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Michael Weekes

and 11 more

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.

Guangming Wang

and 4 more

Tam Hunt

and 1 more

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.

Susanne Schilling*^

and 9 more

Jessica mead

and 6 more

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.  

Mark Ferris

and 14 more

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.

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Continuous infusion of magnesium sulfate: an adjuvant therapy to treat acute severe asthma.Daniele de Avila Dalmora (1), Patricia Miranda Lago (1), Jordana Vaz Hendler (2), João Carlos Batista Santana (1), Liane Esteves Daudt (1)Affiliation:Universidade Federal Rio Grande do Sul (Medicine School)Hospital de Clinicas de Porto AlegreCorresponding Author:Profa. Patricia Miranda LagoEmail: [email protected] OF INTERESTSThe authors declare that there is no conflict of interest.To editorAsthma is a significant cause of morbidity and mortality, particularly in severe cases. In such instances, the use of intravenous magnesium sulfate has emerged as an adjuvant therapy to help manage acute exacerbations, that are unresponsive to first-line treatments. While the efficacy of magnesium sulfate in improving symptoms in asthmatic patients has been well documented, the assessment of its potential side effects in pediatric patients is limited.By investigating the side effects of continuous magnesium sulfate 6 hours infusion in a pediatric emergency department in Southern Brazil, the authors aim was to determine if treatment could be a good and safe option in severe cases.This case series study was submitted to and approved by the Ethics Committee, with registration number 23635618.1.0000.5327. All parents of children participating in the study signed an informed consent document. There were no losses during the research period. The investigation was carried out from June 2022 to May 2023, in the Emergency Department (14 beds) of a public, general and university hospital from Porto Alegre.Throughout the period of continuous magnesium sulfate infusion, all selected children were closely monitored and accompanied by emergency pediatricians. The magnesium sulfate prescription was carried out by the attending physician in accordance with the unit’s care protocol. The initial therapy management included oxygen administration via nasal catheter or Venturi mask based on saturation and/or respiratory dysfunction, single-dose oral prednisolone, and rescue nebulization with salbutamol and ipratropium, during 1 to 2 hours. The patients who didn’t improve, received the continuous infusion of 50 mg/kg/h dose of magnesium sulfate for 6 hours, with a maximum daily dosage of 8000 mg. The blood sample was collected immediately after the completion of the infusion to assess the serum magnesium levels. The asthma crise severity was classified by the modified Wood-Downes score.Patients between 3 and 14 years old with acute severe asthma were included in the study. Children who had nephropathy, heart disease, chronic pneumopathies excluding asthma, and genetic syndromes associated with pulmonary involvement were excluded.The data was collected and recorded using the institutional REDCap (Research Electronic Data Capture) system. The variables evaluated included age, gender, weight, height, serum magnesium levels, presence of side effects, presence of pneumonia, viral infection and clinical evolution assessed using the modified Wood-Downes severity score (Figure 1). The outcomes analyzed were the length of stay in the pediatric emergency room, time of oxygen supplementation, need for admission to a pediatric intensive care unit (PICU), use of ventilatory support and mortality.The authors analyzed the data using IBM SPSS Statistics version 20.0. The Kolmogorov-Smirnov test was used to assess the normality of variables. Categorical variables were presented as percentages and compared using the χ2 test. Continuous variables without asymmetrical distribution were expressed as medians and compared using the Mann-Whitney or Kruskal-Wallis tests.The study included a total of 42 patients that met the inclusion criteria, among them, 24 males (57.1%) and 18 females (42.9%). The patients mean age was 5.7 years old, with a range from 3 to 12 years. The BMI calculations showed that none of the patients were overweight or obese (BMI 17.5±2.6). Before the administration of continuous magnesium sulfate infusion for 6 hours, the score values ranged from 3 to 5 (median 4 ). And after 6-hour infusion, the scores decreased significantly to a range from 3 to 1 (median 2 ) (p < 0.001) (Table 1).There was important clinical improvement after 6 hours infusion in 30 patients (72%), as assessed by variations in the clinical severity score, with a reduction of at least 1 point. However, 12 patients (28%) did not respond to magnesium sulfate, even with adequate serum levels. There was no difference regarding the age, BMI, gender, virus detection or pneumonia, comparing responsive and unresponsive children. The study methodology considered as unresponsive all patients that necessitated more than once magnesium infusion, received multiple therapies like intravenous salbutamol, had no improvement in clinical scores, required intensive care in the Pediatric Intensive Care Unit (PICU) and/or ventilatory support.The magnesium serum level after infusion was 4.7 mg/dl (no difference between respond or not). The length of stay median in the pediatric emergency department was 2 days, with an interquartile range of 2 to 4. It is important to mention that none of the patients required respiratory support.Concerning to the side effects, no events were reported during or after the 6-hour intravenous infusion of magnesium sulfate, as nausea, drowsiness, vision changes, muscle weakness or other neurological symptoms, hypotension, respiratory distress, arrhythmia, and burning sensation or redness in the application route. There were no statistical differences between cardiac frequency and systolic blood pressure during infusion (2,4 and 6 hours), but a significant reduction in respiratory rate was detected (Figure 1).The asthma management in the emergency service necessitates prompt action to reverse symptoms and avoid respiratory failure. The standard therapy approach involves repeated administration of bronchodilators and corticosteroids, but in some cases, it is not enough for clinical improve. An Intravenous magnesium sulfate had been employed in cases of acute severe asthma that do not respond to initial management (1,2)The Magnesium sulfate induces muscle relaxation, leading to bronchodilation, and presents a rapid onset of action. To maintain a sustained relaxation effect, continuous infusion is required, otherwise its use is limited by its short half-life of 2.7 hours. In the asthma treatment, the Magnesium can be administered as a single-dose bolus. However, to obtain a prolonger effect, the administration via continuous infusion emerged as an attempt to compensate for its rapid renal elimination (3-6).This case series that evaluated 42 patients with acute severe asthma treated with a 6-hour infusion of magnesium sulfate showed clinical response by an improved Wood-Downes severity score at the end of the infusion as described by Gross and Irazuzta, and no side effects, that wasn’t study yet for other authors (3,4).It is important observed that this research is a case series performed in a single center, with a limited number of patients. Despite the study limitations, the results corroborate findings of other researches in the medical literature (3-6). The use of continuous infusion of magnesium sulfate for 6-hours emerged as an interesting treatment option to the management of acute severe asthma, showing safety as analyzed by the side effects, and resulting in better clinical outcomes. The authors believe that further multicenter and randomized studies with larger sample size are recommended to confirm efficacy and safety.FIGURE 1 Evolution of vital signs during the infusion

Derşan Onur

and 2 more

Objective: Although high-flow nasal cannula (HFNC) is a commonly used treatment method to manage respiratory distress in children, it may still result in treatment failure requiring advanced airway support. Such treatment failure can lead to increased morbidity and mortality. In light of this, a cross-sectional observational study was conducted in a pediatric intensive care unit (PICU) to identify predictive factors associated with HFNC failure in children. Materials and methods: A total of 187 patients aged between one month and 18 years with moderate to severe respiratory distress treated with HFNC therapy in the PICU between October 2018 and January 2020 were included in the study. Patients with chronic lung disease and cyanotic congenital heart disease were excluded. Clinical assessments included respiratory scores, relevant laboratory data, and treatment outcomes. In the statistical analysis, data variables were evaluated using the Mann–Whitney U test, χ2 test, receiver operating characteristic, and multivariate logistic regression analysis. Results: Analysis of 114 patients revealed a HFNC treatment failure rate of 31.6%. Multivariate logistic regression revealed that the presence of medical comorbidities (OR: 25.8, 95% CI: 2.61-254.5, p=0.005), an increased mRDAI score at the first hour of HFNC therapy (OR: 2.9, 95% CI: 1.32-6.48, p=0.008), and higher PRISM scores (OR: 2.1, 95% CI: 1.44-3.07, p<0.001) were significant predictors of HFNC failure. Conclusions: This study underscores the importance of early identification of predictive factors for HFNC therapy failure to improve management strategies and patient outcomes in pediatric patients with respiratory distress.

Dominik Kirschner

and 8 more

Understanding the intricate dynamics of biodiversity within and across riverine ecosystems, influenced by geological history and environmental factors, is crucial for effective conservation and management strategies. Italy, particularly the Ligurian region, harbors diverse freshwater fish communities and populations shaped by unique geological and hydrological conditions. Here, we investigated the suitability of eDNA-metabarcoding to identify inter- and intraspecific diversity patterns of riverine fish populations along the main drainage divide (MDD) between the Adriatic and Ligurian basins in Northern Italy. We collected 96 aquatic eDNA samples across 48 riverine sites, amplified them using a cytb primer pair and denoised the sequences to retrieve amplicon sequence variants (ASV). We calculated communities’ phylogenetic distance with betaMPD based on genetic distances derived from the ASVs, combined them with conductance-based landscape metrics and applied generalized dissimilarity models (GDM) to assess spatial genetic structure. Our results reveal genetic differentiation among populations of several fish species, with some displaying clustering patterns across the drainage divide and isolation by distance patterns. Overall, taxon richness was significantly higher in the Ligurian sites (25) than in the Adriatic side of the MDD (22), as was ASV richness (205 vs. 196). Our findings highlight the effectiveness of eDNA-metabarcoding in uncovering various facets of diversity, shedding light on hidden genetic diversity within ASVs, and revealing significant spatial genetic structuring in freshwater fish populations across multiple species.

Madhavi Singhal

and 4 more

Objective: Very low birth weight (VLBW) infants often require invasive mechanical ventilation. However, determining when infants should be extubated remains a clinical decision, and extubation trials often fail. Bedside lung ultrasound (LUS) scoring in VLBW infants allows assessment of lung aeration. Lung ultrasound scores may be helpful in determining the success of an extubation attempt. We assessed the utility of the LUS score to predict extubation readiness in VLBW infants and assessed the effect of postnatal steroids on lung ultrasound scores in babies who were ventilated for > 30 days. Study Design: Study participants were invasively mechanically ventilated VLBW infants. We measured infants’ LUS scores before planned extubations, determined the success of the extubation attempt and compared scores between successfully and unsuccessfully extubated infants. Results: VLBW infants (N=45), with gestational age 27±2 weeks and birth weight 858±289 grams, were studied. LUS scores were lower in successfully extubated infants (median 5, IQR 2-8) compared with those of unsuccessfully extubated infants (12, IQR 9.12; p=0.001). No infant with LUS <7 failed extubation. LUS scores were higher in babies ventilated >30 days (median 10, IQR 7-12) compared with babies ventilated <30 days (4; IQR 2-8, P<0.005). In infants ventilated > 30 days, LUS scores did not differ between infants treated or not with postnatal steroids. Conclusions: Lung ultrasound scores are excellent predictors of extubation readiness in VLBW infants. Lung ultrasound scores are higher in chronically ventilated infants. Use of postnatal steroids does not affect the lung ultrasound scores at the time of extubation.

Euibeom Shin

and 2 more

Purpose: To assess the ChatGPT-4 (ChatGPT) large language model (LLM) on tasks relevant to community pharmacy. Methods: ChatGPT was assessed with community pharmacy-relevant test cases involving drug information retrieval, identifying labeling errors, prescription interpretation, decision making under uncertainty and multi-disciplinary consults. Drug information on rituximab, warfarin, and St. John’s wort was queried. The decision-support scenarios consisted of a subject with swollen eyelids, and a maculopapular rash in a subject on lisinopril and ferrous sulfate. The multi-disciplinary scenarios required integration of medication management with nutrition and physical therapy. Results: The responses from ChatGPT-4 for rituximab, warfarin, and St. John’s wort were satisfactory and cited drug databases and drug-specific monographs. ChatGPT identified labeling errors related to incorrect medication strength, form, administration route, unit conversion, and directions. For the patient with inflamed eyelids, the course of action developed by GPT-4 was comparable to the pharmacist’s approach. For the patient with the maculopapular rash, both the pharmacist and ChatGPT placed a drug reaction to either lisinopril or ferrous sulfate at the top of the differential. ChatGPT provided customized vaccination requirements for travel to Brazil, guidance on management of drug allergies, and recovery from a knee injury. ChatGPT provided satisfactory medication management and wellness information for a diabetic on metformin and semaglutide. Conclusions: LLMs have the potential to become a powerful tool in community pharmacy. However, testing in validation studies across diverse pharmacist queries, drug classes, and populations, and engineering to secure patient privacy will be needed to enhance LLM utility.

Yoana Arroyo-Berdugo

and 11 more

Background and purpose Activation of Protein Phosphatase 2A (PP2A), via genetic and pharmacologic modulation of SET, has recently being identified as a promising strategy to therapeutically target acute myeloid leukaemia (AML) carrying KMT2A (MLL) chromosomal translocations (KMT2A-r AML). In this study we investigated the expression of PP2A subunits and the therapeutic potential of forskolin, a cAMP elevating natural compound reported as a PP2A activator. Key results Our data show that PPP2CA is abundantly expressed in KMT2A-r AML cells. Treatment with forskolin arrests proliferation, induces cell death, represses the expression of MYC, HOXA9 and HOXA10 and attenuates the activity of ERK1/2 in KMT2A-r AML cells. Forskolin increases sensitivity to standard-of-care daunorubicin in KMT2A- AML cell lines and PDX. Silencing PPP2CA partially rescues the cytotoxic effect of forskolin, stimulates ERK1/2, inhibits GSK3β, abolishes the forskolin-mediated repression of MYC, but it did not affect the potentiation of response to daunorubicin. This effect was also not dependent on increase of cAMP, but it was due to increase in the intracellular accumulation of daunorubicin, through inhibition of drug efflux pump P-glycoprotein 1 (multidrug resistance protein). Conclusions and implications In conclusion, our findings highlight a novel mechanism of action for forskolin and support a potential role of this natural compound in combination with current conventional agent daunorubicin in the treatment of KMT2A-r A

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Urbanization modifies ecosystem conditions and evolutionary processes. This includes air pollution, mostly as tropospheric ozone (O3), which contributes to the decline of urban and peri-urban forests. A notable case are fir(Abies religiosa) forests in the peripheral mountains southwest of Mexico City, which have been severely affected by O3 pollution since the 1970s. Interestingly, some young individuals exhibiting minimal O3—related damage have been observed within a zone of significant O3 exposure. Using this setting as a natural experiment, we compared asymptomatic and symptomatic individuals of similar age (≤15 years old; n = 10) using histological, metabolomic and transcriptomic approaches. Plants were sampled during days of high (170 ppb) and moderate (87 ppb) O3 concentration. Given that there have been reforestation efforts in the region, with plants from different source populations, we first confirmed that all analysed individuals clustered within the local genetic group when compared to a species-wide panel (Admixture analysis with ~1.5K SNPs). We observed thicker epidermis and more collapsed cells in the palisade parenchyma of needles from symptomatic individuals than from their asymptomatic counterparts, with differences increasing with needle age. Furthermore, symptomatic individuals exhibited lower concentrations of various terpenes (ß-pinene, ß-caryophylene oxide, α-caryophylene and ß-α-cubebene) than asymptomatic trees, as evidenced through GC-MS. Finally, transcriptomic analyses revealed differential expression for thirteen genes related to carbohydrate metabolism, plant defense, and gene regulation. Our results indicate a rapid and contrasting phenotypic response among trees, likely influenced by standing genetic variation and/or plastic mechanisms. They open the door to future evolutionary studies for understanding how O3 tolerance develops in urban environments, and how this knowledge could contribute to forest restoration.

Mohammad Rowshan

and 4 more

Channel coding plays a pivotal role in ensuring reliable communication over wireless channels. With the growing need for ultra-reliable communication in emerging wireless use cases, the significance of channel coding has amplified. Furthermore, minimizing decoding latency is crucial for critical-mission applications, while optimizing energy efficiency is paramount for mobile and the Internet of Things (IoT) communications. As the fifth generation (5G) of mobile communications is currently in operation and 5G-advanced is on the horizon, the objective of this paper is to assess prominent channel coding schemes in the context of recent advancements and the anticipated requirements for the sixth generation (6G). In this paper, after considering the potential impact of channel coding on key performance indicators (KPIs) of wireless networks, we review the evolution of mobile communication standards and the organizations involved in the standardization, from the first generation (1G) to the current 5G, highlighting the technologies integral to achieving targeted KPIs such as reliability, data rate, latency, energy efficiency, spectral efficiency, connection density, and traffic capacity. Following this, we delve into the anticipated requirements for potential use cases in 6G. The subsequent sections of the paper focus on a comprehensive review of three primary coding schemes utilized in past generations and their recent advancements: lowdensity parity-check (LDPC) codes, turbo codes (including convolutional codes), and polar codes (alongside Reed-Muller codes). Additionally, we examine alternative coding schemes like Fountain codes (also known as rate-less codes), sparse regression codes, among others. Our evaluation includes a comparative analysis of error correction performance and the performance of hardware implementation for these coding schemes, providing insights into their potential and suitability for the upcoming 6G era. Lastly, we will briefly explore considerations such as higher-order modulations and waveform design, examining their contributions to enhancing key performance indicators in conjunction with channel coding schemes.
The involvement of users in the product development process can significantly enhance product quality. The relationship between user experience and knowledge in product design contributes to product efficiency during the development phase. Users often struggle to align their perceptions, leading to extended product usage times and an inability to react to potential performance variations. Product manufacturers also face challenges in identifying suitable features that can positively impact product success and marketability. User experience in product interactions, encompassing both aesthetic and functional aspects, plays a pivotal role in influencing user evaluations and distinguishing characteristics crucial for achieving product success. Determining user knowledge’s influence on product success characteristics can provide valuable insights for the new product development process. This study conducted a survey to gather user experiences and knowledge, aiming to enhance the understanding of how users perceive products. This understanding is crucial for identifying product success characteristics, encompassing aspects such as specifications, sustainability, and recognition, which are instrumental in achieving overall product success. The results of the survey indicate that user knowledge, emotional experiences, and product attribute knowledge can assist product designers and manufacturers in identifying key characteristics for success during the early stages of the new product development process.

Christian Mazimpaka

and 14 more

Background: In Rwanda, Community Health Workers (CHWs) serve a crucial function in providing community-based maternal and neonatal health (CBMNH) services. However, limited access to refresher training contributes to knowledge gaps among CHWs, affecting their confidence and ability to execute their roles effectively. This study aimed to evaluate the impact of eLearning on enhancing and maintaining CHWs’ knowledge of CBMNH. Methods: This prospective cohort study, conducted from April-October 2021 in two Rwandan districts, evaluated knowledge acquisition and retention among 36 Community Health Workers (CHWs) participating in an eLearning course. Knowledge scores were measured using a structured questionnaire administered pre-training, post-training, and at a six-month follow-up. Descriptive analysis and paired t-tests were used to assess mean score differences, exploring the effectiveness of this eLearning approach. Results: This study demonstrated an improvement in Community Health Workers’ (CHWs) performance scores following eLearning training, with an average rise from 86.5% to 98.2%. The improvement was sustained at a six-month follow-up. Statistical significance was found between age category and CHWs’ pre and post-test performance (p=0.01, p=0.04 respectively), and between years of experience and pre-test scores (p=0.02), highlighting demographic influences on training outcomes. Conclusions: The results of this study suggest that eLearning is an effective method for enhancing and retaining CHWs’ knowledge of CBMNH. The findings support the use of eLearning as a valuable strategy for strengthening the capacity of CHWs in Rwanda and other countries with similar contexts.

Dan Bayley

and 4 more

The threat from novel marine species introductions is a global issue. When Non-native marine species are introduced to novel environments and become invasive, they can affect biodiversity, industry, ecosystem function, and both human and wildlife health. Isolated areas with sensitive or highly specialised endemic species can be particularly impacted. The global increase in the scope of tourism activities together with a rapidly changing climate, now put these remote ecosystems under threat. In this context, we analyse invasion pathways into South Georgia & the South Sandwich Islands (SGSSI) for marine non-native species via vessel biofouling. The SGSSI archipelago has high biodiversity and endemism, and has historically been highly isolated from the South American mainland. The islands sit just below the Polar Front temperature boundary, affording some protection against introductions. However, the region is now warming and SGSSI increasingly acts as a gateway port for vessel traffic into the wider Antarctic, amplifying invasion likelihood. We use remote AIS vessel-tracking data over a two-year period to map vessel movement and behaviour around South Georgia, and across the ‘Scotia Sea’, ‘Magellanic’, and northern ‘Continental High Antarctic’ ecoregions. We find multiple vessel types from locations across the globe frequently now enter shallow inshore waters and stop for prolonged periods (weeks/months) at anchor. Vessels are active throughout the year and stop at multiple port hubs, frequently crossing international waters and ecoregions. Management recommendations to reduce marine invasion likelihood within SGSSI include initiating benthic and hull monitoring at the identified activity/dispersion hubs of King Edward Point, Bay of Isles, Gold Harbour, St Andrews Bay and Stromness Bay. More broadly, regional collaboration and coordination is necessary at neighbouring international ports. Here vessels need increased pre- and post-arrival biosecurity assessment following set protocols, and improved monitoring of hulls for biofouling to pre-emptively mitigate this threat.

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