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Myocardial fibrosis and calcification associate with adverse outcomes in nonischemic heart failure. Cardiac fibroblasts (CF) transition into myofibroblasts (MF) and osteogenic fibroblasts (OF) to promote myocardial fibrosis and calcification. However, common upstream mechanisms regulating both CF-to-MF transition and CF-to-OF transition remain unknown. microRNAs are promising targets to modulate CF plasticity. Our bioinformatics revealed downregulation of miR-129-5p and upregulation of its targets small leucine-rich proteoglycan Asporin (ASPN) and transcription factor SOX9 as common in mouse and human heart failure (HF). We experimentally confirmed decreased miR-129-5p and enhanced SOX9 and ASPN expression in CF in human hearts with myocardial fibrosis and calcification. miR-129-5p repressed both CF-to-MF and CF-to-OF transition in primary CF, as did knockdown of SOX9 and ASPN. Sox9 and Aspn are direct targets of miR-129-5p that inhibit downstream β-catenin expression. Chronic Angiotensin II infusion downregulated miR-129-5p in CF in WT and TCF21-lineage CF reporter mice, and it was restored by miR-129-5p mimic. Importantly, miR-129-5p mimic not only attenuated progression of myocardial fibrosis, calcification marker expression, and SOX9 and ASPN expression in CF but also restored diastolic and systolic function. Together, we demonstrate miR-129-5p/ASPN and miR-129-5p/SOX9 as potentially novel dysregulated axes in CF-to-MF and CF-to-OF transition in myocardial fibrosis and calcification and the therapeutic relevance of miR-129-5p.

IntroductionSynaptic failure, a hallmark of Alzheimer's disease (AD), is correlated with reduced levels of synaptic proteins. Though people with Down syndrome (DS) are at markedly increased risk for AD (AD-DS), few studies have addressed synapse dysfunction.MethodsSynaptic proteins were measured in the frontal cortex of DS, AD-DS, sporadic AD cases, and controls. The same proteins were examined in the Dp16 model of DS.ResultsA common subset of synaptic proteins were reduced in AD and AD-DS, but not in DS or a case of partial trisomy 21 lacking triplication of APP gene. Pointing to compromised synaptic function, the reductions in AD and AD-DS were correlated with reduced SNARE complexes. In Dp16 mice reductions in syntaxin 1A, SNAP25 and the SNARE complex recapitulated findings in AD-DS; reductions were impacted by both age and increased App gene dose.DiscussionSynaptic phenotypes shared between AD-DS and AD point to shared pathogenetic mechanisms.

BackgroundCOVID-19 infection is generally regarded as an acute self-limiting illness in children, but it can cause significant morbidity and mortality in both healthy and high-risk children. There are limited data on the outcomes of children with congenital heart disease (CHD) and COVID-19. This study aimed to examine the risks of mortality, in-hospital cardiovascular and non-cardiovascular complications in this patient population.MethodsWe analyzed data from hospitalized pediatric patients from 2020 using the nationally representative National Inpatient Sample (NIS). Children hospitalized for COVID-19 were included, and weighted data were used to compare in-hospital mortality and morbidities between children with and without CHD.ResultsOut of 36,690 children admitted with a diagnosis of COVID-19 infection(ICD-10 code:U07.1 and B97.29) during calendar year 2020, 1240 (3.4%) had CHD. The risk of mortality in children with CHD was not significantly higher than those without CHD(1.2% vs. 0.8%, p = 0.50), with adjusted OR (aOR) of 1.7 (95% CI: 0.6-5.3). Tachyarrhythmias and heart block were more likely in CHD children with an aOR of 4.2 (95% CI: 1.8-9.9) and aOR of 5.0 (95% CI: 2.4-10.8), respectively. Similarly, respiratory failure [aOR = 2.0 (1.5-2.8)], respiratory failure requiring non-invasive mechanical ventilation [aOR = 2.7 (1.4-5.2)] and invasive mechanical ventilation [aOR = 2.6 (1.6-4.0)], and acute kidney injury [aOR = 3.4 (2.2-5.4)] were all significantly higher among patients with CHD. Median length of hospital stay in children with CHD was longer than those without CHD [5 days (IQR: 2-11) vs. 3 days (IQR: 2-5), p =

IntroductionCongenital diaphragmatic hernia (CDH) repair is an area of active research. Large defects requiring patches have a hernia recurrence rate of up to 50%. We designed a biodegradable polyurethane (PU)-based elastic patch that matches the mechanical properties of native diaphragm muscle. We compared the PU patch to a non-biodegradable Gore-Tex™ (polytetrafluoroethylene) patch.MethodsThe biodegradable polyurethane was synthesized from polycaprolactone, hexadiisocyanate and putrescine, and then processed into fibrous PU patches by electrospinning. Rats underwent 4 mm diaphragmatic hernia (DH) creation via laparotomy followed by immediate repair with Gore-Tex™ (n = 6) or PU (n = 6) patches. Six rats underwent sham laparotomy without DH creation/repair. Diaphragm function was evaluated by fluoroscopy at 1 and 4 weeks. At 4 weeks, animals underwent gross inspection for recurrence and histologic evaluation for inflammatory reaction to the patch materials.ResultsThere were no hernia recurrences in either cohort. Gore-Tex™ had limited diaphragm rise compared to sham at 4 weeks (1.3 mm vs 2.9 mm, p = 0.003), but no difference was found between PU and sham (1.7 mm vs 2.9 mm, p = 0.09). There were no differences between PU and Gore-Tex™ at any time point. Both patches formed an inflammatory capsule, with similar thicknesses between cohorts on the abdominal (Gore-Tex™ 0.07 mm vs. PU 0.13 mm, p = 0.39) and thoracic (Gore-Tex™ 0.3 mm vs. PU 0.6 mm, p = 0.09) sides.ConclusionThe biodegradable PU patch allowed for similar diaphragmatic excursion compared to control animals. There were similar inflammatory responses to both patches. Further work is needed to evaluate long-term functional outcomes and further optimize the properties of the novel PU patch in vitro and in vivo.Level of evidenceLevel II, Prospective Comparative Study.

BackgroundDespite guidelines recommending narrow-spectrum perioperative antibiotics (NSPA) as prophylaxis for most children undergoing congenital heart disease (CHD) surgery, broad-spectrum perioperative antibiotics (BSPA) are variably used, and their impact on postoperative outcomes is poorly understood.MethodsWe used administrative data from U.S. hospitals participating in the Vizient Clinical Data Base. Admissions from 2011 to 2018 containing a qualifying CHD surgery in children 0-17 years old were evaluated for exposure to BSPA versus NSPA. Propensity score-adjusted models were used to compare postoperative length of hospital stay (PLOS) by exposure group, while adjusting for confounders. Secondary outcomes included subsequent antimicrobial treatment and in-hospital mortality.ResultsAmong 18 088 eligible encounters from 24 U.S. hospitals, BSPA were given in 21.4% of CHD surgeries, with mean BSPA use varying from 1.7% to 96.1% between centers. PLOS was longer for BSPA-exposed cases (adjusted hazard ratio 0.79; 95% confidence interval [CI]: 0.71-0.89, P < .0001). BSPA was associated with higher adjusted odds of subsequent antimicrobial treatment (odds ratio [OR] 1.24; 95% CI: 1.06-1.48), and there was no significant difference in adjusted mortality between exposure groups (OR 2.06; 95% CI: 1.0-4.31; P = .05). Analyses of subgroups with the most BSPA exposure, including high-complexity procedures and delayed sternal closure, also did not find (but could not exclude) a measurable benefit from BSPA on PLOS.ConclusionsBSPA use was common in high-risk populations, and varied substantially between centers. Standardizing perioperative antibiotic practices between centers may reduce unnecessary broad-spectrum antibiotic exposure and improve clinical outcomes.

Background With improving survival of patients with single ventricle physiology who underwent Fontan palliation, there is also an increase in the prevalence of overweight and obesity in these patients. This tertiary care single-center study aims to determine the association of body mass index (BMI) with the clinical characteristics and outcomes in adults with Fontan. Methods and Results Adult patients (aged ≥18 years) with Fontan who were managed at a single tertiary care center between January 1, 2000, and July 1, 2019, and had BMI data available were identified via retrospective review of medical records. Univariate and multivariable (after adjusting for age, sex, functional class, and type of Fontan) linear and logistic regression, as appropriate, were utilized to evaluate associations between BMI and diagnostic testing and clinical outcomes. A total of 163 adult patients with Fontan were included (mean age, 29.9±9.08 years), with a mean BMI of 24.2±5.21 kg/m2 (37.4% of patients had BMI ≥25 kg/m2). Echocardiography data were available for 95.7% of patients, exercise testing for 39.3% of patients, and catheterization for 53.7% of patients. Each SD increase in BMI was significantly associated with decreased peak oxygen consumption (P=0.010) on univariate analysis and with increased Fontan pressure (P=0.035) and pulmonary capillary wedge pressure (P=0.037) on multivariable analysis. In addition, BMI ≥25 kg/m2 was independently associated with heart failure hospitalization (adjusted odds ratio [AOR], 10.2; 95% CI, 2.79-37.1 [P

Germline mosaicisms could be inherited to offspring, which considered as "de novo" in most cases. Paternal germline MECP2 mosaicism has been reported in fathers of girls with Rett syndrome (RTT) previously. For further study, we focused on MECP2 germline mosaicism in males, not only RTT fathers. Thirty-two fathers of RTT girls with MECP2 pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten MECP2 hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm MECP2 mosaicisms. Nine fathers with RTT daughters (28.1%, 9/32) were found to have MECP2 mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with MECP2 c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, MECP2 mosaicism was found in 7 sperm samples (28.0%, 7/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with MECP2 germline mosaicisms were found with MECP2 mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with MECP2 germline mosaicisms. Additionally, there was no linear correlation between MAFs of MECP2 mosaicisms and the age of males with germline MECP2 mosaicisms. Germline MECP2 mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as "de novo", more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.

BackgroundGenetic tests for variants in MYOT (P2; rs1138656462), FLNC (P3a; rs1139799323 or P3b; rs1142918816) and MYOZ3 (P4; rs1142544043) genes are offered commercially to diagnose myofibrillar myopathy (MFM) and type 2 polysaccharide storage myopathy (PSSM2) in Quarter Horses (QH).ObjectivesTo determine if PSSM2-QH has histopathological features of MFM. To compare genotype and allele frequencies of variants P2, P3, P4 between control-QH and PSSM2-QH diagnosed by histopathology.Study designRetrospective cross-sectional.MethodsThe study includes a total of 229 healthy control-QH, 163 PSSM2-QH GYS1 mutation negative. Desmin stains of gluteal/semimembranosus muscle were evaluated. Purported disease alleles P2, P3a, P3b, P4 were genotyped by pyrosequencing. Genotype, allele frequency and total number of variant alleles or loci were compared between phenotypes using additive/genotypic and dominant models and quantitative effects evaluated by multivariable logistic regression.ResultsHistopathological features of MFM were absent in all QH. A P variant allele at any locus was not associated (P > .05) with a histopathological diagnosis of PSSM2 and one or more P variants were common in control-QH (57%) and PSSM2-QH (61%). Allele frequencies (control/PSSM2) were: 0.24/0.21 (P2), 0.07/0.12 (P3a), 0.07/0.11 (P3b) and 0.06/0.08 (P4). P3a and P3b loci were not independent (r2  = 0.894); and not associated with PSSM2 histopathology comparing the haplotype of both P3a and P3b variants to other haplotypes. A receiver operator curve did not accurately predict the PSSM2 phenotype (AUC = 0.67, 95% CI 0.62-0.72), and there was no difference in the total number of variant loci or total variant allele count between control-QH and PSSM2-QH.Main limitationsP3a and P3b were not in complete linkage disequilibrium.ConclusionsThe P2, P3 and P4 variants in genes associated with human MFM were not associated with PSSM2 in 392 QH. Their use would improperly diagnose PSSM2/MFM in 57% of healthy QH and fail to diagnose PSSM2 in 40% of QH with histopathological evidence of PSSM2.

Primary congenital glaucoma (PCG) is a developmental disorder affecting the trabecular meshwork and anterior chamber angle, leading to increased intraocular pressure (IOP) and potential vision loss. The early symptoms of PCG are already apparent during the first medical visits. Early diagnosis is crucial to be able to implement appropriate treatment to prevent the disease from developing as soon as possible. Its onset occurs before age three, with nonspecific symptoms such as eye rubbing, photophobia, and blepharospasm. Despite rare occurrence and heterogeneous prevalence depending on the geographical region, PCG accounts for a significant proportion of childhood blindness. The etiology of PCG involves genetic factors; the kinship of parents may increase its prevalence. Nonspecific symptoms of PCG necessitate vigilant examination to enable early detection. Diagnostic criteria include elevated IOP, optic nerve damage, corneal changes, and visual field defects. Treatment mainly relies on goniotomy and trabeculectomy in combination with pharmacotherapy.

Background: The purpose of this study was to present our experience in patients who had been treated with posterior vertebral column resection (PVCR) for various spinal deformities. Methods: Thirty-seven patients who performed PVCR between 2015 and 2018 were evaluated retrospectively. The mean follow-up period was 24 months (range: 12–50 months). The demographic data of the patients, mean blood loss, amount of blood replacement, duration of operation, intensive care and hospitalization period, PVCR level, instrumentation level, amount of preoperative curvature, amount of postoperative curvature improvement, preoperative and postoperative neurological status, and complications were examined. Angular measurements were performed on X-ray. Results: The mean age of the patients was 37.5 years (range: 3–80 years). PVCR was applied to patients due to different pathologies (congenital, tumor metastasis, posttraumatic kyphosis, revision scoliosis, and infection). The mean operation time was 445.5 min (260–720) with an average blood loss of 1903 ml (400–7000 ml). It was observed that the average local kyphosis angle decreased from 67.65° to 7.42° in 26 patients who were operated for advanced deformity (P < 0.001). When these values were compared in all 34 patients, the preoperative angle value decreased from 55.1° to 3.5° (P < 0.001) and decreased from 70° to 0° in 13 congenital kyphosis patients. Conclusion: PVCR is an effective method for correcting severe spinal deformities and can be used to correct curvature in different patient groups. Level of Evidence: Level 3.

Abstract Background Glanzmann's thrombasthenia (GT) is a congenital platelet disorder affecting approximately 1:1 000 000 people globally and characterized by impaired platelet aggregation and clot retraction. Autosomal recessive, loss‐of‐function, variants in ITGA2B or ITGB3 of the αIIbβ3 receptor cause the disease in humans. A cat affected by Glanzmann's and macrothrombocytopenia was presented to the UC Davis VMTH. Hypothesis/Objectives Severe thrombopathia in this cat has an underlying genetic etiology. Animals A single affected patient, 2 age‐matched clinically healthy controls, and a geriatric population (n = 20) of normal cats. Methods Physical examination and clinical pathology tests were performed on the patient. Flow cytometry and platelet aggregometry analyses for patient phenotyping were performed. Patient and validation cohort gDNA samples were extracted for Sanger sequencing of a previously identified ITGA2B (c.1986delC) variant. Reverse transcriptase PCR was performed on patient and healthy control PRP samples to verify ITGA2B variant consequence. Results A novel c.1986_1987insCC autosomal recessive variant in ITGA2B was identified. This variant was absent in a population of 194 unrelated cats spanning 44 different breeds. Complete loss of ITGA2B transcript and protein expression was verified by RT‐PCR and flow cytometry, explaining the underlying etiology of GT, and likely macrothrombocytopenia, in this cat. Conclusions and Clinical Importance This study emphasizes the role of precision medicine in cardiovascular disease of cats and identified yet another variant that may be of utility for screening in the feline population. This study provides a small‐volume, standardized, successful protocol for adequate platelet RNA isolation and subsequent molecular assessment of gene expression in cats.

Congenital humeroradial synostosis (CHRS) is a rare musculoskeletal condition that significantly affects the mobility of the elbow joint. They occur in various types and forms depending on the types and numbers of bones involved at the elbow. CHRS may present with elbow deformity and limitation of function. Appropriate timely diagnosis and counseling are required since CHRS is mostly managed conservatively according to literature and may prevent avoidable fractures of the radius from attempts by parents to straighten the flexed fixed elbow and finally offer adequate time for delayed surgical intervention which is usually ineffective and unhelpful.

Tuji Mohammed,1 Tesfaye Mulat Jimma,2 Tewodros Tilahun Zerfu,3 Mesfin Etsub Kassaahun3 1Department of Orthopaedic and Traumatology Surgery at St. Paul Millennium Medical College, AaBET Hospital, Addis Abeba, Ethiopia; 2Department of Plastic and Reconstructive Surgery, College of Surgeons of East Central and South Africa, Cure Hospital, Addis Abeba, Ethiopia; 3Department of Pediatric Orthopaedic Surgery, College of Surgeons of East Central and South Africa, Cure Hospital, Addis Abeba, EthiopiaCorrespondence: Tuji Mohammed, Orthopaedic and Traumatology Surgeon, Department of Orthopaedic and Traumatology Surgery at St. Paul Millennium Medical College, AaBET Hospital, Addis Abeba, Ethiopia, Tel +251937525119, Email Tujar5618@gmail.comIntroduction: Thumb hypoplasia is a congenital birth defect in which a child is born with an underdeveloped or missing thumb. It is a rare condition affecting approximately 1 in 100,000 live births and occurs equally in both males and females. Pollicization is a surgical procedure used to treat severe thumb hypoplasia by transferring another finger to the thumb position.Case Presentation: Twin girls aged two years and eight months, born to a 42-year-old para III mother, presented with bilateral thumb hypoplasia. There was no family history of similar complaints, and no consanguinity was identified between their parents. After excluding other associated anomalies, index finger pollicization was performed for all four hands of the children according to modified Buck-Gramcko techniques, with modifications from Ezaki et al.Conclusion: Generally, index pollicization executed with careful preoperative, intraoperative, and postoperative planning will lead to aesthetically and functionally attractive thumbs for children with congenitally severe hypoplasia or absent thumbs.Keywords: pollicization, thumb hypoplasia, congenital, twin baby

Abdominoscrotal hydrocele (ASH) is a relatively rare variant of hydrocele in both adult and pediatric populations. The incidence among adults is

Background Time-domain parameters are less reliable in children due to increased arterial and chest wall compliance. We assessed the ability of indices derived from frequency analysis of photoplethysmography (PPG) and arterial blood pressure (ABP) waveforms to predict the hemodynamic state in children undergoing congenital heart surgery. Methods We analyzed waveforms after cardiopulmonary bypass period in 76 children who underwent total repair of congenital heart disease. Amplitude density of baseline and amplitude modulation in PPG and ABP by respiratory frequency were obtained using fast Fourier transform analysis and normalized by cardiac pulse height (representing respiratory modulations in venous blood [PPG-DC%] and in amplitude [PPG-AC%] at respiratory frequency). The ratio of amplitude density of PPG at the cardiac frequency (CF) to ABP-CF was used to assess vascular compliance. We assessed volume replacement (ml/kg) and vasoactive inotropic score (VIS). Results Children requiring volume replacement > 10 ml/kg (15.8%) showed higher PPG-DC% than those not requiring it (median: 52.4%, 95% CI [24.8, 295.1] vs. 36.7% [10.7, 125.7], P = 0.017). In addition, children with a VIS > 7 (22.4%) showed higher PPG-CF/ABP-CF (3.6 [0.91, 10.8] vs. 1.2 [0.27, 5.5], P = 0.008). On receiver operating characteristic curve analysis, PPG-DC% predicted a higher fluid requirement (area under the curve: 0.71, 95% CI [0.604, 0.816], P = 0.009), while PPG-CF/ABP-CF predicted a higher VIS (0.714, [0.599, 0.812], P = 0.004). Conclusions Frequency domain analysis of PPG and ABP may assess hemodynamic status requiring fluid or vasoactive inotropic therapy after congenital heart surgery.

Congenital variants of the pancreas are being increasingly detected with the widespread use of modern imaging techniques. The underlying embryologic aberration predicts the final appearance of pancreatic development. It is essential to recognize these congenital variants, as many of these have been proven to be associated with pancreatic diseases like recurrent pancreatitis and chronic abdominal pain. Cross-sectional techniques like multidetector computed tomography and magnetic resonance cholangiopancreatography are the most used imaging techniques for the pancreas, where a radiologist comes across these variants. This pictorial aims to classify the type of variant anatomy of the pancreas, their imaging appearances, and their clinical significance.

AA is a frequent surgical condition that demands urgent intervention. It accounts for approximately 6% of all emergency department visits. Situs inversus is a rare condition in which the orientation of asymmetric organs is a mirror image of normal anatomy. It can be partial (involving either the abdominal or thoracic cavities) or complete (situs inversus totalis: transposition of both abdominal and thoracic organs). SIT is very rare, with an incidence of 1 per 5000 to 10,000 live births. It is inherited in an autosomal recessive pattern with incomplete penetrance. LSAA is very rare and can happen in association with other congenital abnormalities such as situs inversus, midgut malrotation (MM), or a usually long right-sided appendix projecting into the left lower quadrant. SIT is responsible for greater than 67% of left-sided appendicitis cases. Due to atypical clinical presentation, the diagnosis of AA can be difficult and often delayed. Hence, a complete medical history, physical examination, laboratory tests, and imaging tools are necessary to reach a correct diagnosis in a timely manner and prevent complications like abscesses, perforations, and peritonitis.We report a case of a 50-year-old male with symptoms of left lower abdominal pain along with fever, nausea, vomiting, and loose stools that were later diagnosed as LSAA in the setting of SIT.

Purpose: To report a rare case of a pediatric dacryolith masquerading as congenital nasolacrimal duct obstruction (CNLDO). Observations: A two-year-old male child presented with history of intermittent epiphora and discharge since the age of six months. Clinical evaluation demonstrated raised tear meniscus height and delayed fluorescein dye disappearance test in the right eye. Lacrimal irrigation of the right eye under general anesthesia demonstrated 90 % regurgitation (subjectively) of mucoid fluid with a hard stop. Nasal endoscopy examination demonstrated a dacryolith obstructing the opening of the nasolacrimal duct (NLD) in the inferior meatus. The dacryolith was teased out of the NLD and following its removal the lacrimal irrigation was freely patent. At six-months post operative follow up, epiphora resolved and the child was asymptomatic. Conclusions and importance: While cases of canaliculitis is uncommon in pediatric age group, it is rare to find a NLD dacryolith in a toddler. To the best of the authors’ knowledge, there are few prior reports on pediatric NLD dacryolith masquerading as CNLDO in a toddler (1–3 years).

Background: Carpal coalition referes to the fusion of two or more carpal bones in the wrist. This has a prevalence of 0.1 % in Caucasian populations, where lunotriquetral coalition is reported as the most common type. The incidence in Asian populations is not known. Most of lunotriquetral coaliations are asymptomatic and are incidently diagnosed, however, they can be the cause of wrist pain at times. Case report: We hereby present a case of 45 years old male with previously asymptomatic lunotriquetral coaliation with fracture through it post-injury. Classification, diagnostic methodology along with management of leunotriquetral coaliation and fracture have been discussed. Conclusion: Most of symptomatic patients with leunotriquetral coalition can be managed conservatively, however at times, symptomatology, instability or associated fractures may warrant for surgical procedures.

We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio-facio-cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.

Neurodevelopmental impairments are the most common extracardiac morbidities among patients with complex congenital heart disease (CHD) across the lifespan. Robust clinical research in this area has revealed several cardiac, medical, and social factors that can contribute to neurodevelopmental outcome in the context of CHD. Studies using brain magnetic resonance imaging (MRI) have been instrumental in identifying quantitative and qualitative difference in brain structure and maturation in this patient population. Full-term newborns with complex CHD are known to have abnormal microstructural and metabolic brain development with patterns similar to those seen in premature infants at approximately 34 to 36 weeks' gestation. With the advent of fetal brain MRI, these brain abnormalities are now documented as they begin in utero, as early as the third trimester. Importantly, disturbed brain development in utero is now known to be independently associated with neurodevelopmental outcome in early childhood, making the prenatal period an important timeframe for potential interventions. Advances in fetal brain MRI provide a robust imaging tool to use in future neuroprotective clinical trials. The causes of abnormal fetal brain development are multifactorial and include cardiovascular physiology, genetic abnormalities, placental impairment, and other environmental and social factors. This review provides an overview of current knowledge of brain development in the context of CHD, common prenatal imaging tools to evaluate the developing fetal brain in CHD, and known risk factors contributing to brain immaturity.

BackgroundNewborn screening (NBS) algorithms for cystic fibrosis (CF) vary in the United State of America and include different cystic fibrosis transmembrane conductance regulator (CFTR) variants. CFTR variant distribution varies among racial and ethnic groups.ObjectiveOur objectives were to identify differences in detection rate by race and ethnicity for CFTR variant panels, identify each US state detection rate for CFTR variant panels, and describe the rate of false-negative NBS and delayed diagnoses by race and ethnicity.MethodsThis is a cross-sectional analysis of the detection rate of at least 1 CFTR variant for seven panels by race and ethnicity in genotyped people with CF (PwCF) or CFTR-related metabolic syndrome (CRMS)/CFTR-related disorders in CF Foundation Patient Registry (CFFPR) in 2020. We estimated the case detection rate of CFTR variant panels by applying the detection rate to Census data. Using data from CFFPR, we compared the rate of delayed diagnosis or false-negative NBS by race and ethnicity.ResultsFor all panels, detection of at least 1 CFTR variant was highest in non-Hispanic White PwCF (87.5%-97.0%), and lowest in Black, Asian, and Hispanic PwCF (41.9%-93.1%). Detection of at least 1 CFTR variant was lowest in Black and Asian people with CRMS/CFTR-related disorders (48.4%-64.8%). States with increased racial and ethnic diversity have lower detection rates for all panels. Overall, 3.8% PwCF had a false-negative NBS and 11.8% had a delayed diagnosis; Black, Hispanic, and mixed-race PwCF were overrepresented.ConclusionCFTR variant panels have lower detection rates in minoritized racial and ethnic groups leading to false-negative NBS, delayed diagnosis, and likely health disparities.

Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome. WHAT THIS PAPER ADDS: Recent advances shed light on the promises of gene replacement therapy with new vectors designed to control the levels of MeCP2 expression. New developments in DNA/RNA editing approaches or reactivation of the silenced X chromosome open the possibility to re-express the native MeCP2 locus at endogenous levels. Current strategies still face limitations in transduction efficiency and future work is needed to improve brain delivery.

BackgroundBrain injury is common in neonates with complex neonatal congenital heart disease (CHD) and affects neurodevelopmental outcomes.ObjectivesGiven advancements in perioperative care, we sought to determine if the rate of preoperative and postoperative brain injury detected by using brain magnetic resonance imaging (MRI) and associated clinical risk factors have changed over time in complex CHD.MethodsA total of 270 term newborns with complex CHD were prospectively enrolled for preoperative and postoperative brain MRIs between 2001 and 2021 with a total of 466 MRI scans. Brain injuries in the form of white matter injury (WMI) or focal stroke and clinical factors were compared across 4 epochs of 5-year intervals with logistic regression.ResultsRates of preoperative WMI and stroke did not change over time. After adjusting for timing of the postoperative MRI, site, and cardiac group, the odds of newly acquired postoperative WMI were significantly lower in Epoch 4 compared with Epoch 1 (OR: 0.29; 95% CI: 0.09-1.00; P = 0.05). The adjusted probability of postoperative WMI declined significantly by 18.7% from Epoch 1 (24%) to Epoch 4 (6%). Among clinical risk factors, lowest systolic, mean, and diastolic blood pressures in the first 24 hours after surgery were significantly higher in the most recent epoch.ConclusionsThe prevalence of postoperative WMI has declined, whereas preoperative WMI rates remain constant. More robust postoperative blood pressures may explain these findings by minimizing periods of ischemia and supporting cerebral perfusion. These results suggest potential modifiable clinical targets in the postoperative time period to minimize the burden of WMI.

We evaluated the association between implementation of state-mandated pulse oximetry screening (POS) and rates of emergency hospitalizations among infants with Critical Congenital Heart Disease (CCHD) and assessed differences in that association across race/ethnicity. We hypothesized that emergency hospitalizations among infants with CCHD decreased after implementation of mandated POS and that the reduction was larger among racial and ethnic minorities compared to non-Hispanic Whites. We utilized statewide inpatient databases from Arizona, California, Kentucky, New Jersey, New York, and Washington State (2010-2014). A difference-in-differences model with negative binomial regression was used. We identified patients with CCHD whose hospitalizations between three days and three months of life were coded as emergency or urgent or occurred through the emergency department. Numbers of emergency hospitalizations aggregated by month and state were used as outcomes. The intervention variable was an implementation of state-mandated POS. Difference in association across race/ethnicity was evaluated with interaction terms between the binary variable indicating the mandatory policy period and each race/ethnicity group. The model was adjusted for state-specific variables, such as percent of female infants and percent of private insurance. We identified 9,147 CCHD emergency hospitalizations. Among non-Hispanic Whites, there was a 22% (Confidence Interval [CI] 6%-36%) decline in CCHD emergency hospitalizations after implementation of mandated POS, on average. This decline was 65% less among non-Hispanic Blacks compared to non-Hispanic Whites. Our study detected an attenuated association with decreased number of emergency hospitalizations among Black compared to White infants. Further research is needed to clarify this disparity.

BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

BackgroundCystic fibrosis (CF) is characterized by reduced growth and lower body weight, which are multifactorial. CF mouse models lack key disease characteristics that predispose to a negative energy balance, such as pulmonary infections or exocrine pancreatic insufficiency, and yet they still exhibit a growth defect and an abnormally increased energy expenditure. Whether adipocyte thermogenesis contributes to the elevated resting energy expenditure in CF mice is unknown.MethodsWe examined the expression of CFTR in thermogenic brown adipose tissue (BAT) and investigated a functional role for CFTR using BAT-specific CFTR null mice (CFTRBATKO).ResultsThe CFTR protein is expressed in mouse BAT at levels comparable to those in the lungs. BAT-specific inactivation of CFTR in mice increases whole-body energy expenditure associated with sympathetic stimulation by cold exposure. Weight gain on a high-fat diet is attenuated in these mice. However, CFTR-deficient brown adipocytes themselves have impaired, rather than enhanced, thermogenic responses. These cells feature decreased lipolysis and blunted activation of the cAMP/PKA signaling pathway in response to adrenergic stimulation. This suggests that compensatory heat production in other tissues likely accounts for the increased systemic energy expenditure seen in CFTRBATKO mice.ConclusionsOur data reveal a new role for CFTR in the regulation of adipocyte thermogenesis.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition. Management should include a multidisciplinary team by various medical subspecialists and therapists. Developmental and behavioral management of PWS and AS in infancy and early childhood includes early intervention services and individualized education programs for school-aged children. Here, we compare and discuss the mechanisms, pathophysiology, clinical features, and management of the two imprinting disorders, PWS and AS.

22q11.2 deletion syndrome, associated with congenital and neuropsychiatric anomalies, is the most common copy number variant (CNV)-associated syndrome. Patient-derived, induced pluripotent stem cell (iPS) models have provided insight into this condition. However, patient-derived iPS cells may harbor underlying genetic heterogeneity that can confound analysis. Furthermore, almost all available models reflect the commonly-found ~ 3 Mb "A-D" deletion at this locus. The ~ 1.5 Mb "A-B" deletion, a variant of the 22q11.2 deletion which may lead to different syndromic features, and is much more frequently inherited than the A-D deletion, remains under-studied due to lack of relevant models. Here we leveraged a CRISPR-based strategy to engineer isogenic iPS models of the 22q11.2 "A-B" deletion. Differentiation to excitatory neurons with subsequent characterization by transcriptomics and cell surface proteomics identified deletion-associated alterations in proliferation and adhesion. To illustrate in vivo applications of this model, we further implanted neuronal progenitor cells into the cortex of neonatal mice and found potential alterations in neuronal maturation. The isogenic models generated here will provide a unique resource to study this less-common variant of the 22q11.2 microdeletion syndrome.

Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent aneuploidy observed in the human population and represents the most common genetic form of intellectual disability and early-onset Alzheimer's disease (AD). Individuals with DS exhibit a wide spectrum of clinical presentation, with a number of organs implicated including the neurological, immune, musculoskeletal, cardiac, and gastrointestinal systems. Decades of DS research have illuminated our understanding of the disorder, however many of the features that limit quality of life and independence of individuals with DS, including intellectual disability and early-onset dementia, remain poorly understood. This lack of knowledge of the cellular and molecular mechanisms leading to neurological features of DS has caused significant roadblocks in developing effective therapeutic strategies to improve quality of life for individuals with DS. Recent technological advances in human stem cell culture methods, genome editing approaches, and single-cell transcriptomics have provided paradigm-shifting insights into complex neurological diseases such as DS. Here, we review novel neurological disease modeling approaches, how they have been used to study DS, and what questions might be addressed in the future using these innovative tools.

Congenital heart disease (CHD) in pregnancy is associated with an increased risk of adverse maternal, obstetric, and neonatal outcomes, plausibly through mechanisms involving abnormal placental development and function. This retrospective study aims to elucidate how maternal CHD influences placental health. Demographic and clinical information were collected via electronic medical record review, and placentas underwent histopathological evaluation. Fifty-three singleton pregnancies were included: 35 participants (66%) were classified as lower cardiovascular risk (modified World Health Organization Classification (mWHO) I, II, II-III), and 18 (34%) were classified as higher cardiovascular risk (mWHO III, IV). 12 participants (23%) had a fetus with small for gestational age (SGA). Maternal vascular malperfusion (53%) and placental abruption (11.6%) were common in this cohort, with prevalence above baseline risk. Participants at higher cardiovascular risk had higher rates of SGA (p = 0.04), subchorionic hematomas (p = 0.01) and birth weight:placental weight

BackgroundLiveborn infants with non-mosaic trisomy 22 are rarely described in the medical literature. Reported lifespan of these patients ranges from minutes to 3 years, with the absence of cardiac anomalies associated with longer-term survival. The landscape for offering cardiac surgery to patients with rare autosomal trisomies is currently evolving, as has been demonstrated recently in trisomies 13 and 18. However, limited available data on patients with rare autosomal trisomies provides a significant challenge in perinatal counseling, especially when there are options for surgical intervention.Case presentationIn this case report, we describe an infant born at term with prenatally diagnosed apparently non-mosaic trisomy 22 and multiple cardiac anomalies, including a double outlet right ventricle, hypoplastic aortic valve and severe aortic arch hypoplasia, who underwent cardiac surgery. The decisions made by her family lending to her progress and survival to this day were made with a focus on the shared decision making model and support in the prenatal and perinatal period. We also review the published data on survival and quality of life after cardiac surgery in infants with rare trisomies.ConclusionsThis patient is the only known case of apparently non-mosaic trisomy 22 in the literature who has undergone cardiac surgery with significant survival benefit. This case highlights the impact of using a shared decision making model when there is prognostic uncertainty.

OBJECTIVE: To determine whether differential exposure to an adverse maternal fetal environment partially explains disparate outcomes in infants with major congenital heart disease (CHD). STUDY DESIGN: Retrospective cohort study utilizing a population-based administrative California database (2011-2017). Primary exposure: Race/ethnicity. Primary mediator: Adverse maternal fetal environment (evidence of maternal metabolic syndrome and/or maternal placental syndrome). OUTCOMES: Composite of 1-year mortality or severe morbidity and days alive out of hospital in the first year of life (DAOOH). Mediation analyses determined the percent contributions of mediators on pathways between race/ethnicity and outcomes after adjusting for CHD severity. RESULTS: Included were 2747 non-Hispanic White infants (reference group), 5244 Hispanic, and 625 non-Hispanic Black infants. Hispanic and non-Hispanic Black infants had a higher risk for composite outcome (crude OR: 1.18; crude OR: 1.25, respectively) and fewer DAOOH (-6 & -12 days, respectively). Compared with the reference group, Hispanic infants had higher maternal metabolic syndrome exposure (43% vs 28%, OR: 1.89), and non-Hispanic Black infants had higher maternal metabolic syndrome (44% vs 28%; OR: 1.97) and maternal placental syndrome exposure (18% vs 12%; OR, 1.66). Both maternal metabolic syndrome exposure (OR: 1.21) and maternal placental syndrome exposure (OR: 1.56) were related to composite outcome and fewer DAOOH (-25 & -16 days, respectively). Adverse maternal fetal environment explained 25% of the disparate relationship between non-Hispanic Black race and composite outcome and 18% of the disparate relationship between Hispanic ethnicity and composite outcome. Adverse maternal fetal environment explained 16% (non-Hispanic Black race) and 21% (Hispanic ethnicity) of the association with DAOOH. CONCLUSIONS: Increased exposure to adverse maternal fetal environment contributes to racial and ethnic disparities in major CHD outcomes.

PURPOSE: To characterize temporal trends and outcomes of delivery hospitalization with maternal congenital heart disease (CHD). MATERIALS AND METHODS: For this repeated cross-sectional analysis, deliveries to women aged 15-54 years with maternal CHD were identified in the 2000-2018 National Inpatient Sample. Temporal trends in maternal CHD were analyzed using joinpoint regression to estimate the average annual percentage change (AAPC) with 95% CIs. The relationship between maternal CHD and several adverse maternal outcomes was analyzed with log-linear regression models. Risk for adverse outcomes in the setting of maternal CHD was further characterized based on additional diagnoses of cardiac comorbidity including congestive heart failure, arrhythmia, valvular disease, pulmonary disorders, and history of thromboembolism. RESULTS: Of 73,109,790 delivery hospitalizations, 51,841 had a diagnosis of maternal CHD (7.1 per 10,000). Maternal CHD rose from 4.2 to 10.9 per 10,000 deliveries (AAPC 4.8%, 95% CI 4.2%, 5.4%). Maternal CHD deliveries with a cardiac comorbidity diagnosis also increased from 0.6 to 2.6 per 10,000 from 2000 to 2018 (AAPC 8.4%, 95% CI 6.3%, 10.6%). Maternal CHD was associated with severe maternal morbidity (adjusted risk ratios [aRR] 4.97, 95% CI 4.75, 5.20), cardiac severe maternal morbidity (aRR 7.65, 95% CI 7.14, 8.19), placental abruption (aRR 1.30, 95% 1.21, 1.38), preterm delivery (aRR 1.47, 95% CI 1.43, 1.51), and transfusion (aRR 2.28, 95% CI 2.14, 2.42). Risk for severe morbidity (AAPC 4.7%, 95% CI 2.5%, 6.9%) and cardiac severe morbidity (AAPC 4.7%, 95% CI 2.5%, 6.9%) increased significantly among women with maternal CHD over the study period. The presence of cardiac comorbidity diagnoses was associated with further increased risk. CONCLUSION: Maternal CHD is becoming more common among US deliveries. Among deliveries with maternal CHD, risk for severe morbidity is increasing. These findings support that an increasing burden of risk from maternal CHD in the obstetric population.

STUDY OBJECTIVE: Infants with genital development considered atypical for assigned female sex may undergo feminizing genitoplasty (clitoroplasty and/or vaginoplasty) in early life. We sought to identify factors associated with parent/caregiver decisions regarding genitoplasty for their children with genital virilization. DESIGN: Longitudinal, observational study SETTING: Twelve pediatric centers in the United States with multidisciplinary differences/disorders of sex development clinics, 2015-2020 PARTICIPANTS: Children under 2 years old with genital appearance atypical for female sex of rearing and their parents/caregivers INTERVENTIONS/OUTCOME MEASURES: Data on the childs diagnosis and anatomic characteristics before surgery were extracted from the medical record. Parents/caregivers completed questionnaires on psychosocial distress, experience of uncertainty, cosmetic appearance of their childs genitalia, and demographic characteristics. Urologists rated cosmetic appearance. For 58 patients from the study cohort with genital virilization being raised as girls or gender-neutral, we compared these data across 3 groups based on the childs subsequent surgical intervention: (i) no surgery (n = 5), (ii) vaginoplasty without clitoroplasty (V-only) (n = 15), and (iii) vaginoplasty and clitoroplasty (V+C) (n = 38). RESULTS: Fathers and urologists ratings of genital appearance were more favorable in the no-surgery group than in the V-only and V+C groups. Clitorophallic length was greater in the V+C group compared with the V-only group, with substantial overlap between groups. Mothers depressive and anxious symptoms were lower in the no-surgery group compared with the V-only and V+C groups. CONCLUSIONS: Surgical decisions were associated with fathers and urologists ratings of genital appearance, the childs anatomic characteristics, and mothers depressive and anxious symptoms. Further research on surgical decision-making is needed to inform counseling practices.

BackgroundCongenital syphilis is preventable through timely access to prenatal care, syphilis screening and treatment of pregnant women diagnosed as infected. In 2018, California had the second highest number of congenital syphilis cases in the United States (U.S.), a nearly twofold increase in cases since 2014. This study assessed gaps in preventing congenital syphilis in the high morbidity region of Kern County, California.MethodsBetween May 2018 and January 2019, we conducted five focus group discussions with pregnant/postpartum women and ten semi-structured interviews with prenatal care providers in Kern County. Focus group and interview data were recorded, transcribed, and analyzed to identify emergent themes pertaining to facilitators and barriers at each step (prenatal care, syphilis screening and treatment) in the congenital syphilis prevention cascade.ResultsGaps in congenital syphilis prevention discussed in focus group discussions with pregnant/postpartum women were related to limited prenatal care access, social-, economic-, and cultural-barriers, and substance use and co-occurring intimate partner/domestic violence. The gaps identified from interviews with prenatal care providers included social economic vulnerabilities of pregnant women and stigma and shame around the vulnerabilities, distrust in medical system, prenatal substance use, limited prenatal substance use disorder treatment facilities, and inadequate provider training on context-specific congenital syphilis management strategies. Gaps in partner notification, screening and treatment for syphilis were brought up by pregnant/postpartum women and prenatal care providers.ConclusionsCongenital syphilis continues to increase in Kern County and throughout the U.S. In high syphilis morbidity areas, comprehensive and tailored public health approaches addressing setting-specific gaps in prenatal screening and treatment are needed.

BackgroundCongenital syphilis (CS) has reemerged as a global maternal and child health crisis. Kern County, California and East Baton Rouge Parish, Louisiana are among the highest CS morbidity regions in the United States. We previously reported on social-ecological and structural barriers to prenatal care and maternal syphilis testing and treatment in these two regions. The aim of this study was to examine perinatal patient's health preferences and perceptions of patient-provider relationships in the prenatal care clinic setting.MethodsBetween May 2018 and January 2019 we conducted 20 in-depth qualitative interviews with prenatal providers and 8 focus group discussions with pregnant and postpartum individuals in Kern County and East Baton Rouge Parish. We applied an adapted health services framework to analyze participants' understanding of health disparities and vulnerable populations; perinatal patient's health and prenatal care preferences; and participants' perspectives of clinical encounters in the context of prenatal care and maternal syphilis testing and treatment.ResultsSite-specific determinants of syphilis infection emerged but participants from both locations felt CS prevention efforts should be prioritized among youth, racial/ethnic minority populations, people experiencing socioeconomic limitations and people with other commonly occurring health conditions. Although perinatal patients expressed clear health preferences, they reported inconsistent receipt of respectful, patient-centered care. Inconsistencies were connected with limited ethnic and cultural competence among providers, and implicit, negative attitudes toward patients using substances, experiencing homelessness, or engaging in sex work. Providers clearly aimed to offer high quality prenatal care. However, some clinic and health systems level factors were thought to reduce positive and communicative patient-provider relationships, contributing to gaps in use of prenatal care and syphilis testing and treatment.ConclusionsOur findings suggest that interventions tailored to address setting-specific determinants (including clinic and health system factors) of disparities in CS risk could improve pregnant people's access to prenatal care and ensure they and their sex partners receive timely syphilis screening and treatment. We recommend all prenatal care providers receive training on how to identify and mitigate implicit biases and provide competent and compassionate patient-centered care.

BackgroundRelationships between gut microbiomes and airway immunity have been established in murine and human studies of allergy and asthma. Early life Lactobacillus supplementation alters the composition and metabolic productivity of the gut microbiome. However, little is known of how Lactobacillus supplementation impacts the gut microbiota in children with cystic fibrosis (CF) and whether specific microbiota states that arise following gut microbiome manipulation relate to pulmonary outcomes.MethodsStool samples were collected from CF patients enrolled in a multi-center, double-blind, randomized placebo-controlled trial of daily Lactobacillus rhamnosus strain GG (LGG) probiotic supplementation over a 12-month period. Fecal 16S rRNA biomarker sequencing was used to profile fecal bacterial microbiota and analyses were performed in QiiME.ResultsBifidobacteria-dominated fecal microbiota were more likely to arise in LGG-treated children with CF (P = 0.04). Children with Bifidobacteria-dominated gut microbiota had a reduced rate of pulmonary exacerbations (IRR = 0.55; 95% CI 0.25 to 0.82; P = 0.01), improved pulmonary function (+ 20.00% of predicted value FEV1; 95% CI 8.05 to 31.92; P = 0.001), lower intestinal inflammation (Calprotectin; Coef =  - 16.53 μg g-1 feces; 95% CI - 26.80 to - 6.26; P = 0.002) and required fewer antibiotics (IRR = 0.43; 95% CI 0.22 to 0.69; P = 0.04) compared to children with Bacteroides-dominated microbiota who were less likely to have received LGG.ConclusionsThe majority of pediatric CF patients in this study possessed a Bacteroides- or Bifidobacteria-dominated gut microbiota. Bifidobacteria-dominated gut microbiota were more likely to be associated with LGG-supplementation and with better clinical outcomes.

BACKGROUND: Congenital dislocation of the knee (CDK) is rare and can cause significant distress in the delivery room to parents and to healthcare providers, especially if the latter are unaware of this condition. It may not be detected by prenatal ultrasound and can be either an isolated finding or associated with other anomalies such as developmental hip dysplasia and genetic syndromes such as Larsen syndrome. Because of the risk of development of contractures, immediate referral to a specialized provider is needed. Poor prognostic factors include an association with a genetic syndrome, limited knee flexion related to severe quadriceps retraction, and absence of anterior skin grooves. A satisfactory outcome can be anticipated in isolated cases with easy reducibility of the knee. CASE REPORT: A term baby presented unexpectedly with left knee dislocation after delivery. The providers, unaware of the condition, immediately consulted the orthopedic service, who assisted in the diagnosis, and appropriate management was initiated. The baby had serial casting of the leg, which was applied for almost 3 months, with excellent results on the clinical examination. CONCLUSIONS: CDK is a rare finding. The diagnosis is primarily clinical and radiographs are used to confirm and assess the degree of the dislocation. The degree of dislocation is important for management and prognosis. Interventions ranging from serial casting to surgery are required as soon as possible. As the CDK can be associated with genetic syndromes or other dysplasias such as developmental dysplasia of the hip and talipes equinovarus, further evaluation for these conditions is warranted. [ABSTRACT FROM AUTHOR]

Environmental toxicants and pollutants are causes of adverse health consequences, including well-established associations between environmental exposures and cardiovascular diseases. Environmental degradation is widely prevalent and has a long latency period between exposure and health outcome, potentially placing a large number of individuals at risk of these health consequences. Emerging evidence suggests that environmental exposures in early life may be key risk factors for cardiovascular conditions across the life span. Children are a particularly sensitive population for the detrimental effects of environmental toxicants and pollutants given the long-term cumulative effects of early-life exposures on health outcomes, including congenital heart disease, acquired cardiac diseases, and accumulation of cardiovascular disease risk factors. This scientific statement highlights representative examples for each of these cardiovascular disease subtypes and their determinants, focusing specifically on the associations between climate change and congenital heart disease, airborne particulate matter and Kawasaki disease, blood lead levels and blood pressure, and endocrine-disrupting chemicals with cardiometabolic risk factors. Because children are particularly dependent on their caregivers to address their health concerns, this scientific statement highlights the need for clinicians, research scientists, and policymakers to focus more on the linkages of environmental exposures with cardiovascular conditions in children and adolescents. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) infection represents a major issue worldwide, since it constitutes the most common viral congenital infection, with a prevalence of 0.58% and 1–5% in developed and developing countries, respectively. According to recent studies, prenatal treatment significantly decreases the risk of vertical CMV transmission, and early intervention may even prevent the termination of pregnancy. This study aimed to investigate the level of awareness of CMV among pregnant patients through a semi-systematic review. Methods: We included all of the original articles investigating knowledge and awareness about CMV infection among pregnant women. Our research included the PubMed database. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, the Covidence system automatically guided us to screen the titles and/or abstracts, and then full-texts, followed by data extraction from the eligible studies. Results: We screened 764 studies altogether, with 13 studies included in this analysis. Knowledge about the existence of CMV infection risk varied between the articles, ranging from 11.4% in a study performed in Ireland to 60% reported in a study on the French population. Studies analyzing the impact of educational interventions on patients' knowledge about preventive measures reported significant improvement compared to their level of awareness before the intervention. Conclusions: Patients' awareness and knowledge about CMV seemed to be generally low or very low during the last decade before the development of effective secondary prevention methods. Educational interventions seem to be effective, and therefore their wide use could be of potential benefit. In the era of available secondary prevention of vertical transmission, it is crucial to concentrate the efforts of different stakeholders to increase the awareness of cCMV among pregnant women. [ABSTRACT FROM AUTHOR]

An absolute erythrocytosis is present when the red cell mass is greater than 125% of the predicted. This is suspected when the hemoglobin or hematocrit is above the normal range. An erythrocytosis can be classified as primary or secondary and congenital or acquired. The commonest primary acquired disorder is polycythemia vera. The diagnostic criteria for PV have evolved over time and this is the main diagnosis managed in hematology clinics. There are a variety of rare congenital causes both primary and secondary. In particular in young patients and/or those with a family history a congenital cause is suspected. There remains a larger cohort with acquired erythrocytosis mainly with non‐hematological pathology. In order to explore for a cause of erythrocytosis, measurement of the erythropoietin level is a first step. A low erythropoietin level indicates a primary cause and a normal or elevated level indicates a secondary etiology. Further investigation is then dictated by initial findings and includes mutational testing with PCR and NGS for those in whom a congenital cause is suspected. Following this possibly bone marrow biopsy, scans, and further investigation as indicated by history and initial findings. Investigation is directed toward the identification of those with a hematological disorder which would be best managed following guidelines in hematology clinics and referral elsewhere in those for whom there are non‐hematological reasons for the elevated hemoglobin. [ABSTRACT FROM AUTHOR]

Prompt medical attention is crucial for congenital intracranial vascular malformations in children and newborns due to potential severe outcomes. Imaging is pivotal for accurate identification, given the diverse risks and treatment strategies. This article aims to enhance the identification and understanding of congenital intracranial vascular abnormalities including arteriovenous malformation, arteriovenous fistula, cavernous malformation, capillary telangiectasia, developmental venous anomaly, and sinus pericranii in pediatric patients. [ABSTRACT FROM AUTHOR]