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Hepatorenal syndrome type 1 (HRS-1) is a unique form of acute kidney injury that affects individuals with decompensated cirrhosis with ascites. The primary mechanism leading to reduction of kidney function in HRS-1 is hemodynamic in nature. Cumulative evidence points to a cascade of events that led to a profound reduction in kidney perfusion. A state of increased intrahepatic vascular resistance characteristic of advanced cirrhosis and portal hypertension is accompanied by maladaptive peripheral arterial vasodilation and reduction in systemic vascular resistance and mean arterial pressure. As a result of a fall in effective arterial blood volume, there is a compensatory activation of the sympathetic nervous system and the renin-angiotensin system, local renal vasoconstriction, loss of renal autoregulation, decrease in renal blood flow, and ultimately a fall in glomerular filtration rate. Systemic release of nitric oxide stimulated by the fibrotic liver, bacterial translocation, and inflammation constitute key components of the pathogenesis. While angiotensin II and noradrenaline remain the critical mediators of renal arterial and arteriolar vasoconstriction, other novel molecules have been recently implicated. Although the above-described mechanistic pathway remains the backbone of the pathogenesis of HRS-1, other noxious elements may be present in advanced cirrhosis and likely contribute to the renal impairment. Direct liver-kidney crosstalk via the hepatorenal sympathetic reflex can further reduce renal blood flow independently of the systemic derangements. Tense ascites may lead to intraabdominal hypertension and abdominal compartment syndrome. Cardio-hemodynamic processes have also been increasingly recognized. Porto-pulmonary hypertension, cirrhotic cardiomyopathy, and abdominal compartment syndrome may lead to renal congestion and complicate the course of HRS-1. In addition, a degree of ischemic or toxic (cholemic) tubular injury may overlap with the underlying circulatory dysfunction and further exacerbate the course of acute kidney injury. Improving our understanding of the pathogenesis of HRS-1 may lead to improvements in therapeutic options for this seriously ill population., (Copyright © 2024 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Adherence to Congestive Heart Failure with reduced Ejection Fraction (CHFrEF) guidelines is not easily attainable everywhere, particularly in countries with a high prevalence of low socioeconomic status, which includes many Middle Eastern countries. However, it is well-established that adherence to the guidelines is associated with lower mortality and morbidity rates., Objective: Our objective is to investigate the adherence to the degree of treatment guideline in CHFrEF within a patient population in the Middle East and correlate the level of compliance both fully and partially with morbidity and mortality outcomes. Methods and Statistics: We conducted a retrospective study on patients with CHFrEF in the Middle East region who were maintained on Sacubitril/Valsartan for up to 4 years (190 patients). This study included follow-up assessments for morbidity and mortality rates and their correlation with the level of adherence to guidelines., Results: Statistical analysis was performed using IBM SPSS® 27th version. In both the partial adherence group and the full adherence group, there was a statistically significant improvement in NYHA (pretreatment and post-treatment) and Ejection fraction (pretreatment and posttreatment). This means that regardless of the level of adherence to the use of Sacubitril/Valsartan in CHFrEF, there was an overall improvement in the morbidity and mortality rates over the four years of follow-up., Conclusion: While we fully support the idea of achieving full CHFrEF guideline adherence, we recognize the difficulty of this task. Nevertheless, this study reinforces the notion that any degree of adherence to guideline is correlated with better morbidity and mortality rates over a long-term follow-up., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Study Objectives: Sleep-disordered breathing (SDB) is common in patients with congestive heart failure and has important implications regarding symptoms and prognosis. However, the burden of SDB on those with heart failure has not been well characterized in developing countries, including Mozambique in sub-Saharan Africa. Diagnosing SDB in individuals with congestive heart failure is important because treatment of SDB may improve outcomes., Methods: Between September 2014 and April 2017, patients hospitalized in a specialized cardiology unit in Maputo, Mozambique with decompensated congestive heart failure were recruited using convenience sampling. We determined the prevalence of SDB and associated risk factors., Results: A total of 165 patients were recruited, of which 145 had evaluable sleep study data. The overall prevalence of SDB in patients with decompensated congestive heart failure was 72%, and of these 46% had Cheyne-Stokes respirations. Male sex, higher body mass index, and lower left ventricular ejection fraction were all associated with a higher likelihood of SDB and more severe SDB. Cheyne-Stokes respirations were associated with male sex, lower ejection fraction, and larger left atrial size., Conclusions: We conclude that in sub-Saharan Africa SDB is common in decompensated congestive heart failure and strongly predicted by demographic and echocardiographic parameters. This study highlights the need for the development of diagnostic tools and management strategies for patients with severe heart failure in resource-limited settings., Citation: Lo S, Mbanze I, Orr JE, et al. The prevalence of sleep-disordered breathing and associated risk factors in patients with decompensated congestive heart failure in Mozambique. J Clin Sleep Med . 2023;19(6):1103-1110., (© 2023 American Academy of Sleep Medicine.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients., Objective: The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF., Methods: Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy)., Results: Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HPpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a "positive" randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials., Conclusion: Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patient with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

Background and Objectives: Pneumonia is the most common cause of death in children under five years of age. Epidemiological factors and the disease burden differ in developing and industrialized countries. The present study is a cross sectional observational study, carried out from August 2018 to August 2020 in Hindu Rao Hospital, to assess the prevalence of congenital heart disease (CHD) in patients with pneumonia in children up to 5 years. The main objectives of the study were to study the prevalence of congestive cardiac failure (CCF) in pneumonia with and without congenital heart disease., Material and Methods: Patients under 5 years of age, presenting with pneumonia during August 2018 to July 2020 were enrolled for study. The bio-data of each patient was documented each patient was clinically evaluated thoroughly and findings noted. Pneumonia was diagnosed on typical history, physical findings, blood investigations and chest radiographic finding of pneumonia infiltrates in either one or both lung fields. All the cases of pneumonia underwent transthoracic 2 Dimensional (2D) and Doppler echocardiography, done by the cardiologist. Any congenital heart disease so found was noted. The type and size of the defects was documented. The ventricular septal defects were classified based on the site and size. The size of the patient ductus arteriosus was also determined. These measurements were taken to evaluate the impact of defect size on pneumonia. CCF was diagnosed when the patient fulfilled the clinical diagnostic criteria of heart failure. All the cases of pneumonia underwent transthoracic 2 Dimensional (2D) and Doppler echocardiography for diagnosis of any congenital heart disease., Results: Mean age of the children with pneumonia was 9.94 months with 77.5% of the cases below 1 year of age. Male predominance was seen with 56.3% males to 43.8% females. Prevalence of congenital heart disease among cases of pneumonia was 12.5% while that of congestive heart failure was 27.5%. Most common CHD observed was VSD (14 cases; 8.8%) followed by PDA, ASD and TGA (4; 2.5% and 3; 1.9% and 1; 0.6% cases respectively). A significant association was observed between presence of congenital heart disease and development of CCF., Conclusion: Our study demonstrates that most patients with pneumonia or recurrent pneumonia are likely to have an underlying illness at the time of pneumonia. Recurrent ALRTI often occurred in children with history of congenital heart diseases (CHD) and is also associated with Congestive Cardiac Failure. Children with CHD are more vulnerable to recurrent respiratory tract infection., Competing Interests: We do not have any conflict of interest., (© 2021 The Authors.)

Objectives: The aim of this study was to assess sex differences in the efficacy and safety of baroreflex activation therapy (BAT) in the BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial., Background: Patients were randomized 1:1 to receive guideline-directed medical therapy (GDMT) alone (control group) or BAT plus GDMT., Methods: Pre-specified subgroup analyses including change from baseline to 6 months in 6-min walk distance (6MWD), quality of life (QoL) assessed using the Minnesota Living With Heart Failure Questionnaire (MLWHQ), New York Heart Association (NYHA) functional class, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were conducted in men versus women., Results: Fifty-three women and 211 men were evaluated. Women had similar baseline NT-proBNP levels, 6MWDs, and percentage of subjects with NYHA functional class III symptoms but poorer MLWHQ scores (mean 62 ± 22 vs. 50 ± 24; p = 0.01) compared with men. Women experienced significant improvement from baseline to 6 months with BAT plus GDMT relative to GDMT alone in MLWHQ score (-34 ± 27 vs. -9 ± 23, respectively; p < 0.01), 6MWD (44 ± 45 m vs. -32 ± 118 m; p < 0.01), and improvement in NYHA functional class (70% vs. 27%; p < 0.01), similar to the responses seen in men, with no significant difference in safety. Women receiving BAT plus GDMT had a significant decrease in NT-proBNP (-43% vs. 7% with GDMT alone; difference -48%; p < 0.01), while in men this decrease was -15% versus 2%, respectively (difference -17%; p = 0.08), with an interaction p value of 0.05., Conclusions: Women in BeAT-HF had poorer baseline QoL than men but demonstrated similar improvements with BAT in 6MWD, QoL, and NYHA functional class. Women had a significant improvement in NT-proBNP, whereas men did not. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196)., Competing Interests: Funding Support and Author Disclosures This study was funded by CVRx. Drs. Lindenfeld and Zannad have served as consultants to CVRx. Ms. Galle is an employee of CVRx. Dr. Ruddy serves as a surgical proctor for CVRx. Mr. Rogers is an employee of NAMSA; and serves as a consultant to CVRx. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Aims: Determine the feasibility of implementing a heart failure (HF) management strategy that (i) uses a device-based, remote, dynamic, multimetric risk stratification model to predict the risk of HF events and (ii) uses a standardized, centrally administered, ambulatory medication intervention protocol to reproducibly and safely decrease elevated risk scores., Methods and Results: Prospective, non-randomized, single-arm, multicenter feasibility study (Intervene-HF) was conducted in HF patients implanted with a cardiac resynchronization therapy with implantable cardio defibrillator (CRT-D) with TriageHF risk score feature. Certified HF nurses (CHFN) in the Medtronic Care Management Services Program implemented an ambulatory medication intervention strategy by following a standardized guided action pathway triggered by risk-based alert. When CHFN received notification of increased risk score (HF care alert), they implemented a 3 day course of diuretic up-titration (PRN) previously prescribed by a physician. Safety was monitored daily. Recovery after PRN was defined as ≥70% recovery of impedance toward baseline levels. Sixty-six patients followed for 8.2 ± 3.9 months had 49 HF care alerts. Twenty-three of 49 alerts did not receive PRN due to protocol-mandated criteria. Twenty-six of 49 alerts received PRN, 22 were completed, and 19 led to impedance recovery. Four interventions were stopped for safety without leading to an adverse event (AE). One of 26 PRNs was followed by a HF event. Eighty-five per cent (22/26) of PRNs were completed without an AE; 69% (18/26) met the recovery criteria., Conclusions: The Intervene-HF study supports the feasibility of testing, in a large randomized clinical trial, an ambulatory medication intervention strategy that is physician-directed, CHFN-implemented, and based on individualized device risk stratification., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: This study aimed to examine the clinical utility of a multisensor, remote, ambulatory diagnostic risk score, TriageHF™, in a real-world, unselected, large patient sample to predict heart failure events (HFEs) and all-cause mortality., Methods and Results: TriageHF risk score was calculated in patients in the Optum ® database who had Medtronic implantable cardiac defibrillator device from 2007 to 2016. Patients were categorized into three risk groups based on probability for having an HFE within 6 months (low risk <5.4%, medium risk ≥5.4 < 20%, and high risk ≥20%). Data were analysed using three strategies: (i) scheduled monthly data download; (ii) alert-triggered data download; and (iii) daily data download. Study population consisted of 22 901 patients followed for 1.8 ± 1.3 years. Using monthly downloads, HFE risk over 30 days incrementally increased across risk categories (odds ratio: 2.8, 95% confidence interval: 2.5-3.2 for HFE, P < 0.001, low vs. medium risk, and odds ratio: 9.2, 95% confidence interval: 8.1-10.3, P < 0.001, medium vs. high risk). Findings were similar using the other two analytic strategies. Using a receiver operating characteristic curve analysis, sensitivity for predicting HFE over 30 days using high-risk score was 47% (alert triggered) and 51% (daily download) vs. 0.5 per patient year unexplained detection rate. TriageHF risk score also predicted all-cause mortality risk over 4 years. All-cause mortality risk was 14% in low risk, 20% in medium risk, and 38% in high risk., Conclusions: TriageHF risk score provides a multisensor remote, ambulatory diagnostic method that predicts both HFEs and all-cause mortality., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Patients with inadequate health literacy and heart failure face high healthcare costs, more hospitalizations, and greater mortality. To address these negative consequences, patients need to improve heart failure self-care. Multiple factors may influence self-care, but the exact model by which they do so is not fully understood., Objectives: The objective of this study was to examine a model exploring the contribution of health literacy, depression, disease knowledge, and self-efficacy to the performance of heart failure self-care., Methods: Using a cross-sectional design, patients were recruited from a heart failure clinic and completed validated assessments of their cognition, health literacy, depression, knowledge, self-efficacy and self-care. Patients were separated into two groups according to their health literacy level: inadequate/marginal and adequate. Differences between groups were assessed with an independent t-test. Hypothesized paths and mediated relationships were estimated and tested using observed variable path analysis., Results: Participants (n = 100) were mainly male (67%), white (93%), and at least had a high school education (85%). Health literacy was associated with disease knowledge (path coefficient=0.346, p = 0.002), depression was negatively associated with self-efficacy (path coefficient=-0.211, p = 0.037), self-efficacy was positively associated with self-care (path coefficient=0.402, p<0.0005), and there was evidence that self-efficacy mediated the link between depression and self-care. There was no evidence of: mediation of the link between health literacy and self-care by knowledge or self-efficacy; positive associations between knowledge and self-efficacy or self-care; or mediation of the disease knowledge and self-care relationship by self-efficacy. Further, depression was associated with self-care indirectly rather than also directly as hypothesized., Conclusions: Self-efficacy and depression are associated with heart failure self-care. Data generated from the model suggest that healthcare professionals should actively engage all patients to gain self-efficacy and address depression to positively affect heart failure self-care., Competing Interests: Declaration of competing interest The authors report no conflicts of interest other than the grant funding received below., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Acute heart failure (AHF) is a complex syndrome associated with high morbidity and mortality. This study aimed to derive a simple risk score with which to identify AHF patients at high risk for an all-cause death event during the first year after hospital discharge., Methods: Three hundred AHF patients from the Heart Failure registry were included in the analysis. Cox regression with a forward-conditional algorithm and bootstrapping procedure was used to build the prognostic score, while c-statistic was used to assess the prognostic performance of the score., Results: Seven variables were independently associated with an all-cause mortality event during the 1-year follow-up (FU): estimated glomerular filtration rate of 40-60; estimated glomerular filtration rate <40 mL/min/1.73 m 2 ; uric acid >450 μmol/L; left-ventricular ejection fraction <45%; sodium <136 mmol/L; systolic blood pressure <115 mmHg; and a positive history of previous heart failure-related decompensation event(s). The score derived from significant variables enabled classification of patients into three risk categories: low (0-2 points), intermediate (3 points), and high (4-6 points). Observed all-cause mortality rates during the 1-year FU were 6.1%, 30.5%, and 80.9% across the three risk categories, respectively. The score demonstrated a high level of discrimination for an all-cause death event in the derivation cohort with the c-statistic value of 0.907 (95% CI, 0.867-0.939; p < 0.0001) and adequate calibration., Conclusions: The S 2 PLiT-UG score is a simple tool with potential for facilitating risk stratification and therapeutic decision-making during the first year after hospitalisation for an AHF event. Future external validation studies are required to confirm its prognostic performance., (Copyright © 2019 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.)

Background: Activation of neurohormonal systems contributes to the progression of heart failure (HF). The mechanism(s) whereby these systems become activated is(are) not fully explained. We determined whether vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is abnormal in dogs with left ventricular (LV) dysfunction in the absence of clinical HF, and the relationship of abnormalities in baroreflexes to the development of the neurohumoral excitatory state., Methods: LV end-systolic and end-diastolic dimensions (echocardiography), arterial baroreflex sensitivity (slope of ΔRR/Δsystolic BP during phenylephrine or nitroglycerin bolus), and neurohumoral profiles (plasma norepinephrine, renin activity, and arginine vasopressin) were measured serially in conscious dogs (n=24) with progressive LV dysfunction due to rapid ventricular pacing. LV dimensions were used to define groups with mild, moderate, and marked LV dilatation (LVD; increase in LV end-diastolic volume <15%, 15-30%, and >30% of control, respectively). Changes in renal nerve activity (RNA) were recorded in response to increases in pulmonary capillary wedge pressure (PCWP) induced by volume infusion in anesthetized, sinoaortic-denervated dogs., Results: Cardiopulmonary baroreflex sensitivity (slope of %ΔRNA/ΔPCWP) for mild LVD (-17.8%/mmHg) was the same as controls (-17.7%/mmHg). However, the slopes of moderate (-5.8%/mmHg) and severe LVD (-1.9%/mmHg) were decreased significantly compared with controls (P < .05). Arterial baroreflex sensitivity was preserved at all stages of LVD. Plasma norepinephrine, renin activity, and arginine vasopressin remained unchanged after 4, 7, and 11 days of pacing., Conclusions: Vagal cardiopulmonary baroreflex control of renal sympathetic nerve activity is blunted early in the development of LVD. These abnormalities precede neurohumoral excitation and abnormal arterial baroreflexes and become apparent when LV end-diastolic volume starts to increase., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Concentrations of endothelin I (ET1) are elevated in CHF patients and, like other biomarkers that reflect hemodynamic status and cardiac pathophysiology, are prognostic. The Singulex assay (Sgx-ET1) measures the active form of ET1, with a short in vivo half-life and the Brahms assay measures C-terminal endothelin-1 (CT-ET1), a modified (degraded) product with longer half-life. We aimed to determine the prognostic importance of active and modified forms of endothelin 1 (Singulex and Brahms assays) in comparison with other commonly measured biomarkers of inflammation, hemodynamic status and cardiac physiology in CHF., Design and Methods: Plasma biomarkers (Sgx-ET1, CT-ET1, NTproBNP, IL-6, TNFα, cTnI, VEGF, hs-CRP, Galectin-3, ST2) were measured in 134 NYHA class II and III CHF patients with systolic dysfunction. Prognostic importance of biomarkers for hospitalization or death were calculated by both logistic regression and Kaplan-Meier survival analyses., Results: CT-ET1 (OR=5.2, 95% CI=1.7-15.7) and Sgx-ET1 (OR=2.9, CI=1.1-7.7) were independent predictors of hospitalization and death and additively predicted events after adjusting for age, sex, and other significant biomarkers. Other biomarkers did not improve the model. Similarly, in Cox regression analysis, only CT-ET1 (HR 3.4, 95% CI=1.4-8.4), VEGF (2.7, 95% CI=1.3-5.4), and Sgx-ET1 (HR 2.6, 95% CI=1.2-5.6) were independently prognostic., Conclusions: Elevated concentrations of endothelin 1 predict mortality and hospitalizations in HF patients. Endothelin 1 was more prognostic than commonly obtained hemodynamic, inflammatory, and fibrotic biomarkers. Two different assays of endothelin 1 independently and synergistically were prognostic, suggesting either complementary information or extreme prognostic importance., (Copyright © 2014 The Canadian Society of Clinical Chemists. All rights reserved.)

Background: Although it is known that trastuzumab causes cardiotoxicity, its extent and reversibility are still in question. Earlier studies have not evaluated consecutive patients with reproducible nuclear ventriculography., Objective: We sought to evaluate the baseline characteristics which predispose patients to increased risk of trastuzumab cardiotoxicity and to determine the natural history of the cardiotoxicity., Methods and Results: Left ventricular ejection fraction (LVEF) was measured in 76 women aged 36-73 years who had been treated with trastuzumab at the University of Maryland Greenebaum Cancer Center. LVEF was determined at baseline and then 3, 6, 9, and 12 months after treatment initiation. Cardiotoxicity was defined as ≥ 16% decrease in LVEF or ≥ 10% decrease in LVEF to <50%. There were no differences in comorbidities, earlier treatment, or demographics between patients with and without trastuzumab-induced cardiomyopathy except that African Americans were more likely to develop decreased LVEF (P < .05). Twenty-one patients (28%) met criteria for cardiotoxicity. Four of those patients were continued on trastuzumab and 17 patients had therapy withheld at some point. Only 1 patient developed symptomatic heart failure requiring inpatient hospitalization. LVEF improved in most patients regardless of whether or not trastuzumab was continued., Conclusions: Decreased LVEF while undergoing trastuzumab therapy occurs frequently and is usually reversible. African Americans had a higher risk of developing decreased LVEF. These findings raise clinically important questions as to whether it is necessary to discontinue trastuzumab for asymptomatic decrease in LVEF and whether African Americans are more predisposed to a decrease in LVEF while receiving trastuzumab. Further studies carefully assessing LVEF should address these hypotheses., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Possible beneficial effects of dietary omega-3 supplementation on patients with congestive heart failure (CHF) were investigated., Methods and Results: 100 patients with CHF who had a tri-chamber pacemaker and automated defibrillator were initially recruited, and 70 agreed to participate.38 patients received 2 g/day of omega-3 and 32 received placebo capsules. BNP level, 6-min walk test and echocardiographic parameters were recorded at baseline and after 6 months of treatment. BNP levels decreased significantly after 6 months in the omega-3 group, from 1766.2 ± 1978.1 pg/mL to 1159.4 ± 1430.9 pg/dL (P < 0.005). Tei index and late diastolic velocity index were significantly improved in treated group. Mortality and hospitalization rates did not differ., Conclusion: The beneficial effects of omega-3 supplementation in patients with CHF were not as clear as hypothesized; however, omega-3 fatty acids can result in small changes in plasma BNP levels and modest improvements in echocardiographically assessed diastolic function (Clinical trial.gov registration: NCT01227837).

Dilated Cardiomyopathy is an uncommon disease in children but morbidity and mortality in affected patients are high. This review discuses clinical presentation, diagnosis, medical management and prognosis of the condition, with an emphasis on recent advances that have influenced management of these children.