 30.3 years). One-third of participants self-reported experiencing at least one episode of amenorrhoea (>3 months without menstruation) for reasons other than hormonal contraceptive use or pregnancy. Three participants (mean age of 41 years, range 30–54) reported having reached menopause at the time of the study. 54 (78.3%) participants were not using any form of contraception. 17 (24.6%) of the participants are mothers (range 1–3 children). 51 of the participants (73.9%) had never been pregnant, and the majority of those who had been pregnant (86.7%) became pregnant in less than 2 years following the onset of desire for pregnancy. Four of the retired players gave birth during their playing career, and the mean time to return to competitive matches following delivery was 22 weeks. The mean Pelvic Floor Distress Inventory-20 score for participants was 72.Conclusion These insights can be used to inform future efforts to promote positive reproductive health outcomes for current, former and future women’s footballers. Research efforts should focus on improving the understanding of how to effectively support women’s footballers in the perinatal period. Best practice guidelines on the use of menstrual cycle monitoring and pelvic health support would improve standards of care for women’s footballers. Stakeholders should consider gender-specific postretirement care for women’s footballers.

Abstract Background Circulating biomarkers of bone formation and resorption are widely used in exercise metabolism research, but their responses to exercise are not clear. This study aimed to quantify group responses and inter-individual variability of P1NP and β-CTX-1 after prolonged, continuous running (60–120 min at 65–75% V̇O2max) in young healthy adult males using individual participant data (IPD) meta-analysis. Methods The protocol was designed following PRISMA-IPD guidelines and was pre-registered on the Open Science Framework prior to implementation ( https://osf.io/y69nd ). Changes in P1NP and β-CTX-1 relative to baseline were measured during, immediately after, and in the hours and days following exercise. Typical hourly and daily variations were estimated from P1NP and β-CTX-1 changes relative to baseline in non-exercise (control) conditions. Group responses and inter-individual variability were quantified with estimates of the mean and standard deviation of the difference, and the proportion of participants exhibiting an increased response. Models were conducted within a Bayesian framework with random intercepts to account for systematic variation across studies. Results P1NP levels increased during and immediately after running, when the proportion of response was close to 100% (75% CrI: 99 to 100%). P1NP levels returned to baseline levels within 1 h and over the next 4 days, showing comparable mean and standard deviation of the difference with typical hourly (0.1 ± 7.6 ng·mL−1) and daily (− 0.4 ± 5.7 ng·mL−1) variation values. β-CTX-1 levels decreased during and up to 4 h after running with distributions comparable to typical hourly variation (− 0.13 ± 0.11 ng·mL−1). There was no evidence of changes in β-CTX-1 levels during the 4 days after the running bout, when distributions were also similar between the running data and typical daily variation (− 0.03 ± 0.10 ng·mL−1). Conclusion Transient increases in P1NP were likely biological artefacts (e.g., connective tissue leakage) and not reflective of bone formation. Comparable small decreases in β-CTX-1 identified in both control and running data, suggested that these changes were due to the markers’ circadian rhythm and not the running intervention. Hence, prolonged continuous treadmill running did not elicit bone responses, as determined by P1NP and β-CTX-1, in this population.

Abstract Background There has been little exploration of the effect of fragility fractures on patient perceptions of their age. The common assumption is that fractures “happen to old people”. In individuals with a fragility fracture, our objective was to explore the experience of feeling old after sustaining a fragility fracture. Methods A secondary analysis of data from 145 community-dwelling women and men participating in six qualitative primary studies was conducted relying on a phenomenological approach. Participants were English-speaking, 45 years and older, who had sustained a recent fragility fracture or reported a history of previous fragility fractures. Data for the analysis included direct statements about feeling old as well any discussions relevant to age post-fracture. Results We highlight two interpretations based on how individuals with a history of fragility fracture talked about age: (1) Participants described feeling old post-fracture. Several participants made explicit statements about being “old”. However, the majority of participants discussed experiences post-fracture that implied that they felt old and had resigned themselves to being old. This appeared to entail a shift in thinking and perception of self that was permanent and had become a part of their identity; and (2) Perceptions of increasing age after sustaining a fracture were reinforced by health care providers, family, and friends. Conclusions Our findings challenge the notion that fractures “happen to old people” and suggest that fractures can make people feel old. Careful consideration of how bone health messages are communicated to patients post-fracture by health care providers is warranted. (Word Count: 248)

Abstract Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Abstract Healthcare-associated infections (HCAIs) are a major cause of morbidity and mortality in critically ill children. Data from adult studies suggest Selective Decontamination of the Digestive tract (SDD) may reduce the incidence of HCAIs and improve survival. There are no data from randomised clinical trials in the paediatric setting. An open label, parallel group pilot cRCT and mixed-methods perspectives study was conducted in six paediatric intensive care units (PICUs) in England. Participants were children (> 37 weeks corrected gestational age, up to 16 years) requiring mechanical ventilation expected to last for at least 48 h. Sites undertook standard care for a period of 9 weeks and were randomised into 3 sites which continued standard care and 3 where SDD was incorporated into infection control practice for eligible children. Interviews and focus groups were conducted for parents and staff working in PICU. 434 children fulfilled eligibility criteria, of whom 368 (85%) were enrolled. This included 207 in the baseline phase (Period One) and 161 in the intervention period (Period Two). In sites delivering SDD, the majority (98%) of children received at least one dose of SDD and of these, 68% commenced within the first 6 h. Whilst admission swabs were collected in 91% of enrolled children, consent for the collection of additional swabs was low (44%). Recruited children were representative of the wider PICU population. Overall, 3.6 children/site/week were recruited compared with the potential recruitment rate for a definitive cRCT of 3 children/site/week, based on data from all UK PICUs. Parents (n = 65) and staff (n = 44) were supportive of the aims of the study, suggesting adaptations for a larger definitive trial including formulation and administration of SDD paste, approaches to consent and ecology monitoring. Stakeholders identified preferred clinical outcomes, focusing on complications of critical illness and quality-of-life. A definitive cRCT in SDD to prevent HCAIs in critically ill children is feasible but should include adaptations to ecology monitoring along with the dosing schedule and packaging into a paediatric specific format. A definitive study is supported by the findings with adaptations to ecology monitoring and SDD administration. Trial Registration: ISRCTN40310490 Registered 30/10/2020.