We show that models that include frequent boosts that protect against symptomatic disease can recover the fluctuations in the I/S ratio that we observe, whereas a classic model without boosting cannot. Furthermore, we show that a boosting model can recover the inverse relationship between the number of symptomatic cases and the I/S ratio observed in the PDCS. These results highlight the importance of robust dengue control efforts, as intermediate dengue control may have the potential to decrease the protective effects of boosting.

We aimed to determine the prevalence and outcome of occult infection with SARS-CoV-2 and influenza in patients presenting with myocardial infarction (MI) without COVID-19 symptoms.

We conducted an observational study from 28 June to 11 August 2020, enrolling patients admitted to the National Institute of Cardiovascular Disease Hospital, Dhaka, Bangladesh, with ST-segment elevation MI (STEMI) or non-ST-segment elevation MI who did not meet WHO criteria for suspected COVID-19. Samples were collected by nasopharyngeal swab to test for SARS-CoV-2 and influenza virus by real-time reverse transcriptase PCR. We followed up patients at 3 months (13 weeks) postadmission to record adverse cardiovascular outcomes all-cause death, new MI, heart failure and new percutaneous coronary intervention or stent thrombosis. Survival analysis was performed using the Kaplan-Meier method.

We enrolled 280 patients with MI, 79% male, mean age 54.5±11.8 years, 140 of whom were diagnosed with STEMI. We found 36 (13%) to be infected with SARS-CoV-2 and 1 with influenza. There was no significant difference between mortality rate observed among SARS-CoV-2 infected patients compared with non-infected (5 (14%) vs 26 (11%); p=0.564). A numerically shorter median time to a recurrent cardiovascular event was recorded among SARS-CoV-2 infected compared with non-infected patients (21 days, IQR 8-46 vs 27 days, IQR 7-44; p=0.378).

We found a substantial rate of occult SARS-CoV-2 infection in the studied cohort, suggesting SARS-CoV-2 may precipitate MI. Asymptomatic patients with COVID-19 admitted with MI may contribute to disease transmission and warrants widespread testing of hospital admissions.

We found a substantial rate of occult SARS-CoV-2 infection in the studied cohort, suggesting SARS-CoV-2 may precipitate MI. Asymptomatic patients with COVID-19 admitted with MI may contribute to disease transmission and warrants widespread testing of hospital admissions.

Progressive cavitating leukoencephalopathy (PCL) is thought to result from mutations in nuclear genes affecting mitochondrial function and energy metabolism. To date, mutations in two subunits of complex I,

and

, have been reported to be related to PCL.

Patients underwent clinical examinations, brain MRI, skin biopsy and muscle biopsy. Whole-genome or whole-exome sequencing was performed on the index patients from two unrelated families with PCL. The effects of the mutations were examined through complementation of the

mutation by cDNA expression.

The common clinical features of the patients in this study were recurring episodes of acute or subacute developmental regression that appeared in the first years of life, followed by gradual remissions and prolonged periods of stability. MRI showed leukoencephalopathy with multiple cavities. Three novel

missense mutations were identified in these families. Complex I deficiency was confirmed in affected individuals’ fibroblasts and a muscle biopsy. Functional and structural analyses revealed that these mutations affect the structural stability and function of the NDUFV2 protein, indicating that defective

function is responsible for the phenotypes in these individuals.

Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in

in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in

and the genotypes causative for PCL.

Here, we report the clinical presentations, neuroimaging and molecular and functional analyses of novel mutations in NDUFV2 in two sibling pairs of two Chinese families presenting with PCL. We hereby expand the knowledge on the clinical phenotypes associated with mutations in NDUFV2 and the genotypes causative for PCL.

Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 (

) confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in

in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.

Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.

PTVs in

were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in

were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in

. However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.

Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of

PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.

Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PALB2 PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.De novo missense variants in KCNH1 encoding Kv10.1 are responsible for two clinically recognisable phenotypes Temple-Baraitser syndrome (TBS) and Zimmermann-Laband syndrome (ZLS). The clinical overlap between these two syndromes suggests that they belong to a spectrum of KCNH1-related encephalopathies. Affected patients have severe intellectual disability (ID) with or without epilepsy, hypertrichosis and distinctive features such as gingival hyperplasia and nail hypoplasia/aplasia (present in 20/23 reported cases).We report a series of seven patients with ID and de novo pathogenic KCNH1 variants identified by whole-exome sequencing or an epilepsy gene panel in whom the diagnosis of TBS/ZLS had not been first considered. Four of these variants, p.(Thr294Met), p.(Ala492Asp), p.(Thr493Asn) and p.(Gly496Arg), were located in the transmembrane domains S3 and S6 of Kv10.1 and one, p.(Arg693Gln), in its C-terminal cyclic nucleotide-binding homology domain (CNBHD). Clinical reappraisal by the referring clinical geneticists confirmed the absence of the distinctive gingival and nail features of TBS/ZLS.Our study expands the phenotypical spectrum of KCNH1-related encephalopathies to individuals with an attenuated extraneurological phenotype preventing a clinical diagnosis of TBS or ZLS. This subtype may be related to recurrent substitutions of the Gly496, suggesting a genotype-phenotype correlation and, possibly, to variants in the CNBHD domain.

Pathogenic

variants are a frequent cause of developmental and epileptic encephalopathy.

We recruited 13 adults (between 18 years and 45 years of age) with

encephalopathy and reviewed their clinical, EEG, neuroimaging and treatment history.

While most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individncern.Ubiquitin protein ligase E3 component n-recognin 5 (UBR5) has been identified as an oncogene in diverse cancers; however, whether its expression was associated with radiosensitivities of non-small cell lung cancer (NSCLC) cells remains unclear. Expression levels of UBR5 in NSCLC tissues and cell lines were examined by immunohistochemical staining and western blotting. Colony formation assay, CCK-8 cell viability assay, flow cytometry, and caspase-3 activity assay were performed to evaluate the radiosensitization of UBR5 knockdown in NSCLC cells, and the underlying mechanism in vitro was also investigated. UBR5 was highly expressed in NSCLC tissues, and its high expression was associated with the poor prognosis in 50 patients with NSCLC. After X-ray irradiation, the protein expression levels of UBR5 were also increased in NSCLC cells. UBR5 inhibition enhanced the radiosensitivity of NSCLC cells by inhibiting the cell viability and inducing apoptosis. Further investigation indicated that UBR5 knockdown-mediated radiosensitization involved the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. Knockdown of UBR5 radiosensitizes NSCLC cells via the inactivation of the PI3K/AKT signal, which provided a novel therapeutic target for NSCLC radiosensitization.

To evaluate whether baseline and changes in cardiovascular health (CVH) were related to incident atrial fibrillation (AF) risk in the elderly population.

From the Korea National Health Insurance Service-Senior cohort, we included 208 598 participants without prior AF (median age 70 (IQR 66-74) years; 90 916 (43.6%) men) who underwent national health check-ups between 1 January 2005 and 31 December 2012. Using the six metrics of the American Heart Association, participants were categorised as having low, moderate and high CVH.

Over a median follow-up of 7.2 years, 7818 cases of incident AF occurred. In multivariable analysis, moderate (HR 0.90; 95% CI 0.86 to 0.94) and high (HR 0.81; 95% CI 0.73 to 0.91) CVH status at baseline were associated with a lower risk of incident AF. However, in 109 695 participants with changes in CVH between the first and second check-ups, the direction of change in CVH scores showed no consistent association with future AF incidence. In newly diagnosed participants with AF, the incidence of the composite outcome (stroke, major bleeding and all-cause death) decreased with every 1-point increase in the baseline CVH score (HR 0.94; 95% CI 0.89 to 0.99).

In the general elderly population, better baseline CVH metrics were associated with lower incident AF risk. In participants with newly diagnosed AF, better CVH was also associated with lower incidence of future composite outcomes. However, the direction of change in CVH status within 2 years showed an inconsistent influence on incident AF risk.

In the general elderly population, better baseline CVH metrics were associated with lower incident AF risk. In participants with newly diagnosed AF, better CVH was also associated with lower incidence of future composite outcomes. However, the direction of change in CVH status within 2 years showed an inconsistent influence on incident AF risk.Cardiogenic shock (CS) remains the leading cause of death in patients hospitalised with acute myocardial infarction with mortality as high as 40%-50% prior to hospital discharge. The failure of inotropic therapy to maintain adequate perfusion and to prevent irreversible end-organ failure has led to attempts to improve outcomes by mechanical circulatory support (MCS) devices. Axial flow ventricular assist devices, namely Impella, are an attractive therapeutic option due to their positive haemodynamic benefits and ease of use. Despite clear beneficial haemodynamic effects, which should significantly impact on the pathophysiology of CS, there are currently no clear data to support their use in the reduction of clinical end points such as cardiac death. This review summarises and critically evaluates the current scientific evidence for the use of axial flow ventricular assist devices and highlights gaps in our understanding. Given such gaps, a consensus multidisciplinary approach, predicated on emphasising timely diagnosis and appropriate use of MCS, is vital to ensure that the right patient is paired with the right device at the right time.

The novel coronavirus (SARS-CoV-2) is a global pandemic. The lack of protective vaccine or treatment led most of the countries to follow the flattening of the infection curve with social isolation measures. There is evidence that socioeconomic inequalities have been shaping the COVID-19 burden among low and middle-income countries. This study described what sociodemographic and socioeconomic factors were associated with the greatest risk of COVID-19 infection and mortality and how did the importance of key neighbourhood-level socioeconomic factors change over time during the early stages of the pandemic in the Rio de Janeiro municipality, Brazil.

We linked socioeconomic attributes to confirmed cases and deaths from COVID-19 and computed age-standardised incidence and mortality rates by domains such as age, gender, crowding, education, income and race/ethnicity.

The evidence suggests that although age-standardised incidence rates were higher in wealthy neighbourhoods, age-standardised mortality rates were higher in deprived areas during the first 2 months of the pandemic. The age-standardised mortality rates were also higher in males, and in areas with a predominance of people of colour, which are disproportionately represented in more vulnerable groups. The population also presented COVID-19 'rejuvenation’, that is, people became risk group younger than in developed countries.

We conclude that there is a strong health gradient for COVID-19 death risk during the early stages of the pandemic. COVID-19 cases continued to move towards the urban periphery and to more vulnerable communities, threatening the health system functioning and increasing the health gradient.

We conclude that there is a strong health gradient for COVID-19 death risk during the early stages of the pandemic. COVID-19 cases continued to move towards the urban periphery and to more vulnerable communities, threatening the health system functioning and increasing the health gradient.

Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in moderate CKD but have not been studied in kidney failure. The study objective is to determine the effectiveness and safety of prasugrel and ticagrelor in kidney failure.

This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all patients on dialysis who received a drug-eluting stent and were alive at 90 days after stent implantation. Inverse probability-weighted Cox proportional hazard models were used. Weights were estimated with propensity scores for multiple treatments.

This cohort included 6648 patients on clopidogrel, 621 on prasugrel, and 449 on ticagrelor. A total of 3279 primary composite (cardiovascular death, myocardial infarction, or stroke) and 2120 clinically relevant bleeding events were observed. The incidence of the primary composite outcome of cardiovascular death, myocardial infarction, or stroke at 12 months was similar across the three treatment groups. The21_04_02_CJN12120720.mp3.Metastasis is initiated and sustained through therapy by cancer cells with stem-like and immune-evasive properties, termed metastasis-initiating cells (MIC). Recent progress suggests that MICs result from the adoption of a normal regenerative progenitor phenotype by malignant cells, a phenotype with intrinsic programs to survive the stresses of the metastatic process, undergo epithelial-mesenchymal transitions, enter slow-cycling states for dormancy, evade immune surveillance, establish supportive interactions with organ-specific niches, and co-opt systemic factors for growth and recurrence after therapy. Mechanistic understanding of the molecular mediators of MIC phenotypes and host tissue ecosystems could yield cancer therapeutics to improve patient outcomes. SIGNIFICANCE Understanding the origins, traits, and vulnerabilities of progenitor cancer cells with the capacity to initiate metastasis in distant organs, and the host microenvironments that support the ability of these cells to evade immune surveillance and regenerate the tumor, is critical for developing strategies to improve the prevention and treatment of advanced cancer. Leveraging recent progress in our understanding of the metastatic process, here we review the nature of MICs and their ecosystems and offer a perspective on how this knowledge is informing innovative treatments of metastatic cancers.Human tumors are composed of diverse malignant and nonmalignant cells, generating a complex ecosystem that governs tumor biology and response to treatments. Recent technological advances have enabled the characterization of tumors at single-cell resolution, providing a compelling strategy to dissect their intricate biology. Here we describe recent developments in single-cell expression profiling and the studies applying them in clinical settings. We highlight some of the powerful insights gleaned from these studies for tumor classification, stem cell programs, tumor microenvironment, metastasis, and response to targeted and immune therapies. SIGNIFICANCE Intratumor heterogeneity (ITH) has been a major barrier to our understanding of cancer. Single-cell genomics is leading a revolution in our ability to systematically dissect ITH. In this review, we focus on single-cell expression profiling and lessons learned in key aspects of human tumor biology.Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due to the critical roles of the TME in regulating tumor progression and modulating response to standard-of-care therapies. Here, we summarize the current knowledge regarding the most advanced TME-directed therapies, which have either been clinically approved or are currently being evaluated in trials, including immunotherapies, antiangiogenic drugs, and treatments directed against cancer-associated fibroblasts and the extracellular matrix. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field. SIGNIFICANCE This review provides a comprehensive analysis of the current therapies targeting the TME, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials.Artificial intelligence (AI) is rapidly reshaping cancer research and personalized clinical care. Availability of high-dimensionality datasets coupled with advances in high-performance computing, as well as innovative deep learning architectures, has led to an explosion of AI use in various aspects of oncology research. These applications range from detection and classification of cancer, to molecular characterization of tumors and their microenvironment, to drug discovery and repurposing, to predicting treatment outcomes for patients. As these advances start penetrating the clinic, we foresee a shifting paradigm in cancer care becoming strongly driven by AI. SIGNIFICANCE AI has the potential to dramatically affect nearly all aspects of oncology-from enhancing diagnosis to personalizing treatment and discovering novel anticancer drugs. Here, we review the recent enormous progress in the application of AI to oncology, highlight limitations and pitfalls, and chart a path for adoption of AI in the cancer clinic.Resistance to anticancer therapies includes primary resistance, usually related to lack of target dependency or presence of additional targets, and secondary resistance, mostly driven by adaptation of the cancer cell to the selection pressure of treatment. Resistance to targeted therapy is frequently acquired, driven by on-target, bypass alterations, or cellular plasticity. Resistance to immunotherapy is often primary, orchestrated by sophisticated tumor-host-microenvironment interactions, but could also occur after initial efficacy, mostly when only partial responses are obtained. Here, we provide an overview of resistance to tumor and immune-targeted therapies and discuss challenges of overcoming resistance, and current and future directions of development. SIGNIFICANCE A better and earlier identification of cancer-resistance mechanisms could avoid the use of ineffective drugs in patients not responding to therapy and provide the rationale for the administration of personalized drug associations. A clear description of the molecular interplayers is a prerequisite to the development of novel and dedicated anticancer drugs. Finally, the implementation of such cancer molecular and immunologic explorations in prospective clinical trials could de-risk the demonstration of more effective anticancer strategies in randomized registration trials, and bring us closer to the promise of cure.Over the past 10 years, circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) have received enormous attention as new biomarkers and subjects of translational research. Although both biomarkers are already used in numerous clinical trials, their clinical utility is still under investigation with promising first results. Clinical applications include early cancer detection, improved cancer staging, early detection of relapse, real-time monitoring of therapeutic efficacy, and detection of therapeutic targets and resistance mechanisms. Here, we propose a conceptual framework of CTC and ctDNA assays and point out current challenges of CTC and ctDNA research, which might structure this dynamic field of translational cancer research. SIGNIFICANCE The analysis of blood for CTCs or cell-free nucleic acids called „liquid biopsy” has opened new avenues for cancer diagnostics, including early detection of tumors, improved risk assessment and staging, as well as early detection of relapse and monitoring of tumor evolution in the context of cancer therapies.Immune checkpoint therapy (ICT) can provide durable clinical responses and improve overall survival. However, only subsets of patients with specific tumor types respond to ICT. Thus, significant challenges remain, including understanding pathways of resistance, optimizing patient selection, improving management of immune-related adverse events, and identifying rational therapeutic combinations. These challenges will need a focused approach encompassing both clinical and basic research, with the integration of reverse translational studies. This integrated approach will lead to identification of potential targets for subsequent clinical trials, which will guide decisions as we develop novel combination strategies to maximize efficacy and minimize toxicities for patients. SIGNIFICANCE ICTs induce durable antitumor responses for subsets of patients with cancer. Recent evidence suggests that rational combinatorial strategies can improve response by overcoming primary and adaptive resistance mechanisms, although these may carry an increased risk of immune-mediated toxicities. This review surveys the current understanding of mechanisms of response and resistance to ICTs and active areas of investigation, and proposes a path forward to improving efficacy and minimizing toxicities through better patient selection and rational combinations.Clinical trials represent a fulcrum for oncology drug discovery and development to bring safe and effective medicines to patients in a timely manner. Clinical trials have shifted from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to become adaptively designed and biomarker-driven evaluations of molecularly targeted agents and immune therapies in selected patient subsets. This review will discuss the scientific, methodological, practical, and patient-focused considerations to transform clinical trials. A call to action is proposed to establish the framework for next-generation clinical trials that strikes an optimal balance of operational efficiency, scientific impact, and value to patients. SIGNIFICANCE The future of cancer clinical trials requires a framework that can efficiently transform scientific discoveries to clinical utility through applications of innovative technologies and dynamic design methodologies. Next-generation clinical trials will offer individualized strategies which ultimately contribute to globalized knowledge and collective learning, through the joint efforts of all key stakeholders including investigators and patients.Technology advancement and the courage to challenge dogma have been key elements that have continuously shifted druggability limits. We illustrate this notion with several recent cancer drug-discovery examples, while also giving an outlook on the opportunities offered by newer modalities such as chemically induced proximity and direct targeting of RNA. Treatment resistance is a major impediment to the goal of durable efficacy and cure, but the confluence of new biological insights, novel drug modalities, and drug combinations is predicted to enable transformative progress in this decade and beyond.The upcoming decade of precision medicine for cancer is moving from the translation of specific genetic findings into clinically relevant improvement to the qualitative analyses of the genomic and immune tumor microenvironment, for an integrated treatment strategy in both metastatic and early disease.Advances in genomic science have transformed our ability to interrogate cancer, revealing biases that drive disparities in minority populations. Cancer disparities research engages diverse ethnic group inclusion as a matter of rigor, to address underrepresentation in genomic data sources, and has led to groundbreaking work, enhancing our understanding of tumor biology.Cancer models have helped solve many mysteries of cancer research, and are poised to bring our understanding to the next level as we dissect the relevance of cancer-associated alleles and heterocellular interactions. However, the ability of cancer models to correctly identify new therapeutic methods has been less fruitful, and a reconsideration of model designs and model applications should help develop more effective approaches for patients.In the next 10 years, gene-engineered T-cell therapies have the potential to provide broad benefit for the treatment of patients with cancer. Advances in immunology, molecular biology, and bioengineering allow the design of gene-engineered T cells that actively target metastatic lesions, specifically recognize and kill cancer cells, and maintain long-term immunologic memory.

The quality of ethics consults is notoriously difficult to measure. Survey-based assessments cannot capture nuances of consultations. To address this gap, we conducted interviews with health professionals who requested ethics consults during the initial phase of the COVID-19 pandemic.

Healthcare professionals requesting ethics consultation between March 2020 and May 2020 at a tertiary academic medical centre were eligible to participate. We asked participants to comment on the consults they called and thematically analysed responses to identify features associated with optimal quality consultations.

Of 14 healthcare providers, 8 (57%) were women and professions were as follows 11 (79%) medical doctors, 1 (7%) social worker, 1 (7%) physician assistant and 1 (7%) nurse practitioner. Two aspects of quality emerged satisfaction and value. Themes within the domain of satisfaction included responsiveness of the ethics consultant, willingness to consult, institutional role of the ethics service and identifyingas implications for ethics consultation services more broadly. Ethics consultation-emphasising both the process and outcome-created valuable moral spaces, promoting thoughtful and ethical responses to dilemmas in patient care. Future assessments should incorporate patient and family/surrogate perspectives and explore the domain of education as an additional quality measure.Health research ethics (HRE) training programmes are being developed and implemented globally, often with a goal of increasing local capacity to assure ethical conduct in health-related research. Yet what it means for there to be sufficient HRE capacity is not well-defined, and there is currently no consensus on outcomes that HRE training programmes should collectively intend to achieve. Without defining the expected outcomes, meaningful evaluation of individual participants and programmes is challenging. In this article, we briefly describe the evolution of formal education in HRE, articulate the need for a framework to define outcomes for HRE training programmes, and provide guidance for developing HRE competency frameworks that define outcomes suited to their contexts. We detail critical questions for developing HRE competency frameworks using a six-step process (1) define the purposes, intended uses and scope of the framework; (2) describe the context in which practice occurs; (3) gather data using a variety of methods to inform the competency framework; (4) translate the data into competencies that can be used in educational programmes; (5) report on the competency development process and results and (6) evaluate and update the competency framework. We suggest that competency frameworks should be feasible to develop using this process, and such efforts promise to contribute to programmatic advancement.This paper considers the proposal to pay people to get vaccinated against the SARS-CoV-2 virus. The first section introduces arguments against the proposal, including less intrusive alternatives, unequal effects on populations and economic conditions that render payment more difficult to refuse. The second section considers arguments favouring payment, including arguments appealing to health equity, consistency, being worth the cost, respect for autonomy, good citizenship, the ends justifying the means and the threat of mutant strains. The third section spotlights long-term and short-term best practices that can build trust and reduce 'vaccine hesitancy’ better than payment. The paper concludes that people who, for a variety of reasons, are reluctant to vaccinate should be treated like adults, not children. Despite the urgency of getting shots into arms, we should set our sights on the long-term goals of strong relationships and healthy communities.

SLE displays large clinical heterogeneity that beyond genetic factors may be determined by environmental exposures. In this Danish nationwide study, we aimed to determine if clinical subsets of SLE were associated with smoking history.

At each of six participating centres, incident or prevalent inpatients and outpatients with SLE were consecutively included. Manifestations forming the basis of SLE classification were registered in an electronic chart system. Patients also provided questionnaire-based data on environmental exposures, including smoking history. Hierarchical cluster analysis was conducted to determine and characterise subsets of patients with similar traits of disease manifestations. Levels of smoking exposure by pack-years were correlated to the identified SLE subsets, as well as discrete SLE manifestations.

The cohort consisted of 485 patients (88% women and 92% Caucasian) with SLE of which 51% were ever smokers. Common disease manifestations comprised non-erosive arthritis (81%), malar ssociations with smoking history.This is a report from the European Society of Gynaecological Oncology State-of-the-Art Virtual Meeting held December 14-16, 2020. The unique 3-day conference offered comprehensive state-of-the-art summaries on the major advances in the treatment of different types of gynecological cancers. Sessions opened with a case presentation followed by a keynote lecture and interactive debates with opinion leaders in the field. The speakers also presented scientific reviews on the clinical trial landscape in collaboration with the European Network of Gynecological Oncological Trial (ENGOT) groups. In addition, the new ESGO-ESRTO-ESP endometrial cancer guidelines were officially presented in public. This paper describes the key information and latest studies that were presented for the first time at the conference.Methylophiopogonanone A (MOA), an abundant homoisoflavonoid bearing a methylenedioxyphenyl moiety, is one of the major constituents in the Chinese herb Ophiopogon japonicas This work aims to assess the inhibitory potentials of MOA against cytochrome P450 enzymes and to decipher the molecular mechanisms for P450 inhibition by MOA. The results showed that MOA concentration-dependently inhibited CYP1A, 2C8, 2C9, 2C19, and 3A in human liver microsomes (HLMs) in a reversible way, with IC50 values varying from 1.06 to 3.43 μM. By contrast, MOA time-, concentration-, and NADPH-dependently inhibited CYP2D6 and CYP2E1, along with KI and kinact values of 207 µM and 0.07 minute-1 for CYP2D6, as well as 20.9 µM and 0.03 minutes-1 for CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in an HLM incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate. Additionally, the potential risks of herb-drug interactions triggered by MOA or MOA-related products were also predicted. Collectively, our findings verify that MOA is a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A but acts as an inactivator of CYP2D6 and CYP2E1. SIGNIFICANCE STATEMENT Methylophiopogonanone A (MOA), an abundant homoisoflavonoid isolated from the Chinese herb Ophiopogon japonicas, is a reversible inhibitor of CYP1A, 2C8, 2C9, 2C19, and 3A but acts as an inactivator of CYP2D6 and CYP2E1. Further investigations demonstrated that a quinone metabolite of MOA could be trapped by glutathione in a human liver microsome incubation system, and CYP2D6, 1A2, and 2E1 were the major contributors to catalyze the metabolic activation of MOA to the corresponding O-quinone intermediate.Sodium dichloroacetate (DCA) is an investigational drug that shows promise in the treatment of acquired and congenital mitochondrial diseases, including myocardial ischemia and failure. DCA increases glucose utilization and decreases lactate production, so it may also have clinical utility in reducing lactic acidosis during labor. In the current study, we tested the ability of DCA to cross the placenta and be measured in fetal blood after intravenous administration to pregnant ewes during late gestation and labor. Sustained administration of DCA to the mother over 72 hours achieved pharmacologically active levels of DCA in the fetus and decreased fetal plasma lactate concentrations. Multicompartmental pharmacokinetics modeling indicated that drug metabolism in the fetal and maternal compartments is best described by the DCA inhibiting lactate production in both compartments, consistent with our finding that the hepatic expression of the DCA-metabolizing enzyme glutathione transferase zeta1 was decreased in the ewes and their fetuses exposed to the drug. We provide the first evidence that DCA can cross the placental compartment to enter the fetal circulation and inhibit its own hepatic metabolism in the fetus, leading to increased DCA concentrations and decreased fetal plasma lactate concentrations during its parenteral administration to the mother. SIGNIFICANCE STATEMENT This study was the first to administer sodium dichloroacetate (DCA) to pregnant animals (sheep). It showed that DCA administered to the mother can cross the placental barrier and achieve concentrations in fetus sufficient to decrease fetal lactate concentrations. Consistent with findings reported in other species, DCA-mediated inhibition of glutathione transferase zeta1 was also observed in ewes, resulting in reduced metabolism of DCA after prolonged administration.Time-dependent inhibition (TDI) of CYP3A is an important mechanism underlying numerous drug-drug interactions (DDIs), and assays to measure this are done to support early drug research efforts. However, measuring TDI of CYP3A in human liver microsomes (HLMs) frequently yields overestimations of clinical DDIs and thus can lead to the erroneous elimination of many viable drug candidates from further development. In this investigation, 50 drugs were evaluated for TDI in HLMs and suspended human hepatocytes (HHEPs) to define appropriate boundary lines for the TDI parameter rate constant for inhibition (kobs) at a concentration of 30 µM. In HLMs, a kobs value of 0.002 minute-1 was statistically distinguishable from control; however, many drugs show kobs greater than this but do not cause DDI. A boundary line defined by the drug with the lowest kobs that causes a DDI (diltiazem) was established at 0.01 minute-1 Even with this boundary, of the 33 drugs above this value, only 61% cause a DDI (true positive rate). A corresponding analysis was done using HHEPs; kobs of 0.0015 minute-1 was statistically distinguishable from control, and the boundary was established at 0.006 minute-1 Values of kobs in HHEPs were almost always lower than those in HLMs. These findings offer a practical guide to the use of TDI data for CYP3A in early drug-discovery research. SIGNIFICANCE STATEMENT Time-dependent inhibition of CYP3A is responsible for many drug interactions. In vitro assays are employed in early drug research to identify and remove CYP3A time-dependent inhibitors from further consideration. This analysis demonstrates suitable boundaries for inactivation rates to better delineate drug candidates for their potential to cause clinically significant drug interactions.Complement factor H (CFH) is the major inhibitor of the alternative pathway of the complement system and is structurally related to beta2-glycoprotein I, which itself is known to bind to ligands, including coagulation factor XI (FXI). We observed reduced complement activation when FXI activation was inhibited in a baboon model of lethal systemic inflammation, suggesting cross-talk between FXI and the complement cascade. It is unknown whether FXI or its activated form, activated FXI (FXIa), directly interacts with the complement system. We explored whether FXI could interact with and inhibit the activity of CFH. We found that FXIa neutralized CFH by cleavage of the R341/R342 bonds. FXIa reduced the capacity of CFH to enhance the cleavage of C3b by factor I and the decay of C3bBb. The binding of CFH to human endothelial cells was also reduced after incubating CFH with FXIa. The addition of either short- or long-chain polyphosphate enhanced the capacity of FXIa to cleave CFH. FXIa also cleaved CFH that was present on endothelial cells and in the secretome from blood platelets. The generation of FXIa in plasma induced the cleavage of CFH. Moreover, FXIa reduced the cleavage of C3b by factor I in serum. Conversely, we observed that CFH inhibited FXI activation by either thrombin or FXIIa. Our study provides, to our knowledge, a novel molecular link between the contact pathway of coagulation and the complement system. These results suggest that FXIa generation enhances the activity of the complement system and thus may potentiate the immune response.CD4+ T cells enable the critical B cell humoral immune protection afforded by most effective vaccines. We and others have recently identified an alternative source of help for B cells in mice, invariant NK T (iNKT) cells. iNKT cells are innate glycolipid-specific T cells restricted to the nonpolymorphic Ag-presenting molecule CD1d. As such, iNKT cells respond to glycolipids equally well in all people, making them an appealing adjuvant for universal vaccines. We tested the potential for the iNKT glycolipid agonist, α-galactosylceramide (αGC), to serve as an adjuvant for a known human protective epitope by creating a nanoparticle that delivers αGC plus antigenic polysaccharides from Streptococcus pneumoniae αGC-embedded nanoparticles activate murine iNKT cells and B cells in vitro and in vivo, facilitate significant dose sparing, and avoid iNKT anergy. Nanoparticles containing αGC plus S. pneumoniae polysaccharides elicits robust IgM and IgG in vivo and protect mice against lethal systemic S. pneumoniae However, codelivery of αGC via nanoparticles actually eliminated Ab protection elicited by a T-independent S. pneumoniae vaccine. This is consistent with previous studies demonstrating iNKT cell help for B cells following acute activation, but negative regulation of B cells during chronic inflammation. αGC-containing nanoparticles represent a viable platform for broadly efficacious vaccines against deadly human pathogens, but their potential for eliminating B cells under certain conditions suggests further clarity on iNKT cell interactions with B cells is warranted.Macrophages play an important role in the pathogenesis of systemic lupus erythematosus-associated diffuse alveolar hemorrhage (DAH). The immunomodulation of macrophage responses might be a potential approach for the prevention and treatment of DAH. Erythropoietin (EPO) could regulate macrophage bioactivities by binding to the EPO receptor expressing on macrophages. This study assessed the effects of EPO on DAH protection using an immune-mediated DAH murine model with macrophages as the major contributor. A DAH murine model was established in female C57BL/6 mice by an i.p. injection of pristane. We found that EPO administration alleviates DAH by reducing pulmonary macrophages recruitment and promoting phenotype switch toward M2 macrophages in vivo. EPO drove macrophages to the anti-inflammatory phenotype in the primary murine bone marrow-derived macrophages and macrophages cell line RAW 264.7 with LPS, IFN-γ, and IL-4 in vitro. Moreover, EPO treatment increases the expression of EPOR and decreases the expression of miR-494-3p, resulting in increased phosphorylation of JAK2 and STAT3. In conclusion, EPO can be a potential therapeutic agent in DAH by reducing cell apoptosis and regulating macrophage polarization through the EPOR/JAK2/STAT3 axis. Further studies are also needed to validate the direct target of miR-494-3p in regulating JAK2/STAT3 signaling transduction.HSV-1 infection of the cornea causes a severe immunoinflammatory and vision-impairing condition called herpetic stromal keratitis (SK). The virus replication in corneal epithelium followed by neutrophil- and CD4+ T cell-mediated inflammation plays a dominant role in SK. Although previous studies demonstrate critical functions of type I IFNs (IFN-α/β) in HSV-1 infection, the role of recently discovered IFN-λ (type III IFN), specifically at the corneal mucosa, is poorly defined. Our study using a mouse model of SK pathogenesis shows that HSV-1 infection induces a robust IFN-λ response compared with type I IFN production at the corneal mucosal surface. However, the normal progression of SK indicates that the endogenous IFN responses are insufficient to suppress HSV-1-induced corneal pathology. Therefore, we examined the therapeutic efficacy of exogenous rIFN-λ during SK progression. Our results show that rIFN-λ therapy suppressed inflammatory cell infiltration in the cornea and significantly reduced the SK pathologic condition. Early rIFN-λ treatment significantly reduced neutrophil and macrophage infiltration, and IL-6, IL-1β, and CXCL-1 production in the cornea. Notably, the virucidal capacity of neutrophils and macrophages measured by reactive oxygen species generation was not affected. Similarly, ex vivo rIFN-λ treatment of HSV-1-stimulated bone marrow-derived neutrophils significantly promoted IFN-stimulated genes without affecting reactive oxygen species production. Collectively, our data demonstrate that exogenous topical rIFN-λ treatment during the development and progression of SK could represent a novel therapeutic approach to control HSV-1-induced inflammation and associated vision impairment.

Corticosteroids are a potential therapeutic agent for patients with COVID-19 pneumonia. The RECOVERY (Randomised Trials in COVID-19 Therapy) trial provided data on the mortality benefits of corticosteroids. The study aimed to determine the association between corticosteroid use on mortality and infection rates and to define subgroups who may benefit from corticosteroids in a real-world setting.

Clinical data were extracted that included demographic, laboratory data and details of the therapy, including the administration of corticosteroids, azithromycin, hydroxychloroquine, tocilizumab and anticoagulation. The primary outcome was in-hospital mortality. Secondary outcomes included intensive care unit (ICU) admission and invasive mechanical ventilation. Outcomes were compared in patients who did and did not receive corticosteroids using the multivariate Cox regression model.

4313 patients were hospitalised with COVID-19 during the study period, of whom 1270 died (29.4%). When administered within the first 7 days after admission, corticosteroids were associated with reduced mortality (OR 0.73, 95% CI 0.55 to 0.97, p=0.03) and decreased transfers to the ICU (OR 0.72, 95% CI 0.47 to 1.11, p=0.02). This mortality benefit was particularly impressive in younger patients (<65 years of age), females and those with elevated inflammatory markers, defined as C reactive protein ≥150 mg/L (p≤0.05), interleukin-6 ≥20 pg/mL (p≤0.05) or D-dimer ≥2.0 µg/L (p≤0.05). Therapy was safe with similar rates of bacteraemia and fungaemia in corticosteroid-treated and non-corticosteroid-treated patients.

In patients hospitalised with COVID-19 pneumonia, corticosteroid use within the first 7 days of admission decreased mortality and ICU admissions with no associated increase in bacteraemia or fungaemia.

In patients hospitalised with COVID-19 pneumonia, corticosteroid use within the first 7 days of admission decreased mortality and ICU admissions with no associated increase in bacteraemia or fungaemia.A 64-year-old woman was acutely referred to the Department of Otorhinolaryngology, Head and Neck Surgery, Aalborg University Hospital due to rapidly progressing neck swelling, fever and dysphagia. Clinical examination revealed submental swelling, trismus and laryngeal inflammation. A contrast-enhanced CT scan showed infection in the deep neck spaces with multiple abscesses. The patient underwent acute surgery and antimicrobial therapy was initiated and she was transferred to an intensive care unit. Three additional surgical procedures were needed before sufficient drainage was achieved. There was growth of different oral commensals from four separate pus aspirates, while Eggerthia catenaformis was cultured in all samples. Due to the extent of the infection, the patient stayed in the intensive care unit for 16 days, but recovered completely due to adequate surgery and antimicrobial therapy for 4 weeks. Here we present the third reported case of a severe deep neck space infection with multiple abscesses due to E. catenaformis.Pulmonary alveolar proteinosis (PAP) is a rare pulmonary condition which leads to excessive accumulation of proteinaceous material within the alveoli. Idiopathic pulmonary haemosiderosis (IPH) is another orphan lung disease and results in recurrent alveolar haemorrhage. This case study describes a case of these two rare pathologies occurring together. A man in his 50s presented with a 6-week history of haemoptysis and worsening dyspnoea. A CT scan of the thorax showed multifocal, bilateral ground glass opacification with a wide differential diagnosis. Full autoantibody screen including myositis panel and coeliac screen were negative. Bronchoscopy with bronchoalveolar lavage and tissue from a transbronchial lung cryobiopsy were non-diagnostic. Tissue from a video-assisted thoracoscopic surgery biopsy confirmed a diagnosis of PAP with IPH as a second separate pathology. The association of IPH and PAP has not previously been described. We discuss these conditions and postulate how and if they may be related.Chronic otorrhoea from a tympanic membrane perforation is common. We present the case of a patient who had already received seemingly adequate treatment for his condition in the past. Yet, he presented to our outpatient clinic with worsening otalgia and otorrhoea, progressive hearing loss and a new tympanic membrane perforation. After a thorough otological evaluation, the patient’s medical history and the histological specimen from a previous operation were reviewed. The findings met the diagnostic criteria of eosinophilic otitis media. After treatment with topic triamcinolone through the perforated tympanic membrane, the patient’s otalgia subsided, hearing levels were improved and the size of the tympanic membrane perforation decreased.A young male in his early 30s presented to us with increasing swelling at the umbilicus, and an umbilical hernia was diagnosed. At laparoscopic intraperitoneal onlay mesh (IPOM) repair, an unexpected finding of a thin innocuous-looking fibrous film over the small bowel was noted. This finding presented a dilemma as to the probable pathology of this material, and a decision had to be made on whether laparoscopic IPOM could be continued. It was prudently decided to abandon the plan of placing a mesh intraperitoneally and an open repair of the umbilical hernia was done. In retrospect this was a wise decision, as, after 7 months he had to have a laparotomy for intestinal obstruction, when the classic thick fibrous encapsulating abdominal cocoon was seen. Hence here we have followed the evolution of the abdominal cocoon from its original asymptomatic phase to the classic encapsulating sclerosing peritonitis with probably laparoscopic gas insufflation being the precipitating factor.