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Nick K. Jones1,2*, Lucy Rivett1,2*, Chris Workman3, Mark Ferris3, Ashley Shaw1, Cambridge COVID-19 Collaboration1,4, Paul J. Lehner1,4, Rob Howes5, Giles Wright3, Nicholas J. Matheson1,4,6¶, Michael P. Weekes1,7¶1 Cambridge University NHS Hospitals Foundation Trust, Cambridge, UK2 Clinical Microbiology & Public Health Laboratory, Public Health England, Cambridge, UK3 Occupational Health and Wellbeing, Cambridge Biomedical Campus, Cambridge, UK4 Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK5 Cambridge COVID-19 Testing Centre and AstraZeneca, Anne Mclaren Building, Cambridge, UK6 NHS Blood and Transplant, Cambridge, UK7 Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK*Joint first authorship¶Joint last authorshipCorrespondence: [email protected] UK has initiated mass COVID-19 immunisation, with healthcare workers (HCWs) given early priority because of the potential for workplace exposure and risk of onward transmission to patients. The UK’s Joint Committee on Vaccination and Immunisation has recommended maximising the number of people vaccinated with first doses at the expense of early booster vaccinations, based on single dose efficacy against symptomatic COVID-19 disease.1-3At the time of writing, three COVID-19 vaccines have been granted emergency use authorisation in the UK, including the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech). A vital outstanding question is whether this vaccine prevents or promotes asymptomatic SARS-CoV-2 infection, rather than symptomatic COVID-19 disease, because sub-clinical infection following vaccination could continue to drive transmission. This is especially important because many UK HCWs have received this vaccine, and nosocomial COVID-19 infection has been a persistent problem.Through the implementation of a 24 h-turnaround PCR-based comprehensive HCW screening programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT), we previously demonstrated the frequent presence of pauci- and asymptomatic infection amongst HCWs during the UK’s first wave of the COVID-19 pandemic.4 Here, we evaluate the effect of first-dose BNT162b2 vaccination on test positivity rates and cycle threshold (Ct) values in the asymptomatic arm of our programme, which now offers weekly screening to all staff.Vaccination of HCWs at CUHNFT began on 8th December 2020, with mass vaccination from 8th January 2021. Here, we analyse data from the two weeks spanning 18thto 31st January 2021, during which: (a) the prevalence of COVID-19 amongst HCWs remained approximately constant; and (b) we screened comparable numbers of vaccinated and unvaccinated HCWs. Over this period, 4,408 (week 1) and 4,411 (week 2) PCR tests were performed from individuals reporting well to work. We stratified HCWs <12 days or > 12 days post-vaccination because this was the point at which protection against symptomatic infection began to appear in phase III clinical trial.226/3,252 (0·80%) tests from unvaccinated HCWs were positive (Ct<36), compared to 13/3,535 (0·37%) from HCWs <12 days post-vaccination and 4/1,989 (0·20%) tests from HCWs ≥12 days post-vaccination (p=0·023 and p=0·004, respectively; Fisher’s exact test, Figure). This suggests a four-fold decrease in the risk of asymptomatic SARS-CoV-2 infection amongst HCWs ≥12 days post-vaccination, compared to unvaccinated HCWs, with an intermediate effect amongst HCWs <12 days post-vaccination.A marked reduction in infections was also seen when analyses were repeated with: (a) inclusion of HCWs testing positive through both the symptomatic and asymptomatic arms of the programme (56/3,282 (1·71%) unvaccinated vs 8/1,997 (0·40%) ≥12 days post-vaccination, 4·3-fold reduction, p=0·00001); (b) inclusion of PCR tests which were positive at the limit of detection (Ct>36, 42/3,268 (1·29%) vs 15/2,000 (0·75%), 1·7-fold reduction, p=0·075); and (c) extension of the period of analysis to include six weeks from December 28th to February 7th 2021 (113/14,083 (0·80%) vs 5/4,872 (0·10%), 7·8-fold reduction, p=1x10-9). In addition, the median Ct value of positive tests showed a non-significant trend towards increase between unvaccinated HCWs and HCWs > 12 days post-vaccination (23·3 to 30·3, Figure), suggesting that samples from vaccinated individuals had lower viral loads.We therefore provide real-world evidence for a high level of protection against asymptomatic SARS-CoV-2 infection after a single dose of BNT162b2 vaccine, at a time of predominant transmission of the UK COVID-19 variant of concern 202012/01 (lineage B.1.1.7), and amongst a population with a relatively low frequency of prior infection (7.2% antibody positive).5This work was funded by a Wellcome Senior Clinical Research Fellowship to MPW (108070/Z/15/Z), a Wellcome Principal Research Fellowship to PJL (210688/Z/18/Z), and an MRC Clinician Scientist Fellowship (MR/P008801/1) and NHSBT workpackage (WPA15-02) to NJM. Funding was also received from Addenbrooke’s Charitable Trust and the Cambridge Biomedical Research Centre. We also acknowledge contributions from all staff at CUHNFT Occupational Health and Wellbeing and the Cambridge COVID-19 Testing Centre.

Scene flow tracks the three-dimensional (3D) motion of each point in adjacent point clouds. It provides fundamental 3D motion perception for autonomous driving and server robot. Although the Red Green Blue Depth (RGBD) camera or Light Detection and Ranging (LiDAR) capture discrete 3D points in space, the objects and motions usually are continuous in the macro world. That is, the objects keep themselves consistent as they flow from the current frame to the next frame. Based on this insight, the Generative Adversarial Networks (GAN) is utilized to self-learn 3D scene flow with no need for ground truth. The fake point cloud of the second frame is synthesized from the predicted scene flow and the point cloud of the first frame. The adversarial training of the generator and discriminator is realized through synthesizing indistinguishable fake point cloud and discriminating the real point cloud and the synthesized fake point cloud. The experiments on Karlsruhe Institute of Technology and Toyota Technological Institute (KITTI) scene flow dataset show that our method realizes promising results without ground truth. Just as human, the proposed method can identify the similar local structures of two adjacent frames even without knowing the ground truth scene flow. Then, the local correspondence can be correctly estimated, and further the scene flow is correctly estimated.   Corresponding author(s) Email: [email protected]

Leukocyte differential test is a widely performed clinical procedure for screening infectious diseases. Existing hematology analyzers require labor-intensive work and a panel of expensive reagents. Here we report an artificial-intelligence enabled reagent-free imaging hematology analyzer (AIRFIHA) modality that can accurately classify subpopulations of leukocytes with minimal sample preparation. AIRFIHA is realized through training a two-step residual neural network using label-free images of isolated leukocytes acquired from a custom-built quantitative phase microscope. By leveraging the rich information contained in quantitative phase images, we not only achieved high accuracy in differentiating B and T lymphocytes, but also classified CD4 and CD8 cells, therefore outperforming the classification accuracy of most current hematology analyzers. We validated the performance of AIRFIHA in a randomly selected test set and cross-validated it across all blood donors. Owing to its easy operation, low cost, and accurate discerning capability of complex leukocyte subpopulations, we envision AIRFIHA is clinically translatable and can also be deployed in resource-limited settings, e.g., during pandemic situations for the rapid screening of infectious diseases.  Corresponding author(s) Email:    [email protected],  [email protected]

Tam Hunt [1], Jonathan SchoolerUniversity of California Santa Barbara Synchronization, harmonization, vibrations, or simply resonance in its most general sense seems to have an integral relationship with consciousness itself. One of the possible “neural correlates of consciousness” in mammalian brains is a combination of gamma, beta and theta synchrony. More broadly, we see similar kinds of resonance patterns in living and non-living structures of many types. What clues can resonance provide about the nature of consciousness more generally? This paper provides an overview of resonating structures in the fields of neuroscience, biology and physics and attempts to coalesce these data into a solution to what we see as the “easy part” of the Hard Problem, which is generally known as the “combination problem” or the “binding problem.” The combination problem asks: how do micro-conscious entities combine into a higher-level macro-consciousness? The proposed solution in the context of mammalian consciousness suggests that a shared resonance is what allows different parts of the brain to achieve a phase transition in the speed and bandwidth of information flows between the constituent parts. This phase transition allows for richer varieties of consciousness to arise, with the character and content of that consciousness in each moment determined by the particular set of constituent neurons. We also offer more general insights into the ontology of consciousness and suggest that consciousness manifests as a relatively smooth continuum of increasing richness in all physical processes, distinguishing our view from emergentist materialism. We refer to this approach as a (general) resonance theory of consciousness and offer some responses to Chalmers’ questions about the different kinds of “combination problem.”  At the heart of the universe is a steady, insistent beat: the sound of cycles in sync…. [T]hese feats of synchrony occur spontaneously, almost as if nature has an eerie yearning for order. Steven Strogatz, Sync: How Order Emerges From Chaos in the Universe, Nature and Daily Life (2003) If you want to find the secrets of the universe, think in terms of energy, frequency and vibration.Nikola Tesla (1942) I.               Introduction Is there an “easy part” and a “hard part” to the Hard Problem of consciousness? In this paper, we suggest that there is. The harder part is arriving at a philosophical position with respect to the relationship of matter and mind. This paper is about the “easy part” of the Hard Problem but we address the “hard part” briefly in this introduction.  We have both arrived, after much deliberation, at the position of panpsychism or panexperientialism (all matter has at least some associated mind/experience and vice versa). This is the view that all things and processes have both mental and physical aspects. Matter and mind are two sides of the same coin.  Panpsychism is one of many possible approaches that addresses the “hard part” of the Hard Problem. We adopt this position for all the reasons various authors have listed (Chalmers 1996, Griffin 1997, Hunt 2011, Goff 2017). This first step is particularly powerful if we adopt the Whiteheadian version of panpsychism (Whitehead 1929).  Reaching a position on this fundamental question of how mind relates to matter must be based on a “weight of plausibility” approach, rather than on definitive evidence, because establishing definitive evidence with respect to the presence of mind/experience is difficult. We must generally rely on examining various “behavioral correlates of consciousness” in judging whether entities other than ourselves are conscious – even with respect to other humans—since the only consciousness we can know with certainty is our own. Positing that matter and mind are two sides of the same coin explains the problem of consciousness insofar as it avoids the problems of emergence because under this approach consciousness doesn’t emerge. Consciousness is, rather, always present, at some level, even in the simplest of processes, but it “complexifies” as matter complexifies, and vice versa. Consciousness starts very simple and becomes more complex and rich under the right conditions, which in our proposed framework rely on resonance mechanisms. Matter and mind are two sides of the coin. Neither is primary; they are coequal.  We acknowledge the challenges of adopting this perspective, but encourage readers to consider the many compelling reasons to consider it that are reviewed elsewhere (Chalmers 1996, Griffin 1998, Hunt 2011, Goff 2017, Schooler, Schooler, & Hunt, 2011; Schooler, 2015).  Taking a position on the overarching ontology is the first step in addressing the Hard Problem. But this leads to the related questions: at what level of organization does consciousness reside in any particular process? Is a rock conscious? A chair? An ant? A bacterium? Or are only the smaller constituents, such as atoms or molecules, of these entities conscious? And if there is some degree of consciousness even in atoms and molecules, as panpsychism suggests (albeit of a very rudimentary nature, an important point to remember), how do these micro-conscious entities combine into the higher-level and obvious consciousness we witness in entities like humans and other mammals?  This set of questions is known as the “combination problem,” another now-classic problem in the philosophy of mind, and is what we describe here as the “easy part” of the Hard Problem. Our characterization of this part of the problem as “easy”[2] is, of course, more than a little tongue in cheek. The authors have discussed frequently with each other what part of the Hard Problem should be labeled the easier part and which the harder part. Regardless of the labels we choose, however, this paper focuses on our suggested solution to the combination problem.  Various solutions to the combination problem have been proposed but none have gained widespread acceptance. This paper further elaborates a proposed solution to the combination problem that we first described in Hunt 2011 and Schooler, Hunt, and Schooler 2011. The proposed solution rests on the idea of resonance, a shared vibratory frequency, which can also be called synchrony or field coherence. We will generally use resonance and “sync,” short for synchrony, interchangeably in this paper. We describe the approach as a general resonance theory of consciousness or just “general resonance theory” (GRT). GRT is a field theory of consciousness wherein the various specific fields associated with matter and energy are the seat of conscious awareness.  A summary of our approach appears in Appendix 1.  All things in our universe are constantly in motion, in process. Even objects that appear to be stationary are in fact vibrating, oscillating, resonating, at specific frequencies. So all things are actually processes. Resonance is a specific type of motion, characterized by synchronized oscillation between two states.  An interesting phenomenon occurs when different vibrating processes come into proximity: they will often start vibrating together at the same frequency. They “sync up,” sometimes in ways that can seem mysterious, and allow for richer and faster information and energy flows (Figure 1 offers a schematic). Examining this phenomenon leads to potentially deep insights about the nature of consciousness in both the human/mammalian context but also at a deeper ontological level.

Cannabis sativa is an extraordinarily versatile species. Hemp and its cousin marijuana, both C. sativa, have been used for millennia as a source of fibre, oil and for medicinal, spiritual and recreational purposes. Because the consumption of Cannabis can have psychoactive effects, the plant has been widely banned throughout the last century. In the past decade, evidence of its medicinal properties did lead to the relaxation of legislation in many countries around the world. Consequently, the genetics and development of Cannabis as well as Cannabis-derived products are the subject of renewed attention.Here, we review the biology of C. sativa, including recent insights from taxonomy, morphology and genomics, with an emphasis on the genetics of cannabinoid synthesis. Because the female Cannabis flower is of special interest as the site of cannabinoid synthesis, we explore flower development, flowering time well as the species’ unique sex determination system in detail. Furthermore, we outline the tremendous medicinal, engineering, and environmental opportunities that Cannabis bears. Together, the picture emerges that our understanding of Cannabis biology currently progresses at an unusual speed. A future challenge will be to preserve the multi-purpose nature of Cannabis, and to harness its medicinal properties and sustainability advantages simultaneously.

Quantum chemistry must evolve if it wants to fully leverage the benefits of the internet age, where the world wide web offers a vast tapestry of tools that enable users to communicate and interact with complex data at the speed and convenience of a button press. The Open Chemistry project has developed an open source framework that offers an end-to-end solution for producing, sharing, and visualizing quantum chemical data interactively on the web using an array of modern tools and approaches. These tools build on some of the best open source community projects such as Jupyter for interactive online notebooks, coupled with 3D accelerated visualization, state-of-the-art computational chemistry codes including NWChem and Psi4 and emerging machine learning and data mining tools such as ChemML and ANI. They offer flexible formats to import and export data, along with approaches to compare computational and experimental data.

This paper responds to one by Graham Martin and colleagues, who offered a critique of my previous publications on masks for the lay public in the Covid-19 pandemic. I address their charges that my co-authors and I had misapplied the precautionary principle; drawn conclusions that were not supported by empirical research; and failed to take account of potential harms. But before that, I remind Martin et al that the evidence on mask wearing goes beyond the contested trials and observational studies they place centre stage. I set out some key findings from basic science, epidemiology, mathematical modelling, case studies and natural experiments, and use this rich and diverse body of evidence as the backdrop for my rebuttal of their narrowly-framed objections. I challenge my critics’ apparent assumption that a particular kind of systematic review should be valorised over narrative and real-world evidence, since stories are crucial to both our scientific understanding and our moral imagination. I conclude by thanking my academic adversaries for the intellectual sparring match, but exhort them to remember our professional accountability to a society in crisis. It is time to lay straw men to rest and engage, scientifically and morally, with the dreadful tragedy that is unfolding across the world.

This Supporting information includes interactive plots, videos, and data captured while performing evaluation and validation experiments for our paper. 

The construct of wellbeing has been criticised as a neoliberal construction of western individualism that ignores wider systemic issues including increasing burden of chronic disease, widening inequality, concerns over environmental degradation and anthropogenic climate change. While these criticisms overlook recent developments, there remains a need for biopsychosocial models that extend theoretical grounding beyond individual wellbeing, incorporating overlapping contextual issues relating to community and environment. Our first GENIAL model \cite{Kemp_2017} provided a more expansive view of pathways to longevity in the context of individual health and wellbeing, emphasising bidirectional links to positive social ties and the impact of sociocultural factors. In this paper, we build on these ideas and propose GENIAL 2.0, focusing on intersecting individual-community-environmental contributions to health and wellbeing, and laying an evidence-based, theoretical framework on which future research and innovative therapeutic innovations could be based. We suggest that our transdisciplinary model of wellbeing - focusing on individual, community and environmental contributions to personal wellbeing - will help to move the research field forward. In reconceptualising wellbeing, GENIAL 2.0 bridges the gap between psychological science and population health health systems, and presents opportunities for enhancing the health and wellbeing of people living with chronic conditions. Implications for future generations including the very survival of our species are discussed.  

Floral plantings are promoted to foster ecological intensification of agriculture through provisioning of ecosystem services. However, a comprehensive assessment of the effectiveness of different floral plantings, their characteristics and consequences for crop yield across global regions is lacking. Here we quantified the impacts of flower strips and hedgerows on pest control and pollination services in adjacent crops using a global dataset of 529 sites. Flower strips, but not hedgerows, enhanced pest control services in adjacent fields by 16% on average. However, effects on crop pollination and yield were more variable. Our synthesis identifies several important drivers of variability in effectiveness of plantings: pollination services declined exponentially with distance from plantings, and perennial and older flower strips with higher flowering plant diversity enhanced pollination more effectively. These findings provide promising pathways to optimize floral plantings to more effectively contribute to ecosystem service delivery and ecological intensification of agriculture in the future.

Researchers' ability to accurately screen fossil and subfossil specimens for preservation of DNA and protein sequences remains limited. Thermal exposure and geologic age are usable proxies for sequence preservation on a broad scale but are of nominal use for specimens of similar depositional environments. Cell and tissue biomolecular histology is thus proposed as a novel proxy for determining sequence preservation potential of ancient specimens with improved accuracy. Biomolecular histology as a proxy is hypothesized to elucidate why fossils/subfossils of some depositional environments preserve sequences while others do not and to facilitate selection of ancient specimens for use in molecular studies.

IntroductionConsistent with World Health Organization (WHO) advice [1], UK Infection Protection Control guidance recommends that healthcare workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) should use fluid resistant surgical masks type IIR (FRSMs) as respiratory protective equipment (RPE), unless aerosol generating procedures (AGPs) are being undertaken or are likely, when a filtering face piece 3 (FFP3) respirator should be used [2]. In a recent update, an FFP3 respirator is recommended if “an unacceptable risk of transmission remains following rigorous application of the hierarchy of control” [3]. Conversely, guidance from the Centers for Disease Control and Prevention (CDC) recommends that HCWs caring for patients with COVID-19 should use an N95 or higher level respirator [4]. WHO guidance suggests that a respirator, such as FFP3, may be used for HCWs in the absence of AGPs if availability or cost is not an issue [1].A recent systematic review undertaken for PHE concluded that: “patients with SARS-CoV-2 infection who are breathing, talking or coughing generate both respiratory droplets and aerosols, but FRSM (and where required, eye protection) are considered to provide adequate staff protection” [5]. Nevertheless, FFP3 respirators are more effective in preventing aerosol transmission than FRSMs, and observational data suggests that they may improve protection for HCWs [6]. It has therefore been suggested that respirators should be considered as a means of affording the best available protection [7], and some organisations have decided to provide FFP3 (or equivalent) respirators to HCWs caring for COVID-19 patients, despite a lack of mandate from local or national guidelines [8].Data from the HCW testing programme at Cambridge University Hospitals NHS Foundation Trust (CUHNFT) during the first wave of the UK severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic indicated a higher incidence of infection amongst HCWs caring for patients with COVID-19, compared with those who did not [9]. Subsequent studies have confirmed this observation [10, 11]. This disparity persisted at CUHNFT in December 2020, despite control measures consistent with PHE guidance and audits indicating good compliance. The CUHNFT infection control committee therefore implemented a change of RPE for staff on “red” (COVID-19) wards from FRSMs to FFP3 respirators. In this study, we analyse the incidence of SARS-CoV-2 infection in HCWs before and after this transition.

In the previous work [6], we classified the solutions to a family of systems of Klein-Gordon equations with non-negative energy below the ground state into two parts: one blows up in finite time while the other extends to a global solution. In the present work, we strengthen this result, showing that these global solutions are indeed scattering in the energy space. Here we adapted Kenig-Merle’s concentration-compactness approach to the system.

Tissue levels of Alternaria allergen Alt a 1 reflect recurrence of refractory airway diseases.To the Editors,The quantification of Alternaria allergen in the local airway tissues is quite unknown, while Alternaria alternata is a widespread fungal species in the airway discharge and known to be one source of aeroallergens which contribute to development of asthma (1,2) and chronic rhinosinusitis (CRS) (3,4). We have recently been established the method for quantifying allergen in the local airway tissues (5). Since Alt a 1 is the main sensitizing allergen component and it is useful in diagnosis and immunotherapy (6), we have measured the levels of Alt a 1 in the local airway tissues and examined whether the quantification of Alt a 1 could reflect the allergic airway inflammation and recurrence of refractory allergic respiratory diseases.We obtained nasal polyp tissues from 64 patients with refractory CRS with nasal polyp (CRSwNP) and homogenized them. The tissue levels of Alt a 1, Alternaria specific IgE, IL-4, IL-5, IL-13, IL-33, galectin-10 in nasal polyp supernatant were measured. The tissue eosinophil numbers were also counted. We searched for the existence of postoperative nasal polyp for in the medical records in order to examine the usefulness of Alt a 1 as a predictor of nasal polyp recurrence after surgery.First, we measured the levels of Alt a 1 in airway tissues and ROC curve based on nasal polyp recurrence data was developed, with a cut-off value of 1.84 ng/g of local Alt a 1 (AUC = 0.75, Figure 1A). According to the presence or absence of nasal polyp recurrence, patients were divided into two groups and the levels of Alt a 1 were compared. The tissue levels of Alt a 1 were significantly higher in recurrence group. (p < 0.01, Figure 1B). Kaplan–Meier curves at the cut-off point of the local tissue Alt a 1 levels shows that of the recurrence-free rate in the low- Alt a 1 group is lower rate than that in the high- Alt a 1 group (p < 0.05, log-rank test, Figure 1C).We further measured Alternaria specific IgE level in the airway tissues in order to determine the sensitization to Alt a 1. The levels of Alt a 1 in nasal polyps had a significant positive correlation with the levels of Alternaria specific IgE (rs=0.56, p<0.0001, Figure 2A). We divided patients into two groups according to the local tissue levels of local Alt a 1, and compared the levels of Alternaria-specific IgE antibody between two groups. As result, the levels of Alternaria-specific IgE antibody were significantly higher in high- Alt a 1 group than those in low- Alt a 1 group. (p<0.0001, Figure 2B)Fungi induce alarmins which promote the development of type 2 response via increase in the number of eosinophils, accompanied by an increase in innate lymphoid cells (ILCs) and effector cells such as mast cells (7,8). We measured the level of type2 cytokines (IL-4, IL-5, IL-13) in the airway tissues and analyzed between high- and low- Alt a 1group respectively in order to assess the contribution of type2 inflammation to local allergic reaction to Alternaria alterna . Patients were divided into two groups according to the tissue levels of Alt a 1. The levels of IL-4 were significantly higher in high- Alt a 1 group than those in low- group. IL-4 plays an essential role in IgE class switching and production. The levels of IL-5 and IL-13 didn’t show significant difference but tended to be higher in the high- Alt a 1 group. (Figure 2C)Epithelial cells which activated by antigens induce proinflammatory responses due to the production of alarmins. Alternaria alternataexposure evokes IL-33 secretion and extracellular DNA from the airway epithelium, which functions as an alarmin to stimulate type 2 immunity in airway diseases (9). The levels of IL-33 in NPs were significantly higher in high- Alt a 1 group than those in the low- group (Figure 2C). Galectin-10 is relatively eosinophil specific protein which released from cytolytic cells is expected to be a biomarker for activated eosinophils in eosinophilic inflammatory diseases (10). The levels of galectin-10 in the airway tissues were significantly higher in high Alt a 1 group than low group. (Figure 2C)This is the first report to have quantified the levels of Alt a 1 in airway tissues and investigated the association to the type2 molecules of allergic reaction. Alternaria alterna is common fungi as an environmental antigen and the increase in the local tissue levels of Alt a 1 were associated with the recurrence of refractory CRSwNP. These results might explain the tissue levels of Alt a 1 can be a predictor of recurrence for refractory respiratory airway disease.

In this paper, we introduce a novel Jungck iteration scheme characterized by second-order convergence. We verify its validity and accuracy using polynomiography. Additionally, we establish that existing well-known iteration schemes for approximating the fixed point of a general mapping exhibit identical convergence rates under specific conditions.

Total laparoscopic hysterectomy (TLH) is the complete hysterectomy including transection of the uterine vessels and opening/closure of the vaginal vault performed laparoscopically. This procedure can be performed as an alternative to total abdominal hysterectomy in many cases. In this short communication, we would like to share our experience of 1000 cases of total hysterectomy done laparoscopically witbout having caused any intraoperative or post operative complications.

Endometriosis is a common gynecological condition characterized by the presence of endometrial-like tissue outside the uterus, leading to chronic pelvic pain and infertility. This review aims to provide an overview of recent advances in the diagnosis and management of endometriosis. The article discusses the pathogenesis, clinical presentation, diagnostic modalities, and treatment options for endometriosis. Additionally, it highlights emerging technologies and novel therapeutic approaches that show promise in improving patient outcomes. By summarizing the current state of knowledge, this review aims to guide clinicians in providing optimal care for patients with endometriosis.

Aim: To compare the effect of delayed cord clamping versus milking of umbilical cord on initial hematocrit in term and near-term neonates. Methods: This randomized controlled trial included 374 pregnant women of more than 34 weeks period of gestation. They were randomized into umbilical cord milking group and delayed cord clamping group. In umbilical cord milking group, 119 underwent vaginal delivery and 68 underwent caesarean section. In delayed cord clamping group, 117 underwent vaginal delivery and 70 underwent caesarean section. Results: Mean hematocrit in cord sample was 47.02±7.13% in umbilical cord milking group and 48.04±8.36% in delayed cord clamping group and the difference was not statistically significant (p=0.21). Mean hematocrit at 30±6 hours was 54.48±5.84% in umbilical cord milking group and 50.9±7.1% in delayed cord clamping group and the difference was statistically significant(p=0.01). Requirement of phototherapy in umbilical cord milking group was 18.18% and in delayed cord clamping group was 19.25%(p=0.79). Rate of neonatal intensive care unit admissions was 2.67% in umbilical cord milking group and 7.49% in delayed cord clamping group(p=0.034). Conclusion: Umbilical cord milking lead to significant increase in hematocrit levels without increasing the requirement of phototherapy and neonatal intensive care unit admissions. Hence, umbilical cord milking can be used as an alternative to delayed cord clamping in both term and near-term neonates.

Purpose: To study the antiplatelet mechanisms of ticagrelor. Experimental design: Platelets underwent activation with 20 μM ADP for 30 seconds followed by inhibition with 2 nM ticagrelor for another 30 seconds. Mass-spectrometry-based phosphoproteomic technique was applied to obtain phosphorylation spectra in platelets. Results: We successfully quantified 2285 phosphopeptides with high confidence in 1189 phosphoproteins. Compared with intact platelets, ADP-activated platelets showed significant upregulation of PDE5ASer102 and downregulation of 178 phosphopeptides in 154 proteins. Gene Ontology analysis showed that downregulated phosphoproteins were enriched in molecular functions and pathways associated with RNA processing and surveillance. After ticagrelor treatment, we identified 53 significantly regulated phosphopeptides, including 17 upregulated and 36 downregulated, in 45 phosphoproteins. Eight phosphopeptides in STIM1, DENND4C, TNIK, BCL9L, DBN1, DOCK10, FRMD4B, and PRKAR2B were significantly downregulated after ADP stimulation and significantly upregulated after adding ticagrelor. They were mainly implicated in regulation of Ca2+ flow, Wnt/β-catenin signaling, and cytoskeleton remodeling, suggesting their potential role as mediators in ticagrelor-related signaling pathways. Conclusions and clinical relevance: By sequential activation and inhibition of platelets using mutual competitive inhibitors, ADP and ticagrelor, we demonstrated alternations in phosphorylation status of phosphoproteins, which could help to interpret the mechanism of bleeding complications associated with ticagrelor.

Obstacles related to the continuous cropping of sweetpotato ( Ipomoea batatas (L.) Lam.) restrict its intensive production. However, the effects of continuous cropping on soil properties and/or the rhizosphere microbial community are largely unclear. In this study, we analysed changes in rhizosphere soil chemical properties and microbial communities of sweetpotato across different cultivation years. We observed that the microbial diversity and complexity of the fungal ecological network in rhizosphere soils of sweetpotato were decreased after 5 years of continuous cropping, with significant enrichment in Sphingobium, Gemmatimonas, Volutella, and Neoidriella. Tuber yield, soil pH, and available potassium (AK) content were significantly reduced after continuous cropping, with the soil microbial community having the highest correlation with pH, AK, and ammonium nitrogen (NH 4 +-N). Specifically, soil pH and AK were positively correlated with Bacillus and Gaiella, and negatively correlated with some plant-pathogenic fungi ( Volutella and Neoidriella), while NH 4 +-N showed the opposite trend. In addition, soil pH, AK, and the relative abundance of Bacillus were positively correlated with tuber yield, while Volutella showed the opposite trend. In summary, the continuous cropping of sweetpotato negatively affects rhizosphere soil health, resulting in imbalanced soil fertility and increased abundance of pathogens. These results improve our understanding of factors driving obstacles faced with the continuous cropping of sweetpotato, enabling future studies and the development of technologies to overcome these obstacles.

Exciton binding energy ( E b) has been regarded as a critical parameter in charge separation during photovoltaic conversion. Minimizing the E b of the photovoltaic materials can facilitate the exciton dissociation in low-driving force organic solar cells (OSCs) and thus improve the power conversion efficiency (PCE), nevertheless, diminishing the E b with deliberate design principles remains a significant challenge. Herein, bulky side chain as steric hindrance structure was inserted into Y-series acceptors to minimize the E b by modulating the intra- and inter-molecular interaction. Theoretical and experimental results indicate that steric hindrance-induced weaker intra-molecular interactions but stronger inter-molecular interaction can strengthen the molecular polarizability, increase the overlap of electronic orbitals between molecules and facilitate delocalized pathway charge transfer, thereby resulting in a low E b. The conspicuously reduced E b obtained in Y-ChC5 with pinpoint steric hindrance modulation can minimize the detrimental effects on exciton dissociation in low-driving-force OSCs, achieving a remarkable PCE of 19.1% with over 95% internal quantum efficiency. Our study provides a new molecular design rationale to reduce the exciton binding energy.

DRUG İNDUCED ENTEROCOLİTİS SYNDROME WİTH AMOXİCİLLİN/CLAVUNATE AND SAFE ALTERNATİVE BETA LACTAM ANTİBİOTİC

IntroductionIntracranial calcifications are frequently observed in radiological examinations and are generally benign. Subcortical white matter calcifications however warrant further clinical and radiological investigation due to potential associations with infections, metabolic and inherited disorders like Sturge-Weber Syndrome and Fahr disease (1). One rare cause of subcortical calcification would be dural arteriovenous fistula (DAVF), where abnormal connections form between dural venous sinuses, cortical, or leptomeningeal veins, and arterial feeders often from meningeal or scalp arteries (2). DAVFs account for 10-15% of intracranial vascular malformations (3). The etiology of DAVFs remains controversial. Acquired factors like dural venous sinus thrombosis and trauma are linked to adult-onset cases, while congenital factors likely underlie DAVFs presenting in pediatric patients (4). The most common location for DAVF is at the transverse-sigmoid junction, with a slight left-sided predominance (6). Radiologically, DAVFs with chronic venous hypertension or reflux are associated with intracranial hemorrhage or focal areas of cerebral edema (7).As of now, only seven case reports of subcortical white matter calcifications associated with DAVF have been documented. These cases show variability in the distribution of intracranial calcifications, including focal lobar calcifications, unilateral supratentorial brain, bilateral symmetrical supratentorial brain, and basal ganglia calcifications (8-14). In this case study, we present a 57-year- with new symmetric subcortical white matter calcifications within the supratentorial brain and dentate nuclei. These calcifications developed over 2 years on a background of untreated DAVF with chronic venous hypertension. This case study emphasizes the potential morbidity associated with untreated dural arteriovenous fistula (DAVF) over an extended period.

THE IMPORTANCE OF FOLLOW-UP OF ESOPHAGEAL EOSINOPHILIA IN CHILDREN WITH SEVERE COW’S MILK ALLERGYTo the Editor:The current understanding of the intricate interplay between food allergy (FA) and eosinophilic esophagitis (EoE) remains incomplete, particularly in patients with severe manifestations of FA or those undergoing oral immunotherapy (OIT). EoE has been recognized as part of the atopic march1, as it shares type 2 inflammation and poses a risk of progression to other atopic diseases, including IgE-mediated food allergy (IgE-FA). However, the incidence of EoE even before food reintroduction2 raises doubts about whether this group represents a subtype of FA and how esophageal changes develop. In clinical practice, there are concerns about underdiagnosing EoE and its potential long-term complications, especially in children whose symptoms are often nonspecific and may be masked by adaptive behaviors3. The proposed longitudinal study aims to characterize esophageal eosinophilia (EE) in children with IgE-mediated cow’s milk allergy (IgE-CMA) and compare clinical and endoscopic findings between patients with and without esophageal symptoms over one year of follow-up.Patients aged 6 to 18 years were recruited from a Brazilian IgE-CMA reference center between 2019-2022. They underwent a standard routine, which included inquiries about esophageal symptoms, laboratory tests, and esophagogastroduodenoscopy (EGD) with biopsy. With the assistance of caregivers, patients verbally reported the frequency and intensity of esophageal symptoms over the last month. Adaptive eating behaviors were assessed using the IMPACT acronym4. Patients who confirmed the persistence of at least one esophageal symptom were classified as symptomatic. Caregivers completed the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) v2.05during the same visit. The specific IgEs for CM, α-lactalbumin, β-lactoglobulin, casein, egg, soy, wheat, peanut, Brazil nut, codfish, and shrimp were measured using the ImmunoCAP® method. Serum levels of eosinophils and total IgE were also collected.Subsequently, all patients underwent EGD, with at least 4-6 esophageal biopsies (proximal/mid and distal esophagus), along with gastric and duodenal biopsies. Macroscopic characteristics were described using the Endoscopic Reference Score (EREFS)6, completed by the same endoscopist. The histological evaluation included eosinophil count per high-power field (hpf) in each region. Biopsies were evaluated by a single pathologist trained in the EoE Histologic Scoring System (EoEHSS)7 for both proximal/mid and distal regions. The presence of ≥ 15 eos/hpf in the esophageal mucosa was designated as EE. After excluding other causes of EE, symptomatic patients were classified as EoE, while asymptomatic patients were classified as asymptomatic esophageal eosinophilia (aEE). EGD was repeated after at least 8 weeks of treatment for EoE or 1-year follow-up without intervention for aEE. See supplemental data for the detailed methodology.Thirty-three patients with IgE-CMA were assessed. Most were male (57.6%) with a median age of 8.75 years. 84.8% had other atopic conditions, with nearly all reporting prior CM anaphylaxis (87.8%), and 75.7% still reacted to baked milk. The frequency of EE was 45.4%, with 21.2% diagnosed with EoE and 24.2% with aEE. Regarding clinical data, statistically significant differences were not observed between the groups with and without EE (see Table 1). Laboratory tests showed higher results in the EE group but without statistical significance. The percentage of patients sensitized to other food allergens besides CM was similar between the two groups.Comparing patients with EoE and aEE, most of the clinical data did not differ statistically between the groups. A higher median age was found in those with EoE (10.3 vs 8.2 years, p=0.03), along with higher specific IgE values for CM and casein (p=0.02 and p=0.008, respectively). The percentage of patients sensitized to another food allergen was higher in the EoE group (85.7% vs 50%), but this difference did not reach statistical significance. The eosinophil count in the esophagus was statistically similar between the groups, with a predominance of non-diffuse distribution in both. None of the patients exhibited eosinophilia in the stomach or duodenum suggestive of other eosinophilic gastrointestinal diseases8.Table 2 illustrates the comparison of scores between the EoE and aEE groups. EoE patients had significantly higher median PEESS v2.0 total scores (p=0.01), particularly in domains associated with pain and dysphagia (p=0.02). Specifically, four questions were able to distinguish patients with EoE (1, 9, 11, and 12). EREFS scores were similar between the groups, although the frequency of abnormal macroscopy was higher in EoE patients (100% vs 37.5%, p=0.02). EoEHSS also showed no significant differences between the groups. During the follow-up period (see Table 3), most EoE patients achieved clinical and histological remission with omeprazole treatment, including the resolution of fibrosis. Among the 8 patients with aEE, 6 (75%) remained asymptomatic after one year. Of the 6 repeated EGDs, 3 revealed normal histology. The remaining 3 exhibited persistent fibrosis, involving 2 patients who maintained aEE and one who developed EoE.This is the first follow-up study in patients with IgE-CMA that evaluated EE beyond eosinophil counts, utilizing standardized EoE scores in childhood. A high frequency of EE was observed, particularly associated with severe cases of IgE-CMA, highlighting the importance of EoE screening among FA-IgE patients. Given the absence of reliable clinical markers for predicting EE, the challenge persists in identifying symptomatic patients who require EGD. While the use of PEESS contributed to EoE diagnosis in this study, we acknowledge the practical limitations of understanding sporadic complaints or oligosymptomatic patients. To grade PEESS questions or to assess the social impacts of symptoms could provide deeper insights into esophageal involvement. Another noteworthy finding of this study is the possibility of disease activity even before symptom onset, as endoscopic and histological features related to EE were similar between symptomatic and asymptomatic patients. However, since we still lack markers to define active EoE aside from clinical symptoms, debates continue regarding whether aEE should be considered a precursor to EoE or merely a transient phenomenon9.Diagnosing EoE is a relevant concern in IgE-FA patients, especially for those eligible for OIT. In this study, patients with EoE were distinguished from those with aEE by older age and higher levels of CM-specific IgE. However, due to the low incidence of EoE during this follow-up, predicting which aEE patients should be treated over time remains challenging. The phenotype definition could also contribute to understanding this progression. In both EE groups, our results suggest the predominance of a non-fibrostenotic phenotype with favorable outcomes over a period without changes in CM intake: (1) EREFS and EoESS features were mainly inflammatory, regardless of symptom presence, with most showing reversal of fibrosis during follow-up. (2) Histologic remission occurred spontaneously in asymptomatic patients or after omeprazole treatment in the majority of patients with EoE. As this is a small sample of pediatric patients followed for a short period, further follow-up studies will be necessary to confirm whether other IgE-FA groups exhibit a similar disease course.In line with previous research involving FA patients2,10, this study suggests that EoE originates from the sustained activity of inflammatory mediators, regardless of the presence of a food antigen in the esophagus. Especially in atopic individuals, characterized by type 2 immune dysregulation, further investigation is warranted to determine whether eosinophils play a protective or harmful role over time. Consequently, conducting additional research to elucidate the natural progression of EoE, including its underlying mechanisms and factors influencing its course, is essential. This deeper understanding not only promises to facilitate the development of more effective diagnostic and prognostic tools but also to pave the way for timely therapeutic interventions.Word count: 1999Keywords: eosinophilic esophagitis, esophageal eosinophilia, cow’s milk allergy, children, PEESS, EREFS, EoEHSS