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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: 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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Matthew Hardy

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The Central Valley of California (CVC) and Mid-Atlantic (MA) in the U.S. are critical sites for wintering waterfowl. Mapping waterfowl distributions using weather radar aids in the targeted adaptive management by highlighting important waterfowl habitats. Additionally, mapping broadscale waterfowl distributions improves food security by allowing government agencies and commercial poultry operations to better understand the interface between wild and domestic birds that is related to risk of highly pathogenic avian influenza outbreaks. Improving understanding of predictors of wintering waterfowl distributions at both local and landscape scales will allow facility managers and regulatory agencies to make more informed risk management decisions. We used 9 years (2014–2023) of data from the US NEXRAD network to model winter waterfowl distributions in the CVC and MA as a function of weather, temporal, and environmental characteristics using boosted regression tree modelling. We captured the spatial-temporal variability in effect size of 28 different covariates within two geographic regions which are critical to nationwide waterfowl management and have a high density of commercial poultry. In general, environmental, and geographic predictors had the strongest relative effect on predicting wintering waterfowl distributions in both regions, while effects of land cover composition were more regionally and temporally specific. Increased daily mean temperature was a major predictor of increasing waterfowl distributions in both regions throughout the winter. Increasing waterfowl densities in the CVC are strongly tied to the flooding of the landscape and rice availability, whereas waterfowl in the MA, where water is less limiting, are generally governed by waste grain availability and emergent wetland on the landscape. Waterfowl distributions in the MA increased closer to the Atlantic coast and lakes, while in the CVC they were higher nearer to lakes. Our findings promote understanding of the predictors of winter waterfowl densities in relationship with biosecurity of commercial poultry nationally.

Ashley Jia Wen Yip

and 6 more

Today in the 幸运飞行艇168官方开奖 modern world, allergic diseases, also described as atopic allergies, are classified as a type of multifactorial disorder due to the complex interplay between genetics, environment, and socioeconomic factors that influence the disease’s manifestation, severity, and one’s predisposition to allergic diseases. It is undeniable that many reported studies have pointed out that the mast cell is one of the main key players involved in triggering an allergic reaction. In order to improve our current understanding of the molecular and cellular mechanisms underlying allergy, various mast cell lines have been employed in vitro to study the pathogenesis of allergic diseases for the past decades. However, there is no consensus on many fundamental aspects associated with their use, such as the effects of culture media composition and the type of inducer used for cell degranulation. As the standardization of research protocols and disease models is crucial, we hereby present the outcome of a systematic review of scientific articles that used three major in vitro mast cell lines (HMC-1, LAD2, and RBL-2H3) to study allergy. This systematic review described the cell source, culture conditions, inducers used for degranulation, and mediators released for examination. We hope that the present systematic review may help to standardize the use of in vitro mast cell lines in allergy research and serve as a user’s guide to understand the fundamental aspects of allergy as well to develop an effective allergy therapy in the future for the betterment of human good health and wellbeing.

MAHESH ASALKAR

and 4 more

Objectives: Primary: 1. To Analyze prevalence of various endometrial pathologies among patients presenting with abnormal uterine bleeding. Secondary : 1. To study age wise distribution of various endometrial pathologies. 2. To study age wise clinical presentation (symptomatology) in patients with AUB. 3. To assess the feasibility and compare different techniques of collecting endometrial sample. Design and setting: A single center prospective cross sectional study at teaching institute Population/Sample : 150 females from 18-70 years presenting with abnormal uterine bleeding. Endometrial sample was obtained either by OPD Pipelle brush or Surgical Dilatation and Curettage method or hysteroscopy. Outcome measures : Endometrial sampling methods used, Endometrial Pathology, Age groups wise clinical and pathological correlation, Feasibility of technique used. Statistical Analysis was done by using Epi-Info-7 software. Results :Commonest age group presenting with AUB was 41-50 (40%) years ,64 % were para 3 or more, Proliferative and secretary changes, 53(35.3%) and 24(16%) cases while endometrial hyperplasia without atypia 18 (12%) cases and with atypia7cases(4.7% ),endometrial carcinoma 5 cases(3.3%) while endometrial polyp was seen in 8 cases(5.3% ). Heavy menstrual bleeding with normal duration was commonest presentation in 64%. Endometrial sampling technical failure was seen in 2 cases with pipelle biopsy while in 7 cases inadequate sample was obtained with pipelle and dilatation and curettage. Uterine perforation was seen in one case which was managed conservatively. Conclusion: Technical failure and inadequate sample needs to be addressed considering background high risk factors, TVS imaging and repeat sample and use of hysteroscopy may be offered case to case basis.

Mahyar Rafiei

and 1 more

Background Since the COVID-19 outbreak, various studies have shown that hypokalemia is a common disorder, and it has been established that abnormalities in inflammatory biomarkers and complete blood count test (CBC) parameters are associated with the severity of the disease. So, this study investigates the association between hypokalemia and abnormalities in biomarkers of inflammation and CBC parameters, as well as the severity of COVID-19. Methods This single-centered cross-sectional study was conducted on 527 adult COVID-19 patients admitted to Afzalipour Hospital in Kerman, Iran, between March 2021 and March 2022. All patients had positive PCR tests, and their data was collected from electronic records. The relationship between hypokalemia and laboratory results, length of hospitalization, ICU admission, and mortality was analyzed by SPSS 27. Results A total of 527 COVID-19 patients with an average age of 53.6 years and an average duration of hospitalization of 7.89 days were reviewed retrospectively. Most of the patients were hospitalized in the general wards (90.5%) and recovered (89.2%). In this study, the prevalence of hypokalemia was 12%, and there was no significant correlation with demographic data or laboratory findings, including ESR, CRP, LDH, lymphocyte, and platelet counts. There was also no association between hypokalemia and length of hospitalization, ICU admission, or mortality. Conclusion In total, it was found that 12% of COVID-19 patients had hypokalemia, and no significant association was found between hypokalemia and demographic data, laboratory findings, duration of hospital stay, ICU admission, or mortality.

Xinye Hu

and 2 more

Avichal Rajpal

and 10 more

Dengue Viral Infection (DVI) has emerged as one of tropical belts’ most common mosquito-borne diseases worldwide. This study was an attempt to evaluate the patterns of renal involvement in DVI and its effect on morbidity and mortality arising from the illness. This study was conducted on 170 patients hospitalized with the diagnosis of Dengue fever in the Emergency department of the Post Graduate Institute of Medical Education and Research, Chandigarh, from July 2022 to September 2023. All clinical and laboratory parameters of the patient were recorded. To evaluate patterns of renal involvement, patients underwent urine dipstick, urine routine and microscopy, spot urine protein/creatinine ratio, creatinine and ultrasonography. Patients with renal involvement were followed up for four weeks and 12 weeks. The median age was 36 years, with 60% male patients. A total of 51 patients (30%) had renal involvement, and 36 (21.17%) had Acute Kidney injury. Ten patients developed KDIGO Stage 3 AKI, of which 7 required renal replacement therapy. Forty-seven (27.6%) patients developed urinary abnormalities (which included proteinuria, hematuria, and active sediments in urine). Patients with renal involvement had significantly higher mortality (p-value <0.001). Among the patients who survived, renal abnormalities resolved in all except one, who progressed to chronic kidney disease. Renal biopsy was done in three patients, and cast nephropathy was seen in all. This study establishes that renal involvement accompanies higher mortality in patients with DVI, thereby underscoring the importance of its evaluation for the management and prognostication of patients.

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Monoclonal antibodies (MAbs) are powerful therapeutic tools in modern medicine and represent a rapidly expanding multi-billion USD market. While bioprocesses are generally well understood and optimized for MAbs, online quality control remains challenging. Notably, N-glycosylation is a critical quality attribute of MAbs as it affects binding to Fcγ receptors (FcγR), impacting the efficacy and safety of MAbs. Traditional N-glycosylation characterization methods are ill-suited for online monitoring of a bioreactor; in contrast, surface plasmon resonance (SPR) represents a promising avenue, as SPR biosensors can record MAb-FcγR interactions in real-time and without labelling. In this study, we produced five lots of differentially glycosylated Trastuzumab (TZM) and finely characterized their glycosylation profile by HILIC-UPLC chromatography. We then compared the interaction kinetics of these MAb lots with four FcγRs including FcγRIIA and FcγRIIB at 5 oC and 25 oC. When interacting with FcγRIIA/B at low temperature, the differentially glycosylated MAb lots exhibited distinct kinetic behaviours, contrary to room-temperature experiments. Galactosylated TZM (1) and core fucosylated TZM (2) could be discriminated and even quantified using an analytical technique based on the area under the curve (AUC) of the signal recorded during the dissociation phase of a SPR sensorgram describing the interaction with FcγRIIA (1) or FcγRII2B (2). Because of the rapidity of the proposed method (less than 5 minutes per measurement) and the small sample concentration it requires (as low as 30 nM, exact concentration not required), it could be a valuable process analytical technology for MAb glycosylation monitoring.

Ivy Bourgeault

and 2 more

The global health workforce crisis, simmering for decades, was brought to a rolling boil by the COVID-19 Pandemic in 2020. With scarce literature, evidence, or best practices to draw from, countries around the world moved to flex their workforces to meet acute challenges of the pandemic, facing demands related to patient volume, patient acuity, and worker vulnerability and absenteeism. One early hypothesis suggested that the acute, short-term pandemic phase would be followed by several waves of resource demands extending over the longer term. However, as the acute phase of the pandemic abated, temporary workforce policies expired and others were repealed with a view of returning to “normal”. The workforce needs of subsequent phases of pandemic effects were largely ignored despite our new equilibrium resting nowhere near our pre-COVID baseline. In this paper, we describe Canada’s early pandemic workforce response. We report the results of an environmental scan of the early workforce strategies adopted in Canada during the first COVID wave of the COVID 19 pandemic. Within a three-part framework for supporting a sustainable health workforce, we describe 470 strategies and policies that aimed to increase the numbers and flexibility of health workers in Canada, and to maximise their continued availability to work. These strategies targeted all types of health workers and roles, enabling changes to the places health work is done, the way in which care is delivered, and the mechanisms by which it is regulated. Telehealth strategies and virtual care were the most prevalent, followed by role expansion, licensure flexibility, mental health supports for workers, and return to practice of retirees. We explore the degree to which these short-term, acute response strategies might be adapted or extended to support the evolving workforce’s long-term needs.

Tara Lamont

and 2 more

There is a gap between healthcare workforce research and decision-making in policy and practice. This matters more than ever given the urgent staffing crisis, with shortfalls of key workers and increasing service pressures. As a national research network, we held the first ever UK forum on health and care workforce research and evidence in March 2023 which aimed to bridge this gap. We brought together clinical and system leaders, policymakers and regulators with workforce researchers. Fifteen sessions convened by leading experts combined knowledge exchange with deliberative dialogue over two days. Topics ranged from workforce analytics, forecasting, international migration to interprofessional working. In these small groups, important knowledge gaps were identified, where existing research had not reached decision-makers. Managers were not aware of accepted high quality evidence in areas like the relationship between registered nurse staffing levels and patient outcomes. Participants also identified important gaps in research, both topic area and study design. More work is needed to engage new disciplines, from labour economics and occupational health to academic human resources. Mobilising knowledge across disciplines will strengthen the quality and range of research as well as identifying relevant and novel interventions. Discussion at the forum highlighted a number of national and local workforce initiatives which had been implemented at pace, from virtual wards to e-rostering and apprentice levies, without a good evidence base or concurrent evaluation. The pandemic had accelerated many changes, including important shifts in skill mix and new roles with little learning from other countries and systems. Existing evaluations were often small-scale or focused on individual, rather than organisational, solutions in areas such as staff wellbeing. The paper provides a summary of an emerging UK workforce research agenda developed at the forum meeting, together with actions to build workforce research capacity and increase reach of findings into policy and practice.

Simone Hettmer

and 1 more

The AYA gap for rhabdomyosarcomaSimone Hettmer1 and Lars H. Lindner2Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.Department of Medicine III, LMU University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.To whom correspondence should be addressed. Email: . Phone: +49 761 270-45140; Fax: +49 761 270-4518Cancer is the leading cause of death among adolescents and young adults (AYAs). Cancers diagnosed during the AYA period - defined by the National Cancer Institute as the age from 15 to 39 years - account for approximately 5% of all cancers [1]. As per the national report on the status of cancer (study period 2015-2019, [1]), 5-year relative survival rates for both children and AYAs suffering from cancer are high (85.1% for children and 85.8% for AYAs), and improvements in survival over time appear to be similar for both age groups [1]. Yet, the spectrum of cancer types diagnosed in AYAs varies widely. The most common malignancies are female breast cancer (15%), thyroid cancer (15%), testicular cancer (8%) and melanomas (7%) [1], but AYAs may also suffer from so-called pediatric cancers with peak incidence during childhood. When compared to their childhood counterparts, worse outcomes were reported for AYAs diagnosed with pediatric cancers, including but not limited to leukemias [2] and sarcomas [3]. This „AYA gap“ is of concern to both pediatric and adult oncologists.The accompanying paper by Harrison et al examines a cohort of 2151 patients with rhabdomyosarcomas (RMS) enrolled in consecutive Children’s Oncology Group (COG) trials, including 19% AYAs aged 15-39 years and 81% children aged 0-14 years [4]. Compared to children with RMS, AYAs experienced significantly lower 5-year event-free survival (EFS; 44% vs. 67%) and 5-year overall survival (OS; 52% vs. 78%). These observations are in line with a recent retrospective analysis of nearly 2000 patients treated on European paediatric Soft Tissue Sarcoma Group (EpSSG) protocols [3]. Importantly, relative survival of AYAs with RMS treated on EpSSG and COG protocols appears to be better [3, 4] than the survival observed in epidemiological studies such as EUROCARE-5 (39,6% 5-year relative survival among RMS patients aged 15–19 years, and 36·4% for those aged 20–39 years; study period 2000-2007 [5]). Survival benefits for AYA patients treated on pediatric RMS protocols are consistent with previous observations in AYAs receiving treatment according to pediatric acute lymphoblastic leukemia (ALL) protocols [2] or at pediatric cancer centers/ sites with pediatric oncology expertise [6]. AYA cancer patients appear to benefit from chemotherapy dose intensities higher than what is generally prescribed to older patients. They may also draw advantages from pediatric standards with respect to planning of multimodal treatment and cancer staging. For example, the bone marrow (rarely ever involved in adult-type soft tissue sarcomas (STS)) is the most frequent site of metastases in AYAs with RMS treated within the COG cohort reported by Harrison et al [4] and should always be considered when planning pre-treatment examinations of AYAs with RMS. All taken together, adult oncology providers of AYA patients with RMS are well advised to consult their pediatric oncology colleagues and/ or consider referral to an institution with pediatric oncology expertise.AYA cancer patients treated on pediatric protocols – including those suffering from RMS - still experience worse outcomes than their pediatric counterparts [2]. There is ample evidence to support higher risk biology, more aggressive clinical phenotypes and higher rates of early treatment failures in AYAs diagnosed with pediatric cancers – including leukemias andsarcomas- compared to children diagnosed with the same malignancies [2-4]. For RMS tumors, higher rates of alveolar histology tumors and metastatic disease in AYAs were observed in the COG cohort reported here [4], as well as in the EpSSG and other retrospective studies [3, 7]. In addition to higher-risk disease manifestation, more frequent treatment-related toxicities and higher rates of withdrawal from treatment contribute to worse outcomes of AYAs compared to children with cancer [2]. There is a direct association between age and treatment-related deaths for patients undergoing ALL treatment on pediatric protocols [2]. Harrison et al do not comment on differences in treatment-related toxicities between children and AYAs with RMS, but higher rates of vincristine neurotoxicity, nausea and pain were previously reported in older adolescents undergoing RMS treatment on pediatric protocols. Even in the absence of higher-grade toxicities, a high burden of low-grade adverse events can have a major impact on the ability to function in daily life, continue education, maintain employment or participate in social activities. Many AYAs with cancer need to rely more on their parents/ support persons, which threatens their age-appropriate strive for autonomy and may result in them rebelling against treatment recommendations or failing to self- manage complex medication plans [8]. Active involvement of AYAs in the development of a care plan, which considers dignity, normalcy and family/ social relationships may improve compliance and, ultimately, treatment success.RMS is the most common STS in children and adolescents and often referred to as a pediatric cancer. Nevertheless, it occurs at any age, and up to 40% of all cases are diagnosed in adults (including seniors) [9]. The molecular and histological heterogeneity of pediatric RMS was studied intensively in recent years [10]. However, the insights provided by Harrison et al [4] and Ferrrai et al [3] emphasize that the remarkable diversity apparent across the RMS spectrum is multidimensional. Distinct clinical and biological characteristics of RMS diagnosed in different age groups deserve further attention. The two main pediatric RMS subtypes are embryonal and alveolar RMS, whereas pleomorphic RMS and RMS not otherwise specified are predominant in older adults and considered fundamentally different cancers [9]. To obtain a better understanding of RMS diagnosed in AYAs, future study efforts should aim at investigating the full spectrum of the disease and differentially consider the molecular underpinnings and therapeutic requirements of RMS diagnosed at opposite ends of the AYA age range.
Touch is important for many aspects of our daily activities. One of the most important tactile characteristics is its perceived intensity. However, quantifying the intensity of perceived tactile stimulation beyond subjective self-reports remains challenging. Here, we show that pupil responses can objectively index the intensity of tactile stimulation in the absence of overt participant responses. In Experiment 1 (n=32), we stimulated three reportedly differentially sensitive body locations (finger, forearm, calf) with a single tap of a tactor while tracking pupil responses. Tactile stimulation resulted in greater pupil dilation than a baseline without stimulation. Furthermore, pupils dilated more for the more sensitive location (finger) than for the less sensitive locations (forearm, calf). In Experiment 2 (n=20) we extended these findings by manipulating the intensity of the stimulation with three different intensities, here a short vibration, always at the little finger. Again, pupils dilated more when being stimulated at higher intensities as compared to lower intensities. In summary, pupils dilated more for more sensitive parts of the body at constant stimulation intensity and for more intense stimulation at constant location. Taken together, the results show that the intensity of perceived tactile stimulation can be objectively measured with pupil responses – and that such responses are a versatile marker for touch research. Our findings may pave the way for previously impossible objective tests of tactile sensitivity, for example in minimally conscious state patients.

Gioia Giusti

and 4 more

Interoception is mainly related to morpho-functional characteristics of the insula, which shows hypnotizability-related differences in grey matter volume. Interoceptive accuracy (IA, measured by the heartbeat counting task and by HEP, heartbeat evoked cortical potential) is lower in high (highs) than in low hypnotizables (lows). The aim of the present study was to investigate IA in highs, lows, and medium hypnotizables (mediums), who represent most of the population (according to the Stanford Hypnotic Susceptibility Scale (SHSS), Form A), during a session including a simple relaxation (Part 1) and three trials of consecutive open eyes, closed eyes, heartbeat counting and post-counting conditions (Part 2). ECG and EEG were recorded in 14 highs, 14 mediums and 18 lows. HEP were extracted throughout the entire session and IA index was obtained for the heartbeat counting task. In Part 1, significant hypnotizability-related differences were observed in the right central region in both early and late HEP components, with lows showing positive and highs/mediums negative HEP amplitudes. In Part 2, the same group differences were limited to the early HEP component. Moreover, in the left frontal regions, only mediums modified their HEP during the counting task with respect to the open/closed eyes conditions, whereas highs displayed HEP differences between counting and post-counting rest. In conclusion, highs and mediums seem to be more similar than mediums and lows regarding HEP, despite the absence of differences in the counting task. Nonetheless, a negative correlation between SHSS scores and HEP amplitudes was observed in the regions showing group differences.

Ruby M Yee

and 5 more

Tanja Kalic

and 21 more

Background: Recent studies indicated that fish-allergic patients may safely consume certain fish species. Multiplex IgE testing facilitates the identification of species tolerated by individual patients. Methods: Sera were collected from 263 fish-allergic patients from Austria, China, Denmark, Luxembourg, Norway and Spain. Specific (s) IgE to parvalbumins (PVs) from 10 fish species along with IgE to 7 raw and 6 heated fish extracts was quantified using a research version of the ALEX 2 assay. IgE-signatures of individual patients and patient groups were analyzed using SPSS and R. Results: sIgE to alpha-PV from ray, a cartilaginous fish, was not detected in 78% of the patients while up to 41% of the patients, depending on their country of origin, tested negative for at least one beta-PV. sIgE values were highest for mackerel and tuna PVs (>10 kUA/L) and significantly lower for cod (4.9 kUA/L) and sole PVs (2.55 kUA/L). 17% of the patients, although negative for PVs, tested positive for the respective fish extracts. Based on the absence of IgE to PVs and extracts, up to 21% of the patients were identified as potentially tolerating one or more bony fish. Up to 90% of the patients tested negative for ray. The probability of negativity to one fish based on negativity to others was calculated. Negativity to tuna and mackerel emerged as a good marker of negativity to additional bony fish. Conclusion: Measuring sIgE to PVs and extracts from evolutionary distant fish species indicates bony and cartilaginous fish species for tolerance-confirming food challenges.

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