Discover and publish cutting edge, open research.

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.

Background: Total body irradiation (TBI) is a pivotal part of conditioning prior to hematopoietic stem cell transplantation (HSCT) for childhood acute lymphoblastic leukemia (ALL), yet evidence regarding the effect of TBI delivery techniques on acute and late toxicities is sparse. Design: In a national cohort of pediatric HSCT-recipients we compared 3 TBI schedules from different time-periods: (1) TBI 12 Gray (Gy) delivered in 3 fractions from 2008-2011 (n=12), (2) 6 fractions with 2-dimensional (2D) planning technology from 2012- 2015 (n=16) and (3) 6 fractions with 3D-planning intensity-modulated radiotherapy (IMRT) from 2016-2020 (n=14). Results: The 5-year event-free survival was 75.0%, 81.3% and 81.3% in cohorts 1,2 and 3, respectively. Acute toxicity assessed as maximum ferritin and C-reactive protein during the first 3 months post-HSCT did not differ between cohorts, nor did the time to first hospital discharge (median 28, 32 and 31 days, p=0.25). The incidences of acute graft-versus-host disease (GvHD) (66%, 56%, 71%) and chronic GvHD (25%, 31% and 14%) were comparable. Pulmonary function assessed by spirometry did not differ significantly. More patients in cohort 1 developed cataract, with a 5-year cataract-free survival of 33.3%, 79% and 100% in cohorts 1,2 and 3, respectively. There was a non-significant tendency towards more endocrinopathies in cohort 1 compared to cohorts 2 and 3. Conclusion: The change of modality did not result in more relapses. More fractionation improved outcome with a lower incidence of cataract and a tendency towards fewer endocrinopathies. The effect of 3D-planning-IMRT technology requires further evaluation in larger studies.

Background: Acquired QT-prolongation in children undergoing treatment for acute lymphoblastic leukemia (ALL) is potentially fatal. To date specific recommendations for ECG monitoring during ALL treatment are lacking. Aim: We aimed to assess the prevalence of QT prolongation and explore possible causes in ALL patients undergoing therapy. Methods and Results: A retrospective review of the records of all pediatric ALL patients treated between 2018-2021 at the American University of Beirut was conducted. Patients lacking complete ECG records, baseline ECGs, or those with structural or functional heart disease were excluded from the study. QT interval was measured manually, and the longest measurement was chosen. Bazett’s formula was used to correct for heart rate. All medications, the patient was on at the time of the ECG recording were documented. In addition, the level of electrolytes measured within the preceding 24 hrs of the ECG were analyzed. 28 out of 257 ECGs met prolonged QTcB criteria (≥450 ms or ≥60 ms increase from baseline). Using multivariate analysis, age, cyclophosphamide, fluconazole, and voriconazole maintained their significant association with QTcB prolongation. Hypomagnesemia and hypocalcemia showed association with QTc prolongation by bivariate analysis; however, this association could not be confirmed using Multivariate analysis due to the small sample size. The association between ondansetron and trimethoprim/sulfamethoxazole (TMP-SMX) could not be determined as all patients were receiving those two medications. Importantly, life-threatening Ventricular arrhythmias, Torsade de pointes, did not occur in any of our patients. Conclusion: Our study provides insights into factors contributing to QTcB prolongation, including specific medications, chemotherapeutic agents and possibly hypomagnesemia and hypocalcemia. To better understand these associations, larger prospective studies are necessary. In the interim, it is essential to conduct frequent follow-ups with ECGs when using these medications.

Background/Objectives Acute lymphocytic leukemia (ALL) is the most common pediatric cancer, more incident in Hispanics. The Berlin-Frankfurt-Münster (BFM) protocol for ALL began to be used in hospitals from Rio de Janeiro in the 1980’s. The aim of this study was to determine survival probabilities and prognostic factors for children and adolescents with ALL in the state of Rio de Janeiro (RJ) and to compare these results with other BFM studies. Design/Methods We conducted a survival analysis study with a retrospective cohort of 695 patients aged from zero to 19 years treated with a modified BFM protocols between 1998 and 2018 in four reference hospitals in RJ. Prognostic factors included age, sex, leukocyte count, early response to treatment and cytogenetic risk. The cohort was divided into two periods. We calculated the five- and ten-years event-free survival (EFS), the overall survival (OS) and performed a multivariate analysis using Cox proportional hazards models. Results In the 1 st period the five-year EFS was 50.3% (±3.0) and the OS was 61.5 (±2.9). These rates for high-risk patients (HR) were 33.4% and 47.7%, respectively. In the 2 nd period, the five-year EFS was 61.6% (±2.8) and the OS was 70.5% (±10.6). These rates for HR patients were 57.9% and 63.8%. In the cohort, 51.2% of patients were HR based on BFM classification, 54.7% were HR based on the National Cancer Institute classification, 27.1% had a leukocyte count greater than 50,000 and 28.6% were aged less than one or greater than 10 years. Conclusions Our results led us to hypothesize that delays in treatment, overestimated risk classification on the 8 th day of treatment and/or unique genetic features of our population may be causing a higher leukocyte count at the time of diagnosis and an increased prevalence of HR classification compared to other BFM studies mainly composed by Caucasians.

Successful Sternotomy to Remove an Enlarging Symptomatic Pericardial CystAlexander M. Kravets1, Matthew R. Schill2, Muhammad Faraz Masood21 Department of Surgery, Poznan University of Medical Sciences, Poznan, Poland. Electronic address: [email protected] Division of Cardiothoracic Surgery, Washington University School of Medicine, Barnes-Jewish Hospital, St Louis, Mo.Consent StatementWritten informed consent was obtained from the patient to publish this report in accordance with the journal’s patient consent policy.AbstractPericardial cysts (PCs) are rare. Most are discovered incidentally on radiographic imaging and are asymptomatic. Symptomatic patients may complain of chest pain and dyspnea. Delays in diagnosis and treatment are common. We report the case of a symptomatic 57-year-old female. CT and echocardiography confirmed the diagnosis and location, and the cyst was removed via sternotomy. A systematic approach is desired for the management of PCs.IntroductionCongenital pericardial cysts are fluid-filled, unilocular sacs lined by mesothelial cells. They typically form due to incomplete fusion of the pericardial sac during embryonic development [1]. Acquired pericardial cysts may result from trauma or inflammation of the pericardial sac. PCs occur in 1 in 100,000 patients and comprise 7% of all mediastinal masses [2]. They are most often found in the right cardiophrenic angle (70%) [1].Pericardial cysts were first described at autopsy in the mid-19th century [3]. Pericardial cysts are now most often diagnosed incidentally on radiographic imaging or echocardiography. Most patients are asymptomatic (75%) [2].Symptomatic patients typically complain of chest pain, dyspnea, and other symptoms resulting from the compression of structures adjacent to the pericardial sac. These symptoms may not correlate with physical activity. Worsening of symptoms at night has been reported in some patients. Nocturnal worsening of symptoms is gravity-dependent, resulting from a shift of fluid from the pericardium back into the pericardial sac [3].Patients presenting with symptoms typically experience delays in diagnosis and treatment. An increased awareness of this condition with respect to standardized follow-up and treatment may improve patient outcomes.We report the case of a 57-year-old female who presented with chronic symptoms resulting from a pericardial cyst in the left cardiophrenic angle.Case PresentationA 57-year-old female with a history of COPD and anxiety was referred to our clinic for evaluation of a pericardial cyst that had been incidentally diagnosed nearly two decades prior. She stated that approximately 3-4 years ago she began having hypertension and shortness of breath with activity. She had been recently evaluated for carotid artery disease, which was found to be negative for hemodynamically significant stenosis. She endorsed chest pain on her left side of her chest which could occur at any time. She also endorsed fatigue as well as progressive shortness of breath. She denied having lower extremity edema, orthopnea, PND, dizziness, or palpitations.On imaging, CT revealed a large pericardial cyst measuring 5 cm in diameter (Figure 1). The patient stated feeling as if she had an egg inside her chest. The cyst was confined to the left cardiophrenic angle and was adjacent to the fifth rib along the inner chest wall. Transthoracic echocardiogram was normal with slightly elevated BNP.

Changing CO2 concentrations have and will continue to affect plant growth with consequences for ecosystem functioning. The adaptive capacity of C3 photosynthesis to changes in atmospheric CO2 concentrations is, however, insufficiently investigated so far. Here we focused on the phylogenetic dynamics of maximum carboxylation rate (Vcmax) and maximum electron transport rate (Jmax) – two key determinants of photosynthetic efficiency in C3 plants – and their relation to deep-time dynamics in species diversification, speciation and atmospheric CO2 concentrations during the last 120 million years. We observed very strong positive relationships between photosynthetic efficiency and species diversification as well as speciation rates. Vcmax as well as species speciation and diversification furthermore increased during periods of low prehistoric CO2 concentrations. From our results we conclude strong links between photosynthetic efficiency and evolutionary dynamics in C3 plants. We furthermore conclude, that increasing future CO2 concentrations might rather hinder than facilitate evolutionary dynamics in C3 plants.

Background: Systemic Sclerosis (SSc), an intricate autoimmune disease causing tissue fibrosis, introduces cardiovascular complexities, notably pulmonary hypertension (PH), affecting both survival and quality of life. This study centers on evaluating echocardiographic parameters and endothelial function using Flow Mediated Dilatation (FMD) in SSc patients, aiming to differentiate those with and without pulmonary arterial hypertension (PAH). The emphasis lies in early detection, given the heightened vulnerability of the right ventricle in the presence of PH. Methods: 59 SSc patients and 48 healthy subjects participated, undergoing clinical examinations, echocardiography, FMD assessments, blood analyses, and, when necessary, right heart catheterization (RHC). Results: SSc-PAH patients displayed lower FMD, increased TAPSE <18 mm, RA area >18 cm2, and TRV >280 cm/sec compared to those without PAH and healthy controls. Resting Resistivity Index (RI) was higher in SSc patients, with no significant difference between those with and without PAH. Lower FMD% serves as a predictive marker for adverse cardiovascular outcomes in both SSc and SSc-PAH patients. Stratification by TRV levels and PAH presence reveals notable FMD% variations, emphasizing its potential utility. Conclusions: Early identification of endothelial dysfunction and echocardiographic parameters, such as TAPSE and TRV, could aid in predicting right ventricular dysfunction and PAH in SSc patients.

Blood-filled cysts (BFCs) are considered benign and often asymptomatic, most originate from congenital. However, BFCs of the heart valves are common at autopsy in infants but rare in adults. We report the case of an adult female who presented with a solitary complaint of chest distress on exertion, which led to the discovery of an intracardiac cystic mass on the anterior tricuspid leaflet. A single surgical intervention was sufficient to remove the resected cystic mass. Our case is the first to report a highly unusual blood-filled cyst on the anterior tricuspid leaflet in an adult.

Structures at serine-proline sites in proteins were analyzed using a combination of peptide synthesis with structural methods and bioinformatics analysis of the PDB. Dipeptides were synthesized with the proline derivative (2 S,4 S)-(4-iodophenyl)hydroxyproline [hyp(4-I-Ph)]. The crystal structure of Boc-Ser-hyp(4-I-Ph)-OMe had two molecules in the unit cell. One molecule exhibited cis-proline and a type VIa2 β-turn (BcisD). The cis-proline conformation was stabilized by a C–H/O interaction between Pro C–H α and the Ser side-chain oxygen. NMR data were consistent with stabilization of cis-proline by a C–H/O interaction in solution. The other crystallographically observed molecule had trans-Pro and both residues in the PPII conformation. Two conformations were observed in the crystal structure of Ac-Ser-hyp(4-I-Ph)-OMe, with Ser adopting PPII in one and the β conformation in the other, each with Pro in the δ conformation and trans-Pro. Structures at Ser-Pro sequences were further examined via bioinformatics analysis of the PDB and via DFT calculations. Ser–Pro versus Ala-Pro sequences were compared to identify bases for Ser stabilization of local structures. C–H/O interactions between the Ser side-chain O γ and Pro C–H α were observed in 45% of structures with Ser- cis-Pro in the PDB, with nearly all Ser- cis-Pro structures adopting a type VI β-turn. 53% of Ser- trans-Pro sequences exhibited main-chain C=O i•••H–N i +3 or C=O i•••H–N i +4 hydrogen bonds, with Ser as the i residue and Pro as the i+1 residue. These structures were overwhelmingly either type I β-turns or N-terminal capping motifs on α-helices or a 3 10-helices. These results indicate that Ser-Pro sequences are particularly potent in favoring these structures. In each, Ser is in either the PPII or β conformation, with the Ser O γ capable of engaging in a hydrogen bond with the amide N–H of the i+2 (type I β-turn or 3 10-helix; Ser χ 1 t) or i+3 (α-helix; Ser χ 1 g+) residue. Non-proline cis amide bonds can also be stabilized by C–H/O interactions.

Biodiversity loss has reached critical levels due in part to anthropogenic habitat loss and degradation. These landscape changes are particularly damaging as they can result in fragmenting species distributions into small and isolated populations, resulting in limited gene flow, population declines and reduced adaptive potential. Genetic rescue, the translocation of individuals for the purpose of restoring gene flow, has been shown to produce promising results for fragmented populations but remains relatively under-used due to a lack of long-term data and monitoring of genetic rescue attempts. To promote a better understanding of genetic rescue and its potential risks and benefits over the short-term, we reviewed and analyzed all genetic rescue attempts to date to identify whether genetic diversity increases following rescue, and if this change is associated with increased fitness. Our review identified only 19 genetic rescue studies, that included experimental, natural, and conservation motivated, with the majority of studies being on mammals. We used a Bayesian meta-analytical approach to examine the relationship between fitness and genetic diversity. We found that genetic diversity, as represented by heterozygosity, was a positive predictor of population fitness, and this relationship extended to the third-generation post-rescue. These data suggest a single introduction can have lasting fitness benefits, supporting translocation as another tool to ensure conservation success. Given the limited number of studies with long-term data, we echo the need for genetic monitoring of translocations to ascertain whether genetic rescue may also limit the loss of adaptive potential in the long-term.

Chlamydia psittaci ( C. psittaci) is an obligate intracellular bacterium that replicates in neutrophils, a significant producer of reactive oxygen species(ROS). However, the effect of ROS on C. psittaci infection and whether C. psittaci regulates ROS production in neutrophils is unclear. When C. psittaci infects neutrophils, it can induce the production of a small amount of ROS, affect the assembly of NADPH oxidase through p38/ERK signaling pathways, and actively block the ROS produced by PMA-stimulated neutrophils. Importantly, this study may provide new insights into the molecular pathogenesis and immune escape of C. psittaci.

Viewing interfaces as collective role of urban spatial planning and early childcare education approach, the study documents urban built space challenges of preschools in the context of rapid urbanization. It aims at identifying policy, institutional and practice gaps in addressing preschool infrastructure, education, and early childhood care policy implementation in Addis Ababa. A case study of private and public pre-schools was considered. A qualitative design was used to collect data from secondary and primary sources. Data on pre-school policies, practices, regulations, and data on implementation were collected. Key informant interviews were used to collect primary data, including the perspectives of policy-makers and implementers. The thematic data analysis revealed that, urban planning lacks a detail working plan at local level that can be translated to action in addressing the challenges of preschools. The spatial plan and education policy do not incorporate early childhood care and education infrastructure demands of the preschools observed. Thus, policy and institutional gaps need to be recognized and addressed to solve the challenges of preschool infrastructure and to create a conducive space for early childhood education in Addis Ababa.

Membrane proteins play a significant role in ion transport across cell membranes. They act as channels or transporters that allow ions to move across the membrane. Channels are typically selective for specific ions, while transporters move multiple types of ions. These proteins use energy from ATP or the electrochemical gradient to move ions against their concentration gradient. The movement of ions through these proteins generates an electrical potential difference across the membrane, which is important for various physiological processes. Noticeably, the epithelial tissues form barriers that separate different compartments in the body, such as the lumen of the gut, the ducts of glands, and the external environment. Epithelial cells play a significant role in ion transport and current in biological systems. For example, epithelial cells in the gut are responsible for the absorption of nutrients and water, and they use ion channels and transporters to move ions such as sodium, potassium, and chloride across their membranes. This process creates an electrical potential difference across the epithelial cell layer, leading to the generation of a current that drives ion movement. Importantly, the disruptions in membrane proteins and epithelial transport are implicated in many diseases, including cystic fibrosis, hypertension, arrhythmia, kidney disease, diarrhea, and renal failure. Studying the mechanisms will identify potential therapeutic targets and develop treatments for these diseases.