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Abstract We report the successful treatment of a patient with refractory follicular lichen planus (LP) with topical ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, which resulted in significant improvement of lesional skin within 1 month of daily use.

Abstract Passive acoustic monitoring (PAM) is commonly used to obtain year‐round continuous data on marine soundscapes harboring valuable information on species distributions or ecosystem dynamics. This continuously increasing amount of data requires highly efficient automated analysis techniques in order to exploit the full potential of the available data. Here, we propose a benchmark, which consists of a public dataset, a well‐defined task and evaluation procedure to develop and test automated analysis techniques. This benchmark focuses on the special case of detecting animal vocalizations in a real‐world dataset from the marine realm. We believe that such a benchmark is necessary to monitor the progress in the development of new detection algorithms in the field of marine bioacoustics. We ultimately use the proposed benchmark to test three detection approaches, namely ANIMAL‐SPOT, Koogu and a simple custom sequential convolutional neural network (CNN), and report performances. We report the performance of the three detection approaches in a blocked cross‐validation fashion with 11 site‐year blocks for a multi‐species detection scenario in a large marine passive acoustic dataset. Performance was measured with three simple metrics (i.e., true classification rate, noise misclassification rate and call misclassification rate) and one combined fitness metric, which allocates more weight to the minimization of false positives created by noise. Overall, ANIMAL‐SPOT performed the best with an average F metric of 0.83, followed by the custom CNN with an average fitness metric of 0.79 and finally Koogu with an average fitness metric of 0.59. The presented benchmark is an important step to advance in the automatic processing of the continuously growing amount of PAM data that are collected throughout the world's oceans. To ultimately achieve usability of developed algorithms, the focus of future work should be laid on the reduction of the false positives created by noise.

ABSTRACT Background Impaired myocardial function and arrhythmia are important manifestations of Marfan syndrome (MFS). Studies assessing myocardial fibrosis in relation to these manifestations are scarce. Methods This cross‐sectional, single‐center study assessed ventricular volumes, ventricular function, and myocardial fibrosis by cardiac magnetic resonance imaging (CMR) in patients with MFS harboring a (likely) pathogenic FBN1 variant. The presence and extent of fibrosis were assessed by late gadolinium enhancement (LGE) and extracellular volume measurement (ECV). Data on 24‐h Holter monitoring and clinical data were extracted from electronic patient records. Results The study included 32 unselected patients with MFS (median age 38 years [range 10–69], 41% women). No focal myocardial fibrosis was detected. Six patients (21%) had diffuse fibrosis (ECV > 29%). No association was found between the presence of diffuse fibrosis and clinically relevant myocardial dysfunction. Five patients (16%) had reduced left ventricular ejection fraction (LVEF 29%. Patients with MAD had increased indexed LV volumes (median end‐diastolic volume, 92 mL/m2 [IQR, 78–100] vs. 78 mL/m2 [IQR, 71–87]; median end‐systolic volume, 31 mL/m2 [IQR, 23–46] vs. 22 mL/m2 [IQR, 21–28]), also after adjusting for the presence of mitral and aortic valve regurgitation. No differences in ECV were seen between patients with and without MAD. Conclusions In this cohort of patients with MFS, focal myocardial fibrosis was not detected using CMR. Although diffuse fibrosis was observed in 21% of patients, no evident connection to clinically relevant myocardial dysfunction was found. Further studies should evaluate the impact of diffuse fibrosis on clinical outcome prediction.

Abstract Erythrocytosis or polycythemia refers to a true or apparent increase in hemoglobin or hematocrit. When no etiology of erythrocytosis is identified, people are diagnosed with “idiopathic erythrocytosis” (IE). The identification of new contributing genes has recently improved the diagnostic workup of IE. As such mutations within the SH2B3 gene, which codes for the LNK protein and negatively regulates the JAK‐STAT pathway, have been identified in cases diagnosed as IE. This reports describes the presence of a previously undescribed germline SH2B3 variant p.(Thr335ArgfsTer4) within IE and emphasizes the advantages of gene panel sequencing as second step in the diagnostic work‐up.

Abstract Following a request from the European Commission, the European Food Safety Authority (EFSA) assessed the 2022 post‐market environmental monitoring (PMEM) report on the cultivation of Cry1Ab‐expressing maize event MON 810. Overall, the 2022 PMEM report provides no evidence of adverse effects of maize MON 810 cultivation. It shows a high level of compliance with refuge requirements by Spanish and Portuguese farmers growing maize MON 810, but uncertainty remains on compliance in areas where the clustered surface of maize MON 810 farms exceeds 5 ha. There are no signs of practical resistance to Cry1Ab in the field in corn borer populations collected in north‐eastern Spain in 2022, although a decrease in Cry1Ab susceptibility in Mediterranean corn borer populations from this area cannot be excluded. Information retrieved through farmer questionnaires in Spain and from the scientific literature reveals no unanticipated adverse effects on human and animal health or the environment arising from the cultivation of maize MON 810. Uncertainties remain on whether ‘very highly’ and ‘extremely’ sensitive non‐target lepidoptera are potentially exposed to harmful amounts of MON 810 pollen. EFSA notes that several recommendations made in the frame of the assessment of previous PMEM reports remain unaddressed and identified additional shortcomings in the 2022 PMEM report that require further consideration by the consent holder in future annual PMEM reports. Particularly, EFSA emphasises the urgent need to increase the sensitivity of the insect resistance monitoring strategy and implement mitigation measures to ensure that the exposure of non‐target lepidoptera to maize MON 810 pollen is reduced to levels of no concern.

Abstract Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor–naive patients from SIMPLIFY‐1 (NCT01969838), a double‐blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1‐grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.

Abstract Myelofibrosis (MF) is a clonal malignancy frequently characterized by anemia and in 10%–20% of cases it can evolve into blast phase (BP). Anemia in MF is associated with reduced survival and ‐in primary MF‐ also with an increased probability of BP. Conventional treatments for anemia have limited effectiveness in MF. Within a dataset of 1752 MF subjects largely unexposed to ruxolitinib (RUX), BP incidence was 2.5% patients per year (p‐y). This rate reached respectively 4.3% and 4.5% p‐y in case of patients with common terminology criteria for adverse events (CTCAE) grade 3/4 and grade 2 anemia, respectively, that represented together 32% of the cohort. Among 273 MF cases treated with RUX, BP incidence was 2.89% p‐y and it reached 4.86% p‐y in subjects who started RUX with CTCAE grade 2 anemia (one third of total). Within patients with red blood cell transfusion‐dependency at 6 months of RUX (21% of the exposed), BP rate was 4.2% p‐y. Our study highlights a relevant incidence of BP in anemic MF patients, with a similar rate whether treated with or without RUX. These findings will help treating physicians to make decisions on the safety profile of innovative anemia treatments.

Abstract Distyly, a floral dimorphism that promotes outcrossing, is controlled by a hemizygous genomic region known as the S‐locus. Disruptions of genes within the S‐locus are responsible for the loss of distyly and the emergence of homostyly, a floral monomorphism that favors selfing. Using whole‐genome resequencing data of distylous and homostylous individuals from populations of Primula vulgaris and leveraging high‐quality reference genomes of Primula we tested, for the first time, predictions about the evolutionary consequences of transitions to selfing on S‐genes. Our results reveal a previously undetected structural rearrangement in CYPᵀ associated with the shift to homostyly and confirm previously reported, homostyle‐specific, loss‐of‐function mutations in the exons of the S‐gene CYPᵀ. We also discovered that the promoter and intronic regions of CYPᵀ in distylous and homostylous individuals are conserved, suggesting that down‐regulation of CYPᵀ via mutations in its promoter and intronic regions is not a cause of the shift to homostyly. Furthermore, we found that hemizygosity is associated with reduced genetic diversity in S‐genes compared with their paralogs outside the S‐locus. Additionally, the shift to homostyly lowers genetic diversity in both the S‐genes and their paralogs, as expected in primarily selfing plants. Finally, we tested, for the first time, long‐standing theoretical models of changes in S‐locus genotypes during early stages of the transition to homostyly, supporting the assumption that two copies of the S‐locus might reduce homostyle fitness.

Background. Paraneoplastic secretion of beta-subunit of human chorionic gonadotropin (β-HCG) in pulmonary carcinoma is rare. Case Presentation. A 65-year-old man presented with bilateral gynaecomastia with abnormally high levels of β-hCG and elevated oestradiol, progesterone, and testosterone levels on April 7, 2023. After excluding testicular malignancy, CT scan of the chest and abdomen revealed bilateral pulmonary lesions. Transthoracic biopsy confirmed malignancy with choriocarcinoma. MRI of the brain showed a solitary brain metastasis, while on a subsequent 18F-FDG PET/CT, no other metastatic lesions were seen. The patient was treated with chemoimmunotherapy carboplatin-etoposide-pembrolizumab with good partial response. Conclusion. Our case of a presumably stage IV dedifferentiated mNSCLC presenting as an extragonadal β-hCG secreting pulmonary choriocarcinoma is a very rare tumor with a poor prognosis. Its biology, origin, and treatment remain to be elucidated. Cancer genome sequencing is necessary for the identification of the origin and seeking treatment.

Abstract Objective To evaluate the relationship between pre‐operative PSA value, 68Ga‐prostate‐specific‐membrane‐antigen (PSMA) PET performance and oncologic outcomes after salvage lymph node dissection (sLND) for biochemical recurrent prostate cancer (PCa). Patients and methods The study included 164 patients diagnosed with ≤2 pelvic lymph‐node recurrence(s) of PCa documented on 68Ga‐PSMA PET scan and treated with pelvic ± retroperitoneal sLND at 11 high‐volume centres between 2012 and 2019. Pathologic findings were correlated to PSA values at time of sLND, categorized in early (1.5 ng/ml). Clinical recurrence (CR)‐free survival after sLND was calculated using multivariable analyses and plotted over pre‐operative PSA value. Results Median [interquartile range (IQR)] PSA at sLND was 1.1 (0.6, 2.0) ng/ml, and 131 (80%) patients had one positive spot at PET scan. All patients received pelvic sLND, whereas 91 (55%) men received also retroperitoneal dissection. Median (IQR) number of node removed was 15 (6, 28). The rate of positive pathology increased as a function of pre‐operative PSA value, with highest rates for patients with pre‐operative PSA > 1.5 ng/ml (pelvic‐only sLNDs: 84%; pelvic + retroperitoneal sLNDs: 90%). After sLND, PSA ≤ 0.3 ng/ml was detected in 67 (41%) men. On multivariable analyses, pre‐operative PSA was associated with PSA response (p

Abstract Following a request from the European Commission, the European Food Safety Authority (EFSA) assessed the 2021 post‐market environmental monitoring (PMEM) report on the cultivation of Cry1Ab‐expressing maize event MON 810. Evidence provided in the PMEM report shows that farmers growing maize MON 810 in Spain complied partially with refuge requirements, while full compliance was achieved in Portugal. Cry1Ab susceptibility tests performed on European and Mediterranean corn borer populations collected from north‐eastern Spain in 2021 indicated no symptoms of resistance evolution to maize MON 810. However, unexpected damage to maize MON 810 plants was observed in a field trial in the province of Girona (north‐eastern Spain), which may point to the presence of resistance alleles in this region. Information retrieved through farmer questionnaires and the scientific literature reveals no unanticipated adverse effects on human and animal health or the environment arising from the cultivation of maize MON 810. Overall, EFSA concludes that the evidence reported in the 2021 PMEM report does not invalidate its previous conclusions on the safety of maize MON 810. The possible presence of Cry1Ab resistance alleles at frequencies leading to damage to maize MON 810 plants in Girona requires twofold actions: (1) increase monitoring efforts in this area; and (2) implement remedial measures to limit the suspected evolution and spread of resistance. As in previous years, EFSA identified shortcomings on resistance monitoring that need revision. In particular, full refuge compliance must be achieved in Spain. Moreover, the sensitivity of the monitoring plan must be increased, which can be achieved by replacing the current susceptibility assays by periodic F2 screens. EFSA also recommends the consent holder to revise the farmer questionnaires to account for the emergence of teosinte as a noxious agricultural weed in maize MON 810‐growing areas in Spain.

Abstract Multisystem Inflammatory Syndrome in Adult (MIS‐A) is a rare COVID‐19 complication, presenting as fever with laboratory evidence of inflammation, severe illness requiring hospitalization and multisystem organ involvement. We report on a 25‐year‐old man presenting with fever, rash, abdominal pain, diarrhoea and vomiting following prior asymptomatic COVID‐19 infection. He developed refractory shock and type 1 respiratory insufficiency requiring mechanical ventilation. Diagnostic testing revealed significant inflammation, anemia, thrombocytopenia, acute kidney injury, hepatosplenomegaly, colitis, lymphadenopathy and myocarditis necessitating inotropy. Ventilatory, vasopressor and inotropic support was weaned following pulse corticosteroids and intravenous immunoglobulins. Heart failure therapy was started. Short‐term follow‐up shows resolution of inflammation and cardiac dysfunction.

Abstract Introduction Adolescent girls and young women (AGYW) face barriers that jeopardize their prevention‐effective use of daily oral pre‐exposure prophylaxis (PrEP). We sought to understand factors that influence AGYW's prolonged breaks in PrEP use, and their decisions to re‐initiate or discontinue using PrEP in the context of a community‐based adherence support intervention. Methods In‐depth interviews (IDIs) were conducted between December 2019 and April 2021 with purposively selected AGYW (aged 16–25) enrolled in the Community PrEP Study (CPS) in Buffalo City Metro Health District, Eastern Cape Province, South Africa. AGYW were offered monthly PrEP for 24 months at two community‐based study sites. Interview guides were informed by the Information‐Motivation‐Behavioural Skills Model, and data were analysed using illustrative code reports and a case analysis. Results A total of 603 participants were enrolled and initiated on PrEP in the parent study. Fifty‐three IDIs were conducted with 50 CPS participants. Findings revealed that external factors (e.g. local movement, school holidays and medication side‐effects) and social conflicts (e.g. discretion and partner mistrust) directly influenced breaks in PrEP usage. A decrease in one's self‐perception of HIV risk prolonged the duration of these “PrEP breaks.” Once PrEP refill visits were missed, some AGYW delayed returning for refills out of fear of being scolded by study staff. The differences between those participants who eventually re‐initiated PrEP and those who disengaged from PrEP use can be attributed to social support and encouragement, level of familiarity with PrEP, risk perceptions, self‐initiated discussions with staff and diminishing side effects. Conclusions Despite implementing a community‐based PrEP delivery platform and behavioural intervention that included support for daily oral PrEP adherence and disclosure, participants struggled with consistent daily oral PrEP use. Unpredictable life events, including local movement and schooling schedules, in addition to being judged for their perceived behaviours, pose a challenge for consistent pill pick‐up for AGYW and habit formation. Long‐acting injectable PrEP may mitigate a number of these external barriers. Interventions that integrate long‐term planning skills, how to navigate existing social judgements and how to access sources of social support may further improve habit formation for PrEP use, regardless of its formulation.

Abstract Children treated in a pediatric intensive care unit (PICU) are at risk of distress and pain. This study investigated if aromatherapy massage can reduce children's distress and improve comfort. This observational before‐after study was performed in a 22‐bed PICU in Cape Town, South Africa. The aromatherapy massage consisted of soft massaging using the “M‐technique” and a 1% blend of essential oils of Lavender (Lavandula angustifolia), German Chamomile (Matricatia recutita) and Neroli (Citrus aurantium) mixed with a grapeseed carrier oil. All present children were eligible, except those who had recently returned, were asleep or deemed unstable. The primary outcome was distress measured with the COMFORT‐Behavior scale (COMFORT‐B). Secondary outcomes were heart rate, oxygen saturation (SatO2), the Numeric Rating Scale (NRS)‐Anxiety and pain assessed by the NRS‐Pain scale. Outcomes variables were evaluated with Wilcoxon signed‐rank test and multiple regression analysis. The intervention was applied to 111 children, fifty‐one of whom (45.9%) were younger than three years old. The group median COMFORT‐B score before intervention was 15 (IQR 12–19), versus 10 (IQR 6–14) after intervention. Heart rate and NRS‐Anxiety were significantly lower after the intervention (P

Abstract Background The cause of the motor neuron (MN) death that drives terminal pathology in amyotrophic lateral sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards MNs, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Because MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle‐secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology. Methods Sporadic ALS patients were confirmed to be ALS according to El Escorial criteria and were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS‐R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n = 27) or deltoids of aged‐matched healthy subjects (n = 30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RT‐qPCR, and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human‐derived iPSC MNs and on healthy human myotubes, with untreated cells used as controls. Results An accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy‐derived denervation‐naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome‐like vesicles and disruption of RNA‐processing. Compared with vesicles from healthy control myotubes, when administered to healthy MNs the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA‐processing proteins. The RNA‐processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient MNs was abolished by anti‐CD63 immuno‐blocking of vesicle uptake. Conclusions ALS muscle vesicles are shown to be toxic to MNs, which establishes the skeletal muscle as a potential source of vesicle‐mediated toxicity in ALS.

Abstract Background Brown adipose tissue (BAT) has been primarily researched as a potential target for mitigating obesity. However, the physiological significance of BAT in relation to cachexia remains poorly understood. The objective of this study was to investigate the putative contribution of BAT on different components of energy metabolism in emphysematous chronic obstructive pulmonary disease (COPD) patients. Methods Twenty COPD patients (mean ± SD age 62 ± 6, 50% female, median [range] BMI 22.4 [15.1–32.5] kg/m2 and 85% low FFMI) were studied. Basal metabolic rate (BMR) was assessed by ventilated hood, total daily energy expenditure (TDEE) by doubly labelled water and physical activity by triaxial accelerometry. BMR was adjusted for fat‐free mass (FFM) as assessed by deuterium dilution. Analysis of BAT and WAT was conducted in a subset of ten patients and six age‐matched, gender‐matched and BMI‐matched healthy controls. BAT glucose uptake was assessed by means of cold‐stimulated integrated [18F]FDG positron‐emission tomography and magnetic resonance imaging. WAT was collected from subcutaneous abdominal biopsies to analyse metabolic and inflammatory gene expression levels. Lung function was assessed by spirometry and body plethysmography and systemic inflammation by high sensitivity C‐reactive protein. Results Mean TDEE was 2209 ± 394 kcal/day, and mean BMR was 1449 ± 214 kcal/day corresponding to 120% of predicted. FFM‐adjusted BMR did not correlate with lung function or C‐reactive protein. Upon cooling, energy expenditure increased, resulting in a non‐shivering thermogenesis of (median [range]) 20.1% [3.3–41.3] in patients and controls. Mean BAT glucose uptake was comparable between COPD and controls (1.5 [0.1–6.2] vs. 1.1 [0.7–3.9]). In addition, no correlation was found between BMR adjusted for FFM and BAT activity or between cold‐induced non‐shivering energy expenditure and BAT activity. Gene expression levels of the brown adipocyte or beige markers were also comparable between the groups. No (serious) adverse events were reported. Conclusions Although COPD patients were hypermetabolic at rest, no correlation was found between BMR or TDEE and BAT activity. Furthermore, both BAT activity and gene expression levels of the brown adipocyte or beige markers were comparable between COPD patients and controls.

Abstract Purpose To evaluate the cancer research effort of some major countries over two 5‐year periods (2010–2014 and 2015–2019) on the basis of scientific publications and interventional clinical trial metrics and to analyze the relationship between research effort and cancer burden (incidence and mortality). Materials and Methods Clinical trials were extracted from ClinicalTrials.gov using a specific query. Publications were identified in Web of Science (WoS) using a query based on keywords and were then analyzed using InCites, a bibliometric tool. Bibliometric indicators were computed per country and per period. Results During 2010–2019, 1 120 821 cancer‐related publications were identified in WoS, with 447 900 and 672 921 (+50%) articles respectively published in 2010–2014 and 2015–2019. Meanwhile, 38% and 7% of the articles were published in oncology and cell biology journals, respectively. Exactly 30% of the published articles were contributed by the USA. In the study period, China strongly increased its production and overspecialization. Apart from China, which had a low normalized citation impact (NCI), almost all countries increased their NCIs; in particular, France's NCI increased from 1.69 to 2.44. As for clinical trials, over 36 856 were opened worldwide during that period. Over 17 000 (46.5%) opened in the USA, which remained the leader during the study period. China ranked second worldwide in terms of the number of open trials in 2015–2019. Results revealed that the 17 cancer localizations versus cancer burden and research effort showed no evident relationship. Conclusion The results may provide a scientific basis for decision making for continued research. Based on bibliometric data, this type of study will aid public health policymaking and lead to a more transparent public fund allocation.

Abstract Genetically modified maize GA21 × T25 was developed by crossing to combine two single events: GA21 and T25. The GMO Panel previously assessed the two single maize events and did not identify safety concerns. No new data on the single maize events were identified that could lead to modification of the original conclusions on their safety. The molecular characterisation, comparative analysis (agronomic, phenotypic and compositional characteristics) and the outcome of the toxicological, allergenicity and nutritional assessment indicate that the combination of the single maize events and of the newly expressed proteins in maize GA21 × T25 does not give rise to food and feed safety and nutritional concerns. The GMO Panel concludes that maize GA21 × T25, as described in this application, is as safe as its conventional counterpart and the non‐GM reference varieties tested, and no post‐market monitoring of food and feed is considered necessary. In the case of accidental release of viable maize GA21 × T25 grains into the environment, this would not raise environmental safety concerns. The post‐market environmental monitoring plan and reporting intervals are in line with the intended uses of maize GA21 × T25. Post‐market monitoring of food and feed is not considered necessary. The GMO Panel concludes that maize GA21 × T25 is as safe as its conventional counterpart and the non‐GM reference varieties tested, with respect to potential effects on human and animal health and the environment.

Abstract Brain administration of human platelet lysates (HPL) is a potential emerging biotherapy of neurodegenerative and traumatic diseases of the central nervous system. HPLs being prepared from pooled platelet concentrates, thereby increasing viral risks, manufacturing processes should incorporate robust virus‐reduction treatments. We evaluated a 19 ± 2‐nm virus removal nanofiltration process using hydrophilic regenerated cellulose hollow fibers on the properties of a neuroprotective heat‐treated HPL (HPPL). Spiking experiments demonstrated >5.30 log removal of 20–22‐nm non‐enveloped minute virus of mice‐mock particles using an immuno‐quantitative polymerase chain reaction assay. The nanofiltered HPPL (NHPPL) contained a range of neurotrophic factors like HPPL. There was >2 log removal of extracellular vesicles (EVs), associated with decreased expression of pro‐thrombogenic phosphatidylserine and procoagulant activity. LC‐MS/MS proteomics showed that ca. 80% of HPPL proteins, including neurotrophins, cytokines, and antioxidants, were still found in NHPPL, whereas proteins associated with some infections and cancer‐associated pathways, pro‐coagulation and EVs, were removed. NHPPL maintained intact neuroprotective activity in Lund human mesencephalic dopaminergic neuron model of Parkinson's disease (PD), stimulated the differentiation of SH‐SY5Y neuronal cells and showed preserved anti‐inflammatory function upon intranasal administration in a mouse model of traumatic brain injury (TBI). Therefore, nanofiltration of HPL is feasible, lowers the viral, prothrombotic and procoagulant risks, and preserves the neuroprotective and anti‐inflammatory properties in neuronal pre‐clinical models of PD and TBI.

Abstract All irreversible Bruton tyrosine kinase (Btk) inhibitors including ibrutinib and acalabrutinib induce platelet dysfunction and increased bleeding risk. New reversible Btk inhibitors were developed, like MK‐1026. The mechanism underlying increased bleeding tendency with Btk inhibitors remains unclear. We investigated the effects of ibrutinib, acalabrutinib and MK‐1026 on platelet function in healthy volunteers, patients and Btk‐deficient mice, together with off‐target effects on tyrosine kinase phosphorylation. All inhibitors suppressed GPVI‐ and CLEC‐2‐mediated platelet aggregation, activation and secretion in a dose‐dependent manner. Only ibrutinib inhibited thrombus formation on vWF‐co‐coated surfaces, while on collagen this was not affected. In blood from Btk‐deficient mice, collagen‐induced thrombus formation under flow was reduced, but preincubation with either inhibitor was without additional effects. MK‐1026 showed less off‐target effects upon GPVI‐induced TK phosphorylation as compared to ibrutinib and acalabrutinib. In ibrutinib‐treated patients, GPVI‐stimulated platelet activation, and adhesion on vWF‐co‐coated surfaces were inhibited, while CLEC‐2 stimulation induced variable responses. The dual inhibition of GPVI and CLEC‐2 signalling by Btk inhibitors might account for the increased bleeding tendency, with ibrutinib causing more high‐grade bleedings due to additional inhibition of platelet‐vWF interaction. As MK‐1026 showed less off‐target effects and only affected activation of isolated platelets, it might be promising for future treatment.

Abstract Originally described as a risk factor for autism, CHD8 loss‐of‐function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8‐related phenotype with the description of two unrelated patients who presented with childhood‐onset progressive dystonia. Whole‐exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild‐to‐moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder‐associated genes whose mutations can also result in dystonia‐dominant phenotypes.

Abstract Weedy rice is a representative of the extensive group of feral weeds that derive from crops, but has returned to the lifestyle of a wild species. These weeds develop either from a hybridization of crops with wild relatives (exoferality), or by mutation of crops to weedy forms (endoferality). Due to the close relation of weed and crop, the methods for weed‐targeted containment are limited to date. A deeper understanding of the development of such weeds might help to design more efficient and sustainable approaches for weed management. Weedy rice poses a serious threat to rice yields worldwide. It is widely accepted that weedy rice has originated independently in different regions all over the world. However, details of its evolution have remained elusive. In the current study, we investigated the history of weedy rice in northern Italy, the most important rice‐growing area in Europe. Our approach was to analyze genes related to weedy traits (SD1, sh4, Rc) in weedy rice accessions compared to cultivars, and to integrate these results with phenotypic and physiological data, as well as historical information about rice farming in Italy. We arrive at a working model for the timeline of evolution of weedy rice in Italy indicating that both exoferality and endoferality acted as forces driving the development of the diverse weedy rice populations found in the region today. Models of weed evolution can help to predict the direction which weed development might take and to develop new, sustainable methods to control feral weeds.

IGFBP‐3, the most abundant IGFBP and the main carrier of insulin‐like growth factor I (IGF‐I) in the circulation, can bind IGF‐1 with high affinity, which attenuates IGF/IGF‐IR interactions, thereby resulting in antiproliferative effects. The C‐terminal domain of insulin‐like growth factor‐binding protein‐3 (IGFBP‐3) is known to contain an 18‐basic amino acid motif capable of interacting with either humanin (HN) or hyaluronan (HA). We previously showed that the 18‐amino acid IGFBP‐3 peptide is capable of binding either HA or HN with comparable affinities to the full‐length IGFBP‐3 protein and that IGFBP‐3 can compete with the HA receptor, CD44, for binding HA. Blocking the interaction between HA and CD44 reduced viability of A549 human lung cancer cells. In this study, we set out to better characterize IGFBP‐3‐HA interactions. We show that both stereochemistry and amino acid identity are important determinants of the interaction between the IGFBP‐3 peptide and HA and for the peptide's ability to exert its cytotoxic effects. Binding of IGFBP‐3 to either HA or HN was unaffected by glycosylation or reduction of IGFBP‐3, suggesting that the basic 18‐amino acid residue sequence of IGFBP‐3 remains accessible for interaction with either HN or HA upon glycosylation or reduction of the full‐length protein. Removing N‐linked oligosaccharides from CD44 increased its ability to compete with IGFBP‐3 for binding HA, while reduction of CD44 rendered the protein relatively ineffective at blocking IGFBP‐3‐HA interactions. We conclude that both deglycosylation and disulfide bond formation are important for CD44 to compete with IGFBP‐3 for binding HA.

Objective The specialty of emergency medicine and recognition of the need for emergency care continue to grow globally. The specialty and emergency care systems vary according to context. This study characterizes the specialty of emergency medicine around the world, trends according to region and income level, and challenges for the specialty. Methods We distributed a 56‐question electronic survey to all members of the American College of Emergency Physicians International Ambassador Program between March 2019 and January 2020. The Ambassador Program leadership designed the survey covering specialty recognition, workforce, system components, and emergency medicine training. We analyzed results by country and in aggregate using SAS software (SAS Institute Inc). We tested the associations between World Bank income group and number of emergency medicine residency‐trained physicians (RTPs) and emergency medicine specialty recognition using non‐parametric Fisher's exact testing. We performed inductive coding of qualitative data for themes. Results Sixty‐three out of 78 countries’ teams (80%) responded to the survey. Response countries represented roughly 67% of the world's population and included countries in all World Bank income groups. Fifty‐four countries (86%) recognized emergency medicine as a specialty. Ten (16%) had no emergency medicine residency programs, and 19 (30%) had only one. Eight (11%) reported having no emergency medicine RTPs and 30 (48%) had 5 emergency medicine RTPs per 100,000 population, all high income. All 5 low‐income countries in the sample had

Abstract Teosinte, wild maize relatives originating from Mexico and Central America, emerged as a noxious agricultural weed in France and Spain. In 2016, the European Food Safety Authority (EFSA) issued a technical report that assessed the available scientific information on teosinte for its relevance for the environmental risk assessment (ERA) and risk management (RM) of genetically modified (GM) maize MON810, Bt11, 1507 and GA21 for cultivation. It was concluded that the impact of insect resistance and/or herbicide tolerance in GM teosinte hybrid progeny (potentially acquired through hybridisation between GM maize and teosinte) on target and non‐target organisms, the abiotic environment and biogeochemical cycles would be very low under EU conditions. Following a request of the European Commission, EFSA evaluated whether the ERA conclusions and RM recommendations of EFSA (2016) remain applicable, or require revision in light of new scientific evidence on teosinte that has become available since the publication of EFSA (2016). A protocol was developed to clarify the interpretation of the terms of reference of the mandate and make them operational. The assessment relied on evidence retrieved via an extensive literature search and from reports of the Competent Authorities of France and Spain, and on hearing expert testimonies. A limited collection of 18 publications of varying relevance and quality was retrieved and assessed. Based on this evidence, it is concluded that the ERA conclusions and RM recommendations of EFSA (2016) remain applicable, except those pertaining to the use of glyphosate‐based herbicides on maize GA21 which should be considered under Regulation (EC) No 1107/2009. In infested agricultural areas (especially in regions where maize MON810 is widely grown), weed management measures implemented to monitor, control and/or eradicate teosinte must remain in place, as they will contribute to further reduce the low vertical gene flow potential between GM maize and EU teosinte.

Abstract Finger millet [Eleusine coracana (L.) Gaertn.] is a critical subsistence crop in eastern Africa and southern Asia but has few genomic resources and modern breeding programs. To aid in the understanding of finger millet genomic organization and genes underlying disease resistance and agronomically important traits, we generated a F2:3 population from a cross between E. coracana (L.) Gaertn. subsp. coracana accession ACC 100007 and E. coracana (L.) Gaertn. subsp. africana , accession GBK 030647. Phenotypic data on morphology, yield, and blast (Magnaporthe oryzae) resistance traits were taken on a subset of the F2:3 population in a Kenyan field trial. The F2:3 population was genotyped via genotyping‐by‐sequencing (GBS) and the UGbS‐Flex pipeline was used for sequence alignment, nucleotide polymorphism calling, and genetic map construction. An 18‐linkage‐group genetic map consisting of 5,422 markers was generated that enabled comparative genomic analyses with rice (Oryza sativa L.), foxtail millet [Setaria italica (L.) P. Beauv.], and sorghum [Sorghum bicolor (L.) Moench]. Notably, we identified conserved acrocentric homoeologous chromosomes (4A and 4B in finger millet) across all species. Significant quantitative trait loci (QTL) were discovered for flowering date, plant height, panicle number, and blast incidence and severity. Sixteen putative candidate genes that may underlie trait variation were identified. Seven LEUCINE‐RICH REPEAT‐CONTAINING PROTEIN genes, with homology to nucleotide‐binding site leucine‐rich repeat (NBS‐LRR) disease resistance proteins, were found on three chromosomes under blast resistance QTL. This high‐marker‐density genetic map provides an important tool for plant breeding programs and identifies genomic regions and genes of critical interest for agronomic traits and blast resistance.

Abstract Virtual communities of practice (VCoPs) facilitate distance learning and mentorship by engaging members around shared knowledge and experiences related to a central interest. The American College of Emergency Physicians and Emergency Medicine Residents’ Association's Global Emergency Medicine Student Leadership Program (GEM‐SLP) provides a valuable model for building a VCoP for GEM and other niche areas of interest. This VCoP facilitates opportunities for experts and mentees affiliated with these national organizations to convene regularly despite barriers attributed to physical distance. The GEM‐SLP VCoP is built around multiple forms of mentorship, monthly mentee‐driven didactics, academic projects, and continued engagement of program graduates in VCoP leadership. GEM‐SLP fosters relationships through (1) themed mentoring calls (career paths, work/life balance, etc); (2) functional mentorship through didactics and academic projects; and (3) near‐peer mentoring, provided by mentors near the mentees’ stage of education and experience. Monthly mentee‐driven didactics focus on introducing essential GEM principles while (1) critically analyzing literature based on a journal article; (2) building a core knowledge base from a foundational textbook; (3) applying knowledge and research to a project proposal; and (4) gaining exposure to training and career opportunities via mentor career presentations. Group academic projects provide a true GEM apprenticeship as mentees and mentors work collaboratively. GEM‐SLP mentees found the VCoP beneficial in building fundamental GEM skills and knowledge and forming relationships with mentors and like‐minded peers. GEM‐SLP provides a framework for developing mentorship programs and VCoPs in emergency medicine, especially when niche interests or geographic distance necessitate a virtual format.

Abstract This report describes the successful treatment of two patients with trigeminal neuropathy by using gasserian ganglion stimulation. Case reports: The first case report deals with a 53‐year‐old woman suffering from right‐sided facial pain after a gamma knife lesion for schwannoma of the right inner ear. For 9 years, several interventions with the aim of relieving the pain were unsuccessful; in fact, they had aggravated the symptoms. A trial with a neurostimulator at the level of the Gasser ganglion had an immediately positive effect on her score for facial pain, which decreased from 7.3 to 0 on a visual analog scale, assessed during a period of 2 months. Additionally, the patient had weaned off all her medication by the end of the period. The second case report describes a 64‐year‐old man suffering from trigeminal neuropathy, which mainly manifested itself as an itch. For a period of 15 years, neither medication nor several interventions were effective. A trial with an electrode at the level of the Gasser ganglion reduced his pain score from 7.0 to 1.5 on a visual analog scale, assessed during a period of three months. His medication could be limited to pregabalin 150 mg bidaily. In contrast, prior to the implantation, his oral medication consisted of pregabalin 75 mg up to five times a day. Conclusion: These case reports show that stimulation of the gasserian ganglion is a successful, minimally invasive, and non‐destructive treatment in refractory trigeminal neuropathy and should be considered earlier in the treatment algorithm of trigeminal neuropathy.

Abstract Background This study evaluated the 3D angle between the joint moment and the joint angular velocity vectors at the intrinsic foot joints, and investigated if these joints are predominantly driven or stabilized during gait. Methods The participants were 20 asymptomatic subjects. A four-segment kinetic foot model was used to calculate and estimate intrinsic foot joint moments, powers and angular velocities during gait. 3D angles between the joint moment and the joint angular velocity vectors were calculated for the intrinsic foot joints defined as follows: ankle joint motion described between the foot and the shank for the one-segment foot model (hereafter referred as Ankle), and between the calcaneus and the shank for the multi-segment foot model (hereafter referred as Shank-Calcaneus); joint motion described between calcaneus and midfoot segments (hereafter referred as Chopart joint); joint motion described between midfoot and metatarsus segments (hereafter referred as Lisfranc joint); joint motion described between first phalanx and first metatarsal (hereafter referred as First Metatarso-Phalangeal joint). When the vectors were approximately aligned, the moment was considered to result in propulsion (3D angle 120o) at the joint. When the vectors are approximately orthogonal (3D angle close to 90°), the moment was considered to stabilize the joint. Results The results showed that the four intrinsic joints of the foot are never fully propelling, resisting or being stabilized, but are instead subject to a combination of stabilization with propulsion or resistance during the majority of the stance phase of gait. However, the results also show that during pre-swing all four the joints are subject to moments that result purely in propulsion. At heel off, the propulsive configuration appears for the Lisfranc joint first at terminal stance, then for the other foot joints at pre-swing in the following order: Ankle, Chopart joint and First Metatarso-Phalangeal joint. Conclusions Intrinsic foot joints adopt a stabilized-resistive configuration during the majority of the stance phase, with the exception of pre-swing during which all joints were found to adopt a propulsive configuration. The notion of stabilization, resistance and propulsion should be further investigated in subjects with foot and ankle disorders.