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2.
J Assoc Nurses AIDS Care ; 35(5): 437-449, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39137316

RESUMO

ABSTRACT: Long-acting injectable cabotegravir (CAB-LA) was US Food and Drug Administration-approved in 2021. However, little is known about providers' CAB-LA knowledge, attitudes, challenges, and prescribing preferences for transgender women patients. Understanding this is critical to developing new pre-exposure prophylaxis (PrEP) interventions tailored to transgender women. We conducted 45-min, in-depth Zoom interviews (IDIs) with United States-based health care providers who prescribe PrEP to transgender women. IDIs focused on providers' CAB-LA knowledge/acceptability, willingness to prescribe CAB-LA to transgender women, potential challenges, and solutions to mitigate challenges. Providers ( N = 17) had a mean age of 43 years, and 35.4% ( n = 6) identified as people of color. Most ( n = 12) had basic knowledge of CAB-LA but wanted additional training. All participants found CAB-LA acceptable and were willing to prescribe. Most ( n = 11) anticipated minimal challenges to implementation. Others ( n = 4) reported potential issues, including logistical/scheduling concerns that impede CAB-LA integration and staffing concerns. Many providers expressed support for self-injection ( n = 13) and injections at "drop-in" clinics ( n = 8) to overcome challenges.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Pessoal de Saúde , Profilaxia Pré-Exposição , Piridonas , Pesquisa Qualitativa , Pessoas Transgênero , Humanos , Pessoas Transgênero/psicologia , Pessoas Transgênero/estatística & dados numéricos , Feminino , Adulto , Estados Unidos , Masculino , Profilaxia Pré-Exposição/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Pessoal de Saúde/psicologia , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Pessoa de Meia-Idade , Conhecimentos, Atitudes e Prática em Saúde , Injeções , Acessibilidade aos Serviços de Saúde , Preparações de Ação Retardada , Atitude do Pessoal de Saúde , Entrevistas como Assunto , Dicetopiperazinas
4.
JBMR Plus ; 8(8): ziae083, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39035786

RESUMO

Maternal Parathyroid Hormone-related Protein (PTHrP) is involved in the placental transport of calcium. Autonomous overproduction of PTHrP is a rare cause of hypercalcemia in pregnancy. Prior cases of PTHrP-induced hypercalcemia in pregnancy have been managed with either dopamine agonists, fetal delivery, termination of pregnancy, or mastectomy. However, PTHrP level normalization following mastectomy has not previously been documented. Herein, we present a 39-year-old female hospitalized at 19 weeks of gestation for acute encephalopathy due to PTHrP induced hypercalcemic crisis (calcium 15.8 mg/dL, PTHrp 46.5 pmol/L [normal 0-3.4]). Mammary hyperplasia resulting in gigantomastia significantly impaired her ability to ambulate and perform activities of daily living. She remained hypercalcemic during hospitalization despite aggressive hydration, calcitonin, and 2 weeks of dopamine agonist treatment. Bisphosphonate therapy was not administered due to pregnancy and potential effects on the fetus. Our patient underwent bilateral mastectomy along with excision of a large axillary mass. The pathology of all three specimens revealed mammary stromal hyperplasia. PTHrP was undetectable on post-op day 2 and calcium normalized by post-op day 3. At discharge, she was able to ambulate independently. To our knowledge, this is the first reported case of PTHrP induced hypercalcemia related to gigantomastia, documenting resolution of hypercalcemia, and PTHrP levels following mastectomy. Mastectomy is a potential option in the second trimester for pregnant patients with PTHrP induced severe hypercalcemia due to gigantomastia, refractory to treatment with dopamine agonist therapy.

5.
Ann Surg Oncol ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38954091

RESUMO

BACKGROUND: Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer. Although mammography is known to have low sensitivity for ILC, there are no data to guide the optimal surveillance after treatment. We explored surveillance strategies after breast-conserving surgery (BCS) for ILC and determined the proportion of imaging-detected recurrences versus interval cancers. METHODS: From an institutional database of 813 women, we retrospectively identified patients who underwent BCS for stage I-III ILC and subsequently had a recurrence. We categorized patients by surveillance strategy and determined the modality of recurrence detection. Interval cancer rates for local recurrences were compared across surveillance strategies using the Chi-square test. We evaluated overall survival with the log-rank test and a Cox proportional hazards model. RESULTS: We included 58 patients with ILC who had a recurrence after BCS. Of these, 22 (37.9%) had local recurrence, 27 (46.6%) had distant recurrence, and 9 (15.5%) had both local and distant recurrence. Most patients underwent routine mammographic surveillance (65.2%), with 19.6% having supplemental breast magnetic resonance imaging (MRI) and 15.2% having no surveillance. The interval cancer rate was significantly higher in the mammographic surveillance group compared with the MRI surveillance group (61.9% vs. 16.7%; p < 0.001). CONCLUSION: In this study of patients with recurrence after BCS for primary treatment of stage I-III ILC, we found that most local recurrences were not detected by surveillance mammography. These data support further investigation of supplemental imaging beyond mammography specifically for patients with ILC who undergo BCS.

6.
J Alzheimers Dis ; 100(4): 1145-1159, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38995790

RESUMO

Background: Recent research has shown beneficial results for music-based interventions (MBIs) for persons living with Alzheimer's disease and related dementias (AD/ADRD), but reports often lack sufficient detail about the MBI methodology, which reduces replicability. A detailed checklist for best practices in how to report MBIs was created in 2011 by Robb and colleagues to remedy the lack of detail in MBI descriptions. The implementation of the checklist specifically in AD/ADRD research has not been established. Given the complexity of music and the variety of uses for research and health, specific MBI descriptions are necessary for rigorous replication and validation of study results. Objective: This systematic mapping review utilized the "Checklist for Reporting Music-Based Interventions" to evaluate the current state of MBI descriptive specificity in AD/ADRD research. Methods: Research articles testing MBIs and reviews of MBI efficacy published between January 2015 and August 2023 were scored using the checklist and the results were summarized. Results: Forty-eight studies were screened, and reporting was inconsistent across the 11 checklist criteria. Ten out of 48 studies fully reported more than 5 of the 11 criteria. Only one of the 11 scoring criteria was at least partially reported across 47 of 48 studies. Conclusions: Thorough reporting of intervention detail for MBIs remains limited in AD/ADRD MBI research. This impedes study validation, replication, and slows the progress of research and potential application of music in practice. Greater implementation of the reporting guidelines provided by Robb and colleagues would move the field of MBI research for AD/ADRD forward more quickly and efficiently.


Assuntos
Demência , Musicoterapia , Humanos , Musicoterapia/métodos , Demência/terapia , Demência/psicologia , Lista de Checagem/métodos , Doença de Alzheimer/terapia , Doença de Alzheimer/psicologia
7.
Genome Biol Evol ; 16(8)2024 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-39031594

RESUMO

Transposable elements (TEs) are repetitive DNA sequences which create mutations and generate genetic diversity across the tree of life. In amniote vertebrates, TEs have been mainly studied in mammals and birds, whose genomes generally display low TE diversity. Squamates (Order Squamata; including ∼11,000 extant species of lizards and snakes) show as much variation in TE abundance and activity as they do in species and phenotypes. Despite this high TE activity, squamate genomes are remarkably uniform in size. We hypothesize that novel, lineage-specific genome dynamics have evolved over the course of squamate evolution. To understand the interplay between TEs and host genomes, we analyzed the evolutionary history of the chicken repeat 1 (CR1) retrotransposon, a TE family found in most tetrapod genomes which is the dominant TE in most reptiles. We compared 113 squamate genomes to the genomes of turtles, crocodilians, and birds and used ancestral state reconstruction to identify shifts in the rate of CR1 copy number evolution across reptiles. We analyzed the repeat landscapes of CR1 in squamate genomes and determined that shifts in the rate of CR1 copy number evolution are associated with lineage-specific variation in CR1 activity. We then used phylogenetic reconstruction of CR1 subfamilies across amniotes to reveal both recent and ancient CR1 subclades across the squamate tree of life. The patterns of CR1 evolution in squamates contrast other amniotes, suggesting key differences in how TEs interact with different host genomes and at different points across evolutionary history.


Assuntos
Evolução Molecular , Genoma , Répteis , Retroelementos , Animais , Répteis/genética , Répteis/classificação , Filogenia , Lagartos/genética , Galinhas/genética
8.
Neurodegener Dis ; 24(2): 54-70, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38865972

RESUMO

INTRODUCTION: Manual motor problems have been reported in mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the specific aspects that are affected, their neuropathology, and potential value for classification modeling is unknown. The current study examined if multiple measures of motor strength, dexterity, and speed are affected in MCI and AD, related to AD biomarkers, and are able to classify MCI or AD. METHODS: Fifty-three cognitively normal (CN), 33 amnestic MCI, and 28 AD subjects completed five manual motor measures: grip force, Trail Making Test A, spiral tracing, finger tapping, and a simulated feeding task. Analyses included (1) group differences in manual performance; (2) associations between manual function and AD biomarkers (PET amyloid ß, hippocampal volume, and APOE ε4 alleles); and (3) group classification accuracy of manual motor function using machine learning. RESULTS: Amnestic MCI and AD subjects exhibited slower psychomotor speed and AD subjects had weaker dominant hand grip strength than CN subjects. Performance on these measures was related to amyloid ß deposition (both) and hippocampal volume (psychomotor speed only). Support vector classification well-discriminated control and AD subjects (area under the curve of 0.73 and 0.77, respectively) but poorly discriminated MCI from controls or AD. CONCLUSION: Grip strength and spiral tracing appear preserved, while psychomotor speed is affected in amnestic MCI and AD. The association of motor performance with amyloid ß deposition and atrophy could indicate that this is due to amyloid deposition in and atrophy of motor brain regions, which generally occurs later in the disease process. The promising discriminatory abilities of manual motor measures for AD emphasize their value alongside other cognitive and motor assessment outcomes in classification and prediction models, as well as potential enrichment of outcome variables in AD clinical trials.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/classificação , Disfunção Cognitiva/fisiopatologia , Doença de Alzheimer/classificação , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Feminino , Masculino , Idoso , Força da Mão/fisiologia , Idoso de 80 Anos ou mais , Desempenho Psicomotor/fisiologia , Peptídeos beta-Amiloides/metabolismo , Hipocampo/patologia , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Testes Neuropsicológicos
9.
JAMA Netw Open ; 7(6): e2416499, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38865125

RESUMO

Importance: Neighborhood deprivation has been associated with increased breast cancer mortality among White women, but findings are inconsistent among Black women, who experience different neighborhood contexts. Accounting for interactions among neighborhood deprivation, race, and other neighborhood characteristics may enhance understanding of the association. Objective: To investigate whether neighborhood deprivation is associated with breast cancer mortality among Black and White women and whether interactions with rurality, residential mobility, and racial composition, which are markers of access, social cohesion, and segregation, respectively, modify the association. Design, Setting, and Participants: This population-based cohort study used Georgia Cancer Registry (GCR) data on women with breast cancer diagnosed in 2010 to 2017 and followed-up until December 31, 2022. Data were analyzed between January 2023 and October 2023. The study included non-Hispanic Black and White women with invasive early-stage (I-IIIA) breast cancer diagnosed between 2010 and 2017 and identified through the GCR. Exposures: The Neighborhood Deprivation Index (NDI), assessed in quintiles, was derived through principal component analysis of 2011 to 2015 block group-level American Community Survey (ACS) data. Rurality, neighborhood residential mobility, and racial composition were measured using Georgia Public Health Department or ACS data. Main Outcomes and Measures: The primary outcome was breast cancer-specific mortality identified by the GCR through linkage to the Georgia vital statistics registry and National Death Index. Cox proportional hazards regression was used to estimate age-adjusted and multivariable-adjusted hazard ratios (HRs) and 95% CIs for the association between neighborhood deprivation and breast cancer mortality. Results: Among the 36 795 patients with breast cancer (mean [SD] age at diagnosis, 60.3 [13.1] years), 11 044 (30.0%) were non-Hispanic Black, and 25 751 (70.0%) were non-Hispanic White. During follow-up, 2942 breast cancer deaths occurred (1214 [41.3%] non-Hispanic Black women; 1728 [58.7%] non-Hispanic White women). NDI was associated with an increase in breast cancer mortality (quintile 5 vs 1, HR, 1.36; 95% CI, 1.19-1.55) in Cox proportional hazards models. The association was present only among non-Hispanic White women (quintile 5 vs 1, HR, 1.47; 95% CI, 1.21-1.79). Similar race-specific patterns were observed in jointly stratified analyses, such that NDI was associated with increased breast cancer mortality among non-Hispanic White women, but not non-Hispanic Black women, irrespective of the additional neighborhood characteristics considered. Conclusions and Relevance: In this cohort study, neighborhood deprivation was associated with increased breast cancer mortality among non-Hispanic White women. Neighborhood racial composition, residential mobility, and rurality did not explain the lack of association among non-Hispanic Black women, suggesting that factors beyond those explored here may contribute to breast cancer mortality in this racial group.


Assuntos
Negro ou Afro-Americano , Neoplasias da Mama , Características de Residência , População Branca , Humanos , Feminino , Neoplasias da Mama/mortalidade , Neoplasias da Mama/etnologia , População Branca/estatística & dados numéricos , Pessoa de Meia-Idade , Negro ou Afro-Americano/estatística & dados numéricos , Georgia/epidemiologia , Características de Residência/estatística & dados numéricos , Idoso , Adulto , Características da Vizinhança/estatística & dados numéricos , Estudos de Coortes , Sistema de Registros , Disparidades nos Níveis de Saúde
10.
Clin Cancer Res ; 30(17): 3904-3918, 2024 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-38848043

RESUMO

PURPOSE: Uterine leiomyosarcoma (LMS) is an aggressive sarcoma and a subset of which exhibits DNA repair defects. Polo-like kinase 4 (PLK4) precisely modulates mitosis, and its inhibition causes chromosome missegregation and increased DNA damage. We hypothesize that PLK4 inhibition is an effective LMS treatment. EXPERIMENTAL DESIGN: Genomic profiling of clinical uterine LMS samples was performed, and homologous recombination (HR) deficiency scores were calculated. A PLK4 inhibitor (CFI-400945) with and without an ataxia telangiectasia mutated (ATM) inhibitor (AZD0156) was tested in vitro on gynecologic sarcoma cell lines SK-UT-1, SKN, and SK-LMS-1. Findings were validated in vivo using the SK-UT-1 xenograft model in the Balb/c nude mouse model. The effects of CFI-400945 were also evaluated in a BRCA2-knockout SK-UT-1 cell line. The mechanisms of DNA repair were analyzed using a DNA damage reporter assay. RESULTS: Uterine LMS had a high HR deficiency score, overexpressed PLK4 mRNA, and displayed mutations in genes responsible for DNA repair. CFI-400945 demonstrated effective antitumor activity in vitro and in vivo. The addition of AZD0156 resulted in drug synergism, largely due to a preference for nonhomologous end-joining DNA repair. Compared with wild-type cells, BRCA2 knockouts were more sensitive to PLK4 inhibition when both HR and nonhomologous end-joining repairs were impaired. CONCLUSIONS: Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacologic inhibition of ATM enhanced the efficacy of the PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy.


Assuntos
Dano ao DNA , Reparo do DNA , Leiomiossarcoma , Proteínas Serina-Treonina Quinases , Neoplasias Uterinas , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , Humanos , Animais , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Leiomiossarcoma/genética , Leiomiossarcoma/tratamento farmacológico , Leiomiossarcoma/patologia , Neoplasias Uterinas/genética , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/patologia , Camundongos , Linhagem Celular Tumoral , Reparo do DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Morfolinas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Indóis/farmacologia , Indóis/uso terapêutico , Piridinas , Quinolinas
11.
Water Res ; 259: 121879, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38865915

RESUMO

Wastewater-based epidemiology (WBE) has been demonstrably successful as a relatively unbiased tool for monitoring levels of SARS-CoV-2 virus circulating in communities during the COVID-19 pandemic. Accumulated biobanks of wastewater samples allow retrospective exploration of spatial and temporal trends for public health indicators such as chemicals, viruses, antimicrobial resistance genes, and the possible emergence of novel human or zoonotic pathogens. We investigated virus resilience to time, temperature, and freeze-thaw cycles, plus the optimal storage conditions to maintain the stability of genetic material (RNA/DNA) of viral +ssRNA (Envelope - E, Nucleocapsid - N and Spike protein - S genes of SARS-CoV-2), dsRNA (Phi6 phage) and circular dsDNA (crAssphage) in wastewater. Samples consisted of (i) processed and extracted wastewater samples, (ii) processed and extracted distilled water samples, and (iii) raw, unprocessed wastewater samples. Samples were stored at -80 °C, -20 °C, 4 °C, or 20 °C for 10 days, going through up to 10 freeze-thaw cycles (once per day). Sample stability was measured using reverse transcription quantitative PCR, quantitative PCR, automated electrophoresis, and short-read whole genome sequencing. Exploring different areas of the SARS-CoV-2 genome demonstrated that the S gene in processed and extracted samples showed greater sensitivity to freeze-thaw cycles than the E or N genes. Investigating surrogate and normalisation viruses showed that Phi6 remains a stable comparison for SARS-CoV-2 in a laboratory setting and crAssphage was relatively resilient to temperature variation. Recovery of SARS-CoV-2 in raw unprocessed samples was significantly greater when stored at 4 °C, which was supported by the sequencing data for all viruses - both time and freeze-thaw cycles negatively impacted sequencing metrics. Historical extracts stored at -80 °C that were re-quantified 12, 14 and 16 months after original quantification showed no major changes. This study highlights the importance of the fast processing and extraction of wastewater samples, following which viruses are relatively robust to storage at a range of temperatures.


Assuntos
DNA Viral , Congelamento , RNA Viral , SARS-CoV-2 , Temperatura , Águas Residuárias , Águas Residuárias/virologia , COVID-19/virologia
12.
Oncologist ; 29(9): e1159-e1168, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-38856325

RESUMO

BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.


Assuntos
Neoplasias da Mama , Neoplasias Colorretais , Segunda Neoplasia Primária , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/patologia , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/epidemiologia , Neoplasias Primárias Múltiplas/genética , Masculino , Fatores Etários , Fatores de Risco
13.
Environ Sci Pollut Res Int ; 31(31): 43874-43895, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38910184

RESUMO

Use of waste wood biomass for bioenergy produces wood ash as a by-product; this ash is typically landfilled, but can potentially play an important role in soil improvement and forest restoration. In particular, high-carbon wood ash biochar (HCWAB) could supply nutrients, improve substrate water-holding capacity and pH, and emulate the ecosystem benefits of wildfire residues. Thickened tailings sites at metal mines across Canada are subject to stringent restoration regulations that entail planting of native trees to promote rapid reforestation. While HCWAB may prove beneficial in this context, field trials have been very limited to date. We conducted a large-scale, replicated field trial on sand-capped tailings at an operational gold mine in the Canadian boreal forest to assess the impact of HCWAB (at dosages of 0, 6.4, 12.8, and 19.1 t/ha) on survival and growth of four native tree species, as well as substrate chemical properties and element uptake in tree tissues. After 2 years, the survival of planted, native trees was highest at low to moderate application rates; HCWAB dosages above 13 t/ha presented reduced tree survival to levels comparable to unamended substrates. Tree growth was higher across all HCWAB doses relative to growth in samples planted on untreated substrates; tree species and initial size also had large impacts on final tree survival and aboveground growth. The survival of Betula papyrifera was significantly higher than other species, while smaller transplanted trees in general survived in greater numbers compared to larger size classes. Volunteer herbaceous vegetation significantly increased at the higher HCWAB application dosages and tree performance was negatively correlated with vegetation cover, consistent with a resource competition effect. HCWAB additions to sand-capped mine tailings did not significantly alter tree tissue concentrations or substrate availability of potentially toxic metals (Cd, Cu, Al). We conclude that low to moderate dosages of HCWAB on sand-capped tailings, particularly between 6.4 and 12.8 t/ha, may offer benefits to early tree survival, growth, and substrate nutrient status without causing significant risks of phytotoxicity and recommend future field trials focus on strategies to reduce tree competition with competing vegetation.


Assuntos
Carvão Vegetal , Mineração , Árvores , Madeira , Carvão Vegetal/química , Madeira/química , Areia , Carbono , Solo/química , Canadá
14.
Cell Host Microbe ; 32(7): 1074-1088.e5, 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38917809

RESUMO

Cyclic oligonucleotide-based signaling system (CBASS) is an antiviral system that protects bacteria from phage infection and is evolutionarily related to human cGAS-STING immunity. cGAS-STING signaling is initiated by the recognition of viral DNA, but the molecular cues activating CBASS are incompletely understood. Using a screen of 975 type I CBASS operon-phage challenges, we show that operons with distinct cGAS/DncV-like nucleotidyltransferases (CD-NTases) and CD-NTase-associated protein (Cap) effectors exhibit marked patterns of phage restriction. We find that some type I CD-NTase enzymes require a C-terminal AGS-C immunoglobulin (Ig)-like fold domain for defense against select phages. Escaper phages evade CBASS via protein-coding mutations in virion assembly proteins, and acquired resistance is largely operon specific. We demonstrate that the phage Bas13 prohead protease interacts with the CD-NTase EcCdnD12 and can induce CBASS-dependent growth arrest in cells. Our results define phage virion assembly as a determinant of type I CBASS immune evasion and support viral protein recognition as a putative mechanism of cGAS-like enzyme activation.


Assuntos
Bacteriófagos , Evasão da Resposta Imune , Humanos , Bacteriófagos/genética , Óperon , Nucleotidiltransferases/metabolismo , Nucleotidiltransferases/genética , Proteínas Virais/metabolismo , Proteínas Virais/genética , Transdução de Sinais , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Peptídeo Hidrolases/metabolismo , Peptídeo Hidrolases/genética
15.
Blood Adv ; 8(13): 3507-3518, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38739715

RESUMO

ABSTRACT: Little is known about risk factors for central nervous system (CNS) relapse in mature T-cell and natural killer cell neoplasms (MTNKNs). We aimed to describe the clinical epidemiology of CNS relapse in patients with MTNKN and developed the CNS relapse In T-cell lymphoma Index (CITI) to predict patients at the highest risk of CNS relapse. We reviewed data from 135 patients with MTNKN and CNS relapse from 19 North American institutions. After exclusion of leukemic and most cutaneous forms of MTNKNs, patients were pooled with non-CNS relapse control patients from a single institution to create a CNS relapse-enriched training set. Using a complete case analysis (n = 182), including 91 with CNS relapse, we applied a least absolute shrinkage and selection operator Cox regression model to select weighted clinicopathologic variables for the CITI score, which we validated in an external cohort from the Swedish Lymphoma Registry (n = 566). CNS relapse was most frequently observed in patients with peripheral T-cell lymphoma, not otherwise specified (25%). Median time to CNS relapse and median overall survival after CNS relapse were 8.0 and 4.7 months, respectively. We calculated unique CITI risk scores for individual training set patients and stratified them into risk terciles. Validation set patients with low-risk (n = 158) and high-risk (n = 188) CITI scores had a 10-year cumulative risk of CNS relapse of 2.2% and 13.4%, respectively (hazard ratio, 5.24; 95% confidence interval, 1.50-18.26; P = .018). We developed an open-access web-based CITI calculator (https://redcap.link/citicalc) to provide an easy tool for clinical practice. The CITI score is a validated model to predict patients with MTNKN at the highest risk of developing CNS relapse.


Assuntos
Neoplasias do Sistema Nervoso Central , Humanos , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Linfoma de Células T/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/mortalidade , Prognóstico , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia , Linfoma Extranodal de Células T-NK/diagnóstico , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/terapia , Fatores de Risco , Recidiva , Células Matadoras Naturais , Adulto Jovem
16.
J Pain Res ; 17: 1815-1827, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38799276

RESUMO

Background: Pain management physicians are increasingly focused on limiting prescription opioid abuse, yet existing tools for monitoring adherence have limited accuracy. Medication event monitoring system (MEMS) is an emerging technology for tracking medication usage in real-time but has not been tested in chronic pain patients on long-term opioid regimens. Objective: We conducted a pilot clinical trial to investigate the utility of MEMS for monitoring opioid adherence and compared to traditional methods including self-report diaries, urine drug screen (UDS), and physicians' opinions. Methods: Opioid-maintained chronic pain patients were recruited from a pain management clinic. Participants (n=28) were randomly assigned to either receive MEMS bottles containing their opioid medication for a 90-day period or to continue using standard medication bottles. MEMS bottles were configured to record and timestamp all bottle openings and the number of pills that were removed from the bottle (via measurement of weight change). Results: Participants who received MEMS demonstrated highly heterogenous dosing patterns, with a substantial number of patients rapidly removing excessive amounts of medication and/or "stockpiling" medication. By comparison, physicians rated all participants as either "totally compliant" or "mostly compliant". UDS results did not reveal any illicit drug use, but 25% of participants (n=7) tested negative for their prescribed opioid metabolite. MEMS data did not correlate with physician-rated adherence (P=0.24) and UDS results (P=0.77). MEMS data consistently revealed greater non-adherence than self-report data (P<0.001). Conclusion: These results highlight the limits in our understanding of naturalistic patterns of daily opioid use in chronic pain patients as well as support the use of MEMS for detecting potential misuse as compared to routine adherence monitoring methods. Future research directions include the need to determine how MEMS could be used to improve patient outcomes, minimize harm, and aid in clinical decision-making. Trial Registration: This study was preregistered on ClinicalTrials.gov (NCT03752411).

17.
PLoS One ; 19(5): e0300053, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38743683

RESUMO

Considering the growing interest in clinical applications of neuromodulation, assessing effects of various modulatory approaches is increasingly important. Monosynaptic spinal reflexes undergo depression following repeated activation, offering a means to quantify neuromodulatory influences. Following spinal cord injury (SCI), changes in reflex modulation are associated with spasticity and impaired motor control. To assess disrupted reflex modulation, low-frequency depression (LFD) of Hoffman (H)-reflex excitability is examined, wherein the amplitudes of conditioned reflexes are compared to an unconditioned control reflex. Alternatively, some studies utilize paired-pulse depression (PPD) in place of the extended LFD train. While both protocols induce similar amounts of H-reflex depression in neurologically intact individuals, this may not be the case for persons with neuropathology. We compared the H-reflex depression elicited by PPD and by trains of 3-10 pulses to an 11-pulse LFD protocol in persons with incomplete SCI. The amount of depression produced by PPD was less than an 11-pulse train (mean difference = 0.137). When compared to the 11-pulse train, the 5-pulse train had a Pearson's correlation coefficient (R) of 0.905 and a coefficient of determination (R2) of 0.818. Therefore, a 5-pulse train for assessing LFD elicits modulation similar to the 11-pulse train and thus we recommend its use in lieu of longer trains.


Assuntos
Reflexo H , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/complicações , Humanos , Reflexo H/fisiologia , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Estimulação Elétrica
18.
J Pharm Bioallied Sci ; 16(Suppl 1): S156-S158, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38595474

RESUMO

Introduction: The application of the antioxidants after the teeth are bleached has been advocated to fasten the restorative process post-bleaching. The motive of this study was to examine and assess the micro-tensile binding strength of bleached enamel to the resin using a variety of antioxidant solutions. Finding the reason for the tooth fracture was the secondary outcome measured. Materials and Methods: An in vitro study was planned with 100 human extracted teeth, with 20 in each group with one as controls and 4 others tested for the antioxidants sodium ascorbate, epigallocatechin gallate, chitosan, and proanthocyanidin application. The bond strength of bleached enamel to the resin was well as the failure type was assessed after the values were noted and compared using the ANOVA and Tukey's methods keeping P < 0.05 as significant. Results: Epigallocatechin gallate specimens displayed the maximum micro-tensile bond strength under the investigational circumstances, whereas controls displayed the lowest micro-tensile bond strength. There was statistical alteration in micro-tensile bond strengths between all the groups except between epigallocatechin gallate vs chitosan and sodium ascorbate vs proanthocyanidin. High statistical significance was seen between the control and the antioxidant groups as well as between sodium ascorbate and epigallocatechin gallate and chitosan. Conclusion: The antioxidant chemicals significantly augmented the bond strength of bleached enamel to the resin that had been bleached. Also, when compared to the other experimental groups, epigallocatechin gallate and chitosan treatment displayed the greatest mean bond strength values.

19.
Child Dev ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563089

RESUMO

Two studies examine how social object histories from collaborative experiences influenced North American children (N = 160, 5-10 years) thinking about the value of digital objects (48% male/51% female; 51% White/24% Black/11% Asian). With forced-choice judgments, Study 1 found (moderate-large effects) that children viewed digital and physical objects with social histories as more special than objects without such histories. On a 10-point scale, Study 2 found (large effects) that children rated digital objects with positive social histories as more special than objects with negative ones. Overall, the studies found that children's tendencies to use object history to understand object value extends into digital contexts. They also reveal how an unexplored kind of history-social history-affects judgments.

20.
Addit Manuf ; 842024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38567361

RESUMO

The working curve informs resin properties and print parameters for stereolithography, digital light processing, and other photopolymer additive manufacturing (PAM) technologies. First demonstrated in 1992, the working curve measurement of cure depth vs radiant exposure of light is now a foundational measurement in the field of PAM. Despite its widespread use in industry and academia, there is no formal method or procedure for performing the working curve measurement, raising questions about the utility of reported working curve parameters. Here, an interlaboratory study (ILS) is described in which 24 individual laboratories performed a working curve measurement on an aliquot from a single batch of PAM resin. The ILS reveals that there is enormous scatter in the working curve data and the key fit parameters derived from it. The measured depth of light penetration Dp varied by as much as 7x between participants, while the critical radiant exposure for gelation Ec varied by as much as 70x. This significant scatter is attributed to a lack of common procedure, variation in light engines, epistemic uncertainties from the Jacobs equation, and the use of measurement tools with insufficient precision. The ILS findings highlight an urgent need for procedural standardization and better hardware characterization in this rapidly growing field.

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