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Naive pluripotent stem cells have the highest developmental potential but their in vivo existence in the blastocyst is transient. Here we report a blastocyst motif substrate for the in vitro reversion of mouse and human pluripotent stem cells to a naive state. The substrate features randomly varied microstructures, which we call motifs, mimicking the geometry of the blastocyst. Motifs representing mouse-blastocyst-scaled curvature ranging between 15 and 62 mm-1 were the most efficient in promoting reversion to naivety, as determined by time-resolved correlative analysis. In these substrates, apical constriction enhances E-cadherin/RAC1 signalling and activates the mechanosensitive nuclear transducer YAP, promoting the histone modification of pluripotency genes. This results in enhanced levels of pluripotency transcription factor NANOG, which persist even after cells are removed from the substrate. Pluripotent stem cells cultured in blastocyst motif substrates display a higher development potential in generating embryoid bodies and teratomas. These findings shed light on naivety-promoting substrate design and their large-scale implementation.
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PURPOSE: Aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid-conjugated mannosylated dextran derivative (Al[18F]F-NOTA-D10CM) is a new tracer for PET imaging. We report here on in vitro and in vivo validation of the tracer's ability to target the macrophage mannose receptor CD206. METHODS: First, the uptake of intravenously (i.v.) administered Al[18F]F-NOTA-D10CM was compared between wild-type (WT) and CD206-/- knockout (KO) mice. C57BL/6N mice were injected with complete Freund's adjuvant (CFA) in the left hind leg and the uptake of Al[18F]F-NOTA-D10CM after i.v. or intradermal (i.d.) injection was studied at 5 and 14 days after CFA induction of inflammation. Healthy C57BL/6N mice were studied as controls. Mice underwent PET/CT on consecutive days with [18F]FDG, i.v. Al[18F]F-NOTA-D10CM, and i.d. Al[18F]F-NOTA-D10CM. After the last imaging, Al[18F]F-NOTA-D10CM was i.v. injected for an ex vivo biodistribution study and autoradiography of inflamed tissues. Blood plasma samples were analyzed using high-performance liquid chromatography. To evaluate the specificity of Al[18F]F-NOTA-D10CM binding, an in vitro competitive displacement study was performed on inflamed tissue sections using autoradiography. CD206 expression was assessed by immunohistochemical staining. RESULTS: Compared with WT mice, the uptake of Al[18F]F-NOTA-D10CM was significantly lower in several CD206-/- KO mice tissues, including liver (SUV 8.21 ± 2.51 vs. 1.06 ± 0.16, P < 0.001) and bone marrow (SUV 1.63 ± 0.37 vs. 0.22 ± 0.05, P < 0.0001). The uptake of i.v. injected Al[18F]F-NOTA-D10CM was significantly higher in inflamed ankle joint (SUV 0.48 ± 0.13 vs. 0.18 ± 0.05, P < 0.0001) and inflamed foot pad skin (SUV 0.41 ± 0.10 vs. 0.04 ± 0.01, P < 0.0001) than in the corresponding tissues in healthy mice. The i.d.-injected Al[18F]F-NOTA-D10CM revealed differences between CFA-induced lymph node activation and lymph nodes in healthy mice. Ex vivo γ-counting, autoradiography, and immunohistochemistry supported the results, and a decrease of ~ 80% in the binding of Al[18F]F-NOTA-D10CM in the displacement study with excess NOTA-D10CM confirmed that tracer binding was specific. At 60 min after i.v. injection, an average 96.70% of plasma radioactivity was derived from intact Al[18F]F-NOTA-D10CM, indicating good in vivo stability. The uptake of Al[18F]F-NOTA-D10CM into inflamed tissues was positively associated with the area percentage of CD206-positive staining. CONCLUSION: The uptake of mannosylated dextran derivative Al[18F]F-NOTA-D10CM correlated with CD206 expression and the tracer appears promising for inflammation imaging.
Subject(s)
Dextrans , Fluorine Radioisotopes , Lectins, C-Type , Mannose Receptor , Mannose-Binding Lectins , Receptors, Cell Surface , Animals , Mice , Lectins, C-Type/metabolism , Receptors, Cell Surface/metabolism , Mannose-Binding Lectins/metabolism , Tissue Distribution , Dextrans/chemistry , Mannose/chemistry , Positron Emission Tomography Computed Tomography , Mice, Inbred C57BL , Macrophages/metabolism , Isotope Labeling , Heterocyclic Compounds, 1-RingABSTRACT
MDM2 is a gene that encodes a protein involved in cell survival, growth, and DNA repair. It has been implicated in the development and progression of glioblastoma (GBM). Inhibition of the MDM2-p53 interaction has emerged as a promising strategy for treating GBM. In this study, we performed comprehensive transcriptomic expression analysis from diverse datasets and observed MDM2 overexpression in a subset of GBM cases. MDM2 negatively regulates the major onco-suppressor p53. The interaction between MDM2 and p53 is a promising target for cancer therapy, as it can trigger p53-mediated cell death in response to different stress conditions, such as oncogene activation or DNA damage. In this study, we have identified a peptide-based inhibition of MDM2 as a therapeutic strategy for GBM. We have further validated the stability of the MDM2-peptide interaction using a molecular structural dynamics approach. The major trajectories, including root mean square of deviation (RMSD), root mean square of fluctuation (RMSF), and radius of gyration (RoG), indicate that the candidate peptides have a more stable binding compared to the native ligand and control drug. The stability of the binding interaction was further estimated by MMGBSA analysis, which also suggests that MDM2 has a stable binding with both peptide molecules. Based on these results, peptides P-1843 and P-3837 could be tested further for experimental validation to confirm their targeted inhibition of MDM-2. This approach could provide a highly selective and efficient inhibitor with potentially fewer side effects and less toxicity compared to small drug-based molecules.
Subject(s)
Glioblastoma , Peptides , Proto-Oncogene Proteins c-mdm2 , Tumor Suppressor Protein p53 , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/metabolism , Humans , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/pathology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , Peptides/chemistry , Peptides/pharmacology , Dose-Response Relationship, Drug , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Structure-Activity Relationship , Transcriptome/drug effects , Molecular Structure , Gene Expression Profiling , Molecular Dynamics SimulationABSTRACT
18F-Labeled [60]fullerene-based molecular spherical nucleic acids (MSNAs), consisting of a human epidermal growth factor receptor 2 (HER2) mRNA antisense oligonucleotide sequence with a native phosphodiester and phosphorothioate backbone, were synthesized, site-specifically labeled with a positron emitting fluorine-18 and intravenously administrated via tail vein to HER2 expressing HCC1954 tumor-bearing mice. The biodistribution of the MSNAs was monitored in vivo by positron emission tomography/computed tomography (PET/CT) imaging. MSNA with a native phosphodiester backbone (MSNA-PO) was prone to rapid nuclease-mediated degradation, whereas the corresponding phosphorothioate analogue (MSNA-PS) with improved enzymatic stability showed an interesting biodistribution profile in vivo. One hour after the injection, majority of the radioactivity was observed in spleen and liver but also in blood with an average tumor-to-muscle ratio of 2. The prolonged radioactivity in blood circulation may open possibilities to the targeted delivery of the MSNAs.
Subject(s)
Fullerenes , Neoplasms , Nucleic Acids , Mice , Humans , Animals , Positron Emission Tomography Computed Tomography/methods , Tissue Distribution , Positron-Emission Tomography/methods , Neoplasms/diagnostic imaging , Fluorine Radioisotopes , Cell Line, TumorABSTRACT
The Finnish-variant late infantile neuronal ceroid lipofuscinosis, also known as CLN5 disease, is caused by mutations in the CLN5 gene. Cln5 is strongly expressed in the developing brain and expression continues into adulthood. CLN5, a protein of unknown function, is implicated in neurodevelopment but detailed investigation is lacking. Using Cln5-/- embryos of various ages and cells harvested from Cln5-/- brains we investigated the hitherto unknown role of Cln5 in the developing brain. Loss of Cln5 results in neuronal differentiation deficits and delays in interneuron development during in utero period. Specifically, the radial thickness of dorsal telencephalon was significantly decreased in Cln5-/- mouse embryos at embryonic day 14.5 (E14.5), and expression of Tuj1, an important neuronal marker during development, was down-regulated. An interneuron marker calbindin and a mitosis marker p-H3 showed down-regulation in ganglionic eminences. Neurite outgrowth was compromised in primary cortical neuronal cultures derived from E16 Cln5-/- embryos compared with WT embryos. We show that the developmental deficits of interneurons may be linked to increased levels of the repressor element 1-silencing transcription factor, which we report to bind to glutamate decarboxylase (Gad1), which encodes GAD67, a rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA). Indeed, adult Cln5-/- mice presented deficits in hippocampal parvalbumin-positive interneurons. Furthermore, adult Cln5-/- mice presented deficits in hippocampal parvalbumin-positive interneurons and showed age-independent cortical hyper excitability as measured by electroencephalogram and auditory-evoked potentials. This study highlights the importance of Cln5 in neurodevelopment and suggests that in contrast to earlier reports, CLN5 disease is likely to develop during embryonic stages.
Subject(s)
Brain/growth & development , Glutamate Decarboxylase/genetics , Interneurons/metabolism , Lysosomal Membrane Proteins/genetics , Neuronal Ceroid-Lipofuscinoses/genetics , Animals , Brain/metabolism , Cell Differentiation , Cell Line , Cells, Cultured , Embryo, Mammalian/metabolism , Female , Gene Expression Regulation, Developmental , Humans , Male , Mice , Neuronal Ceroid-Lipofuscinoses/metabolism , Neurons/cytology , Neurons/metabolism , Parvalbumins/metabolism , Repressor Proteins/genetics , Tubulin/metabolismABSTRACT
BACKGROUND: The maternal 25-hydroxy vitamin D (25OHD) insufficiency is related to adverse maternal and neonatal outcome. The 25OHD content of breast milk is dependent on 25OHD status of the mothers. We undertook this study to ascertain the 25OHD status and its determinants in the nursing mothers of the south Punjab, Pakistan. METHODS: We recruited 67 mothers for this cross-sectional study by convenience sampling from August 2010 to June 2011 to ascertain their serum 25OHD level & its determinants. We used SPSS 23.0 for analyses. RESULTS: The mean age of the mothers was 25.75 ± 4.4 years. The median age (and mode) was 25 years (range 18-37 years). The majority of mothers were less than 25 years of age (62.7%), uneducated (68.7%), from rural area (70.1%), lived in open houses with ample sun exposure (85.1%) and belonged to low socioeconomic strata (71.6%). Serum 25OHD ranged from 7.2 to 43.8 nmol/L with a mean of 20.87 ± 7.69 nmol/L. The median and mode were 21.8 nmol/L & 24.0 nmol/L, respectively. The proportion of mothers with 25OHD < 20 nmol/L (severe deficiency) was 44.8%, < 30 nmol/L (deficiency) 49.3% and < 50 nmol/L (insufficiency) 5.9%. All had 25OHD below 50 nmol/L. The oral supplementation with vitamin D (vD) was the only significant determinant of vitamin D sufficiency. CONCLUSIONS: The majority of Pakistani mothers in south Punjab are vD deficient & universal vD supplementation is the need of the hour to improve health outcomes in mothers & infants.
Subject(s)
Mothers/statistics & numerical data , Vitamin D Deficiency/epidemiology , Vitamin D/analogs & derivatives , Adolescent , Adult , Breast Feeding/statistics & numerical data , Cross-Sectional Studies , Dietary Supplements/statistics & numerical data , Female , Humans , Pakistan/epidemiology , Sunlight , Vitamin D/blood , Vitamin D Deficiency/blood , Young AdultABSTRACT
OBJECTIVE: To determine the clinical presentations and outcomes of the children suffering from tuberculous meningitis. METHODS: This prospective, descriptive study was conducted at the Children's Hospital and the Institute of Child Health, Multan, Pakistan, from February to December 2015. The Pakistan Paediatric Association scoring chart for tuberculosis was used as a tool for the probable diagnosis. The clinical symptoms with their durations were noted. Clinical stages of tuberculous meningitis, cerebrospinal fluid analysis and computerised tomography brain findings were noted for each patient. The outcomes in the form of death or neurological disabilities at the time of hospital discharge were noted. SPSS 19 was used for data analysis. RESULTS: Of the 40 participants, 25(62.5%) were males and 15(37.5%) were females. The mean age of the patients was 4.24±3.32 years. Besides, 26(65%) patients were less than 5 years of age. All the patients (100%) were categorised as stage 3 tuberculous meningitis. The history of prolonged duration of fever 39(97.55%) and altered level of sensorium 40(100%) were the most common clinical presentations. Moreover, 2(5%) patients died during this study. All the 38(95%) survivors had neurological disabilities. There were motor deficits in 37(97.4%) patients, altered level of sensorium in 35(92%), cranial nerve palsies in 9(23.5%), epilepsy in 29(76.3%) and hydrocephalus in 32(84%) patients. CONCLUSIONS: The children were the most vulnerable group for the worst form of tuberculous meningitis and had a grave outcome.
Subject(s)
Tuberculosis, Meningeal , Cerebrospinal Fluid/cytology , Child , Child, Preschool , Female , Humans , Hydrocephalus , Male , Neuroimaging , Pakistan , Prospective Studies , Tertiary Care Centers , Treatment Outcome , Tuberculosis, Meningeal/diagnosis , Tuberculosis, Meningeal/epidemiology , Tuberculosis, Meningeal/mortality , Tuberculosis, Meningeal/therapy , Ventriculoperitoneal ShuntABSTRACT
C-reactive protein (CRP) is intricately sensitive marker of inflammation, infection, and tissue damage. Role in the prognosis of heart diseases has been recently discovered. This study aimed to develop a cost-effective and high-sensitivity CRP immunoassay for use in cardiac risk assessment. Assay was optimized for coating, blocking of capturing antibody, dilution, and reaction time of the conjugate and sample volume. For normal reference range, CRP was determined in serum samples from apparently healthy volunteers. For clinical validation, CRP was determined in samples of acute coronary syndrome patients by in-house and commercial assays. The lower detection limit of in-house assay was 0.16 µg/L. Intra and inter assay imprecision was 4.39%, 4.6% and 8.6%, 9.3%, respectively. The correlation between the CRP levels by the two assays was r = 0.861. Sensitivity, specificity, predictive value for a positive test, and a negative test of in-house assay was 95.3%, 92.8%, 95.3%, and 92.8%, respectively. At lower-end CRP levels of both kits correlated very well but showed variation at upper end. In-house assay showed high sensitivity and reliability at lower end and it is hoped that will help to evaluate cardiac risk assessment (after improvement at upper end) in clinically poor settings.
Subject(s)
C-Reactive Protein/analysis , Enzyme-Linked Immunosorbent Assay/methods , Reagent Kits, Diagnostic , Enzyme-Linked Immunosorbent Assay/standards , Female , Humans , Male , Middle Aged , Reagent Kits, Diagnostic/standardsABSTRACT
OBJECTIVE: We sought to determine the attributes of successful and unsuccessful fellowship applicants of the American Board of Obstetrics and Gynecology Inc (ABOG)-approved fellowship programs and to identify salient differences between subspecialty applicants. STUDY DESIGN: Anonymous questionnaires were completed by obstetrics and gynecology fellowship applicants using a web-based survey after match day of 2012. Fellowship applicant practices were evaluated and included importance of prematch preparations, interview process, networking practices, and postmatch reflections. RESULTS: A total of 327 fellowship applicants applying to programs accredited by the ABOG were surveyed, and 200 completed the survey (61% response rate). A comparison between prematch educational preparations pursued by applicants showed that matched applicants were more likely to come from allopathic medical schools (94%), attain membership in Alpha Omega Alpha and/or Phi Beta Kappa (27%), and receive a letter of recommendation from a nationally known subspecialist (77%) than unmatched applicants (P = .03, .005, and .007, respectively). Applicants to reproductive endocrinology and infertility were more likely than female pelvic medicine and reconstructive surgery to be members of academic honor societies (P = .008). Research publication was common among matched subspecialist applicants, with over half publishing 1-3 peer-reviewed manuscripts prior to matching. Applicants to gynecologic oncology did more visiting electives than any other specialty applicants (P < .001). CONCLUSION: Successful obstetrics and gynecology fellowship applicants have superior prematch preparations, strong letters of recommendation from leaders in their field of interest, and multiple research publications. These data will guide applicants to a critical self-analysis before deciding to apply.
Subject(s)
Education, Medical, Graduate/statistics & numerical data , Fellowships and Scholarships/statistics & numerical data , Gynecology/education , Obstetrics/education , Fellowships and Scholarships/classification , Female , Humans , Male , Specialty Boards , Surveys and Questionnaires , United StatesABSTRACT
This paper addresses the critical issue of leading edge erosion (LEE) on modern wind turbine blades (WTBs) caused by solid particle impacts. LEE can harm the structural integrity and aerodynamic performance of WTBs, leading to reduced efficiency and increased maintenance costs. This study employs a novel particle-based approach called hybrid peridynamics-discrete element method (PD-DEM) to model the impact of solid particles on WTB leading edges and target material failure accurately. It effectively captures the through-thickness force absorption and the propagation of stresses within the leading edge coating system composed of composite laminates. The amount of mass removed and the mean displacement of the target material points can be reliably calculated using the current method. Through a series of tests, the research demonstrates the method's ability to predict impact force changes with varying particle size, velocity, impact angles and positions. Moreover, this study offers a significant improvement in erosion prediction capability and the development of design specifications. This work contributes to the advancement of WTB design and maintenance practices to mitigate LEE effectively.
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Microplastics in marine environments come from various sources, and over the years, their buildup in marine environments suggests an inevitable need for the safe mitigation of plastic pollution. Microplastics are one of the chief and hazardous components of marine pollution, as they are transferred through the food chain to different trophic levels, affecting living organisms. They are also a source of transfer for pathogenic organisms. Upon transfer to humans, several toxic effects can occur. This review aims to assess the accumulation of microplastics in marine environments globally, the threat posed to humans, and the biodegradation potential of bacteria and fungi for future mitigation strategies. The versatility of bacteria and fungi in the biodegradation of different types of plastics has been discussed, with a focus on the microbial majority that has been cultivated in labs from the marine environment. We also propose that the exploration of yet-to-be-cultivated microbial majority can be a way forward for employing future strategies to mitigate microplastics.
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Cardiovascular diseases (CVDs) are known as life-threatening illnessescaused by severe abnormalities in the cardiovascular system. They are a leading cause of mortality and morbidity worldwide.Nanotechnology integrated substantialinnovations in cardiovascular diagnostic and therapeutic at the nanoscale. This in-depth analysis explores cutting-edge methods for diagnosing CVDs, including nanotechnological interventions and crucial components for identifying risk factors, developing treatment plans, and monitoring patients' progress with chronic CVDs.Intensive research has gone into making nano-carriers that can image and treat patients. To improve the efficiency of treating CVDs, the presentreview sheds light on a decision-tree-based solution by investigating recent and innovative approaches in CVD diagnosis by utilizing nanoparticles (NPs). Treatment choices for chronic diseases like CVD, whose etiology might take decades to manifest, are very condition-specific and disease-stage-based. Moreover, thisreview alsobenchmarks the changing landscape of employing NPs for targeted and better drug administration while examining the limitations of various NPs in CVD diagnosis, including cost, space, time, and complexity. To better understand and treatment of cardiovascular diseases, the conversation moves on to the nano-cardiovascular possibilities for medical research.We also focus on recent developments in nanoparticle applications, the ways they might be helpful, and the medical fields where they may find future use. Finally, this reviewadds to the continuing conversation on improved diagnosis and treatment approaches for cardiovascular disorders by discussing the obstacles and highlighting the revolutionary effects of nanotechnology.
Subject(s)
Cardiovascular Diseases , Cardiovascular System , Nanoparticles , Humans , Cardiovascular Diseases/therapy , Cardiovascular Diseases/drug therapy , Nanoparticles/therapeutic useABSTRACT
Nelumbo nucifera (lotus plant) is an important member of the Nelumbonaceae family. This review summarizes the studies conducted on it since the past 15 years to provide an understanding on future areas of focus. Different parts of this plant, that is, leaves, roots, and seeds, have been used as food and for the treatment of various diseases. Polysaccharides have been extracted from different parts using different methods. The manuscript reviews the methods of extraction of polysaccharides used for leaves, roots, and seeds, along with their yield. Some methods can provide better yield while some provide better biological activity with low yield. The composition and structure of extracted polysaccharides have been determined in some studies. Although monosaccharide composition has been determined in various studies, too little information about the structure of polysaccharides from N. nucifera is available in the current literature. Different useful biological activities have been explored using in vivo and in vitro methods, which include antioxidant, antidiabetic, antitumor, anti-osteoporotic, immunomodulatory, and prebiotic activities. Antitumor activity from polysaccharides of lotus leaves is yet to be explored, besides lotus root has been underexplored as compared to other parts (leaves and seeds) according to our literature survey. Studies dedicated to the successful use of combination of extraction methods can be conducted in future. The plant provides a therapeutic as well as nutraceutical potential; however, antimicrobial activity and synergistic relationships of polysaccharides from different parts of the plant need further exploration.
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Introduction: Intellectual disability (ID) is a lifelong disability that affects an individualâ§s learning capacity and adaptive behavior. Such individuals depend on their families for day-to-day survival and pose a significant challenge to the healthcare system, especially in developing countries. ID is a heterogeneous condition, and genetic studies are essential to unravel the underlying cellular pathway for brain development and functioning. Methods: Here we studied a female index patient, born to a consanguineous Pakistani couple, showing clinical symptoms of ID, ataxia, hypotonia, developmental delay, seizures, speech abnormality, and aggressive behavior. Whole exome sequencing (WES) coupled with Sanger sequencing was performed for molecular diagnosis. Further, 3D protein modeling was performed to see the effect of variant on protein structure. Results: WES identified a novel homozygous missense variant (c.178T>C; p.Tyr60His) in the ANK3 gene. In silico analysis and 3-dimensional (3D) protein modeling supports the deleterious impact of this variant on the encoding protein, which compromises the proteinâ§s overall structure and function. Conclusion: Our finding supports the clinical and genetic diversity of the ANK3 gene as a plausible candidate gene for ID syndrome. Intelligence is a complex polygenic human trait, and understanding molecular and biological pathways involved in learning and memory can solve the complex puzzle of how cognition develops. Intellectual disability (ID) is defined as a deficit in an individualâ§s learning and adaptive behavior at an early age of onset [American Psychiatric Association, 2013]. It is one of the major medical, and cognitive disorders with a prevalence of 1-3% in the population worldwide [Leonard and Wen, 2002]. ID often exists with other disabling mental conditions such as autism, attention deficit hyperactivity disorder, epilepsy, schizophrenia, bipolar disorder, or depression. Almost half of the cases appear to have a genetic explanation that ranges from cytogenetically visible abnormalities to monogenic defects [Flint, 2001; Ropers, 2010; Tucker-Drob et al., 2013]. Intellectual disability is a genetically heterogeneous condition, and more than 700 genes have been identified to cause ID alone or as a part of the syndrome. Research in X-linked ID has identified more than 100 disease-causing genes on the X chromosome that play a role in cognition; however, research into autosomal causes of ID is still ongoing [Vissers et al., 2016].
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OBJECTIVES: We determined the pulse oximetry benefit in pediatric pneumonia mortality risk stratification and chest-indrawing pneumonia in-hospital mortality risk factors. METHODS: We report the characteristics and in-hospital pneumonia-related mortality of children aged 2-59 months who were included in the Pneumonia Research Partnership to Assess WHO Recommendations dataset. We developed multivariable logistic regression models of chest-indrawing pneumonia to identify mortality risk factors. RESULTS: Among 285,839 children, 164,244 (57.5%) from hospital-based studies were included. Pneumonia case fatality risk (CFR) without pulse oximetry measurement was higher than with measurement (5.8%, 95% confidence interval [CI] 5.6-5.9% vs 2.1%, 95% CI 1.9-2.4%). One in five children with chest-indrawing pneumonia was hypoxemic (19.7%, 95% CI 19.0-20.4%), and the hypoxemic CFR was 10.3% (95% CI 9.1-11.5%). Other mortality risk factors were younger age (either 2-5 months [adjusted odds ratio (aOR) 9.94, 95% CI 6.67-14.84] or 6-11 months [aOR 2.67, 95% CI 1.71-4.16]), moderate malnutrition (aOR 2.41, 95% CI 1.87-3.09), and female sex (aOR 1.82, 95% CI 1.43-2.32). CONCLUSION: Children with a pulse oximetry measurement had a lower CFR. Many children hospitalized with chest-indrawing pneumonia were hypoxemic and one in 10 died. Young age and moderate malnutrition were risk factors for in-hospital chest-indrawing pneumonia-related mortality. Pulse oximetry should be integrated in pneumonia hospital care for children under 5 years.
Subject(s)
Malnutrition , Pneumonia , Child , Humans , Female , Infant , Child, Preschool , Hospital Mortality , Pneumonia/diagnosis , Oximetry , World Health Organization , Risk AssessmentABSTRACT
Clinical evidence suggests that some patients diagnosed with coronavirus disease 2019 (COVID-19) experience a variety of complications associated with significant morbidity, especially in severe cases during the initial spread of the pandemic. To support early interventions, we propose a machine learning system that predicts the risk of developing multiple complications. We processed data collected from 3,352 patient encounters admitted to 18 facilities between April 1 and April 30, 2020, in Abu Dhabi (AD), United Arab Emirates. Using data collected during the first 24 h of admission, we trained machine learning models to predict the risk of developing any of three complications after 24 h of admission. The complications include Secondary Bacterial Infection (SBI), Acute Kidney Injury (AKI), and Acute Respiratory Distress Syndrome (ARDS). The hospitals were grouped based on geographical proximity to assess the proposed system's learning generalizability, AD Middle region and AD Western & Eastern regions, A and B, respectively. The overall system includes a data filtering criterion, hyperparameter tuning, and model selection. In test set A, consisting of 587 patient encounters (mean age: 45.5), the system achieved a good area under the receiver operating curve (AUROC) for the prediction of SBI (0.902 AUROC), AKI (0.906 AUROC), and ARDS (0.854 AUROC). Similarly, in test set B, consisting of 225 patient encounters (mean age: 42.7), the system performed well for the prediction of SBI (0.859 AUROC), AKI (0.891 AUROC), and ARDS (0.827 AUROC). The performance results and feature importance analysis highlight the system's generalizability and interpretability. The findings illustrate how machine learning models can achieve a strong performance even when using a limited set of routine input variables. Since our proposed system is data-driven, we believe it can be easily repurposed for different outcomes considering the changes in COVID-19 variants over time.
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Background: The existing World Health Organization (WHO) pneumonia case management guidelines rely on clinical symptoms and signs for identifying, classifying, and treating pneumonia in children up to 5 years old. We aimed to collate an individual patient-level data set from large, high-quality pre-existing studies on pneumonia in children to identify a set of signs and symptoms with greater validity in the diagnosis, prognosis, and possible treatment of childhood pneumonia for the improvement of current pneumonia case management guidelines. Methods: Using data from a published systematic review and expert knowledge, we identified studies meeting our eligibility criteria and invited investigators to share individual-level patient data. We collected data on demographic information, general medical history, and current illness episode, including history, clinical presentation, chest radiograph findings when available, treatment, and outcome. Data were gathered separately from hospital-based and community-based cases. We performed a narrative synthesis to describe the final data set. Results: Forty-one separate data sets were included in the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) database, 26 of which were hospital-based and 15 were community-based. The PREPARE database includes 285 839 children with pneumonia (244 323 in the hospital and 41 516 in the community), with detailed descriptions of clinical presentation, clinical progression, and outcome. Of 9185 pneumonia-related deaths, 6836 (74%) occurred in children <1 year of age and 1317 (14%) in children aged 1-2 years. Of the 285 839 episodes, 280 998 occurred in children 0-59 months old, of which 129 584 (46%) were 2-11 months of age and 152 730 (54%) were males. Conclusions: This data set could identify an improved specific, sensitive set of criteria for diagnosing clinical pneumonia and help identify sick children in need of referral to a higher level of care or a change of therapy. Field studies could be designed based on insights from PREPARE analyses to validate a potential revised pneumonia algorithm. The PREPARE methodology can also act as a model for disease database assembly.
Subject(s)
Pneumonia , Male , Child , Humans , Infant , Infant, Newborn , Child, Preschool , Female , Pneumonia/drug therapy , Case Management , World Health Organization , Algorithms , ResearchABSTRACT
INTRODUCTION: Existing risk assessment tools to identify children at risk of hospitalised pneumonia-related mortality have shown suboptimal discriminatory value during external validation. Our objective was to derive and validate a novel risk assessment tool to identify children aged 2-59 months at risk of hospitalised pneumonia-related mortality across various settings. METHODS: We used primary, baseline, patient-level data from 11 studies, including children evaluated for pneumonia in 20 low-income and middle-income countries. Patients with complete data were included in a logistic regression model to assess the association of candidate variables with the outcome hospitalised pneumonia-related mortality. Adjusted log coefficients were calculated for each candidate variable and assigned weighted points to derive the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) risk assessment tool. We used bootstrapped selection with 200 repetitions to internally validate the PREPARE risk assessment tool. RESULTS: A total of 27 388 children were included in the analysis (mean age 14.0 months, pneumonia-related case fatality ratio 3.1%). The PREPARE risk assessment tool included patient age, sex, weight-for-age z-score, body temperature, respiratory rate, unconsciousness or decreased level of consciousness, convulsions, cyanosis and hypoxaemia at baseline. The PREPARE risk assessment tool had good discriminatory value when internally validated (area under the curve 0.83, 95% CI 0.81 to 0.84). CONCLUSIONS: The PREPARE risk assessment tool had good discriminatory ability for identifying children at risk of hospitalised pneumonia-related mortality in a large, geographically diverse dataset. After external validation, this tool may be implemented in various settings to identify children at risk of hospitalised pneumonia-related mortality.
Subject(s)
Pneumonia , Child , Humans , Income , Infant , Pneumonia/diagnosis , Risk AssessmentABSTRACT
As an analytic tool in medicine, deep learning has gained great attention and opened new ways for disease diagnosis. Recent studies validate the effectiveness of deep learning algorithms for binary classification of skin lesions (i.e., melanomas and nevi classes) with dermoscopic images. Nonetheless, those binary classification methods cannot be applied to the general clinical situation of skin cancer screening in which multi-class classification must be taken into account. The main objective of this research is to develop, implement, and calibrate an advanced deep learning model in the context of automated multi-class classification of skin lesions. The proposed Deep Convolutional Neural Network (DCNN) model is carefully designed with several layers, and multiple filter sizes, but fewer filters and parameters to improve efficacy and performance. Dermoscopic images are acquired from the International Skin Imaging Collaboration databases (ISIC-17, ISIC-18, and ISIC-19) for experiments. The experimental results of the proposed DCNN approach are presented in terms of precision, sensitivity, specificity, and other metrics. Specifically, it attains 94 % precision, 93 % sensitivity, and 91 % specificity in ISIC-17. It is demonstrated by the experimental results that this proposed DCNN approach outperforms state-of-the-art algorithms, exhibiting 0.964 area under the receiver operating characteristics (AUROC) in ISIC-17 for the classification of skin lesions and can be used to assist dermatologists in classifying skin lesions. As a result, this proposed approach provides a novel and feasible way for automating and expediting the skin lesion classification task as well as saving effort, time, and human life.
Subject(s)
Melanoma , Nevus , Skin Neoplasms , Dermoscopy , Humans , Melanoma/diagnostic imaging , Neural Networks, Computer , Skin Neoplasms/diagnostic imagingABSTRACT
This study was designed to preparecarboxyl-functionalized poly (N-isopropylacrylamide) PNIPAM microgels having excellent catalytic properties.Recently, researchers are trying to fabricate cost effective and efficient hybrid catalytic materials for the synthesis of nitrogenous compounds along with enhanced optical properties. For the same motive, synthesis of carboxyl-functionalized PNIPAM microgels was performed by using polymerization of soap-free emulsion of N-isopropyl acrylamide, which is NIPAM along with acrylic acid (AA). The thiol group was introduced through the imide bond mediated by carbodiimide, between carboxyl-functionalized microgels through carboxyl group and aminoethanethiol (AET). Copper, Palladium and Cu/Pd nanoparticles were incorporated successfully into thiol-functionalized PNIPAM microgels through metals thiol linkage. The synthesized microgels and hybrid encompassing metallic nanoparticles were characterized in detail by using Transmission electron microscopy (TEM), Scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray photoelectron (XPS) and Fourier transformed infrared spectroscopy for structural interpretation. The thermal properties of the pure and hybrid microgels were inspected by TG analysis. The prepared nanocomposites PNIPAM-Cu, PNIPAM-Pd and PNIPAM-Cu/Pd exhibited decent catalytic properties for the degradation of 4-Nitrophenol and methylene blue, but the bimetallic Cu/Pd have remarkable catalytic properties. The catalytic reaction followed pseudo-first-order reaction with rate constants 0.223 min-1, 0.173 min-1 for 4-Nitrophenol and methylene blue in that order. In this study,we were able to establish that Cu/Pd hybrid is an efficient catalyst for 4-Nitrophenol and methylene blue as compared to its atomic analogue.