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A photochemical synthesis of biologically relevant benzyl oxindoles is presented via electron‐donor acceptor (EDA) complex strategy. This exogenous photocatalyst‐free method describes the formation of a new electron donor‐acceptor complex based on potassium carbonate and thianthrenium salts for C(sp2)−C(sp3) bond formation. This transition‐metal free reaction allows a rapid increase in oxindoles molecular complexity chemical space, tolerating different functional groups as well as sophisticated biomolecules. The scalability and sustainability of this method is highlighted by an important waste recovery protocol. Mechanistic investigations support the formation of an EDA complex that induces a radical chain, and the applicability of this method is showcased by straightforward derivatization reactions. [ABSTRACT FROM AUTHOR]

Hydroxytrifluoroethyl and trifluoroacetyl groups are of utmost importance in biologically active compounds, but methods to tether these motifs to organic architectures have been limited. Typically, the preparation of these compounds relied on the use of strong bases or multistep routes. The renaissance of radical chemistry in photocatalytic, transition metal mediated, and hydrogen atom transfer (HAT) processes have allowed the installation of these medicinally relevant fluorinated motifs. This review provides an overview of the methods available for the direct synthesis of hydroxytrifluoroethyl‐ and trifluoroacetyl‐derived compounds governed by single‐electron transfer processes. [ABSTRACT FROM AUTHOR]

Summary: Juvenile myelomonocytic leukaemia (JMML) is characterized by gene variants that deregulate the RAS signalling pathway. Children with neurofibromatosis type 1 (NF‐1) carry a defective NF1 allele in the germline and are predisposed to JMML, which presumably requires somatic inactivation of the NF1 wild‐type allele. Here we examined the two‐hit concept in leukaemic cells of 25 patients with JMML and NF‐1. Ten patients with JMML/NF‐1 exhibited a NF1 loss‐of‐function variant in combination with uniparental disomy of the 17q arm. Five had NF1 microdeletions combined with a pathogenic NF1 variant and nine carried two compound‐heterozygous NF1 variants. We also examined 16 patients without clinical signs of NF‐1 and no variation in the JMML‐associated driver genes PTPN11, KRAS, NRAS or CBL (JMML‐5neg) and identified eight patients with NF1 variants. Three patients had microdeletions combined with hemizygous NF1 variants, three had compound‐heterozygous NF1 variants and two had heterozygous NF1 variants. In addition, we found a high incidence of secondary ASXL1 and/or SETBP1 variants in both groups. We conclude that the clinical diagnosis of JMML/NF‐1 reliably indicates a NF1‐driven JMML subtype, and that careful NF1 analysis should be included in the genetic workup of JMML even in the absence of clinical evidence of NF‐1. [ABSTRACT FROM AUTHOR]

Ionic covalent organic frameworks (iCOFs) are crystalline materials with stable porous structures. They hold great potential for ion transport, particularly as solid‐state electrolytes (SSEs) for all‐solid‐state lithium metal batteries (ASSLMBs). However, achieving an ionic conductivity of over 10−3 S cm−1 at room temperature using pure‐iCOF‐based SSEs, even adding additives such as lithium salts, is challenging as the voids work as strong resistances. Thus, highly conductive iCOFs typically require quasi‐solid‐state configurations with organic solvents or plasticizers. In this study, composites comprising iCOFs and poly(ionic liquid) (PIL) are prepared to make all‐solid‐state iCOFs electrolytes with an exceptional ionic conductivity up to 1.50 × 10−3 S cm−1 and a high Li+ transference number of > 0.80 at room temperature. Combined experimental and computational studies show that the co‐coordination and competitive coordination mechanism established between the PIL, lithium bis(trifluoromethanesulfonyl)imide (LiTFSI), and iCOFs enabled rapid Li+ transport while restricting TFSI− movement. ASSLMB cells, made of composite SSEs and LiFePO4 composite cathode, demonstrate an initial discharge capacity of 141.5 mAh g−1 at 1C and r.t., with an impressive capacity retention of 87% up to 800 cycles. Overall, this work presents a breakthrough approach for developing advanced SSEs for next‐generation high‐energy‐density ASSLMBs. [ABSTRACT FROM AUTHOR]

Summary: Background: Hepatic steatosis is a common finding in liver histopathology and the hallmark of metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as non‐alcoholic fatty liver disease (NAFLD), whose global prevalence is rising. Aims: To review the histopathology of hepatic steatosis and its mechanisms of development and to identify common and rare disease associations. Methods: We reviewed literature on the basic science of lipid droplet (LD) biology and clinical research on acute and chronic liver diseases associated with hepatic steatosis using the PubMed database. Results: A variety of genetic and environmental factors contribute to the development of chronic hepatic steatosis or steatotic liver disease, which typically appears macrovesicular. Microvesicular steatosis is associated with acute mitochondrial dysfunction and liver failure. Fat metabolic processes in hepatocytes whose dysregulation leads to the development of steatosis include secretion of lipoprotein particles, uptake of remnant lipoprotein particles or free fatty acids from blood, de novo lipogenesis, oxidation of fatty acids, lipolysis and lipophagy. Hepatic insulin resistance is a key feature of MASLD. Seipin is a polyfunctional protein that facilitates LD biogenesis. Assembly of hepatitis C virus takes place on LD surfaces. LDs make important, functional contact with the endoplasmic reticulum and other organelles. Conclusions: Diverse liver pathologies are associated with hepatic steatosis, with MASLD being the most important contributor. The biogenesis and dynamics of LDs in hepatocytes are complex and warrant further investigation. Organellar interfaces permit co‐regulation of lipid metabolism to match generation of potentially toxic lipid species with their LD depot storage. [ABSTRACT FROM AUTHOR]

Catalytic valveless micropumps, and membraneless fuel cells are the class of devices that utilize the decomposition of hydrogen peroxide (H2O2) into water and oxygen. Nonetheless, a significant obstacle that endures within the discipline pertains to the pragmatic open circuit potential (OCP) of hydrogen peroxide FCs (H2O2 FCs), which fails to meet the theoretical OCP. Additionally, bubble formation significantly contributes to this disparity, as it disrupts the electrolyte's uniformity and interferes with reaction dynamics. In addition, issues such as catalyst degradation and poor kinetics can impact the overall cell efficiency. The development of high‐performance H2O2‐FCs necessitates the incorporation of selective electrocatalysts with a high surface area. However, porous micro‐structures of the electrode impedes the transport of fuel and the removal of reaction byproducts, thereby hindering the attainment of technologically significant rates. To address these challenges, including bubble formation, the review highlights the potential of integrating electrokinetic and bubble‐driven micropumps. An alternative approach involves the spatiotemporal separation of fuel and oxidizer through the use of laminar flow‐based fuel cell (LFFC). The present review addresses multifaceted challenges of H2O2‐powered FCs, and proposes integration of electrokinetic and bubble‐driven micropumps, emphasizing the critical role of bubble management in improving H2O2 FC performance. [ABSTRACT FROM AUTHOR]

In this study, the performance of a binder‐free LiNi0.6Co0.2Mn0.2O2 (NMC622) positive electrode utilizing single‐walled carbon nanotubes (SWCNTs) is investigated and compared to the conventional state‐of‐the‐art NMC622 composite positive electrode. The binder‐free electrode has been prepared without using toxic and expensive N‐Methyl‐2‐pyrrolidone (NMP) solvent and it is free‐standing that allows a wider range of applications such as flexible devices. Electrochemical techniques such as cyclic voltammetry, electrochemical impedance spectroscopy, and galvanostatic charge–discharge reveal that the binder‐free positive electrode performance is similar to the conventional composite cathodes, deducing that only ≈1% of SWCNTs perform well not only as a conductive agent but also as a binder. The NMC622 composite electrode with SWCNTs provided specific capacity of 135.8 mAh g−1 at a 5C rate during discharge, with above 97% capacity retention after the rate capability test in a half cell. [ABSTRACT FROM AUTHOR]

The article discusses the crystal structure of the MAGEA4 MHD-RAD18 R6BD complex and compares it to the AlphaFold2 prediction. The authors found that the binding mode of the RAD18 R6BD peptide in the crystal structure is flipped compared to the AlphaFold2 model. They also highlight the limitations of AlphaFold2, emphasizing that it is a statistical method based on existing experimental structures and may be biased by those structures. The authors conclude that their structural elucidation provides molecular evidence to clarify the confusion caused by the AlphaFold2 modeling and can aid in the development of MAGEA4-RAD18 antagonists for cancer treatment. [Extracted from the article]

The complement is a conserved cascade that plays a central role in the innate immune system. To maintain a delicate equilibrium preventing excessive complement activation, complement inhibitors are essential. One of the major fluid-phase complement inhibitors is C4b-binding protein (C4BP). Human C4BP is a macromolecular glycoprotein composed of two distinct subunits, C4BPα and C4BPβ. These associate with vitamin K-dependent protein S (ProS) forming an ensemble of co-occurring higher-order structures. Here, we characterize these C4BP assemblies. We resolve and quantify isoforms of purified human serum C4BP using distinct single-particle detection techniques: charge detection mass spectrometry, and mass photometry accompanied by high-speed atomic force microscopy. Combining cross-linking mass spectrometry, glycoproteomics, and structural modeling, we report comprehensive glycoproteoform profiles and full-length structural models of the endogenous C4BP assemblies, expanding knowledge of this key complement inhibitor's structure and composition. Finally, we reveal that an increased C4BPα to C4BPβ ratio coincides with elevated C-reactive protein levels in patient plasma samples. This observation highlights C4BP isoform variation and affirms a distinct role of co-occurring C4BP assemblies upon acute phase inflammation. Synopsis: C4b-binding protein complement inhibitor forms co-occurring assemblies in human serum. Here, by using an integrative structural biology approach, structural and compositional details of C4BP are exposed, resulting in structural models of full-length glycosylated C4BP assemblies. Integrating high-speed atomic force microscopy and cross-linking mass spectrometry we present full-length structural models of C4BP, a spider-like assembly of C4BPα and C4BPβ, non-covalently interacting with vitamin K-dependent protein S. Dominant C4BP variants in healthy human serum are C4BP(β+) captured and analyzed by single molecule mass photometry and charge detection mass spectrometry. Quantitative serum proteomics reveals that C4BP variant composition changes during acute phase inflammation, with an increase in α7 variant abundance. Structual analysis of complement inhibitor C4BP uncovers full-length spider-like assemblies of C4BPα and C4BPβ subunits and composition changes during acute phase inflammation. [ABSTRACT FROM AUTHOR]

Metal halide perovskite photodiodes have garnered extensive attention owing to their favorable optoelectronic properties, rendering them attractive for visible, near‐infrared, and X‐ray sensors. However, their predominant reliance on solution‐processing deposition techniques poses challenges for seamless integration into existing industrial processes. In this study, this limitation is addressed by developing fully vacuum‐processed perovskite photodiodes with varying hole transport layers (HTL). These findings underscore the critical role of HTL selection in influencing the dark and noise current characteristics of the diodes. With an optimized HTL, photodiodes are obtained with low noise current (≈3 10−14 A Hz−1/2) and high specific detectivity (≈1012 Jones at 710 nm at −0.5 V). The photodiodes are also tested as X‐ray detectors and are found to be stable under X‐ray radiation, with state‐of‐the‐art sensitivity of 33 ± 4 µC Gy−1 cm−2 and a low limit of detection of 2.0 ± 1.6 µG s−1. These insights contribute to the development of perovskite photodiodes with improved performance and broader industrial applicability. [ABSTRACT FROM AUTHOR]

Summary: In the early 1900s, Erwin Baur established Antirrhinum majus as a model system, identifying and characterising numerous flower colour variants. This included Picturatum/Eluta, which restricts the accumulation of magenta anthocyanin pigments, forming bullseye markings on the flower face.We identified the gene underlying the Eluta locus by transposon‐tagging, using an Antirrhinum line that spontaneously lost the nonsuppressive el phenotype. A candidate MYB repressor gene at this locus contained a CACTA transposable element. We subsequently identified plants where this element excised, reverting to a suppressive Eluta phenotype. El alleles inhibit expression of anthocyanin biosynthetic genes, confirming it to be a regulatory locus. The modes of action of Eluta were investigated by generating stable transgenic tobacco lines, biolistic transformation of Antirrhinum petals and promoter activation/repression assays.Eluta competes with MYB activators for promoter cis‐elements, and also by titrating essential cofactors (bHLH proteins) to reduce transcription of target genes. Eluta restricts the pigmentation established by the R2R3‐MYB factors, Rosea and Venosa, with the greatest repression on those parts of the petals where Eluta is most highly expressed.Baur questioned the origin of heredity units determining flower colour variation in cultivated A. majus. Our findings support introgression from wild species into cultivated varieties. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Wilson's disease may progress to cirrhosis and clinically significant portal hypertension (CSPH). We aimed to assess the prevalence and prognostic impact of CSPH‐related features on hepatic decompensation and transplant‐free survival in patients with Wilson's disease. Methods and Results: About 137 patients with Wilson's disease (Leipzig score ≥4), followed for a median observation period of 9.0 (3.9–17.7) years at the Vienna General Hospital, were included in this retrospective study. Overall, 49 (35.8%) developed features of CSPH: 14 (10.2%) varices, 40 (29.2%) splenomegaly, 20 (14.6%) ascites, 18 (13.1%) hepatic encephalopathy and 3 (2.2%) experienced acute variceal bleeding. Overall, 8 (5.8%) patients died, including three deaths caused by CSPH‐related complications. Within 10 years, compensated patients with features of CSPH developed more decompensation events (8.3% vs. 1.5% in patients without CSPH, p = 0.3) and had worse transplant‐free‐survival (91.7% vs. 98.6%), which further declined in patients with hepatic decompensation (26.7%, log‐rank: p < 0.0001). Patients with liver stiffness <15 kPa and normal platelets (≥150 G/L) were less likely to decompensate within 10 years (2.6% vs. 8.4%, p = 0.002) and had a better 10‐year transplant‐free‐survival (97.7% vs. 83.9%, p = 0.006). Conclusions: Patients with Wilson's disease developing features of CSPH are at an increased risk for hepatic decompensation and liver‐related mortality, warranting for regular screening and timely initiation of effective CSPH‐directed treatments. [ABSTRACT FROM AUTHOR]

Objective Method Results Conclusions Ranked‐choice voting (RCV) is increasingly seen as a way to reduce political polarization and increase voter choice in elections, but little is known about its effect on candidate fundraising. In 2022, Alaska held its first election using a nonpartisan Top 4 primary followed by a ranked‐choice general election. We analyze the effect of this new system on campaign financing practices in state legislative elections. There are many reasons to expect RCV to increase campaign spending, broaden the donor pool, and prompt donors to support candidates to whom they would not otherwise contribute.We measure changes in fundraising over the past decade in Alaska legislative elections. We conduct a network analysis of campaign contributors in Alaska for the 2018, 2020, and 2022 state legislative elections.RCV had minimal consequences for campaign fundraising. Our ability to draw broader conclusions about the relationship between RCV and campaign finance is complicated by unusual features of Alaska politics.There is little evidence that the adoption of a Top 4/RCV system in Alaska had immediate effects on campaign finance in state legislative elections. However, patterns may change as legislators and donors adapt to the new system. [ABSTRACT FROM AUTHOR]

Isothiazolones are important heterocyclics with pharmacological potency such as anti‐inflammatory, anticancer, antimicrobial, and robust biocidal (used in agrochemicals). This study seeks to provide mechanistic insight into the chemo‐ and regio‐selectivities of the [3 + 2] cycloaddition reaction of 5‐benzoyl‐3(2H)‐isothiazolone (A1) with two stable nitrile oxides, that is, mesitonitrile oxide (A2) and dichlorobenzonitrile oxide (A3) using M06‐2X hybrid density functional calculations coupled with the 6‐311G (d, p) basis sets. Mesitonitrile oxide A2 chemo‐selectively adds across the carbonyl of the benzyl group of A1 while dichloro benzonitrile oxide A3 preferentially adds across the ethylene center of A1. Derivatization of A1 with electron‐donating groups lowers the activation barriers by a very minute margin ranging from 0.1 to 0.5 kcal/mol whereas electron‐withdrawing groups significantly decrease the energetics of the reaction by a margin of 1.1 to 2.5 kcal/mol. Solvation with chloroform does not affect the selectivity of the reaction but tends to increase both activation and reaction energies of the various routes. Analysis of the Parr function on different reactive sites of A1 shows the addition of A2 via the atomic center with the largest Mullikan atomic spin densities. Substitution of the S‐heteroatom with C, O, or N does not affect the regioselectivity of the reaction but lowers the activation energies in the reaction of A1 with A3. The global electron density transfer (GEDT) values predict a polar reaction between A1 and A2 whereas the reaction of A1 and A3 is non‐polar. [ABSTRACT FROM AUTHOR]

This work demonstrates a method to design photonic surfaces by combining femtosecond laser processing with the inverse design capabilities of tandem neural networks that directly link laser fabrication parameters to their resulting textured substrate optical properties. High throughput fabrication and characterization platforms are developed that generate a dataset comprising 35280 unique microtextured surfaces on stainless steel with corresponding measured spectral emissivities. The trained model utilizes the nonlinear one‐to‐many mapping between spectral emissivity and laser parameters. Consequently, it generates predominantly novel designs, which reproduce the full range of spectral emissivities (average root‐mean‐squared‐error < 2.5%) using only a compact region of laser parameter space 25 times smaller than what is represented in the training data. Finally, the inverse design model is experimentally validated on a thermophotovoltaic emitter design application. By synergizing laser‐matter interactions with neural network capabilities, the approach offers insights into accelerating the discovery of photonic surfaces, advancing energy harvesting technologies. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Maggots in a wound ("myiasis") cannot be considered maggot therapy (therapeutic myiasis) unless, at a minimum, the species is known to be safe and effective, and the maggots have been properly disinfected. Documenting treatment details is critical and allows us to determine the cause of problems, if they arise. [ABSTRACT FROM AUTHOR]

Introduction: In patients with an increased bleeding tendency, extensive diagnostic blood testing is often performed. When results of tier 1 assays of primary haemostasis are normal, protocols recommend additional testing to rule out rare disorders including coagulation factor XIII (FXIII) and α2‐antiplasmin (α2AP) deficiency. Aim: To evaluate the added diagnostic value of FXIII and α2AP levels in patients with a bleeding disorder of unknown cause (BDUC). Methods: A retrospective monocentre cohort study between August 2011 and August 2023 was conducted. In all patients with bleeding tendencies and normal diagnostic tests for von Willebrand disease and platelet function, FXIII and α2AP were measured. Results: We included 158 consecutive patients; mean ISTH‐BAT scores were 8.2 (SD ± 3.7) in children, 6.2 (SD ± 2.1) in men and 10.6 (SD ± 3.3) in women. Median age was 37 (range 5–79) years, 88.6% of patients were female. Patients displayed median FXIII activity of 111% (IQR = 97–131) and median α2AP activity of 112% (IQR = 103–119). Three (1.9%) patients had FXIII levels < 50%, respectively 43%, 45% and 46%. Corresponding ISTH‐BAT scores were 7, 12 and 14. No α2AP levels < 60% was observed. No significant association was found between FXIII levels and ISTH‐BAT scores. Conclusion: In our cohort of BDUC patients, no clinical relevant FXIII deficiencies were detected; absolute values were well above the 30% cutoff considered adequate for normal haemostasis. No α2AP deficiencies were detected. These data suggest that in BDUC patients, measuring FXIII or AP activity is of limited value. [ABSTRACT FROM AUTHOR]

KEY IDEAS: Anti‐D cannot agglutinate red cells of any Del phenotype in routine serology.Many individuals with East Asian ancestry who type D‐negative in serology harbor a Del phenotype.Almost all such individuals carry one distinct DEL variant, dubbed Asian‐type DEL, known as RHD*01EL.01, RHD*DEL1, RHD:c.1227G>A, formerly known as RHD(K409K).Clinical evidence strongly suggests that Asian‐type DEL individuals can safely be transfused with RhD‐positive blood and do not need anti‐D prophylaxis in pregnancy. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is becoming increasingly important in nuclear medicine and drug discovery. To date, the development of many potential PET tracers is hampered by the lack of suitable synthetic pathways for their preparation. This is particularly true for the highly desired radiolabeling of compounds bearing [18F]CF3‐groups. For instance, S(O)nCF3‐groups (n=0, 1, 2) serve as structural motif in a range of biologically active compounds, but their radiosynthesis remains largely unprecedented (for n=1, 2). Herein, we describe general methods for the radiosynthesis of 18F‐labeled aryl trifluoromethyl sulfones, ‐sulfoxides, and ‐sulfides. All three methods are operationally straightforward, start from widely available precursors, i.e., sulfonyl fluorides and thiophenols, and make use of the recently established [18F]Ruppert‐Prakash reagent. Further, the syntheses display good functional group tolerance as demonstrated by the 18F‐labeling of more than 40 compounds. The applicability of the new method is demonstrated by the radiolabeling of three bioactive molecules, optionally to be used as PET tracers. In a broader context, this work presents a substantial expansion of the chemical space of radiofluorinated structural motifs to be used for the development of new PET tracers. [ABSTRACT FROM AUTHOR]

The feasibility to discriminate potentially asbestos‐containing components from asbestos‐free concrete based on camera images using the example of wall demolition waste is investigated. For this, three types of asbestos substitute materials and two types of concrete are crushed and photographed. The classification of the fragment images is carried out with a) morphological and texture features and b) with features automatically extracted by the pretrained MobileNetV3 network. Feret diameters, circularity, and others served as morphological descriptors. The texture was described by measures of grey‐level intensity, as obtained from the grey‐level co‐occurrence matrix. Support vector machines are found to achieve classification accuracies above 99 % based on the automatically extracted features. The presented identification approach is promising to automate the treatment process of asbestos‐containing materials from construction and demolition waste, which is effortful and requires expert knowledge to this day. [ABSTRACT FROM AUTHOR]

The amyotrophic lateral sclerosis (ALS) functional rating scale‐revised (ALSFRS‐R) has become the most widely utilized measure of disease severity in patients with ALS, with change in ALSFRS‐R from baseline being a trusted primary outcome measure in ALS clinical trials. This is despite the scale having several established limitations, and although alternative scales have been proposed, it is unlikely that these will displace ALSFRS‐R in the foreseeable future. Here, we discuss the merits of delta FS (ΔFS), the slope or rate of ALSFRS‐R decline over time, as a relevant tool for innovative ALS study design, with an as yet untapped potential for optimization of drug effectiveness and patient management. In our view, categorization of the ALS population via the clinical determinant of post‐onset ΔFS is an important study design consideration. It serves not only as a critical stratification factor and basis for patient enrichment but also as a tool to explore differences in treatment response across the overall population; thereby, facilitating identification of responder subgroups. Moreover, because post‐onset ΔFS is derived from information routinely collected as part of standard patient care and monitoring, it provides a suitable patient selection tool for treating physicians. Overall, post‐onset ΔFS is a very attractive enrichment tool that is, can and should be regularly incorporated into ALS trial design. [ABSTRACT FROM AUTHOR]

Summary: Background and Objective: The aim was assessing a short training for healthcare providers on patient‐focused counselling to treat childhood obesity in primary care, along with dietitian‐led workshops and educational materials. Methods: Randomized clustered trial conducted with paediatrician‐nurse pairs (Basic Care Units [BCU]) in primary care centres from Tarragona (Spain). BCUs were randomized to intervention (MI) (motivational interview, dietitian‐led education, and educational materials) or control group (SC, standard care). Participants were 8–14‐year‐old children with obesity, undergoing 1–11 monthly treatment visits during 1 year at primary care centres. The primary outcome was BMI z‐score reduction. Results: The study included 44 clusters (23 MI). Out of 303 allocated children, 201 (n = 106 MI) completed baseline, final visits, and at least one treatment visit and were included in the analysis. BMI z‐score reduction was −0.27 (±0.31) in SC, versus −0.36 (±0.35) in MI (p = 0.036). Mixed models with centres as random effects showed greater reductions in BMI in MI than SC; differences were B = −0.11 (95% CI: −0.20, −0.01, p = 0.025) for BMI z‐score, and B = −2.06 (95% CI: −3.89, −0.23, p = 0.028) for BMI %. No severe adverse events related to the study were notified. Conclusion: Training primary care professionals on motivational interviewing supported by dietitians and educational materials, enhanced the efficacy of childhood obesity therapy. [ABSTRACT FROM AUTHOR]

Background: Infantile hemangiomas are common vascular tumors in children. Propranolol has proven effective in treating infantile hemangiomas and while generally safe, has potential risk for more serious side effects of hypoglycemia, hypotension, bradycardia, bronchospasm, and cardiovascular or respiratory compromise. Current prescribing guidelines recommend initiating propranolol doses at 1 mg/kg/day, with up‐titration to 2 mg/kg/day. This study aims to compare the incidence of adverse events in infants and children treated with propranolol initiated at 1 mg/kg/day versus being initiated directly at 2 mg/kg/day. Methods: A retrospective cohort study was conducted using medical records of patients receiving propranolol therapy for infantile hemangiomas between October 2018–March 2021 at the Children's Hospital of Philadelphia. Patients were categorized by initial propranolol dosage: 1 or 2 mg/kg/day. The primary outcome measures included parent‐reported adverse events, hypotension (defined by the Pediatric Advanced Life Support criteria), and bradycardia (defined as <1st percentile for age) following propranolol initiation. Results: Out of the 244 patients identified, 123 were initiated at the 1 mg/kg/day dose, and 121 at the 2 mg/kg/day dose. There was no significant difference in the incidence of adverse events between the two groups (p =.057). Additionally, among patients initiated at 2 mg/kg/day, there were no significant differences in the incidence of age‐related or weight‐related adverse events for those younger than 2 months or those in the 1st or 2nd quartile for weight (p =.53). Conclusion: Infants and children initiated at 2 mg/kg/day did not demonstrate an increased incidence of adverse events associated with propranolol compared to those initiated at 1 mg/kg/day. These findings provide clinical evidence for the practice of accelerated propranolol initiation dosing. [ABSTRACT FROM AUTHOR]

Issue Addressed: The Sydney Local Health District (SLHD) Health Promotion Unit was awarded a Cancer Institute NSW grant to raise awareness of bowel cancer and promote the National Bowel Cancer Screening Program (NBCSP) among Aboriginal communities in SLHD. The COVID‐19 pandemic thwarted initial plans for face‐to‐face workshops and plans pivoted to digital products and dissemination of messages on a range of communication platforms. Discussion: The coronavirus (COVID‐19) pandemic provided staff with the freedom, flexibility, and ability to be creative in ways not possible prior to the pandemic and ultimately ended up with a superior product with a reach further than anticipated. A more comprehensive suite of digital resources addressing barriers to bowel cancer screening in the Aboriginal community was produced that is able to be used more broadly. These resources have reached a much larger population group through websites, social media, as well as TV and radio advertisements, and have the potential to be used and adapted in other local health districts and states across Australia. Conclusion: Adapting an Aboriginal bowel cancer screening awareness program to a digital platform is a promising approach. So What?: COVID‐19 provided an opportunity to create new long‐lasting partnerships and to be creative beyond the scope of the original grant. This in turn produced a product with a reach further than anticipated that can also be built on and sustained. [ABSTRACT FROM AUTHOR]

Background: Calcitriol, the active form of vitamin D (also known as 1,25‐dihydroxycholecalciferol), improves the phenotype and increases frataxin levels in cell models of Friedreich ataxia (FRDA). Objectives: Based on these results, we aimed measuring the effects of a calcitriol dose of 0.25 mcg/24h in the neurological function and frataxin levels when administered to FRDA patients for a year. Methods: 20 FRDA patients where recluted and 15 patients completed the treatment for a year. Evaluations of neurological function changes (SARA scale, 9‐HPT, 8‐MWT, PATA test) and quality of life (Barthel Scale and Short Form (36) Health Survey [SF‐36] quality of life questionnaire) were performed. Frataxin amounts were measured in isolated platelets obtained from these FRDA patients, from heterozygous FRDA carriers (relatives of the FA patients) and from non‐heterozygous sex and age matched controls. Results: Although the patients did not experience any observable neurological improvement, there was a statistically significant increase in frataxin levels from initial values, 5.5 to 7.0 pg/μg after 12 months. Differences in frataxin levels referred to total protein levels were observed among sex‐ and age‐matched controls (18.1 pg/μg), relative controls (10.1 pg/μg), and FRDA patients (5.7 pg/μg). The treatment was well tolerated by most patients, and only some of them experienced minor adverse effects at the beginning of the trial. Conclusions: Calcitriol dosage used (0.25 mcg/24 h) is safe for FRDA patients, and it increases frataxin levels. We cannot rule out that higher doses administered longer could yield neurological benefits. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: CD59 deficiency due to rare germline variants in the CD59 gene causes disabilities, ischemic strokes, neuropathy, and hemolysis. CD59 deficiency due to common somatic variants in the PIG‐A gene in hematopoietic stem cells causes paroxysmal nocturnal hemoglobinuria. The ISBT database lists one nonsense and three missense germline variants that are associated with the CD59‐null phenotype. To analyze the genetic diversity of the CD59 gene, we determined long‐range CD59 haplotypes among individuals from different ethnicities. Methods: We determined a 22.7 kb genomic fragment of the CD59 gene in 113 individuals using next‐generation sequencing (NGS), which covered the whole NM_203330.2 mRNA transcript of 7796 base pairs. Samples came from an FDA reference repository and our Ethiopia study cohorts. The raw genotype data were computationally phased into individual haplotype sequences. Results: Nucleotide sequencing of the CD59 gene of 226 chromosomes identified 216 positions with single nucleotide variants. Only three haplotypes were observed in homozygous form, which allowed us to assign them unambiguously as experimentally verified CD59 haplotypes. They were also the most frequent haplotypes among both cohorts. An additional 140 haplotypes were imputed computationally. Discussion: We provided a large set of haplotypes and proposed three verified long‐range CD59 reference sequences, based on a population approach, using a generalizable rationale for our choice. Correct long‐range haplotypes are useful as template sequences for allele calling in high‐throughput NGS and precision medicine approaches, thus enhancing the reliability of clinical diagnostics. Long‐range haplotypes can also be used to evaluate the influence of genetic variation on the risk of transfusion reactions or diseases. [ABSTRACT FROM AUTHOR]

Objective: To investigate the prevalence and natural history of POLG disease in the Norwegian population. Methods: A national, population‐based, retrospective study using demographic, clinical, and genetic data of patients with genetically confirmed POLG disease. The patients were diagnosed between 2002 and 2022, and were included into the Norwegian POLG Patient Registry. Patients were stratified according to age at disease onset (early <12 years, juvenile to adult 12–40 years, late ≥40 years) and resident region. Results: Ninety‐one patients were included. The point prevalence of POLG disease was 1:149,253. Birth prevalence was 1:48,780. Median age at clinical onset was 16 years (range: 2 months to 70 years). Onset occurred early in 35% (32 out of 91), juvenile‐adult in 55% (50 out of 91) and late in 10% (9 out of 91). A distinct seasonal pattern in disease onset was observed, with 57% (52 out of 91) presenting between May and August. Forty‐five patients (49%) had acute exacerbations that required intensive care, and this affected 72% of those in the early‐onset group. The mortality rate was 54% (49 out of 91), with a median time from disease onset to death of 3 years (range: 1 month to 36 years). Interpretation: We provide the point prevalence and birth prevalence of POLG disease in the first nationwide study in which epidemiological and clinical data were integrated. Seasonal variations in clinical onset may offer valuable insights into disease mechanisms and modifying factors. The findings from this study are crucial for quantifying the disease burden, and contribute to evidence‐based healthcare planning. [ABSTRACT FROM AUTHOR]

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD‐A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search. [ABSTRACT FROM AUTHOR]

The purpose of the investigation was to evaluate the utility of ChatGPT, a state‐of‐the‐art language model developed by Open AI, in the context of civil engineering education. To achieve this objective, 44 civil engineering students from a large state university in the United States were recruited and asked to respond to three questions pertaining to Construction Surveying and Geomatics. The students were then introduced to ChatGPT and provided with guidelines on how the platform could be utilized for educational purposes, including obtaining answers to questions like those presented to them earlier. The students were then given the opportunity to leverage ChatGPT to obtain responses to questions they had been presented with earlier and any other related queries of interest. Subsequently, the students were asked to provide written responses to the same questions they were presented with earlier, but without access to ChatGPT or its response, to assess any knowledge gains. The investigation also captured the student's acceptance and perceived usability based on their experience of using ChatGPT. The findings indicated that the student's written responses were more thorough, detailed, and informative after utilizing ChatGPT. The results also revealed that ChatGPT was largely well‐received by the students and they held a positive perception of the AI platform. The findings can inform efforts targeted at successfully integrating AI tools for civil engineering education. [ABSTRACT FROM AUTHOR]

Summary: European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo‐HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia‐free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse‐plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2‐year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo‐HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group. [ABSTRACT FROM AUTHOR]

Introduction: We used a Programme Science platform, to generate evidence to support the implementation of programmes for sex workers in Africa. Female sex workers are estimated to make up 1.6% (1.3%–1.8%) of the population of women aged 15−49 years in Zimbabwe. We highlight how programme science can be used to help distinguish between when, where and with whom programmes need to be implemented and discuss two case studies that exemplify implementing better (Case study 1 (1 June 2019−30 June 2021) Optimizing implementation of a risk differentiated microplanning intervention) and implementing differently (Case study 2 (1 October 2016−30 September 2022) Reorientating implementation of DREAMS for young women selling sex). Methods: Zimbabwe's nationally scaled programme for sex workers was established in 2009 in partnership with sex workers to provide comprehensive services for sex workers and generate evidence for programme design, implementation and scale up. Since inception, comprehensive data have been collected from all sex workers seeking services. As the scope of service provision has expanded so has the scope of data collection and analysis. At enrolment, sex workers are assigned an alphanumeric unique identifier which links consultations within and across programme sites. We conduct descriptive analyses of the Key Population (KP) programme data to guide programme implementation and redesign, embedding programmatic qualitative enquiry as required. Results: Two case studies describing different approaches to programme optimization are presented. In the first, an optimization exercise was used to strengthen programme implementation ensuring that the KP programme got back on track after SARS‐COV‐2. In the second, an in‐depth review of research and programme data led to a re‐orientation of the DREAMS programme to ensure that young women at the highest risk of HIV acquisition were enrolled and had access to DREAMS social support interventions in turn strengthening their uptake of HIV prevention. Conclusions: Optimizing and sustaining HIV care and treatment programmes requires effective delivery with sufficient scale and intensity for population impact. Our programme science approach guided the scale up of the KP programme in Zimbabwe, providing evidence to support strategy, implementation and ongoing management, and importantly helping us distinguish between when we needed to just implement, implement better or implement differently. [ABSTRACT FROM AUTHOR]

We examine whether improved cross‐border regulatory cooperation and information exchange affect corporate tax avoidance. We find that the improvement in the regulators' capacity to access to information in foreign countries through their entrance into the Multilateral Memorandum of Understanding (MMoU) effectively reduces corporate tax avoidance. Moreover, the effect of the MMoU on corporate tax avoidance is stronger for firms that are less income mobile and have no significant subsidiaries in tax havens. Collectively, these findings support the conjecture that the strengthened cross‐border regulatory cooperation and information exchange provided by the MMoU creates a positive externality in reducing corporate tax avoidance behavior. [ABSTRACT FROM AUTHOR]

Summary: Background: Sneddon syndrome is an occlusive vasculopathy that presents clinically with generalized livedo racemosa on the skin and transient ischemic attacks, strokes, and cognitive or motor deficits in the central nervous system. Antiplatelet or anticoagulant therapy is recommended. Due to the limited therapeutic efficacy and the resulting serious complications, we propose combination therapy with additional infusion cycles of alprostadil and captopril and report initial long‐term results. Patients and methods: We performed a systematic retrospective analysis of all patients with primary Sneddon syndrome who received combination therapy in our clinic between 1995 and 2020. Therapeutic outcomes were evaluated using descriptive statistics compared to historical controls receiving monotherapy. We also analyzed the event rate of complications when combination therapy was discontinued. Results: During the 99.7 patient‐years of follow‐up, there were no transient ischemic attacks and the stroke rate dropped to 0.02 per patient‐year. In comparison, the rates of transient ischemic attacks and strokes in the historical controls ranged from 0.08 to 0.035 per patient‐year. After discontinuation of alprostadil therapy, eight events occurred in three patients. Conclusions: Combination therapy reduces the long‐term incidence of ischemic events in patients with primary Sneddon syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Improving the delivery of existing evidence‐based interventions to prevent and diagnose HIV is key to Ending the HIV Epidemic in the United States. Structural barriers in the access and delivery of related health services require municipal or state‐level policy changes; however, suboptimal implementation can be addressed directly through interventions designed to improve the reach, effectiveness, adoption or maintenance of available interventions. Our objective was to estimate the cost‐effectiveness and potential epidemiological impact of six real‐world implementation interventions designed to address these barriers and increase the scale of delivery of interventions for HIV testing and pre‐exposure prophylaxis (PrEP) in three US metropolitan areas. Methods: We used a dynamic HIV transmission model calibrated to replicate HIV microepidemics in Atlanta, Los Angeles (LA) and Miami. We identified six implementation interventions designed to improve HIV testing uptake ("Academic detailing for HIV testing," "CyBER/testing," "All About Me") and PrEP uptake/persistence ("Project SLIP," "PrEPmate," "PrEP patient navigation"). Our comparator scenario reflected a scale‐up of interventions with no additional efforts to mitigate implementation and structural barriers. We accounted for potential heterogeneity in population‐level effectiveness across jurisdictions. We sustained implementation interventions over a 10‐year period and evaluated HIV acquisitions averted, costs, quality‐adjusted life years and incremental cost‐effectiveness ratios over a 20‐year time horizon (2023–2042). Results: Across jurisdictions, implementation interventions to improve the scale of HIV testing were most cost‐effective in Atlanta and LA (CyBER/testing cost‐saving and All About Me cost‐effective), while interventions for PrEP were most cost‐effective in Miami (two of three were cost‐saving). We estimated that the most impactful HIV testing intervention, CyBER/testing, was projected to avert 111 (95% credible interval: 110–111), 230 (228–233) and 101 (101–103) acquisitions over 20 years in Atlanta, LA and Miami, respectively. The most impactful implementation intervention to improve PrEP engagement, PrEPmate, averted an estimated 936 (929–943), 860 (853–867) and 2152 (2127–2178) acquisitions over 20 years, in Atlanta, LA and Miami, respectively. Conclusions: Our results highlight the potential impact of interventions to enhance the implementation of existing evidence‐based interventions for the prevention and diagnosis of HIV. [ABSTRACT FROM AUTHOR]

Background: In Tanzania, inadequate infrastructures and shortages of trauma‐response training exacerbate trauma‐related fatalities. McGill University's Centre for Global Surgery introduced the Trauma and Disaster Team Response course (TDTR) to address these challenges. This study assesses the impact of simulation‐based TDTR training on care providers' knowledge/skills and healthcare processes to enhance patient outcomes. Methods: The study used a pre‐post‐interventional design. TDTR, led by Tanzanian instructors at Muhimbili Orthopedic Institute from August 16–18, 2023, involved 22 participants in blended online and in‐person approaches with simulated skills sessions. Validated tools assessed participants' knowledge/skills and teamwork pre/post‐interventions, alongside feedback surveys. Outcome measures included evaluating 24‐h emergency department patient arrival‐to‐care time pre‐/post‐TDTR interventions, analyzed using parametric and non‐parametric tests based on data distributions. Results: Participants' self‐assessment skills significantly improved (median increase from 34 to 58, p < 0.001), along with teamwork (median increase from 44.5 to 87.5, p < 0.003). While 99% of participants expressed satisfaction with TDTR meeting their expectations, 97% were interested in teaching future sessions. The six‐month post‐intervention arrival‐to‐care time significantly decreased from 29 to 13 min, indicating a 55.17% improvement (p < 0.004). The intervention led to fewer ward admissions (35.26% from 51.67%) and more directed to operating theaters (29.83% from 16.85%), suggesting improved patient management (p < 0.018). Conclusion: The study confirmed surgical skills training effectiveness in Tanzanian settings, highlighting TDTR's role in improving teamwork and healthcare processes that enhanced patient outcomes. To sustain progress and empower independent trauma educators, ongoing refresher sessions and expanding TDTR across low‐ and middle‐income countries are recommended to align with global surgery goals. [ABSTRACT FROM AUTHOR]

Turn‐taking interactions are foundational to the development of social, communicative, and cognitive skills. In infants, vocal turn‐taking experience is predictive of infants' socioemotional and language development. However, different forms of turn‐taking interactions may have different effects on infant vocalizing. It is presently unknown how caregiver vocal, non‐vocal and multimodal responses to infant vocalizations compare in extending caregiver‐infant vocal turn‐taking bouts. In bouts that begin with an infant vocalization, responses that maintain versus change the communicative modality may differentially affect the likelihood of further infant vocalizing. No studies have examined how caregiver response modalities that either matched or differed from the infant acoustic (vocal) modality might affect the temporal structure of vocal turn‐taking beyond the initial serve‐and‐return exchanges. We video‐recorded free‐play sessions of 51 caregivers with their 9‐month‐old infants. Caregivers responded to babbling most often with vocalizations. In turn, caregiver vocal responses were significantly more likely to elicit subsequent infant babbling. Bouts following an initial caregiver vocal response contained significantly more turns than those following a non‐vocal or multimodal response. Thus prelinguistic turn‐taking is sensitive to the modality of caregivers' responses. Future research should investigate if such sensitivity is grounded in attentional constraints, which may influence the structure of turn‐taking interactions. [ABSTRACT FROM AUTHOR]

Aims: To establish which components of energy balance mediate the clinically significant weight loss demonstrated with use of cotadutide, a glucagon‐like peptide‐1 (GLP‐1)/glucagon receptor dual agonist, in early‐phase studies. Materials and Methods: We conducted a phase 2a, single‐centre, randomized, placebo‐controlled trial in overweight and obese adults with type 2 diabetes. Following a 16‐day single‐blind placebo run‐in, participants were randomized 2:1 to double‐blind 42‐day subcutaneous treatment with cotadutide (100–300 μg daily) or placebo. The primary outcome was percentage weight change. Secondary outcomes included change in energy intake (EI) and energy expenditure (EE). Results: A total of 12 participants (63%) in the cotadutide group and seven (78%) in the placebo group completed the study. The mean (90% confidence interval [CI]) weight change was −4.0% (−4.9%, −3.1%) and −1.4% (−2.7%, −0.1%) for the cotadutide and placebo groups, respectively (p = 0.011). EI was lower with cotadutide versus placebo (−41.3% [−66.7, −15.9]; p = 0.011). Difference in EE (per kJ/kg lean body mass) for cotadutide versus placebo was 1.0% (90% CI −8.4, 10.4; p = 0.784), assessed by doubly labelled water, and −6.5% (90% CI −9.3, −3.7; p < 0.001), assessed by indirect calorimetry. Conclusion: Weight loss with cotadutide is primarily driven by reduced EI, with relatively small compensatory changes in EE. [ABSTRACT FROM AUTHOR]

The specification of requirements and tests are crucial activities in automotive development projects. However, due to the increasing complexity of automotive systems, practitioners fail to specify requirements and tests for distributed and evolving systems with complex interactions when following traditional development processes. To address this research gap, we propose a technique that starts with the early identification of validation concerns from a stakeholder perspective, which we use to systematically design tests that drive a scenario‐based modeling and analysis of system requirements. To ensure complete and consistent requirements and test specifications in a form that is required in automotive development projects, we develop a Model‐Based Systems Engineering (MBSE) methodology. This methodology supports system architects and test designers in the collaborative application of our technique and in maintaining a central system model, in order to automatically derive the required specifications. We evaluate our methodology by applying it at KOSTAL (Tier1 supplier) and within student projects as part of the masters program Embedded Systems Engineering. Our study corroborates that our methodology is applicable and improves existing requirements and test specification processes by supporting the integrated and stakeholder‐focused modeling of product and validation systems, where the early definition of stakeholder and validation concerns fosters a problem‐oriented, iterative and test‐driven requirements modeling. [ABSTRACT FROM AUTHOR]

Background: This study focuses on biomarkers in infants after open heart surgery, and examines the association of high‐sensitive troponin T (hs‐cTnT), interleukin‐6 (IL‐6), and interleukin‐8 (IL‐8) with postoperative acute kidney injury (AKI), ventilatory support time and need of vasoactive drugs. Methods: Secondary exploratory study from a double‐blinded clinical randomized trial (Mile‐1) on 70 infants undergoing open heart surgery with cardiopulmonary bypass (CPB). In this sub‐study, the entire study population was examined without considering the study drugs. The biomarkers' peak concentration (highest concentration at 2 or 6 h post‐CPB) were used for statistical analyses. Results: Peak IL‐8, hs‐cTnT, and IL‐6 occurred at 2 h post‐CPB for 96%, 79%, and 63% of the patients, respectively. The odds ratio of developing AKI2‐3 for IL‐6 > 293 pg/mL was 23.4 (95% CI 5.3;104.0), for IL‐8 > 100 pg/mL it was 11.5 (3.0;44.2), and for hs‐cTnT >5597 pg/mL it was 6.1 (1.5; 24.5). In more than two third of the patients with the highest peak concentrations of IL‐8, IL‐6, and hs‐cTnT, there was a need for ventilatory support for >24 h and use of vasoactive drugs at 24 h post‐CPB, while in less than one third of the patients with the lowest peak concentrations of IL‐8 and hs‐cTnT such requirements were observed. Conclusions: The peak biomarker concentrations and CPB‐time strongly predicted AKI2‐3, with IL‐6 and IL‐8 emerging as strongest predictors. Furthermore, our findings suggest that measuring hs‐cTnT and IL‐8 just 2 h post‐CPB‐weaning may assist in identifying infants suitable for early extubation and highlight those at risk of prolonged ventilation. [ABSTRACT FROM AUTHOR]

Purpose: This paper proposes a novel self‐supervised learning framework that uses model reinforcement, REference‐free LAtent map eXtraction with MOdel REinforcement (RELAX‐MORE), for accelerated quantitative MRI (qMRI) reconstruction. The proposed method uses an optimization algorithm to unroll an iterative model‐based qMRI reconstruction into a deep learning framework, enabling accelerated MR parameter maps that are highly accurate and robust. Methods: Unlike conventional deep learning methods which require large amounts of training data, RELAX‐MORE is a subject‐specific method that can be trained on single‐subject data through self‐supervised learning, making it accessible and practically applicable to many qMRI studies. Using quantitative T1$$ {\mathrm{T}}_1 $$ mapping as an example, the proposed method was applied to the brain, knee and phantom data. Results: The proposed method generates high‐quality MR parameter maps that correct for image artifacts, removes noise, and recovers image features in regions of imperfect image conditions. Compared with other state‐of‐the‐art conventional and deep learning methods, RELAX‐MORE significantly improves efficiency, accuracy, robustness, and generalizability for rapid MR parameter mapping. Conclusion: This work demonstrates the feasibility of a new self‐supervised learning method for rapid MR parameter mapping, that is readily adaptable to the clinical translation of qMRI. [ABSTRACT FROM AUTHOR]

Previous studies have suggested a relationship between the number of CAG triplet repeats in the HTT gene and neurodegenerative diseases not related to Huntington's disease (HD). This study seeks to investigate whether the number of CAG repeats of HTT is associated with the risk of developing certain tauopathies and its influence as a modulator of the clinical and neuropathological phenotype. Additionally, it aims to evaluate the potential of polyglutamine staining as a neuropathological screening. We genotyped the HTT gene CAG repeat number and APOE‐ℰ isoforms in a cohort of patients with neuropathological diagnoses of tauopathies (n=588), including 34 corticobasal degeneration (CBD), 98 progressive supranuclear palsy (PSP) and 456 Alzheimer's disease (AD). Furthermore, we genotyped a control group of 1070 patients, of whom 44 were neuropathologic controls. We identified significant differences in the number of patients with pathological HTT expansions in the CBD group (2.7%) and PSP group (3.2%) compared to control subjects (0.2%). A significant increase in the size of the HTT CAG repeats was found in the AD compared to the control group, influenced by the presence of the Apoliprotein E (APOE)‐ℰ4 isoform. Post‐mortem assessments uncovered tauopathy pathology with positive polyglutamine aggregates, with a slight predominance in the neostriatum for PSP and CBD cases and somewhat greater limbic involvement in the AD case. Our results indicated a link between HTT CAG repeat expansion with other non‐HD pathology, suggesting they could share common neurodegenerative pathways. These findings support that genetic or histological screening for HTT repeat expansions should be considered in tauopathies. [ABSTRACT FROM AUTHOR]

For aging‐related research, there is a pressing need to attend to the dissemination and implementation of evidence‐based interventions. Some aging‐related interventions with established effectiveness may be poorly disseminated and implemented due to behavioral, organizational, payment, or other constraints. To provide insight into the beginning to end process of translation and implementation, we present a case history of the three‐decade progression of Hospital at Home (HaH) now nearing national dissemination. We summarize research at various phases with particular attention to implementation considerations. Reviewing over three decades of HaH‐related research dating from initial discovery to translation and implementation, we found that the content and importance of different constructs (e.g., inner practice vs. outer environmental setting) and the choice of implementation strategies differed depending on implementation context (testing of effectiveness, scaling, or sustainability). Early effectiveness studies mostly examined implementation issues related to the intervention, the practice setting, and the individuals involved. However, explicit and early consideration of scale and sustainment was not the primary focus. For example, HaH program intake is primarily through hospital emergency departments (ED). Initial efforts would have benefited from incorporating strategies (e.g., incorporating ED leadership into program leadership) to address night and weekend admissions. Many regulatory barriers did not surface during initial considerations. Considering implementation issues late may contribute to delay in bringing discoveries to population impact. The experience with HaH suggests that scale and sustainability bear earlier consideration because barriers and facilitators to implementation are likely to be different in content and importance at different phases of implementation. [ABSTRACT FROM AUTHOR]

Plasma‐derived medicinal products (PDMPs) are recognized internationally as essential medicines required to treat various acute and chronic conditions including congenital deficiencies of plasma proteins in haemophilia and primary immune deficiency. Global provision of these medicines is dominated by a small number of commercial companies, influencing the price and availability of the products. Achieving a level of strategic independence from this dominance is now seen as a public health priority in many countries. During the Regional Congress of the International Society for Blood Transfusion (ISBT) in Cape Town, South Africa, in November 2023, around 50 delegates from 24 countries participated in a workshop (WS) organized jointly by the International Plasma and Fractionation Association (IPFA) and the ISBT Working Party on Global Blood Safety on pathways towards provision of PDMPs from domestic plasma independent of commercial purchase in the open market. The WS was structured around three themes, each addressed by a separate group: Quality/safety requirements for plasma for fractionation (PfF) Stepwise access for safe plasma proteins Approaching contract fractionation A synthesis of conclusions from these groups included the following: The need to acquire support from government authorities for a national plasma policy, recognizing the difficulties posed by unstable political and bureaucratic environments. The value of embedding plasma and PDMPs within a patient blood management (PBM) paradigm to promote optimal clinical use of PDMPs. Training of blood/plasma collection personnel in the relevant principles of Good Manufacturing Practice (GMP), coupled with regulatory oversight of plasma product production in the engaged jurisdictions. Appreciation that limited access to contract fractionation may necessitate a stepwise approach, which may include small‐scale preparation of versions of essential plasma proteins as an intermediate phase towards the manufacture of industrial‐scale PDMPs from domestic plasma. [ABSTRACT FROM AUTHOR]

Despite intensified efforts to better quantify Internal Tide dynamics over past decades, large uncertainties remain regarding their distribution and lifecycle in the ocean. In particular, internal tide incoherence (loss of time‐regularity) has limited our ability to characterize, understand, and predict internal tides, challenging the exploitation of new‐generation wide‐swath satellite altimeters. Based on a realistic high‐resolution numerical simulation, we quantify the internal tide distribution and incoherence properties in the North Atlantic. We quantify IT incoherence for sea level and surface currents, and for different vertical modes independently. Our results show that typical decorrelation timescale induced by the mesoscale turbulence are rather short—below 25 days for the first vertical mode. It further exhibits a strong dependence of the internal tide incoherence with location, reflecting regions of enhanced eddy activity, and with vertical mode number—higher baroclinic modes being much more incoherent with shorter decorrelation timescale. Plain Language Summary: Internal tides are perturbations of currents and density that propagate in the ocean (i.e., internal waves) and are generated when the astronomical tide flows over underwater topographic features. Because of interactions with other types of currents in the ocean, the corresponding signal is not perfectly regular in time, which has limited our understanding and ability to predict these motions for decades. In this study, we quantify this loss‐of‐regularity of the internal tides based on a numerical simulation of the North Atlantic. Key Points: Surface signatures of semidiurnal coherent and incoherent internal tides are quantified and decomposed into vertical mode contributionsIntra‐annual decorrelation time scale is typically less than 20 days for the first baroclinic mode, and less than 10 days for higher modesMean levels of incoherence of sea level and current are 55% and 68% (variance fraction), reflecting a larger high mode content in currents [ABSTRACT FROM AUTHOR]

This study investigates the germination requirements of 12 plant species native to the Argyle region of the east Kimberley, a biodiverse monsoonal tropical region characterized by high temperatures, high evaporation, and episodic seasonal rainfall. The research involved quality assessment of mature seeds, followed by dormancy alleviation and laboratory‐based germination to determine the responses of seeds to a range of temperatures (5–40°C) in terms of germination speed (T10), mean germination time, and maximum germination proportion. Data were then modeled to calculate the optimal temperature to support germination for each species. The results showed that germination rapidly commences in response to a wide range of temperatures typical of the wet season (November–February) in the east Kimberley, though germination for most species was still high (>50%) after exposure to temperatures as low as 15°C. Mean optimal temperature for germination across all species was 25.8 ± 1.5°C, with minimal variation between most species, the exception being Dodonaea physocarpa, which preferred cooler temperatures (Topt = 14.0°C). The speed of germination was also rapid (T10 = 1–3 days) across all species at the optimal germination temperature. The findings suggest that temperature is not a limiting factor for germination in this region and that the onset and intensity of the wet season are the most significant factors determining successful germination, emergence, and seedling establishment. The study underscores the importance of species‐specific understanding of environmental temperatures required for seed germination in seed‐based restoration efforts and informs the planning of direct seeding works, thus enhancing restoration outcomes. [ABSTRACT FROM AUTHOR]