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Michael Weekes

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

Guangming Wang

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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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We hypothesized that cell energy metabolic profiles correlate with normal, dysplastic, and tumor cell/tissue statuses and may be indicators of aggressiveness in oral squamous cell carcinoma (OSCC) cells.The energy-related proteins that were differentially expressed in human OSCC fragments (n=3) and their adjacent epithelial tissue (TAE) were verified using mass spectrometry. Immunohistochemistry for 4-hydroxynonenal (4-HNE) was performed to evaluate the oxidative stress patternsin OSCC (n=10), epithelial dysplasia (n=9), and normal epithelial (n=4) biopsies. The metabolic modulation of OSCC aggressiveness was investigated in human OSCC cell lines with different levels of epithelial–mesenchymal transition proteins. All OSCC fragments exhibited an increase in glycolysis-related proteins and a decrease in mitochondrial activity compared to the TAE region (p<0.05), probably due to the downregulation of pyruvate dehydrogenase and antioxidant proteins. Additionally, the OSCC cell line with a mesenchymal profile (SCC25) had a lower mitochondrial mass and membrane potential and generated lower levels of reactive oxygen and nitrogen species than the TAE region. When we analyzed 4-HNE, the reactive species levels were increased in the epithelial regions of OSCC and potentially malignant lesions. A decrease in the levels of 4-HNE/reactive species was observed in the connective tissue underlying the dysplastic regions and the OSCC invasion zone.Thus, aggressive OSCC is associated with high glycolytic and oxidative metabolism and low mitochondrial and antioxidant activities, which vary according to the differentiation level of the tumor cells and the stage of carcinogenesis.

Kenneth Mlay

and 3 more

Background: In most Low and Middle-Income Countries (LMICs), enrolment in community-based health insurance (CBHI) is still low. In Sub-Saharan Africa enrolment rate is less than 10%. There have been efforts and strategies being put in place in many countries to overcome this problem. In 1996, Tanzania introduced Community Health Fund (CHF) which was modified in 2011 whereby the government came up with the improved community health fund (iCHF). The introduction of iCHF was intended to improve service delivery to the population where an electronic integrated management information system was introduced. Objective: This study was set to explore the drivers for implementing the e-claim process of improved Community Health Funds from two districts in Central Tanzania. Methods: An exploratory case study design using a qualitative approach was adopted to explore information on the drivers of the implementation of the iCHF electronic claim process in Mkalama and Iramba districts in Singida region. In-depth interviews were used to collect data from the Eighteen (18) participants including regional health managers, district health managers, Information Technology (IT) officers, facility in charge and iCHF focal persons from dispensaries, health centres and hospitals. Data were analyzed using a thematic content analysis. Results: The drivers for implementing the iCHF e-claim process were adherence to supervision directives and government policy, resource management and client satisfaction but the e-claim system does not attract Health Community Workers (HCWs) to comply with the iCHF e-claim process Conclusion: The iCHF e-claim process is inadequately implemented and does not attract Health care workers (HCWs) due to the challenges that have been observed. These findings inform decision makers to joint efforts to improve the implementation of iCHF claim process from all levels of stakeholders.

Shihan Chen

and 6 more

Background: Linguistic concordance between healthcare providers and patients is critical for ensuring quality healthcare. Professional interpretation can be expensive and challenging to access. This scoping review aimed to explore the evidence on the role and education of medical students as interpreters in caring for patients with limited language proficiency (LLP), and to determine the benefits and risks associated with this practice. Methods: A scoping review using the Joanna Briggs Institute methodology was conducted. Six literature databases were searched systematically between 1946 – 02 Aug 2023. All publications discussing the use of medical students as interpreters in healthcare settings were included. Retained documents were analyzed using Covidence, with coding by two raters and regular team discussions. A thematic analysis framework was used. Results: Thirteen articles met the eligibility criteria. Multilingual medical students are frequently asked to interpret in healthcare settings. This was found to be advantageous in reducing communication barriers, improving care quality, and contributing to students’ clinical experience. Concerns were raised regarding the lack of knowledge on the professional obligations of interpreters. Interpretation training programs for medical students have been implemented at selective healthcare centres and demonstrated successful results in providing care to LLP patients. Conclusions: Medical students play an important role in addressing language barriers in healthcare institutions when serving LLP patients, by combining their unique position in the healthcare team with their medical, linguistic, and cultural competency skills. Academic institutions stand to benefit from offering interpretation training programs and integrating medical students as a resource towards delivering language-concordant care.

Shunichiro Yasuda

and 3 more

Adrenal infarction with latent myelodysplastic/myeloproliferative neoplasm, unclassifiable with JAK2 V617F mutationShunichiro Yasuda1, Momoko Chiba1, Rie Nishitani2 and Takako Watanabe21Department of Hematology, Tokyo Kyosai Hospital, Tokyo, Japan2Department of Diabetes, Endocrinology and Metabolism, Tokyo Kyosai Hospital,Tokyo, JapanCorrespondence: Shunichiro Yasuda, M.D., Ph.D.Hematology Division Tokyo Kyosai Hospital 2-3-8 Nakameguro Meguro-ku Tokyo, 153-8934, JapanTel: +81-3-3712-3151 Fax 81-3-3793-5582E-mail:[email protected] TYPE: Case reportAUTHOR CONTRIBUTIONSSY, MC, RN, TW: were involved in the patient care and management. SY, MC and RN: prepared the initial draft of the manuscript. SY, MC, TW: edited the draft and reviewed the manuscript. All authors approved the final version of the manuscript and agreed to be accountable for any aspects related to the accuracy or integrity of the work.ACKNOWLEDGMENTSThe authors would like to thank all clinicians involved in this case and Editage (www.editage.jp) for the English language editing.FUNDING INFROMATIONThere is no funding for this article.CONFLICT OF INTEREST STATEMENTThe authors have no conflicts of interest relevant to the content of this article.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are available from the corresponding author upon reasonable request.ETHICS STATEMENTThis manuscript confirms to the provisions of the Declaration of Helsinki in 1995 (as revised in Brazil 2013).CONSENTWritten informed consent was obtained from the patient to publish this report in accordance with the journal‘s patient consent policy.Key Clinical MessageHematopoietic neoplasms are considered a differential diagnosis when encountering adrenal infarction. We should recognize thatJAK2 V617F mutation can cause thrombogenicity even if there are no abnormal findings in the blood cell counts.AbstractAdrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46-year-old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U), featuring a JAK2 V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2 V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms.Key words; adrenal infarction, myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U), JAK2 V617F, CHIPINTRODUCTIONAdrenal infarction is a rare condition that occasionally develops in a hypercoagulable state 1. Antiphospholipid antibody syndrome (APS), COVID-19 infection, and heparin-induced thrombocytopenia (HITT) have been reported as underlying diseases of adrenal infarction1-3. Adrenal infarctions have also been rarely linked to myeloproliferative neoplasms (MPN), such as polycythemia vera (PV) and essential thrombocythemia (ET) 4,5.Myelodysplastic/myeloproliferative neoplasm (MDS/MPN) is a hematological disorder that exhibits characteristics of both MDS and MPN6,7. According to the revised version of the 4th edition of the World Health Organization (WHO) classification, the categories of MDS/MPN include chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), and MDS/MPN-unclassifiable (MDS/MPN-U)6-8. The diagnosis of MDS/MPN-U is based on ruling out any other subtype of MDS/MPN 7,8. Approximately 25% of cases with MDS/MPN-U have JAK2 V617F mutations8, which is a major mutation in patients with MPN9. As patients with MDS/MPN-U exhibit MPN characteristics, they may have a high risk of thrombosis. However, due to the rarity of this disease, the frequency of thrombosis in patients with MDS/MPN-U has not yet been thoroughly investigated.Herein, we present a case of JAK2 V617F-positive MDS/MPN-U with adrenal infarction. The present case had a unique clinical course in which the platelet count of the patient was almost normal at the time of adrenal infarction; however, later, the counts increased, and the characteristics of MPN became apparent. We report this case with a discussion of the thrombogenicity caused by the JAK2 V617F mutation and review previously reported cases of adrenal infarction in myeloid neoplasms.CASE HISTORY/ EXAMINATIONA 46-year-old previously healthy man presented to our emergency department with epigastric and left hypochondrial pain. He had no history of medication or family history of thrombophilia. On physical examination, his body temperature was 37.1 °C, blood pressure was 152/101 mmHg, heart rate was 118 bpm, and oxygen saturation was 97%. Electrocardiography (ECG) findings were normal, and chest radiograph showed no abnormalities. Blood tests revealed a slight increase in the platelet count (42.6×104/μL) and mild anemia (Hemoglobin: 12.9g/dL); the COVID-19 antigen test was negative. Contrast-enhanced computed tomography (CT) showed left adrenal hypertrophy and non-contrast-enhancing areas of the adrenal gland. Additionally, there was increased density of adipose tissue and fluid retention around the left adrenal gland (Fig.1A). Subsequently, he received a diagnosis of left adrenal infarction. The patient was urgently admitted to our hospital, and heparin 10000 U/day was initiated (Fig. 2). While the adrenal infarction was unilateral, there were no signs of adrenal insufficiency based on vital signs and laboratory data.DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS AND TREATMENTDue to the potential for adrenal insufficiency, we initiated the administration of hydrocortisone as a steroid cover. Endocrine examinations indicated the maintenance of the adrenal function of the patient; consequently, the hydrocortisone dose was tapered and terminated. His epigastric and left hypochondrial pain steadily relieved, and follow-up contrast-enhanced CT on day 7 revealed resolution of the left adrenal infarction (Fig.1B). Subsequently, we transitioned the antithrombotic therapy from heparin 10000U/day to edoxaban 30 mg/day, and the patient was discharged on day 16. As for the thrombotic predisposition that led to the adrenal infarction, the increase in platelet counts was not remarkable. Both protein C activity and protein S activities were within the normal range(148% and 73%, respectively). The lupus anticoagulant was negative. Hence, we could not find any causes of adrenal infarction.OUTCOME AND FOLLOW-UPSoon after discharge from our hospital, the patient suffered from a headache. Considering the possibility of edoxaban-induced headache, edoxaban treatment was discontinued on day 20. Two months later, he presented to our hospital with a persistent headache despite discontinuing edoxaban treatment. He was diagnosed with cerebral venous thrombosis (CVT) on contrast-enhanced magnetic resonance imaging (MRI), and edoxaban treatment was resumed on day 88. Simultaneously, the patient presented with right hypochondrial pain, and contrast-enhanced CT showed mild hypertrophy of the right adrenal gland (Fig.1C). He was clinically diagnosed with right adrenal infarction. Furthermore, abdominal aortic mural thrombosis was incidentally detected on contrast-enhanced CT. Regarding multiple arteriovenous thromboses in a short period, his thrombotic predisposition was examined again. Blood tests showed that various autoantibodies were all negative, and the patient did not have diabetes or dyslipidemia (Table.1). However, the platelet counts, which were almost normal at the time of the first admission, gradually increased (Fig.2). Suspecting MPN, especially ET, we examined the presence of JAK2 V617F mutation, which was found to be positive. Bone marrow aspiration showed no increase in the blasts but showed dysplastic features in granulocytes, erythroblasts, and megakaryocytes; a chromosomal abnormality with der(1;7)(q10;p10) was found in 20 out of 20 cells. Bone marrow biopsy showed no bone marrow fibrosis. WT1mRNA was slightly high (71 copies/µgRNA). Since our patient had characteristics of both MDS and MPN and the diagnostic criteria for other MDS/MPN subtypes were not fulfilled, he was diagnosed with MDS/MPN-U. At the same time, the patient was aware of a rash resembling urticaria rash and pruritus on both lower legs, with mild increase in eosinophils (8.1%). The rash and pruritus improved with the use of an antihistamine cream. Since his thrombocytosis was not remarkable (59.7×10⁴/µL) and von Willebrand Factor (vWF) ristocetin cofactor activity (vWF:RCo) did not decrease (89%), the risk of bleeding might not be high 10,11. The patient was then treated with edoxaban (30 mg/day) and aspirin (100 mg/day).On day 131, the patient was admitted to our hospital again for close examination and treatment because his platelet counts further increased (Fig.2) and the development of a new thrombosis was expected. After admission, contrast-enhanced MRI and contrast-enhanced CT were performed, which showed resolution of all arteriovenous thromboses, including the right adrenal infarction (Fig.1D). The platelet counts rose to approximately 100×10⁴/µL; therefore, hydroxyurea 500 mg/day was started on day 137 as cytoreductive therapy, which was increased to 1000 mg/day on day 140. His eosinophil count also gradually increased with a skin rash flare-up. A skin biopsy was performed, leading to the pathological diagnosis of leukocytoclastic vasculitis, which was considered closely related to MDS with der(1;7)(q10;p10)10,11. After the hydroxyurea treatment, both the platelet and eosinophil counts decreased, leading to no recurrence of new thrombosis or improvement of the skin rash. Both JAK2 V617F allele burden and the copy numbers of WT1mRNA increased in our patient, suggesting that MDS/MPN-U progressed. Furthermore, MDS with der(1;7)(p10;q10) complicated by eosinophilia has aggressive clinical features and a poor prognosis 13,14. As the prognosis of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor in patients with MDS/MPN-U who have progressive disease or severe complications 12, earlier allo-HSCT might be preferable. After obtaining adequate informed consent, including the risks and benefits of allo-HSCT, the patient was transferred to the transplantation center to receive allo-HSCT at the optimal time.DISCUSSIONIn this manuscript, we present a case of JAK2 V617F-positive MDS/MPN-U with multiple thromboses, including adrenal infarction. Although the precise mechanisms of thrombogenesis in MDS/MPN-U have not been elucidated, we speculate that MDS/MPN-U caused multiple thromboses since our patient did not have any other risk factors for thrombosis or a thrombotic predisposition. Notably, the first adrenal infarction occurred when the platelet count was only slightly elevated and MDS/MPN was not apparent. To date, various mechanisms of thrombogenesis byJAK2 V617F have been reported; 1) JAK2 V617F-positive neutrophils and monocytes release inflammatory cytokines, leading to arteriosclerosis and arterial thrombosis 13. 2)JAK2 V617F-positive neutrophils activate β1/2 integrin, promoting venous thrombosis 14,15. 3) Vascular endothelial cell expression of JAK2 V617F promotes a prothrombotic state due to increased P-selectin expression 16. Recently, Clonal Hematopoiesis (CH) has been identified and genetic mutations associated with the disease have been detected before the development of hematological malignancies 17,18. In addition, when CH occurs and the variant allele frequency (VAF) exceeds 2%, it is called CH with indeterminate potential (CHIP) 17.JAK2 V617F-CHIP holders had a higher incidence of both arterial and venous thromboses than non-holders 17. In the present case, JAK2 V617F-CHIP may have been associated with the thrombogenicity of adrenal infarction.Previously, five cases of myeloid neoplasms that developed into adrenal infarctions have been reported (Table.2). Among these cases, two patients with ET had JAK2 V617F mutations 4,5. Indeed, one patient developed adrenal infarction before the diagnosis of ET, indicating that JAK2 V617F-CHIP was closely associated with adrenal infarction, as in our case 4. However, one patient with MDS/MPN-U did not harbor the JAK2 V617F mutation19, indicating that other gene mutations may contribute to the thrombogenesis in MDS/MPN-U. Furthermore, one case with MDS had adrenal infarction with no other thrombotic predisposition, such as MPN, suggesting that the hypercoagulable state associated with MDS may contribute to thrombogenesis 20. With reference to these case reports, other factors as well asJAK2 V617F mutation, may have caused the adrenal infarction in our case with MDS/MPN-U. A previous study suggested that SF3B1 may be a risk factor for thrombosis in MDS/MPN-RS-T, a subtype of MDS/MPN21. At present, SF3B1 mutation analysis is required for the accurate classification of MDS/MPN subtypes according to the latest 5th WHO classification. However, SF3B1 analysis can only be performed at a limited number of centers in Japan and is not available at our hospital. If SF3B1 or other gene mutation analyses become widespread and can be performed in daily practice, more accurate predictions can be made regarding the risk of thrombosis in MDS/MPN subtypes in the future.All six cases in Table.2, including the current case, developed complications such as adrenal insufficiency and thromboses at other sites. Among the six patients, five had bilateral adrenal infarction4,5,19,20,22 and four developed primary adrenal insufficiency that required steroid replacement therapies4,19,20,22. In our case, the adrenal infarction was unilateral and improved soon after edoxaban treatment. Although our patient subsequently developed adrenal infarction contralaterally, the lesions of adrenal infarction were small; therefore, the patient did not develop adrenal insufficiency.Among the six patients shown in Table.2, four developed thromboses at other sites, including one case of angina pectoris that required percutaneous coronary intervention 5. Our patient simultaneously developed CVT, abdominal aortic mural thrombosis, and adrenal infarction. In accordance with the recommendations of a previous study on the combination of antiplatelet and anticoagulant drugs for arteriovenous thrombosis in patients with MPN 23, the patient was treated with edoxaban and aspirin, and all thromboses disappeared.Although the six cases in Table.2 did not develop adrenal hemorrhagic infarction, they sometimes occurred after adrenal infarction. The mechanisms underlying adrenal infarction and adrenal hemorrhagic infarction are not fully understood; however, it is hypothesized that they are related to the unique vascular anatomy of the adrenal gland4,19,24. When treating adrenal infarction, attention should be paid to adrenal hemorrhagic infarction. In particular, patients with MPN have an increased risk of bleeding owing to a decrease in vWF activity associated with an increase in the platelet count25. Therefore, patients with adrenal infarction who have characteristics of MPN should be examined for vWF activity before starting treatment with antithrombotic agents.Patients with MDS/MPN-U generally have a poor prognosis with a median overall survival of 12.4 months, as reported by a previous study8. Although the efficacy of ruxolitinib or hypomethylating agents for MDS/MPN-U has been reported26,27, they are not curative, and the only curative treatment option is allo-HSCT 12. Since patients with severe complications before allo-HSCT have a worse prognosis, management of these complications is crucial for patients with MDS/MPN-U. Although our patient had multiple arteriovenous thromboses, they were managed with antithrombotic agents, and the patient was eventually transferred to the transplantation center without any complications.CONCLUSIONWe report a case of JAK2 V617F-positive MDS/MPN-U with adrenal infarction. Hematopoietic neoplasms are considered a differential diagnosis when encountering adrenal infarction with unknown causes. Even if there are no abnormal findings in the blood cell counts at the time of adrenal infarction, they should be carefully monitored, and when MPN is suspected, JAK2 V617F mutation should be examined. Finally, patients with adrenal infarction of hematopoietic neoplasms often have complications, and management of these complications is crucial, especially in patients eligible for allo-HSCT.REFERENCES1. Espinosa G, Santos E, Cervera R, et al. Adrenal involvement in the antiphospholipid syndrome: clinical and immunologic characteristics of 86 patients. Med (Baltim) . Mar 2003;82(2):106-18. doi:10.1097/00005792-200303000-000052. VanderVeer EA, Torbiak RP, Prebtani AP, Warkentin TE. Spontaneous heparin-induced thrombocytopenia syndrome presenting as bilateral adrenal infarction after knee arthroplasty. BMJ Case Rep . Dec 29 2019;12(12)doi:10.1136/bcr-2019-2327693. Leyendecker P, Ritter S, Riou M, et al. Acute adrenal infarction as an incidental CT finding and a potential prognosis factor in severe SARS-CoV-2 infection: a retrospective cohort analysis on 219 patients.Eur Radiol . Feb 2021;31(2):895-900. doi:10.1007/s00330-020-07226-54. Hada Y, Yamada A, Kobayashi T, et al. Bilateral Adrenal Infarction that Developed in Latent Essential Thrombocythemia. Intern Med . Jun 21 2023;doi:10.2169/internalmedicine.1947-235. Iemura T, Mano C, Oba A, et al. [Essential thrombocythemia accompanied by adrenal infarction]. Rinsho Ketsueki . 2019;60(2):106-111. doi:10.11406/rinketsu.60.1066. Palomo L, Meggendorfer M, Hutter S, et al. Molecular landscape and clonal architecture of adult myelodysplastic/myeloproliferative neoplasms. Blood . Oct 15 2020;136(16):1851-1862. doi:10.1182/blood.20190042297. Gerke MB, Christodoulou I, Karantanos T. Definitions, Biology, and Current Therapeutic Landscape of Myelodysplastic/Myeloproliferative Neoplasms. Cancers (Basel) . Jul 27 2023;15(15)doi:10.3390/cancers151538158. DiNardo CD, Daver N, Jain N, et al. Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy.Leukemia . Apr 2014;28(4):958-61. doi:10.1038/leu.2014.89. Luque Paz D, Kralovics R, Skoda RC. Genetic basis and molecular profiling in myeloproliferative neoplasms. Blood . Apr 20 2023;141(16):1909-1921. doi:10.1182/blood.202201757810. Agha A, Bateman H, Sterrett A, Valeriano-Marcet J. Myelodysplasia and malignancy-associated vasculitis. Curr Rheumatol Rep . Dec 2012;14(6):526-31. doi:10.1007/s11926-012-0281-311. Komura A, Meguri Y, Matsubara C, et al. [Myelodysplastic syndrome with der (1;7)(q10;p10) complicated with eosinophilia and organizing pneumonia]. Rinsho Ketsueki . 2023;64(7):619-625. doi:10.11406/rinketsu.64.61912. Kurosawa S, Shimomura Y, Tachibana T, et al. Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic/Myeloproliferative Neoplasms-Unclassifiable: A Retrospective Nationwide Study of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant . Sep 2020;26(9):1607-1611. doi:10.1016/j.bbmt.2020.05.01313. Perner F, Perner C, Ernst T, Heidel FH. Roles of JAK2 in aging, inflammation, hematopoiesis and malignant Transformation. Cells . Aug 8 2019;8(8)doi:10.3390/cells808085414. Gupta N, Edelmann B, Schnoeder TM, et al. JAK2-V617F activates β1-integrin-mediated adhesion of granulocytes to vascular cell adhesion molecule 1. Leukemia . May 2017;31(5):1223-1226. doi:10.1038/leu.2017.2615. Edelmann B, Gupta N, Schnoeder TM, et al. JAK2-V617F promotes venous thrombosis through β1/β2 integrin activation. J Clin Invest . Oct 1 2018;128(10):4359-4371. doi:10.1172/jci9031216. Guy A, Gourdou-Latyszenok V, Le Lay N, et al. Vascular endothelial cell expression of JAK2(V617F) is sufficient to promote a pro-thrombotic state due to increased P-selectin expression. Haematologica . Jan 2019;104(1):70-81. doi:10.3324/haematol.2018.19532117. Misaka T, Kimishima Y, Yokokawa T, Ikeda K, Takeishi Y. Clonal hematopoiesis and cardiovascular diseases: role of JAK2V617F. J Cardiol . Jan 2023;81(1):3-9. doi:10.1016/j.jjcc.2022.02.00118. Yokokawa T, Misaka T, Kimishima Y, et al. Clonal hematopoiesis and JAK2V617F mutations in patients with cardiovascular disease. JACC CardioOncol . Mar 2021;3(1):134-136. doi:10.1016/j.jaccao.2021.01.00119. Hoshino Y, Manaka K, Sato J, et al. Recurrent bilateral adrenal infarction with myelodysplastic/myeloproliferative neoplasm-unclassifiable (MDS/MPN-U): a case report. BMC Endocr Disord . Jun 5 2023;23(1):128. doi:10.1186/s12902-023-01384-520. Lockett HA, Hamilton-Wood C, Vaidya B. Addison’s disease due to bilateral adrenal infarction in a patient with myelodysplastic Syndrome.Eur J GEN Med . 2011;8:72-74.21. Nathan DI, Feld J, El Jamal SM, Mascarenhas J, Tremblay D. Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis: Ringing in a new future. Leuk Res . Apr 2022;115:106820. doi:10.1016/j.leukres.2022.10682022. Hirata R, Tago M, Yamashita S, et al. Acute abdominal pain due to atypical bilateral adrenal infarction in acute myeloid leukemia with alterations related to myelodysplasia: A case report. Clin Case Rep . Oct 2023;11(10):e7925. doi:10.1002/ccr3.792523. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol . Dec 2020;95(12):1599-1613. doi:10.1002/ajh.2600824. Michiels JJ, Berneman Z, Schroyens W, Krestin GP. Bilateral adrenal swelling as a cause of chest, back, and upper abdominal pain in essential thrombocythemia and polycythemia vera is due to microvascular ischemic thrombosis rather than to hemorrhage. Ann Hematol . Dec 2002;81(12):691-4. doi:10.1007/s00277-002-0500-525. Awada H, Voso MT, Guglielmelli P, Gurnari C. Essential thrombocythemia and acquired von Willebrand syndrome: The shadowlands between thrombosis and bleeding. Cancers (Basel) . Jun 30 2020;12(7)doi:10.3390/cancers1207174626. Al-Kali A, Abou Hussein AK, Patnaik M, et al. Hypomethylating agents (HMAs) effect on myelodysplastic/myeloproliferative neoplasm unclassifiable (MDS/MPN-U): single institution experience. Leuk Lymphoma . Nov 2018;59(11):2737-2739. doi:10.1080/10428194.2018.143670527. Wang Q, Dai HP, Liu DD, et al. Efficacy of ruxolitinib in a patient with myelodysplastic/myeloproliferative neoplasm unclassifiable and co-mutated JAK2, SF3B1 and TP53. Leuk Res Rep . 2020;14:100229. doi:10.1016/j.lrr.2020.100229Figure legendsFigure 1. Contrast-enhanced CT showing development (A) and improvement of (B) left adrenal infarction. Contrast-enhanced CT showing development (C) and improvement (D) of right adrenal infarction.A) The arrow shows left adrenal hypertrophy and non-contrast-enhanced areas, and arrowheads show increased lipid concentrations and fluid retention around the left adrenal gland. The patient was diagnosed with left adrenal infarction. B) The left adrenal infarction improved. C) The arrow indicates mild hypertrophy of the right adrenal gland. He was diagnosed with a right adrenal infarction. D) The right adrenal infarction improved.Figure 2. Clinical course of adrenal infarction withJAK2 V617F-positive MDS/MPN-U with der(1;7)(p10;q10).Plt, platelet; Eo, eosinophil; vWF:Rco, von Willebrand Factor ristocetin cofactor activity;U, unit; Lt, left; Rt, right; AI, adrenal infarction; CVT, cerebral venous thrombosis; AMT, aortic mural thrombosis. BMA, bone marrow aspiration; BMB, bone marrow biopsy

pooneh tabibi

and 2 more

1 INTRODUCTIONHyper IgD Syndrome (HIDS) is a rare autosomal recessive autoinflammatory condition, determined by recurrent febrile attacks associated with lymphadenopathy, arthralgia, diarrhea, abdominal pain, and skin rash (1, 2). This disorder was first described in 1984 by Jos van der Meer(3).This disease has an early onset, generally in infancy, and febrile crises recur at varying intervals. Fever flares have a sudden onset and last approximately 4 to 6 days. An attack begins with chills, and patients often complain of weakness, headache, nausea, and diarrhea (1, 4). The hallmark characteristic of the syndrome is the presence of recurrent episodes of fever and chills, often accompanied by skin rashes (5). HIDS is caused by a mutation in the mevalonate kinase (MVK) gene, which results in a lack of mevalonate kinase enzyme activity (6, 7). Mevalonate kinase is a key enzyme in isoprenoid biosynthesis and is involved in a wide range of essential cellular processes and the synthesis of cholesterol (8).According to our current knowledge of the genetics and pathophysiology of HIDS, the diagnosis can be made in a patient with frequent episodes of fever and the usual findings associated with recording mutations in MVK or high levels of mevalonic acid, a substrate of mevalonate kinase, in the urine of patients during attacks (9). Whereas before the discovery of the MVK gene as the cause of HIDS, the presence of high serum IgD levels was necessary for the diagnosis of HIDS (10). Today, the importance of increased IgD without genetic or biochemical findings remains uncertain (9).Early diagnosis and treatment of HIDS patients is momentous, because it prevents irreversible organ damage and improves the quality of life of patients (11). Management of HIDS focuses primarily on symptomatic relief of febrile episodes and prevention of complications. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered as first-line treatment for pain and fever associated with HIDS episodes. In some patients, immunomodulatory therapy may be recommended to help control the frequency and severity of episodes (12, 13).In this case report, we presented a girl with a long history of fever episodes and skin manifestations, in whom a mutation in the MVK gene could be identified.

Majani Edward

and 3 more

Mounting evidence reveals a captivating connection between oral health and cardiovascular health, prompting a surge in scientific curiosity and potential solutions for reducing global cardiovascular disease burden. This paper delves into this intricate relationship, highlighting the prevalence of oral diseases and their association with various systemic conditions. Studies exploring the potential link between poor oral hygiene, particularly periodontal disease, and cardiovascular illnesses like heart attack, stroke, and heart failure are examined. While the precise causal mechanisms remain under investigation, potential explanations involving chronic inflammation, shared risk factors, and even genetic susceptibilities are discussed. Despite the lack of definitive proof that treating gum disease directly prevents heart problems, the robust correlation necessitates prioritizing good oral hygiene practices. Regular brushing, flossing, and dental checkups are emphasized as preventive measures against periodontal disease and its potential contribution to cardiovascular risks. Addressing shared risk factors like diabetes and smoking further strengthens the protective shield against both oral and heart health concerns.The paper underscores the importance of public health initiatives promoting oral hygiene awareness, particularly among vulnerable populations facing limited access to dental care. Additionally, the crucial role of ongoing research in elucidating the exact mechanisms linking oral and cardiovascular health is highlighted, paving the way for future development of targeted interventions and personalized prevention strategies. In conclusion, while the mysteries surrounding the precise cause-and-effect relationship between oral and cardiovascular health persist, the compelling evidence presented demands a proactive approach. Prioritizing good oral hygiene, addressing shared risk factors, and advocating for accessible dental care stand as powerful tools in our collective fight against these prevalent health challenges.

Dietmar Kültz

and 9 more

Botryllus schlosseri, is a model marine invertebrate for studying immunity, regeneration, and stress-induced evolution. Conditions for validating its predicted proteome were optimized using nanoElute® 2 deep-coverage LCMS, revealing up to 4,930 protein groups and 20,984 unique peptides per sample. Spectral libraries were generated and filtered to remove interferences, low-quality transitions, and only retain proteins with >3 unique peptides. The resulting DIA assay library enabled label-free quantitation of 3,426 protein groups represented by 22,593 unique peptides. Quantitative comparisons of a laboratory-raised with two field-collected populations revealed (1) a more unique proteome in the laboratory-raised population, and (2) proteins with high/low individual variabilities in each population. DNA repair/replication, ion transport, and intracellular signaling processes were unique in laboratory-cultured colonies. Spliceosome and Wnt signaling proteins were the least variable (highly functionally constrained) in all populations. In conclusion, we present the first colonial tunicate’s deep quantitative proteome analysis, identifying functional protein clusters associated with laboratory conditions, different habitats, and strong versus relaxed abundance constraints. These results empower research on B. schlosseri with proteomics resources and enable quantitative molecular phenotyping of changes associated with transfer from in situ to ex situ and from in vivo to in vitro culture conditions.

Manisha Yadav

and 1 more

Background: Fetal cardiac rhythm disruptions pose significant challenges to prenatal and postnatal well-being. These disruptions, encompassing various arrhythmias, necessitate timely diagnosis and precise management. Transabdominal fetal echocardiography has become a crucial diagnostic tool for evaluating fetal arrhythmias, enabling tailored interventions. Objectives: This retrospective study aims to examine 40 cases of fetal arrhythmias at our institution, shedding light on common abnormalities, diagnostic intricacies, and therapeutic strategies. Methods: A seven-year retrospective analysis was conducted at a tertiary-level hospital in South India. Cases with sustained fetal arrhythmias were reviewed, considering gestational age, types of arrhythmias, associated anomalies, and maternal factors. The diagnostic process involved transabdominal fetal echocardiography, emphasizing M-Mode and pulsed wave Doppler measurements. Results: Fetal bradyarrhythmias were predominant (57.5%, 23/40), with complete heart blocks being a primary cause. Hydrops was observed in 20% (8/40) of cases. Structural cardiac anomalies were present in 27.5%(11/40) of cases, with maternal antibody positivity noted in 22.5% (9/40). Management varied, including intrauterine and postnatal interventions based on the gestational period, severity of rhythm disturbance, and structural abnormalities. Few ectopic cases exhibited spontaneous regression. Fetal tachyarrhythmias(20%; 8/40) included supraventricular tachycardia (62.5%; 5/8), atrial flutter (12.5%, 1/8), junctional ectopic tachycardia (12.5%, 1/8), and ventricular tachycardia (12.5%, 1/8). Combined digoxin and flecainide showed success, especially in hydrops-associated cases. Conclusion: This study provides insights into the diverse presentations, diagnostic challenges, and therapeutic approaches in managing fetal arrhythmias. The findings underscore the critical role of accurate prenatal diagnosis for tailored therapeutic interventions. While advancements have been made, persistent challenges necessitate ongoing innovation. Call for further research to refine treatment strategies and collaboration among multidisciplinary teams remains paramount for these uncommon conditions.

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Karma Norbu

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Introduction: Scrub typhus is a neglected life threatening acute febrile illness caused by bacteria Orientia tsutsugamushi and it is a vector-borne zoonotic disease. In 2009, scrub typhus outbreak at Gedu has awakened Bhutan on the awareness and testing of the disease.Information and data of the study highlights the need for in depth surveillance, awareness among prescribers and initiate preventive measures in the country. Methods: We used retrospective descriptive study through review of laboratory registers across three health centres in Zhemgang district, south central Bhutan. The laboratories registers have been transcribed into CSV file using Microsoft excel. Variables of interest were collected from the registers and then analysed using open statistical software R, (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria.) And use of mStats package, (MyoMinnOo (2020). mStats: Epidemiological DataAnalysis. R package version 3.4.0.) Results: Of the total 922 tests prescribed for suspected scrub typhus in the three health centers in Zhemgang, only 8.2 % (n=76) were tested positive. Of these, Panbang Hospital had highest reported positive for scrub typhus with 56.6 %( n=43) followed by Yebilaptsa Hospital 35.5 %( n=27) and Zhemgang Hospital with 7.9 %( n=6). The female gender is comparably more affected as opposed to male with 57.9% (n=44) of the positive cases being female. The prevalence of scrub typhus seems to be affected by the seasonal variation as the months of Spring, Summer and Autumn together accounts for 98.7%(n=75) of total positive cases. The year 2019 noted significant scrub typhus cases accounting to 89.5 %(n=68) of the total positive cases over the two years. Conclusions:The overall tests tested positive of the scrub typhus infection within two years was 8.2%.

Selahattin Semiz

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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

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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

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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.

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