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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: mpw1001@cam.ac.ukThe 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: wanghesheng@sjtu.edu.cn

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:    rjzhou@cuhk.edu.hk,  rishikesh.pandey@uconn.edu

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: Pacemakers are an essential tool in managing bradyarrhythmias. Using the large Nationwide Inpatient Sample (NIS) database, we evaluated complications, trends and mortality rates of pacemakers over 2016 2020. Methods: We utilized International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) coding for our study. We evaluated clinical predictors, complications and mortality of pacemakers using the NIS database. Results: Significant independent Clinical predicators for pacer insertion are: NSTEMI: OR, 1.85; 95% CI, 1.80–1.91; p<0.001, hypertension: OR, 4.26; 95% CI, 4.19–4.34; p<0.001, hyperlipidemia: OR, 3.01; 95% CI, 2.97–3.05; p<0.001, atrial fibrillation/flutter: OR, 4.68 95% CI, 4.62–4.74; p<0.001, diabetes: OR, 1.49; 95% CI, 1.47–1.51; p<0.001, chronic kidney disease: OR, 1.99; 95% CI, 1.97–2.02; p<0.001, smoking: OR, 1.41; 95% CI, 1.31–1.43; p<0.001, COPD: OR, 1.11; 95% CI, 1.09–1.13; p<0.001, valvular heart disease: OR, 5.31; 95% CI, 5.21–5.41; p<0.001, systolic heart failure: OR, 1.98; 95% CI, 1.94–2.02; p<0.001, prior PCI: OR, 2.30; 95% CI, 2.26–2.34; p<0.001, obesity 1.19; 95% CI, 1.17–1.22; p<0.001), history of CABG{:OR, 2.48; 95% CI, 2.43–2.52; p<0.001, STEMI: OR, 1.86; 95% CI, 1.79–1.93; p<0.001, history of cardiomyopathy: OR, 1.90; 95% CI, 1.78–2.03; p<0.001, and endocarditis: OR, 1.77; 95% CI, 1.53–2.04; p<0.001. Pacemaker complication rates is around 2% Mortality around 1.44% Conclusion: We found many predictors for the need of pacemaker insertion. Mortality and complications have remained low over recent years.

In this study, Hemogram and C-reactive Protein measurement values of individuals who applied to Afyonkarahisar State Hospital with suspicion of Covid-19 disease and whose Covid-19 test result was positive (+) were analyzed. The material of this study consisted of Hemogram and C-reactive Protein parameter measurement values of patients with positive (+) Covid-19 test results (n=357) and healthy individuals with negative (-) Covid-19 test results (n=50). IBM SPSS 20.0 package program was used for statistical analysis of the data obtained. As a result of the holistic evaluation of the analysis results of the study and statistical comparison of the study groups and all age ranges, it was observed that the CRP measurement value of the patient study group increased significantly compared to the control group. In terms of hemogram measurement values, NEU, NEU% measurements of the patient study group increased, PLT, LYM, EOS, LYM% measurements decreased and statistical difference significance was determined (p<0.05). In this study, the changes in the biochemical and hematologic blood parameter values of the SARS-CoV-2 virus, the causative agent of Covid-19 disease, were examined. It is thought that the data obtained as a result of the study will contribute to researchers working in this field.

A document by Wenda Zhang. Click on the document to view its contents.

Abstract: - Background: HER2 receptor expression is associated with poor prognosis across a wide variety of cancers including breast cancer, biliary tract cancer, and urothelial cancers amongst others. Despite this, HER2 targeted therapy such as trastuzumab has proven to improve clinical outcomes amongst patients. Furthermore, trastuzumab combination drugs have demonstrated even better outcomes amongst patients with various HER2 positive malignancies. - Case: A 61 year-old man with a diagnosis of stage IV cancer was initially started on atezolizumab but experienced disease progression 2 years later as evidenced by a CT chest/abdomen/pelvis with contrast. The patient was then treated with pembrolizumab with an excellent response until four years later where the patient’s urothelial cancer progressed further. The patient was then started on gemcitabine/carboplatin and transitioned to trastuzumab emtansine plus atezolizumab until a CT chest/abdomen/pelvis showed disease progression one year later. The patient was then transitioned to enfortumab vedotin for one cycle before starting trastuzumab deruxtecan for four cycles with a CT chest/abdomen/pelvis performed on 12/21/2022 after the fourth trastuzumab deruxtecan cycle showing a partial response. - Conclusion: Trastuzumab deruxtecan is approved in the USA to treat unresectable or metastatic HER2-positive breast cancer in adults who have received two or more prior anti-HER2-based regimens in the metastatic setting. While there are promising trials underway that describe clinical utility of trastuzumab deruxtecan in various different HER2 positive malignancies, more evidence is needed. In our patient’s case, trastuzumab deruxtecan led to a durable response with stabilization of his stage IV urothelial cancer despite progression on a variety of different first line chemotherapy agents typically used in metastatic urothelial cancer. - Keywords: urothelial cancer, HER2 positive, ERBB2 positive, trastuzumab deruxtecan, durable anticancer

Glucagon-like peptide-1(GLP-1) is an incretin hormone secreted primarily from the intestinal L-cells in response to meals. GLP-1 is a key regulator of energy metabolism and food intake. It has been proven that P9 protein from A. muciniphila could increase GLP-1 release and improve glucose homeostasis in HFD-induced mice. To obtain an engineered Lactococcus lactis which produced P9 protein，mature polypeptide chain of P9 was codon-optimized, fused with N-terminal signal peptide Usp45, and expressed in L. lactis NZ9000. Heterologous secretion of P9 by recombinant L. lactis NZP9 were successfully detected by SDS-PAGE and western blotting. Notably, the supernatant of L. lactis NZP9 stimulated GLP-1 production of NCI-H716 cells. The relative expression level of GLP-1 biosynthesis gene GCG and PCSK1 were upregulated by 1.63 and 1.53 folds, respectively. The engineered strain L. lactis NZP9 was more effective than A. muciniphila BAA-835 in stimulating the intestinal L cells to produce GLP-1. To our knowledge, this is the first report on the secretory expression of carboxyl-terminal processing protease P9 from A. muciniphila in L. lactis. Our results suggest that genetically engineered L. lactis which expressed P9 may have therapeutic potential for the treatment of diabetes, obesity and other metabolic disorders.

Pattern recall performance is associated with basic cognitive skills such as working memory (WM) that temporally stores information. The performance may also associate with expertise knowledge that utilizes long-term working memory (LTWM) to retrieve information in long-term memory. However, the role of WM and LTWM in pattern recall tasks are still not clarified. Also, the role of WM and LTWM in task demand and developmental differences of players remain unclear. Further, memory retrieval is associate with vagally-mediated heart rate variability (vmHRV) level. Thus, we examined the effect of WM and LTWM in pattern recall tasks by participants setting two phases separately represent WM and LTWM abilities. We situated varied task demand by situation complexities, taken investigation on the developmental difference by recruited adolescent (U15) and adult (U23) female soccer players. vmHRV was measured during all tasks. The results show the adult group performed better than adolescents in the radial error (RE) of LTWM phase. Moreover, RE of WM phase was predicted by age in low and medium complexity. RE of LTWM phase was predicted by soccer experience in all situation complexities and predicted by vmHRV in medium and high situation complexities. The results indicate that the LTWM phase of pattern recall has a stronger association with soccer experience and validity in distinguishing age groups than the WM phase. Additionally, vmHRV can serve as a score predictor in the LTWM phase, specifically in complex conditions, and plays an important role in pattern recall evaluation among female soccer players.

Objective: Scalp electroencephalogram (EEG) provides a substantial amount of data about information processing in the human brain. In the context of conventional event-related potential (ERP analysis), it is typically assumed that individual trials share similar properties and stem from comparable neural sources, especially when employing group-level methods (including cluster analysis). However, those group analyses can miss important information about the relevant neural process due to a rough estimation of the brain activities of individual subjects while selecting a fixed time window for all the subjects. Method: We designed a multi-set consensus clustering method to examine cognitive processes at the single-trial level. The obtained clusters for the trials were processed via consensus clustering at the individual subject level. The proposed method effectively identified the time window of interest for each individual subject. Results: The proposed method was applied to real EEG data from the active visual oddball task experiment to qualify the P3 component. Our early findings disclosed that the estimated time windows for individual subjects can provide more precise ERP identification than considering a fixed time window for all subjects. Moreover, based on standardized measurement error and established bootstrap for single-trial EEG, our assessments revealed suitable stability for the calculated scores for the identified P3 component. Significance: The new method provides a more realistic and information-driven understanding of the single trials’ contribution towards identifying the ERP of interest in individual ERP potential data.

Key Points: • A U-Net is refined to forecast seven atmospheric variables on global scale, falling behind the state-of-the-art by only one day. • Forecasts are generated on the HEALPix mesh, facilitating the development of location invariant convolution kernels. • Without converging to climatology, the model produces stable and realistic states 13 of the atmosphere in 365-days rollouts. Abstract: We present a parsimonious deep learning weather prediction model on the Hierarchical Equal Area isoLatitude Pixelization (HEALPix) to forecast seven atmospheric variables for arbitrarily long lead times on a global approximately 110 km mesh at 3h time resolution. In comparison to state-of-the-art machine learning weather forecast models, such as Pangu-Weather and GraphCast, our DLWP-HPX model uses coarser resolution and far fewer prognostic variables. Yet, at one-week lead times its skill is only about one day behind the state-of-the-art numerical weather prediction model from the European Centre for Medium-Range Weather Forecasts. We report successive forecast improvements resulting from model design and data-related decisions, such as switching from the cubed sphere to the HEALPix mesh, inverting the channel depth of the U-Net, and introducing gated recurrent units (GRU) on each level of the U-Net hierarchy. The consistent east-west orientation of all cells on the HEALPix mesh facilitates the development of location-invariant convolution kernels that are successfully applied to propagate global weather patterns across our planet. Without any loss of spectral power after two days, the model can be unrolled autoregressively for hundreds of steps into the future to generate stable and realistic states of the atmosphere that respect seasonal trends, as showcased in one year simulations. Our parsimonious DLWP-HPX model is research-friendly and potentially well-suited for sub-seasonal and seasonal forecasting. Plain Language Summary: Weather forecasting is traditionally realized by numerical weather prediction models that solve physical equations to simulate the progression of the atmosphere. Numerical methods are compute intense and their performance is increasingly challenged by less compute demanding and highly sophisticated machine learning approaches. Yet, a downside of these new models is their reliability: They are not guaranteed to generate physically plausible states, which often prevents them from generating stable and realistic forecasts beyond two weeks into the future. Here, a parsimonious machine learning model is developed to forecast just seven variables of the atmosphere (compared to more than 800 in numerical models and 69 or 218 in competitive machine learning models) over an entire year. Despite the small number of variables, our model generates forecasts that only fall behind expensive state-of-the-art predictions by a single day. That is, our error in a seven-days forecast matches that of a state-of-the-art forecast at day eight. Advancing weather forecasts with research friendly and parsimonious machine learning models beyond two weeks promises to extend horizons for planning in various fields that impact environment, economy, and society. 

In this text, we detail the rise in conjunctivitis cases reported in Karachi, Pakistan over the month of August 2023 and assess the potential contributing factors, that include the city’s humid weather, worsening air quality and less-than-expected rainfall in the ongoing Monsoon season. Additionally, the practice of hand hygiene which was implemented rigorously during the COVID-19 pandemic is recognized to have had a positive impact towards control of various infections that spread in a similar fashion as the virus, including conjunctivitis. Since a decrease in compliance with hand hygiene measures in the post-pandemic world, this rise in ‘pink-eye’ cases calls for initiation of ground-level research led by ophthalmologists to obtain a true prevalence of the condition. This review will also serve as the foundation for the initiation of policies dictating hygiene implementation and planning of awareness campaigns for the general public that can serve as effective preventative measures in order to curb the spread of this condition.

Aim: Worldwide climate-driven shifts in the distribution of species is of special concern when it involves habitat-forming species. In the coastal environment, large Laminarian algae – kelps – form key coastal ecosystems that support complex and diverse food webs. Among kelps, Macrocystis pyrifera is the most widely distributed habitat-forming species and provides essential ecosystem services. This study aimed to establish the main drivers of future distributional changes on a global scale and use them to predict both future habitat suitability. Location: Global Methods: Using species distribution models (SDM), we examined the changes in global distribution of M. pyrifera under different emission scenarios with a focus on the Southeastern Pacific shores. To constrain the drivers of our simulations to the most important factors controlling kelp forest distribution across spatial scales, we explored a suite of environmental variables and validated the predictions derived from the SDMs. Results: Minimum sea surface temperature was the single most important variable explaining the global distribution of suitable habitat for M. pyrifera. Under different climate change scenarios, we always observed a decrease of suitable habitat at low latitudes, while an increase was detected in other regions, mostly at high latitudes. Along the Southeast Pacific, we observed an upper range contraction of -17.08°S of latitude for 2100 under the RCP8.5 scenario, implying a loss of habitat suitability throughout the coast of Peru and poleward to -27.83°S in Chile. Along the area of Northern Chile where a complete habitat loss is predicted by our model, natural stands are under heavy exploitation. Main conclusions: The loss of habitat suitability will take place worldwide: significant impacts on marine biodiversity and ecosystem functioning are likely. Furthermore, changes in habitat suitability are a harbinger of massive impacts in the socio-ecological systems of the Southeastern Pacific.

Background: Alcohol Use Disorder (AUD) is a debilitating condition characterized by an individual’s inability to control their alcohol consumption despite adverse consequences. Understanding the neurological aspects of AUD is crucial for effective intervention. This review encompassed a comprehensive search of reputable databases, revealing key insights. Objective: To gain a better understanding of the neurological environment of alcoholism and to shed light on the role of various neurotransmitters in the phenomenon of alcoholism. Methods: A comprehensive search of online databases, including PubMed, EMBASE, Web of Science, and Google Scholar, was conducted to identify relevant articles. Results: Neurotransmitters such as dopamine, GABA, serotonin, and glutamate play pivotal roles in alcoholism. A disrupted balance of these neurotransmitters contributes to the development and maintenance of AUD. Genetic factors also heavily influence susceptibility to alcoholism, with ADH1B and ALDH2 genes displaying significant impacts on risk. Conclusion: This review will provide a detailed overview of the neurobiology of alcohol addiction, followed by recent studies published in the genetics of alcohol addiction, molecular mechanism and detailed information on the various acute and chronic neurological manifestations of alcoholism for the Future research.

Arachis pintoi (Fabaceae) is a common relative of the cultivated peanut, and folds its four leaflets up to look like one at night. The adaptive significance of this behavior (foliar nyctinasty) is unknown. To test the hypothesis that leaflet folding alone can deter herbivores, a leaf preference experiment was performed on Chromacris trogon grasshoppers. Small oval cutouts were made from leaves of the grasshopper’s preferred food source, Iochroma arborescens (Solanaceae), and were combined with small pieces of tape and dry grass to construct artificial leaves resembling the day and night form of A. pintoi. In the experiment, groups of three grasshoppers were starved for 24 hours and then placed in petri dishes containing one closed and one open artificial leaf. After 30 six-hour trials, the average herbivory of open leaves was 12.3%, while closed leaves was 5.2% (p = 0.00145), indicating a significant preference for open leaves. This suggests that the folded configuration of A. pintoi leaves can be a defense against herbivory.