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In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing. ispartof: IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS vol:26 issue:11 pages:5282-5286 ispartof: location:United States status: published

Neural processing of the speech envelope is of crucial importance for speech perception and comprehension. This envelope processing is often investigated by measuring neural synchronization to sinusoidal amplitude-modulated stimuli at different modulation frequencies. However, it has been argued that these stimuli lack ecological validity. Pulsatile amplitude-modulated stimuli, on the other hand, are suggested to be more ecologically valid and efficient, and have increased potential to uncover the neural mechanisms behind some developmental disorders such a dyslexia. Nonetheless, pulsatile stimuli have not yet been investigated in pre-reading and beginning reading children, which is a crucial age for developmental reading research. We performed a longitudinal study to examine the potential of pulsatile stimuli in this age range. Fifty-two typically reading children were tested at three time points from the middle of their last year of kindergarten (5 years old) to the end of first grade (7 years old). Using electroencephalography, we measured neural synchronization to syllable rate and phoneme rate sinusoidal and pulsatile amplitude-modulated stimuli. Our results revealed that the pulsatile stimuli significantly enhance neural synchronization at syllable rate, compared to the sinusoidal stimuli. Additionally, the pulsatile stimuli at syllable rate elicited a different hemispheric specialization, more closely resembling natural speech envelope tracking. We postulate that using the pulsatile stimuli greatly increases EEG data acquisition efficiency compared to the common sinusoidal amplitude-modulated stimuli in research in younger children and in developmental reading research. ispartof: NEUROIMAGE vol:277 ispartof: location:United States status: accepted

The effects of sex on human facial morphology have been widely documented. Because sexual dimorphism is relevant to a variety of scientific and applied disciplines, it is imperative to have a complete and accurate account of how and where male and female faces differ. We apply a comprehensive facial phenotyping strategy to a large set of existing 3D facial surface images. We investigate facial sexual dimorphism in terms of size, shape, and shape variance. We also assess the ability to correctly assign sex based on shape, both for the whole face and for subregions. We applied a predefined data-driven segmentation to partition the 3D facial surfaces of 2446 adults into 63 hierarchically linked regions, ranging from global (whole face) to highly localized subparts. Each facial region was then analyzed with spatially dense geometric morphometrics. To describe the major modes of shape variation, principal components analysis was applied to the Procrustes aligned 3D points comprising each of the 63 facial regions. Both nonparametric and permutation-based statistics were then used to quantify the facial size and shape differences and visualizations were generated. Males were significantly larger than females for all 63 facial regions. Statistically significant sex differences in shape were also seen in all regions and the effects tended to be more pronounced for the upper lip and forehead, with more subtle changes emerging as the facial regions became more granular. Males also showed greater levels of shape variance, with the largest effect observed for the central forehead. Classification accuracy was highest for the full face (97%), while most facial regions showed an accuracy of 75% or greater. In summary, sex differences in both size and shape were present across every part of the face. By breaking the face into subparts, some shape differences emerged that were not apparent when analyzing the face as a whole. The increase in facial shape variance suggests possible evolutionary origins and may offer insights for understanding congenital facial malformations. Our classification results indicate that a high degree of accuracy is possible with only parts of the face, which may have implications for biometrics applications. ispartof: JOURNAL OF ANATOMY vol:243 issue:2 ispartof: location:England status: Published online

ADHD is the most common neurodevelopmental disorder presenting to child and adolescent mental health, paediatric, and primary care services. Timely and effective interventions to address core ADHD symptoms and co-occurring problems are a high priority for healthcare and society more widely. While much research has reported on the benefits and adverse effects of different interventions for ADHD, these individual research reports and the reviews, meta-analyses and guidelines summarizing their findings are sometimes inconsistent and difficult to interpret. We have summarized the current evidence and identified several methodological issues and gaps in the current evidence that we believe are important for clinicians to consider when evaluating the evidence and making treatment decisions. These include understanding potential impact of bias such as inadequate blinding and selection bias on study outcomes; the relative lack of high-quality data comparing different treatments and assessing long-term effectiveness, adverse effects and safety for both pharmacological and non-pharmacological treatments; and the problems associated with observational studies, including those based on large national registries and comparing treatments with each other. We highlight key similarities across current international clinical guidelines and discuss the reasons for divergence where these occur. We discuss the integration of these different perspective into a framework for person/family-centered evidence-based practice approach to care that aims to achieve optimal outcomes that prioritize individual strengths and impairments, as well as the personal treatment targets of children and their families. Finally, we consider how access to care for this common and impairing disorder can be improved in different healthcare systems., European Child & Adolescent Psychiatry, 32 (8), ISSN:1435-165X, ISSN:1018-8827

Purpose FOXP3 deficiency results in severe multisystem autoimmunity in both mice and humans, driven by the absence of functional regulatory T cells. Patients typically present with early and severe autoimmune polyendocrinopathy, dermatitis, and severe inflammation of the gut, leading to villous atrophy and ultimately malabsorption, wasting, and failure to thrive. In the absence of successful treatment, FOXP3-deficient patients usually die within the first 2 years of life. Hematopoietic stem cell transplantation provides a curative option but first requires adequate control over the inflammatory condition. Due to the rarity of the condition, no clinical trials have been conducted, with widely unstandardized therapeutic approaches. We sought to compare the efficacy of lead therapeutic candidates rapamycin, anti-CD4 antibody, and CTLA4-Ig in controlling the physiological and immunological manifestations of Foxp3 deficiency in mice. Method We generated Foxp3-deficient mice and an appropriate clinical scoring system to enable direct comparison of lead therapeutic candidates rapamycin, nondepleting anti-CD4 antibody, and CTLA4-Ig. Results We found distinct immunosuppressive profiles induced by each treatment, leading to unique protective combinations over distinct clinical manifestations. CTLA4-Ig provided superior breadth of protective outcomes, including highly efficient protection during the transplantation process. Conclusion These results highlight the mechanistic diversity of pathogenic pathways initiated by regulatory T cell loss and suggest CTLA4-Ig as a potentially superior therapeutic option for FOXP3-deficient patients.

The link between the gut and the brain in Parkinson's disease (PD) pathogenesis is currently a subject of intense research. Indeed, gastrointestinal dysfunction is known as an early symptom in PD and inflammatory bowel disease (IBD) has recently been recognised as a risk factor for PD. The leucine-rich repeat kinase 2 (LRRK2) is a PD- and IBD-related protein with highest expression in immune cells. In this study, we provide evidence for a central role of LRRK2 in gut inflammation and PD. The presence of the gain-of-function G2019S mutation significantly increases the disease phenotype and inflammatory response in a mouse model of experimental colitis based on chronic dextran sulphate sodium (DSS) administration. Bone marrow transplantation of wild-type cells into G2019S knock-in mice fully rescued this exacerbated response, proving the key role of mutant LRRK2 in immune cells in this experimental colitis model. Furthermore, partial pharmacological inhibition of LRRK2 kinase activity also reduced the colitis phenotype and inflammation. Moreover, chronic experimental colitis also induced neuroinflammation and infiltration of peripheral immune cells into the brain of G2019S knock-in mice. Finally, combination of experimental colitis with overexpression of α-synuclein in the substantia nigra aggravated motor deficits and dopaminergic neurodegeneration in G2019S knock-in mice. Taken together, our results link LRRK2 with the immune response in colitis and provide evidence that gut inflammation can impact brain homeostasis and contribute to neurodegeneration in PD. ispartof: ACTA NEUROPATHOLOGICA vol:146 issue:2 ispartof: location:Germany status: Published online

AIM: To create a shortened, more user-friendly Second Edition of the Dyskinesia Impairment Scale (DIS-II) to assess dystonia and choreoathetosis, and evaluate its construct validity and reliability. METHOD: Scale development included an online expert meeting (n = 21) and iterative discussions within the research group (n = 6). A Rasch measurement model analysis on DIS scores from individuals with dyskinetic cerebral palsy or inherited/idiopathic dystonia (n = 123, 74 males, mean age 14 years, SD 5 years) was performed to evaluate the construct validity and reliability of the DIS-II. RESULTS: The DIS-II evaluates dystonia and choreoathetosis in action and rest in 11 body regions, with action items scored from 0 to 3 and rest items 0 to 2. The number of videos to record are reduced from 26 to 14 and the items to score are reduced from 144 to 88. Rating scale functioning, goodness-of-fit evaluation, principal component analysis, and targeting met the predefined quality criteria of the study and construct validity was therefore considered good. Furthermore, person reliability indicated that the DIS-II can separate individuals into eight distinct ability levels. INTERPRETATION: The DIS-II provides valid and reliable measures for dystonia and choreoathetosis, and reduces the administration and scoring time compared with the DIS. The DIS-II logit scores (interval level data) enhance comparison over time and between individuals in clinical practice and research. WHAT THIS PAPER ADDS: Compared with the Dyskinesia Impairment Scale (DIS), the shortened edition (DIS-II) requires half of the number of videos to be scored. The DIS-II has a simplified rating scale, requiring scoring of 88 instead of 144 items. The DIS-II has shown excellent reliability and good construct validity. The interval properties of the DIS-II are superior to the ordinal level outcome measures of the DIS. ispartof: DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY vol:65 issue:5 pages:683-690 ispartof: location:England status: published

Aims Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. Methods and results Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. Conclusion The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. Classification of evidence Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.

Background Violence in psychosis has been linked to antisocial behavior and psychopathy traits. Psychopathy comprises aspects of interpersonal, affective, lifestyle, and antisocial traits which may be differently involved in violent offending by persons with psychotic disorders. We explored psychopathy subdomains among violent offenders with and without a psychotic disorder. Methods 46 males, with a history of severe violence, with (n = 26; age 35.85 ± 10.34 years) or without (n = 20; age 39.10 ± 11.63 years) a diagnosis of a psychotic disorder, were assessed with the Psychopathy Checklist-Revised (PCL-R). PCL-R was split into subdomains following the four-facet model. Group differences in total and subdomain scores were analyzed with a general linear model with covariates. Results Total PCL-R scores did not differ between the groups (p = 0.61, Cohen’s d = 0.17). The violent offenders without psychotic disorders had higher facet 2 scores than the patient group with psychotic disorders (p = 0.029, Cohen’s d = 0.77). Facet 1, 3, or 4 scores did not differ between the groups. Controlling for age did not alter the results. Conclusion Patients with a psychotic disorder and a history of severe violence have lower affective psychopathy scores than violent offenders without psychotic disorders. This observation may point toward distinct underlying mechanisms for violence and may provide a target for focused treatment and prevention.

Eosinophilia and eosinophil activation are recurrent features in various reactive states and certain hematologic malignancies. In patients with hypereosinophilia (HE), HE-induced organ damage is often encountered and may lead to the diagnosis of a hypereosinophilic syndrome (HES). A number of known mechanisms and etiologies contribute to the development of HE and HES. Based on these etiologies and the origin of eosinophils, HE and HES are divided into primary forms where eosinophils are clonal cells, reactive forms where an underlying reactive or neoplastic condition is detected and eosinophils are considered to be "non-clonal" cells, and idiopathic HE and HES in which neither a clonal nor a reactive underlying pathology is detected. Since 2012, this classification and the related criteria have been widely accepted and regarded as standard. However, during the past few years, new developments in the field and an increasing number of markers and targets have created a need to update these criteria and the classification of HE and HES. To address this challenge, a Working Conference on eosinophil disorders was organized in 2021. In this conference, a panel of experts representing the relevant fields, including allergy, dermatology, hematology, immunology, laboratory medicine, and pathology, met and discussed new markers and concepts as well as refinements in definitions, criteria and classifications of HE and HES. The outcomes of this conference are presented in this article and should assist in the diagnosis and management of patients with HE and HES in daily practice and in the preparation and conduct of clinical trials. ispartof: ALLERGY vol:78 issue:1 pages:47-59 ispartof: location:Denmark status: published

Lead is an environmental hazard that should be addressed worldwide. Over time, human lead exposure in the western world has decreased drastically to levels comparable to those among humans living in the preindustrial era, who were mainly exposed to natural sources of lead. To re-evaluate the potential health risks associated with present-day lead exposure, a two-pronged approach was applied. First, recently published population metrics describing the adverse health effects associated with lead exposure at the population level were critically assessed. Next, the key results of the Study for Promotion of Health in Recycling Lead (SPHERL; NCT02243904) were summarized and put in perspective with those of the published population metrics. To our knowledge, SPHERL is the first prospective study that accounted for interindividual variability between people with respect to their vulnerability to the toxic effects of lead exposure by assessing the participants' health status before and after occupational lead exposure. The overall conclusion of this comprehensive review is that mainstream ideas about the public and occupational health risks related to lead exposure urgently need to be updated because a large portion of the available literature became obsolete given the sharp decrease in exposure levels over the past 40 years. ispartof: HYPERTENSION RESEARCH vol:46 issue:2 pages:395-407 ispartof: location:England status: published

Rationale: The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear. Objectives: To investigate within-individual patterns of morbidity of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood. Methods: We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (filaggrin [FLG] mutations and 17q21 variants), increase the risk of multimorbidity. Measurements and Main Results: Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema1wheeze1rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern. FLG mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (FLG by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity. Conclusions: Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.

Aims While electrocardiogram (ECG) characteristics have been associated with life-threatening ventricular arrhythmias (LTVA) in dilated cardiomyopathy (DCM), they typically rely on human-derived parameters. Deep neural networks (DNNs) can discover complex ECG patterns, but the interpretation is hampered by their ‘black-box’ characteristics. We aimed to detect DCM patients at risk of LTVA using an inherently explainable DNN. Methods and results In this two-phase study, we first developed a variational autoencoder DNN on more than 1 million 12-lead median beat ECGs, compressing the ECG into 21 different factors (F): FactorECG. Next, we used two cohorts with a combined total of 695 DCM patients and entered these factors in a Cox regression for the composite LTVA outcome, which was defined as sudden cardiac arrest, spontaneous sustained ventricular tachycardia, or implantable cardioverter-defibrillator treated ventricular arrhythmia. Most patients were male (n = 442, 64%) with a median age of 54 years [interquartile range (IQR) 44–62], and median left ventricular ejection fraction of 30% (IQR 23–39). A total of 115 patients (16.5%) reached the study outcome. Factors F8 (prolonged PR-interval and P-wave duration, P Conclusion Inherently explainable DNNs can detect patients at risk of LTVA which is mainly driven by P-wave abnormalities.

Ovarian lesions have a wide range of sonomorphological features with numerous different underlying benign and malignant histologies. Based on the studies conducted by the International Ovarian Tumor Analysis (IOTA) group, ovarian masses can currently be reliably characterized by ultrasound. In the following article, we explain how to use the IOTA terms and definitions and we provide insight into how to safely triage patients with an ovarian mass. ispartof: ULTRASCHALL IN DER MEDIZIN vol:43 issue:6 ispartof: location:Germany status: published

SARS-CoV-2 is a newly emerged coronavirus, causing the global pandemic of respiratory coronavirus disease (COVID-19). The type I interferon (IFN) pathway is of particular importance for anti-viral defense and recent studies identified that type I IFNs drive early inflammatory responses to SARS-CoV-2. Here, we use a mouse model of SARS-CoV-2 infection, facilitating viral entry by intranasal recombinant Adeno-Associated Virus (rAAV) transduction of hACE2 in wildtype (WT) and type I IFN receptor-1 deficient (Ifnar1–/–) mice, to study the role of type I IFN signalling and innate immune responses during SARS-CoV-2 infection. Our data show that type I IFN signalling is essential for inducing anti-viral effector responses to SARS-CoV-2, control of virus replication, and to prevent enhanced disease. Furthermore, hACE2-Ifnar1–/– mice had increased gene expression of the chemokine Cxcl1 and airway infiltration of neutrophils as well as reduced and delayed production of monocyte-recruiting chemokine CCL2. hACE2-Ifnar1–/– mice showed altered recruitment of inflammatory myeloid cells to the lung upon SARS-CoV-2 infection, with a shift from Ly6C+ to Ly6C– expressing cells. Together, our findings suggest that type I IFN signalling deficiency results in a dysregulated innate immune response to SARS-CoV-2 infection.

19 páginas, 9 figuras, 1 tabla., Mobile genetic elements control their life cycles by the expression of a master repressor, whose function must be disabled to allow the spread of these elements in nature. Here, we describe an unprecedented repression-derepression mechanism involved in the transfer of Staphylococcus aureus pathogenicity islands (SaPIs). Contrary to the classical phage and SaPI repressors, which are dimers, the SaPI1 repressor StlSaPI1 presents a unique tetrameric conformation never seen before. Importantly, not just one but two tetramers are required for SaPI1 repression, which increases the novelty of the system. To derepress SaPI1, the phage-encoded protein Sri binds to and induces a conformational change in the DNA binding domains of StlSaPI1, preventing the binding of the repressor to its cognate StlSaPI1 sites. Finally, our findings demonstrate that this system is not exclusive to SaPI1 but widespread in nature. Overall, our results characterize a novel repression-induction system involved in the transfer of MGE-encoded virulence factors in nature., This work was supported by grants MR/V000772/1, MR/M003876/1 and MR/S00940X/1 from the Medical Research Council (UK), BB/N002873/1, BB/S003835/1 and BB/V002376/1 from the Biotechnology and Biological Sciences Research Council (BBSRC, UK), Wellcome Trust201531/Z/16/Z, and ERC-ADG-2014 Proposal n◦670932 Dut-signal from EU to J.R.P.; grants PID2019-108541GB-I00 from Spanish Government (Ministerio de Econom´ıa y Competitividad y Ministerio de Ciencia e Innovacion) and PROMETEO ´ /2020/012 from Valencian Government to A.M.; grants MOE2017-T2-2-163 and MOE2019-T2-2-162 from the Ministry of Education to J.C.; and grant NIHR01 AI083255 to G.C. J.T. was supported by NIH IRACDA Grant K12GM093857 to Virginia Commonwealth University. We acknowledge Diamond Light Source for time on Beamline I03 for X-ray crystallography and B21 for SEC-SAXS under Proposal 16258. L.M.-R. was the recipient of a Spanish postdoctoral fellowship from Fundacion Ram ´ on Areces (2018–2020). J.R.P. is ´thankful to the Royal Society and the Wolfson Foundation for providing him support through a Royal Society Wolfson Fellowship. Funding for open access charge: University funds.

Africa's rural population continues to expand rapidly, and labor productivity in agriculture and many rural-off farm activities remains low. This review uses the lens of a dual economy and the associated patterns of agricultural, rural, and structural transformation to review the evolution of Africa's rural employment and its inclusiveness. Many African countries still find themselves in an early stage of the agricultural and rural transformation. Given smaller sectoral productivity gaps than commonly assumed, greater size effects, and larger spillovers, investment in agriculture and the rural off-farm economy remains warranted to broker the transition to more and more productive rural employment. The key policy questions thus become how best to invest in the agri-food system (on and increasingly also off the farm) and how best to generate demand for nonagricultural goods and services that rural households can competitively produce. Informing these choices continues to present a major research agenda, with digital technologies, the imperative of greening, and intra-African liberalization raising many unarticulated and undocumented opportunities and challenges.

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.

SUMMARY On average, 49–63% of people with intellectual disabilities and/or autism spectrum disorder (ASD) are prescribed psychotropic medications to treat psychopathology, including psychiatric illness, behaviours that challenge and the core symptoms and associated behaviours of these developmental disorders. In many cases, psychotropics, particularly antipsychotics, are used off-label without a proper indication, particularly to manage behaviours that challenge. The RCTs show moderate evidence supporting the efficacy of low-dose risperidone and some preliminary evidence for aripiprazole in treating behaviours that challenge among children with ASD and/or intellectual disabilities. The RCT-based evidence for the other psychotropics is equivocal, so no definitive conclusions can be made on their efficacy. Polypharmacy and the use of high doses of antipsychotics are prevalent in this population, leading to the risk of adverse events and drug–drug interactions. Despite various national and international guidelines, and government initiatives encouraging reduced psychotropic use, there is little evidence of this happening; on the contrary, the use of antidepressants, mood stabilisers and benzodiazepines may be increasing. A concerted multi-agency effort is urgently needed to address this significant public health concern of the overmedication of people with intellectual disabilities and/or ASD.

ispartof: PLANT PRODUCTION SCIENCE vol:25 issue:4 pages:484-500 status: published

BACKGROUND: Recombinant human ADAMTS13 (rADAMTS13) is a key protein in fundamental research for investigating its mode of action and the pathophysiology of thrombotic thrombocytopenic purpura (TTP). However, the expression of rADAMTS13 is quite low in mammalian cells, which makes the production of the protein time-consuming and labor-intensive. OBJECTIVES: We aimed at increasing the yield of rADAMTS13 by (1) using a more optimal signal peptide (SP) and (2) constructing an N-terminal fusion protein of ADAMTS13 with human serum albumin domain 1 (AD1-ADAMTS13). METHODS: Six SPs were investigated to select the most optimal SP. Expression plasmids containing the most optimal SP and ADAMTS13 cDNA or the fusion construct AD1-ADAMTS13 were generated and transiently transfected into CHOEBNALT85 cell-line. Expression levels of rADAMTS13 in expression medium were analyzed and compared with the expression level of rADAMTS13 with native SP (nat-SP). RESULTS: Expression of rADAMTS13 with coagulation factor VII (FVII) SP was 3-fold higher (16.00 μg/ml) compared with the expression with nat-SP (5.03 μg/ml). The highest yields were obtained with AD1-ADAMTS13 protein with a 15-fold higher concentration (78.22 μg/ml) compared with the expression with nat-SP. The rADAMTS13 expressed with FVII-SP retained its activity (104.0%) to cleave von Willebrand factor, whereas AD1-ADAMTS13 demonstrated even higher activity (144.3%). CONCLUSION: We succeeded in generating expression vectors that yield (1) rADAMTS13 at higher levels because of more optimal FVII-SP and (2) high levels of AD1-ADAMTS13 N-terminal fusion protein. The highest expression levels were obtained with AD1-ADAMTS13 N-terminal fusion protein, which is paving the way for highly efficient protein production. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:20 issue:10 pages:2379-2385 ispartof: location:England status: published

Dysphagia, which refers to difficult and/or disordered swallowing, is a common problem associated with various neurological diseases such as stroke, motor neuron diseases and neurodegenerative diseases. Traditionally, dysphagia treatments are either compensatory, which includes modifications of bolus texture or feeding posture, or rehabilitative, which includes behavioral exercises and sensory stimulation. Despite being widely adopted in clinical practice, recent views have challenged the clinical efficacy of these treatments due to the low level of evidence supported by mainly non-controlled studies. As such, with advancements in technology and scientific research methods, recent times have seen a surge in the development of novel dysphagia treatments and an increasing number of robust randomized controlled clinical trials. In this review, we will review the clinical evidence of several newly introduced treatments for dysphagia in the last two decades, including rehabilitative exercises, biofeedback, pharmacological treatments, neuromodulation treatments and soft robotics. Despite the recent improvements in the quality of evidence for the efficacy of dysphagia treatments, several critical issues, including heterogeneity in treatment regimens, long-term treatment effects, underlying mechanisms of some neuromodulation treatments, and the effects of these techniques in non-stroke dysphagia, remain to be addressed in future clinical trials. ispartof: NEUROPSYCHIATRIC DISEASE AND TREATMENT vol:18 pages:2251-2263 ispartof: location:New Zealand status: published

BACKGROUND: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. METHODS: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. RESULTS: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. CONCLUSION: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab. ispartof: EUROPEAN JOURNAL OF CANCER vol:174 pages:221-231 ispartof: location:England status: published

Even though it has been more than a decade since renal denervation (RDN) was first used to treat hypertension and an intense effort on researching this therapy has been made, it is still not clear how RDN fits into the antihypertensive arsenal. There is no question that RDN lowers blood pressure (BP), it does so to an extent at best corresponding to one antihypertensive drug. The procedure has an excellent safety record. However, it remains clinically impossible to predict whose BP responds to RDN and whose does not. Long-term efficacy data on BP reduction are still unconvincing despite the recent results in the SPYRAL HTN-ON MED trial; experimental studies indicate that reinnervation is occurring after RDN. Although BP is an acceptable surrogate endpoint, there is complete lack of outcome data with RDN. Clear indications for RDN are lacking although patients with resistant hypertension, those with documented increase in activity of the sympathetic system and perhaps those who desire to take fewest medication may be considered. ispartof: JOURNAL OF HYPERTENSION vol:40 issue:10 pages:1859-1875 ispartof: location:Netherlands status: published

Domestic production of ginger (Zingiber officinale) and turmeric (Curcuma longa) rhizomes is increasing. The objective of this study was to compare growth and rhizome yield of these crops using different container volumes and planting densities. Two greenhouse experiments that lasted 28 weeks each were conducted. In Expt. I, one sprouted rhizome of a single ginger variety (Bubba Blue) and four turmeric varieties (Hawaiian Red, BKK, White Mango, and Black) were transplanted into either small (1.5 gal) or large (13.3 gal) round containers. In Expt. II, either one or three sprouted rhizomes of two ginger varieties (Bubba Blue and Madonna) and two turmeric varieties (Indira Yellow and Hawaiian Red) were transplanted into either large (13.3 gal) or medium (3.9 gal) round containers. In Expt. I, there were an increase in plant growth and yield with increasing container volume, as both crops produced more than double the shoot, root, and rhizome fresh weight (FW) when grown in large compared with small containers. In Expt. II, rhizome yield of ginger was 44% higher in medium than large containers, and container volume did not affect yield in turmeric. Total dry weight (DW) was higher in plants grown in the larger container volume in both species in Expt. I, and turmeric only in Expt. II. However, ginger in Expt. II had an 18% higher plant DW in the medium compared with the large container. The higher density in Expt. II increased yield and biomass production per container compared with the lower density, regardless of variety and container volume. Overall, net revenue per container was higher in Expt. II than Expt. I because of the higher rhizome yield. In Expt. I, the higher yield of ginger compared with turmeric increased sales revenue of this species, despite a lower sales price per kilogram. In contrast, the higher yield of turmeric in Expt. II resulted in higher sales revenue and net revenue per container compared with ginger. Based on our results, medium containers could be used to minimize material and space costs for ginger and turmeric production under the conditions evaluated in our study.

Chemotherapy; Quality of life; Symptoms Quimioterapia; Calidad de vida; Síntomas Quimioteràpia; Qualitat de vida; Símptomes Background In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. Methods Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1–16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. Results Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77–13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08–12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. Conclusions Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain. This work was supported by Regeneron Pharmaceuticals, Inc., and Sanofi.

Objective: This study aims to determine the clinical leadership levels of nurse managers and related factors Methods: This descriptive study was conducted on 109 nurse managers working at six hospitals – including four public hospitals, one private hospital, and one university hospital. The data was collected using Clinical Leadership Scale (CLS) including their personal and demographic information, as well as their clinical leadership traits. Results: The participants had a total mean score of 2.72±0.19 on clinical leadership scale. The mean scores of the improving services subscale were higher in female nurse managers than those of male counterparts. Participants who formally studied on management earned higher mean scores for the overall CLS and its setting direction subscale than those who did not. Likewise, the participants who formally studied on leadership earned higher mean scores for the overall CLS and its personal qualities subscale than those who did not. These findings were statistically significant (p

Climate warming is a ubiquitous stressor in freshwater ecosystems, yet its interactive effects with other stressors are poorly understood. We address this knowledge gap by testing the ability of three contrasting null models to predict the joint impacts of warming and a range of other aquatic stressors using a new database of 296 experimental combinations. Despite concerns that stressors will interact to cause synergisms, we found that net impacts were usually best explained by the effect of the stronger stressor alone (the dominance null model), especially if this stressor was a local disturbance associated with human land use. Prediction accuracy depended on stressor identity and how asymmetric stressors were in the magnitude of their effects. These findings suggest we can effectively predict the impacts of multiple stressors by focusing on the stronger stressor, as habitat alteration, nutrients and contamination often override the biological consequences of higher temperatures in freshwater ecosystems.

Cellular senescence is a stress response elicited by different molecular insults. Senescence results in cell cycle exit and is characterised by multiple phenotypic changes such as the production of a bioactive secretome. Senescent cells accumulate during ageing and are present in cancerous and fibrotic lesions. Drugs that selectively kill senescent cells (senolytics) have shown great promise for the treatment of age-related diseases. Senescence plays paradoxical roles in cancer. Induction of senescence limits cancer progression and contributes to therapy success, but lingering senescent cells fuel progression, recurrence, and metastasis. In this review, we describe the intricate relation between senescence and cancer. Moreover, we enumerate how current anti-cancer therapies induce senescence in tumour cells and how senolytic agents could be deployed to complement anticancer therapies. "One-two punch" therapies aim to first induce senescence in the tumour followed by senolytic treatment to target newly exposed vulnerabilities in senescent tumour cells. "One-two punch" represents an emerging and promising new strategy in cancer treatment. Future challenges of "one -two punch" approaches include how to best monitor senescence in cancer patients to effectively survey their efficacy.

Aims We aimed at assessing the influence of above- and below-ground environmental conditions over the performance of Centaurea jacea L., a drought-resistant grassland forb species. Methods Transpiration rate, CO2 assimilation rate, leaf water potential, instantaneous and intrinsic water use efficiency, temperature, relative humidity, vapor pressure deficit and soil water content in one plant and root length density in four plants, all grown in custom-made columns, were monitored daily for 87 days in the lab. The soil water isotopic composition in eleven depths was recorded daily in a non-destructive manner. The isotopic composition of plant transpiration was inferred from gas chamber measurements. Vertical isotopic gradients in the soil column were created by adding labeled water. Daily root water uptake (RWU) profiles were computed using the multi-source mixing model Stable Isotope Analysis in R (Parnell et al. PLoS ONE 5(3):1–5, 2010). Results RWU occurred mainly in soil layer 0–15 cm, ranging from 79 to 44%, even when water was more easily available in deeper layers. In wet soil, the transpiration rate was driven mainly by vapor pressure deficit and light intensity. Once soil water content was less than 0.12 cm3 cm− 3, the computed canopy conductance declined, which restricted leaf gas exchange. Leaf water potential dropped steeply to around − 3 MPa after soil water content was below 0.10 cm3 cm− 3. Conclusion Our comprehensive data set contributes to a better understanding of the effects of drought on a grassland species and the limits of its acclimation in dry conditions.

BACKGROUND: A triple storage (TS) set allows for pathogen inactivation (PI) treatment of triple-dose apheresis platelet products with amotosalen + UVA. We evaluated the quality and metabolic parameters of platelet concentrates (PCs) pathogen inactivated and stored for 7 days. MATERIALS AND METHODS: Twelve triple-dose products collected with two different apheresis platforms were treated with amotosalen+UVA. Products were split into three single-dose units. Testing was made pretreatment, after splitting, at days 5 and 7 of storage. RESULTS: Single-dose PI PCs had a mean platelet content of 2.89 ± 0.35 x 1011 . From baseline to day 7, pH remained stable (7.1 ± 0.1 vs. 7.0 ± 0.1), pO2 increased (11.3 ± 2.4 vs. 18.3 ± 3.5 kPa) as did LDH (201 ± 119 vs. 324 ± 203 U/L) and lactate (3.6 ± 1.7 vs. 12.1 ± 1.5 mmol/L) (all p

Objective To qualitatively and quantitatively assess integrated segmentation of three convolutional neural network (CNN) models for the creation of a maxillary virtual patient (MVP) from cone-beam computed tomography (CBCT) images. Materials and methods A dataset of 40 CBCT scans acquired with different scanning parameters was selected. Three previously validated individual CNN models were integrated to achieve a combined segmentation of maxillary complex, maxillary sinuses, and upper dentition. Two experts performed a qualitative assessment, scoring-integrated segmentations from 0 to 10 based on the number of required refinements. Furthermore, experts executed refinements, allowing performance comparison between integrated automated segmentation (AS) and refined segmentation (RS) models. Inter-observer consistency of the refinements and the time needed to create a full-resolution automatic segmentation were calculated. Results From the dataset, 85% scored 7–10, and 15% were within 3–6. The average time required for automated segmentation was 1.7 min. Performance metrics indicated an excellent overlap between automatic and refined segmentation with a dice similarity coefficient (DSC) of 99.3%. High inter-observer consistency of refinements was observed, with a 95% Hausdorff distance (HD) of 0.045 mm. Conclusion The integrated CNN models proved to be fast, accurate, and consistent along with a strong interobserver consistency in creating the MVP. Clinical relevance The automated segmentation of these structures simultaneously could act as a valuable tool in clinical orthodontics, implant rehabilitation, and any oral or maxillofacial surgical procedures, where visualization of MVP and its relationship with surrounding structures is a necessity for reaching an accurate diagnosis and patient-specific treatment planning.

Xeno-nucleic acids (XNAs) are synthetic genetic polymers with backbone structures composed of non-ribose or non-deoxyribose sugars. Phosphonomethylthreosyl nucleic acid (pTNA), a type of XNA that does not base pair with DNA or RNA, has been suggested as a possible genetic material for storing synthetic biology information in cells. A critical step in this process is the synthesis of XNA episomes using laboratory-evolved polymerases to copy DNA information into XNA. Here, we investigate the polymerase recognition of pTNA nucleotides using X-ray crystallography to capture the post-catalytic complex of engineered polymerases following the sequential addition of two pTNA nucleotides onto the 3'-end of a DNA primer. High-resolution crystal structures reveal that the polymerase mediates Watson-Crick base pairing between the extended pTNA adducts and the DNA template. Comparative analysis studies demonstrate that the sugar conformation and backbone position of pTNA are structurally more similar to threose nucleic acid than DNA even though pTNA and DNA share the same six-atom backbone repeat length. Collectively, these findings provide new insight into the structural determinants that guide the enzymatic synthesis of an orthogonal genetic polymer, and may lead to the discovery of new variants that function with enhanced activity. ispartof: NUCLEIC ACIDS RESEARCH vol:50 issue:17 pages:9663-9674 ispartof: location:England status: published

ispartof: CHEMOECOLOGY vol:32 issue:4-5 pages:171-180 status: published

Biomedical science is rapidly developing in terms of more transparency, openness and reproducibility of scientific publications. This is even more important for all studies that are based on results from basic semen examination. Recently two concordant documents have been published: the 6th edition of the WHO Laboratory Manual for the Examination and Processing of Human Semen, and the International Standard ISO 23162:2021. With these tools, we propose that authors should be instructed to follow these laboratory methods in order to publish studies in peer-reviewed journals, preferable by using a checklist as suggested in an Appendix to this article.

INTRODUCTION: Media guidelines for the responsible reporting of suicide are a recognized universal suicide prevention intervention. While implemented in numerous countries, including Australia, little is known about whether they are cost-effective. We aimed to determine the cost-effectiveness of Mindframe, the national initiative implementing media guidelines in Australia. METHOD: We conducted a modelled economic evaluation (5-year time-horizon) incorporating two types of economic analysis: (i) return-on-investment (ROI) comparing estimated cost savings from the intervention to the total intervention cost, and (ii) cost-effectiveness analysis comparing the net intervention costs to health outcomes: suicide deaths prevented and quality-adjusted life-years (QALYs). We also included uncertainty analyses to propagate parameter uncertainty and sensitivity analyses to test the robustness of the model outputs to changes in input parameters and assumptions. RESULTS: The estimated ROI ratio for the main analysis was 94:1 (95% uncertainty interval [UI]: 37 to 170). The intervention was associated with cost savings of A$596M (95% UI: A$228M to A$1,081M), 139 (95% UI: 55 to 252) suicides prevented and 107 (95% UI: 42 to 192) QALYs gained. The intervention was dominant, or cost-saving, compared with no intervention with results being robust to sensitivity analysis but varying based on the conservativeness of the parameters entered. CONCLUSION: Mindframe was found to be cost-saving, and therefore, worthy of investment and inclusion as part of national suicide prevention strategies. ispartof: SUICIDE AND LIFE-THREATENING BEHAVIOR vol:52 issue:5 pages:1048-1057 ispartof: location:England status: published

The management of bio-invasions relies upon the development of methods to trace their origin and expansion. Cointroduced parasites, especially monogenean flatworms, are ideal tags for the movement of their hosts due to their short generations, direct life cycles and host specificity. However, they are yet to be applied to trace the intraspecific movement of host lineages in their native ranges. As proof of this concept, we conducted a comparative phylogeographic analysis based upon two mitochondrial markers of a globally invasive frog Xenopus laevis and its monogenean parasite Protopolystoma xenopodis in its native range in southern Africa and invasive range in Europe. Translocation of lineages was largely masked in the frog's phylogeography. However, incongruent links between host and parasite phylogeography indicated host switches from one host lineage to another after these were brought into contact in the native range. Thus, past translocation of host lineages is revealed by the invasion success of its cointroduced parasite lineage. This study demonstrates that parasite data can serve as an independent line of evidence in invasion biology, also on the intraspecific level, shedding light on previously undetected invasion dynamics. Based upon the distribution of these invasive parasite lineages, we infer that there is widespread anthropogenic translocation of this frog, not only via official export routes, but also facilitated by the frog's use as live bait by angling communities. Synthesis and applications. Data from cointroduced, host-specific parasites, as tags for translocation, can add value to investigations in invasion biology and conservation. A better understanding of the translocation history and resulting genetic mixing of host and parasite lineages in the native range can shed light on the genetic make-up of parasite assemblages cointroduced to the invasive range. Knowledge of the intraspecific movement of different lineages of animals in their native ranges also has conservation implications, since contact between divergent lineages of hosts and parasites can facilitate host switches and altered parasite dynamics in both native and invasive populations. Therefore, we recommend the inclusion of parasite data as a more holistic approach to the invasion ecology of animals on the intraspecific level. The authors express their heartfelt thanks to the anonymous reviewers who provided invaluable advice to improve the earlier drafts of this manuscript. We acknowledge the financial support of the National Research Foundation (NRF) of South Africa. Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and the NRF does not accept any liability in this regard. ALS received funding from the DST-NRF Centre of Excellence for Invasion Biology (South Africa) and the NRF South African Institute for Aquatic Biodiversity. LHdP is indebted to the NRF Foundational Biodiversity Information Programme (no. 120782) for financial support. The project utilised the infrastructure of the Unit for Environmental Sciences and Management, NorthWest University (South Africa). This research was supported by EMBRC Belgium—FWO project GOH3817N. Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and the NRF does not accept any liability in this regard. NK and MPMV are financed by the Special Research Fund of Hasselt University (BOF21PD01 and BOF20TT06, respectively). The authors express their sincere thanks to a number of persons who assisted in the collection of the frogs. Guénolé le Peutrec, Jean Secondi, Natasha Kruger and Rodolphe Olivier helped with the collection in France. Rui Rebelo provided access to frogs from Portugal. In South Africa, several farm owners graciously gave permission for collection to take place on their properties and provided lodging for the research team: Fanus and Olga Kritzinger, William and Christa van Zyl, Dave Schlebusch, Fanus and Carin Oberholzer, Danie and Annalise Marais, Johan Hamann, Tobie Bielt, Gert Bench, Stoffel Labuschagne, Jannie and Susan van Rensburg, Jan Meintjies, Marthinus Hartman, Douw and Louise de Jager and Ernest de Villiers. Lastly, Mathys Schoeman, Clarke Scholtz, Andrea Darvall, Willie Landman, Ferdi de Lange, John Measey and Roxanne Viviers assisted with the collection of frogs at the remainder of the localities in South Africa. The authors are also indebted to numerous local recreational fishermen who were willing to share details about their use of Xenopus laevis across South Africa. The utilisation of the frogs and the research protocols were approved by the Animal Care, Health and Safety in Research Ethics (AnimCare) Committee of the Faculty of Health Sciences of the North-West University (ethics number: NWU-0380-16-A5-01). Animals from the South African populations were sampled under the permits 0056-AAA007-00224 (CapeNature) and FAUNA 1343-2017 (Northern Cape) provided by the Department of Economic Development, Environmental Affairs and Tourism.

Bacteria are social organisms that commonly live in dense communities surrounded by a multitude of other species. The competitive and cooperative interactions between these species not only shape the bacterial communities but also influence their susceptibility to antimicrobials. While several studies have shown that mixed-species communities are more tolerant toward antimicrobials than their monospecies counterparts, only limited empirical data are currently available on how interspecies interactions influence resistance development. We here propose a theoretic framework outlining the potential impact of interspecies social behavior on different aspects of resistance development. We identify factors by which interspecies interactions might influence resistance evolution and distinguish between their effect on (a) the emergence of a resistant mutant and (b) the spread of this resistance throughout the population. Our analysis indicates that considering the social life of bacteria is imperative to the rational design of more effective antibiotic treatment strategies with a minimal hazard for resistance development. ispartof: ANNUAL REVIEW OF MICROBIOLOGY vol:76 pages:179-192 ispartof: location:United States status: published

Introduction:Pain is a multidimensional factor and core domain of psoriatic arthritis (PsA). This analysis aimed to quantify the role of potential inflammation-associated outcomes on pain reduction in patients with PsA receiving tofacitinib, using mediation modeling. Methods:Pooled data were from two phase 3 studies (OPAL Broaden and OPAL Beyond) of patients with active PsA treated with tofacitinib 5mg twice daily or placebo. Mediation modeling was utilized to quantify the indirect effects (via Itch Severity Item [ISI], C-reactive protein [CRP] levels, swollen joint count [SJC], Psoriasis Area and Severity Index [PASI], and enthesitis [using Leeds Enthesitis Index]) and direct effects (representing all other factors) of tofacitinib treatment on pain improvement. Results:The initial model showed that tofacitinib treatment affects pain, primarily indirectly, via ISI, CRP, SJC, PASI, and enthesitis (overall 84.0%;P = 0.0009), with 16.0% (P = 0.5274) attributable to the direct effect. The model was respecified to exclude SJC and PASI. Analysis of the final model revealed that 29.5% (P = 0.0579) of tofacitinib treatment effect on pain was attributable to the direct effect, and 70.5% (P P = 0.0002), 15.3% (P = 0.0107), and 17.8% (P = 0.0157) of the tofacitinib treatment effect on pain, respectively. Conclusions:The majority of the effect of tofacitinib on pain was collectively mediated by itch, CRP, and enthesitis, with itch being the primary mediator of treatment effect. Trial Registration: NCT01877668, NCT01882439.

Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration. ispartof: BRAIN vol:145 issue:12 pages:4349-4367 ispartof: location:England status: published

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

BACKGROUND: Respiratory disease is the most common presenting complaint at veterinary clinics and a priority concern for equid owners and veterinary practitioners in Ethiopia. OBJECTIVES: This study aimed to report the molecular detection of EHV-2 and EHV-5 and to assess the risk factors associated with infection in working equids in central Ethiopia. METHODS: Nasopharyngeal swabs were collected from 58 horses and donkeys to detect EHV-2 and EHV-5 using PCR targeting the conserved region of glycoprotein B (gB) genes. RESULTS: From 58 equids, EHV-5 and EHV-2 were detected in 20 (34.5%) and 19 (32.8%) equids, respectively. Concurrent infection with EHV-2 and EHV-5 was found in 6 (10.3%) equids who exhibited respiratory clinical signs. EHV-2 was detected in a significantly higher (p = 0.002) proportion of horses (54.5%; n = 18) than donkeys (4%; n = 1). In contrast, EHV-5 was detected in a significantly higher (p = 0.004) proportion of donkeys (56%; n = 14) compared to horses (18.2% n = 6). EHV-2-positive equids were seven times more likely to display clinical signs of respiratory disease than EHV-2-negative equids (Odds ratio (OR) = 6.9; 95%CI: 1.72-27.60). However, statistically significant (p = 0.832) difference was not observed for EHV-5. EHV-2 was detected in a significantly higher (p = 0.004) proportion of female (50%; n = 16) compared to male equids (11.5%; n = 3). CONCLUSIONS: This study revealed the molecular detection of EHV-2 and EHV-5 in horses and donkeys residing in central Ethiopia. The association between EHV-2-test-positive equids and displaying of clinical signs of respiratory disease was observed, which suggests EHV-2 involvement in the development of respiratory disease; however, it deserves further investigation. ispartof: VETERINARY MEDICINE AND SCIENCE vol:8 issue:6 pages:2396-2403 ispartof: location:England status: published

BACKGROUND: While sexuality and intimacy are suggested to contribute to quality of life (QoL), it is striking that the sexual problems of head and neck cancer patients have not been adequately studied. OBJECTIVES: Our aim was to prospectively assess the impact of head and neck cancer and its treatment on sexuality and intimacy. MATERIAL AND METHODS: A questionnaire study with a 6-month follow-up period was conducted at the University Hospitals Leuven, Belgium, using the Maudsley marital questionnaire (MMQ), the sexual adjustment questionnaire (SAQ) and the short sexual functioning scale (SSFS) to prospectively assess the impact of head and neck cancer and its treatment on sexuality and intimacy. RESULTS: Twelve patients (67%) reported a negative impact on their sexuality and/or intimacy. There were significant declines in marital, sexual and general life satisfaction (p < 0.000) at the 6-month follow-up as compared to baseline. There was a significant increase in frustration after sexual activity (p = 0.031). Sexual desire was also impacted, with a near doubling of patients reporting a decline. The perceived importance of discussing sexual issues with one's physician significantly increased from 7 to 16 patients (p = 0.004). CONCLUSIONS: Sexual problems are common after head and neck cancer treatment. Using a screening instrument can help to identify patients that need intervention. Discussing sexuality and intimacy issues that patients may face before, during and after treatment can have a positive impact on QoL. ispartof: DENTAL AND MEDICAL PROBLEMS vol:59 issue:3 pages:323-332 ispartof: location:Poland status: published

BACKGROUND: Falls among psychiatric inpatients are common and have significant health consequences. The purpose of this study is to systematically review the published research on risk factors and consequences. METHODS: PubMed and Embase were searched for relevant studies. A total of 18 studies were included in this systematic review. The heterogeneity and low quality of the reviewed studies limit the generalizability of the results. RESULTS: Several intrinsic and extrinsic factors are reported. Some of these factors are unique to psychiatric inpatients such as acute mental state, psychotic symptoms, and bipolar disorder leading to cognitive distortions and risk-taking; psychotropic medications inducing side effects like sedation and orthostatic hypotension; while others are similar to those found among general medical inpatients. CONCLUSION: Given the clinical importance of a fall and its implication on residential treatment, there is a need for targeted fall prevention programs. In order to further identify and quantify these risks and consequences, prospective research and additional study designs, describing and recording risk factors in a systematic and standardized way with the underlying etiological processes in mind, are needed. ispartof: ALPHA PSYCHIATRY vol:23 issue:5 pages:217-222 ispartof: location:Turkey status: published

Background and Aims Combination atezolizumab/bevacizumab is the gold standard for first-line treatment of unresectable hepatocellular carcinoma (HCC). Our study investigated the efficacy and safety of combination therapy in older patients with HCC. Methods 191 consecutive patients from eight centres receiving atezolizumab and bevacizumab were included. Overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) defined by RECIST v1.1 were measured in older (age ≥ 65 years) and younger (age

Microplastic pollution is increasingly recognised as a global environmental challenge which stems from the rapid growth of the use of petrochemical-derived plastic. As researchers and practitioners face a myriad of environmental challenges, oceanic microplastic pollution has so far dominated interest. However, airborne microplastics present an increasing environmental and public health concern. There is currently a need for research addressing this emerging challenge, and at the same time, the lack of knowledge and consensus regarding airborne microplastics presents an obstacle to action. The purpose of this study is to utilise a participatory Structured Decision-Making (SDM) approach to understand the perspectives of a range of stakeholders involved in the microplastics landscape, and subsequently refine common research priorities and knowledge gaps to advance the field. Through two participatory workshops, we first defined shared objectives of stakeholders and then negotiated best courses of action to achieve these objectives based on discussion between stakeholders and facilitators. The qualitative approach taken has enabled the full, complex and multidisciplinary aspects of the research into airborne microplastic pollution to be considered. Our findings highlight some important potential consequences of airborne microplastic pollution, including impacts on human health, and the need for more interdisciplinary research, and collaborative, integrated approaches in this area. As a result of the first workshop, five fundamental objectives on the theme of airborne microplastics were identified. As a direct consequence of this, participants identified 84 actions split across eight themes, which are outlined later in this paper.

Studies of bureaucrats and bureaucracy have contributed to our understanding of the social production of indifference (Herzfeld 1992). However, in this article, I argue that this focus obscures the centrality of feelings, affect and emotions in their everyday functioning. Drawing on twelve months of ethnographic fieldwork in Malawi with civil servants of the Department of Disaster Management Affairs, I show empirically how they did not—nor did they strive to—appear indifferent. Rather, feelings, affect and emotions shaped the ways in which they allocated assistance and instantiated the state in the aftermath of Cyclone Idai. Despite its general material constraints, these relief interventions enabled the Malawi state to be present and provide resources to some of its citizens, constituting (it as) a state of relief.

OBJECTIVE: Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL). METHODS: The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of disease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28). RESULTS: This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS. CONCLUSIONS: Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL. ispartof: GYNECOLOGIC ONCOLOGY vol:166 issue:3 pages:494-502 ispartof: location:United States status: published

Background: Cognitive aids (CAs) are clinical tools guiding clinical decision-making during critical events in the operating room. They may counteract the adverse effects of stress on the non-technical skills of the attending clinician(s). Although most clinicians acknowledge the importance of CAs, their uptake in clinical practice seems to be lagging behind. This situation has led us to investigate which features of CAs may enhance their uptake. Therefore, in this systematic review we explored the optimums regarding the 1) timing to consult the CA, 2) person consulting the CA, 3) location of the CA in the operating room, 4) CA design (paper vs. electronic), 5) CA lay-out, 6) reader of the CA and 7) if the use of CAs in the form of decision support tools lead to improved outcome. Methods: Seven PICO-questions guided our literature search in 4 biomedical databases (MEDLINE, Embase, Web of Science and Google Scholar). We selected English-language randomized controlled trials (RCTs), observational studies and expert opinions discussing the use of cognitive aids during life-threatening events in the operating theatre. Articles discussing non-urgent or non-operating room settings were excluded. The quality of evidence was evaluated with the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We found 7 RCTs, 14 observational studies and 6 expert opinions. All trials were conducted in a simulation environment. The person who should trigger the use of a cognitive aid and the optimal timing of its initiation, could not be defined by the current literature. The ideal location of the cognitive aids remains also unclear. A favorable lay-out of an aid should be well-structured, standardized and easily readable. In addition, several potentially beneficial design features are described. RCT’s could not demonstrate a possible superiority of either electronic or paper-based aids. Both have their advantages and disadvantages. Furthermore, electronic decision support tools are potentially associated with an enhanced performance of the clinician. Likewise, the presence of a reader was associated with an improved performance of key steps in the management of a critical event. However, it remains unclear who should fulfill this role. Conclusion: Several features of the design or utilization of CAs may play a role in enhancing the uptake of CAs in clinical practice during the management of a critical event in the operating room. However, robust evidence supporting the use of a certain feature over another is lacking.

Background Ambulatory monitoring is gaining popularity in mental and somatic health care to capture an individual's wellbeing or treatment course in daily-life. Experience sampling method collects subjective time-series data of patients' experiences, behavior, and context. At the same time, digital devices allow for less intrusive collection of more objective time-series data with higher sampling frequencies and for prolonged sampling periods. We refer to these data as parallel data. Combining these two data types holds the promise to revolutionize health care. However, existing ambulatory monitoring guidelines are too specific to each data type, and lack overall directions on how to effectively combine them. Methods Literature and expert opinions were integrated to formulate relevant guiding principles. Results Experience sampling and parallel data must be approached as one holistic time series right from the start, at the study design stage. The fluctuation pattern and volatility of the different variables of interest must be well understood to ensure that these data are compatible. Data have to be collected and operationalized in a manner that the minimal common denominator is able to answer the research question with regard to temporal and disease severity resolution. Furthermore, recommendations are provided for device selection, data management, and analysis. Open science practices are also highlighted throughout. Finally, we provide a practical checklist with the delineated considerations and an open-source example demonstrating how to apply it. Conclusions The provided considerations aim to structure and support researchers as they undertake the new challenges presented by this exciting multidisciplinary research field.