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Frontiers in Pediatrics 2020Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth... (Review)
Review
Abnormally excessive growth results from perturbation of a complex interplay of genetic, epigenetic, and hormonal factors that orchestrate human growth. Overgrowth syndromes generally present with inherent health concerns and, in some instances, an increased risk of tumor predisposition that necessitate prompt diagnosis and appropriate referral. In this review, we introduce some of the more common overgrowth syndromes, along with their molecular mechanisms, diagnostics, and medical complications for improved recognition and management of patients affected with these disorders.
PubMed: 33194904
DOI: 10.3389/fped.2020.574857 -
Cell Oct 2020Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes...
Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from over 12,000 genes across 32 normal human tissues. Tissue-specific or tissue-enriched proteins were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode tissue-specific proteins. Discordance of RNA and protein enrichment revealed potential sites of synthesis and action of secreted proteins. The tissue-specific distribution of proteins also provides an in-depth view of complex biological events that require the interplay of multiple tissues. Most importantly, our study demonstrated that protein tissue-enrichment information can explain phenotypes of genetic diseases, which cannot be obtained by transcript information alone. Overall, our results demonstrate how understanding protein levels can provide insights into regulation, secretome, metabolism, and human diseases.
Topics: Gene Expression; Gene Expression Profiling; Humans; Proteome; Proteomics; RNA; RNA, Messenger; Transcriptome
PubMed: 32916130
DOI: 10.1016/j.cell.2020.08.036 -
Current Opinion in Genetics &... Jun 2021The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders... (Review)
Review
The 16p11.2 BP4 and BP5 region, is a recurrent ∼600kb copy number variant (CNV), and deletions are one of the most frequent etiologies of neurodevelopmental disorders and autism spectrum disorder with an incidence of approximately 1/2000. Deletion carriers have delays in early neurodevelopment that most specifically impair speech, phonology and language in 70%. Intelligence quotient is shifted 1.8 standard deviations lower than family controls without the deletion. Other common neurobehavioral conditions include motor coordination difficulties (60%) and autism (20-25%). Unprovoked seizures are common (24%) and readily treated and resolve with age in many. Obesity evolves throughout childhood and by adulthood 75% are obese. Congenital anomalies are more common than the general population. The deletion is associated with an increase in brain volumes across all areas of the brain, changes in the white matter microstructural properties, and early electrophysiological cortical responses from auditory cortex. Studies of genetically defined conditions, particularly CNVs that are not associated with profound disabilities, provide homogeneity to study genetic impact on brain development, structure, and function to better understand complex neurobehavioral phenotypes such as autism.
Topics: Autistic Disorder; Chromosome Deletion; Chromosome Disorders; Chromosomes, Human, Pair 16; DNA Copy Number Variations; Gene Deletion; Genetic Association Studies; Humans; Intellectual Disability; Language Development Disorders; Neurodevelopmental Disorders; Neuroimaging; Obesity; Seizures; White Matter
PubMed: 33667823
DOI: 10.1016/j.gde.2021.01.011 -
JAMA Sep 2020Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.
OBJECTIVE
To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.
INTERVENTIONS
Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.
MAIN OUTCOMES AND MEASURES
The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.
RESULTS
Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.
CONCLUSIONS AND RELEVANCE
Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04292730.
Topics: Adenosine Monophosphate; Administration, Intravenous; Aged; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Administration Schedule; Female; Hospitalization; Humans; Male; Middle Aged; Odds Ratio; Pandemics; Patient Acuity; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32821939
DOI: 10.1001/jama.2020.16349 -
Gut Microbes 2023Irritable bowel syndrome (IBS) is a heterogeneous condition with multifactorial pathogenesis. We studied deeply phenotyped individuals with microbiota sequencing...
Irritable bowel syndrome (IBS) is a heterogeneous condition with multifactorial pathogenesis. We studied deeply phenotyped individuals with microbiota sequencing enrolled in the American Gut Project. The IBS subjects were matched by age, gender, body mass index, geography, and dietary patterns with non-IBS controls. A total of 942 subjects with IBS-Diarrhea (IBS-D), IBS-Constipation (IBS-C), unclassified IBS (IBS-U), and 942 non-IBS controls were included. We compared taxonomic and functional composition of gut microbiota based on 16S sequencing data and linked them with clinical characteristics and dietary factors. Subjects with IBS-D or IBS-U but not IBS-C showed significantly reduced bacterial diversity (Shannon; p < .01). Distinct bacterial signatures were associated with different IBS subtypes, and the related functional changes were related to IBS pathogenesis, such as the increased hydrogen sulfide production pathway in IBS-D and the increased palmitoleate biosynthesis pathway in IBS-C. IBS subjects with depression showed lower abundance of and higher abundance of than those without depression. The relative abundance of microbial short-chain fatty acid production pathways was significantly lower in IBS patients with depression than those without depression in all three subtypes. Female, younger age in IBS-D, and older age in IBS-C were associated with more severe microbiota dysbiosis, and distinct dietary factors had significant effects on the gut microbiota in different IBS subtypes. Our analysis identified the compositional uniqueness of gut microbiota in different IBS subtypes. Distinct associations of the gut microbiota with depression in IBS provide insights into shared pathways in disease pathogenesis. These findings highlight the importance of personalized gut microbiome modulation approaches in different subtypes for optimal therapeutic effects.
Topics: Humans; Female; Irritable Bowel Syndrome; Gastrointestinal Microbiome; Diarrhea; Constipation; Dysbiosis; Bacteria; Feces
PubMed: 36573834
DOI: 10.1080/19490976.2022.2157697