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1.
Article in English | MEDLINE | ID: mdl-38743639

ABSTRACT

Background: Antipsychotics carry a higher-risk profile than other psychotropic medications and may be prescribed for youth with conditions in which other first-line treatments are more appropriate. This study aimed to evaluate the population-level effect of the Safer Use of Antipsychotics in Youth (SUAY) trial, which aimed to reduce person-days of antipsychotic use among participants. Methods: We conducted an interrupted time series analysis using segmented regression to measure changes in prescribing trends of antipsychotic initiation rates pre-SUAY and post-SUAY trial at four U.S. health systems between 2013 and 2020. Results: In our overall model, adjusted for age and insurance type, antipsychotic initiation rates decreased by 0.73 (95% confidence interval [CI]: 0.30, 1.16, p = 0.002) prescriptions per 10,000 person-months before the SUAY trial. In the first quarter following the start of the trial, there was an immediate decrease in the rate of antipsychotic initiations of 6.57 (95% CI: 0.99, 12.15) prescriptions per 10,000 person-months. When comparing the posttrial period to the pretrial period, there was an increase of 1.09 (95% CI: 0.32, 1.85) prescriptions per 10,000 person-months, but the increasing rate in the posttrial period alone was not statistically significant (0.36 prescriptions per 10,000 person-months, 95% CI: -0.27, 0.99). Conclusion: The declining trend of antipsychotic initiation seen between 2013 and 2018 (pre-SUAY trial) may have naturally reached a level at which prescribing was clinically warranted and appropriate, resulting in a floor effect. The COVID-19 pandemic, which began in the final three quarters of the posttrial period, may also be related to increased antipsychotic medication initiation.

2.
Article in English | MEDLINE | ID: mdl-38572809

ABSTRACT

BACKGROUND: Differential diagnosis of amelanotic/hypomelanotic melanoma among solitary flat pink lesions is challenging, due to limited clinical and dermoscopic clues. Dermoscopy and reflectance confocal microscopy assessments improve diagnostic accuracy, but their combined capacity among solitary flat pink lesions is yet to be defined. OBJECTIVES: To determine (i) whether diagnostic accuracy is improved with combined dermoscopy and reflectance confocal microscopy, (ii) a model to estimate probability of flat amelanotic/hypomelanotic melanoma among solitary flat pink lesions. METHODS: A retrospective single-centre study of solitary flat pink lesions, excised for suspected malignancy between 2011 and 2022 was performed. Images were independently evaluated by two dermatologists, blinded to histopathological diagnosis. Diagnostic performance was evaluated on the receiver operating characteristic curve and the area under the curve. Predictive features were identified by univariate and multivariate logistic regression analyses. A final predictive nomogram of independent risk factors was calculated by backward likelihood ratio. Hypothesis being tested was formulated before data collection. RESULTS: A total of 184 patients (87 females, 47.3%) were included; mean age was 57.6 years (19-95). Combined dermoscopy and reflectance confocal microscopy was more sensitive (83%, CI 69.2-92.4 and 91.5%, CI 79.6-97.6) than dermoscopy alone (76.6%, CI 62.0-87.7 and 85.1%, CI 71.7-93.8). Predictive features defined the new model, including linear irregular vessels (4.26-folds, CI 1.5-12.1), peripheral pigment network (6.07-folds, CI 1.83-20.15), remnants of pigmentation (4.3-folds, CI 1.27-14.55) at dermoscopy and atypical honeycomb (9.98-folds, CI 1.91-51.96), disarranged epidermal pattern (15.22-folds, CI 2.18-106.23), dendritic pagetoid cells in the epidermis (3.77-folds, CI 1.25-11.26), hypopigmented pagetoid cells (27.05-folds, CI 1.57-465.5), and dense and sparse nests (3.68-folds, CI 1.24-10.96) in reflectance confocal microscopy. Diagnostic accuracy of the model was high (AUC 0.91). CONCLUSIONS: Adjunctive reflectance confocal microscopy increases diagnostic sensitivity of flat amelanotic/hypomelanotic melanoma differential diagnosis. The proposed model requires validation.

3.
Nat Neurosci ; 27(5): 913-926, 2024 May.
Article in English | MEDLINE | ID: mdl-38528202

ABSTRACT

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.


Subject(s)
Ion Channels , Lymphatic Vessels , Meninges , Mice, Transgenic , Animals , Lymphatic Vessels/metabolism , Ion Channels/metabolism , Ion Channels/genetics , Mice , Meninges/metabolism , Cerebrospinal Fluid/metabolism , Hydrocephalus/genetics , Mechanotransduction, Cellular/physiology , Mice, Inbred C57BL , Female , Male , Pyrazines , Thiadiazoles
4.
Nat Commun ; 15(1): 1520, 2024 Feb 19.
Article in English | MEDLINE | ID: mdl-38374083

ABSTRACT

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα in C. elegans. Untargeted metabolomics of a ß-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a ß-cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a ß-methyl fatty acid, bemeth#1, which mimics the activity of microbiota-dependent becyp#1 but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated ß-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans Proteins/metabolism , PPAR alpha/metabolism , Escherichia coli/genetics , Escherichia coli/metabolism , Fatty Acids/metabolism , Cyclopropanes/metabolism
5.
Prenat Diagn ; 44(2): 124-130, 2024 02.
Article in English | MEDLINE | ID: mdl-36919753

ABSTRACT

OBJECTIVE: We evaluate survival of fetuses with severe Lower Urinary Tract Obstruction (LUTO) based on bladder morphology. We hypothesize that fetuses with a "floppy" appearing bladder on initial prenatal ultrasound will have worse infant outcomes than fetuses with full/rounded bladders. METHOD: We retrospectively reviewed all cases of LUTO evaluated in our fetal center between January 2013 and December 2021. Ultrasonographic assessment, renal biochemistry, and bladder refilling contributed to a "favorable" or "unfavorable" evaluation. Bladder morphology on initial ultrasound was classified as "floppy" or "full/rounded." Vesicoamniotic shunting was offered for favorably evaluated fetuses. Baseline demographics, ultrasound parameters, prenatal evaluations of fetal renal function, and infant outcomes were collected. Fetuses diagnosed with severe LUTO were included in analysis using descriptive statistics. The primary outcome measured was survival at 6 months of life. RESULTS: 104 LUTO patients were evaluated; 24 were included in analysis. Infant survival rate at 6 months was 60% for rounded bladders and 0% for floppy bladders (p = 0.003). Bladder refill adequacy was lower in fetuses with floppy bladders compared with rounded bladders (p value < 0.00001). CONCLUSION: We propose that bladder morphology in fetuses with severe LUTO may be a prognostication factor for predicting infant outcomes and provides a valuable, noninvasive assessment tool.


Subject(s)
Fetal Diseases , Urethral Obstruction , Pregnancy , Infant , Female , Humans , Urinary Bladder/diagnostic imaging , Retrospective Studies , Urethral Obstruction/diagnostic imaging , Urethral Obstruction/surgery , Ultrasonography, Prenatal , Fetal Diseases/diagnostic imaging , Fetus
6.
J Urol ; 210(6): 886-887, 2023 12.
Article in English | MEDLINE | ID: mdl-37782915
7.
bioRxiv ; 2023 Aug 31.
Article in English | MEDLINE | ID: mdl-37693574

ABSTRACT

Fatty acid desaturation is central to metazoan lipid metabolism and provides building blocks of membrane lipids and precursors of diverse signaling molecules. Nutritional conditions and associated microbiota regulate desaturase expression1-4, but the underlying mechanisms have remained unclear. Here, we show that endogenous and microbiota-dependent small molecule signals promote lipid desaturation via the nuclear receptor NHR-49/PPARα in C. elegans. Untargeted metabolomics of a ß-oxidation mutant, acdh-11, in which expression of the stearoyl-CoA desaturase FAT-7/SCD1 is constitutively increased, revealed accumulation of a ß-cyclopropyl fatty acid, becyp#1, that potently activates fat-7 expression via NHR-49. Biosynthesis of becyp#1 is strictly dependent on expression of cyclopropane synthase by associated bacteria, e.g., E. coli. Screening for structurally related endogenous metabolites revealed a ß-methyl fatty acid, bemeth#1, whose activity mimics that of microbiota-dependent becyp#1, but is derived from a methyltransferase, fcmt-1, that is conserved across Nematoda and likely originates from bacterial cyclopropane synthase via ancient horizontal gene transfer. Activation of fat-7 expression by these structurally similar metabolites is controlled by distinct mechanisms, as microbiota-dependent becyp#1 is metabolized by a dedicated ß-oxidation pathway, while the endogenous bemeth#1 is metabolized via α-oxidation. Collectively, we demonstrate that evolutionarily related biosynthetic pathways in metazoan host and associated microbiota converge on NHR-49/PPARα to regulate fat desaturation.

9.
J Pediatr Urol ; 19(6): 742.e1-742.e8, 2023 12.
Article in English | MEDLINE | ID: mdl-37537091

ABSTRACT

INTRODUCTION: OnabotulinumtoxinA is used as treatment for refractory idiopathic and neurogenic detrusor overactivity in children. Many patients perform intermittent self-catheterization and therefore have higher rates of asymptomatic bacteriuria, which may increase their risk of symptomatic urinary tract infection (UTI) following treatment. Multiple injections are often needed due to the short-term efficacy of onabotulinumtoxinA treatment, which may also increase the risk of UTI. OBJECTIVE: We aim to evaluate whether a sterile urinary tract is necessary to decrease the risk of postoperative UTI in pediatric patients treated with onabotulinumtoxinA. STUDY DESIGN: A retrospective review of patients undergoing intradetrusor onabotulinumtoxinA injection from 2014 to 2021 was performed. Demographic data, clinical characteristics, antibiotic treatment and culture results were collected. A positive urine culture was defined as ≥ 103 CFU/ml of uropathogenic bacteria. Our primary outcome was symptomatic UTI within 14 days of the procedure. RESULTS: 103 patients underwent 158 treatments with onabotulinumtoxinA. The incidence of postoperative UTI was 3.2%. The incidence of symptomatic postoperative UTI in patients with asymptomatic bacteriuria compared to those with sterile urine was not significantly different (3.8% vs 0%, p = 0.57). Obtaining a preoperative urinalysis or urine culture did not affect the incidence of postoperative UTI (p = 0.54). The number needed to treat with antibiotics to prevent one postoperative UTI was 27. The incidence of postoperative UTI was highest in patients with low-risk bladders (p = 0.043). Prior history of multi-drug resistant UTI was a risk factor for postoperative UTI (p = 0.048). DISCUSSION: For children undergoing onabotulinumtoxinA injection, there are no evidence-based recommendations regarding antibiotic prophylaxis and the need to screen for and treat asymptomatic bacteruria prior to treatment. Our study addresses this important clinical question, and shows no difference in the rate of postoperative UTI between patients with asymptomatic bacteriuria and those with sterile urine. Patients with a history of multi-drug resistant UTI are at increased risk of symptomatic postoperative UTI and may benefit from preoperative urine testing and treatment. Limitations of our retrospective study include its small sample size in the face of such a low incidence of our primary outcome. CONCLUSIONS: The risk of UTI following onabotulinumtoxinA injection in children is low. The presence of sterile urine at the time of surgery does not significantly decrease the risk of postoperative UTI. Routine treatment of asymptomatic bacteriuria prior to surgery results in a large number of patients receiving unnecessary antibiotics. As a result, we recommend against preoperative urine testing for most asymptomatic patients.


Subject(s)
Bacteriuria , Botulinum Toxins, Type A , Urinary Bladder, Neurogenic , Urinary Tract Infections , Humans , Child , Bacteriuria/diagnosis , Bacteriuria/drug therapy , Bacteriuria/etiology , Urinary Bladder, Neurogenic/complications , Urinary Bladder, Neurogenic/drug therapy , Retrospective Studies , Anti-Bacterial Agents/therapeutic use , Urinary Tract Infections/diagnosis , Urinary Tract Infections/drug therapy , Urinary Tract Infections/etiology , Urinalysis , Postoperative Complications
10.
Iowa Orthop J ; 43(1): 23-29, 2023.
Article in English | MEDLINE | ID: mdl-37383866

ABSTRACT

Background: The COVID-19 pandemic and its effects on the orthopaedic match process are yet to be fully understood and should be explored. We hypothesize that the cancellation of away rotations due to the COVID-19 pandemic would decrease the variability of where students matched into orthopaedic residency compared to pre-pandemic years. Methods: Accredited orthopaedic programs were collected from the Accreditation Council for Graduate Medical Education (ACGME) database. Rosters of orthopaedic residency classes for the years 2019, 2020, and 2021 were compiled across all orthopaedic programs in the United States. Data collection for the incoming 2021 orthopaedic surgery residents was carried out by reviewing each program's website, Instagram, and Twitter. Results: Data for the incoming orthopaedic surgery residents from the 2021 National Residency Match Program (NRMP) were collected. 25.7% of incoming residents matched at their home institution. Data collection for the 2020 and 2019 orthopaedic residency classes yielded 19.2% and 19.5% home institution match rates, respectively. When examining likelihood to match into an orthopaedic residency program in ones own's state, we found that in the 2021 match cycle, 39.3% of applicants matched within their state, while 34.3% and 33.4% of incoming residents matched in 2020 and 2019, respectively. Conclusion: To keep our patients and staff safe, visiting externship rotations were suspended in the 2021 Match cycle. As we continue to navigate the shifting waters of the COVID-19 pandemic, it is important to understand how our choices affect the dynamics of applying into residency training and beyond. This study demonstrates that a higher percentage of applicants that matched into orthopaedic residency remained at their home program compared to the previous two years before the pandemic. This indicates that programs tended to rank their home applicants, and that applicants tended to rank their home programs, higher than those that were less familiar. Level of Evidence: IV.


Subject(s)
COVID-19 , Internship and Residency , Orthopedic Procedures , Humans , Pandemics , Accreditation
11.
Cell Rep ; 42(7): 112682, 2023 07 25.
Article in English | MEDLINE | ID: mdl-37355988

ABSTRACT

Human bone marrow (BM) plasma cells are heterogeneous, ranging from newly arrived antibody-secreting cells (ASCs) to long-lived plasma cells (LLPCs). We provide single-cell transcriptional resolution of 17,347 BM ASCs from five healthy adults. Fifteen clusters are identified ranging from newly minted ASCs (cluster 1) expressing MKI67 and high major histocompatibility complex (MHC) class II that progress to late clusters 5-8 through intermediate clusters 2-4. Additional ASC clusters include the following: immunoglobulin (Ig) M predominant (likely of extra-follicular origin), interferon responsive, and high mitochondrial activity. Late ASCs are distinguished by G2M checkpoints, mammalian target of rapamycin (mTOR) signaling, distinct metabolic pathways, CD38 expression, utilization of tumor necrosis factor (TNF)-receptor superfamily members, and two distinct maturation pathways involving TNF signaling through nuclear factor κB (NF-κB). This study provides a single-cell atlas and molecular roadmap of LLPC maturation trajectories essential in the BM microniche. Altogether, understanding BM ASC heterogeneity in health and disease enables development of new strategies to enhance protective ASCs and to deplete pathogenic ones.


Subject(s)
Bone Marrow , Plasma Cells , Adult , Humans , Antibody-Producing Cells/metabolism , Histocompatibility Antigens Class II/metabolism , Single-Cell Analysis , Bone Marrow Cells
12.
Transl Behav Med ; 13(9): 625-634, 2023 09 12.
Article in English | MEDLINE | ID: mdl-37130336

ABSTRACT

STAR-Caregivers Virtual Training and Follow-up (STAR-VTF) is an evidence-based intervention that teaches family caregivers how to manage behavioral and psychological symptoms of dementia. The study objective was to identify what adaptations to STAR-VTF are needed to improve cultural relevance for Latino caregivers. A qualitative research study was conducted that interviewed Spanish- and English-speaking caregivers of people with dementia who self-identify as Hispanic/Latino (N = 30) and healthcare and social service providers of older Latino clients and/or Latino family caregivers (N = 14). Thematic analysis methods were applied to code and analyze interview transcripts. The codebook was theory-driven, relying mainly on codes that directly represented components of the Cultural Treatment Adaptation Framework. Based on the content of the excerpts, the codes were sorted into themes that represented opportunities to culturally adapt STAR-VTF. Three themes were identified: (i) there was a need to increase awareness about dementia and decrease stigma; (ii) semantics mattered as certain words and phrases could be stigmatizing, offensive, or culturally inappropriate; and (iii) there was a need to incorporate into program materials the traditional family structure and nature of caregiving in Latino families. Based on findings, adaptations were performed on STAR-VTF that included expanding content to improve understanding of dementia, revising language that was viewed as problematic, and adding cultural examples to reflect the range of family involvement in caring for people living with dementia and multigenerational living. Findings from this qualitative research study advance understanding of the Latino caregiver experience and how to modify programs to better serve their needs.


STAR-Caregivers Virtual Training and Follow-up (STAR-VTF) is an evidence-based intervention that teaches family caregivers how to manage behavioral and psychological symptoms of dementia. The study objective was to identify what adaptations to STAR-VTF are needed to improve cultural relevance for Latino caregivers. Thirty Spanish- and English-speaking caregivers of people living with dementia who self-identify as Hispanic/Latino and 14 providers of healthcare and social services were interviewed. Interview transcripts were analyzed using thematic analysis methods. The Cultural Treatment Adaptation Framework guided data collection and analysis. Three themes were identified: (i) there was a need to increase awareness about dementia and decrease stigma; (ii) semantics mattered as certain words and phrases could be stigmatizing, offensive, or culturally inappropriate; and (iii) there was a need to incorporate into program materials the traditional family structure and nature of caregiving in Latino families. Adaptations were performed on STAR-VTF, including expanding content to improve understanding of dementia, revising language that was viewed as problematic, and adding cultural examples to reflect the range of family involvement in caring for people living with dementia and multigenerational living. Findings from this study advance understanding of the Latino caregiver experience and how to modify programs to better serve their needs.


Subject(s)
Caregivers , Dementia , Humans , Caregivers/psychology , Dementia/therapy , Qualitative Research , Hispanic or Latino/psychology , Health Facilities
13.
J Am Chem Soc ; 145(21): 11611-11621, 2023 05 31.
Article in English | MEDLINE | ID: mdl-37192367

ABSTRACT

Nucleosides are essential cornerstones of life, and nucleoside derivatives and synthetic analogues have important biomedical applications. Correspondingly, production of non-canonical nucleoside derivatives in animal model systems is of particular interest. Here, we report the discovery of diverse glucose-based nucleosides in Caenorhabditis elegans and related nematodes. Using a mass spectrometric screen based on all-ion fragmentation in combination with total synthesis, we show that C. elegans selectively glucosylates a series of modified purines but not the canonical purine and pyrimidine bases. Analogous to ribonucleosides, the resulting gluconucleosides exist as phosphorylated and non-phosphorylated forms. The phosphorylated gluconucleosides can be additionally decorated with diverse acyl moieties from amino acid catabolism. Syntheses of representative variants, facilitated by a novel 2'-O- to 3'-O-dibenzyl phosphoryl transesterification reaction, demonstrated selective incorporation of different nucleobases and acyl moieties. Using stable-isotope labeling, we further show that gluconucleosides incorporate modified nucleobases derived from RNA and possibly DNA breakdown, revealing extensive recycling of oligonucleotide catabolites. Gluconucleosides are conserved in other nematodes, and biosynthesis of specific subsets is increased in germline mutants and during aging. Bioassays indicate that gluconucleosides may function in stress response pathways.


Subject(s)
Nucleosides , Ribonucleosides , Animals , Caenorhabditis elegans , Oligonucleotides
14.
Mol Ecol ; 32(13): 3382-3402, 2023 07.
Article in English | MEDLINE | ID: mdl-37009938

ABSTRACT

Understanding the drivers of evolutionary innovation provides a crucial perspective of how evolutionary processes unfold across taxa and ecological systems. It has been hypothesised that the Southern Ocean provided ecological opportunities for novelty in the past. However, the drivers of innovation are challenging to pinpoint as the evolutionary genetics of Southern Ocean fauna are influenced by Quaternary glacial-interglacial cycles, oceanic currents and species ecology. Here we examined the genome-wide single nucleotide polymorphisms of the Southern Ocean brittle stars Ophionotus victoriae (five arms, broadcaster) and O. hexactis (six arms, brooder). We found that O. victoriae and O. hexactis are closely-related species with interspecific gene flow. During the late Pleistocene, O. victoriae likely persisted in a connected deep water refugium and in situ refugia on the Antarctic continental shelf and around Antarctic islands; O. hexactis persisted exclusively within in situ island refugia. Within O. victoriae, contemporary gene flow linking to the Antarctic Circumpolar Current, regional gyres and other local oceanographic regimes was observed. Gene flow connecting West and East Antarctic islands near the Polar Front was also detected in O. hexactis. A strong association was detected between outlier loci and salinity in O. hexactis. Both O. victoriae and O. hexactis are associated with genome-wide increase in alleles at intermediate-frequencies; the alleles associated with this peak appear to be species specific, and these intermediate-frequency variants are far more excessive in O. hexactis. We hypothesise that the peak in alleles at intermediate frequencies could be related to adaptation in the recent past, linked to evolutionary innovations of increase in arm number and a switch to brooding from broadcasting, in O. hexactis.


Subject(s)
Echinodermata , Genetic Variation , Animals , Antarctic Regions , Genetic Variation/genetics , Echinodermata/genetics , Biological Evolution , Genomics
15.
Nat Chem Biol ; 19(6): 676-686, 2023 06.
Article in English | MEDLINE | ID: mdl-37024728

ABSTRACT

Recent studies have revealed that Caenorhabditis elegans and other nematodes repurpose products from biochemical degradation pathways for the combinatorial assembly of complex modular structures that serve diverse signaling functions. Building blocks from neurotransmitter, amino acid, nucleoside and fatty acid metabolism are attached to scaffolds based on the dideoxyhexose ascarylose or glucose, resulting in hundreds of modular ascarosides and glucosides. Genome-wide association studies have identified carboxylesterases as the key enzymes mediating modular assembly, enabling rapid compound discovery via untargeted metabolomics and suggesting that modular metabolite biosynthesis originates from the 'hijacking' of conserved detoxification mechanisms. Modular metabolites thus represent a distinct biosynthetic strategy for generating structural and functional diversity in nematodes, complementing the primarily polyketide synthase- and nonribosomal peptide synthetase-derived universe of microbial natural products. Although many aspects of modular metabolite biosynthesis and function remain to be elucidated, their identification demonstrates how phenotype-driven compound discovery, untargeted metabolomics and genomic approaches can synergize to facilitate the annotation of metabolic dark matter.


Subject(s)
Genome-Wide Association Study , Nematoda , Animals , Nematoda/metabolism , Caenorhabditis elegans/metabolism , Metabolomics/methods , Nucleosides
17.
J Pediatr Urol ; 19(3): 296.e1-296.e8, 2023 06.
Article in English | MEDLINE | ID: mdl-36750396

ABSTRACT

INTRODUCTION: Ureteral obstruction following pediatric kidney transplantation occurs in 5-8% of cases. We describe our experience with percutaneous antegrade ureteroplasty for the treatment of ureteral stricture in pediatric kidney transplant patients. METHODS: We retrospectively reviewed all pediatric kidney transplantation patients who presented with ureteral stricture and underwent percutaneous antegrade ureteroplasty at our institution from July 2009 to July 2021. Variables included patient demographics, timing of presentation, location and extent of stricture, ureteroplasty technique and clinical outcomes. Our primary outcome was persistent obstruction of the kidney transplant. RESULTS: Twelve patients met inclusion criteria (4.2% of all transplants). Median age at time of ureteroplasty was 11.5 years (range: 3-17.5 years). Median time from kidney transplantation to ureteroplasty was 3 months. Patency was maintained in 50% of patients. Seven patients (58.3%) required additional surgery. Four patients developed vesicoureteral reflux. Patients with persistent obstruction had a longer time from transplant to ureteroplasty compared to those who achieved patency (19.3 vs 1.3 months, p = 0.0163). Of those treated within 6 months after transplantation, two patients (25%) required surgery for persistent obstruction (p = 0.06). All patients treated >1 year after transplantation had persistent obstruction following ureteroplasty (p = 0.06). CONCLUSION: Percutaneous antegrade ureteroplasty can be considered a viable minimally invasive treatment option for pediatric patients who develop early ureteral obstruction (<6 months) following kidney transplantation. In patients who are successfully treated with ureteroplasty, 67% can develop vesicoureteral reflux into the transplant kidney. Patients who fail early percutaneous ureteroplasty or develop obstruction >1 year after transplantation are best managed with surgical intervention.


Subject(s)
Kidney Transplantation , Ureter , Ureteral Obstruction , Vesico-Ureteral Reflux , Humans , Child , Child, Preschool , Adolescent , Ureteral Obstruction/etiology , Ureteral Obstruction/surgery , Kidney Transplantation/adverse effects , Vesico-Ureteral Reflux/etiology , Constriction, Pathologic/etiology , Constriction, Pathologic/surgery , Retrospective Studies , Ureter/surgery , Treatment Outcome
19.
Nat Commun ; 14(1): 320, 2023 01 19.
Article in English | MEDLINE | ID: mdl-36658169

ABSTRACT

Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and sex determination mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, increases food consumption, reduces lifespan, and accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provide a blueprint for the discovery of sex-dependent metabolites in other animals.


Subject(s)
Caenorhabditis elegans Proteins , Caenorhabditis elegans , Animals , Male , Caenorhabditis elegans/metabolism , Metabolome , Caenorhabditis elegans Proteins/metabolism , Metabolomics/methods , Longevity
20.
World Neurosurg ; 172: e250-e255, 2023 Apr.
Article in English | MEDLINE | ID: mdl-36610642

ABSTRACT

OBJECTIVE: The Internet is a source of health information for patients. Quality of information available to patients is varied and uncontrolled. Physicians should be familiar with the overall quality of the information. This review provides an evaluation of YouTube's current patient accessible health information on the topic of lumbar disc herniation (LDH). METHODS: YouTube was queried using 3 different search strings: (1) "disc herniation", (2) "lumbar disc herniation", or (3) "lower back disc herniation". Video duplicates, non-English, or those that contained no audio or were not relevant to LDH were excluded. The first 50 videos per search string were evaluated. Two reviewers independently assessed videos. Parameters included duration, upload date, number of views, number of likes, views per day, and likes per day. A scoring system was used to grade the videos for their performance on diagnosis and treatment of LDH. RESULTS: The first 50 videos produced a total number of hits of 50,500, 29,100, and 22,100, respectively. Strong agreement, assessed using intraclass correlation coefficient (ICC), was demonstrated between readers for both diagnostic scores (ICC 0.921, 95% CI 0.866-0.953) and treatment scores (ICC 0.916, 95% CI 0.855-0.951). Educational Physician videos had significantly greater diagnostic and treatment scores compared to non-physician videos (9.54 vs. 7.05, P = 0.048, and 6.53 vs. 5.3, P = 0.004). CONCLUSIONS: YouTube videos pertaining to LDH were found to have low overall quality. Physicians should be cognizant about information sources readily available to patients as they may influence patient expectations and preconceptions.


Subject(s)
Social Media , Humans , Information Sources , Video Recording , Patients , Information Dissemination
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