RESUMO
Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.
Assuntos
Imunidade Inata , Doenças Pulmonares Intersticiais , Humanos , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/patologia , Animais , Imunidade Adaptativa , Imunoterapia , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Pulmão/patologia , Pulmão/imunologiaRESUMO
Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that reveal the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane (TM) domain of NPC1. At pH 8.0, similar structures of NPC1 were obtained in nanodiscs and in detergent at resolutions of 3.6 Å and 3.0 Å, respectively. A tunnel connecting the N-terminal domain (NTD) and the transmembrane sterol-sensing domain (SSD) was unveiled. At pH 5.5, the NTD exhibits two conformations, suggesting the motion for cholesterol delivery to the tunnel. A putative cholesterol molecule is found at the membrane boundary of the tunnel, and TM2 moves toward formation of a surface pocket on the SSD. Finally, the structure of the NPC1-NPC2 complex at 4.0 Å resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD).
Assuntos
Colesterol/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lisossomos/metabolismo , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Proteínas de Fluorescência Verde/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Modelos Moleculares , Nanopartículas/química , Nanopartículas/ultraestrutura , Proteína C1 de Niemann-Pick , Domínios Proteicos , Homologia Estrutural de Proteína , Relação Estrutura-AtividadeRESUMO
DNA replication in eukaryotes generates DNA supercoiling, which may intertwine (braid) daughter chromatin fibers to form precatenanes, posing topological challenges during chromosome segregation. The mechanisms that limit precatenane formation remain unclear. By making direct torque measurements, we demonstrate that the intrinsic mechanical properties of chromatin play a fundamental role in dictating precatenane formation and regulating chromatin topology. Whereas a single chromatin fiber is torsionally soft, a braided fiber is torsionally stiff, indicating that supercoiling on chromatin substrates is preferentially directed in front of the fork during replication. We further show that topoisomerase II relaxation displays a strong preference for a single chromatin fiber over a braided fiber. These results suggest a synergistic coordination-the mechanical properties of chromatin inherently suppress precatenane formation during replication elongation by driving DNA supercoiling ahead of the fork, where supercoiling is more efficiently removed by topoisomerase II. VIDEO ABSTRACT.
Assuntos
Cromatina/química , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Torque , Cromatina/metabolismo , Replicação do DNA , DNA Super-Helicoidal/química , Células HeLa , Humanos , Pinças Ópticas , Saccharomyces cerevisiaeRESUMO
The current human reference genome, GRCh38, represents over 20 years of effort to generate a high-quality assembly, which has benefitted society1,2. However, it still has many gaps and errors, and does not represent a biological genome as it is a blend of multiple individuals3,4. Recently, a high-quality telomere-to-telomere reference, CHM13, was generated with the latest long-read technologies, but it was derived from a hydatidiform mole cell line with a nearly homozygous genome5. To address these limitations, the Human Pangenome Reference Consortium formed with the goal of creating high-quality, cost-effective, diploid genome assemblies for a pangenome reference that represents human genetic diversity6. Here, in our first scientific report, we determined which combination of current genome sequencing and assembly approaches yield the most complete and accurate diploid genome assembly with minimal manual curation. Approaches that used highly accurate long reads and parent-child data with graph-based haplotype phasing during assembly outperformed those that did not. Developing a combination of the top-performing methods, we generated our first high-quality diploid reference assembly, containing only approximately four gaps per chromosome on average, with most chromosomes within ±1% of the length of CHM13. Nearly 48% of protein-coding genes have non-synonymous amino acid changes between haplotypes, and centromeric regions showed the highest diversity. Our findings serve as a foundation for assembling near-complete diploid human genomes at scale for a pangenome reference to capture global genetic variation from single nucleotides to structural rearrangements.
Assuntos
Mapeamento Cromossômico , Diploide , Genoma Humano , Genômica , Humanos , Mapeamento Cromossômico/normas , Genoma Humano/genética , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas , Padrões de Referência , Genômica/métodos , Genômica/normas , Cromossomos Humanos/genética , Variação Genética/genéticaRESUMO
The divergence of chimpanzee and bonobo provides one of the few examples of recent hominid speciation1,2. Here we describe a fully annotated, high-quality bonobo genome assembly, which was constructed without guidance from reference genomes by applying a multiplatform genomics approach. We generate a bonobo genome assembly in which more than 98% of genes are completely annotated and 99% of the gaps are closed, including the resolution of about half of the segmental duplications and almost all of the full-length mobile elements. We compare the bonobo genome to those of other great apes1,3-5 and identify more than 5,569 fixed structural variants that specifically distinguish the bonobo and chimpanzee lineages. We focus on genes that have been lost, changed in structure or expanded in the last few million years of bonobo evolution. We produce a high-resolution map of incomplete lineage sorting and estimate that around 5.1% of the human genome is genetically closer to chimpanzee or bonobo and that more than 36.5% of the genome shows incomplete lineage sorting if we consider a deeper phylogeny including gorilla and orangutan. We also show that 26% of the segments of incomplete lineage sorting between human and chimpanzee or human and bonobo are non-randomly distributed and that genes within these clustered segments show significant excess of amino acid replacement compared to the rest of the genome.
Assuntos
Evolução Molecular , Genoma/genética , Genômica , Pan paniscus/genética , Filogenia , Animais , Fator de Iniciação 4A em Eucariotos/genética , Feminino , Genes , Gorilla gorilla/genética , Anotação de Sequência Molecular/normas , Pan troglodytes/genética , Pongo/genética , Duplicações Segmentares Genômicas , Análise de Sequência de DNARESUMO
The metabolite acetyl-coenzyme A (acetyl-CoA) is the required acetyl donor for lysine acetylation and thereby links metabolism, signaling, and epigenetics. Nutrient availability alters acetyl-CoA levels in cancer cells, correlating with changes in global histone acetylation and gene expression. However, the specific molecular mechanisms through which acetyl-CoA production impacts gene expression and its functional roles in promoting malignant phenotypes are poorly understood. Here, using histone H3 Lys27 acetylation (H3K27ac) ChIP-seq (chromatin immunoprecipitation [ChIP] coupled with next-generation sequencing) with normalization to an exogenous reference genome (ChIP-Rx), we found that changes in acetyl-CoA abundance trigger site-specific regulation of H3K27ac, correlating with gene expression as opposed to uniformly modulating this mark at all genes. Genes involved in integrin signaling and cell adhesion were identified as acetyl-CoA-responsive in glioblastoma cells, and we demonstrate that ATP citrate lyase (ACLY)-dependent acetyl-CoA production promotes cell migration and adhesion to the extracellular matrix. Mechanistically, the transcription factor NFAT1 (nuclear factor of activated T cells 1) was found to mediate acetyl-CoA-dependent gene regulation and cell adhesion. This occurs through modulation of Ca2+ signals, triggering NFAT1 nuclear translocation when acetyl-CoA is abundant. The findings of this study thus establish that acetyl-CoA impacts H3K27ac at specific loci, correlating with gene expression, and that expression of cell adhesion genes are driven by acetyl-CoA in part through activation of Ca2+-NFAT signaling.
Assuntos
Acetilcoenzima A/metabolismo , Sinalização do Cálcio , Adesão Celular , Movimento Celular , Glioblastoma/metabolismo , Fatores de Transcrição NFATC/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , Acetilação , Animais , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/patologia , Glucose/metabolismo , Histonas/metabolismo , Camundongos NusRESUMO
Etoposide is a broadly employed chemotherapeutic and eukaryotic topoisomerase II poison that stabilizes cleaved DNA intermediates to promote DNA breakage and cytotoxicity. How etoposide perturbs topoisomerase dynamics is not known. Here we investigated the action of etoposide on yeast topoisomerase II, human topoisomerase IIα and human topoisomerase IIß using several sensitive single-molecule detection methods. Unexpectedly, we found that etoposide induces topoisomerase to trap DNA loops, compacting DNA and restructuring DNA topology. Loop trapping occurs after ATP hydrolysis but before strand ejection from the enzyme. Although etoposide decreases the innate stability of topoisomerase dimers, it increases the ability of the enzyme to act as a stable roadblock. Interestingly, the three topoisomerases show similar etoposide-mediated resistance to dimer separation and sliding along DNA but different abilities to compact DNA and chirally relax DNA supercoils. These data provide unique mechanistic insights into the functional consequences of etoposide on topoisomerase II dynamics.
Assuntos
DNA Topoisomerases Tipo II , Inibidores da Topoisomerase II , Humanos , Etoposídeo/farmacologia , Inibidores da Topoisomerase II/farmacologia , DNA Topoisomerases Tipo II/genética , DNARESUMO
While maintaining the integrity of the genome and sustaining bioenergetics are both fundamental functions of the cell, potential crosstalk between metabolic and DNA repair pathways is poorly understood. Since histone acetylation plays important roles in DNA repair and is sensitive to the availability of acetyl coenzyme A (acetyl-CoA), we investigated a role for metabolic regulation of histone acetylation during the DNA damage response. In this study, we report that nuclear ATP-citrate lyase (ACLY) is phosphorylated at S455 downstream of ataxia telangiectasia mutated (ATM) and AKT following DNA damage. ACLY facilitates histone acetylation at double-strand break (DSB) sites, impairing 53BP1 localization and enabling BRCA1 recruitment and DNA repair by homologous recombination. ACLY phosphorylation and nuclear localization are necessary for its role in promoting BRCA1 recruitment. Upon PARP inhibition, ACLY silencing promotes genomic instability and cell death. Thus, the spatial and temporal control of acetyl-CoA production by ACLY participates in the mechanism of DNA repair pathway choice.
Assuntos
ATP Citrato (pro-S)-Liase/metabolismo , Acetilcoenzima A/metabolismo , Proteína BRCA1/metabolismo , Núcleo Celular/enzimologia , Quebras de DNA de Cadeia Dupla , Reparo de DNA por Recombinação , Células A549 , ATP Citrato (pro-S)-Liase/genética , Acetilação , Animais , Proteína BRCA1/genética , Núcleo Celular/efeitos dos fármacos , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular , Instabilidade Genômica , Glucose/metabolismo , Células HCT116 , Células HeLa , Histonas/metabolismo , Humanos , Melanoma Experimental/enzimologia , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos Endogâmicos C57BL , Fosforilação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Ligação Proteica , Processamento de Proteína Pós-Traducional , Interferência de RNA , Reparo de DNA por Recombinação/efeitos dos fármacos , Pontos de Checagem da Fase S do Ciclo Celular , Serina , Fatores de Tempo , Transfecção , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismoRESUMO
Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted.
Assuntos
Artrite Reumatoide , Doenças Pulmonares Intersticiais , Humanos , Encurtamento do Telômero , Telômero/genética , Artrite Reumatoide/genética , Artrite Reumatoide/complicações , Doenças Pulmonares Intersticiais/complicações , FumarRESUMO
BACKGROUND AND AIMS: Understanding the mechanisms of HCC progression and metastasis is crucial to improve early diagnosis and treatment. This study aimed to identify key molecular targets involved in HCC metastasis. APPROACH AND RESULTS: Using whole-transcriptome sequencing of patients' HCCs, we identified and validated midline 1 interacting protein 1 (MID1IP1) as one of the most significantly upregulated genes in metastatic HCCs, suggesting its potential role in HCC metastasis. Clinicopathological correlation demonstrated that MID1IP1 upregulation significantly correlated with more aggressive tumor phenotypes and poorer patient overall survival rates. Functionally, overexpression of MID1IP1 significantly promoted the migratory and invasive abilities and enhanced the sphere-forming ability and expression of cancer stemness-related genes of HCC cells, whereas its stable knockdown abrogated these effects. Perturbation of MID1IP1 led to significant tumor shrinkage and reduced pulmonary metastases in an orthotopic liver injection mouse model and reduced pulmonary metastases in a tail-vein injection model in vivo . Mechanistically, SP1 transcriptional factor was found to be an upstream driver of MID1IP1 transcription. Furthermore, transcriptomic sequencing on MID1IP1-overexpressing HCC cells identified FOS-like 1 (FRA1) as a critical downstream mediator of MID1IP1. MID1IP1 upregulated FRA1 to subsequently promote its transcriptional activity and extracellular matrix degradation activity of matrix metalloproteinase MMP9, while knockdown of FRA1 effectively abolished the MID1IP1-induced migratory and invasive abilities. CONCLUSIONS: Our study identified MID1IP1 as a regulator in promoting FRA1-mediated-MMP9 signaling and demonstrated its role in HCC metastasis. Targeting MID1IP1-mediated FRA1 pathway may serve as a potential therapeutic strategy against HCC progression.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica , Transdução de Sinais/genéticaRESUMO
Despite advances in next generation sequencing (NGS), genetic diagnoses remain elusive for many patients with neurologic syndromes. Long-read sequencing (LRS) and optical genome mapping (OGM) technologies improve upon existing capabilities in the detection and interpretation of structural variation in repetitive DNA, on a single haplotype, while also providing enhanced breakpoint resolution. We performed LRS and OGM on two patients with known chromosomal rearrangements and inconclusive Sanger or NGS. The first patient, who had epilepsy and developmental delay, had a complex translocation between two chromosomes that included insertion and inversion events. The second patient, who had a movement disorder, had an inversion on a single chromosome disrupted by multiple smaller inversions and insertions. Sequence level resolution of the rearrangements identified pathogenic breaks in noncoding sequence in or near known disease-causing genes with relevant neurologic phenotypes (MBD5, NKX2-1). These specific variants have not been reported previously, but expected molecular consequences are consistent with previously reported cases. As the use of LRS and OGM technologies for clinical testing increases and data analyses become more standardized, these methods along with multiomic data to validate noncoding variation effects will improve diagnostic yield and increase the proportion of probands with detectable pathogenic variants for known genes implicated in neurogenetic disease.
RESUMO
Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S-transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector.
Assuntos
Aedes/genética , Infecções por Arbovirus/virologia , Arbovírus , Genoma de Inseto/genética , Genômica/normas , Controle de Insetos , Mosquitos Vetores/genética , Mosquitos Vetores/virologia , Aedes/virologia , Animais , Infecções por Arbovirus/transmissão , Arbovírus/isolamento & purificação , Variações do Número de Cópias de DNA/genética , Vírus da Dengue/isolamento & purificação , Feminino , Variação Genética/genética , Genética Populacional , Glutationa Transferase/genética , Resistência a Inseticidas/efeitos dos fármacos , Masculino , Anotação de Sequência Molecular , Família Multigênica/genética , Piretrinas/farmacologia , Padrões de Referência , Processos de Determinação Sexual/genéticaRESUMO
Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies.
Assuntos
Artrite Reumatoide , Imunossupressores , Doenças Pulmonares Intersticiais , Humanos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/fisiopatologia , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Imunossupressores/uso terapêutico , Progressão da Doença , Antirreumáticos/uso terapêutico , Abatacepte/uso terapêutico , Prognóstico , Ácido Micofenólico/uso terapêutico , Rituximab/uso terapêutico , Capacidade Vital , Piridonas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Azatioprina/uso terapêutico , IndóisRESUMO
OBJECTIVE: The purpose of this study is to examine diabetes distress as a potential mediator of the relationship between depression symptoms and diabetes outcomes, including hemoglobin A1c (hemoglobin A1c [HbA1c]) and diabetes management behaviors in a clinical sample of adolescents and young adults. METHODS: In a pediatric diabetes clinic, 716 youth (ages 12-21 years) completed measures of diabetes distress (Problem Areas in Diabetes-Teen [PAID-T]), a single-item of diabetes distress, and depression (Patient Health Questionnaire [PHQ-9]) as part of standard care. Electronic health records were extracted for the "Six Habits" and glycemic management (HbA1c). RESULTS: Overall, 3.6% (n = 26) of adolescents had clinically elevated diabetes distress and depression symptoms, 5.0% had diabetes distress alone, 8.7% had depression symptoms alone, and 82.7% had neither clinical elevation of diabetes distress nor depression symptoms. Results of mediation analysis demonstrated diabetes distress (both full and single-item measures) fully mediated the relationship between depression symptoms and HbA1c (p < .001). Also, mediation analysis results showcase incomplete mediation of the effect of the Six Habits score on HbA1c appears by PAID-T Diabetes Distress. CONCLUSIONS: In a clinical sample of youth with type 1 diabetes, both depressive symptoms and diabetes distress are associated with HbA1c. Furthermore, diabetes distress fully mediates the relationship between depressive symptoms and HbA1c. As part of standard clinical care, the single-item screener for diabetes distress captured similar results as the full-scaled PAID-T. With limited clinical resources, providers may consider focusing assessment and interventions on the psychological factor of diabetes distress within the diabetes clinic to maximize the impact on glycemic control and consider the use of single-item screening to identify distress.
Assuntos
Depressão , Diabetes Mellitus Tipo 1 , Hemoglobinas Glicadas , Humanos , Diabetes Mellitus Tipo 1/psicologia , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Adolescente , Masculino , Feminino , Criança , Adulto Jovem , Depressão/psicologia , Depressão/diagnóstico , Hemoglobinas Glicadas/análise , Angústia Psicológica , Programas de Rastreamento , Estresse Psicológico/psicologia , AdultoRESUMO
BACKGROUND: Atypical lobular hyperplasia (ALH) is typically diagnosed via needle core biopsy (NCB) and is commonly removed surgically in light of upgrade to malignancy rates of 1%-5%. As studies on radiographic outcomes of ALH managed by active surveillance (AS) are limited, we investigated the upgrade rates of surgically excised ALH as well as radiographic progression during AS. METHODS: In this retrospective study, 125 patients with 127 ALH lesions diagnosed via NCB at Weill Cornell Medicine from 2015 to 2021 were included. The upgrade rate to cancer was determined for patients who had surgical management ≤6 months after biopsy. Among patients with ALH managed by AS, we investigated radiographic progression on 6-month interval imaging. RESULTS: Of 127 ALH lesions, 75% (n = 95) were immediately excised and 25% (n = 32) were observed under AS. The upgrade rate of immediately excised ALH was 2.1% (n = 2; invasive ductal carcinoma [IDC], T1N0 and IDC, and T1Nx). In the AS cohort, no ALH lesions progressed radiographically during the follow-up period of 22.5 months (median), with all remaining stable (50%, n = 16), resolving (47%, n = 15), or decreasing in size (3%, n = 1). CONCLUSIONS: In this study, NCB-diagnosed ALH had a low upgrade to malignancy rate (2.1%), and no ALH lesions managed by AS progressed radiographically during the follow-up period of 22.5 months. These results support AS as the favorable option for patients with pure ALH on biopsy, with surgical excision for lesions that progress on surveillance.
Assuntos
Neoplasias da Mama , Conduta Expectante , Humanos , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Idoso , Adulto , Biópsia com Agulha de Grande Calibre , Hiperplasia/cirurgia , Hiperplasia/patologia , Progressão da Doença , Resultado do TratamentoRESUMO
OBJECTIVE: The transition from pediatric to adult care for young adults with diabetes represents an important but often challenging time characterized by a shift from a family-centered care model of pediatrics to a patient-centered care model of adult medicine. We developed a structured transition program based on an adult receivership model at a large academic medical center to improve care coordination and patient satisfaction with the transition process. METHODS: From 2016 to 2020, we implemented a series of quality improvement efforts for young adults aged 18 to 23 years with diabetes by incorporating best practices from the American Diabetes Association guidelines on care for emerging adults. We measured transition orientation attendance, patient satisfaction, hemoglobin A1c (HbA1c) pre- and post-transfer, and care gaps to determine the impact of the program. RESULTS: In this study, 307 individuals with type 1 diabetes and 16 individuals with type 2 diabetes were taken care of by the adult endocrinology department at the University of Michigan between January 1, 2016 and October 31, 2020. We observed high attendance rates (86% among internal transfers) and favorable patient satisfaction scores for the transition orientation session. Despite the glycemic challenges posed during the transition, HbA1c modestly yet significantly improved 1-year after transfer (-0.4%, P < .01). CONCLUSION: We successfully established and maintained a young adult diabetes transition program using a quality improvement approach. Future work will focus on reducing care gaps at the time of transfer, assessing long-term retention rates, and enhancing care coordination for patients referred from outside the health network.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Transição para Assistência do Adulto , Humanos , Adulto Jovem , Criança , Hemoglobinas Glicadas , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 1/terapia , Satisfação do PacienteRESUMO
OBJECTIVE: To evaluate the associations between household food insecurity and diabetes risk factors among lower-income US adolescents. DESIGN: Cross-sectional analysis. Household food security status was measured using the 18-item Food Security Survey Module. Simple and multivariable linear and logistic regressions were used to assess the association between food security status and fasting plasma glucose (FPG), oral glucose tolerance test (OGTT), HbA1C and homoeostatic model assessment - insulin resistance (HOMA-IR). The analyses were adjusted for household and adolescent demographic and health characteristics. SETTING: USA. PARTICIPANTS: 3412 US adolescents aged 12-19 years with household incomes ≤300 % of the federal poverty line from the National Health and Nutrition Examination Survey cycles 2007-2016. RESULTS: The weighted prevalence of marginal food security was 15·4 % and of food insecurity was 32·9 %. After multivariate adjustment, adolescents with food insecurity had a 0·04 % higher HbA1C (95 % CI 0·00, 0·09, P-value = 0·04) than adolescents with food security. There was also a significant overall trend between severity of food insecurity and higher HbA1C (Ptrend = 0·045). There were no significant mean differences in adolescents' FPG, OGTT or HOMA-IR by household food security. CONCLUSIONS: Food insecurity was associated with slightly higher HbA1c in a 10-year sample of lower-income US adolescents aged 12-19 years; however, other associations with diabetes risk factors were not significant. Overall, this suggests slight evidence for an association between food insecurity and diabetes risk in US adolescents. Further investigation is warranted to examine this association over time.
Assuntos
Diabetes Mellitus , Resistência à Insulina , Humanos , Adolescente , Inquéritos Nutricionais , Estudos Transversais , Hemoglobinas Glicadas , Abastecimento de Alimentos , Fatores de Risco , Insegurança AlimentarRESUMO
Rationale: Relatives of patients with familial interstitial pneumonia (FIP) are at increased risk for pulmonary fibrosis and develop preclinical pulmonary fibrosis (PrePF). Objectives: We defined the incidence and progression of new-onset PrePF and its relationship to survival among first-degree relatives of families with FIP. Methods: This is a cohort study of family members with FIP who were initially screened with a health questionnaire and chest high-resolution computed tomography (HRCT) scan, and approximately 4 years later, the evaluation was repeated. A total of 493 asymptomatic first-degree relatives of patients with FIP were evaluated at baseline, and 296 (60%) of the original subjects participated in the subsequent evaluation. Measurements and Main Results: The median interval between HRCTs was 3.9 years (interquartile range, 3.5-4.4 yr). A total of 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100,000 person-years (95% confidence interval, 511-1,831 per 100,000 person-years). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared with 15.4% of those without PrePF (P = 0.002). Usual interstitial pneumonia by HRCT (P < 0.0002) and baseline quantitative fibrosis score (P < 0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P < 0.001). Conclusions: The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). Although PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.
Assuntos
Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Humanos , Estudos de Coortes , Incidência , Dispneia , Pulmão , Estudos RetrospectivosRESUMO
ABSTRACT: Hydrophilic polymer embolism from vascular medical devices is an underrecognized clinical entity that can cause deleterious end-organ ischemia and culminate in mortality. This is concerning as we are in the era where minimally invasive procedures are commonplace. Diagnosis is often made retrospectively after obtaining histopathological tissue samples showing endoluminal, cerebriform, amorphous, anucleate, basophilic, nonrefractile, nonpolarizable foreign body material. We detail 2 more cases of cutaneous hydrophilic polymer embolism to underscore its salient clinicopathological features and increase awareness of this important iatrogenic entity.
Assuntos
Embolia , Humanos , Embolia/patologia , Embolia/etiologia , Feminino , Masculino , Polímeros/efeitos adversos , Polímeros/química , Idoso , Interações Hidrofóbicas e Hidrofílicas , Pessoa de Meia-Idade , Corpos Estranhos/patologia , Corpos Estranhos/complicaçõesRESUMO
BACKGROUND: Interprofessional collaborative care such as a split-shared care model involving family physicians and community pharmacists can reduce the economic burden of diabetes management. This study aimed to evaluate the economic outcome of a split-shared care model between family physicians and community pharmacists within a pharmacy chain in managing people with uncontrolled type 2 diabetes and polypharmacy. METHOD: This was a multi-center, parallel arm, open label, randomized controlled trial comparing the direct and indirect economic outcomes of people who received collaborative care involving community pharmacists (intervention) versus those who received usual care without community pharmacist involvement (control). People with uncontrolled type 2 diabetes, defined as HbA1c > 7.0% and taking ≥ 5 chronic medications were included while people with missing baseline economic data (such as consultation costs, medication costs) were excluded. Direct medical costs were extracted from the institution's financial database while indirect costs were calculated from self-reported gross income and productivity loss, using Work Productivity Activity Impairment Global Health questionnaire. Separate generalized linear models with log link function and gamma distribution were used to analyze changes in direct and indirect medical costs. RESULTS: A total of 175 patients (intervention = 70, control = 105) completed the trial and were included for analysis. The mean age of the participants was 66.9 (9.2) years, with majority being male and Chinese. The direct medical costs were significantly lower in the intervention than the control group over 6 months (intervention: -US$70.51, control: -US$47.66, p < 0.001). Medication cost was the main driver in both groups. There were no significant changes in productivity loss and indirect costs in both groups. CONCLUSION: Implementation of split-shared visits with frontline community partners may reduce economic burden for patient with uncontrolled type 2 diabetes and polypharmacy. TRIAL REGISTRATION: Clinicaltrials.gov Reference Number: NCT03531944 (Date of registration: June 6, 2018).