Publications

Export 432 results:
Sort by: Author Title Type [ Year  (Desc)]
Submitted
Eissa, I. H., H. Mohammad, O. A. Qassem, W. Younis, T. M. Abdelghany, A. Elshafeey, M. A. R. M. Moustafa, M. N. Seleem, and A. S. Mayhoub, "{Diphenylurea derivatives for combating methicillin-and vancomycinresistant Staphylococcus aureus}", {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}, vol. {130}, {23 RUE LINOIS, 75724 PARIS, FRANCE}, {ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER}, pp. {73-85}, {APR 21}, Submitted. Abstract

{A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin-and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structureactivity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics. (C) 2017 Elsevier Masson SAS. All rights reserved.}

HUSSEIN, G. A. D. H. A. S. S. A. N. G. A. D., M. Chen, P. - P. Qi, Q. - K. Cui, Y. Yu, W. - H. Hu, Y. Tian, Q. - X. Fan, Z. - X. Gao, M. - W. Feng, et al., "Aquaculture industry development, annual price analysis and out-of-season spawning in largemouth bass Micropterus salmoides", Aquaculture, vol. 519, issue 30 March 2020, pp. 734901, Submitted.
Tobail, O., E. Quiroga-González, J. Carstensen, and H. Föll, Supporting Material, , Submitted. Abstract
n/a
Bhangu, A., A. O. Ademuyiwa, M. L. Aguilera, P. Alexander, S. W. Al-Saqqa, G. Borda-Luque, A. Costas-Chavarri, T. M. Drake, F. Ntirenganya, E. J. Fitzgerald, et al., "Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study", The Lancet Infectious DiseasesThe Lancet Infectious Diseases: Elsevier, Submitted. AbstractWebsite

BackgroundSurgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world.BackgroundSurgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world.

2022
Méndez-Sánchez, N., E. Bugianesi, R. G. Gish, F. Lammert, H. Tilg, M. H. Nguyen, S. K. Sarin, N. Fabrellas, S. Zelber-Sagi, J. - G. Fan, et al., "Global multi-stakeholder endorsement of the MAFLD definition", The Lancet Gastroenterology & HepatologyThe Lancet Gastroenterology & Hepatology, vol. 7, issue 5: Elsevier, pp. 388 - 390, 2022. AbstractWebsite
n/a
Quirke, J. C. K., G. C. Sati, A. Sonousi, M. Gysin, K. Haldimann, E. C. Böttger, A. Vasella, S. N. Hobbie, and D. Crich, "Structure-Activity Relationships for 5′′ Modifications of 4,5-Aminoglycoside Antibiotics", ChemMedChem, vol. n/a, issue n/a: John Wiley & Sons, Ltd, pp. e202200120, 2022. AbstractWebsite

Abstract Modification at the 5??-position of 4,5-disubstituted aminoglycoside antibiotics (AGAs) to circumvent inactivation by aminoglycoside modifying enzymes (AMEs) is well known. Such modifications, however, unpredictably impact activity and affect target selectivity thereby hindering drug development. A survey of 5??-modifications of the 4,5-AGAs and the related 5-O-furanosyl apramycin derivatives is presented. In the neomycin and the apralog series, all modifications were well-tolerated, but other 4,5-AGAs require a hydrogen bonding group at the 5??-position for maintenance of antibacterial activity. The 5??-amino modification resulted in parent-like activity, but reduced selectivity against the human cytosolic decoding A site rendering this modification unfavorable in paromomycin, propylamycin, and ribostamycin. Installation of a 5??-formamido group and, to a lesser degree, a 5??-ureido group resulted in parent-like activity without loss of selectivity. These lessons will aid the design of next-generation AGAs capable of circumventing AME action while maintaining high antibacterial activity and target selectivity.

Hernández-Molina, G., B. Kostov, P. Brito-Zerón, A. Vissink, T. Mandl, A. C. Hinrichs, L. Quartuccio, C. Baldini, R. Seror, A. Szántó, et al., "Characterization and outcomes of 414 patients with primary SS who developed hematological malignancies.", Rheumatology (Oxford, England), 2022. Abstract

OBJECTIVE: To characterize 414 patients with primary SS who developed hematological malignancies and to analyze how the main SS- and lymphoma-related features can modify the presentation patterns and outcomes.

METHODS: By January 2021, the Big Data Sjögren Project Consortium database included 11 966 patients fulfilling the 2002/2016 classification criteria. Hematological malignancies diagnosed according to the World Health Organization (WHO) classification were retrospectively identified.

RESULTS: There were 414 patients (355 women, mean age 57 years) with hematological malignancies (in 43, malignancy preceded at least one year the SS diagnosis). 376 (91%) patients had mature B cell malignancy, nearly half MALT lymphoma (n = 197), followed by DLBCL (n = 67), nodal MZL lymphoma (n = 29), CLL/SLL (n = 19) and follicular lymphoma (n = 17). Rates of complete response, relapses and death were 80%, 34% and 13%, respectively, with a 5-year survival rate of 86.5% after a mean follow-up of 8 years. There were significant differences in age at diagnosis (younger in MALT, older in CLL/SLL), predominant clinical presentation (glandular enlargement in MALT lymphoma, peripheral lymphadenopathy in nodal MZL and FL, constitutional symptoms in DLBCL, incidental diagnosis in CLL/SLL), therapeutic response (higher in MALT lymphoma, lower in DLBCL) and survival (better in MALT, nodal MZL and FL, worse in DLBCL).

CONCLUSION: In the largest reported study of hematological malignancies complicating primary SS, we confirm the overwhelming predominance of B cell lymphomas, especially MALT, with the salivary glands being the primary site of involvement. This highly-specific histopathological scenario is linked with the overall good prognosis with a 5-year survival rate of nearly 90%.

Iqbal, T., M. Ashraf, S. Afsheen, A. Masood, M. T. Qureshi, S. T. Obediat, M. F. Hamed, and M. S. Othman, "Copper sulfide (CuS) doped with carbon quantum dots (CQD) as an efficient photo catalyst", Optical Materials, vol. 125: Elsevier, pp. 112116, 2022. Abstract
n/a
Ahmad, M., M. T. Qureshi, W. Rehman, N. H. Alotaibi, A. Gul, R. A. S. Hameed, M. Al Elaimi, M. F. H. Abd El-kader, M. Nawaz, and R. Ullah, "Enhanced photocatalytic degradation of RhB dye from aqueous solution by biogenic catalyst Ag@ ZnO", Journal of Alloys and Compounds, vol. 895: Elsevier, pp. 162636, 2022. Abstract
n/a
on Collaborative, G. H. R. G. C. ’s N. - C. D., "Impact of the COVID-19 pandemic on patients with paediatric cancer in low-income, middle-income and high-income countries: a multicentre, international, observational cohort study", BMJ Open, vol. 12, no. 4: British Medical Journal Publishing Group, 2022. AbstractWebsite

Objectives Paediatric cancer is a leading cause of death for children. Children in low-income and middle-income countries (LMICs) were four times more likely to die than children in high-income countries (HICs). This study aimed to test the hypothesis that the COVID-19 pandemic had affected the delivery of healthcare services worldwide, and exacerbated the disparity in paediatric cancer outcomes between LMICs and HICs.Design A multicentre, international, collaborative cohort study.Setting 91 hospitals and cancer centres in 39 countries providing cancer treatment to paediatric patients between March and December 2020.Participants Patients were included if they were under the age of 18 years, and newly diagnosed with or undergoing active cancer treatment for Acute lymphoblastic leukaemia, non-Hodgkin’s lymphoma, Hodgkin lymphoma, Wilms’ tumour, sarcoma, retinoblastoma, gliomas, medulloblastomas or neuroblastomas, in keeping with the WHO Global Initiative for Childhood Cancer.Main outcome measure All-cause mortality at 30 days and 90 days.Results 1660 patients were recruited. 219 children had changes to their treatment due to the pandemic. Patients in LMICs were primarily affected (n=182/219, 83.1%). Relative to patients with paediatric cancer in HICs, patients with paediatric cancer in LMICs had 12.1 (95% CI 2.93 to 50.3) and 7.9 (95% CI 3.2 to 19.7) times the odds of death at 30 days and 90 days, respectively, after presentation during the COVID-19 pandemic (p<0.001). After adjusting for confounders, patients with paediatric cancer in LMICs had 15.6 (95% CI 3.7 to 65.8) times the odds of death at 30 days (p<0.001).Conclusions The COVID-19 pandemic has affected paediatric oncology service provision. It has disproportionately affected patients in LMICs, highlighting and compounding existing disparities in healthcare systems globally that need addressing urgently. However, many patients with paediatric cancer continued to receive their normal standard of care. This speaks to the adaptability and resilience of healthcare systems and healthcare workers globally.Data are available on reasonable request. Deidentified date will be shared on request.

ElMetnawy, W. H., M. Qenawi, S. Sabet, and H. Bassiony, "Mutation patterns of epidermal growth factor receptor gene in non-small cell lung cancer among Egyptian patients", EGYPTIAN JOURNAL OF BASIC AND APPLIED SCIENCES, vol. 9, issue 1, pp. 77-90, 2022.
Abdel-Ghaffar, F., K. G. Varjabedian, M. Fol, N. Talal, S. A. Quraishy, and R. Abdel-Gaber, "Pharyngodon mamillatus (Nematoda: Pharyngodonidae) in the ocellated skink Chalcides ocellatus (Squamata: Scincidae) from Egypt: Light and scanning electron microscopic studies", Microscopy Research and Technique, vol. Online ahead of print, 2022.
Ibrahim, Y. F., T. M. Kosan, T. C. Quynh, and M. Yousif, "Rings whose cyclics are U-modules", Journal of Algebra and Its Applications, vol. 21, issue 1, 2022.
Soliman, A. A. - H. S., N. M. Kamal, M. W. Abukhatwah, G. E. M. Mashad, I. A. E. R. Gowaad, Y. A. Halabi, S. A. Alalyani, S. A. Qari, and W. E. Afifi, "Sexual maturity of children on regular hemodialysis: Role of testosterone and estradiol, a tertiary multicenter experience.", Medicine, vol. 101, issue 6, pp. e28689, 2022. Abstractmedi-101-e28689.pdf

ABSTRACT: A big problem is the delayed growth and sexual maturity in children with chronic kidney disease (CKD) with the consequent reduction in adults' height. Testosterone and estradiol have significant physiologic changes in children suffering from CKD, resulting in delayed puberty. We aim to assess blood levels of these hormones in patients with CKD-5 on regular hemodialysis.One hundred-six participants were enrolled in the current study, 56 of whom had CKD on hemodialysis 3 times a week 4 hours per session, and 60 healthy age- and gender-matched children acted as controls. Full history was taken, and a clinical review was performed on both patients and controls. The pubertal assessment was performed according to Tanner's classification and laboratory investigations of total and free serum (s.) testosterone in boys and s.estradiol in girls.Patients' weight and height were considerably lower than controls. The free and total s.testosterone of patients were significantly reduced. The same applies to s.estradiol levels which were substantially reduced in comparison to controls. In both patients and controls, Tanner staging & male total s.testosterone levels and female s.estradiol levels had significant positive associations. There was a negative association between the sex hormones levels and the disease's and dialysis duration in the patients' group.S.testosterone and s.estradiol levels were significantly low in CKD patients on dialysis and were positively correlated with delayed pubertal growth observed in those patients.

Soliman, A. A. - H. S., N. M. Kamal, M. W. Abukhatwah, G. E. M. Mashad, I. A. E. R. Gowaad, Y. A. Halabi, S. A. Alalyani, S. A. Qari, and W. E. Afifi, "Sexual maturity of children on regular hemodialysis: Role of testosterone and estradiol, a tertiary multicenter experience.", Medicine, vol. 101, issue 6, pp. e28689, 2022. Abstractmedi-101-e28689_sexual_maturity.pdf

ABSTRACT: A big problem is the delayed growth and sexual maturity in children with chronic kidney disease (CKD) with the consequent reduction in adults' height. Testosterone and estradiol have significant physiologic changes in children suffering from CKD, resulting in delayed puberty. We aim to assess blood levels of these hormones in patients with CKD-5 on regular hemodialysis.One hundred-six participants were enrolled in the current study, 56 of whom had CKD on hemodialysis 3 times a week 4 hours per session, and 60 healthy age- and gender-matched children acted as controls. Full history was taken, and a clinical review was performed on both patients and controls. The pubertal assessment was performed according to Tanner's classification and laboratory investigations of total and free serum (s.) testosterone in boys and s.estradiol in girls.Patients' weight and height were considerably lower than controls. The free and total s.testosterone of patients were significantly reduced. The same applies to s.estradiol levels which were substantially reduced in comparison to controls. In both patients and controls, Tanner staging & male total s.testosterone levels and female s.estradiol levels had significant positive associations. There was a negative association between the sex hormones levels and the disease's and dialysis duration in the patients' group.S.testosterone and s.estradiol levels were significantly low in CKD patients on dialysis and were positively correlated with delayed pubertal growth observed in those patients.

Tawfik, A., S. Ismail, M. Elsayed, M. A. Qyyum, and M. Rehan, "Sustainable microalgal biomass valorization to bioenergy: Key challenges and future perspectives", Chemosphere, vol. 296, issue June 2022, pp. 133812, 2022.
2021
Sonousi, A., J. C. K. Quirke, P. Waduge, T. Janusic, M. Gysin, K. Haldimann, S. Xu, S. N. Hobbie, S. - H. Sha, J. Schacht, et al., "An Advanced Apralog with Increased in vitro and in vivo Activity toward Gram-negative Pathogens and Reduced ex vivo Cochleotoxicity", ChemMedChem, vol. 16, issue 2: John Wiley & Sons, Ltd, pp. 335 - 339, 2021. AbstractWebsite

Abstract We describe the convergent synthesis of a 5-O-?-D-ribofuranosyl-based apramycin derivative (apralog) that displays significantly improved antibacterial activity over the parent apramycin against wild-type ESKAPE pathogens. In addition, the new apralog retains excellent antibacterial activity in the presence of the only aminoglycoside modifying enzyme (AAC(3)-IV) acting on the parent, without incurring susceptibility to the APH(3?) mechanism that disables other 5-O-?-D-ribofuranosyl 2-deoxystreptamine type aminoglycosides by phosphorylation at the ribose 5-position. Consistent with this antibacterial activity, the new apralog has excellent 30?nM activity (IC50) for the inhibition of protein synthesis by the bacterial ribosome in a cell-free translation assay, while retaining the excellent across-the-board selectivity of the parent for inhibition of bacterial over eukaryotic ribosomes. Overall, these characteristics translate into excellent in?vivo efficacy against E. coli in a mouse thigh infection model and reduced ototoxicity vis à vis the parent in mouse cochlear explants.

Akowuah, E., R. A. Benson, E. J. Caruana, G. Chetty, J. Edwards, S. Forlani, G. Gradinariu, G. J. Murphy, A. Y. Oo, A. J. Patel, et al., "Early outcomes and complications following cardiac surgery in patients testing positive for coronavirus disease 2019: An international cohort study", The Journal of Thoracic and Cardiovascular SurgeryThe Journal of Thoracic and Cardiovascular Surgery, vol. 162, issue 2: Elsevier, pp. e355 - e372, 2021. AbstractWebsite
n/a
Glasbey, J., A. Ademuyiwa, A. Adisa, E. Alameer, A. P. Arnaud, F. Ayasra, J. Azevedo, A. Minaya-Bravo, A. Costas-Chavarri, J. Edwards, et al., "Effect of COVID-19 pandemic lockdowns on planned cancer surgery for 15 tumour types in 61 countries: an international, prospective, cohort study", The Lancet OncologyThe Lancet Oncology, vol. 22, issue 11: Elsevier, pp. 1507 - 1517, 2021. AbstractWebsite
n/a
Al-Mushhin, A. A. M., S. H. Qari, M. A. Fakhr, G. S. H. Alnusairi, T. S. Alnusaire, A. A. ALrashidi, A. A. H. A. Latef, O. M. Ali, A. A. Khan, and M. H. Soliman, "Exogenous Myo-Inositol Alleviates Salt Stress by Enhancing Antioxidants and Membrane Stability via the Upregulation of Stress Responsive Genes in Chenopodium quinoa L.", Plants, vol. 10, issue 11, pp. 2416, 2021. AbstractWebsite

Myo-inositol has gained a central position in plants due to its vital role in physiology and biochemistry. This experimental work assessed the effects of salinity stress and foliar application of myo-inositol (MYO) on growth, chlorophyll content, photosynthesis, antioxidant system, osmolyte accumulation, and gene expression in quinoa (Chenopodium quinoa L. var. Giza1). Our results show that salinity stress significantly decreased growth parameters such as plant height, fresh and dry weights of shoot and root, leaf area, number of leaves, chlorophyll content, net photosynthesis, stomatal conductance, transpiration, and Fv/Fm, with a more pronounced effect at higher NaCl concentrations. However, the exogenous application of MYO increased the growth and photosynthesis traits and alleviated the stress to a considerable extent. Salinity also significantly reduced the water potential and water use efficiency in plants under saline regime; however, exogenous application of myo-inositol coped with this issue. MYO significantly reduced the accumulation of hydrogen peroxide, superoxide, reduced lipid peroxidation, and electrolyte leakage concomitant with an increase in the membrane stability index. Exogenous application of MYO up-regulated the antioxidant enzymes’ activities and the contents of ascorbate and glutathione, contributing to membrane stability and reduced oxidative damage. The damaging effects of salinity stress on quinoa were further mitigated by increased accumulation of osmolytes such as proline, glycine betaine, free amino acids, and soluble sugars in MYO-treated seedlings. The expression pattern of OSM34, NHX1, SOS1A, SOS1B, BADH, TIP2, NSY, and SDR genes increased significantly due to the application of MYO under both stressed and non-stressed conditions. Our results support the conclusion that exogenous MYO alleviates salt stress by involving antioxidants, enhancing plant growth attributes and membrane stability, and reducing oxidative damage to plants.

Alnusairi, G. S. H., Y. S. A. Mazrou, S. H. Qari, A. A. Elkelish, M. H. Soliman, M. Eweis, K. Abdelaal, G. A. El-Samad, M. F. M. Ibrahim, and N. ElNahhas, "Exogenous Nitric Oxide Reinforces Photosynthetic Efficiency, Osmolyte, Mineral Uptake, Antioxidant, Expression of Stress-Responsive Genes and Ameliorates the Effects of Salinity Stress in Wheat", Plants, vol. 10, issue 8, pp. 1693, 2021. AbstractWebsite

Salinity stress is one of the major environmental constraints responsible for a reduction in agricultural productivity. This study investigated the effect of exogenously applied nitric oxide (NO) (50 μM and 100 μM) in protecting wheat plants from NaCl-induced oxidative damage by modulating protective mechanisms, including osmolyte accumulation and the antioxidant system. Exogenously sourced NO proved effective in ameliorating the deleterious effects of salinity on the growth parameters studied. NO was beneficial in improving the photosynthetic efficiency, stomatal conductance, and chlorophyll content in normal and NaCl-treated wheat plants. Moreover, NO-treated plants maintained a greater accumulation of proline and soluble sugars, leading to higher relative water content maintenance. Exogenous-sourced NO at both concentrations up-regulated the antioxidant system for averting the NaCl-mediated oxidative damage on membranes. The activity of antioxidant enzymes increased the protection of membrane structural and functional integrity and photosynthetic efficiency. NO application imparted a marked effect on uptake of key mineral elements such as nitrogen (N), potassium (K), and calcium (Ca) with a concomitant reduction in the deleterious ions such as Na+. Greater K and reduced Na uptake in NO-treated plants lead to a considerable decline in the Na/K ratio. Enhancing of salt tolerance by NO was concomitant with an obvious down-regulation in the relative expression of SOS1, NHX1, AQP, and OSM-34, while D2-protein was up-regulated.

Qari, S. H., A. F. Alrefaei, A. B. Ashoor, and M. H. Soliman, "Genotoxicity and Carcinogenicity of Medicinal Herbs and Their Nanoparticles", Nutraceuticals, vol. 1, issue 1, pp. 31 - 41, 2021. AbstractWebsite

Medicinal plants (MPs) account for 70–80% of use in primary care around the world, and this percentage indicates that the number of MP users is high; thus, it is necessary to focus studies on medicinal herbs to ensure their proper use. In addition, MPs have strong genotoxic effects, as some types of MPs can cause DNA damage. Any substance that raises the risk of cancer or a tumor in an organism is called a carcinogen. There are many genotoxic and carcinogenic substances in the environment that can directly or indirectly affect genetic material. There are also nanoparticles (NPs) derived from MPs. Carbon-based NPs contain many nanoscale materials, such as fullerenes and carbon nanotubes, as well as metals such as gold (Au), silver (Ag), and aluminum (Al). Unfortunately, few studies are concerned with the carcinogenicity of NPs from MPs, whereas many researchers are interested in genotoxic assessment. For this reason, there is an urgent need for more studies into the safety of MPs and NPs. Therefore, this study reviewed the genotoxicity and carcinogenicity of MPs and their derived NPs. We also emphasized the need for strict regulation and monitoring of MP usage.

Wright, N. J., A. J. M. Leather, N. Ade-Ajayi, N. Sevdalis, J. Davies, D. Poenaru, E. Ameh, A. Ademuyiwa, K. Lakhoo, E. R. Smith, et al., Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study, , vol. 398, issue 10297, pp. 325 - 339, 2021. AbstractWebsite

SummaryBackground
Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality.
Methods
We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis.
Findings
We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality.
Interpretation
Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030.
Funding
Wellcome Trust.

Wang, J., P. R. Ahimaz, S. Hashemifar, J. Khlevner, J. A. Picoraro, W. Middlesworth, M. M. Elfiky, J. Que, Y. Shen, and W. K. Chung, Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing, , vol. 29, issue 1, pp. 122 - 130, 2021. AbstractWebsite

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.

Qiao, L., L. Xu, L. Yu, J. Wynn, R. Hernan, X. Zhou, C. Farkouh-Karoleski, U. S. Krishnan, J. Khlevner, A. De, et al., Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene, , vol. 108, issue 10, pp. 1964 - 1980, 2021. AbstractWebsite

SummaryCongenital 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.

Tourism