Catheter ablation is currently the therapeutic approach of choice for many patients with accessory pathways. Despite the high success rate of radiofrequency ablation of the left lateral accessory pathways, a rather uncommon manifestation is intra-atrial conduction block at the level of the mitral isthmus. We report 2 cases of orthodromic atrioventricular reentrant tachycardia using a concealed left-sided accessory pathway with an abrupt change in the activation of the coronary sinus from an eccentric to concentric sequence after ablation delivery. The electrophysiological characteristics and the underlying mechanism of the intra-atrial conduction block are commented on. Careful mapping and assessment of relative conduction are helpful to document the diagnosis of intra-atrial conduction block. Familiarity with the likelihood of intra-atrial block during left lateral accessory pathway ablation is needed to avoid the erroneous elucidation that a second accessory pathway is present and to identify correctly the ablation site of interest. Despite the high success rate of CA in patients with a left lateral AP, a rather uncommon pertinent caveat is the intraprocedural occurrence of an intra-atrial conduction block at the mitral isthmus level.A 38-year-old woman with a history of supraventricular tachycardia was referred to our hospital for invasive management. The 12-lead electrocardiogram during sinus rhythm was normal. After obtaining signed informed consent from the patient, 2 quadripolar diagnostic catheters and 1 decapolar catheter were positioned via the right femoral access at the His, the right ventricular (RV) apex, and the coronary sinus (CS), respectively.Programmed atrial stimulation showed decremental AV conduction without dual AV node physiology. During RV pacing, an eccentric atrial activation sequence with non-decremental conduction properties was documented. Following incremental ventricular pacing, a narrow QRS, short RP tachycardia with a 1:1 AV relationship was induced at a stable cycle length (CL) of 320 ms. Overdrive pacing from the RV apex at a CL 20 ms shorter than the tachycardia CL (TCL) revealed a V–A–H–V response upon pacing termination. The difference in the: post-pacing interval (PPI) minus TCL ruled out AV nodal re-entry tachycardia (AVNRT). Therefore, an orthodromic AV re-entrant tachycardia (ORT) via a left-sided AP was diagnosed. and 1C. Deployment of ablation lesions at this site resulted in the immediate termination of the tachycardia. However, the ORT was still induced reproducibly with a prolonged V–A interval. Meticulous mapping identified the site of earliest retrograde atrial activation at a slightly more anterior location, where additional lesions were delivered, resulting in the further prolongation of the V–A interval (from 150 to 184 ms) and reversal of the retrograde atrial activation sequence to a concentric pattern . The TCL remained unaffected. Interestingly, the V–A interval at the lateral mitral annulus, distal to the level of the deployed lesions, was shorter than the V–A recorded septally  and 1E, despite the presence of a proximal-to-distal CS activation. These findings suggested an intra-atrial block at the posterolateral mitral annulus, proximal to the AP insertion, resulting in a counterclockwise propagation of the retrograde wavefront along the mitral annulus, with a concentric CS activation sequence. Additional RF delivery distally to the last lesions terminated the tachycardia. Post-ablation ventricular pacing demonstrated concentric retrograde atrial activation with decremental conduction properties. Furthermore, the ablation catheter positioned at the mitral annulus laterally to the CS catheter was activated later than the distal CS bipole . No tachycardia was inducible following atrial or ventricular pacing. The patient remained asymptomatic during a 4-month follow-up.Subsequently, AP mapping was performed using an irrigated catheter via a transseptal approach. The earliest retrograde atrial activation was documented at the posterolateral mitral annulus (4 o’clock in the left anterior oblique [LAO] projection), distal to the 1-2 bipole of the CS catheter . Following RF energy delivery at this point, the atrial activation changed to a concentric sequence without any effect on the TCL. Despite the concentric atrial activation sequence in the CS, the ablation catheter recorded continuous V–A activation at the lateral mitral annulus, which was earlier than the atrial activation recorded by the His catheter . Additional RF application was delivered in a more lateral position (3 o’clock in the LAO 40° projection) compared to the previous lesion, resulting in the termination of the tachycardia. Following ablation, the tachycardia was no longer inducible, while ventricular pacing demonstrated a ventriculoatrial dissociation, thus confirming the successful elimination of the AP .A 52-year-old man with a history of previous CA of a concealed, left lateral AP and recurrent supraventricular tachycardia was referred for a redo CA. The presence of a free-wall AP was confirmed by ventricular pacing, which demonstrated non-decremental conduction with eccentric atrial activation and a relatively long V–A interval. During ventricular pacing, an ORT was induced. Mapping of the AP was performed after gaining access in the left atrium (LA). At a posterolateral site of the mitral annulus, a very short V–A interval with a fractionated atrial electrogram was recorded, suggesting a good target site for ablation 5 Atypical AVNRT with an eccentric retrograde left-sided activation can be present in 6% of patients with AVNRT, which needs to be differentiated from an ORT using a left-sided AP.6 A possible explanation of the eccentric retrograde activation sequence during AVNRT could also be the involvement of the ligament of Marshall as part of the circuit.7 The presence of a long PPI–TCL during tachycardia and the presence of decremental properties strongly support the diagnosis of an atypical AVNRT. In our cases, corrected PPI–TCL was <110 ms and the SA–VA difference was <85 ms during tachycardia, and non-decremental conduction properties during ventricular pacing were observed, ruling out AVNRT.One of the important clues in the localization of an AP during an ORT is the analysis of the retrograde atrial activation sequence. An ORT with an eccentric atrial activation sequence rules out the participation of a right, septal or posteroseptal AP, while a concentric CS activation pattern usually excludes the participation of a left AP in the tachycardia circuit. However, in the case of a narrow QRS tachycardia with an eccentric retrograde activation sequence, electrophysiology testing and specific maneuvers are needed to rule out atrial tachycardia and atypical AVNRT..We report these 2 cases of ORT via a left-sided AP with an intraprocedural change in retrograde atrial activation during RF energy delivery, from an eccentric to a concentric sequence. A possible mechanism of this phenomenon is the occurrence of an intra-atrial conduction block at the mitral isthmus level medial to the insertion of the AP. As a result, there is still retrograde atrial activation via the AP, but with intra-atrial impulse propagation in a counterclockwise direction, thus depolarizing the inferior LA in a concentric sequence. The above-described propagation of the depolarization wavefront, in the context of the underlying intra-atrial block, explains the change in CS activation from an eccentric to a concentric pattern during tachycardia, with delayed activation of the proximal CS compared to the lateral mitral annulus distally to the level of the block Familiarity with the likelihood of an intra-atrial block during left lateral AP ablation is needed to avoid erroneous elucidation that a second AP is present. Assessment of relative conduction time proximal and distal to the ablation level is helpful to elucidate the direction of propagation wavefront during tachycardia.2 However, intra-atrial conduction block can occur even in a wide mitral isthmus, possibly because of areas of pre-existing functional block or scar.8Luria et al. reported that intra-atrial conduction block may occur in 6.9% of left free-wall AP cases following RF delivery along the mitral isthmus, which anatomically is the narrower conductive tissue between the mitral annulus and the left inferior pulmonary vein.9 Once the RF lesion eliminates the lateral atrial insertion of the AP, the atrial activation may be modified from an eccentric to a concentric or midline pattern if a second atrial limb of the AP connects to the proximal CS. However, if this hypothesis held true in our cases, we would expect a probable change in the TCL and a later retrograde atrial activation in the lateral as compared to the posterior mitral annulus. Finally, it is worth noting that bidirectional intra-atrial conduction block can occur after an unsuccessful endocardial ablation of APs, which may have a subepicardial or an epicardial course requiring an epicardial ablation from the CS.10Rarely, the presence of an AP with multiple bundles connecting the ventricle to the atrium at a lateral but also more posterior portions of the mitral annulus could be another explanation of this phenomenon.An intra-atrial conduction block at the level of the mitral isthmus may occur during the CA of left-sided APs. Complete or partial intra-atrial block should be suspected when an abrupt change in the atrial activation sequence is noted during CA at the posterolateral and lateral aspects of the mitral annulus. Recognition of this phenomenon is necessary for the accurate location of the site of interest and successful AP ablation while avoiding unnecessary lesion deployment.


Normally, antigens from the extracellular environment are not involved in the MHC-I-mediated pathway. Antigen-presenting cells (APCs), such as dendritic cells and macrophages, can collect exogenous proteins through endocytosis and then present antigens by not only conventional MHC-II but also MHC-I molecules, a process known as cross-presentation  molecules on the surface of all nucleated cells can present antigenic peptides derived from endogenous proteins to priming CD8entation . For CD8e memory . Howevere memory . Surprise memory , 5, whicScience found for the first time that the paired immunoglobulin-like receptor-A (PIR-A) expressed on mast cells, B cells, myeloid lineage cells, and dendritic cells in mice could promote graft rejection via direct binding to MHC-I molecules on allografts when mice immunized with allogeneic splenocytes were rechallenged with the allogeneic ones from the same source donor (H-2 type). In sharp contrast, these mice did not mount heightened rejection when rechallenged with third-party grafts (different H-2 type). This memory-like rejection of grafts could last for several weeks and was only attributed to the clonal expansion of Ly6Chi monocytes and macrophages after the initial stimulation. Blocking PIR-A from recognizing MHC-I with a specific antibody can inhibit the specific memory of myeloid cells and improve the transplant outcome in mice  β-glucan, LPS and flagellin from the extracellular environment, while PIR-A or Ly49 binds MHC-I on the membrane of nucleated cells. MHC-I-mediated memory is specific, more resembling the adaptive immune memory   . In the rophages .in vitro and then used as a cellular vaccine in vivo to relieve some autoimmune diseases or allograft rejection. Tumor antigen-specific memory NK cells mediated by Ly49C/I could be induced in vitro and exclusively expanded in vivo to convert into effector NK cells or to awaken accompanying cells to attack the corresponding tumor. Attractive issues with great challenge remain to be settled in the future. Since the formation of innate immune memory mediated by PRR is usually influenced by epigenetic modification, we raise the possibility that there are potential epigenetic, metabolic, and functional differences between myeloid cells/NK cells acquiring memory via PIR-A/Ly49 or PRR/Ly49 signaling pathway. Obviously, solving these questions and exploring new receptors with potential to initiate non-specific and specific innate immune cell memories will provide a broader and deeper insight into the complicated immune memory network and assist man to reunite these distinct types of memories to orchestrate an entire immune response.Collectively, the finding by Dai et al. has a strong impact on the definition of traditional innate immune memory, greatly enriching the connotation of innate immune memory but also advancing our understanding of differentiation of non-specific or specific innate immune memory cells and their correlation with adaptive immune cell memory , and Guangzhou City Science and Technology Program Synergistic Innovation Major Project (grant number: 201604020146) to FX.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


OBJECTIVES/GOALS: 1. Understand the association between patient perceptions of care measured by the Interpersonal Processes of Care (IPC) Survey and glycemic control, appointment no-shows/cancellations and medication adherence in patients with type II diabetes. 2. Determine how these relationships differ by race for non-Hispanic White and Black patients. METHODS/STUDY POPULATION: This is a cross-sectional study of a random sample of 100 White and 100 Black Type II diabetic patients followed in Duke primary care clinics and prescribed antihyperglycemic medication. We will recruit through email and phone calls. Enrolled patients will complete the Interpersonal Processes of Care Short Form and Extent of Medication Adherence survey to measure patient perceptions of care (predictor) and medication adherence (secondary outcome). No show appointments and cancellations (secondary outcomes) and most recent hemoglobin A1c (primary outcome) will be collected from the Electronic Medical Record. We will also collect basic demographic information, insurance status, financial security, significant co-morbidities, and number and type  of antihyperglycemic medications. RESULTS/ANTICIPATED RESULTS: -The study is powered to detect a 0.6% difference in HbA1c, our primary outcome, between high and low scorers on the Interpersonal Processes of Care subdomains. -We expect that higher patient scores in the positive domains of the IPC survey and lower DISCUSSION/SIGNIFICANCE OF IMPACT: This study will provide information to develop and implement targeted interventions to reduce racial and ethnic disparities in patients with Type II diabetes. We hope to gain information on potentially modifiable factors in patient-provider interactions that can be intervened upon to improve prevention and long-term outcomes in these populations.


Results suggest that having controlled for body size and body shape, performing EHS and being an early developer (identified by a positive MO slope parameter) benefits children in physical fitness and motor performance tasks.Regular participation in strength and conditioning activities positively correlates with health-related benefits in sports . Maturity offset (MO) is a recognized parameter in fitness outcome assessment. The aims of the present study are to analyze cross-sectional allometric development of motor performances in a sample of adolescents and relate scaled motor performance to the estimated amount and type of physical activity and biological maturity status in 771 subjects aged 14–19 years. Three physical fitness components were evaluated using field tests . Extra hours of sport after school (EHS) and MO were the covariates. The model to predict the physical performance variables was: Y = a · M Physical activity is positively associated with good health outcomes for children and young people: psychosocial and cognitive development , fitnessA robust classification of physical activity includes the type of activity, with different training plans for team or individual sports practice. Individual sports athletes train for months to achieve peak fitness and performance in a single event or a series of events ,8. Diffecriteria .2 increases with gender-specific, age-driven and maturity status-driven concurrent changes in morphological covariates, with the timing of these alterations specific to individuals. Furthermore, based on ratio-scaled peak oxygen uptake, the delivery/utilization of oxygen is facilitated by increased fat-free mass, thus favouring lighter weight and penalizing heavier youths [Moreover, fitness performance is also influenced by an individual’s somatotype . Multile Welsman  suggester youths ,13.To avert arriving at incorrect conclusions and misinterpretation of data, and additive polynomial model has been developed to analyze and interpret data –17  in a sample of adolescents and related the scaled motor performance to the estimated amount and type of physical activity and biological maturity status. We believe that an analysis based on a non-linear approach can account for the exponential growth changes that affect sports performance. In addition, determining the physical activity with the most effective impact on young persons’ sports performance could provide a useful guide for health mentors.The study was conducted in January 2019 and involved 771 adolescents  attending a high school in northern Italy. Inclusion criteria were: physical fitness certificate; regular physical education (PE) class attendance; no physical impairments or illnesses or neurological disorders; if history of orthopedic injury, then older than 1 year before inclusion in the study.The cross-sectional cohort design provides a descriptive measure for boys and girls separately. The Ethics Committee approved the study of the Lombardy Regional School Board (UP 1819–15). Teachers and students received written information about the study purpose and procedure. Informed consent was obtained from participants’ parents or legal guardians. Participants were free to withdraw from the study at any time.Tests were conducted by a team of master’s degree students in PE during school time for PE . The stuAnthropometric measurements were taken by trained operators . Standing height was measured to the nearest 0.5 cm (Seca Stadiometer 208) without shoes, feet together, and head in the Frankfort plane. Body mass was measured to the nearest 0.5 kg , with participants wearing minimal clothing. Waist circumference (WC) was measured over the naked skin with flexible bands (Seca) to the nearest 0.1 cm, half-way between the lower rib and the top of the iliac crest at the end of gentle expiration, according to Fredrik’s guidelines ,23.Three physical fitness components were evaluated using field tests from the Eurofit test battery , as admiStanding Broad Jump : frSit-Ups : TheShuttle Run Test 10 x 5 m : TwoData on physical activity and sports participation were collected via a self-reported questionnaire  administSports can be divided into two categories according to the effects of the environment on motor skills: open and closed sports . Open spSports can also be divided into two categories according to competitions: individual and team sports. Individual sports are characterized by individual performance against another single participant, while team sports involve two or more members who compete against the opposite team .Continuing debate surrounds the interpretation of the influence of body size, composition, and shape on physical fitness testing of children and adolescents of different socioeconomic status  and cultData analysis was performed using SPSS Statistics . The multiplicative model  with allThe advantage of the model is that it has proportional body-size components and a multiplicative error that assumes that ε increases proportionally with the physical performance variable Y . Linear regression analysis or analysis of covariance (ANCOVA) of Ln(Y) can then be used to estimate the unknown parameters of the log-transformed model:The model  can be lP<0.05.Other categorical or group differences within the sample  can be explored by allowing the constant intercept parameter Ln(a) to vary for each group by introducing them as fixed factors (plus possible interactions) within an ANCOVA  dependent variables and the terms Ln(M), Ln(H), Ln(WC), EHS, and MO in The multiplicative model  relatingWith positive height (H) and negative mass (M), and waist (WC) exponents, the model suggests that being taller but lighter (less body mass) with a smaller waist circumference is the optimal body shape associated with SBJ.Fitting Model  revealedA significant positive contribution to predict log-transformed SBJ distance was noted for extra hours of sports (EHS) and maturity offset (MO) (both P <0.001).The multiplicative model relating the number of sit-ups performed in 30 s (SUP) to the body-size components using The model  fitted tA significant contribution to predict log-transformed SUP distance was noted for extra hours of sports (EHS) and maturity offset (MO) (both P <0.001). As expected, EHS was positively related, whereas MO was negatively related to the number of sit-ups in 30 s.The model relating the shuttle-run-test performance  to the body-size components using A significant contribution to predict log-transformed SHR speed was noted for extra hours of sports (EHS) and maturity offset (MO) (both P <0.001). As expected, EHS and MO were positively related to the shuttle run speed.With this study, we investigated the relationships between biological maturation/body shape characteristics  and physical fitness using field tests  in a cohort of adolescents . The allThe ectomorphic subjects performed better on the SBJ  and the Nevill et al.  suggesteIn the comparison of the differences between males and females, the boys appear more ectomorphic . The antExtra hours of sports were the first predictor of performance on the three tests  Figs  and 4, iOne limitation of the present study is that the self-report questionnaire could have been more robust in design  developed as an instrument for cross-national monitoring of physical activity and inactivity). Moreover, physical fitness assessment should include an aerobic test. However, due to the large amount of data and the school setting of the study, these choices were made to promote student compliance.This study provides information about strength status in adolescents: children with an ectomorphic body shape, due to their taller physique and reduced body mass, performed better on the speed-agility and the explosive strength tests, as reported previously . A linea


Europe is in the midst of a COVID-19 epidemic and a number of non-pharmaceutical public health and social measures have been implemented, in order to contain the transmission of severe acute respiratory syndrome coronavirus 2. These measures are fundamental elements of the public health approach to controlling transmission but have proven not to be sufficiently effective. Therefore, the European Centre for Disease Prevention and Control has conducted an assessment of research gaps that can help inform policy decisions regarding the COVID-19 response. We have identified research gaps in the area of non-pharmaceutical measures, physical distancing, contact tracing, transmission, communication, mental health, seasonality and environment/climate, surveillance and behavioural aspects of COVID-19. This prioritisation exercise is a step towards the global efforts of developing a coherent research road map in coping with the current epidemic but also developing preparedness measures for the next unexpected epidemic. Non-pharmaceutical public health measures are currently playing a very important role in reducing the spread of COVID-19 . FurtherThe European Centre for Disease Prevention and Control (ECDC) has commented on gaps in knowledge and research in a number of technical guidance documents , 4. OtheThe World Health Organization (WHO) has developed a research and development (R&D) Blueprint in order to rapidly expand scientific knowledge on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), to track its spread and virulence and to provide advice to countries and individuals on control measures . Key knoGather data and develop a robust system for reporting. Harmonised gathering and sharing of data at national and subnational levels by public health authorities is essential to better manage the lifting of measures.Create a framework for contact tracing and alerting with the possible use of mobile apps, while respecting data privacy.Testing capacities must be expanded and harmonised. Fast and reliable testing is key to swift diagnoses and to measure the population's acquired immunity. The Commission has presented guidelines on coronavirus tests.The capacity and resilience of health care systems should be increased. Particularly, to address the predicted rise in infections after rolling back the containment measures. The EU budget has been mobilised to help.The availability of medical and PPE should be improved. The Commission supports Member States by stockpiling and distributing supplies and equipment via rescEU and Joint Procurement.Develop and fast-track the introduction and distribution of vaccines, treatments and medicines. The deployment of safe and effective vaccines against SARS-CoV-2 and variants of concern would be essential in putting an end to the coronavirus outbreak.In order to refine the specific COVID-19 research priorities for non-pharmaceutical public health and social measures we conducted an assessment with the ECDC Public Health Emergency (PHE) experts working on the response to the COVID-19 pandemic.The European roadmap to lifting coronavirus containment measures describes how to gradually lift the non-pharmaceutical public health and social measures, and how to enter the recovery phase and revitalising society and the economy. Three criteria to be fulfilled before the non-pharmaceutical public health and social measures should be lifted, have been defined. They include epidemiological criteria, health system capacity and monitoring capacity to quickly detect and isolate infected individuals. To do so, a number of steps need to be taken and include:The current state of COVID-19 science and the existing knowledge gaps were assessed through daily automatic searches of the peer-reviewed literature in PubMed with the following search string: ‘COVID-19’[Supplementary Concept] OR ‘severe acute respiratory syndrome coronavirus 2’[Supplementary Concept] OR ‘COVID-19 vaccine’[Supplementary Concept] OR ‘COVID-19 serotherapy’[Supplementary Concept] OR ‘COVID-19 diagnostic testing’[Supplementary Concept] OR ‘COVID-19 drug treatment’[Supplementary Concept] OR ‘LAMP assay’[Supplementary Concept]* OR ‘Coronavirus Infections’[Mesh:noexp] OR ‘Wuhan coronavirus’[TW] OR ‘Wuhan seafood market pneumonia virus’[TW] OR COVID19[TW] OR ‘COVID-19’[TW] OR ‘COVID-2019’[TW] OR ‘coronavirus disease 2019’[TW] OR ‘SARS-CoV-2’[TW] OR SARS2[TW] OR ‘2019-nCoV’[TW] OR ‘2019 novel coronavirus’[TW] OR ‘severe acute respiratory syndrome coronavirus 2’[TW] OR ‘2019 novel coronavirus infection’[TW] OR ‘coronavirus disease 2019’[TW] OR ‘coronavirus disease-19’[TW] OR ‘novel coronavirus’[TW] OR coronavirus[TW] OR ‘SARS-CoV-19’[TW] OR ‘SARS-CoV-2019’[TW].The retrieved publications were collated in an Endnote database and subjected to a review of title and abstract by two investigators (IJQD and SRK). Relevant publications of high quality and impact were compiled into a weekly digest and distributed to ECDC PHE experts working on infection prevention and control (IPC), clinical aspects of COVID-19, experts in microbiology, preparedness, response, surveillance, scientific evidence and modelling. Moreover, specific literature searches in these disciplines were conducted to complement the general search on COVID-19 science. New scientific breakthroughs in the field of COVID-19 epidemiology were presented to ECDC technical experts at a daily roundtable and technical group meetings at ECDC in order to continuously update ECDC PHE technical experts about the latest developments in the field and research gaps.Based on the technical expertise of these ECDC PHE experts and based on requests from the European Commission and EU Member States the research gaps for non-pharmaceutical public health and social measures were assessed using a two-phased approach: first, ECDC PHE experts were consulted about research areas which will require an expanded evidence base according to their technical assessment. Relevant information on this topic was used as a reference point , 6, 8. TIn a second round, these ECDC PHE experts were requested to prioritise the research gaps for non-pharmaceutical public health and social measures based on the public health impact and importance. Disagreements regarding these priorities were resolved during PHE expert team meetings. This document was shared with the Health Security Committee of the European Commission for feedback from the different member states.In light of the WHO R&D Blueprint and the European roadmap , 8, knowThe selection of research gaps below includes the most relevant areas for public health and those which may have a direct impact on the modification or adaptation of measures. These research priorities are outlined to complement the European roadmap to lifting COVID-19 containment measures .The compilation of this overview of research gaps is based on the daily review of the global epidemiologic situation by the ECDC epidemic intelligence team. Moreover, it is also based on a review of the thematic areas that are covered by the PHE team at ECDC.As Europe is facing a resurgence of the pandemic following relaxation of social distancing measures, the need for understanding the effectiveness of countermeasures that are applicable and appropriate for a variety of settings is urgent. A number of important research gaps remain that need to be addressed in order to contain the transmission of COVID-19. Of particular importance is the need to better understand the mechanism of transmission of COVID-19 and which non-pharmaceutical measures are the most effective at mitigating the epidemic.These research gaps can only be achieved by collectively respecting the framework for successful research partnerships in global health . This ouThese global research efforts confirm the persistence of knowledge gaps regarding non-pharmaceutical public health and social measures. International collaborations between teams and transparency in this process will reduce duplication of work and provide a clearer picture of the epidemiology of COVID-19. It can help accelerate and optimise the implementation of non-pharmaceutical public health and social measures to help contain the spread of SARS-CoV-2. It can also provide a strategic approach to counter the infodemic of mis/disinformation associated with the COVID-19 pandemic, which requires swift, regular, systematic and coordinated action from multiple sectors of society and government . WHO devThis prioritisation exercise for research on non-pharmaceutical public health and social measures is a step towards the global efforts of developing a coherent research road map  in copinNone.https://www.ecdc.europa.eu/en.The data that support the findings of this study are openly available at:


Dear Editor,1 forming the barrier for the access of CRISPR-based gene-editing tools to the mtDNA. Furthermore, mitochondrial genome lacks similar repair systems for the protection of nuclear genome from DNA damage after induction of double-strand break by programmable nuclease such as ZFN, TALEN etc., which results in the elimination of target mtDNA5 instead of mutation installation on mtDNA in contrast to the outcome of indel formation on nuclear DNA6. Recent studies positioned DdCBE as a promising technology to install targeted mutations or introduce transmissible mutations of base conversion in mammalian mtDNA10 rather than eliminate them with previous ZF- or TALE-based nuclease5. Thus, DdCBE has the potential to model mitochondrial disease mutations, correct pathogenic variants, and expand our knowledge of mitochondrial biology. However, it is worth mentioning that these studies have found that DdCBE can cause low-frequent off-target events on mtDNA10. As indicated, the off-target profile of DdCBE remained to be comprehensively investigated by additional research for their systematic effect on mtDNA as well as nuclear genome.Mitochondrial DNA (mtDNA) is encapsulated by the organelle membrane12 to evaluate the off-target effect of DdCBE on both mtDNA and nuclear DNA modification. At first, we in vitro transcribed two pairs of DdCBE mRNA targeting the mtDNA ND5 gene (G12918 and C12336) and injected them with Cre mRNA into one blastomere of two-cell embryos derived from Ai9 background leaving another blastomere uninjected  analysis  method previously developed by usted Fig. . Therebysis Fig. . Sanger 12. Unexpectedly, we identified about 1500 and 1000 single-nucleotide variants (SNVs) with significant confidence as potential off-target editing events for G12918 and C12336-targeting DdCBE in edited cells using unedited cells as SNV calling references  in N-terminal region of DdCBE protein, our results imply that MTS seems to fail in blocking the entry of DdCBE into nuclear in mammalian cells. It would be interesting in the future to examine whether extra or different MTS could reduce off-target editing of DdCBE on nuclear DNA. In addition, expressing DdCBE in embryos may result in different results from when editing is done in differentiated cells. Therefore, it would be necessary when the technique available in the future to clarify different propensity of DdCBE off-target activity in somatic cells than embryonic cells. Taken together, our finding on off-target activity of DdCBE towards nuclear genome necessitate the strong need to optimize DdCBE for specific base editing on mtDNA especially before being used for treating mitochondrial diseases.In summary, we showed for the first time that DdCBE cause thousands of off-target SNVs enriched for C-to-T/G-to-A conversion in the entire nuclear genome, which is two times the SNV number resulted from low-fidelity base editor BE3. Unlike the substrate preference of cytosine deaminase APOBEC1 in BE3 protein for ssDNA, DddASupplementary Figures and Tables


The distribution of single Stop Signal Reaction Times (SSRT) in the stop signal task (SST) has been modelled with two general methods: a nonparametric method by Hans Colonius (1990) and a Bayesian parametric method by Dora Matzke, Gordon Logan and colleagues (2013). These methods assume an equal impact of the preceding trial type (go/stop) in the SST trials on the SSRT distributional estimation without addressing the relaxed assumption. This study presents the required model by considering a two-state mixture model for the SSRT distribution. It then compares the Bayesian parametric single SSRT and mixture SSRT distributions in the usual stochastic order at the individual and the population level under ex-Gaussian (ExG) distributional format. It shows that compared to a single SSRT distribution, the mixture SSRT distribution is more varied, more positively skewed, more leptokurtic and larger in stochastic order. The size of the results’ disparities also depends on the choice of weights in the mixture SSRT distribution. This study confirms that mixture SSRT indices as a constant or distribution are significantly larger than their single SSRT counterparts in the related order. This result offers a vital improvement in the SSRT estimations. Inhibition refers to the ability to suppress actively, interrupt or delay an action . Inhibito 200 ms .Several models have been proposed to evaluate and describe response inhibition in the stop-signal paradigm including the deadline model, the independent horse race model, the interactive horse race model and the Hanes–Carpenter model ,10,11,12There are several estimation methods of SSRT depending on two contexts in the SST literature: (i) as a constant index, or (ii) as a distribution of non-constant random variable. Within each context, these methods mentioned below refined the earlier proposed methods given their associated contexts see .n stop signal delays Referring to ant SSRT . FurtherEquation . The fouEquation :(1)SSRTCSeveral researchers have shown that merely focusing on measures of central tendency in reaction times RT, including SSRT, gives insufficient information regarding the data’s nature. For instance, different clinical groups may have the same mean reaction times. However, the shape of their distributions differs in several aspects. The differences are in their tails, as seen in an ADHD group compared to the controls , or theiReferring to Equation  19]. Al. AlfGORTribution . Next, tribution . Finallyribution ). on storibution . Assumin and (7) :(5)FSSRTHowever, as mentioned by Logan , there iThere are only two studies in the SST literature that partially answered this question when SSRT is considered as constant index ,15. HereGiven that constant SSRT index can be considered as a degenerate random variable, the above results partially shed light on the proposed question for the case of a non-degenerate SSRT random variable. However, it is still unknown whether the constant index related results hold for general SSRT random variable, in which order context these comparisons over random variables can be conducted and in which mechanism the pairwise comparisons of the involved paired sets of random variables is conducted.This study offers an estimation of the SSRT distribution given the relaxed assumption of equal impact of the preceding trial type (go/stop) on the current stop trial SSRT distribution. It uses the notion of two-state mixtures  and propEquation  and (ii)This study’s data and design are previously described in . The stuform see . In this1Type-A SST data cluster: all trial preceded by go trials See 2Type-B SST data cluster: all trials preceded by stop trials See 3Type-S Single SST data cluster: all trials when considered for one single SSRT distribution4Type-M Mixture SST data cluster: all trials when considered for the mixture SSRT distribution.In this study, four types of SST data clusters were identified as shown in A random sample of 44 participants was selected for further analysis. The entire stop signal task data for each participant was partitioned to type-A and type-B cluster types see . These pEquation  (see AppEquation .Heathcote (1996)  formulatFinally, this random variable is right-skewed and leptokurtic with the following variance, skewness and kurtosis shape statistics:Given single SSRT by Equation  are natuIn the Bayesian context and using IBPA and under Ex-Gaussian parametric assumption, we have The first four moments of the Mixture SSRT are as follows:Consequently, the variance, the skewness and the kurtosis of the Mixture SSRT are computed byRemark 1.Using new Equation  for SSRTRemark 2.The mixture modelling for SSRT proposed here can be applied with other non-Ex-Gaussian parametric RT distributions such as Ex-Wald, Wald,  Gamma, WFor each participant IBPA under Ex-Gaussian parametric distribution was run three times: one for its associated cluster type-A, cluster type-B and single type-S SST data . We then calculated the mean posterior estimates of t-test  within a real numbers contexts and (ii) within a real-valued random variables context. For the first set of comparisons, paired sion 9.4 ) were co R.3.4.3 ) were coGiven two sets of stop signal reaction times distributions rder <st . Our proStep (1): Two-Stage Bayesian Parametric Approach (TSBPA) This proposed analysis is neither completely hierarchical Bayesian analysis nor completely conventional meta-analysis. It has components of both methods. On the one hand, it has two separates one-stage Bayesian analyses. On the other hand, it calculates overall population-level estimates in the second analysis with consideration of non-zero correlations. Referring to Equation , we defiStage (1)DataIndividual PriorsIn the TSBPA See , the datsoftware . FinallyStage (2)DataPriorsStep (2): Paired Samples Parametric Distribution Test (PSPDT) This proposed test can be considered as a distributional counterpart of the paired z-test in the real numbers. Using overall estimates in Step (1), we then conduct the following paired samples parametric distribution test hypothesis testing for We reject the null hypothesis The Two-Sample K–S test analysis was conducted with R3.4.3 software as before. The hypothesis testing in (17) were repeated for other comparisons between cluster type SSRT indices including Remark 3.The test (17) with The results are divided into three subsections. In This section includes two sets of descriptive results: First, the results for cluster-type related mean and standard deviation of the Ex-Gaussian SSRT. Second, the results for cluster-type-related shape statistics skewness and kurtosis of the involved random variables. Throughout these results, as it is shown in vely see . The desGiven summary statistics and shape statistics comparison results between single SSRT and mixture SSRT, one naturally considers comparing their associated distributions. In the next section, we deal with this topic.This section deals with individual and overall level estimations of Single SSRT and Mixture SSRT and their usual stochastic order comparisons.p-values for the sample of 44 subjects based on IBPA. Similar hypothesis testing is conducted replacing ≠ with < and > in an alternative test. With two participants exception (case 34 case 37), the result shows that controlling for Family-Wise Error Rate(FWER) with Bonferroni’s correction  the single SSRT is smaller than the mixture SSRT in stochastic order. This result is consistent with the direction of constant index SSRT results [ results .We test the hypothesis (17) from TSBPA given uninformative priors for an overall conclusion using a paired samples parametric distribution test. The choice of TSBPA rather than HBPA was out of consideration for pairwise non-zero correlations in the second stage of the analysis. One key missing characteristic in the HBPA is the relaxing assumption of zero correlation of mean posterior parameters at the individual level. This assumption is violated given cluster-S SSRT mean posterior parameters Pearson correlations p-value < 0.0562) and Mixture SSRT. Furthermore, given consideration of mean of SSRT distribution as its point index estimation, the result regarding the comparison of single SSRT versus Mixture SSRT is consistent with the direction of the frequentist results asAs we observe from In this and the previous section, we considered the cluster type weight This section compares the descriptive statistics of mean, variance and the entire distribution of SSRT indices in terms of individual optimal weights. By definition, the optimal weight en trial . The folen trial :Proposition 1.The weight Note that the fitted ExG parameters First, to study the impact of individual weights on the disparities of the mean estimations across indices, we consider average differences of the new index Second, to examine the impact of individual weights on the disparities of the variance estimations across indices, similar to the case in In particular, the average variance differences attains its maximum value atp-values. p-value = 0.0562, and it is the strongest when p-value = 0.0152. Finally, the disparity at the optimal weight p-values of 0.0262 and 0.0312, respectively.Finally, to explore the impact of cluster type weights This study presented a mixture Bayesian parametric approach for a more illuminating SSRT distribution estimation by considering two subtype SST cluster information suggesting a new estimation of the SSRT distribution. Furthermore, it introduced two novel statistical methodologies accompanied by their empirical applications: TSBPA and PSPDT. It was hypothesised that considering cluster type information in the new mixture SSRT distribution calculations would impact the estimation of SSRT distribution. This yields to a distributional counterpart to the case of constant index SSRT ,15.The descriptive and shape statisticsThe distributional comparisons at the individual level and the population levelWith the validity of the results in the first two observations across the entire spectrum of the weightsThe results confirmed the hypothesis through three observations:Similar to the constant index SSRT , in mostThis study confirmed that SSRT depends on non-horse race-related factors in each round of SST experimental trial, such as memory aftereffects and proportion of cluster type stop trials. It has shed light on the preparation aspect of choice stop signal reaction times by treating the previous trial type’s aftereffects as memory in the two-state mixture model . BesidesThis study’s findings for the SSRT distribution were consistent with the constant index SSRT when considering the impact of sub-cluster types in the estimations ,15. In dOn the one hand, if we look at the two sides of the Equation  as degenThis study’s novel statistical methodological contributions involved the Two-Stage Bayesian Parametric Approach (TSBPA) and the Paired Samples Parametric Distribution Test (PSPDT). TSBPA’s advantage was that it considers the underlying non-zero correlation between estimated mean posterior parameters at the first stage in the second stage’s final calculations. This feature is neglected in HBPA. PSPDT offered a novel method to compare paired sets of parametric random variables using the two-samples KS test. An application of both proposed methods was provided in this study.There are limitations in the current study. First, the sample size was relatively small Equation . Here, wpurposes . FinallyThe proposed approach in modelling the SSRT distribution in this study should be replicated in future research in several different directions. This further work may shed light on further unknown corners. New work includes (i) considering the larger number of SST trials, (ii) examining the order of trials, (iii) expanding these methods to other clinical populations, (iv) considering trigger failures in the modelling, (v) interpreting the shape statistics and (vi) estimating signal respond reaction times (SRRT).First, research has recommended that reliable estimates of SSRT for adults requires 200 SST trials with 50 stops . TherefoSecond, additional research to this study must address the presumption of equal impact in the order of trials for the same cluster type weights Third, after this study, the work should apply the proposed Fourth, there are trigger failures that impact the estimations . Given tFifth, this study merely reported and compared the shape statistics for skewness and kurtosis across the cluster type SSRTs, single SSRT and the mixture SSRT distributions. There is a need to investigate these shape statistics’ psychiatric and psychopathological interpretations given the ex-Gaussian parametric distribution assumption.Finally, this study and the earlier study in  addresseThere has been a great deal of interest in the aftereffects of inhibition on the estimation of SSRT in the SST literature from the early 1990s. This study addressed the problem in part and presented a two-state mixture model of SSRT distribution by considering the prior trial type with results consistent with the constant SSRT index results in the literature . The res


Assisted living (AL) communities with memory care licenses are disproportionately located in affluent and predominantly White communities and Black older adults are underrepresented in AL. But little is known about characteristics of AL that care for Black residents. We estimated the association of facility-level characteristics as proxy measures for AL resources, such as memory care designations and percentage of dual-eligible residents, across low (0-5%), medium (5-10%) and high (>10%) percentages of Black residents. We found broad differences among communities in the three levels of Black-resident prevalence. High percentage of Black residents was associated with large differences in the percentage of Medicaid-enrolled residents . ALs with high Black populations were less likely to have a memory-care designation than ALs with medium and low percentages of Black residents .


Stevioside is a diterpenoid glycoside consisting of an aglycone (steviol) and three glucose molecules. It is commonly used as an anti-hyperglycemic food because of its non-caloric property. Therefore, it is of interest to document the interactions of steviosidewith AKT & PPAR-γ proteins using Autodock Vina PyRx docking techniques. Results of the docking studies indicate that stevioside had more than two hydrogen bond interactions with the AKT and PPAR γ protein for further consideration. Diabetes is widely recognized as one of the leading causes of death in the world . High-faThe AKT (PDB ID: 3QKM) and PPR gamma (PDB ID: 2PRG) atomic coordinates have been retrieved from the RCSB PDB (protein data bank) database, charge assignment, solution measurements and fragment volumes to the protein have been performed using Autodock Tool 4(ADT) prior to analysis or docking. The protein molecule was then optimized for molecular docking by the Autodock Tool.Stevioside's 2D structure has been retrieved from the pubchem database and translated into the.pdb file format by using online smile translator. In order to enhance the analysis, ligand was first standardized and converted into PDBQT format using the PyRxVirtual Screening Tool (python prescription 0.8) graphical user interface version.AutoDock (V. 4.0) was used in the PyRx Interface to validate the binding capabilities of the interactions between Stevioside and AKT & PPAR gamma ,15. DuriStevioside is a particular high-affinity AKT protein compound. The results of the docking analysis shown in The results of docking studies indicate that Stevioside with PPAR gamma complex had the least binding affinity of-6.5 Kcal / mol. The least binding affinity suggests that Stevioside forms a stable complex with PPAR gamma. This also forms four hydrogeninteractions with the amino acids LYS-373, GLN-437, THR-440 and GLU-448. Details of hydrogen bond interactions are shown in Interactions among Stevioside and AKT & PPAR gamma proteins were explored to evaluate potential binding affinity using Autodock Vina PyRx docking techniques. The interaction between the two docking complexes has been contrasted on the basis of their bindingstrength, which in turn involves interaction of hydrogen bonding and other bonding between proteins and ligands. The binding energy provided by the interaction between Stevioside and AKT & PPAR gamma proteins was summarized in Table 1(see PDF). Daisy et al. statedin 2012 that a minimum docking energy has been needed for the formation of a ligand-receptor complex such that the ligand has been buried in the receptor cavity. According to Daisy et al. 2012, Stevioside has been bound to the cavity of AKT & PPAR gamma sinceit has a minimum docking energy of-9.6 kcal / mol with AKT and-6.5 kcal / mol with PPAR gamma protein. The participation of H-bond interactions enabled the complex to obtain the accepted configuration of the complex structure .AnalysiWe show the molecular docking analysis of stevioside with targets AKT and PPAR gamma in the context of diabetics.


A farm-to-landscape scale modelling framework combining regulating services and life cycle assessment mid-point impacts for air and water was used to explore the co-benefits and trade-offs of alternative management futures for grazing livestock farms. Two intervention scenarios were compared: one using on-farm interventions typically recommended following visual farm audits  and the other using mechanistical understanding of nutrient and sediment losses to water . At farm scale, reductions in business-as-usual emissions to water of total phosphorus (TP) and sediment, using both the visually-based and mechanistically-based scenarios, were <5%. These limited impacts highlighted the important role of land drains and the lack of relevant on-farm measures in current recommended advisory lists for the soil types in question. The predicted impacts of both scenarios on free draining soils were significantly higher; TP reductions of ∼9%  and ∼20%  compared with corresponding respective estimates of >20% and >35% for sediment. Key co-benefits at farm scale included reductions in nitrous oxide emissions and improvements in physical soil quality, whereas an increase in ammonia emissions was the principal trade-off. At landscape scale, simulated reductions in business-as-usual losses were <3% for both pollutants for both scenarios. The visually-based and mechanistically-based scenarios narrowed the gaps between current and modern background sediment loads by 6% and 11%, respectively. The latter scenario also improved the reduction of GWP100 relative to business-as-usual by 4%, in comparison to 1% for the former. However, with the predicted increase of ammonia emissions, both eutrophication potential and acidification potential increased . The discrepancy of on-farm intervention efficacy across spatial scales generated by non-agricultural water pollutant sources is a key challenge for addressing water quality problems at landscape scale.  •Monitoring data frames visually- and mechanistically-based intervention scenarios.•Farm to landscape modelling explores mitigation scenario co-benefits/trade-offs.•Farm scenarios reduced total phosphorus (TP) and sediment by <5% on drained soils.•Farm scenarios reduced TP and sediment by up to ∼20% and >35% on free draining soils.•Reductions in nitrous oxide emissions are the main co-benefit at farm and landscape scales. OverstoThe mitigation of DWPA is a complex challenge . EffortsAccordingly, we explored the potential outcomes of two on-farm mitigation scenarios for less favoured area (LFA) grazing livestock farms in SW England. One is based on current on-farm advice and the other uses mechanistic evidence on sediment and phosphorus (P) mobilization and delivery resulting from high resolution monitoring. A farm-to-landscape scale modelling framework was employed to assess the technically feasible co-benefits and trade-offs of each scenario relative to business-as-usual (BAU) at both farm and catchment scales. The hypotheses tested were: (i) the mechanistically-devised scenario will deliver greater reductions in water pollution than the visually-based scenario – addressing the evidence gap for assessment of mechanistically-defined management scenarios, rather than more conventional change in land cover scenarios; (ii) the efficacies of the intervention scenarios will be affected by soil drainage status dependent pathways – addressing the failure of many agri-system models to represent the assisted/preferential drainage pathway and its implications for intervention impacts explicitly; (iii) there are potential tradeoffs and co-benefits at farm scale and; (iv) non-agricultural water pollutant sources will generate a spatial mismatch of efficacy between farm and landscape scale – addressing the evidence gap for explicit representation of this mismatch in much existing modelling work.22). The North Wyke Farm Platform (NWFP) is in the upper reaches of the waterbody with hydrologically-isolated catchments ranging in size from 1.62 to 8.08 ha. Each catchment is equipped for monitoring rainfall and soil moisture, as well as discharge and water quality parameters  using flume laboratories  and the land use can be divided into two: upland moorland comprising low intensity rough grazing grassland and a lowland agricultural area with a mixed grassland and cropping landscape. Long-term (1981–2010) average annual rainfall ranges between 1478.2 mm and 2468.1 mm for the upland area and between 957.5 and 1502.0 mm for the lowland agricultural area. While 15 soil series have been mapped in the study landscape, only six represent >5% of the catchment area on an individual basis . The domThe upper River Taw has been assessed in conjunction with the chemical requirements of the EU Water Framework Directive (WFD) and judged to be failing due to elevated phosphate levels. Here, despite the landscape scale environmental objective being based on orthophosphate, it is important to acknowledge that water quality outcomes for phosphorus (P) will strongly reflect inputs of all forms of this nutrient, meaning that it is more appropriate to consider both OP and TP export and the capacity to improve management of all P forms . The upp33.1Our work integrated  monitori3.2https://nwfp.rothamsted.ac.uk/). Further details are provided in Data on precipitation, flow and water quality, comprising turbidity, OP and TP, for four sub-catchments . To avoid uncertainty from multiple rating curves in the period of record before 1998, the potential impacts of past water abstraction on low flow (up to 1999) and a known underestimation of flow (during 2000), only data between 2001 and 2017 were used without modification for further analysis and modelling. Monitored TSS and TP concentrations for the same periods were extracted from the Environmental Agency's Water Quality Data Archive  for the same station . For the period 2001–2017, there were 95 and 170 valid samples for TSS and TP, respectively. Monthly loads were estimated using the algorithms  and reported Countryside Stewardship (CS) uptake . Further background on the farm scale module is provided in supplementary information. More information on the grazing livestock farms in the study area is also included in supplementary information.CSM is a modelling framework for assessing farm-to-landscape scale impacts of land use and management under BAU or alternative scenarios . It has solution . Soil drunctions  were useunctions . Farm anunctions . These runctions  generateunctions  were revCi is the catchment scale total agricultural load for pollutant i, k represents a combination of AAR and soil drainage status, HC represent holding counts and FL represents the pollutant loads at farm scale. Ci was estimated using standard spatial join GIS procedures in ArcGIS 10.4.Module 2 scales out within the farming sector from farm to landscape scale using farm holding counts and types and their spatial distributions in the study catchment. Here, the farm type specific export coefficients from module 1 are used to generate the total emissions for BAU or the intervention scenarios using equation Module 3 is used to estimate the spatial mis-match arising from nutrient and sediment loads from non-agricultural sources. These calculations utilize SEPARATE (Sector Pollutant AppoRtionment for the AquaTic Environment) reported in detail by Module 4 calculates temporal mis-match for the efficacy of on-farm intervention scenarios associated with landscape scale factors likely to generate a temporal lag in water quality outcomes . This moCL) determined by catchment specific erosion risk, slope and land cover (BL) and the intervention scenarios (SL), SP is calculated using equation SP is based on the relative exceedance of the critical annual sediment load (nd cover . AccordiBP), the relative changes resulting from the intervention scenarios (IS) were calculated using equation Taking the impacts for BAU as the baseline  fraction. Monitoring data from four field scale catchments on the NWFP clearly demonstrates that P loss to water from this ruminant livestock grazed farm platform is significantly related to winter storm-associated sediment transport. This relationship becomes even more pronounced when the daily averages are plotted , has provided both the opportunity and urgent need to revise agricultural policy. A significant shift here relates to the move away from area-based payments , but in both cases, the farm scale reductions amounted to <5% of BAU losses a. SimilaThe most important co-benefits of the two intervention scenarios concern reductions in nitrous oxide emissions and improvements in physical soil quality, confirming hypothesis (iii). Positive impacts on the former are predicted at farm scale for LFA farms a and forScaling up to the catchment scale in the study area underscores the importance of non-agricultural P sources. The combination of a high ratio of OP to TP and its timing at low flow periods is a good indicator of important contributions from steady and continuous discharge from non-storm related delivery landscape sources, e.g., known point sources including sewage treatment works and a creamery plant . Tappin 6All modelling has limitations. An important limitation in our work is that the interactions between interventions are assumed to be multiplicative in the absence of experimental evidence on the impacts of multiple combinations of best management practices on multiple outcomes. In some cases, the efficacy of individual interventions is based on expert judgment, since again, the empirical evidence base is lacking either for specific or all combinations of rainfall and soil type. Whilst the uptake rates of best management practices under BAU were based on a combination of strategic and bespoke surveys, ensuring this information is completely up to date for all farms in a locality is an ongoing challenge and uncertainty. The LCA work presented here calculated mid-point impacts for water based on pollutant delivery to watercourses and did not include any explicit consideration of pollutant fate during delivery through the river channel system. Nitrogen losses from agriculture include organic rather than just inorganic species, and there remains a need to incorporate such losses as relevant empirical evidence accumulates for different farm types in different geographies.7The main practical implication of this study concerns the urgent need to scope and support the implementation of engineering solutions for addressing the shortcomings of current best management options for reducing pollutant emissions to water on soils with artificial underdrainage. Here, options include cutting back field drains from watercourses to provide space for artificial wetlands which act as sumps and which can include reactive barrier materials such as woodchip . To help8BAU best management in agriculture is not delivering the intended environmental outcomes meaning there is a need to explore alternative pathways to sustainable agriculture taking explicit account of co-benefits and trade-offs. This can be tackled with modelling. Our findings confirmed that a mechanistically-based scenario can deliver slightly greater reductions in pollutant emissions to water from LFA grazing livestock farms than a visually-based scenario, but that the impacts of both scenarios on pollutant emissions to water from such farm systems will be greater on free draining rather than seasonally-waterlogged soils with artificial drainage. The mechanistically-based scenario was forecast to deliver strong co-benefits for reductions in nitrous oxide emissions and improvements in soil quality, but with trade-offs for energy use due to compaction management and ammonia emissions. The spatial mismatch imparted by non-agricultural sources of water pollution reduces the efficacy of on-farm measures for water quality protection at landscape scale. One implication is that structural land cover changes will be required on LFA grazing livestock farms, and indeed other farm system types, to meet policy objectives. Future research will need to continue exploring mechanistically-based intervention scenarios but with an end point inclusive of emerging agricultural policy priorities including net zero.Yusheng Zhang: Methodology, Validation, Writing – original draft, Writing – review & editing. Bruce Griffith: Investigation, Data curation. Steve Granger: Investigation. Hadewij Sint: Data curation. Adrian L. Collins: Funding acquisition, Project administration, Supervision, Methodology, Writing – original draft, Writing – review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


We present a case of a chronic mass-forming pancreatitis (CMFP) detected by 18F-choline (FCH) PET/CT in a male affected by prostate cancer. FCH PET/CT scan showed a focal uptake in the uncinate process of the pancreas, later diagnosed as a CMFP at biopsy. Although the physiological distribution of FCH in the pancreas, a careful interpretation of the images in this area is warranted.


Laser powder bed fusion (LPBF) is an additive manufacturing technology with the capability of printing complex metal parts directly from digital models. Between two available emission modes employed in LPBF printing systems, pulsed wave (PW) emission provides more control over the heat input compared to continuous wave (CW) emission, which is highly beneficial for printing parts with intricate features. However, parts printed with pulsed wave LPBF (PW-LPBF) commonly contain pores, which degrade their mechanical properties. In this study, we reveal pore formation mechanisms during PW-LPBF in real time by using an in-situ high-speed synchrotron x-ray imaging technique. We found that vapor depression collapse proceeds when the laser irradiation stops within one pulse, resulting in occasional pore formation during PW-LPBF. We also revealed that the melt ejection and rapid melt pool solidification during pulsed-wave laser melting resulted in cavity formation and subsequent formation of a pore pattern in the melted track. The pore formation dynamics revealed here may provide guidance on developing pore elimination approaches. The laser powder bed fusion (LPBF) additive manufacturing (AM) process is a 3D printing technology, which selectively melts powders in successive thin layers to build three dimensional parts directly from digital models without the constraints of traditional manufacturing methods. Currently, the use of LPBF is rapidly growing with multiple industrial applications, such as in the medical, aerospace, defense, and automobile industries .One of the primary distinctions between commercial LPBF systems is the type of laser emission mode employed . In contWhile pore formation during the CW-LPBF process has been studied extensively with post-processing diagnostic techniques , in-situIn this study, we revealed the dynamics and mechanisms of pore formation during the PW-LPBF process by utilizing in-situ high-speed X-ray imaging with 100 ps temporal resolution and ~2 μm spatial resolution. The results of this study are vital for developing processing parameters to mitigate pore formation and therefore improve the mechanical performance and reliability of parts printed using PW-LPBF. In addition, the results of this research may have implications in other areas where pulsated laser is used ,19,20,21High-speed high-resolution X-ray imaging  was utilized to probe pore formation dynamics during PW-LPBF in real time . The schThe high-speed X-ray imaging system is composed of a miniature laser powder bed setup which is clamped between two glassy carbon container walls. A pseudo pink X-ray beam, with 1st harmonic energy at 24.7~25.3) keV penetrates through the metal and powder while a downstream detection system converts the transmitted x-ray beam into a visible light image using a scintillator. The converted signal is then recorded by a high-speed camera with a 10× magnification and spatial resolution of approximately 2 μm per pixel ,23,24,25.7~25.3 kton is defined as the time period when the laser is “on” in each pulse, called the laser-on period, and toff denotes the time period when laser is “off” between the end of the pulse and the beginning of the consecutive pulse, called the laser-off period (see the inset of The key parameters to define the pulse in pulsed laser melting are frequency and laser duty cycle. The frequency D4σ diameter of ~100 μm was modulated by a square wave to emit with a given peak power at varying laser frequency (up to 50 kHz) and laser duty cycle (up to 99%) to perform single track laser melting on both powder bed and bare substrate samples. The laser scan velocity was varied from 0.3 to 1.5 m/s in the experiments.An ytterbium fiber laser with the wavelength of 1070 nm, maximum output power of 520 W and a i) was divided by the intensity of corresponding pixel in Frame (i + 2), such that the motionless part in the image was converted to blank background [The recorded x-ray images were processed using ImageJ to reduce the noise and enhance the contrast in each frame. The solid–liquid interface was identified in X-ray images by image processing where the image intensity at each pixel of Frame  is decreased via the decrease in laser scan speed. This results in the formation of the overlap between melt pools of the consecutive pulses. We constructed schematics to illustrate the formation mechanisms of the cavity pattern and pore pattern. The mechanism of cavity pattern formation is displayed in At the laser parameters setting used here, we did not observe the cavity pattering mechanism in Al6061 substrates. This can be ascribed to the higher thermal conductivity of Al6061 relative to Ti-6Al-4V . In The collapse of vapor depression, when laser irradiation stops at the end of the laser-on period in one pulse, was observed to occasionally induce pores during the PW-LPBF process under varying laser frequencies and duty cycles.The melt pool and depression zone size changed with laser frequency and duty cycle. With the increase of the laser frequency or decrease of the duty cycle, the melt pool size and consequently the depression zone size decreased during PW-LPBF.Our experimental observations did not reveal any correlation between the size nor the number of pores and the laser frequency or duty cycle.In the depression/keyhole mode laser melting, at a low laser frequency with large point distance, cavity formation proceeds via the rapid solidification of the thin molten metal layer around the vapor cavity, which subsequently results in the formation of a cavity pattern in the substrate material.In the depression/keyhole mode laser melting, at a low laser frequency with small point distance, the interaction of the cavity with the melt pool in the consecutive pulse results in the formation of closed pores and a pore pattern.The results of this study will help the understanding of the PW-LPBF process and guide the development of processing approaches to mitigate pores.In summary, pore formation dynamics during pulsed wave LPBF AM process were directly observed by utilizing synchrotron x-ray imaging technique. The main conclusions are as follows:


Follow-up care is crucial but challenging for disease management particularly in rural areas with limited healthcare resources and clinical capacity, yet few studies have been conducted from the perspective of rural primary care physicians (PCPs). We assessed the frequency of follow-up care delivered by rural PCPs for hypertension and type 2 diabetes – the two most common long-term conditions.We conducted a multi-centre, self-administered survey study built upon existing general practice course programmes for rural PCPs in four provinces. Information on follow-up care delivery were collected from rural PCPs attending centralised in-class teaching sessions using a set of close-ended, multiple choice questions. Binary logistic regression analysis was performed to examine physician-level factors associated with non-attainment of the target frequency of follow-up care for hypertension and type 2 diabetes, respectively. The final sample consisted of rural PCPs from 52 township-level regions. The Complex Samples module was used in the statistical analysis to account for the multistage sample design.The overall response rate was 91.4%. Around one fifth of PCPs in rural practices did not achieve the target frequency of follow-up care delivery . Higher education level of physicians, increased volume of daily patients seen, and no provision of home visits were risk factors for non-attainment of the target frequency of follow-up care for both conditions. Moreover, village physicians with less working experiences tended to have less frequent follow-up care delivery in type 2 diabetes management.Efforts that are solely devoted to enhancing rural physicians’ education may not directly translate into strong motivation and active commitment to service provision given the possible existence of clinical inertia and workload-related factors. Risk factors identified for target non-attainment in the follow-up care delivery may provide areas for capacity building programmes in rural primary care practice. As the major preventable risk factors for cardiovascular disease (CVD) and premature death, hypertension and type 2 diabetes present long-lasting challenges to global public health as reflected by the enormous burden of morbidity and disability –3. AlongLike many other developing countries, China is facing challenges with the awareness, treatment and control of long-term conditions such as hypertension and type 2 diabetes in rural areas , 9. A hiIn the context of the nationwide BPH service provision, the follow-up care for hypertension and type 2 diabetes including general assessment of overall health, recommendations on lifestyles, and review of medical regime are indispensable for improving population health in primary care . A substA recommended frequency of 4 times per year for follow-up care delivery has been suggested in the recent Chinese national standards (3rd edition) for delivering BPH service in people diagnosed with hypertension or type 2 diabetes . NeverthThis was a multi-centre, survey study built upon existing course programmes on general practice (GP) education and training for rural primary care physicians (PCPs) in four provinces in China. In Yunnan and Guizhou provinces (western China), and Henan province , a theoretical-practical training programme with centralised in-class teaching sessions was launched by the Chinese General Practice Young Professionals Alliance in 2019. This was partnered with the Chinese Medical Association to enrol PCPs in rural clinical practice for continuing medical education. Meanwhile in Guangdong province (southern China), a GP Professional Boost-up Training Programme was concurrently launched by the Guangdong Primary Healthcare Association (GDPHA)  – an offThe survey study was conducted on the sites where centralised in-class teaching sessions were held in each province. A set of close-ended, multiple choice questions drawn from literature review were used to gather self-report information from village physicians. The content validity of the survey was assessed by an expert panel consisting of two epidemiologists (YW and YC), two public health professionals (HHXW and YTL), and two GP consultants (HYD and JJW) who reviewed each item with regard to the relevancy and clarity. A pilot study was conducted among a systematic sample of 12 rural PCPs. The purpose of the project was introduced by the course instructor and questionnaires were disseminated to eligible class attendees by the on-site teaching assistant at the beginning of the course session. Participants were guided to return the anonymous, self-administered questionnaires to the course instructor during the session break. All the original questionnaires, upon the on-site check for completeness and correctness, were sent by postal mail to the study coordinating centre at Sun Yat-Sen University.We aimed to recruit at least 80% of rural PCPs fulfilling the eligibility criteria from centralised in-class teaching sessions, and a minimum of 120 PCPs were anticipated in each of the four provinces. The criteria of target subjects were those who 1) worked as rural primary care clinicians affiliated with village clinics or countryside infirmaries; 2) had class attendance on the day of data collection; and 3) practicing community-based follow-up care for hypertension and type 2 diabetes on a regular basis. Those who practiced chronic disease management in primary care for less than 12 months were excluded. The data collection was completed in August 2019 and the final sample consisted of rural PCPs from 52 township-level administrative regions.We collected anonymous data on age, gender, ethnics, education level, years of GP working experiences, number of patients seen per day, physician-perceived healthcare needs, services delivered on chronic disease management, and settings and frequencies of follow-up care for hypertension and type 2 diabetes. In this study, we referred to the recent national standards for Basic Public Health Services (3rd edition) in China, where a frequency of 4 times per year for follow-up care delivery has been set as a recommended target in the hypertension and type 2 diabetes management .p value < 0.05 was considered statistically significant. All statistical analyses were done in IBM SPSS Statistics 25  and the Complex Samples module was used to account for the multistage sample design.Two trained medical students independently entered the data with double entry verification in EpiData 3.1 (Denmark). Statistics with standard error (SE) or 95% confidence interval (CI), where appropriate, were applied in descriptive analysis. We conducted binary logistic regression analysis to examine physician-level factors associated with non-attainment of the target frequency of follow-up care for hypertension and type 2 diabetes, respectively, after controlling for confounders. A 20:1 rule was used for regression analysis where a minimum number of 400 participants was conservatively required for a regression model consisting of up to 20 independent predictor categories. A Informed consent was obtained from all participants in the study. Data anonymisation was performed by removing subject identifiers from the dataset prior to data analysis. Ethics approval was granted from the School of Public Health Biomedical Research Ethics Review Committee at Sun Yat-Sen University (Ref: SYSUSPH2019032) in accordance with the Declaration of Helsinki 2013.p < 0.001) and had shorter length of years in practicing primary care than their counterparts with lower education level (p < 0.001) (Table 1).A total of 602 rural PCPs responded to the survey, with an overall response rate of 91.4%. No significant differences existed in the response rates at each study site. The mean age of survey respondents was 38.6 (SE 0.5) years, with one fifth of subjects aged 50 years and above. Male and female physicians accounted for an approximately equal proportion (51.5% vs 48.5%). More than one third (40.4%) of physicians were ethnic minorities. Slightly over half (53.3%) of participants had more than ten years of practicing primary care in rural areas. Nearly one third (30.6%) of survey participants had routine clinical encounters with over 20 patients per day. Over two thirds (71.8% [432/602]) of village physicians did not complete an undergraduate education. In general, survey participants with undergraduate education or above were younger ((Table 2).Around one fifth of village physicians did not achieve the target frequency of follow-up care for hypertension and type 2 diabetes in the study. They reported a follow-up frequency of less than 4 times per year for hypertension (18.7%) and type 2 diabetes (21.6%), respectively. The majority of rural PCPs performed follow-up care through mixed clinic-based consultations and home visits, albeit a small proportion  of follow-up care were delivered in clinic-based consultation rooms only p < 0.001), tracking of medication-taking behaviours , and tailored advice given on self-management  in follow-up care . In routine primary care practice, however, rural PCPs with higher education level tended to report less delivery of community-based activities, in particular health promotion and education programmes  to manage hypertension and type 2 diabetes when compared to those with lower education level .A significantly higher proportion of rural PCPs who recognised greater healthcare needs was observed among those having undergraduate education level or above when compared to their counterparts who had lower education level. These self-perceived healthcare needs included the monitoring of disease complications , having higher volume of patients seen per day , and who did not perform home visits as part of the service delivery  were more prone to be at risk for non-attainment of the target frequency of follow-up care delivery. Physicians with shorter lengths of time spent in rural primary care tended to practice less frequent follow-up care for type 2 diabetes , whilst such association was not significant for hypertension management (Table 3).Rural PCPs with undergraduate education level or above (adjusted odds ratio [aOR] = 1.52, We found that according to this self-administered survey, around one fifth of PCPs in rural practices were unable to achieve a target frequency of 4 times per year for hypertensive and type 2 diabetic follow-up care delivery. When compared to village physicians with lower education level, those with higher education level perceived greater healthcare needs for follow-up care, but reported less community-based service delivery. Higher education level, increased daily patient volume, and no provision of home visits were physician-level risk factors associated with non-attainment of the target frequency of follow-up care for both conditions. In addition, village physicians with less working experiences tended to have less frequent follow-up care delivery in the diabetes management.Follow-up care is of great importance to the management of long-term conditions such as hypertension and diabetes as patients often require ongoing treatment and continuous care. Nearly 40% of the total Chinese population live in rural areas as of 2018, accounting for the second largest proportion of the rural population of the world . HoweverWe found that more than two thirds of rural PCPs participated in the study did not have an undergraduate education, which is consistent with other studies –33. WhilPrevious documents have reported the inability or failure of physicians to initiate or intensify therapy when a more aggressive course is recommended by guidelines, known as ‘clinical inertia’ in routine practice . This coThe physician’s adherence to recommended clinical guidelines on follow-up care delivery may also be influenced by self-perceived workload. Workload characteristics such as the number of patients seen or administrative burdens have been reported to be associated with physician’s job satisfaction , 41, 42.Our results suggested that the delivery of home visits as part of follow-up care also played a role. It is believed that home visits can strengthen patient-physician relationship and help physicians understand patient’s culture and preferences, adding knowledge and insights to GP profession . A home Follow-up care is crucial for community-based hypertension and type 2 diabetes management particularly in low-resource settings, yet few studies have been conducted from the perspective of village physicians. We collected data from rural PCPs including ethnic minorities with a variety of geographic locations in southern, western and central China to increase the diversity of study subjects. A focus was placed on community-based follow-up care for the two conditions that are most prevalent health problems both nationally and globally. A Complex Sample design was accounted for in the analysis to improve statistically valid inferences. However, our results should be interpreted with caution. Firstly, as primary care providers are geographically dispersed across the vast expanse of rural areas, it is less feasible to visit each GP clinic for subject recruitment. Instead, study participants were approached in the setting of centralised in-class sessions where village physicians came to attend for continuing medical education through existing GP course programmes. As those who did not enrol in such programmes during the study period were not captured, it may affect the generalisability of our findings to the entire village physicians in China. Secondly, the reliance on physician’s self-report of follow-up care delivery may subject to recall bias due to the absence of available data retrieved from electronic health record system. Thirdly, confounders potentially associated with care delivery such as job satisfaction may not be fully adjusted for in this study, and a physician self-report survey will inevitably restrict inclusion of questions relating to individual characteristics at patient-level. Accordingly, we were unable to differentiate whether patients aren’t coming back out of their own volition versus because of the provider, despite the possibility that patient-level barriers such as transportation, financial burden and schedule conflicts might play a role , 46. FouOur findings could increase the understanding of follow-up care delivery among rural PCPs and inform areas for capacity building programmes targeted village physicians in rural primary care practice. It is worthy of note that patients who are at high risk of cardiovascular events may need more intensive follow-up care, and therefore the hindering factors identified in our study for achieving the recommended goal frequency of follow-up care may bear greater primary care challenges , 51. IntPhysician-level factors were associated with the routine delivery of community-based, follow-up care for hypertension and type 2 diabetes in rural primary care settings in China. Physicians with higher education level perceived greater healthcare needs for follow-up care; however, they reported less delivery of community-based disease management activities. Higher education level, increased daily patient volume, and no provision of home visits served as risk factors associated with non-attainment of the target frequency of follow-up care for both hypertension and type 2 diabetes. Rural primary care physicians with these risk factors should be given particular attention in future GP development programmes to scale-up capacities in managing long-term conditions in rural areas.


In this work, we present a novel scheme for nonlinear hyperspherical estimation using the von Mises–Fisher distribution. Deterministic sample sets with an isotropic layout are exploited for the efficient and informative representation of the underlying distribution in a geometrically adaptive manner. The proposed deterministic sampling approach allows manually configurable sample sizes, considerably enhancing the filtering performance under strong nonlinearity. Furthermore, the progressive paradigm is applied to the fusing of measurements of non-identity models in conjunction with the isotropic sample sets. We evaluate the proposed filtering scheme in a nonlinear spherical tracking scenario based on simulations. Numerical results show the evidently superior performance of the proposed scheme over state-of-the-art von Mises–Fisher filters and the particle filter. The use of inferences on (hyper-)spherical states is ubiquitous in a large variety of application scenarios, such as protein structure prediction , rigid-bThe recursive estimation of hyperspherical random variables using the von Mises–Fisher distribution is nontrivial due to its nonlinear and periodic nature on directional manifolds . Samplesgiven in  for odd Although a random sampling-based von Mises–Fisher filter is effective for nonlinear hyperspherical estimation, it cannot deliver reproducible results and may lack runtime efficiency . Therefore, deterministic sample sets are desired for an efficient and accurate representation of the underlying distribution. Reminiscent of the unscented Kalman filter (UKF) for linear domains, the so-called unscented von Mises–Fisher filter (UvMFF) was proposed in  on unit There remains considerable space for improvement for state-of-the-art von Mises–Fisher filtering schemes in the area of high-performance hyperspherical estimation. The deterministic sampling method used in the current UvMFF  only allise term , leadingGenerating deterministic sample sets of configurable sizes for continuous distributions was originally investigated in Euclidean spaces. In , determiIn the context of recursive estimation based on distributions from directional statistics , determirections  and thenrections . The samAlthough non-identity measurement models can be handled by enlarging the sizes of deterministic samples in the update step, considerably large sample sizes are still desired in the face of degeneration issues . Thus, there remains the necessity to improve sample utilization. In , a novelTo date, there exists no flexible deterministic sampling scheme for von Mises–Fisher distributions. Existing optimization-based paradigms may have undesirable properties, such as local minima or a deteriorated runtime, for large sample sizes, which prohibit their deployment to online estimation tasks. Furthermore, no sample-efficient method is available for von Mises–Fisher filtering with non-identity measurement models.In consideration of the state-of-the-art approaches above, we propose a novel algorithm for von Mises–Fisher distributions in arbitrary dimensions to obtain deterministic sample sets with manually configurable sizes. Based on hyperspherical geometries, samples are drawn coherently to the isotropic dispersion of the underlying distribution without optimization while satisfying the requirement of the unscented transform. Moreover, a novel progressive update scheme is developed in conjunction with the proposed sampling approach for nonlinear von Mises–Fisher filtering. Furthermore, an extensive evaluation of nonlinear spherical estimation is provided. Compared with existing von Mises–Fisher filtering schemes and the particle filter, the proposed progressive von Mises–Fisher filter using isotropic sample sets delivers superior performance with regard to tracking accuracy, runtime and memory efficiency.The remainder of the paper is structured as follows. Preliminaries for the von Mises–Fisher distributions and the corresponding hyperspherical geometry are given in d-dimensional Euclidean space. In the context of recursive Bayesian estimation, we denote the posterior density of the state at time step t, which relates to all measurements up to time step t, by t. The rest of the symbols used are explained in the course of the following pages.We use underlined lowercase variables d. mean resultant vector of the von Mises–Fisher distribution as followsDefined on the unit hypersphere To obtain the concentration Equation , which cThe von Mises–Fisher distribution quantifies hyperspherical uncertainty in relation to the geodesic curve length on the manifold to the mode. To establish the proposed deterministic sampling scheme, we first investigate the hyperspherical domain from the perspective of Riemannian geometry . Any poiWhen expressing logarithm-mapped points  algebra .Considering the isotropic dispersion of the von Mises–Fisher distribution, we design a sample set layout with one sun sample at the mode surrounded by r-th orbit on Algorithm 1: Isotropic Deterministic SamplingThe proposed isotropic deterministic sampling scheme is detailed in Algorithm 1 and illustrated in thm from   Dirichlet kernel  Dλ(ζ) anNote that Equation  does notsolve in Matlab) to solve Equation  For a generic transition density, we first represent the posterior density Equation  now turnSimilarly, the noise distribution Equation  is then shown in , the pre(2) When the noise term ribution ; namely,Equation  can be eTo obtain the predicted density in Equation , we firsEquation  through Equation . By convfound in   for strong nonlinearities or non-identity measurement models with peaky likelihoods due to the sample degeneration.l components:k-th progression step. Thus, we obtainTherefore, we develop a novel update approach by deploying the proposed isotropic sampling to a progressive measurement update scheme . More spAlgorithm 2: Isotropic Progressive UpdateThe procedure above is detailed with pseudo-code in Algorithm 2. We first initialize the posterior density with that obtained from the prediction step and set the remaining progression horizon to Equation   of the state The additive measurement noise is zero-mean Gaussian-distributed; namely, We set the covariance Three variants from the von Mises–Fisher filtering framework are considered for the evaluation: the plain von Mises–Fisher filter (vMFF) based on random sampling, the unscented von Mises–Fisher filter (UvMFF) using deterministic sample sets and the progressive UvMFF (Prog-UvMFF), which fuses the measurements via progressions. The threshold Equation  is set troach in . To geneS2, n=5)  and the The scenario is simulated for 30 time steps in each run. A total of 1000 Monte Carlo runs is used for the evaluation. A broad scale of sample sizes . Mixtures of von Mises–Fisher distributions can be exploited for more exact modeling, and corresponding recursive estimators are promising.


Sentinel lymph nodes normally are examined with ultra-staging, and non-sentinel nodes usually are examined only with routine technique. Low-volume metastasis (micrometastasis and isolated tumor cells) can be missed by classical pathologic analysis. For ability to consider the sentinel node technique as safe, clinicians must be sure that its negative predictive value (NPV) is 100%.To validate the sentinel lymph node technique from the low-volume metastasis point of view, the “Histopathological validation of sentinel lymph nodes study”,The sentinel node technique is a safe technique. The future lies in standard use of the sentinel node technique for early-stage cervical cancer patients instead of lymphadenectomy. Clinicians are awaiting the results of Senticol 3