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One of the most exceptional adaptations to extreme drought is found in the sister group to tetrapods, the lungfishes (Dipnoi), which can aestivate inside a mucus cocoon for multiple years at reduced metabolic rates with complete cessation of ingestion and excretion. However, the function of the cocoon tissue is not fully understood. Here we developed a new more natural laboratory protocol for inducing aestivation in the West African lungfish, Protopterus annectens, and investigated the structure and function of the cocoon. We used electron microscopy and imaging of live tissue-stains to confirm that the inner and outer layers of the paper-thin cocoon are composed primarily of living cells. However, we also repeatedly observed extensive bacterial and fungal growth covering the cocoon and found no evidence of anti-microbial activity in vitro against E. coli for the cocoon tissue in this species. This classroom discovery-based research, performed during a course-based undergraduate research experience course (CURE), provides a robust laboratory protocol for investigating aestivation and calls into the question the function of this bizarre vertebrate adaptation., Competing Interests: Conflict of Interest The authors declare no conflict of interest.

In order to understand the coordinated proteome changes associated with differentiation of a cultured cell pluripotency model, protein expression changes induced by treatment of NT2 embryonal carcinoma cells with retinoic acid were monitored by mass spectrometry. The relative levels of over 5000 proteins were mapped across distinct cell fractions. Analysis of the chromatin fraction revealed major abundance changes among chromatin proteins and epigenetic pathways between the pluripotent and differentiated states. Protein complexes associated with epigenetic regulation of gene expression, chromatin remodelling (e.g., SWI/SNF, NuRD) and histone-modifying enzymes (e.g., Polycomb, MLL) were found to be extensively regulated. We therefore investigated histone modifications before and after differentiation, observing changes in the global levels of lysine acetylation and methylation across the four canonical histone protein families, as well as among variant histones. We identified the set of proteins with affinity to peptides housing the histone marks H3K4me3 and H3K27me3, and found increased levels of chromatin-associated histone H3 tail trimming following differentiation that correlated with increased expression levels of cathepsin proteases. We further found that inhibition of cathepsins B and D reduces histone H3 clipping. Overall, the work reveals a global reorganization of the cell proteome congruent with differentiation, highlighting the key role of multiple epigenetic pathways, and demonstrating a direct link between cathepsin B and D activity and histone modification.

Compostable materials constitute roughly half of waste generated globally, but only 5% of waste is actually processed through composting, suggesting that expanding compost programs may be an effective way to process waste. Compostable waste, if properly collected and processed, has value-added end use options including: residential and park landscaping, remediation of brownfield sites, and as growing media in urban agriculture (UA). Since 2001, our lab has partnered with The Food Project, a non-profit focused on youth leadership development through urban farming. From 2006 to 2022 we collected compost materials that were delivered to the farm from a variety of local sources and analyzed a suite of biogeochemical properties including lead (Pb) concentrations, organic carbon, and grain size distribution. Pb concentrations of Boston's municipal compost always exceeded the current City of San Francisco soil and compost purchase standard (80 μg/g). In 2012 Boston's composting program was halted when it exceeded the 400 μg/g Environmental Protection Agency's Pb in soil benchmark. Urban Pb is geomobile and must be managed to minimize resuspension and transport of fines whose Pb concentration is often elevated compared to bulk compost. Consequently, urban farmers have to source lower Pb compost from suburban suppliers at significantly greater cost. Over a 15 year period and through several city vendor contracts, Pb concentrations in municipal compost remain at levels that warrant continued surveillance and risk assessment., Competing Interests: The authors declare no conflicts of interest relevant to this study., (© 2024 The Authors. GeoHealth published by Wiley Periodicals LLC on behalf of American Geophysical Union.)

Background: The impact of strategies for rapid diagnostic screening of Candida auris on hospital operations has not been previously characterized. We describe the implementation of in-house polymerase chain reaction (PCR) testing on admission for screening of colonization with C. auris, associated process improvements, and financial impact., Methods: This study was conducted across an integrated health system. Patients were tested based on risk factors for C. auris carriage. Pre-intervention, the PCR was sent out to a reference laboratory, and postintervention was performed in-house. Changes in the incidence rates (IRs) of C. auris present on admission (CA-POA) and C. auris hospital-onset fungemia (CA-HOF) were assessed using interrupted time series analysis. The economic impact on isolation and testing costs was calculated., Results: Postintervention, the IR of CA-POA doubled (IRR, 2.57; 95% CI, 1.16-5.69; P = .02) compared with the pre-intervention period. The baseline rate of CA-HOF was increasing monthly by 14% (95% CI, 1.05-1.24; P = .002) pre-intervention, while during the postintervention period there was a change in slope with a monthly decrease in IR of 13% (95% CI, 0.80-0.99; P = .02). The median turnaround time (TAT) of the results (interquartile range) was reduced from 11 (8-14) days to 2 (1-3) days. Savings were estimated to be between $772 513.10 and $3 730 480.26., Conclusions: By performing in-house PCR for screening of C. auris colonization on admission, we found a doubling of CA-POA rates, a subsequent decrease in CA-HOF rates, reduced TAT for PCR results, and more efficient use of infection control measures. In-house testing was cost-effective in a setting of relatively high prevalence among individuals with known risk factors., Competing Interests: Potential conflicts of interest. None of the authors declares any potential conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Surgical intervention is an important treatment modality for advanced rheumatic heart disease (RHD). This study aimed to describe patient characteristics and outcomes from cardiac surgery for RHD in patients referred to the only tertiary paediatric hospital in Western Australia., Methods: An analysis of patient characteristics and cardiac surgery outcomes in patients with RHD was undertaken, using data from clinical cardiac databases, medical notes, and correspondence from rural outreach clinics., Results: 29 patients (59% female, 97% Aboriginal, Māori or Pacific Islander) underwent 41 valve interventions over 34 cardiac surgeries for RHD between 2000-2018. Median age at first surgery was 12.2 (range 4-16) years. Severe mitral regurgitation (MR) was the most common indication for primary surgery (62%), followed by mixed mitral regurgitation/aortic regurgitation (21%) and severe aortic regurgitation (17%). Mitral valve repair was the most common valve intervention (56%). Two patients had mitral valve replacement (MVR) at first operation, two patients had MVR at second operation and two had MVR at third operation. There was no early mortality. One patient required early (<30 days) reoperation for aortic valve repair failure. Two patients had late reoperations at 3.3 and 6.1 months after the first procedure for MR. Four (14%) patients experienced documented ARF recurrences. Late mortality occurred in 3 (10%) patients, all due to cardiac causes. On last follow-up echocardiogram 5 patients (17%) had moderate MR and none had severe MR., Conclusions: This is the first study to describe characteristics and outcomes in WA paediatric patients having surgery for RHD. Outcomes are comparable to similar studies, with favourable long-term survival., Competing Interests: Conflicts of Interest There are no conflicts of interest to disclose. Competing Interest Statement No competing interests., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Objectives: To assess the mid-term performance of CardioCel for the repair of congenital heart defects., Methods: Data were retrospectively collected from databases and hospital records in 3 congenital cardiac surgery centres in Australia. Kaplan-Meier curves and log-rank tests were used to test for associations between patient age, gender, patch type and site of implantation. Multivariable Cox regression was used to test whether any specific implantation site was associated with reintervention risk, after adjusting for age group, gender and patch type., Results: A total of 1184 CardioCel patches were implanted in 752 patients under the age of 18 years. Median age at implant was 12 months [interquartile range (IQR) 3.6-84]. Median follow-up was 2.1 years (IQR 0.6-4.6). Probability of freedom from CardioCel-related reintervention was 93% [95% confidence interval (CI) 91-95] at 1 year, 91% (95% CI 88-93) at 3 years and 88% (95% CI 85-91) at 5 years, respectively. On multivariable regression analysis, aortic valve repair had a higher incidence of reintervention [hazard ratio (HR) = 7.15, P = 0.008] compared to other sites. The probability of reintervention was higher in neonates (HR = 6.71, P = 0.0007), especially when used for augmentation of the pulmonary arteries (HR = 14.38, P = 0.029), as compared to other age groups., Conclusions: CardioCel can be used for the repair of a variety of congenital heart defects. In our study, in patients receiving a CardioCel implant, reinterventions were higher when CardioCel was used to augment the pulmonary arteries in neonates and for aortic valve repair as compared to other sites., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Discrete central endovascular pulmonary arterial lesions raise clinical concern for malignancy such as primary pulmonary artery sarcoma. We present a case of a female in her late teens who had an obstructive mid right pulmonary artery lesion found on follow-up imaging 15 years after Tetralogy of Fallot repair. The lesion was in the vicinity of a previously ligated Blalock-Taussig shunt and causing right PA stenosis with delayed perfusion to the right lung, and a flow-related distal left PA aneurysm. The lesion was excised and confirmed histologically to be inflammatory in nature. Intraoperative microbiology demonstrated growth of the Kytococcus species, and she was managed with 6 weeks of intravenous antibiotics, with a full recovery., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rheumatic heart disease (RHD) is the most common form of acquired heart disease worldwide. In RHD, volume loading from mitral regurgitation leads to left ventricular (LV) dilatation, increased wall stress, and ultimately LV dysfunction. Improved understanding of LV dynamics may contribute to refined timing of intervention. We aimed to characterize and compare left ventricular remodelling between rheumatic heart disease (RHD) severity groups by way of serial echocardiographic assessment of volumes and function in children., Methods: Children with RHD referred to Perth Children's Hospital (formally Princess Margaret Hospital) (1987-2020) were reviewed. Patients with longitudinal pre-operative echocardiograms at diagnosis, approximately 12 months and at most recent follow-up, were included and stratified into RHD severity groups. Left ventricular (LV) echocardiographic parameters were assessed. Adjusted linear mixed effect models were used to compare interval changes., Results: 146 patients (median age 10 years, IQR 6-14 years) with available longitudinal echocardiograms were analysed. Eighty-five (58.2%) patients had mild, 33 (22.6%) moderate and 28 (19.2%) severe RHD at diagnosis. Mean duration of follow-up was 4.6 years from the initial diagnosis. Severe RHD patients had significantly increased end-systolic volumes (ESV) and end-diastolic volumes (EDV) compared to mild/moderate groups at diagnosis (severe versus mild EDV mean difference 27.05 ml/m 2 , p < 0.001, severe versus moderate EDV mean difference 14.95 ml/m 2 , p = 0.006). Mild and moderate groups experienced no significant progression of changes in volume measures. In severe RHD, LV dilatation worsened over time. All groups had preserved cardiac function., Conclusions: In mild and moderate RHD, the lack of progression of valvular regurgitation and ventricular dimensions suggest a stable longer-term course. Significant LV remodelling occurred at baseline in severe RHD with progression of LV dilatation over time. LV function was preserved across all groups. Our findings may guide clinicians in deciding the frequency and timing of follow-up and may be of clinical utility during further reiterations of the Australia and New Zealand RHD Guidelines., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Despite growing awareness of neurodevelopmental impairments in children with congenital heart disease (CHD), there is a lack of large, longitudinal, population-based cohorts. Little is known about the contemporary neurodevelopmental profile and the emergence of specific impairments in children with CHD entering school. The performance of standardised screening tools to predict neurodevelopmental outcomes at school age in this high-risk population remains poorly understood. The NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) trial randomised 1371 children <2 years of age, investigating the effect of gaseous nitric oxide applied into the cardiopulmonary bypass oxygenator during heart surgery. The NITRIC follow-up study will follow this cohort annually until 5 years of age to assess outcomes related to cognition and socioemotional behaviour at school entry, identify risk factors for adverse outcomes and evaluate the performance of screening tools., Methods and Analysis: Approximately 1150 children from the NITRIC trial across five sites in Australia and New Zealand will be eligible. Follow-up assessments will occur in two stages: (1) annual online screening of global neurodevelopment, socioemotional and executive functioning, health-related quality of life and parenting stress at ages 2-5 years; and (2) face-to-face assessment at age 5 years assessing intellectual ability, attention, memory and processing speed; fine motor skills; language and communication; and socioemotional outcomes. Cognitive and socioemotional outcomes and trajectories of neurodevelopment will be described and demographic, clinical, genetic and environmental predictors of these outcomes will be explored., Ethics and Dissemination: Ethical approval has been obtained from the Children's Health Queensland (HREC/20/QCHQ/70626) and New Zealand Health and Disability (21/NTA/83) Research Ethics Committees. The findings will inform the development of clinical decision tools and improve preventative and intervention strategies in children with CHD. Dissemination of the outcomes of the study is expected via publications in peer-reviewed journals, presentation at conferences, via social media, podcast presentations and medical education resources, and through CHD family partners., Trial Registration Number: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry as 'Gene Expression to Predict Long-Term Neurodevelopmental Outcome in Infants from the NITric oxide during cardiopulmonary bypass to improve Recovery in Infants with Congenital heart defects (NITRIC) Study - A Multicentre Prospective Trial'., Trial Registration: ACTRN12621000904875., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Planning for surgical intervention for patients with complex congenital heart disease requires a comprehensive understanding of the individual's anatomy. Cinematic rendering (CR) is a novel technique that purportedly builds on traditional volume rendering (VR) by converting CT image data into clearly defined 3D reconstructions through the stimulation and propagation of light rays. The purpose of this study was to compare CR to VR for the understanding of critical anatomy in unoperated complex congenital heart disease., Methods: In this retrospective study, CT data sets from 20 sequential scanned cases of unoperated paediatric patients with complex congenital heart disease were included. 3D images were produced at standardised and selected orientations, matched for both VR and CR. The images were then independently reviewed by two cardiologists, two radiologists and two surgeons for overall image quality, depth perception and the visualisation of surgically relevant anatomy, the coronary arteries and the pulmonary veins., Results: Cinematic rendering demonstrated significantly superior image quality, depth perception and visualisation of surgically relevant anatomy than VR., Conclusion: Cinematic rendering is a novel 3D CT-rendering technique that may surpass the traditionally used volumetric rendering technique in the provision of actionable pre-operative anatomical detail for complex congenital heart disease., (© 2023 The Royal Australian and New Zealand College of Radiologists.)

Background: Vascular rings, including right aortic arch with aberrant left subclavian artery (RAA-ALSCA), double aortic arch (DAA) and pulmonary artery sling (PAS), are congenital anomalies that may cause airway and oesophageal compression. As prenatal detection has improved, literature comparing clinical outcomes of antenatally versus postnatally diagnosed cases continues to emerge. The aim is to define a statewide tertiary paediatric institution's clinical profile and outcomes of prenatal versus postnatally diagnosed isolated vascular rings., Method: A retrospective single-centre review of isolated RAA-ALSCA, DAA and PAS between 1 January 1999 and 31 December 2020 was conducted. Clinical characteristics, surgical and follow-up information were collected. Antenatal and postnatally diagnosed groups were compared., Results: Out of 123 cases diagnosed with isolated vascular rings, 98 (79.7%) cases had RAA-ALSCA, 21 (17.1%) with DAA, 4 (3.3%) with PAS. The antenatal detection rate was 73.6% in the past decade; 20.3% had a genetic disorder, of which 48% had 22q11.21 microdeletion. Of prenatally diagnosed cases, 31.3% developed symptoms, commonly stridor and dysphagia, at a median age of 2.0 months (IQR 0.0-3.0), compared to a median age of diagnosis for the postnatal cohort of 9 months (IQR 1.0-40.7). Postnatally diagnosed cases were more likely to present with symptoms, primarily respiratory distress, than prenatally diagnosed cases (p=0.006). Fifty-nine (59) cases (50% antenatally diagnosed) required vascular ring division; 6.8% had residual symptoms following surgery., Discussion: Antenatal diagnosis has improved and leads to better parental awareness and more timely, appropriate intervention. Postnatally diagnosed patients were older, more likely to be symptomatic, underwent more investigations and were commenced on more medications for symptom management prior to diagnosis. One in five cases of isolated vascular ring anomalies carried a genetic diagnosis, which has important implications on prenatal counselling and genetic testing., (Copyright © 2023 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Cancer immunotherapy is shifting paradigms in cancer care. T cells are an indispensable component of an effective antitumor immunity and durable clinical responses. However, the complexity of the tumor microenvironment (TME), which consists of a wide range of cells that exert positive and negative effects on T cell function and survival, makes achieving robust and durable T cell responses difficult. Additionally, tumor biology, structural and architectural features, intratumoral nutrients and soluble factors, and metabolism impact the quality of the T cell response. We discuss the factors and interactions that modulate T cell function and survive in the TME that affect the overall quality of the antitumor immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mani, Andrews and Obeng.)

Introduction: This single-centre retrospective study explores demographics and outcomes of patients who underwent a modified Blalock-Taussig shunt (MBTS) over a 22-year period. The predominant surgical approach in this study is a lateral thoracotomy, in contrast to a midline sternotomy. Risks and outcomes of this approach are compared with national and international literature., Materials and Methods: Demographic, anatomical, clinical, surgical and outcome data of all patients who underwent a MBTS between 2000 and 2022 were collected and analysed, excluding Norwood procedures, which are not performed at this institution. Short- and long-term morbidity and mortality is described., Results: Over the 22-year study period, 185 MBTS were performed in 162 patients, at a median age of 16 days (interquartile range [IQR] 5-59 days) and weight of 3.47 kg (IQR 3-4.25 kg, minimum weight 2 kg). Of these, 79% of patients had a biventricular circulation. Cardiac diagnoses included both univentricular and biventricular anatomy; tetralogy of Fallot (TOF) (36%), transposition of the great arteries/ventricular septal defect/pulmonary stenosis (TGA/VSD/PS) (11%), pulmonary atresia with intact ventricular septum (PA/IVS) (23%), pulmonary atresia with ventricular septal defect (PA/VSD) (14%), other (16%). The most common size of MBTS was 4 mm (71%); 93% were performed via a lateral thoracotomy. There were 47 cases of major operative morbidity, which did not differ significantly with cardiac diagnosis. Overall all-cause mortality was 13.5%. Early operative mortality was 4.3%. Mortality varied with cardiac diagnosis, 6% with TOF and 19% with PA/IVS. There was no era effect on mortality rates, however a lower frequency of major morbidity (23% vs 7%, p=0.03) was observed in the most recent third of the study period. Risk factors for shunt reintervention or mortality included weight <2.5 kg (HR=2.79 [1.37, 5.65], p=0.005), and pre- (HR=3.31 [1.86, 5.9], p<0.001) or postoperative lactic acidosis (HR=1.37 [1.25,1.5], p<0.001). These rates are comparable to those in the literature, with the predominant approach a midline sternotomy., Conclusion: Mortality rates and risk factors for adverse outcomes are comparable to those previously reported for both univentricular and biventricular groups. These results highlight that outcomes of MBTS performed via lateral thoracotomy are comparable to those by midline sternotomy as reported in the literature. Operating via the lateral approach may be advantageous as it avoids the complications of a midline sternotomy., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Anxiety disorders are the most common mental health concerns affecting Canadian children and adolescents. The Canadian Paediatric Society has developed two position statements that summarize current evidence regarding the diagnosis and management of anxiety disorders. Both statements offer evidence-informed guidance to support paediatric health care providers (HCPs) making decisions around the care of children and adolescents with these conditions. The objectives of Part 1, which focuses on assessment and diagnosis, are to: (1) review the epidemiology and clinical characteristics of anxiety disorders and (2) describe a process for assessment of anxiety disorders. Specific topics are reviewed, including prevalence, differential diagnosis, co-occurring conditions, and the process of assessment. Approaches are offered for standardized screening, history-taking, and observation. Associated features and indicators that distinguish anxiety disorders from developmentally appropriate fears, worries, and anxious feelings are considered. Note that when the word 'parent' (singular or plural) is used, it includes any primary caregiver and every configuration of family., (© Canadian Paediatric Society 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Anxiety disorders are the most common mental health concerns affecting Canadian children and adolescents. The Canadian Paediatric Society has developed two position statements that summarize current evidence regarding the diagnosis and management of anxiety disorders. Both statements offer evidence-informed guidance to support paediatric health care providers (HCPs) making decisions around the care of children and adolescents with these conditions. The objectives of Part 2, which focuses on management, are to: (1) review the evidence and context for a range of clinical approaches that combine behavioural and pharmacological interventions to effectively address impairment, (2) describe the roles of education and psychotherapy in the prevention and treatment of anxiety disorders, and (3) outline the use of pharmacotherapy, with side effects and risks. Recommendations for managing anxiety are based on current guidelines, review of the literature, and expert consensus. Note that when the word 'parent' (singular or plural) is used, it includes any primary caregiver and every configuration of family., (© Canadian Paediatric Society 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Assessment and feedback is a common implementation strategy to improve healthcare provider fidelity to clinical guidelines. For immunization guidelines, fidelity is often measured with doses administered during eligible visits. Adding a patient refusal measure captures provider fidelity more completely (i.e., all instances of a provider recommending a vaccine, resulting in vaccination or refusal) and enables providers to track patient vaccine hesitancy patterns. However, many electronic health record (EHR) systems have no structured field to document multiple instances of refusals for specific vaccines, and existing billing codes for refusal are not vaccine specific. This study assessed the feasibility of a novel method for refusal documentation used in a study focused on human papillomavirus (HPV) vaccine., Methods: An observational, descriptive-comparative, mixed-methods study design was used to conduct secondary data analysis from an implementation-effectiveness trial. The parent trial compared coach-based versus web-based practice facilitation, including assessment and feedback, to increase HPV vaccination in 21 community-based private pediatric practices. Providers were instructed to document initial HPV vaccine refusals in the EHR's immunization forms and subsequent refusals using dummy procedure codes, for use in assessment and feedback reports. This analysis examined adoption and maintenance of the refusal documentation method during eligible well visits, identified barriers and facilitators to documentation and described demographic patterns in patient refusals., Results: Seven practices adopted the refusal documentation method. Among adopter practices, documented refusals started at 2.4% of eligible well visits at baseline, increased to 14.2% at the start of implementation, peaked at 24.0%, then declined to 18.8%. Barriers to refusal documentation included low prioritization, workflow integration and complication of the billing process. Facilitators included high motivation, documentation instructions and coach support. Among adopter practices, odds of refusing HPV vaccine were 25% higher for patients aged 15-17 years versus 11-12 years, and 18% lower for males versus females., Conclusions: We demonstrated the value of patient refusal documentation for measuring HPV vaccination guideline fidelity and ways that it can be improved in future research. Creation of vaccine-specific refusal billing codes or EHR adaptations to enable documenting multiple instances of specific vaccine refusals would facilitate consistent refusal documentation. Trial Registration NCT03399396 Registered in ClinicalTrials.gov on 1/16/2018., (© 2022. The Author(s).)

Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes., (© 2022. The Author(s).)

Solid organ transplant (SOT) recipients are at high risk for severe disease with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Emerging variants of concern have disproportionately affected this population. Data on severity and outcomes with the Omicron variant in SOT recipients are limited. Thus we conducted this single-center, retrospective cohort study of SOT recipients diagnosed with SARS-CoV-2 infection from December 18, 2021 to January 18, 2022, when prevalence of the Omicron variant was more than 80%-95% in the community. Univariate and multivariate logistic regression analysis was performed to identify risk factors for hospital admission. We identified 166 SOT patients: 112 (67.5%) kidney, 22 (13.3%) liver, 10 (6.0%) lung, seven (4.2%) heart, and 15 (9.0%) combined transplants. SARS-CoV-2 vaccine series was completed in 59 (35.5%) recipients. Ninety-nine (59.6%) and 13 (7.8%) recipients received casirivimab/imdevimab and sotrovimab, respectively. Fifty-three (32%) recipients required hospital admission, of which 19 (35.8%) required intensive care unit level of care. Median follow-up was 50 (interquartile range, 25-59) days, with mortality reported in six (3.6%) patients. Risk factors identified for hospital admission were African American race (p < .001, odds ratio [OR] 4.00, 95% confidence interval [CI] 1.84-8.70), history of coronary artery disease (p = .031, OR 3.50, 95% CI 1.12-10.87), and maintenance immunosuppression with corticosteroids (p = .048, OR 2.00, 95% CI 1.01-4.00). In conclusion, contrary to that in the general population, we found a higher hospital admission rate in SOT recipients with omicron variant infection. Further studies to investigate the efficacy of newer treatments are necessary, even as outcomes continue to improve., (© 2022 Wiley Periodicals LLC.)

Background: Breakthrough infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) has occurred in populations with high vaccination rates., Methods: In a longitudinal cohort study, pre-breakthrough infection sera for Omicron breakthroughs (n = 12) were analyzed. Assays utilized include a laboratory-developed solid phase binding assay to recombinant spike protein, a commercial assay to the S1 domain of the spike protein calibrated to the World Health Organization (WHO) standard, and a commercial solid-phase surrogate neutralizing activity (SNA) assay. All assays employed spike protein preparations based on sequences from the Wuhan-Hu-1 strain., Results: Pre-breakthrough binding antibody titers ranged from 1:800 to 1:51,200 for the laboratory-developed binding assay, which correlated well and agreed quantitatively with the commercial spike S1 domain WHO calibrated assay. SNA was detected in 10/12 (83%) samples., Conclusions: Neither high binding titers nor SNA were markers of protection from Omicron infection/re-infection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In this paper, we address the controversies of epidemic control planning by developing a novel Simulation-Deep Reinforcement Learning (SiRL) model. COVID-19 reminded constituents over the world that government decision-making could change their lives. During the COVID-19 pandemic, governments were concerned with reducing fatalities as the virus spread but at the same time also maintaining a flowing economy. In this paper, we address epidemic decision-making regarding the interventions necessary given of the epidemic based on the purpose of the decision-maker. Further, we intend to compare different vaccination strategies, such as age-based and random vaccination, to shine a light on who should get priority in the vaccination process. To address these issues, we propose a simulation-deep reinforcement learning (DRL) framework. This framework is composed of an agent-based simulation model and a governor DRL agent that can enforce interventions in the agent-based simulation environment. Computational results show that our DRL agent can learn effective strategies and suggest optimal actions given a specific epidemic situation based on a multi-objective reward structure. We compare our DRL agent's decisions to government interventions at different periods of time during the COVID-19 pandemic. Our results suggest that more could have been done to control the epidemic. In addition, if a random vaccination strategy that allows super-spreaders to get vaccinated early were used, infections would have been reduced by 32% at the expense of 4% more deaths. We also show that a behavioral change of fully quarantining 10% of the risky individuals and using a random vaccination strategy leads to a reduction of the death toll by 14% and 27% compared to the age-based vaccination strategy that was implemented and the New Jersey reported data, respectively. We have also demonstrated the flexibility of our approach to be applied to other locations by validating and applying our model to the COVID-19 case in the state of Kansas., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Summary: Missense mutations that change protein stability are strongly associated with human genetic disease. With the recent availability of predicted structures for all human proteins generated using the AlphaFold2 prediction model, genome-wide assessment of the stability effects of genetic variation can, for the first time, be easily performed. This facilitates the interrogation of personal genetic variation for potentially pathogenic effects through the application of stability metrics. Here, we present a novel tool to prioritize variants predicted to cause strong instability in essential proteins. We show that by filtering by ΔΔG values and then prioritizing by StabilitySort Z-scores, we are able to more accurately discriminate pathogenic, protein-destabilizing mutations from population variation, compared with other mutation effect predictors., Availability and Implementation: StabilitySort is available as a web service (https://www.stabilitysort.org), as a data download for integration with other tools (https://www.stabilitysort.org/download) or can be deployed as a standalone system from source code (https://gitlab.com/baaron/StabilitySort)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims/hypothesis: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets., Methods: We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets., Results: The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m 2 ) and DKD (microalbuminuria or worse) phenotype (p=9.8×10 -9 ; although not withstanding correction for multiple testing, p>9.3×10 -9 ). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p<2.7×10 -6 ). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10 -6 ). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10 -11 ). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10 -8 ] and negatively with tubulointerstitial fibrosis [p=2.0×10 -9 ], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10 -16 ], and SNX30 expression correlated positively with eGFR [p=5.8×10 -14 ] and negatively with fibrosis [p<2.0×10 -16 ])., Conclusions/interpretation: Altogether, the results point to novel genes contributing to the pathogenesis of DKD., Data Availability: The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( https://t1d.hugeamp.org/downloads.html ; https://t2d.hugeamp.org/downloads.html ; https://hugeamp.org/downloads.html )., (© 2022. The Author(s).)

An accurate and well-rounded understanding of child development is essential to optimize child functioning and health. The First Six Years Developmental Attainments chart empowers clinicians to give parenting guidance and to evaluate age-specific developmental attainment of their pediatric patients. A practical knowledge translation tool, the chart integrates a comprehensive array of developmental skill attainments, citing the range of sources from classic to current literature. It includes definitions, explanations, and examples for skills, attainment age range, percentile, and oldest age of attainment where available so that the reader can 'estimate the age' for a child's skills in each developmental sector. Sub-headings focus the clinician's search for skills. This updated office reference is of critical use when clinicians guide parents with strategies suited to the child's level of developmental skills. With levels of evidence described, this clinical tool could be used for future national or international studies to develop strategies most useful for clinicians, trainees of different levels, and parents supporting child development., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Adult growth hormone deficiency (AGHD) is a rare and serious condition associated with significant morbidity, including reduced quality of life, and is underdiagnosed and often missed in patients. Although the onset of AGHD can occur in either childhood or adulthood, adult-onset AGHD is more difficult to identify as it lacks the auxologic signs caused by GHD during childhood, includes symptoms that tend to be nonspecific, and lacks reliable, simple biomarker testing options. A panel of 9 patients with AGHD (3 with childhood onset; 6 with adult onset) was assembled to share their first-hand experiences, to help reveal important areas of need, increase health literacy, and to raise awareness about GHD among patients, caregivers, and healthcare practitioners. Interviews with patients yielded valuable insights from the patient perspective to supplement prior knowledge about AGHD symptomatology, biomarker testing, and treatment outcomes. Some patients described a burdensome and ineffective screening process that sometimes included many visits to different specialists, repeated rounds of biomarker testing, and, in some cases, excessive delays in AGHD diagnosis. All patients expressed frustration with insurance companies that often resist and/or delay treatment authorization and reimbursement and frequently require additional testing to verify the diagnosis, often leading to treatment gaps. These findings emphasize the necessity of more efficient identification and screening of patients with possible AGHD, better recognition by clinicians and insurance providers of the importance of sustained GH replacement therapy during adulthood, and better patient support for accessing and maintaining uninterrupted GH replacement therapy for patients with documented AGHD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: Standard-of-care treatment for patients with newly diagnosed glioblastoma (GBM) after surgery or biopsy includes concurrent chemoradiation followed by maintenance temozolomide (TMZ) with tumor treating fields (TTFields). Preclinical studies suggest TTFields and radiotherapy work synergistically. We report the results of our trial evaluating the safety of TTFields used concurrently with chemoradiation., Methods: This is a single-arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma and a Karnofsky performance score (KPS) of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with TMZ (75 mg/m 2 daily) and TTFields (200 kHz). Maintenance therapy included TMZ and continuation of TTFields. Scalp-sparing radiation treatment was used to reduce radiation dermatitis. Radiation treatment was delivered through the TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment., Results: There were 30 patients enrolled, including 20 (66.7%) men and 10 (33.3%) women, with a median age of 58 years (range 19 to 77 years). Median KPS was 90 (range 70 to 100). A total of 12 (40%) patients received a gross total resection and 18 (60%) patients had a subtotal resection. A total of 12 (40%) patients had multifocal disease at presentation. There were 20 (66.7%) patients who had unmethylated O(6)-methylguanine-DNA-methyltransferase (MGMT) promotor status and 10 (33.3%) patients who had methylated MGMT promoter status. Median follow-up was 15.2 months (range 1.7 to 23.6 months). Skin adverse events were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. The primary end point was met; no TTFields discontinuation occurred during the evaluation period due to high grade scalp toxicity. A total of 27 (90%) patients had progression, with a median progression-free survival (PFS) of 9.3 months (95% confidence interval (CI): 8.5-11.6 months). The 1-year progression-free survival was 23% (95% CI: 12%-45%). The median overall survival (OS) was 15.8 months (95% CI: 12.5 months-infinity). The 1-year overall survival was 66% (95% CI: 51%-86%)., Conclusions: Concurrent TTFields with scalp-sparing chemoradiation is a feasible and well-tolerated treatment option with limited toxicity. A phase 3, randomized clinical trial (EF-32, clinicaltrials.gov Identifier: NCT04471844) investigating the clinical benefit of concurrent TTFields with chemoradiation treatment is currently enrolling., Clinical Trial Registration: Clinicaltrials.gov, identifier NCT03477110., Competing Interests: WS: Consulting for Brainlab, Varian, and Novocure; research funding for clinical trial from Novocure and Regeneron. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Miller, Song, Ali, Niazi, Bar-Ad, Martinez, Glass, Alnahhas, Andrews, Judy, Evans, Farrell, Werner-Wasik, Chervoneva, Ly, Palmer, Liu and Shi.)

Polysorbate 80 (PS80) functions as a dispersing agent or solubilizer in many pharmaceuticals, and as a stabilizer in biopharmaceuticals. Topical or parenteral administration of low doses of PS80 in biopharmaceuticals has been associated with mild allergic reactions, including local injection site reactions in humans. High doses of PS80, such as levels found in traditional Chinese herbal parenteral medicines, have been linked to systemic effects consistent with anaphylactoid-type reactions, which are characterized by the direct release of histamine from mast cells (degranulation). Nonclinical safety assessments of PS80 in vivo have mainly focused on canine model systems, a species established to be particularly sensitive to PS80. However, there is conflicting data about the dose and route of administration of PS80 required to elicit an anaphylactoid-type reaction in this model system. Therefore, studies using multiple dosing regimens in anesthetized and conscious dogs including a combination of cardiovascular data, clinical signs, and biomarkers of mast cell degranulation were conducted. An intravenous (IV) bolus of 1 mg/kg PS80 (0.25% w/v) elicited a positive anaphylactoid reaction including increased heart rate, hypotension, and clinical signs associated with anaphylactoid reactions (e.g., reddened muzzle). However, a full reaction was not observed with a subcutaneous (SC) injection of PS80 (0.25% w/v) up to 20 mg/kg and IV bolus or IV infusions up to 0.5 mg/kg. These data establish a threshold dose for eliciting an anaphylactoid reaction in canine which varies depending on the route of administration as well as the rate of PS80 infusion.

Defining reference models for population variation, and the ability to study individual deviations is essential for understanding inter-individual variability and its relation to the onset and progression of medical conditions. In this work, we assembled a reference cohort of neuroimaging data from 82 sites (N=58,836; ages 2-100) and used normative modeling to characterize lifespan trajectories of cortical thickness and subcortical volume. Models are validated against a manually quality checked subset (N=24,354) and we provide an interface for transferring to new data sources. We showcase the clinical value by applying the models to a transdiagnostic psychiatric sample (N=1985), showing they can be used to quantify variability underlying multiple disorders whilst also refining case-control inferences. These models will be augmented with additional samples and imaging modalities as they become available. This provides a common reference platform to bind results from different studies and ultimately paves the way for personalized clinical decision-making., Competing Interests: SR, CF, RD, SK, TW, MZ, PB, AW, SV, DA, LH, JB, PD, PM, RM, AS, CS, IT, ED, SC, BP, MH, SB, LH, DA, CW, LW, RZ, AM No competing interests declared, OA is a consultant for HealthLytix and received speaker's honorarium from Lundbeck and Sunovion, HR received speaker's honorarium from Lundbeck and Janssen, CB is director and shareholder of SBGNeuro Ltd, (© 2022, Rutherford et al.)

Objectives: Previous studies investigating risk factors associated with reoperation or mortality after repair of complete atrioventricular septal defect (CAVSD) often have not included sizeable cohorts undergoing modified single-patch repair. Both double patch and modified single-patch techniques have been widely used in Australia since the 1990s. Using a large multi-institutional cohort, we aimed to identify risk factors associated with reoperation or mortality following CAVSD repair., Methods: Between January 1990 and December 2015, a total of 829 patients underwent biventricular surgical repair of CAVSD in Australia at 4 centres. Patients with associated tetralogy of Fallot and other conotruncal abnormalities were excluded. Demographic details, postoperative outcomes including reoperation and survival, and associated risk factors were analysed., Results: Fifty-six patients (6.8%) required early reoperation (≤30 days) for significant left atrioventricular valve regurgitation or residual septal defects. Freedom from reoperation at 10, 15 and 20 years was 82.7%, 81.1% and 77%, respectively. Patients without Down syndrome and moderate left atrioventricular valve regurgitation on postoperative echocardiogram were found to be independent risk factors for reoperation. Operative mortality was 3.3%. Overall survival at 10, 15 and 20 years was 91.7%, 90.7% and 88.7%, respectively. Prior pulmonary artery banding was a predictor for mortality, while later surgical era (2010-2015) was associated with a reduction in mortality risk., Conclusions: Improved survival in the contemporary era is in keeping with improvements in surgical management and higher rates of primary CAVSD repair over time. The presence of residual moderate left atrioventricular valve regurgitation on postoperative echocardiography is an important factor associated with reoperation and close surveillance is essential to allow timely reintervention. Primary CAVSD repair at age <3 months should be preferenced to palliation with pulmonary artery banding due to the association of pulmonary artery banding with mortality in the long-term., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

We present a case with congenital syndromic asplenia associated with immune deficiency, glandular hypospadias and cryptorchidism. Genetic analysis identified a likely pathogenic de novo variant in NR2F2. Pathogenic NR2F2 variants have been associated with other congenital anomalies affecting the central axis, such as congenital heart disease and diaphragmatic hernia, which were not part of our patient's clinical features. The association between NR2F2 and asplenia (including glandular hypospadias and cryptorchidism) has been described in animal models and our report is the first expanding the NR2F2 clinical spectrum in humans to include asplenia., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC., Competing Interests: Declaration of interests I.S., P.S. and J.S. (in conjunction with the University of Toronto) are listed as inventors on a patent (publication number 20190091205) for the use of EMI1 (and structurally related analogues), midostaurin, gilteritinib and AZD7762 (and structurally related analogues) in the treatment of mutant EGFR-mediated non-small-cell lung cancer., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Noninvasive prenatal tests (NIPTs) detect fetal chromosomal anomalies with high clinical sensitivity and specificity. We examined the performance of a paired-end sequencing-based NIPT in the detection of genome-wide fetal chromosomal anomalies including common trisomies, sex chromosomal aneuploidies (SCA), rare autosomal aneuploidies (RAAs), and partial deletions/duplications ≥7 Mb., Methods: Frozen plasma samples from pregnant women were tested using the VeriSeq NIPT Solution v2 assay. All samples were previously tested with a laboratory-developed NIPT and had known clinical outcomes. Individuals performing the sequencing were blinded to clinical outcome data. Clinical sensitivity and specificity were determined for basic (chromosomes 21, 18, 13, X, and Y) and genome-wide screening modes., Results: Of 2335 samples that underwent genome-wide analysis, 28 did not meet QC requirements, resulting in a first-pass assay failure rate of 1.2%. Basic screening analysis, excluding known mosaics, correctly classified 130/130 trisomy 21 samples (sensitivity >99.9%, 95% confidence interval [CI] 97.1%-100%), 41/41 trisomy 18 samples (sensitivity >99.9%, 95% CI 91.4%-100%), and 26/26 trisomy 13 samples (sensitivity >99.9%, 95% CI 87.1%-100%) with 6 false-positive results; specificities ≥99.90% were reported for all 3 trisomies. Concordance for SCAs ranged from 90.5%-100%. Genome-wide screening analysis including known mosaics correctly classified 27/28 RAAs and 20/27 partial deletions/duplications with a specificity of 99.80% for both anomalies, and an overall genome-wide specificity for all anomalies of 99.34%., Conclusions: The VeriSeq NIPT Solution v2 assay enables accurate identification of fetal aneuploidy, allowing detection of genome-wide fetal chromosomal anomalies with high clinical sensitivities and specificities and a low assay failure rate.Clinical Trial Notification [CTN] identification number [ID]: CT-2018-CTN-01585-1 v1, Protocol: NIPT T05 002., (© American Association for Clinical Chemistry 2021.)

Inflammation and its timely resolution are critical to ensuring effective host defence and appropriate tissue repair after injury. Unresolved inflammation typifies many renal pathologies. The key drivers of the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. However, these are associated with undesirable side effects including immune suppression. More recently, there is growing appreciation that specialized lipid mediators [SPMs] including lipoxins promote the resolution of inflammation and endogenous repair mechanisms without compromising host defence. We discuss the pro-resolving bioactions of lipoxins and recent work that aims to harness their therapeutic potential in the context of kidney disease., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Herein we measured CD4+ T-cell responses against common cold coronaviruses (CCC) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in high-risk health care workers (HCW) and community controls. We observed higher levels of CCC-reactive T cells in SARS-CoV-2-seronegative HCW compared to community donors, consistent with potential higher occupational exposure of HCW to CCC. We further show that SARS-CoV-2 T-cell reactivity of seronegative HCW was higher than community controls and correlation between CCC and SARS-CoV-2 responses is consistent with cross-reactivity and not associated with recent in vivo activation. Surprisingly, CCC T-cell reactivity was decreased in SARS-CoV-2-infected HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses, either directly or indirectly. This result was unexpected, but consistently detected in independent cohorts derived from Miami and San Diego. CD4+ T-cell responses against common cold coronaviruses (CCC) are elevated in SARS-CoV-2 seronegative high-risk health care workers (HCW) compared to COVID-19 convalescent HCW, suggesting that exposure to SARS-CoV-2 might interfere with CCC responses and/or cross-reactivity associated with a protective effect., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A subset of individuals with type 1 diabetes mellitus (T1DM) are predisposed to developing diabetic kidney disease (DKD), the most common cause globally of end-stage kidney disease (ESKD). Emerging evidence suggests epigenetic changes in DNA methylation may have a causal role in both T1DM and DKD. The aim of this exploratory investigation was to assess differences in blood-derived DNA methylation patterns between individuals with T1DM-ESKD and individuals with long-duration T1DM but no evidence of kidney disease upon repeated testing to identify potential blood-based biomarkers. Blood-derived DNA from individuals (107 cases, 253 controls and 14 experimental controls) were bisulphite treated before DNA methylation patterns from both groups were generated and analysed using Illumina's Infinium MethylationEPIC BeadChip arrays (n = 862,927 sites). Differentially methylated CpG sites (dmCpGs) were identified (false discovery rate adjusted p ≤ × 10 -8 and fold change ± 2) by comparing methylation levels between ESKD cases and T1DM controls at single site resolution. Gene annotation and functionality was investigated to enrich and rank methylated regions associated with ESKD in T1DM., Results: Top-ranked genes within which several dmCpGs were located and supported by functional data with methylation look-ups in other cohorts include: AFF3, ARID5B, CUX1, ELMO1, FKBP5, HDAC4, ITGAL, LY9, PIM1, RUNX3, SEPTIN9 and UPF3A. Top-ranked enrichment pathways included pathways in cancer, TGF-β signalling and Th17 cell differentiation., Conclusions: Epigenetic alterations provide a dynamic link between an individual's genetic background and their environmental exposures. This robust evaluation of DNA methylation in carefully phenotyped individuals has identified biomarkers associated with ESKD, revealing several genes and implicated key pathways associated with ESKD in individuals with T1DM.

To safely re-open economies and prevent future outbreaks, rapid, frequent, point-of-need, SARS-CoV-2 diagnostic testing is necessary. However, existing field-deployable COVID-19 testing methods require the use of uncomfortable swabs and trained providers in PPE, while saliva-based methods must be transported to high complexity laboratories for testing. Here, we report the development and clinical validation of High-Performance Loop-mediated isothermal Amplification (HP-LAMP), a rapid, saliva-based, SARS-CoV-2 test with a limit of detection of 1.4 copies of virus per µl of saliva and a sensitivity and specificity with clinical samples of > 96%, on par with traditional RT-PCR based methods using swabs, but can deliver results using only a single fluid transfer step and simple heat block. Testing of 120 patient samples in 40 pools comprised of 5 patient samples each with either all negative or a single positive patient sample was 100% accurate. Thus, HP-LAMP may enable rapid and accurate results in the field using saliva, without need of a high-complexity laboratory.

Using nonlinear mathematical models and experimental data from laboratory and clinical studies, we have designed new combination therapies against COVID-19.

Acceptable palatability of an oral dosage form is crucial to patient compliance. Excipients can be utilised within a formulation to mask the bitterness of a drug. One such category is the bitter-blockers. This term is used inconsistently within the literature and has historically been used to describe any additive which alters the taste of an unpleasant compound. This review defines a bitter-blocker as a compound which interacts with the molecular pathway of bitterness at a taste-cell level and compiles data obtained from publication screening of such compounds. Here, a novel scoring system is created to assess their potential utility in a medicinal product using factors such as usability, safety, efficacy and quality of evidence to understand their taste-masking ability. Sodium acetate, sodium gluconate and adenosine 5'monophophate each have a good usability and safety profile and are generally regarded as safe and have shown evidence of bitter-blocking in human sensory panels. These compounds could offer a much needed option to taste-mask particularly aversive medicines where traditional methods alone are insufficient., (Copyright © 2020 Elsevier B.V. All rights reserved.)

When South Florida became a hot spot for COVID-19 disease in March 2020, we faced an urgent need to develop test capability to detect SARS-CoV-2 infection. We assembled a transdisciplinary team of knowledgeable and dedicated physicians, scientists, technologists, and administrators who rapidly built a multiplatform, polymerase chain reaction- and serology-based detection program, established drive-through facilities, and drafted and implemented guidelines that enabled efficient testing of our patients and employees. This process was extremely complex, due to the limited availability of needed reagents, but outreach to our research scientists and multiple diagnostic laboratory companies, and government officials enabled us to implement both Food and Drug Administration authorized and laboratory-developed testing-based testing protocols. We analyzed our workforce needs and created teams of appropriately skilled and certified workers to safely process patient samples and conduct SARS-CoV-2 testing and contact tracing. We initiated smart test ordering, interfaced all testing platforms with our electronic medical record, and went from zero testing capacity to testing hundreds of health care workers and patients daily, within 3 weeks. We believe our experience can inform the efforts of others when faced with a crisis situation., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The University of Miami entered into a management agreement with Lab Corp on May 3, 2020, with Lab Corp agreeing to provide management for a broad range of clinical laboratory tests conducted on UM in-patients. M.M. is a member of the Viracor Eurofins medical advisory board., (© The Author(s) 2020.)

Severe acute respiratory syndrome coronavirus 2 is associated with severe disease in patients with hematologic malignancy. We report a series of patients with underlying hematologic malignancy and coronavirus disease of 2019 with discrepancy between radiographic findings and molecular testing. Initial chest x-ray findings should raise suspicion in immunosuppressed patients with typical clinical presentation even with negative initial testing., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: The mechanisms of attrition of the Fontan population have been poorly characterised and it is unclear whether some of the deaths are potentially preventable. We analysed the circumstances of late death in patients with a Fontan circulation, with a special focus on identifying lesions amenable to intervention that may have contributed to the decline of their circulation., Methods: Between 1975 and 2018, a total of 105 patients from a Bi-National Registry died beyond 1 year after Fontan completion, at a median age of 18.6 (IQR 13.8-26.0) years old, 12.7 (IQR 6.0-19.3) years after Fontan completion., Results: A total of 105 patients died-63 patients (60%) with an atriopulmonary (AP) Fontan, 21 patients (20%) with a lateral tunnel (LT) and 21 patients (20%) with an extracardiac conduit (ECC). 72 patients (69%) were reviewed within 2 years preceding death, with 32% (23/72) deemed to be clinically well. Fontan circulatory failure was the most common cause of death in 42 patients (45%). Other causes of death included sudden death/arrhythmia (19%), perioperative death (12%), neurological complication (7%) and thromboembolism (7%). All patients with an LT or ECC who died from Fontan failure had at least one surgical defect that was amenable to intervention at time of death., Conclusions: Conventional clinical surveillance has been insensitive in detecting a significant proportion of patients at risk of late death. Fontan circulatory failure contributes to half of the late deaths. Patients with an LT or ECC Fontan who died with a clinical picture of circulation failure may have potentially correctable lesions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Atrioventricular valve regurgitation is known to adversely impact outcomes of single-ventricle palliation, and valve repair rarely provides long-lasting results. Closure of a atrioventricular valve can sometimes be performed, but the long-term outcomes of this manoeuvre are unknown., Methods: This retrospective study was conducted using patient data extracted from an existing bi-national, population-based registry of survivors of the Fontan procedure., Results: Between January 1975 and June 2018, 1574 patients survived to hospital discharge with an intact Fontan circulation. Of these patients, 128 with a common atrioventricular valve were excluded. Thirty-eight patients underwent closure of an atrioventricular valve, and complete follow-up data were available for 36 patients. Twenty-nine patients underwent closure of the tricuspid valve and 7 patients underwent closure of the mitral valve. Seventeen patients underwent valve closure prior to Fontan, 13 patients underwent valve closure concomitant with Fontan and 6 patients underwent valve closure post-Fontan. Valve closure was performed using a patch technique in 29 cases and with direct suture in 7 cases. At the most recent echocardiography, 33 patients had no regurgitation, 2 patients had recurrent mild regurgitation and 1 patient had no echocardiographic follow-up. Six patients required reintervention post-valve closure and 7 patients required permanent pacemaker insertion post-valve closure. Freedom from reintervention at 1, 5 and 18 years post-valve closure was 86% [95% confidence interval (CI) 76-98%], 83% (95% CI 72-96%) and 83% (95% CI 72-96%), respectively., Conclusion: Atrioventricular valve closure is an effective surgical technique in selected patients with a single ventricle providing long-lasting competency in the majority of cases., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Introduction: Timely management of sepsis has become an urgent concern among most hospitals. Institutions have been searching for unique ways to increase the quality of care and timely adherence to proven therapies. The objective of this study was to determine the impact of an Adult Code Sepsis Protocol on the rate of SEP-1 perfect score attainment (PSA) among patients who presented to the emergency department (ED) with severe sepsis or septic shock, as defined by the Centers for Medicare and Medicaid Services (CMS)., Methods: This was a retrospective, observational cohort study in a 35-bed tertiary care hospital ED from December 2016 to February 2018. Adults (≥18 years of age) who met the CMS-case definition of severe sepsis or septic shock presenting to the ED either prior to or after implementation of an Adult Code Sepsis Protocol were included., Results: The primary outcome of SEP-1 PSA, which was abstracted in an all-or-none fashion, increased from 30.7% to 71.3% (p < 0.001). Inpatient mortality was reduced from 4% to 0% (p = 0.011) after protocol implementation. Protocol initiation also resulted in a significant reduction in both time to initiation of appropriate, empiric and effective antimicrobial therapy, based on culture results by 48 and 111 min, respectively (p < 0.001). There were no significant differences in other secondary outcomes including ICU length-of-stay, readmission, or economic outcome measures., Conclusions: The addition of an Adult Code Sepsis Protocol in the ED significantly increased the rate of SEP-1 PSA, reduced inpatient mortality, and improved the time to initiation of effective antimicrobial therapy., Competing Interests: Declaration of Competing Interest Authors of this presentation have nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation., (Copyright © 2019 Elsevier Inc. All rights reserved.)