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While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.
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INTRODUCTION: Traditional strategies for grouping congenital heart defects (CHDs) using birth defect registry data do not adequately address differences in expected clinical consequences between different combinations of CHDs. We report a lesion-specific classification system for birth defect registry-based outcome studies. METHODS: For Core Cardiac Lesion Outcome Classifications (C-CLOC) groups, common CHDs expected to have reasonable clinical homogeneity were defined. Criteria based on combinations of Centers for Disease and Control-modified British Pediatric Association (BPA) codes were defined for each C-CLOC group. To demonstrate proof of concept and retention of reasonable case counts within C-CLOC groups, Texas Birth Defect Registry data (1999-2017 deliveries) were used to compare case counts and neonatal mortality between traditional vs. C-CLOC classification approaches. RESULTS: C-CLOC defined 59 CHD groups among 62,262 infants with CHDs. Classifying cases into the single, mutually exclusive C-CLOC group reflecting the highest complexity CHD present reduced case counts among lower complexity lesions (e.g., 86.5% of cases with a common atrium BPA code were reclassified to a higher complexity group for a co-occurring CHD). As expected, C-CLOC groups had retained larger sample sizes (i.e., representing presumably better-powered analytic groups) compared to cases with only one CHD code and no occurring CHDs. DISCUSSION: This new CHD classification system for investigators using birth defect registry data, C-CLOC, is expected to balance clinical outcome homogeneity in analytic groups while maintaining sufficiently large case counts within categories, thus improving power for CHD-specific outcome association comparisons. Future outcome studies utilizing C-CLOC-based classifications are planned.
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Cardiopatias Congênitas , Sistema de Registros , Humanos , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/classificação , Recém-Nascido , Feminino , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/classificação , Lactente , Texas/epidemiologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Masculino , Mortalidade Infantil/tendênciasRESUMO
Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression. We tested these findings in vivo. Linear modeling of CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes revealed 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo. Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro; autosomal responses to Xi and/or Y dosage were largely cell-type specific (â¼2.6-fold more variation than sex-chromosomal responses). Targets of the sex-chromosomal transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro. We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable, yet they modulate autosomal and Xa genes in a cell-type-specific fashion.
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Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.
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The challenges of IT adoption in the healthcare sector have generated much interest across a range of research communities, including Information Systems (IS) and Health Informatics (HI). Given their long-standing interest in IT design, development, implementation, and adoption to improve productivity and support organisational transformation, the IS and HI fields are highly correlated in their research interests. Nevertheless, the two fields serve different academic audiences, have different research foci, and theorise IT artifacts differently. We investigate the dyadic relationship between health information systems (HIS) research in IS and HI through the communication patterns between the two fields. We present the citation analysis results of HIS research published in IS and HI journals between 2000 and 2020. The results revealed that despite the two fields sharing a common interest, communication between them is limited and only about specific topics. Potentially relevant ideas and theories generated in IS have not yet been sufficiently recognised by HI scholars and incorporated into the HI literature. However, the upward trend of HIS publications in IS indicates that IS has the potential to contribute more to HI.
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Bibliometria , Informática Médica , Comunicação Acadêmica , Humanos , Informática Médica/métodos , Comunicação Acadêmica/tendências , Sistemas de Informação/estatística & dados numéricosRESUMO
Recent research showed that precision medicine can identify new treatment strategies for patients with childhood cancers. However, it is unclear which patients will benefit most from precision-guided treatment (PGT). Here we report consecutive data from 384 patients with high-risk pediatric cancer (with an expected cure rate of less than 30%) who had at least 18 months of follow-up on the ZERO Childhood Cancer Precision Medicine Program PRecISion Medicine for Children with Cancer (PRISM) trial. A total of 256 (67%) patients received PGT recommendations and 110 (29%) received a recommended treatment. PGT resulted in a 36% objective response rate and improved 2-year progression-free survival compared with standard of care (26% versus 12%; P = 0.049) or targeted agents not guided by molecular findings (26% versus 5.2%; P = 0.003). PGT based on tier 1 evidence, PGT targeting fusions or commenced before disease progression had the greatest clinical benefit. Our data show that PGT informed by comprehensive molecular profiling significantly improves outcomes for children with high-risk cancers. ClinicalTrials.gov registration: NCT03336931.
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Neoplasias , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Criança , Neoplasias/genética , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Feminino , Masculino , Adolescente , Pré-Escolar , Lactente , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
ConspectusChemists have long been inspired by biological photosynthesis, wherein a series of excited-state electron transfer (ET) events facilitate the conversion of low energy starting materials such as H2O and CO2 into higher energy products in the form of carbohydrates and O2. While this model for utilizing light-driven charge transfer to drive catalytic reactions thermodynamically "uphill" has been extensively adapted for small molecule activation, molecular machines, photoswitches, and solar fuel chemistry, its application in organic synthesis has been less systematically developed. However, the potential benefits of these approaches are significant, both in enabling transformations that cannot be readily achieved using conventional thermal chemistry and in accessing distinct selectivity regimes that are uniquely enabled by excited-state mechanisms. In this Account, we present work from our group that highlights the ability of visible light photoredox catalysis to drive useful organic transformations away from their equilibrium positions, addressing a number of long-standing synthetic challenges.We first discuss how excited-state ET enabled the first general methods for the catalytic anti-Markovnikov hydroamination of unactivated alkenes with alkyl amines. In these reactions, an excited-state iridium(III) photocatalyst reversibly oxidizes secondary amine substrates to their corresponding aminium radical cations (ARCs). These electrophilic N-centered radicals can then react with olefins to furnish valuable tertiary amine products with complete anti-Markovnikov regioselectivity. Notably, some of these products are less thermodynamically stable than their corresponding amine and alkene starting materials. We next present a strategy for light-driven C-C bond cleavage within various aliphatic alcohols mediated by homolytic activation of alcohol O-H bonds by excited-state proton-coupled electron transfer (PCET). The resulting alkoxy radical intermediates then undergo C-C ß-scission to ultimately provide isomeric linear carbonyl products that are often higher in energy than their cyclic alcohol precursors. Applications of this chemistry for the light-driven depolymerization of lignin biomass, commercial phenoxy resin, hydroxylated polyolefin derivatives, and thermoset polymers are presented as well. We then describe a method for the contrathermodynamic positional isomerization of highly substituted olefins by means of cooperative photoredox and chromium(II) catalysis. In this work, generation of an allylchromium(III) species that can undergo highly regioselective in situ protodemetalation enables access to a less substituted and thermodynamically less stable positional isomer. Product selectivity in this reaction is determined by the large differential in oxidation potentials between differently substituted olefin isomers. Lastly, we discuss a light-driven deracemization reaction developed in collaboration with the Miller group, wherein a racemic urea substrate undergoes spontaneous optical enrichment upon visible light irradiation in the presence of an iridium(III) chromophore, a chiral Brønsted base, and a chiral peptide thiol. Excellent levels of enantioselectivity are achieved via sequential and synergistic proton transfer (PT) and H atom transfer (HAT) steps. Taken together, these examples highlight the ability of excited-state ET events to enable access to nonequilibrium product distributions across a wide range of catalytic, redox-neutral transformations in which photons are the only stoichiometric reagents.
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Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
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Taiwan, identified as pivotal in the Asian drug trafficking chain, has been experiencing a surge in illicit drug-related issues. Wastewater-based epidemiology (WBE) has emerged as a promising approach for comprehensive evaluation of actual illicit drug usage. This study presents the first WBE investigation of illicit drug consumption in Taiwan based on the analysis of wastewater from four wastewater treatment plants (WWTPs) in the Taipei metropolitan area. Additionally, it demonstrates a high correlation between the amounts of illicit drugs seized and influent concentrations over an extended period of time. The reliability of solid-phase extraction and analysis via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was validated for 16 illicit drugs (methamphetamine, ketamine, cocaine, codeine, methadone, morphine, meperidine, fentanyl, sufentanil, para-methoxyamphetamine (PMA), para-methoxymethamphetamine (PMMA), 3,4-methylenedioxymethamphetamine (MDMA), cathinone, methcathinone, mephedrone (MEPH), and 4-methylethcathinone (4-MEC)). Methamphetamine, ketamine, and 4-MEC were consistently detected in all wastewater samples, underscoring their prevalence in the Taipei metropolitan area. Biochemical oxygen demand (BOD) and ammonia nitrogen (ammonia N) were employed to reduce uncertainty in estimations of population size during back-calculation of illicit drug consumption. The results indicate that methamphetamine was the most consumed drug (175-740 mg day-1 1000 people-1), followed by ketamine (22-280 mg day-1 1000 people-1). In addition, urban-related WWTPs exhibited higher consumption of methamphetamine and ketamine than did the suburban-related WWTP, indicating distinct illicit drug usage patterns between suburban and urban regions. Moreover, an examination of temporal trends in wastewater from the Dihua WWTP revealed a persistent predominance of ketamine and methamphetamine, consistent with statistical data pertaining to seizure quantities and urine test results. The study provides encouraging insight into spatial and temporal variations in illicit drug usage in the Taipei metropolitan area, emphasizing the complementary role of WBE in understanding trends in illicit drug abuse.
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Drogas Ilícitas , Águas Residuárias , Poluentes Químicos da Água , Taiwan/epidemiologia , Águas Residuárias/química , Drogas Ilícitas/análise , Poluentes Químicos da Água/análise , Detecção do Abuso de Substâncias/métodos , Humanos , Monitoramento Ambiental , Espectrometria de Massas em Tandem , CidadesRESUMO
Recent in vitro studies of human sex chromosome aneuploidy showed that the Xi ("inactive" X) and Y chromosomes broadly modulate autosomal and Xa ("active" X) gene expression in two cell types. We tested these findings in vivo in two additional cell types. Using linear modeling in CD4+ T cells and monocytes from individuals with one to three X chromosomes and zero to two Y chromosomes, we identified 82 sex-chromosomal and 344 autosomal genes whose expression changed significantly with Xi and/or Y dosage in vivo . Changes in sex-chromosomal expression were remarkably constant in vivo and in vitro across all four cell types examined. In contrast, autosomal responses to Xi and/or Y dosage were largely cell-type-specific, with up to 2.6-fold more variation than sex-chromosomal responses. Targets of the X- and Y-encoded transcription factors ZFX and ZFY accounted for a significant fraction of these autosomal responses both in vivo and in vitro . We conclude that the human Xi and Y transcriptomes are surprisingly robust and stable across the four cell types examined, yet they modulate autosomal and Xa genes - and cell function - in a cell-type-specific fashion. These emerging principles offer a foundation for exploring the wide-ranging regulatory roles of the sex chromosomes across the human body.
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The coexistence of free chlorine and bromide under sunlight irradiation (sunlight/FC with Br-) is unavoidable in outdoor seawater swimming pools, and the formation of brominated disinfection byproducts could act more harmful than chlorinated disinfection byproducts. In this study, benzotriazole was selected as a model compound to investigate the degradation rate and the subsequent formation of disinfection byproducts via sunlight/FC with Br- process. The rate constants for the degradation of benzotriazole under pseudo first order conditions in sunlight/FC with Br- and sunlight/FC are 2.3 ± 0.07 × 10-1 min-1 and 6.0 ± 0.7 × 10-2 min-1, respectively. The enhanced degradation of benzotriazole can be ascribed to the generation of HOâ¢, bromine species, and reactive halogen species (RHS) during sunlight/FC with Br-. Despite the fact that sunlight/FC with Br- process enhanced benzotriazole degradation, the reaction results in increasing tribromomethane (TBM) formation. A high concentration (37.8 µg/L) of TBM was detected in the sunlight/FC with Br-, which was due to the reaction of RHS. The degradation of benzotriazole was notably influenced by the pH value (pH 4 - 11), the concentration of bromide (0 - 2 mM), and free chlorine (1 - 6 mg/L). Furthermore, the concentration of TBM increased when the free chlorine concentrations increased, implying the formation potential of harmful TBM in chlorinated seawater swimming pools.
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Brometos , Cloro , Luz Solar , Triazóis , Poluentes Químicos da Água , Triazóis/química , Brometos/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/análise , Cloro/química , Desinfecção , Trialometanos/química , Água do Mar/química , Desinfetantes/química , Desinfetantes/análiseRESUMO
OBJECTIVES: Recommendations for surgical repair of a congenital heart defect in children with trisomy 13 or trisomy 18 remain controversial, are subject to biases, and are largely unsupported with limited empirical data. This has created significant distrust and uncertainty among parents and could potentially lead to suboptimal care for patients. A working group, representing several clinical specialties involved with the care of these children, developed recommendations to assist in the decision-making process for congenital heart defect care in this population. The goal of these recommendations is to provide families and their health care teams with a framework for clinical decision making based on the literature and expert opinions. METHODS: This project was performed under the auspices of the AATS Congenital Heart Surgery Evidence-Based Medicine Taskforce. A Patient/Population, Intervention, Comparison/Control, Outcome process was used to generate preliminary statements and recommendations to address various aspects related to cardiac surgery in children with trisomy 13 or trisomy 18. Delphi methodology was then used iteratively to generate consensus among the group using a structured communication process. RESULTS: Nine recommendations were developed from a set of initial statements that arose from the Patient/Population, Intervention, Comparison/Control, Outcome process methodology following the groups' review of more than 500 articles. These recommendations were adjudicated by this group of experts using a modified Delphi process in a reproducible fashion and make up the current publication. The Class (strength) of recommendations was usually Class IIa (moderate benefit), and the overall level (quality) of evidence was level C-limited data. CONCLUSIONS: This is the first set of recommendations collated by an expert multidisciplinary group to address specific issues around indications for surgical intervention in children with trisomy 13 or trisomy 18 with congenital heart defect. Based on our analysis of recent data, we recommend that decisions should not be based solely on the presence of trisomy but, instead, should be made on a case-by-case basis, considering both the severity of the baby's heart disease as well as the presence of other anomalies. These recommendations offer a framework to assist parents and clinicians in surgical decision making for children who have trisomy 13 or trisomy 18 with congenital heart defect.
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Procedimentos Cirúrgicos Cardíacos , Cardiopatias Congênitas , Cirurgia Torácica , Lactente , Criança , Humanos , Estados Unidos , Síndrome da Trissomía do Cromossomo 18/diagnóstico , Síndrome da Trissomia do Cromossomo 13/diagnóstico , Consenso , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/cirurgiaRESUMO
PURPOSE: The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS: The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS: A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS: Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.
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Neoplasias da Próstata , Radiocirurgia , Masculino , Humanos , Estudos Retrospectivos , Neoplasias da Próstata/patologia , Intervalo Livre de Progressão , Radiocirurgia/métodosRESUMO
The semiconductor industry has claimed that perfluorooctanesulfonate (PFOS), a persistent per- and polyfluoroalkyl substance (PFAS), has been eliminated from semiconductor production; however, information about the use of alternative compounds remains limited. This study aimed to develop a nontarget approach to discovering diverse PFAS substitutions used in semiconductor manufacturing. A distinct fragment-based approach has been established to identify the hydrophobic and hydrophilic features of acidic and neutral fluorosurfactants through fragments and neutral losses, including those outside the homologous series. Ten sewage samples from 5 semiconductor plants were analyzed with target and nontarget analysis. Among the 20 identified PFAS spanning 12 subclasses, 15 were reported in semiconductor sewage for the first time. The dominant identified PFAS compounds were C4 sulfonamido derivatives, including perfluorobutane sulfonamido ethanol (FBSE), perfluorobutane sulfonamide (FBSA), and perfluorobutane sulfonamido diethanol (FBSEE diol), with maximum concentrations of 482 µg/L, 141 µg/L, and 83.5 µg/L in sewage, respectively. Subsequently, three ultrashort chain perfluoroalkyl acids (PFAAs) were identified in all samples, ranging from 0.004 to 19.9 µg/L. Three effluent samples from the associated industrial wastewater treatment plants (WWTPs) were further analyzed. This finding, that the C4 sulfonamido acetic acid series constitutes a significant portion (65%-82%) of effluents from WWTP3 and WWTP4, emphasizes the conversion of fluorinated alcohols to fluorinated acids during aerobic treatment. The identification of the intermediate metabolites of FBSEE diol, further supported by our laboratory batch studies, prompts the proposal of a novel metabolic pathway for FBSEE diol. The total amount of perfluorobutane sulfonamido derivatives reached 1934 µg/L (90%), while that of PFAAs, which have typically received attention, was only 205 µg/L (10%). This suggests that perfluorobutane sulfonamido derivatives are emerging as a new trend in fluorosurfactants used in the semiconductor industry, serving as PFAS precursors and contributing to the release of their metabolites into the environment.
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Fluorocarbonos , Poluentes Químicos da Água , Esgotos/química , Tensoativos , Poluentes Químicos da Água/análise , Fluorocarbonos/análiseRESUMO
Somatic cells of human males and females have 45 chromosomes in common, including the "active" X chromosome. In males the 46th chromosome is a Y; in females it is an "inactive" X (Xi). Through linear modeling of autosomal gene expression in cells from individuals with zero to three Xi and zero to four Y chromosomes, we found that Xi and Y impact autosomal expression broadly and with remarkably similar effects. Studying sex chromosome structural anomalies, promoters of Xi- and Y-responsive genes, and CRISPR inhibition, we traced part of this shared effect to homologous transcription factors-ZFX and ZFY-encoded by Chr X and Y. This demonstrates sex-shared mechanisms by which Xi and Y modulate autosomal expression. Combined with earlier analyses of sex-linked gene expression, our studies show that 21% of all genes expressed in lymphoblastoid cells or fibroblasts change expression significantly in response to Xi or Y chromosomes.
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Fatores de Transcrição , Cromossomo Y , Humanos , Masculino , Feminino , Fatores de Transcrição/genética , Cromossomos Humanos X/genética , Aberrações dos Cromossomos Sexuais , Expressão Gênica/genéticaRESUMO
Urine source separation, as an innovative concept for the reuse of microlevel nutrients in human urine, has drawn increasing attention recently. Consequently, removing coexisting pharmaceuticals in urine is necessary for further reuse. This study is the first to apply the solar-driven persulfate process (Solar/PS) to the investigation of cephradine (CFD) and caffeine (CAF) degradation in synthetic human urine. The results showed that significantly more degradation of CFD and CAF occurs with the Solar/PS process than with persulfate oxidation and direct sunlight photolysis, respectively. The generated reactive species ·OH, SO4·-, O2·- and 1O2 were identified in the Solar/PS process. While SO4·- played a dominant role at pH 6, it played a minor role at pH 9 due to the lower amount generated under alkaline conditions. The presence of chloride and ammonia negatively impacted the photodegradation of both compounds. In contrast, bicarbonate exhibited no effect on CAF but enhanced CFD degradation owing to its amino-acid-like structure, which has a higher reactivity toward CO3·-. Although total organic carbon (TOC) was partially mineralized after 6 h of operation, no Microtox® toxicity was observed.
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Cefradina , Poluentes Químicos da Água , Humanos , Cafeína , Luz Solar , Fotólise , Oxirredução , Poluentes Químicos da Água/química , Sulfatos/químicaRESUMO
Mechanical loading is integral to bone development and repair. The application of mechanical loads through rehabilitation are regularly prescribed as a clinical aide following severe bone injuries. However, current rehabilitation regimens typically involve long periods of non-loading and rely on subjective patient feedback, leading to muscle atrophy and soft tissue fibrosis. While many pre-clinical studies have focused on unloading, ambulatory loading, or direct mechanical compression, rehabilitation intensity and its impact on the local strain environment and subsequent bone healing have largely not been investigated. This study combines implantable strain sensors and subject-specific finite element models in a pre-clinical rodent model with a defect size on the cusp of critically-sized. Animals were enrolled in either high or low intensity rehabilitation one week post injury to investigate how rehabilitation intensity affects the local mechanical environment and subsequent functional bone regeneration. The high intensity rehabilitation animals were given free access to running wheels with resistance, which increased local strains within the regenerative niche by an average of 44% compared to the low intensity (no-resistance) group. Finite element modeling demonstrated that resistance rehabilitation significantly increased compressive strain by a factor of 2.0 at week 1 and 4.45 after 4 weeks of rehabilitation. The resistance rehabilitation group had significantly increased regenerated bone volume and higher bone bridging rates than its sedentary counterpart (bone volume: 22.00 mm3 ± 4.26 resistance rehabilitation vs 8.00 mm3 ± 2.27 sedentary; bridging rates: 90% resistance rehabilitation vs 50% sedentary). In addition, animals that underwent resistance running had femurs with improved mechanical properties compared to those left in sedentary conditions, with failure torque and torsional stiffness values matching their contralateral, intact femurs (stiffness: 0.036 Nm/deg ± 0.006 resistance rehabilitation vs 0.008 Nm/deg ± 0.006 sedentary). Running on a wheel with no resistance rehabilitation also increased bridging rates (100% no resistance rehabilitation vs 50% sedentary). Analysis of bone volume and von Frey suggest no-resistance rehabilitation may improve bone regeneration and hindlimb functionality. These results demonstrate the potential for early resistance rehabilitation as a rehabilitation regimen to improve bone regeneration and functional recovery.
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Background: Micronized dehydrated human amnion/chorion membrane (mdHACM) has reduced short term post-traumatic osteoarthritis (PTOA) progression in rats when delivered 24 h after medial meniscal transection (MMT) and is being investigated for clinical use as a disease modifying therapy. Much remains to be assessed, including its potential for longer-term therapeutic benefit and treatment effects after onset of joint degeneration. Objectives: Characterize longer-term effects of acute treatment with mdHACM and determine whether treatment administered to joints with established PTOA could slow or reverse degeneration. Hypotheses: Acute treatment effects will be sustained for 6 weeks, and delivery of mdHACM after onset of joint degeneration will attenuate structural osteoarthritic changes. Methods: Rats underwent MMT or sham surgery (left leg). mdHACM was delivered intra-articularly 24 h or 3 weeks post-surgery (n = 5-7 per group). Six weeks post-surgery, animals were euthanized and left tibiae scanned using equilibrium partitioning of an ionic contrast agent microcomputed tomography (EPIC-µCT) to structurally quantify joint degeneration. Histology was performed to examine tibial plateau cartilage. Results: Quantitative 3D µCT showed that cartilage structural metrics (thickness, X-ray attenuation, surface roughness, exposed bone area) for delayed mdHACM treatment limbs were significantly improved over saline treatment and not significantly different from shams. Subchondral bone mineral density and thickness for the delayed treatment group were significantly improved over acute treated, and subchondral bone thickness was not significantly different from sham. Marginal osteophyte degenerative changes were decreased with delayed mdHACM treatment compared to saline. Acute treatment (24 h post-surgery) did not reduce longer-term joint tissue degeneration compared to saline. Histology supported µCT findings and further revealed that while delayed treatment reduced cartilage damage, chondrocytes displayed qualitatively different morphologies and density compared to sham. Conclusion: This study provides insight into effects of intra-articular delivery timing relative to PTOA progression and the duration of therapeutic benefit of mdHACM. Results suggest that mdHACM injection into already osteoarthritic joints can improve joint health, but a single, acute mdHACM injection post-injury does not prevent long term osteoarthritis associated with meniscal instability. Further work is needed to fully characterize the durability of therapeutic benefit in stable osteoarthritic joints and the effects of repeated injections.
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We report a 10-year-old boy with a de novo pathogenic variant in ALDH18A1, a rare form of metabolic cutis laxa, which was complicated by atlantoaxial instability and spinal cord compression following a fall from standing height. The patient required emergent cervical spine fusion and decompression followed by a 2-month hospitalization and rehabilitation. In addition to the core clinical features of joint and skin laxity, hypotonia, and developmental delays, we expand the connective tissue phenotype by adding a new potential feature of cervical spine instability. Patients with pathogenic variants in ALDH18A1 may warrant cervical spine screening to minimize possible morbidity. Neurosurgeons, geneticists, primary care providers, and families should be aware of the increased risk of severe cervical injury from minor trauma.