Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.

Machine learning in action: Revolutionizing intracranial hematoma detection and patient transport decision-making.

Objectives: Traumatic intracranial hematomas represent a critical clinical situation where early detection and management are of utmost importance. Machine learning has been recently used in the detection of neuroradiological findings. Hence, it can be used in the detection of intracranial hematomas and furtherly initiate a management cascade of patient transfer, diagnostics, admission, and emergency intervention. We aim, here, to develop a diagnostic tool based on artificial intelligence to detect hematomas instantaneously, and automatically start a cascade of actions that support the management protocol depending on the early diagnosis. Materials and Methods: A plot was designed as a staged model: The first stage of initiating and training the machine with the provisional evaluation of its accuracy and the second stage of supervised use in a tertiary care hospital and a third stage of its generalization in primary and secondary care hospitals. Two datasets were used: CQ500, a public dataset, and our dataset collected retrospectively from our tertiary hospital. Results: A mean dice score of 0.83 was achieved on the validation set of CQ500. Moreover, the detection of intracranial hemorrhage was successful in 94% of cases for the CQ500 test set and 93% for our local institute cases. Poor detection was present in only 6-7% of the total test set. Moderate false-positive results were encountered in 18% and major false positives reached 5% for the total test set. Conclusion: The proposed approach for the early detection of acute intracranial hematomas provides a reliable outset for generating an automatically initiated management cascade in high-flow hospitals.

Determining the Minimum Dataset for Surgical Patients in Africa: A Delphi Study.

BACKGROUND: It is often difficult for clinicians in African low- and middle-income countries middle-income countries to access useful aggregated data to identify areas for quality improvement. The aim of this Delphi study was to develop a standardised perioperative dataset for use in a registry. METHODS: A Delphi method was followed to achieve consensus on the data points to include in a minimum perioperative dataset. The study consisted of two electronic surveys, followed by an online discussion and a final electronic survey (four Rounds). RESULTS: Forty-one members of the African Perioperative Research Group participated in the process. Forty data points were deemed important and feasible to include in a minimum dataset for electronic capturing during the perioperative workflow by clinicians. A smaller dataset consisting of eight variables to define risk-adjusted perioperative mortality rate was also described. CONCLUSIONS: The minimum perioperative dataset can be used in a collaborative effort to establish a resource accessible to African clinicians in improving quality of care.

Nurses' Priorities for Perioperative Research in Africa.

BACKGROUND: Mortality rates among surgical patients in Africa are double those of surgical patients in high-income countries. Internationally, there is a call to improve access to and safety of surgical and perioperative care. Perioperative research needs to be coordinated across Africa to positively impact perioperative mortality. METHODS: The aim of this study was to determine the top 10 perioperative research priorities for perioperative nurses in Africa, using a research priority-setting process. A Delphi technique with 4 rounds was used to establish consensus on the top 10 perioperative research priorities. In the first round, respondents submitted research priorities. Similar research priorities were amalgamated into single priorities when possible. In round 2, respondents ranked the priorities using a scale from 1 to 10 (of which 1 is the first/highest priority, and 10 is the last/lowest priority). The top 20 (of 31) were determined after round 2. In round 3, respondents ranked their top 10 priorities. The final round was an online discussion to reach consensus on the top 10 perioperative research priorities. RESULTS: A total of 17 perioperative nurses representing 12 African countries determined the top research priorities, which were: (1) strategies to translate and implement perioperative research into clinical practice in Africa, (2) creating a perioperative research culture and the tools, resources, and funding needed to conduct perioperative nursing research in Africa, (3) optimizing nurse-led postoperative pain management, (4) survey of operating theater and critical care resources, (5) perception of, and adherence to sterile field and aseptic techniques among surgeons in Africa (6) surgical staff burnout, (7) broad principles of infection control in surgical wards, (8) the role of interprofessional communication to promote clinical teamwork when caring for surgical patients, (9) effective implementation of the surgical safety checklist and measures of its impact, and (10) constituents of quality nursing care. CONCLUSIONS: These research priorities provide the structure for an intermediate-term research agenda for perioperative research in Africa.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing.

The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF. Thirteen had isolated and 32 had nonisolated EA/TEF; none had a family history of EA/TEF. We identified de novo variants in protein-coding regions, including 19 missense variants predicted to be deleterious (D-mis) and 3 likely gene-disrupting (LGD) variants. Consistent with previous studies of structural birth defects, there is a trend of increased burden of de novo D-mis in cases (1.57-fold increase over the background mutation rate), and the burden is greater in constrained genes (2.55-fold, p = 0.003). There is a frameshift de novo variant in EFTUD2, a known EA/TEF risk gene involved in mRNA splicing. Strikingly, 15 out of 19 de novo D-mis variants are located in genes that are putative target genes of EFTUD2 or SOX2 (another known EA/TEF gene), much greater than expected by chance (3.34-fold, p value = 7.20e-5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identified APC2, AMER3, PCDH1, GTF3C1, POLR2B, RAB3GAP2, and ITSN1 as plausible candidate genes in the etiology of EA/TEF. We conclude that further genomic analysis to identify de novo variants will likely identify previously undescribed genetic causes of EA/TEF.

De novo variants in congenital diaphragmatic hernia identify MYRF as a new syndrome and reveal genetic overlaps with other developmental disorders.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

Perioperative patient outcomes in the African Surgical Outcomes Study: a 7-day prospective observational cohort study.

BACKGROUND: There is a need to increase access to surgical treatments in African countries, but perioperative complications represent a major global health-care burden. There are few studies describing surgical outcomes in Africa. METHODS: We did a 7-day, international, prospective, observational cohort study of patients aged 18 years and older undergoing any inpatient surgery in 25 countries in Africa (the African Surgical Outcomes Study). We aimed to recruit as many hospitals as possible using a convenience sampling survey, and required data from at least ten hospitals per country (or half the surgical centres if there were fewer than ten hospitals) and data for at least 90% of eligible patients from each site. Each country selected one recruitment week between February and May, 2016. The primary outcome was in-hospital postoperative complications, assessed according to predefined criteria and graded as mild, moderate, or severe. Data were presented as median (IQR), mean (SD), or n (%), and compared using t tests. This study is registered on the South African National Health Research Database (KZ_2015RP7_22) and ClinicalTrials.gov (NCT03044899). FINDINGS: We recruited 11 422 patients (median 29 [IQR 10-70]) from 247 hospitals during the national cohort weeks. Hospitals served a median population of 810 000 people (IQR 200 000-2 000 000), with a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 (0·2-1·9) per 100 000 population. Hospitals did a median of 212 (IQR 65-578) surgical procedures per 100 000 population each year. Patients were younger (mean age 38·5 years [SD 16·1]), with a lower risk profile (American Society of Anesthesiologists median score 1 [IQR 1-2]) than reported in high-income countries. 1253 (11%) patients were infected with HIV, 6504 procedures (57%) were urgent or emergent, and the most common procedure was caesarean delivery (3792 patients, 33%). Postoperative complications occurred in 1977 (18·2%, 95% CI 17·4-18·9]) of 10 885 patients. 239 (2·1%) of 11 193 patients died, 225 (94·1%) after the day of surgery. Infection was the most common complication (1156 [10·2%] of 10 970 patients), of whom 112 (9·7%) died. INTERPRETATION: Despite a low-risk profile and few postoperative complications, patients in Africa were twice as likely to die after surgery when compared with the global average for postoperative deaths. Initiatives to increase access to surgical treatments in Africa therefore should be coupled with improved surveillance for deteriorating physiology in patients who develop postoperative complications, and the resources necessary to achieve this objective. FUNDING: Medical Research Council of South Africa.

Gastric tube esophagoplasty for pediatric esophageal replacement.

BACKGROUND: Esophageal replacement in children is indicated in cases of esophageal atresia with or without fistula, in case of long gap esophageal atresia or failed primary repair. Intractable post corrosive esophageal stricture is considered also a major indication for replacement. METHODS: This is a cohort retrospective study of esophageal replacement cases by gastric tube carried out at the pediatric surgery department at Cairo University between 2011 and 2015. We reported 50 patients (30 boys and 20 girls); the ages ranged from 7months to 9years. Esophageal atresia cases were 27 while caustic esophageal stricture cases were 23. Isoperistaltic gastric tube technique was done in 45 patients while antiperistaltic (reversed) gastric tube technique was done in 5 cases. Retrosternal route was chosen in 38 patients while transhiatal route was chosen in 12 patients. RESULTS: Leakage and stricture were the most common complications. We had 5 cases of mortality, which were caused mainly by chest related complications. We had excellent to good results during long term follow up in terms of weight gain, swallowing pattern, quality of life, and overall satisfaction CONCLUSION: Gastric tube is a satisfactory surgical method for esophageal replacement in children. LEVEL OF EVIDENCE: III.

Dumbbell-Shaped Rhabdomyosarcoma: Two-Stage Surgical Resection.

Female neonate admitted to our hospital with an abdominal mass and a thigh mass that were connected as a single dumbbell-shaped mass. CT was done on admission that showed cystic swelling in the thigh with intra-abdominal extension passing under inguinal ligament, most probably lymphangioma. The patient was assessed and prepared for surgery starting with the abdominal part then after two days for the thigh mass. Distal pulses in the lower limbs were assessed intra- and postoperatively following both surgeries. The pathology report showed rhabdomyosarcoma of the embryonal type.

Isolated Thoracoschisis: Case Report and Review of Literature.

A full-term male baby presented at day 2 postnatal with Riedel liver lobe, stomach, and much of the bowel herniating through a thoracic wall defect located just above and lateral to the left nipple. Operative conversion into a gastroschisis-like defect with construction of a silo bag was done. On thorough review of literature, it was found that this is only the second male infant reported with isolated thoracoschisis.