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Significant renal insufficiency is identified as a risk factor for post-transplantation mortality in pediatric heart transplant recipients. This study evaluates simultaneous heart-kidney transplantation listing outcomes compared with heart transplant for pediatric candidates with significant renal insufficiency.The United Network for Organ Sharing registry was searched for patients (January 1987 to March 2020) who were simultaneously listed for a heart-kidney transplantation or for heart transplant with significant renal insufficiency at the time of listing. Significant renal insufficiency was defined as needing dialysis or having a low estimated glomerular filtration rate (lt;40 mL/min). Survival was calculated using Kaplan-Meier analysis.A total of 427 cases were identified; 109 were listed for heart-kidney transplantation, and 318 were listed for heart transplant alone. Median time on the waitlist was 101 days (interquartile range, 28-238) for heart-kidney transplantation listings compared with 39 days (14-86) and 23.5 days (6-51) for heart transplant recipients with a low estimated glomerular filtration rate (P = .002) or on dialysis (P lt; .001), respectively. Of all heart-kidney transplantation listings, 66% (n = 71) received a transplant compared with 54% (n = 173) of heart transplantation with significant renal insufficiency (P = .005) with a mean survival of 14.6 years (12.7-16.4 years) for heart transplant without significant renal insufficiency at transplantation and 7.6 years (5.4-9.9 years) for heart transplant with significant renal insufficiency at transplantation. At 1 year after listing, 69% of heart-kidney transplantation listed recipients were alive, compared with 51% of heart transplant listed recipients (P = .029). Heart-kidney transplantation recipients had better 1-year post-transplantation survival (86%) than heart transplantation with significant renal insufficiency at transplant (66%) (P = .001). There was no significant difference in the 1- and 5-year survivals of those undergoing heart transplantation listed with significant renal insufficiency but no significant renal insufficiency at the time of transplant (89% and 78%) and heart-kidney transplantation recipients (86% and 81%; P = .436).Pediatric candidates with significant renal insufficiency listed for heart-kidney transplantation have superior waitlist and post-transplantation outcomes compared with those listed for heart transplant alone. Patients with significant renal insufficiency should be listed for heart-kidney transplantation, however; if their renal function improves significantly, heart transplant alone appears judicious.

PURPOSE Thyroid autoimmunity has been associated with differentiated thyroid cancer although multiple potential biases might have influenced the results of previous studies. METHODS We conducted a case-control study nested within the cohort of US active-duty personnel 1996-2014 to assess the association between thyroid autoimmunity, defined by serology, and thyroid cancer diagnosis. The primary exposure was thyroid peroxidase (TPO) antibody status 7-10 years before the thyroid cancer index date. We also assessed whether diagnosis of thyroid autoimmunity mediated any associations identified and if thyroid cancer features differed by autoimmunity status. RESULTS Among 451 incident cases of papillary thyroid cancer and matched controls (median age 36 years, 61.4% men), TPO antibody positivity ( v negative) 7-10 years prediagnosis was associated with thyroid cancer (odds ratio [OR] 1.90 [95% CI, 1.33 to 2.70]). Exploratory analyses suggested an increasing risk of thyroid cancer with higher TPO antibody titer (TPO antibody 550-1,399 IU/mL: OR 2.95 [95% CI, 1.37 to 6.36]; and ≥ 1,400 IU/mL: OR 3.91 [95% CI, 1.66 to 9.24]). Positive TPO antibody status remained associated with thyroid cancer after those with diagnosed autoimmunity were excluded, and the association was not mediated by diagnosis of thyroid autoimmunity. Among the cases with diagnosed autoimmunity, 58% thyroid cancers were ≤ 10 mm diameter. CONCLUSION Longstanding prior thyroid autoimmunity up to 10 years before thyroid cancer diagnosis was associated with papillary thyroid cancer risk. The results could not be fully explained by diagnosis of thyroid autoimmunity although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage.

The recent pig heart transplant in a patient at the University of Maryland Medical Center has stimulated renewed interest in the xenotransplantation of organs from genetically engineered pigs. The barriers to the use of pigs as sources of organs have largely been overcome by 2 approaches - (1) the deletion of expression of the three known pig carbohydrate xenoantigens against which humans have preformed antibodies, and (2) the transgenic introduction of human 'protective' proteins, such as complement-regulatory proteins. These gene modifications, coupled with immunosuppressive therapy based on blockade of the CD40/CD154 costimulation pathway, have resulted in survival of baboons with life-supporting pig heart grafts for almost 9 months. The initial clinical success at the University of Maryland reinforces encouraging preclinical results. It suggests that pig hearts are likely to provide an effective bridge to an allotransplant, but their utility for destination therapy remains uncertain. Because of additional complex immunobiological problems, the same approach has been less successful in preclinical lung xenograft transplantation, where survival is still measured in days or weeks. The first formal clinical trials of pig heart transplantation may include patients who do not have access to an allotransplant, those with contraindications for mechanical circulatory support, those in need of retransplantation or with a high level of panel-reactive antibodies. Infants with complex congenital heart disease, should also be considered.

The number of advanced practice providers (APPs) in pediatric critical care has increased dramatically over recent years, leading to increased opportunities to lead resuscitation teams during pediatric emergent events.The aim of this study was to better understand the emergency leadership experience, training, and education that pediatric cardiac intensive care unit APPs receive.This study was a cross-sectional descriptive studying using survey responses. The self-administered survey was administered to APP and attending physician members of the Pediatric Cardiac Intensive Care Society. Survey results were analyzed.One hundred seven pediatric cardiac intensive care unit APPs (n = 53) and attending physicians (n = 54) responded to the survey. Half of APPs felt that attendings allowed APPs to lead emergent events, and 50.9% had never functioned in the team leader role. Most respondents (77.5%) rated their comfort functioning in the role during emergent situations as moderate or lower. Increased APP experience level was associated with a higher number of codes led, increased comfort leading codes, and improved mental model sharing (all Ps.0001). The number of codes an APP had previously led was associated with increased comfort leading codes (P.0001) and mental model sharing (P = .0002). One-third of attendings said they allow APPs to lead codes in their unit. Half of attendings who do not allow APPs to function as the team leader would follow formal training.Opportunities for APPs to function as team leaders during emergent events continue to increase. A leadership educational program would be beneficial to pediatric critical care APPs. It may also have the additional benefit of improving physician comfort with APPs leading code events and patient outcomes.

Context The nature of the relationship between serum thyrotropin (TSH) levels and higher cognitive abilities is unclear, especially within the normal reference range and in the younger population. Objective To assess the relationship between serum TSH levels and mental health and sleep quality parameters (fluid intelligence [Gf], MMSE (Mini-Mental State Examination), depression scores, and, finally, Pittsburgh Sleep Quality Index (PSQI) scores (working memory, processing speed, and executive function) in young adults. Methods This was a retrospective analysis of the data from the Human Connectome Project (HCP). The HCP consortium is seeking to map human brain circuits systematically and identify their relationship to behavior in healthy adults. Included were 391 female and 412 male healthy participants aged 22-35 years at the time of the screening interview. We excluded persons with serum TSH levels outside the reference range (0.4-4.5 mU/L). TSH was transformed logarithmically (log TSH). All the key variables were normalized and then linear regression analysis was performed to assess the relationship between log TSH as a cofactor and Gf as the dependent variable. Finally, a machine learning method, random forest regression, predicted Gf from the dependent variables (including alcohol and tobacco use). The main outcome was normalized Gf (nGf) and Gf scores Results Log TSH was a significant co-predictor of nGF in females (β = 0.31(±0.1), P Conclusion Higher serum TSH levels might be associated with higher Gf scores in young women.

Approximately one in every 700 babies in the United States is born with Down syndrome, or 0.14%. Children with Down syndrome have cognitive impairment and congenital malformations necessitating frequent occurrences of general anesthesia and surgery. The thoughtful perioperative care of children with Down syndrome is relevant and acutely complex for the pediatric anesthesiologist. Behavior, sedation, hypotonia, upper airway obstruction, venous access, and bradycardia are omnipresent concerns apart from the surgical pathology. Down syndrome is also associated with autonomic nervous system dysfunction, a comorbidity that is overlooked in discussions of perioperative care and is described thus far in adults. Autonomic nervous system function or dysfunction may explain the phenotypical features of the perioperative challenges listed above. For this reason, understanding the development and measurement of autonomic nervous system function is important for the pediatric anesthesiologist. Definition and quantification of sympathetic and parasympathetic function will be reviewed.

We used a machine learning approach to analyze the within-gene distribution of missense variants observed in hereditary conditions and cancer. When applied to 840 genes from the ClinVar database, this approach detected a significant non-random distribution of pathogenic and benign variants in 387 (46%) and 172 (20%) genes, respectively, revealing that variant clustering is widespread across the human exome. This clustering likely occurs as a consequence of mechanisms shaping pathogenicity at the protein level, as illustrated by the overlap of some clusters with known functional domains. We then took advantage of these findings to develop a pathogenicity predictor, MutScore, that integrates qualitative features of DNA substitutions with the new additional information derived from this positional clustering. Using a random forest approach, MutScore was able to identify pathogenic missense mutations with very high accuracy, outperforming existing predictive tools, especially for variants associated with autosomal-dominant disease and cancer. Thus, the within-gene clustering of pathogenic and benign DNA changes is an important and previously underappreciated feature of the human exome, which can be harnessed to improve the prediction of pathogenicity and disambiguation of DNA variants of uncertain significance.

Background:Reliable prediction of severe acute kidney injury (AKI) and related poor outcomes has the potential to optimize treatment. The purpose of this study was to modify the renal angina index in pediatric cardiac surgery to predict severe AKI and related poor outcomes. Methods: We performed a multicenter retrospective study with the population divided into a derivation and validation cohort to assess the performance of a modified renal angina index assessed at 8 h after cardiac intensive care unit (CICU) admission to predict a complex outcome of severe day 3 AKI or related poor outcomes (ventilation duration >7 days, CICU length of stay >14 days, and mortality). The derivation sample was used to determine the optimal cut-off value. Results: There were 298 and 299 patients in the derivation and validation cohorts, respectively. The incidence of severe day 3 AKI and the complex outcome was 1.7% and 28% in the derivation and validation cohort. The sensitivity analysis for fulfillment of renal angina was a score >8 with a sensitivity of 63%, specificity of 73%, and negative predictive value of 83%. The cardiac renal angina index predicted the composite outcome with an area under the curve of 0.7 (95% confidence interval: 0.62-0.78). Renal angina patients had a significantly higher probability of the complex outcome when compared to individual risk and injury categories. Conclusions: We operationalized the renal angina index for use after cardiac surgery. Further revision and modification of the construct with integration of biomarkers in a prospective cohort are necessary to refine the prediction model.

Microdeletions and gross deletions are important causes (~20%) of human inherited disease and their genomic locations are strongly influenced by the local DNA sequence environment. This notwithstanding, no study has systematically examined their underlying generative mechanisms. Here, we obtained 42,098 pathogenic microdeletions and gross deletions from the Human Gene Mutation Database (HGMD) that together form a continuum of germline deletions ranging in size from 1bp to 28,394,429bp. We analyzed the DNA sequence within 1-kb of the breakpoint junctions and found that the frequencies of non-B DNA-forming repeats, GC-content, and the presence of seven of 78 specific sequence motifs in the vicinity of pathogenic deletions correlated with deletion length for deletions of length ≤30 bp. Further, we found that the presence of DR, GQ and STR repeats is important for the formation of longer deletions (>30 bp) but not for the formation of shorter deletions (≤30 bp) whilst significantly (Chi-square test P-value30 bp). We provide evidence to support a functional distinction between microdeletions and gross deletions. Finally, we propose that a deletion length cut-off of 25-30bp may serve as an objective means to functionally distinguish microdeletions from gross deletions.

Objective:To assess the training and the future workforce needs of paediatric cardiac critical care faculty.Design:REDCap surveys were sent May−August 2019 to medical directors and faculty at the 120 US centres participating in the Society of Thoracic Surgeons Congenital Heart Surgery Database. Faculty and directors were asked about personal training pathway and planned employment changes. Directors were additionally asked for current faculty numbers, expected job openings, presence of training programmes, and numbers of trainees. Predictive modelling of the workforce was performed using respondents’ data. Patient volume was projected from US Census data and compared to projected provider availability.Measurements and main results:Sixty-six per cent (79/120) of directors and 62% (294/477) of contacted faculty responded. Most respondents had training that incorporated critical care medicine with the majority completing training beyond categorical fellowship. Younger respondents and those in dedicated cardiac ICUs were more significantly likely to have advanced training or dual fellowships in cardiology and critical care medicine. An estimated 49–63 faculty enter the workforce annually from various training pathways. Based on modelling, these faculty will likely fill current and projected open positions over the next 5 years.Conclusions:Paediatric cardiac critical care training has evolved, such that the majority of faculty now have dual fellowship or advanced training. The projected number of incoming faculty will likely fill open positions within the next 5 years. Institutions with existing or anticipated training programmes should be cognisant of these data and prepare graduates for an increasingly competitive market.

Neurofibromatosis type 1 (NF1) is the most frequent disorder associated with multiple café-au-lait macules (CALM) which may either be present at birth or appear during the first year of life. Other NF1-associated features such as skin-fold freckling and Lisch nodules occur later during childhood whereas dermal neurofibromas are rare in young children and usually only arise during early adulthood. The NIH clinical diagnostic criteria for NF1, established in 1988, include the most common NF1-associated features. Since many of these features are age-dependent, arriving at a definitive diagnosis of NF1 by employing these criteria may not be possible in infancy if CALM are the only clinical feature evident. Indeed, approximately 46% of patients who are diagnosed with NF1 later in life do not meet the NIH diagnostic criteria by the age of 1 year. Further, the 1988 diagnostic criteria for NF1 are not specific enough to distinguish NF1 from other related disorders such as Legius syndrome. In this review, we outline the challenges faced in diagnosing NF1 in young children, and evaluate the utility of the recently revised (2021) diagnostic criteria for NF1, which include the presence of pathogenic variants in the NF1 gene and choroidal anomalies, for achieving an early and accurate diagnosis.

Summary Identifying whether a given genetic mutation results in a gene product with increased (gain-of-function; GOF) or diminished (loss-of-function; LOF) activity is an important step toward understanding disease mechanisms because they may result in markedly different clinical phenotypes. Here, we generated an extensive database of documented germline GOF and LOF pathogenic variants by employing natural language processing (NLP) on the available abstracts in the Human Gene Mutation Database. We then investigated various gene- and protein-level features of GOF and LOF variants and applied machine learning and statistical analyses to identify discriminative features. We found that GOF variants were enriched in essential genes, for autosomal-dominant inheritance, and in protein binding and interaction domains, whereas LOF variants were enriched in singleton genes, for protein-truncating variants, and in protein core regions. We developed a user-friendly web-based interface that enables the extraction of selected subsets from the GOF/LOF database by a broad set of annotated features and downloading of up-to-date versions. These results improve our understanding of how variants affect gene/protein function and may ultimately guide future treatment options.

New South Wales has the greatest burden of HIV in Australia, with 2012 and 2013 recording the highest rates of new diagnoses in 20 years. Concurrently, there has been significant changes in antiretroviral treatments and testing paradigms. We compiled a statewide resistance database to characterize changes in HIV-1 resistance mutations over time. Genotypic antiretroviral resistance testing (GART) was performed on request at three reference laboratories using commercial and in-house methods. In total, 7629 HIV-1 polymerase sequences obtained from GART from 2004 to 2013 were retrospectively collated, reformatted, de-identified, and analyzed using Stanford HIVdb program 7.0 and the 2009 World Health Organization (WHO) surveillance drug resistance mutations (SDRMs). Analyses were performed on subgroups of known treatment naives, treatment experienced, and seroconverters. There has been a decrease in overall rates of prevalent drug resistance mutations from 57.8% in 2004 to 21% in 2013. Dual and triple class resistance mutations have decreased from 32.7% in 2004 to 5.8% in 2013 and 16.4% to 1.2%, respectively. In treatment-naive individuals (

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this consensus statement. ispartof: THYROID vol:32 issue:12 pages:1439-1470 ispartof: location:United States status: published

Background Overactive bladder (OAB) syndrome is a symptom complex affecting 12–14% of the UK adult female population. Symptoms include urinary urgency, with or without urgency incontinence, increased daytime urinary frequency and nocturia. OAB has a negative impact on women’s social, physical, and psychological wellbeing. Initial treatment includes lifestyle modifications, bladder retraining, pelvic floor exercises and pharmacological therapy. However, these measures are unsuccessful in 25–40% of women (refractory OAB). Before considering invasive treatments, such as Botulinum toxin injection or sacral neuromodulation, most guidelines recommend urodynamics to confirm diagnosis of detrusor overactivity (DO). However, urodynamics may fail to show evidence of DO in up to 45% of cases, hence the need to evaluate its effectiveness and cost-effectiveness. FUTURE (Female Urgency, Trial of Urodynamics as Routine Evaluation) aims to test the hypothesis that, in women with refractory OAB, urodynamics and comprehensive clinical assessment is associated with superior patient-reported outcomes following treatment and is more cost-effective, compared to comprehensive clinical assessment only. Methods FUTURE is a pragmatic, multi-centre, superiority randomised controlled trial. Women aged ≥ 18 years with refractory OAB or urgency predominant mixed urinary incontinence, and who have failed/not tolerated conservative and medical treatment, are considered for trial entry. We aim to recruit 1096 women from approximately 60 secondary/tertiary care hospitals across the UK. All consenting women will complete questionnaires at baseline, 3 months, 6 months and 15 months post-randomisation. The primary outcome is participant-reported success at 15 months post-randomisation measured using the Patient Global Impression of Improvement. The primary economic outcome is incremental cost per quality-adjusted life year gained at 15 months. The secondary outcomes include adverse events, impact on other urinary symptoms and health-related quality of life. Qualitative interviews with participants and clinicians and a health economic evaluation will also be conducted. The statistical analysis of the primary outcome will be by intention-to-treat. Results will be presented as estimates and 95% CIs. Discussion The FUTURE study will inform patients, clinicians and policy makers whether routine urodynamics improves treatment outcomes in women with refractory OAB and whether it is cost-effective. Trial registration ISRCTN63268739. Registered on 14 September 2017.

Objectives In the vast majority of Children's Hospitals, the critically ill patient can be found in one of three locations: the PICU, the neonatal ICU, and the cardiac ICU. Training, certification, and maintenance of certification for neonatology and critical care medicine are over seen by the Accreditation Council for Graduate Medical Education and American Board of Pediatrics. There is no standardization of training or oversight of certification and maintenance of certification for pediatric cardiac critical care. Data sources The curricula from the twenty 4th year pediatric cardiac critical care training programs were collated, along with the learning objectives from the Pediatric Cardiac Intensive Care Society published "Curriculum for Pediatric Cardiac Critical Care Medicine." Study selection This initiative is endorsed by the Pediatric Cardiac Intensive Care Society as a first step toward Accreditation Council for Graduate Medical Education oversight of training and American Board of Pediatrics oversight of maintenance of certification. Data extraction A taskforce was established of cardiac intensivists, including the directors of all 4th year pediatric cardiac critical care training programs. Data synthesis Using modified Delphi methodology, learning objectives, rotational requirements, and institutional requirements for providing training were developed. Conclusions In the current era of increasing specialized care in pediatric cardiac critical care, standardized training for pediatric cardiac critical care is paramount to optimizing outcomes.

A non-negligible proportion of human pathogenic variants are known to be present as wild type in at least some non-human mammalian species. The standard explanation for this finding is that molecular mechanisms of compensatory epistasis can alleviate the mutations' otherwise pathogenic effects. Examples of compensated variants have been described in the literature but the interacting residue(s) postulated to play a compensatory role have rarely been ascertained. In this study, the examination of five human X-chromosomally encoded proteins (FIX, GLA, HPRT1, NDP and OTC) allowed us to identify several candidate compensated variants. Strong evidence for a compensated/compensatory pair of amino acids in the coagulation FIXa protein (involving residues 270 and 271) was found in a variety of mammalian species. Both amino acid residues are located within the 60-loop, spatially close to the 39-loop that performs a key role in coagulation serine proteases. To understand the nature of the underlying interactions, molecular dynamics simulations were performed. The predicted conformational change in the 39-loop consequent to the Glu270Lys substitution (associated with hemophilia B) appears to impair the protein's interaction with its substrate but, importantly, such steric hindrance is largely mitigated in those proteins that carry the compensatory residue (Pro271) at the neighboring amino acid position.

Objectives Cardiac surgery-associated acute kidney injury occurs commonly following congenital heart surgery and is associated with adverse outcomes. This study represents the first multicenter study of neonatal cardiac surgery-associated acute kidney injury. We aimed to describe the epidemiology, including perioperative predictors and associated outcomes of this important complication. Design This Neonatal and Pediatric Heart and Renal Outcomes Network study is a multicenter, retrospective cohort study of consecutive neonates less than 30 days. Neonatal modification of The Kidney Disease Improving Global Outcomes criteria was used. Associations between cardiac surgery-associated acute kidney injury stage and outcomes (mortality, length of stay, and duration of mechanical ventilation) were assessed through multivariable regression. Setting Twenty-two hospitals participating in Pediatric Cardiac Critical Care Consortium. Patients Twenty-two-thousand forty neonates who underwent major cardiac surgery from September 2015 to January 2018. Interventions None. Measurements and main results Cardiac surgery-associated acute kidney injury occurred in 1,207 patients (53.8%); 983 of 1,657 in cardiopulmonary bypass patients (59.3%) and 224 of 583 in noncardiopulmonary bypass patients (38.4%). Seven-hundred two (31.3%) had maximum stage 1, 302 (13.5%) stage 2, 203 (9.1%) stage 3; prevalence of cardiac surgery-associated acute kidney injury peaked on postoperative day 1. Cardiac surgery-associated acute kidney injury rates varied greatly (27-86%) across institutions. Preoperative enteral feeding (odds ratio = 0.68; 0.52-0.9) and open sternum (odds ratio = 0.76; 0.61-0.96) were associated with less cardiac surgery-associated acute kidney injury; cardiopulmonary bypass was associated with increased cardiac surgery-associated acute kidney injury (odds ratio = 1.53; 1.01-2.32). Duration of cardiopulmonary bypass was not associated with cardiac surgery-associated acute kidney injury in the cardiopulmonary bypass cohort. Stage 3 cardiac surgery-associated acute kidney injury was independently associated with hospital mortality (odds ratio = 2.44; 1.3-4.61). No cardiac surgery-associated acute kidney injury stage was associated with duration of mechanical ventilation or length of stay. Conclusions Cardiac surgery-associated acute kidney injury occurs frequently after neonatal cardiac surgery in both cardiopulmonary bypass and noncardiopulmonary bypass patients. Rates vary significantly across hospitals. Only stage 3 cardiac surgery-associated acute kidney injury is associated with mortality. Cardiac surgery-associated acute kidney injury was not associated with any other outcomes. Kidney Disease Improving Global Outcomes criteria may not precisely define a clinically meaningful renal injury phenotype in this population.

Understanding the role of common polymorphisms in modulating the clinical phenotype when they co‐occur with a disease‐causing lesion is of critical importance in medical genetics. We explored the impact of apparently neutral common polymorphisms, using the gene encoding the urea cycle enzyme, ornithine transcarbamylase (OTC), as a model system. Distinct combinations of genetic backgrounds embracing two missense polymorphisms were created in cis with the pathogenic p.Arg40His replacement. In vitro enzymatic assays revealed that the polymorphic variants were able to modulate OTC activity both in the presence or absence of the pathogenic lesion. First, we found that the combination of the minor alleles of polymorphisms p.Lys46Arg and p.Gln270Arg significantly enhanced enzymatic activity in the wild‐type protein. Second, enzymatic assays revealed that the minor allele of the p.Gln270Arg polymorphism was capable of ameliorating OTC activity when combined in cis with the pathogenic p.Arg40His replacement. Structural analysis predicted that the minor allele of the p.Gln270Arg polymorphism would serve to stabilize the OTC wild‐type protein, thereby corroborating the results of the experimental assays. Our findings demonstrate the potential importance of cis‐interactions between common polymorphic variants and pathogenic missense mutations and illustrate how standing genetic variation can modulate protein function.

This manuscript is one component of a larger series of articles produced by the Neonatal Cardiac Care Collaborative that are published in this supplement of Pediatrics. In this review article, we summarize the contemporary physiologic principles, evaluation, and management of acute care issues for neonates with complex congenital heart disease. A multidisciplinary team of authors was created by the Collaborative’s Executive Committee. The authors developed a detailed outline of the manuscript, and small teams of authors were assigned to draft specific sections. The authors reviewed the literature, with a focus on original manuscripts published in the last decade, and drafted preliminary content and recommendations. All authors subsequently reviewed and edited the entire manuscript until a consensus was achieved. Topics addressed include cardiopulmonary interactions, the pathophysiology of and strategies to minimize the development of ventilator-induced low cardiac output syndrome, common postoperative physiologies, perioperative bleeding and coagulation, and common postoperative complications.

Clinical trials of xenotransplantation (XTx) may start in coming years. Religious views have been mentioned as possible barriers to XTx acceptance. While there have been reports on perspectives of theologians in regard to XTx, no report has studied the perspectives of community religious leaders. A focus group was conducted with a sample of members of the following faith groups: Islam, Catholicism, and Protestantism. Qualitative content analysis was performed to identify interpretive themes. Four themes emerged. Participants were receptive to the idea of XTx and expressed no religious barriers to accepting a pig xenograft as a lifesaving therapy but did express certain concerns. Religious leaders accept the idea of XTx and do not see it as contradictory to their beliefs. However, some concerns were raised. Future studies addressing these concerns and exploring the potential role of religious leaders in educating the community on XTx are needed.

AimTo estimate the minimally important difference (MID) in change in National Eye Institute Visual Function Questionnaire-25 (VFQ-25) composite score using methods aligned with patient perception.MethodsRetrospective analysis of prospectively collected data from adults with primary angle closure or primary angle closure glaucoma enrolled in the Effectiveness, in Angle-closure Glaucoma, of Lens Extraction study. We included data from 335 participants with patient reported visual function (VFQ-25) and health status measured by the EQ-5D-3L over 36 months. We used the recommended anchor-based methods (receiver operating characteristic (ROC), predictive modelling and mean change) to determine the MID of the VFQ-25. EQ-5D-3L anchor change was defined as none (0.075 points).ResultsMean baseline VFQ-25 score was 87.6 (SD 11.8). Estimated MIDs in the change in VFQ-25 scores (95% CI) were 10.5 (1.9 to 19.2); 3.9 (−2.3 to 10.1); 5.8 (1.9 to 7.2) and 8.1 (1.7 to 14.8) for the ‘within-patient’, ‘between-patient’ change, ROC and predictive modelling anchor methods respectively. Excluding estimates from the methodologically weaker ‘within-patient’ method, the MID of a change in VFQ-25 composite score is 5.8 (median value).ConclusionsEstimates of the MID using multiple methods assist in the interpretation of the VFQ scores. In the context of early glaucoma related visual disability, a change score of around six points on the VFQ-25 is likely to be important to patients. Further confirmatory research is required. Studies comparing changes in patient-reported outcome measure scores with a global measure of patients’ perceived change are required.

Comparing observed and expected distributions of categorical outcome variables in randomized controlled trials (RCTs) has been previously used to assess publication integrity. We applied this technique to withdrawals from RCTs.We compared the observed distribution of withdrawals with the expected binomial distribution in six sets of RCTs: four control sets and two sets with concerns about their publication integrity.In the control data sets (n = 13, 115, 71, and 36 trials, respectively), the observed distributions of withdrawals were consistent with the expected distributions, both for the numbers of withdrawals per trial arm and for the differences in withdrawals between trial arms in two-arm RCTs. In contrast, in both sets of RCTs with concerns regarding publication integrity (n = 151 and 35 trials, respectively), there were striking differences between the observed and expected distributions of trial withdrawals. Two-arm RCTs from the two sets with publication integrity concerns were 2.6 (95% confidence interval 2.0-3.3) times more likely to have a difference of 0 or 1 withdrawals between trial arms than control RCTs (P 0.001). Simulating a 50% higher rate of withdrawals in active treatment arms in the largest set of control RCTs still produced an observed distribution of withdrawals per trial arm consistent with the expected distribution.Comparing the observed and expected distribution of trial withdrawals may be a useful technique when considering publication integrity of a body of RCTs.

Introduction: We aimed to characterize acute kidney injury (AKI), fluid overload (FO), and renal replacement therapy (RRT) utilization by diagnostic categories and examine associations between these complications and mortality by category. Methods: To test our hypotheses, we conducted a retrospective multicenter, cohort study including 446 neonates (categories: 209 with cardiac disease, 114 with congenital diaphragmatic hernia [CDH], 123 with respiratory disease) requiring extracorporeal membrane oxygenation (ECMO) between January 1, 2007, and December 31, 2011. Results: AKI, FO, and RRT each varied by diagnostic category. AKI and RRT receipt were most common in those neonates with cardiac disease. Subjects with CDH had highest peak %FO (51% vs. 28% cardiac vs. 32% respiratory; p < 0.01). Hospital survival was 55% and varied by diagnostic category (45% cardiac vs. 48% CDH vs. 79% respiratory; p < 0.001). A significant interaction suggested risk of mortality differed by diagnostic category in the presence or absence of AKI. In its absence, diagnosis of CDH (vs. respiratory disease) (OR 3.04, 95% CL 1.14–8.11) independently predicted mortality. In all categories, peak %FO (OR 1.20, 95% CL 1.11–1.30) and RRT receipt (OR 2.12, 95% CL 1.20–3.73) were independently associated with mortality. Discussion/Conclusions: Physiologically distinct ECMO diagnoses warrant individualized treatment strategies given variable incidence and effects of AKI, FO, and RRT by category on mortality.

Introduction Epidemiologic studies suggest that joint bleeding occurs in patients with mild-to-moderate haemophilia, including women and girls. However, most previous studies on the impacts of haemophilia focus on men with severe disease. Aim To identify unmet needs in men and women with mild-to-moderate haemophilia. Methods The Pain, Functional Impairment, and Quality of Life (P-FiQ) study assessed the impact of pain on functional impairment and health-related quality of life in men with haemophilia A or B of any severity. The Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) study evaluated the psychosocial needs of adults and children with haemophilia B of any severity, including women and girls. Both studies employed patient-reported outcome measures. Results In the P-FiQ study, 16% (62/381) of participants had mild and 13% (50/381) had moderate haemophilia. In the B-HERO-S study, 29% (86/299) of adult participants were female, 25% (74/299) had mild haemophilia, and 63% (189/299) had moderate haemophilia. In addition, 63% (46/74) of patients with mild and 86% (162/189) of patients with moderate haemophilia routinely infused factor products to prevent bleeding. Patients reported difficulty gaining access to factor products (54%; 142/263) and a haemophilia treatment centre (17%; 44/263). During the P-FiQ study, 78% (48/62) of patients with mild and 87% (44/50) with moderate haemophilia described problems with pain on the Brief Pain Inventory. Patients also reported issues with anxiety, depression and relationships. Conclusions Mild-to-moderate haemophilia has physical and psychosocial impacts on patients. We offer some solutions to help alleviate these impacts and resolve unmet needs.

Introduction The experiences of patients with mild-to-moderate haemophilia differ from those of patients with severe haemophilia or those without a bleeding disorder and include a challenging diagnosis and variability in bleeding symptoms and treatment needs. In addition, there is a significant lack of data on mild-to-moderate haemophilia, and many unmet needs remain to be identified and addressed in this group of patients. Methods Challenges for these patients, including women with haemophilia, were identified during a roundtable meeting attended by a group of US-based experts including healthcare professionals (e.g., physicians, nurses, and physical therapists) and patients who live with a bleeding disorder. Results Identified unmet needs included a lack of proper education on the management of their disorder and prompt treatment of bleeds, absenteeism from school and work, and challenges with personal relationships. Initiatives to assist with alleviating these unmet needs were proposed and include suggestions for healthcare professionals, haemophilia treatment centres (HTCs) and national and local organizations within the bleeding disorders community. These included HTC and community engagement programmes for patients with mild-to-moderate haemophilia, revised transition guidelines for these patients as they approach adulthood and revised diagnostic classification of mild and moderate haemophilia. Challenges unique to women with haemophilia and ways to address these issues were also discussed. Conclusion This paper summarizes the challenges, initiatives and suggestions that were identified by the haemophilia experts during the roundtable meeting.

Background:Infants with single ventricle congenital heart disease demonstrate increasing head growth after bidirectional Glenn; however, the expected growth trajectory has not been well described.Aims:1) We will describe the pattern of head circumference growth in the first year after bidirectional Glenn. 2) We will determine if head growth correlates with motor developmental outcomes approximately 12 months after bidirectional Glenn.Methods:Sixty-nine single ventricle patients underwent bidirectional Glenn between 2010 and 2016. Patients with structural brain abnormalities, grade III–IV intra-ventricular haemorrhage, significant stroke, or obstructive hydrocephalus were excluded. Head circumference and body weight measurements from clinical encounters were evaluated. Motor development was measured with Psychomotor Developmental Index of the Bayley Scales of Infant Development, Third Edition. Generalised estimating equations assessed change in head circumference z-scores from baseline (time of bidirectional Glenn) to 12 months post-surgery.Results:Mean age at bidirectional Glenn was 4.7 (2.3) months and mean head circumference z-score based on population-normed data was −1.13 (95% CI −1.63, −0.63). Head circumference z-score increased to 0.35 (95% CI −0.20, 0.90) (p < 0.0001) 12 months post-surgery. Accelerated head growth, defined as an increase in z-score of >1 from baseline to 12 months post-surgery, was present in 46/69 (66.7%) patients. There was no difference in motor Psychomotor Developmental Index scores between patients with and without accelerated head growth.Conclusion:Single ventricle patients demonstrated a significant increase in head circumference after bidirectional Glenn until 10–12 months post-surgery, at which time growth stabilised. Accelerated head growth did not predict sub-sequent motor developmental outcomes.

Clinical trials of kidney xenotransplantation are being considered in the United States. Before this novel procedure can take place, investigators will have to obtain approval from the institutional review board. The consent form that will be used for such a trial and that will receive approval from the institutional review board will be complex. Informed consent-the process by which a research participant provides his/her permission to participate in a clinical trial-is a staple of the research process and most commonly is in the form of a physical document. In the case of a novel procedure with uncertain benefits and risks and a participant population in acute need of a transplant, the consent process is crucial. These complexities may raise several ethical considerations for the initial pig kidney xenotransplantation recipients in the United States that will require adaptations of the required elements of the informed consent process by the US Department of Human and Health Services. The ethical issues include (1) a subject's ability to withdraw from the trial, (2) restrictions on their reproductive rights, and (3) the possibility of the need for quarantine if there is a perceived risk of xenozoonosis. This article aims to discuss ethical considerations that may challenge the general required elements of the informed consent form stipulated by the 45 Code of Federal Regulations 46 of the US Department of Health and Human Services and to suggest recommendations for deliberation.

Pig islet xenotransplantation is a potential treatment for patients with type 1 diabetes. Current efforts are focused on identifying the optimal pig islet source and overcoming the immunological barrier. The optimal age of the pig donors remains controversial since both adult and neonatal pig islets have advantages. Isolation of adult islets using GMP grade collagenase has significantly improved the quantity and quality of adult islets, but neonatal islets can be isolated at a much lower cost. Certain culture media and coculture with mesenchymal stromal cells facilitate neonatal islet maturation and function. Genetic modification in pigs affords a promising strategy to prevent rejection. Deletion of expression of the three known carbohydrate xenoantigens (Gal, Neu5Gc, Sda) will certainly be beneficial in pig organ transplantation in humans, but this is not yet proven in islet transplantation, though the challenge of the ‘4th xenoantigen’ may prove problematic in nonhuman primate models. Blockade of the CD40/CD154 costimulation pathway leads to long-term islet graft survival (of up to 965 days). Anti-CD40mAbs have already been applied in phase II clinical trials of islet allotransplantation. Fc region-modified anti-CD154mAbs successfully prevent the thrombotic complications reported previously. In this review, we discuss (I) the optimal age of the islet-source pig, (ii) progress in genetic modification of pigs, (iii) the immunosuppressive regimen for pig islet xenotransplantation, and (iv) the reduction in the instant blood-mediated inflammatory reaction.

BNT162b2 Vaccine and Emerging SARS-CoV-2 Variants A total of 20 serum samples from 15 persons who received the BNT162b2 vaccine showed strong neutralization activity against recombinant viruses eng...

Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants., Identifying variants capable of causing genetic disease is challenging. The authors use semisupervised learning to predict pathogenic missense variants and their impacts on protein structure and function, enabling a molecular mechanism-driven approach to studying different types of human disease.

International audience; Background: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015.Methods: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164.Findings: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (

The COVID‐19 pandemic has triggered numerous scientific activities aimed at understanding the SARS‐CoV‐2 virus and ultimately developing treatments. Structural biologists have already determined hundreds of experimental X‐ray, cryo‐EM, and NMR structures of proteins and nucleic acids related to this coronavirus, and this number is still growing. To help biomedical researchers, who may not necessarily be experts in structural biology, navigate through the flood of structural models, we have created an online resource, covid19.bioreproducibility.org, that aggregates expert‐verified information about SARS‐CoV‐2‐related macromolecular models. In this paper, we describe this web resource along with the suite of tools and methodologies used for assessing the structures presented therein. This article is protected by copyright. All rights reserved.

In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1, a pandemic. With rapidly accumulating numbers of cases and deaths reported globally2, a vaccine is urgently needed. Here we report the available safety, tolerability and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose-escalation study (ClinicalTrials.gov identifier NCT04368728) among 45 healthy adults (18–55 years of age), who were randomized to receive 2 doses—separated by 21 days—of 10 μg, 30 μg or 100 μg of BNT162b1. BNT162b1 is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 μg was not administered because of the increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared with the 30-μg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second dose. Geometric mean neutralizing titres reached 1.9–4.6-fold that of a panel of COVID-19 convalescent human sera, which were obtained at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate. In a dose-escalation study of the COVID-19 RNA vaccine BNT162b1 in 45 healthy adults, RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second vaccine dose.

Objectives Extracorporeal membrane oxygenation is used to support refractory cardiorespiratory failure. Outcomes and complications when extracorporeal membrane oxygenation is used to support cardiorespiratory failure secondary to arrhythmia in pediatric patients remain poorly defined. Our purpose is to describe pediatric patients requiring extracorporeal membrane oxygenation support for supraventricular arrhythmias in the context of normal cardiac anatomy and congenital heart disease and identify patient/peri-extracorporeal membrane oxygenation variables associated with extracorporeal membrane oxygenation-related complications and survival. Design Retrospective multicenter review from 1993 to 2016. Setting Extracorporeal Life Support Organization registry. Subjects Patients younger than 21 years old requiring extracorporeal membrane oxygenation support for supraventricular arrhythmias. Interventions None. Measurements and main results A total of 342 patients were identified (weight, 3.8 kg [3.2-7.5 kg]; age at extracorporeal membrane oxygenation initiation, 24 d [6-222]; 61% male). Sixty-five percentage survived to hospital discharge. Complications were frequent (85%) and most commonly cardiac related (31%). In multivariable modeling, mortality was associated with congenital heart disease, time from intubation to extracorporeal membrane oxygenation initiation, use of bicarbonate prior to extracorporeal membrane oxygenation, extracorporeal membrane oxygenation duration, and the presence of a complication. The presence of any complication was associated with a three-fold increase in the odds of death. In subgroup analysis of isolated supraventricular arrhythmias patients, similar patient and extracorporeal membrane oxygenation characteristics were associated with outcome. A lower pre-extracorporeal membrane oxygenation pH and PCO2 and site of venous cannulation were associated with complications (p Conclusions Extracorporeal membrane oxygenation use for medically refractory supraventricular arrhythmias was associated with a 65% survival to hospital discharge. However, there was a high rate of complications, the presence of which was associated with decreased survival. Complications appeared to be related to pre-extracorporeal membrane oxygenation clinical status and whether earlier extracorporeal membrane oxygenation cannulation prior to patient deterioration would improve outcomes needs additional evaluation.

Objectives To assess clinically asymptomatic infants with single-ventricle physiology (SVP) for sleep-disordered breathing (SDB) in the supine and car seat positions using polysomnography. Polysomnography results also were compared with results of a standard Car Seat Challenge to measure the dependability of the standard Car Seat Challenge. Study design This was an observational study of 15 infants with SVP. Polysomnography data included Obstructive Index, Central Index, Arousal Index, Apnea Hypopnea Index, and sleep efficiency. Polysomnography heart rate and oxygen saturation data were used to compare polysomnography with the standard Car Seat Challenge. Results Polysomnography demonstrated that all 15 infants had SDB and 14 had obstructive sleep apnea (Obstructive Index ≥1/hour) in both the supine and car seat positions. Infants with SVP had a statistically significant greater median Obstructive Index in the car seat compared with supine position (6.3 vs 4.2; P = .03), and median spontaneous Arousal Index was greater in the supine position compared with the car seat (20.4 vs 15.2; P = .01). Comparison of polysomnography to standard Car Seat Challenge results demonstrated 5 of 15 (33%) of infants with SVP with abnormal Obstructive Index by polysomnography would have passed a standard Car Seat Challenge. Conclusions Infants with SVP without clinical symptoms of SDB may be at high risk for SDB that appears worse in the car seat position. The standard Car Seat Challenge is not dependable in the identification of infants with SVP and SDB. Further studies are warranted to further delineate its potential impact of SDB on the clinical outcomes of infants with SVP.

Background Despite the high prevalence of overweight and obesity in the United States, few studies have assessed the impact of obesity on haemophilia-specific outcomes or experiences/perceptions of healthcare providers (HCPs) treating haemophilia. Aim The Awareness, Care and Treatment In Obesity maNagement to inform Haemophilia Obesity Patient Empowerment (ACTION-TO-HOPE) study was designed to identify HCP insights on the unique challenges of patients with haemophilia and obesity/overweight (PwHO) and the barriers to chronic weight management. Methods An online survey collected data from haemophilia treatment centre-based HCPs. Respondents included 10 adults and 29 paediatric haematologists, 27 nurses/nurse practitioners/physician assistants, 22 physical therapists and 17 social workers. Results Almost all HCPs rated obesity of moderate/high concern and reported that weight significantly affects future health and has an impact on life expectancy, yet fewer than 60% reported discussing the impact of weight on health with their patients. HCPs reported that few PwHO tried to lose weight; not many were 'successful'. HCPs perceived a desire to feel better physically and joint pain as top motivating factors. HCPs believe that PwHO would have less joint bleeding and pain and greater mobility if they lost weight. HCPs viewed lack of exercise and food preferences/habits as the biggest barriers to initiating/maintaining weight loss and therefore recommended increasing exercise and healthier eating to their patients. However, physical activity in this patient population is limited and requires advice and support. Conclusions Most HCPs appreciated the impact of obesity on joint bleeding, pain, and function and quality of life. Reduced food intake and increased activity are the most commonly recommended weight-loss strategies but the least likely to be successful. HCPs desire additional education/materials to understand weight management for PwHO.

BackgroundObservational studies have revealed that type 2 diabetes (T2D) is associated with an increased risk of peripheral artery disease (PAD). However, whether the two diseases share a genetic basis and whether the relationship is causal remain unclear. It is also unclear as to whether these relationships differ between ethnic groups.MethodsBy leveraging large-scale genome-wide association study (GWAS) summary statistics of T2D (European-based:Ncase= 21,926,Ncontrol= 342,747; East Asian-based:Ncase= 36,614,Ncontrol= 155,150) and PAD (European-based:Ncase= 5673,Ncontrol= 359,551; East Asian-based:Ncase= 3593,Ncontrol= 208,860), we explored the genetic correlation and putative causal relationship between T2D and PAD in both Europeans and East Asians using linkage disequilibrium score regression and seven Mendelian randomization (MR) models. We also performed multi-trait analysis of GWAS and two gene-based analyses to reveal candidate variants and risk genes involved in the shared genetic basis between T2D and PAD.ResultsWe observed a strong genetic correlation (rg) between T2D and PAD in both Europeans (rg= 0.51;p-value = 9.34 × 10−15) and East Asians (rg= 0.46;p-value = 1.67 × 10−12). The MR analyses provided consistent evidence for a causal effect of T2D on PAD in both ethnicities (odds ratio [OR] = 1.05 to 1.28 for Europeans and 1.15 to 1.27 for East Asians) but not PAD on T2D. This putative causal effect was not influenced by total cholesterol, body mass index, systolic blood pressure, or smoking initiation according to multivariable MR analysis, and the genetic overlap between T2D and PAD was further explored employing an independent European sample through polygenic risk score regression. Multi-trait analysis of GWAS revealed two novel European-specific single nucleotide polymorphisms (rs927742 and rs1734409) associated with the shared genetic basis of T2D and PAD. Gene-based analyses consistently identified one geneANKFY1and gene-gene interactions (e.g.,STARD10[European-specific] toAP3S2[East Asian-specific];KCNJ11[European-specific] toKCNQ1[East Asian-specific]) associated with the trans-ethnic genetic overlap between T2D and PAD, reflecting a common genetic basis for the co-occurrence of T2D and PAD in both Europeans and East Asians.ConclusionsOur study provides the first evidence for a genetically causal effect of T2D on PAD in both Europeans and East Asians. Several candidate variants and risk genes were identified as being associated with this genetic overlap. Our findings emphasize the importance of monitoring PAD status in T2D patients and suggest new genetic biomarkers for screening PAD risk among patients with T2D.

BACKGROUND & AIMS: Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early-onset ICP (EO-ICP; median age, 19.2 years) and late-onset ICP (LO-ICP; median age, 56.2 years). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, or ACP. METHODS: We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2 studies, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal-Wallis test was used to compare continuous variables across groups and based on genetic variants. RESULTS: Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P=.04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P=.001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P=.001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. CONCLUSIONS: We confirmed previously reported ages at onset of symptoms for EO-ICP and LOICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared to about one-quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

Tyrosine biosynthesis via the shikimate pathway is absent in humans and other animals, making it an attractive target for next-generation antibiotics, which is increasingly important due to the looming proliferation of multidrug-resistant pathogens. Tyrosine biosynthesis is also of commercial importance for the environmentally friendly production of numerous compounds, such as pharmaceuticals, opioids, aromatic polymers, and petrochemical aromatics. Prephenate dehydrogenase (PDH) catalyzes the penultimate step of tyrosine biosynthesis in bacteria: the oxidative decarboxylation of prephenate to 4-hydroxyphenylpyruvate. The majority of PDHs are competitively inhibited by tyrosine and consist of a nucleotide-binding domain and a dimerization domain. Certain PDHs, including several from pathogens on the World Health Organization priority list of antibiotic-resistant bacteria, possess an additional ACT domain. However, biochemical and structural knowledge was lacking for these enzymes. In this study, we successfully established a recombinant protein expression system for PDH from Bacillus anthracis (BaPDH), the causative agent of anthrax, and determined the structure of a BaPDH ternary complex with NAD+ and tyrosine, a binary complex with tyrosine, and a structure of an isolated ACT domain dimer. We also conducted detailed kinetic and biophysical analyses of the enzyme. We show that BaPDH is allosterically regulated by tyrosine binding to the ACT domains, resulting in an asymmetric conformation of the BaDPH dimer that sterically prevents prephenate binding to either active site. The presented mode of allosteric inhibition is unique compared to both the competitive inhibition established for other PDHs and to the allosteric mechanisms for other ACT-containing enzymes. This study provides new structural and mechanistic insights that advance our understanding of tyrosine biosynthesis in bacteria. ENZYMES: Prephenate dehydrogenase from Bacillus anthracis (PDH): EC database ID: 1.3.1.12. DATABASES: Coordinates and structure factors have been deposited in the Protein Data Bank (PDB) with accession numbers PDB ID: 6U60 (BaPDH complex with NAD+ and tyrosine), PDB ID: 5UYY (BaPDH complex with tyrosine), and PDB ID: 5V0S (BaPDH isolated ACT domain dimer). The diffraction images are available at http://proteindiffraction.org with DOIs: https://doi.org/10.18430/M35USC, https://doi.org/10.18430/M35UYY, and https://doi.org/10.18430/M35V0S.

Patients undergoing complex pediatric cardiac surgery remain at considerable risk of mortality and morbidity, and variation in outcomes exists across hospitals. The Pediatric Cardiac Critical Care Consortium (PC4) was formed to improve the quality of care for these patients through transparent data sharing and collaborative learning between participants.The purpose of this study was to determine whether outcomes improved over time within PC4.The study analyzed 19,600 hospitalizations (18 hospitals) in the PC4 clinical registry that included cardiovascular surgery from August 2014 to June 2018. The primary exposure was 2 years of PC4 participation; this provided adequate time for hospitals to accrue data and engage in collaborative learning. Aggregate case mix-adjusted outcomes were compared between the first 2 years of participation (baseline) and all months post-exposure. We also evaluated outcomes from the same era in a cohort of similar, non-PC4 hospitals.During the baseline period, there was no evidence of improvement. We observed significant improvement in the post-exposure period versus baseline for post-operative intensive care unit mortality (2.1% vs. 2.7%; 22% relative reduction [RR]; p = 0.001), in-hospital mortality (2.5% vs. 3.3%; 24% RR; p = 0.001), major complications (10.1% vs. 11.5%; 12% RR; p 0.001), intensive care unit length of stay (7.3 days vs. 7.7 days; 5% RR; p 0.001), and duration of ventilation (61.3 h vs. 70.6 h; 13% RR; p = 0.01). Non-PC4 hospitals showed no significant improvement in mortality, complications, or hospital length of stay.This analysis demonstrates improving cardiac surgical outcomes at children's hospitals participating in PC4. This change appears unrelated to secular improvement trends, and likely reflects PC4's commitment to transparency and collaboration.

The contribution of adverse medication events to clinical deterioration is unknown. This study aimed to determine the frequency and nature of rapid response system (RRS) calls that clinicians perceived were medication-related using RRS quality arm data.Analysis of routine data prospectively collected by clinicians responding to RRS calls in an Australian acute tertiary academic hospital.Between January 2013 and June 2017, 12,221 adult patients triggered the RRS for 25,906 medical emergency team (MET) and 512 code blue calls. Clinicians identified 433 medication-related RRS calls (1.6%) involving 406 patients (3.3%). These included 418 MET calls (1.3 medication-related MET calls per 1000 admissions) and 15 code blue calls (0.045 medication-related code blue calls per 1000 admissions). Medication-related calls occurred earlier in the admission (p = 0.002) and were more common for patients triggering multiple calls during the same admission (p 0.001), compared to non-medication-related calls. Medication-related calls most commonly were triggered by low blood pressure (38.3%) and involved cardiovascular (43.0%) and nervous system medications (36.0%). Dose-related toxicity (n = 178) was the most frequent adverse medication event contributing to medication-related calls.One in 30 patients triggering a RRS call experienced medication-related clinical deterioration, most often due to dose related toxicity of cardiovascular system medications. The perceived frequency and potential preventability of this medication-related harm suggest further research is required to increase recognition of medication-related RRS calls by responding clinicians and to reduce the incidence.

An estimated 5–11% of patients with neurofibromatosis type-1 (NF1) harbour large deletions encompassing the NF1 gene and flanking regions. These NF1 microdeletions are subclassified into type 1, 2, 3 and atypical deletions which are distinguishable from each other by their extent and by the number of genes included within the deletion regions as well as the frequency of mosaicism with normal cells. Most common are type-1 NF1 deletions which encompass 1.4-Mb and 14 protein-coding genes. Type-1 deletions are frequently associated with overgrowth, global developmental delay, cognitive disability and dysmorphic facial features which are uncommon in patients with intragenic pathogenic NF1 gene variants. Further, patients with type-1 NF1 deletions frequently exhibit high numbers of neurofibromas and have an increased risk of malignant peripheral nerve sheath tumours. Genes located within the type-1 NF1 microdeletion interval and co-deleted with NF1 are likely to act as modifiers responsible for the severe disease phenotype in patients with NF1 microdeletions, thereby causing the NF1 microdeletion syndrome. Genotype/phenotype correlations in patients with NF1 microdeletions of different lengths are important to identify such modifier genes. However, these correlations are critically dependent upon the accurate characterization of the deletions in terms of their extent. In this review, we outline the utility as well as the shortcomings of multiplex ligation-dependent probe amplification (MLPA) to classify the different types of NF1 microdeletion and indicate the importance of high-resolution microarray analysis for correct classification, a necessary precondition to identify those genes responsible for the NF1 microdeletion syndrome.

Keith Reemtsma was a pioneer in xenotransplantation, the Honorary Founding President of the International Xenotransplantation Association (in 1998), and a wonderful personality. It is a privilege to be invited to give this lecture in his memory. If he were alive today, he would be delighted to see the progress that has been made in pig organ transplantation into nonhuman primate recipients. This progress has largely resulted from two major advances: (i) the increasing availability of pigs with multiple genetic manipulations aimed at protecting the cells of the organ from the primate immune response and (ii) the introduction of novel immunosuppressive agents that block the CD40/CD154 costimulation pathway. There is strong evidence from numerous in vitro studies that the transplantation of a triple-knockout pig organ, particularly if expressing several human protective proteins, into a patient is likely to be significantly more successful than if that same organ is transplanted into a nonhuman primate recipient. With this fact in mind, and in view of the advances currently being made, the time has surely come when we need to consider moving from the laboratory to the clinic. However, there are still questions we need to definitively resolve: (i) What exact genetic modifications do we need in the organ-source pig? (ii) What exact immunosuppressive regimen will we choose? (iii) How will we monitor the immune response and diagnose and treat rejection? and (iv) How do we plan to prevent or treat potential infectious complications? Furthermore, when these matters have been resolved, which patients will be offered a pig organ in the first trial? We have suggested that patients who are very unlikely to survive until a suitable deceased human donor kidney becomes available are those who should be considered for the initial trials. Assessing public attitudes to xenotransplantation is also important before embarking on a clinical trial. I suggest that progress is much more likely to be made from a small clinical trial than if we persist in carrying out experiments in an animal model that no longer mimics the clinical situation.

Three excellent presentations at an industry-sponsored symposium at the (virtual) congress of the combined IXA/CTRMS (September 23-25, 2021) were directed to the value and limitations of the pig-to-nonhuman primate (NHP) kidney transplantation model. Daniel Firl and James Markmann provided a meta-analysis comparing the results of kidney allotransplantation and xenotransplantation in NHPs during the past 25 years. Remarkably, the authors had identified 73 published reports that included 910 individual experiments. Although recipient survival after allotransplantation was longer, the superiority over the survival of xenografts was less than anticipated. Given the excellent short- and medium-term results of clinical kidney allotransplantation today, these data provide hope that the results of clinical pig kidney xenotransplantation may prove significantly better than in NHPs. The authors identified several factors that were shown to statistically influence the success or failure of xenotransplantation. Jean Kwun provided valuable information relating to the longstanding question of whether the survival of a pig organ would be jeopardized if transplanted into an allosensitized recipient. He demonstrated that pig kidney transplantation in an HLA-sensitized patient may be at a disadvantage, although multiple genetic engineering of the organ-source pig significantly delayed rejection. In the initial clinical trials, therefore, it would seem wise to exclude any patient with evidence of anti-HLA antibodies. Andrew Adams reported longer survival (1 year) of Rhesus monkeys with life-supporting pig kidney grafts than has been achieved previously. Although not consistently achieved, these excellent results were obtained with an anti-CD154mAb-based regimen after CD4

Objective:To assess current demographics and duties of physicians as well as the structure of paediatric cardiac critical care in the United States.Design:REDCap surveys were sent by email from May till August 2019 to medical directors (“directors”) of critical care units at the 120 United States centres submitting data to the Society of Thoracic Surgeons Congenital Heart Surgery Database and to associated faculty from centres that provided email lists. Faculty and directors were asked about personal attributes and clinical duties. Directors were additionally asked about unit structure.Measurements and main results:Responses were received from 66% (79/120) of directors and 62% (294/477) of contacted faculty. Seventy-six percent of directors and 54% of faculty were male, however, faculty Conclusions:Racial and ethnic diversity is markedly deficient in the paediatric cardiac critical care workforce. Although the majority of faculty are male, females make up the majority of the workforce younger than 40 years old. Work hours across all age groups and unit types are high both on- and off-service, with most units providing attending in-house night coverage.

We describe an adolescent withStreptococcus pneumoniaemeningitis and symptomatic high-grade, second-degree atrioventricular block requiring permanent pacemaker placement. It is difficult to ascertain if these two diagnoses were independent or had a causal relationship though ongoing symptoms were not present prior to the infection. Because of this uncertainty, awareness that rhythm disturbances can be cardiac in origin but also secondary to other aetiologies, such as infection, is warranted.