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1.
Ann Otol Rhinol Laryngol ; : 34894231154410, 2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36788443

RESUMO

OBJECTIVES: This study evaluated the content and patient educational quality of YouTube videos on facelift surgery for facial rejuvenation. This study investigated the relationship between education quality compared to video content, video metrics, and popularity. METHODS: Two hundred videos were identified across 4 search terms: "facelift surgery," "facelift surgery what to expect," "facelift surgery patient education," and "what is facelift surgery." Unrelated videos, operating room recordings, medical professional lectures, non-English, non-audio, and testimonials were excluded from review. Video quality was assessed using the Global Quality Score (GQS) (range: 1-5), modified DISCERN score (range: 5-25), and JAMA Benchmark Criteria (range: 0-4). Secondary outcomes included upload source, video metrics (views, likes, dislikes, duration, days since upload, comments), and Video Power Indexto measure popularity. The first 10 comments on videos were characterized as positive, neutral, or negative. RESULTS: One hundred forty-three videos were excluded (43 did not meet criteria, 100 duplicates), and 57 videos were included. Fifty-five videos (96.5%) were uploaded by private medical practices. Overall video quality was poor across all 3 scoring systems: GQS (2.92 ± 1.14), modified DISCERN (13.03 ± 3.64), and JAMA Benchmark Criteria (1.78 ± 0.52). Popularity positively correlated with JAMA Benchmark Criteria (R = .49, P < .05) but did not correlate with other quality criteria. CONCLUSIONS: For patients undergoing facelift surgery, there are limited educational videos on YouTube with few videos detailing indications, alternatives, complications, and the postoperative course. YouTube is a growing resource for patient education and opportunities exist for medical institutions to produce higher-quality videos for prospective patients.

2.
Laryngoscope Investig Otolaryngol ; 8(1): 82-88, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36846427

RESUMO

Objectives: Patients are increasingly relying on YouTube for health information. We objectively evaluated the quality and comprehensiveness of sialendoscopy YouTube videos available to patients. We further investigated the relationship between video content and video popularity. Methods: We identified 150 videos using the search term "sialendoscopy." Videos were excluded if they were lectures for medical professionals, operating room (OR) recordings, unrelated, non-English, or non-audio. Video quality and comprehensiveness were evaluated using modified DISCERN criterion (range: 5-25) and novel sialendoscopy criterion (NSC, range: 0-7), respectively. Secondary outcomes included standard video metrics and Video Power Index to measure popularity. Videos were classified binarily by uploader type as from an academic medical center or from other sources. Results: Twenty-two (14.7%) of 150 videos were included for review, with 7 (31.8%) uploaded from academic medical institutions. One hundred-nine (72.7%) videos were excluded as lectures for medical professionals or OR recordings. Overall mean modified DISCERN (13.45 ± 3.42) and NSC (3.05 ± 0.96) scores were low; however, videos uploaded by academic medical institutions were significantly more comprehensive (NSC mean difference = 0.98, 95% CI: 0.16-1.80, p = .02). There were no significant correlations between video popularity and objective measures of quality or comprehensiveness. Conclusions: This study highlights the paucity and low quality of sialendoscopy videos for patients. More popular videos are not higher quality, and most videos are targeted more toward physicians rather than patients. As YouTube becomes increasingly used by patients, there is opportunity for otolaryngologists to produce more informative videos for patients while implementing targeted strategies to increase viewership. Level of Evidence: NA.

4.
J Cyst Fibros ; 2022 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-36581484

RESUMO

BACKGROUND: Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks. METHODS: Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate. RESULTS: 464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A. CONCLUSIONS: TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.

5.
Cureus ; 14(4): e24352, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35611038

RESUMO

Septic arthritis is a rare but serious complication of both rheumatoid and gouty arthritis and can lead to significant morbidity and even mortality. Here, we report a case of septic arthritis with bacteremia, monosodium urate crystals, and hyperuricemia in a 75-year-old male with long-standing rheumatoid arthritis. Arthrocentesis revealed gram-positive cocci representing group B streptococcus (Streptococcus agalactiae) infection and monosodium urate crystals. A diagnosis of septic arthritis with superimposed acute gouty arthritis was made and the patient was treated accordingly. Management included surgical irrigation and debridement, antibiotic therapy, and systemic glucocorticoids which resulted in a significant improvement in the patient's clinical status.

6.
Am J Otolaryngol ; 43(4): 103483, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35580419

RESUMO

OBJECTIVE: To compare the experiences of patients who received sialendoscopy under general anesthesia (GA) with those who received monitored anesthesia care (MAC). METHODS: Patients who underwent sialendoscopy for sialadenitis or sialolithiasis from July 1, 2020, to July 31, 2021, were offered inclusion to this prospective observational study. A survey was sent to consenting patients on post-operative day 1 to record aspects of their pre-, intra-, and post-operative experience. The primary outcome was overall satisfaction. Secondary outcomes included pain tolerability and preference for similar anesthetic modality in the future. RESULTS: Seventy-five patients completed the post-operative survey (86% response rate), of which 39 patients received GA and 36 received MAC. Patient overall satisfaction was similar between groups (GA: "Poor/Average/Good" = 23%, "Excellent" = 77%; MAC: "Poor/Average/Good" = 25%, "Excellent" = 75%, p = 1.00). Tolerability of immediate post-operative pain was likewise similar between the GA (82%) and MAC (97%) groups (p = 0.058). Patients who received MAC reported intra-operative pain as "none/tolerable" 72% of the time and "uncomfortable" 28% of the time. Patients who received GA would prefer the same anesthetic in the future more often than in the MAC group (85% versus 61%, respectively, OR 3.50, 95% CI 1.17-10.50, p = 0.035). CONCLUSION: In regard to patient satisfaction, both MAC and GA are acceptable anesthetic choices in sialendoscopy for appropriate cases. Patients report similar overall satisfaction and post-operative pain tolerance under either anesthetic modality. Patients who undergo GA report higher rates of preference for similar anesthetic modality in the future. Further study is needed to determine the most appropriate criteria for anesthesia modality selection.


Assuntos
Anestesia Geral , Cálculos das Glândulas Salivares , Humanos , Dor Pós-Operatória , Avaliação de Resultados da Assistência ao Paciente , Estudos Retrospectivos , Cálculos das Glândulas Salivares/cirurgia , Resultado do Tratamento
7.
Nat Genet ; 54(5): 603-612, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35513721

RESUMO

Genome-wide association studies (GWASs) have uncovered hundreds of autoimmune disease-associated loci; however, the causal genetic variants within each locus are mostly unknown. Here, we perform high-throughput allele-specific reporter assays to prioritize disease-associated variants for five autoimmune diseases. By examining variants that both promote allele-specific reporter expression and are located in accessible chromatin, we identify 60 putatively causal variants that enrich for statistically fine-mapped variants by up to 57.8-fold. We introduced the risk allele of a prioritized variant (rs72928038) into a human T cell line and deleted the orthologous sequence in mice, both resulting in reduced BACH2 expression. Naive CD8 T cells from mice containing the deletion had reduced expression of genes that suppress activation and maintain stemness and, upon acute viral infection, displayed greater propensity to become effector T cells. Our results represent an example of an effective approach for prioritizing variants and studying their physiologically relevant effects.


Assuntos
Doenças Autoimunes , Estudo de Associação Genômica Ampla , Alelos , Animais , Doenças Autoimunes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Camundongos , Polimorfismo de Nucleotídeo Único/genética , Sequências Reguladoras de Ácido Nucleico , Linfócitos T
8.
Cell ; 185(9): 1588-1601.e14, 2022 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-35413241

RESUMO

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together, they engender improved protection from disease, termed hybrid immunity. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. Although additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4+ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19 , SARS-CoV-2 , Anticorpos Neutralizantes , Anticorpos Antivirais , COVID-19/imunologia , Humanos , Imunidade Humoral , Glicoproteína da Espícula de Coronavírus , Linfócitos T
9.
J Immunol ; 208(7): 1519-1524, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35288472

RESUMO

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the CNS treated by diverse disease-modifying therapies that suppress the immune system. Severe acute respiratory syndrome coronavirus 2 mRNA vaccines have been very effective in immunocompetent individuals, but whether MS patients treated with modifying therapies are afforded the same protection is not known. This study determined that dimethyl fumarate caused a momentary reduction in anti-Spike (S)-specific Abs and CD8 T cell response. MS patients treated with B cell-depleting (anti-CD20) or sphingosine 1-phosphate receptor agonist (fingolimod) therapies lack significant S-specific Ab response. Whereas S-specific CD4 and CD8 T cell responses were largely compromised by fingolimod treatment, T cell responses were robustly generated in anti-CD20-treated MS patients, but with a reduced proportion of CD4+CXCR5+ circulating follicular Th cells. These data provide novel information regarding vaccine immune response in patients with autoimmunity useful to help improve vaccine effectiveness in these populations.


Assuntos
COVID-19 , Esclerose Múltipla , Vacinas contra COVID-19 , Humanos , Memória Imunológica , Esclerose Múltipla/tratamento farmacológico , SARS-CoV-2
10.
J Cyst Fibros ; 21(4): 675-683, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35190292

RESUMO

BACKGROUND: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study. METHODS: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI). RESULTS: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ­R respiratory domain score, and BMI observed from parent study baseline to Week 96. CONCLUSIONS: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.


Assuntos
Agonistas dos Canais de Cloreto , Fibrose Cística , Aminofenóis , Benzodioxóis , Criança , Agonistas dos Canais de Cloreto/uso terapêutico , Fibrose Cística/diagnóstico , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Progressão da Doença , Homozigoto , Humanos , Indóis , Mutação , Quinolonas
11.
Immunity ; 55(1): 98-114.e5, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34932944

RESUMO

Elevated gene expression of the costimulatory receptor Icos is a hallmark of CD8+ tissue-resident memory (Trm) T cells. Here, we examined the contribution of ICOS in Trm cell differentiation. Upon transfer into WT mice, Icos-/- CD8+ T cells exhibited defective Trm generation but produced recirculating memory populations normally. ICOS deficiency or ICOS-L blockade compromised establishment of CD8+ Trm cells but not their maintenance. ICOS ligation during CD8+ T cell priming did not determine Trm induction; rather, effector CD8+ T cells showed reduced Trm differentiation after seeding into Icosl-/- mice. IcosYF/YF CD8+ T cells were compromised in Trm generation, indicating a critical role for PI3K signaling. Modest transcriptional changes in the few Icos-/- Trm cells suggest that ICOS-PI3K signaling primarily enhances the efficiency of CD8+ T cell tissue residency. Thus, local ICOS signaling promotes production of Trm cells, providing insight into the contribution of costimulatory signals in the generation of tissue-resident populations.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Células T de Memória/imunologia , Transferência Adotiva , Animais , Anticorpos Bloqueadores/metabolismo , Diferenciação Celular , Células Cultivadas , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais
12.
Am J Med Qual ; 37(3): 207-213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34787591

RESUMO

Although the Affordable Care Act (ACA) has been shown to broadly affect access to care, there is little data examining the change in insurance status with regard to nonelective spinal trauma, infection, and tumor patients. The purpose of this study is to evaluate the changes in insurance status before and after implementation of the ACA in patients who present to the emergency room of a single, level 1 trauma and regional spinal cord injury center. Patient demographic and hospital course information were derived from consult notes and electronic medical record review. Spinal consults between January 1, 2013, and December 31, 2015, were initially included. Consults between January 1 and December 31, 2014, were subsequently removed to obtain two separate cohorts reflecting one calendar year prior to ("pre-ACA") and following ("post-ACA") the effective date of implementation of the ACA on January 1, 2014. Compared with the pre-ACA cohort, the post-ACA cohort had a significant increase in insurance coverage (95.0% versus 83.9%, P < 0.001). Post-ACA consults had a significantly shorter length of stay compared with pre-ACA consults (7.94 versus 9.19, P < 0.001). A significantly greater percentage of the post-ACA cohort appeared for clinical follow-up subsequent to their initial consultation compared to the pre-ACA cohort (49.5% versus 35.3%, P < 0.001). Spinal consultation after the implementation of the ACA was found to be a significant positive predictor of Medicaid coverage (odds ratio = 1.96 [1.05, 3.82], P = 0.04) and a significant negative predictor of uninsured status (odds ratio = 0.28 [0.16, 0.47], P < 0.001). Increase in overall insurance coverage, increase in patient follow-up after initial consultation, and decrease in hospital length of stay were all noted after the implementation of the ACA for spinal consultation patients presenting to the emergency department.


Assuntos
Cobertura do Seguro , Patient Protection and Affordable Care Act , Serviço Hospitalar de Emergência , Humanos , Medicaid , Pessoas sem Cobertura de Seguro de Saúde , Estados Unidos
13.
Am J Med Genet A ; 188(2): 556-568, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34726335

RESUMO

Predicting genotype-to-phenotype correlations from genomic variants has been challenging, particularly for genes that have a complex balance of dominant and recessive inheritance for phenotypes. Variants in NMDA receptor components GRIN1, GRIN2A, and GRIN2B cause a myriad of dominant disease phenotypes, with the most common being epilepsy and autism spectrum disorder. Starting from the analysis of a variant of uncertain significance (VUS, GRIN2A G760S), we realized the need for tools to map dominant variants for the components of the NMDA receptor. Some variants within GRIN1, GRIN2A, and GRIN2B exert dominant epilepsy and developmental delay, yet other amino acid variants are conserved and predicted to alter protein function but do not have dominant phenotypes. Common variant annotation tools are not powered to determine pathogenic dominant outcomes. To address this gap, we integrated sequence and structural analyses for GRIN1, GRIN2A, and GRIN2B. Using this approach, we determined that paralog homology mapping and topology can segregate dominant variants, with an elevation of intermolecular contacts between the subunits. Furthermore, demonstrating the general utility of our methodology, we show that 25 VUS within ClinVar also reach a dominant variant annotation, including the GRIN2A G760S variant. Our work suggests paralog homology and protein topology as a powerful strategy within the receptor complex to resolve dominant genetic variants relative to variants that would fit a recessive inheritance, requiring two damaging variants. These strategies should be tested in additional dominant genetic disorders to determine the broader utility.


Assuntos
Transtorno do Espectro Autista , Epilepsia , Epilepsia/genética , Humanos , N-Metilaspartato/genética , Fenótipo , Receptores de N-Metil-D-Aspartato/genética
14.
J Neurodev Disord ; 13(1): 30, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34429070

RESUMO

BACKGROUND: Prenatal exposure to air pollutants is associated with increased risk for neurodevelopmental and neurodegenerative disorders. However, few studies have identified transcriptional changes related to air pollutant exposure. METHODS: RNA sequencing was used to examine transcriptomic changes in blood and cerebral cortex of three male and three female mouse neonates prenatally exposed to traffic-related nano-sized particulate matter (nPM) compared to three male and three female mouse neonates prenatally exposed to control filter air. RESULTS: We identified 19 nPM-associated differentially expressed genes (nPM-DEGs) in blood and 124 nPM-DEGs in cerebral cortex. The cerebral cortex transcriptional responses to nPM suggested neuroinflammation involvement, including CREB1, BDNF, and IFNγ genes. Both blood and brain tissues showed nPM transcriptional changes related to DNA damage, oxidative stress, and immune responses. Three blood nPM-DEGs showed a canonical correlation of 0.98 with 14 nPM-DEGS in the cerebral cortex, suggesting a convergence of gene expression changes in blood and cerebral cortex. Exploratory sex-stratified analyses suggested a higher number of nPM-DEGs in female cerebral cortex than male cerebral cortex. The sex-stratified analyses identified 2 nPM-DEGs (Rgl2 and Gm37534) shared between blood and cerebral cortex in a sex-dependent manner. CONCLUSIONS: Our findings suggest that prenatal nPM exposure induces transcriptional changes in the cerebral cortex, some of which are also observed in blood. Further research is needed to replicate nPM-induced transcriptional changes with additional biologically relevant time points for brain development.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/toxicidade , Poluição do Ar/efeitos adversos , Animais , Córtex Cerebral , Feminino , Masculino , Camundongos , Material Particulado/toxicidade , Gravidez , Transcriptoma
15.
Laryngoscope ; 131(11): E2827-E2832, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34363396

RESUMO

OBJECTIVES/HYPOTHESIS: This study evaluated the quality and comprehensiveness of YouTube videos on hypoglossal nerve stimulation (HNS) for patients. This study also investigated the relationship between video content, video metrics, and popularity. STUDY DESIGN: Cross-sectional study. METHODS: We identified 150 videos using three search terms: "inspire sleep apnea," "hypoglossal nerve stimulation," and "upper airway stimulation." Videos that were unrelated to the use of HNS for obstructive sleep apnea in adults, operating room recordings, lectures for medical professionals, non-English, or non-audio were excluded. Video quality and comprehensiveness were assessed using modified DISCERN criterion (range: 5-25) and novel content criterion (range: 0-12), respectively. Secondary outcomes included video metrics (views, likes, dislikes, comments, and days since upload) and Video Power Index to measure popularity. Outcomes were stratified by video uploader source (medical institutions, medical companies, individual users, other). RESULTS: Users searched YouTube for "inspire sleep apnea" 2.48 times more in 2020 than in 2018. We identified 67 videos for review, with the majority coming from medical institutions (70.2%). Overall, the average-modified DISCERN (13.65 ± 4.88) and novel content (3.87 ± 2.09) scores were low and did not differ between medical institutions or other uploader sources. Higher quality and more comprehensive video content did not correlate with popularity. CONCLUSION: Overall quality and comprehensiveness of information of HNS YouTube videos was low. Given the high demand for information on HNS, there is opportunity for medical institutions to implement new strategies to improve both video content and visibility to patients. LEVEL OF EVIDENCE: NA Laryngoscope, 131:E2827-E2832, 2021.


Assuntos
Eletrodos Implantados/efeitos adversos , Recursos em Saúde/tendências , Nervo Hipoglosso/cirurgia , Apneia Obstrutiva do Sono/terapia , Mídias Sociais/estatística & dados numéricos , Estudos Transversais , Humanos , Nervo Hipoglosso/fisiologia , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Mídias Sociais/provisão & distribuição , Gravação em Vídeo/métodos
16.
Comput Methods Programs Biomed ; 208: 106165, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34118492

RESUMO

BACKGROUND AND OBJECTIVES: Body-worn accelerometers are the most popular method for objectively assessing physical activity in older adults. Many studies have developed generic accelerometer cut-points for defining activity intensity in metabolic equivalents for older adults. However, methodological diversity in current studies has led to a great deal of variation in the resulting cut-points, even when using data from the same accelerometer. In addition, the generic cut-point approach assumes that 'one size fits all' which is rarely the case in real life. This study proposes a machine learning method for personalising activity intensity cut-points for older adults. METHODS: Firstly, raw accelerometry data was collected from 33 older adults who performed set activities whilst wearing two accelerometer devices: GENEActive (wrist worn) and ActiGraph (hip worn). ROC analysis was applied to generate personalised cut-point for each data sample based on a device. Four cut-points have been considered: Sensitivity optimised Sedentary Behaviour; Specificity optimised Moderate to Vigorous Physical Activity; Youden optimised Sedentary Behaviour; and Youden optimised Moderate to Vigorous Physical Activity. Then, an additive regression algorithm trained on biodata features, that concern the individual characteristics of participants, was used to predict the cut-points. As the model output is a numeric cut-point value (and not discrete), evaluation was based on two error metrics, Mean Absolute Error and Root Mean Square Error. Standard Error of estimation was also calculated to measure the accuracy of prediction (goodness of fit) and this was used for performance comparison between our approach and the state-of-the-art. Hold-out and 10-Fold cross validation methods were used for performance validation and comparison. RESULTS: The results show that our personalised approach performed consistently better than the state-of-the-art with 10-Fold cross validation on all four cut-points considered for both devices. For the ActiGraph device, the Standard Error of estimation from our approach was lower by 0.33 (Youden optimised Sedentary Behaviour), 9.50 (Sensitivity optimised Sedentary Behaviour), 0.64 (Youden optimised Moderate to Vigorous Physical Activity) and 22.11 (Specificity optimised Moderate to Vigorous Physical Activity). Likewise, the Standard Error of estimation from our approach was lower for the GENEActiv device by 2.29 (Youden optimised Sedentary Behaviour), 41.65 (Sensitivity optimised Sedentary Behaviour), 4.31 (Youden optimised Moderate to Vigorous Physical Activity) and 347.15 (Specificity optimised Moderate to Vigorous Physical Activity). CONCLUSIONS: personalised cut-point can be predicted without prior knowledge of accelerometry data. The results are very promising especially when we consider that our method predicts cut-points without prior knowledge of accelerometry data, unlike the state-of-the-art. More data is required to expand the scope of the experiments presented in this paper.


Assuntos
Acelerometria , Comportamento Sedentário , Idoso , Exercício Físico , Humanos , Aprendizado de Máquina , Punho
17.
Genes (Basel) ; 12(4)2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33806076

RESUMO

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.


Assuntos
Encéfalo/patologia , Transportadores de Ácidos Dicarboxílicos/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Células-Tronco Neurais/patologia , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Encéfalo/metabolismo , Proliferação de Células , Humanos , Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/genética
18.
Science ; 372(6537)2021 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-33795432

RESUMO

Multivalent display of receptor-engaging antibodies or ligands can enhance their activity. Instead of achieving multivalency by attachment to preexisting scaffolds, here we unite form and function by the computational design of nanocages in which one structural component is an antibody or Fc-ligand fusion and the second is a designed antibody-binding homo-oligomer that drives nanocage assembly. Structures of eight nanocages determined by electron microscopy spanning dihedral, tetrahedral, octahedral, and icosahedral architectures with 2, 6, 12, and 30 antibodies per nanocage, respectively, closely match the corresponding computational models. Antibody nanocages targeting cell surface receptors enhance signaling compared with free antibodies or Fc-fusions in death receptor 5 (DR5)-mediated apoptosis, angiopoietin-1 receptor (Tie2)-mediated angiogenesis, CD40 activation, and T cell proliferation. Nanocage assembly also increases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus neutralization by α-SARS-CoV-2 monoclonal antibodies and Fc-angiotensin-converting enzyme 2 (ACE2) fusion proteins.


Assuntos
Anticorpos/química , Anticorpos/imunologia , Nanoestruturas , Engenharia de Proteínas , Transdução de Sinais , Angiopoietinas/química , Angiopoietinas/imunologia , Angiopoietinas/metabolismo , Anticorpos Monoclonais/química , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/química , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/química , Anticorpos Antivirais/imunologia , Linfócitos B/imunologia , Antígenos CD40/química , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Genes Sintéticos , Humanos , Fragmentos Fc das Imunoglobulinas/química , Ativação Linfocitária , Modelos Moleculares , Ligação Proteica , Receptor TIE-2/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/imunologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Linfócitos T/fisiologia
19.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33881452

RESUMO

A unique population of Foxp3+ regulatory T cells (TRs) resides in visceral adipose tissue (VAT) that regulates adipose inflammation and helps preserve insulin sensitivity. Inducible T cell co-stimulator (ICOS) is highly expressed on effector (e)TRs that migrate to nonlymphoid tissues, and contributes to their maintenance and function in models of autoimmunity. In this study, we report an unexpected cell-intrinsic role for ICOS expression and downstream phosphoinositide 3-kinase (PI3K) signaling in limiting the abundance, VAT-associated phenotype, and function of TRs specifically in VAT. Icos-/- mice and mice expressing a knock-in form of ICOS that cannot activate PI3K had increased VAT-TR abundance and elevated expression of canonical VAT-TR markers. Loss of ICOS signaling facilitated enhanced accumulation of TRs to VAT associated with elevated CCR3 expression, and resulted in reduced adipose inflammation and heightened insulin sensitivity in the context of a high-fat diet. Thus, we have uncovered a new and surprising molecular pathway that regulates VAT-TR accumulation and function.


Assuntos
Tecido Adiposo/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Dieta Hiperlipídica/métodos , Feminino , Fatores de Transcrição Forkhead/imunologia , Inflamação/imunologia , Insulina/imunologia , Resistência à Insulina/imunologia , Gordura Intra-Abdominal/imunologia , Masculino , Camundongos , Obesidade/imunologia , Fosfatidilinositol 3-Quinases/imunologia
20.
J Pancreat Cancer ; 7(1): 1-7, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33569523

RESUMO

Background: Primary pancreatic signet ring cell carcinoma (PPSRCC) is a rare (<1%) poorly reported histopathological variant of pancreatic cancer with ill-defined treatment guidelines. Herein, we describe a case of nonmetastatic PPSRCC in a 45-year-old female. Presentation: A 45-year-old female presented with 3 weeks of abdominal pain radiating to her back. Other pertinent positives included a 20-pound (9.1-kilogram) weight loss and jaundice, with a known 30-pack-year smoking history. CT scan revealed a 4.6 × 3.6 cm hypoattenuating mass in the head of the pancreas (HOP) with dilatation of the common bile duct. Total bilirubin at presentation was elevated, and a biliary stent was placed endoscopically. Subsequent endoscopic ultrasonography revealed a periampullary ulcerated mass involving the HOP and second portion of the duodenum, with pathology revealing poorly differentiated adenocarcinoma with mucinous background and focal signet ring cells. A classic pancreatoduodenectomy (Whipple procedure) was performed. Final pathology revealed a poorly differentiated (G3) pT3/pN2/pM0 PPSRCC with 11 of 16 positive specimen lymph nodes. The tumor had evidence of both KRAS and TP53 mutations and expressed an MUC1+/MUC2-/MUC5AC+ immunophenotype. Medical oncology recommended a 6-month course of adjuvant modified-dose FOLFIRINOX therapy. Conclusion: This report highlights the need for further research into the pathogenesis of gastrointestinal signet ring cell carcinoma to identify and study therapeutic targets that can eventually be translated to PPSRCC treatment. Given the paucity of PPSRCC, adjuvant therapy candidates follow the current literature on more common pancreatic cancer subtypes to guide treatment.

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