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Successful neuromodulation approaches to alter episodic memory require closed-loop stimulation predicated on the effective classification of brain states. The practical implementation of such strategies requires prior decisions regarding electrode implantation locations. Using a data-driven approach, we employ support vector machine (SVM) classifiers to identify high-yield brain targets on a large data set of 75 human intracranial electroencephalogram subjects performing the free recall (FR) task. Further, we address whether the conserved brain regions provide effective classification in an alternate (associative) memory paradigm along with FR, as well as testing unsupervised classification methods that may be a useful adjunct to clinical device implementation. Finally, we use random forest models to classify functional brain states, differentiating encoding versus retrieval versus non-memory behavior such as rest and mathematical processing. We then test how regions that exhibit good classification for the likelihood of recall success in the SVM models overlap with regions that differentiate functional brain states in the random forest models. Finally, we lay out how these data may be used in the design of neuromodulation devices.
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Encéfalo , Electrodos , Electroencefalografía , Memoria Episódica , Bosques Aleatorios , Máquina de Vectores de Soporte , Humanos , Encéfalo/fisiología , Interfaces Cerebro-Computador , Análisis por Conglomerados , Electrodos/normas , Electroencefalografía/métodos , Electroencefalografía/normas , Recuerdo Mental , Aprendizaje Automático no SupervisadoRESUMEN
AIM: Intraventricular haemorrhage (IVH) and periventricular leukomalacia (PVL) in preterm infants are associated with an increased risk of long-term neurodevelopmental impairments (NDI) and cerebral palsy (CP). However, little is known about their impact on early neurodevelopmental outcomes despite increasing evidence highlighting the feasibility and importance of early NDI/CP diagnosis. We aimed to determine the early neurodevelopmental outcomes of preterm infants with IVH and PVL. METHODS: This was a retrospective single-centre cohort study of preterm infants born at <29 weeks gestation or <1000 g birth weight who attended an Early Neurodevelopment Clinic at 3 to 4 months of corrected age. Primary outcomes of early NDI and CP/high-risk CP diagnoses based on Prechtl's General Movements Assessment and the Hammersmith Infant Neurological Examination were compared between infants without IVH and infants with mild IVH (grades I-II), severe IVH (grades III-IV), and severe brain injury (SBI; severe IVH or cystic PVL). RESULTS: Of 313 infants, 52.1% (n = 163), 41.2% (n = 129), 6.7% (n = 21) and 8.6% (n = 27) had no IVH, mild IVH, severe IVH and SBI, respectively. The adjusted odds of early CP/high-risk CP diagnosis were significantly higher in infants with severe IVH (aOR 6.07, 95% CI 1.50-24.50) and SBI (aOR 15.28, 95% CI 3.70-63), but not in those with mild IVH (aOR 1.24, 95% CI 0.49-3.10). However, the adjusted odds of any early NDI were similar across groups. CONCLUSION: Preterm infants with severe IVH and SBI are at increased risk of early CP/high-risk of CP diagnosis at 3 to 4 months of corrected age.
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PURPOSE: This meta-analysis aims to compare the diagnostic and clinical utility of exome sequencing (ES) vs genome sequencing (GS) in pediatric and adult patients with rare diseases across diverse populations. METHODS: A meta-analysis was conducted to identify studies from 2011 to 2021. RESULTS: One hundred sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of ES (0.38, 95% CI 0.36-0.40) and GS (0.34, 95% CI 0.30-0.38) were similar (P = .1). Within-cohort comparison illustrated 1.2-times odds of diagnosis by GS over ES (95% CI 0.79-1.83, P = .38). GS studies discovered a higher range of novel genes than ES studies; yet, the rate of variant of unknown significance did not differ (P = .78). Among high-quality studies, clinical utility of GS (0.77, 95% CI 0.64-0.90) was higher than that of ES (0.44, 95% CI 0.30-0.58) (P < .01). CONCLUSION: This meta-analysis provides an important update to demonstrate the similar diagnostic rates between ES and GS and the higher clinical utility of GS over ES. With the newly published recommendations for clinical interpretation of variants found in noncoding regions of the genome and the trend of decreasing variant of unknown significance and GS cost, it is expected that GS will be more widely used in clinical settings.
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Exoma , Enfermedades Raras , Humanos , Niño , Adulto , Exoma/genética , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Secuencia de Bases , Secuenciación del Exoma , Mapeo CromosómicoRESUMEN
We hypothesized that ruxolitinib may inhibit the immune checkpoint protein, B7H3; and, thus, investigated its effects on this immune inhibitor using multiple myeloma (MM) cell lines, bone marrow (BM) mononuclear cells from MM patients and human MM LAGλ -1A xenografts. Ruxolitinib reduced B7H3 gene and protein expression and increased IL-2 and CD8 gene expression. These results suggest that ruxolitinib inhibition of B7H3 may restore exhausted T-cell activity in the MM BM tumor microenvironment.
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Mieloma Múltiple , Humanos , Mieloma Múltiple/patología , Proteínas de Punto de Control Inmunitario/farmacología , Janus Quinasa 1 , Transducción de Señal , Microambiente TumoralRESUMEN
OBJECTIVES: Dementia assessment includes cognitive and behavioral testing with informant verification. Conventional testing is resource-intensive, with uneven access. Online unsupervised assessments could reduce barriers to risk assessment. The aim of this study was to assess the relationship between informant-rated behavioral changes and participant-completed neuropsychological test performance in older adults, both measured remotely via an online unsupervised platform, the Brain Health Registry (BHR). DESIGN: Observational cohort study. SETTING: Community-dwelling older adults participating in the online BHR. Informant reports were obtained using the BHR Study Partner Portal. PARTICIPANTS: The final sample included 499 participant-informant dyads. MEASUREMENTS: Participants completed online unsupervised neuropsychological assessment including Forward Memory Span, Reverse Memory Span, Trail Making B, and Go/No-Go tests. Informants completed the Mild Behavioral Impairment Checklist (MBI-C) via the BHR Study Partner portal. Cognitive performance was evaluated in MBI+/- individuals, as was the association between cognitive scores and MBI symptom severity. RESULTS: Mean age of the 499 participants was 67, of which 308/499 were females (61%). MBI + status was associated with significantly lower memory and executive function test scores, measured using Forward and Reverse Memory Span, Trail Making Errors and Trail Making Speed. Further, significant associations were found between poorer objectively measured cognitive performance, in the domains of memory and executive function, and MBI symptom severity. CONCLUSION: These findings support the feasibility of remote, informant-reported behavioral assessment utilizing the MBI-C, supporting its validity by demonstrating a relationship to online unsupervised neuropsychological test performance, using a previously validated platform capable of assessing early dementia risk markers.
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Disfunción Cognitiva , Demencia , Femenino , Humanos , Anciano , Masculino , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Función Ejecutiva , Pruebas Neuropsicológicas , Demencia/diagnóstico , Demencia/psicología , Encéfalo , CogniciónRESUMEN
OBJECTIVES: This study aimed to establish a normative profile of health-related quality of life (HRQOL) of the rare disease (RD) population in Hong Kong (HK) and identify potential predictors. METHODS: Between March 2020 and October 2020, patients with RD and caregivers were recruited through Rare Disease Hong Kong, the largest RD patient group alliance in HK. HRQOL was derived using the EQ-5D 3-Level with reference to the established HK value set. Utility scores were stratified according to demographics and disease-related information. Multiple linear regression was performed to explore the associations between patient characteristics and HRQOL. RESULTS: A total of 286 patients, covering 107 unique RDs, reported a mean utility score of 0.53 (SD 0.36). Thirty patients (10.5%) reported negative utility scores, indicating worse-than-death health states. More problems were recorded in the "usual activities" and "self-care" dimensions. Univariate analyses revealed that neurologic diseases, high out-of-pocket expenditure, home modification, and living in public housing or subdivided flats/units were significantly associated with lower HRQOL. A total of 99 caregivers reported a mean utility score of 0.78 (SD 0.17), which was significantly associated with the utility score of patients they took care of (r = 0.32; P = .001). CONCLUSIONS: The normative profile of the RD population was established, which revealed lower HRQOL in the RD population than other chronic disease groups and general population in HK. Findings were corroborated by evidence from other cohorts using EQ-5D, combined as part of a meta-analysis. Identifying predictors highlight areas that should be prioritized to improve HRQOL of RD population through clinical and psychosocial dimensions.
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Estado de Salud , Calidad de Vida , Enfermedad Crónica , Hong Kong/epidemiología , Humanos , Calidad de Vida/psicología , Enfermedades Raras , Encuestas y CuestionariosRESUMEN
BACKGROUND: The androgen receptor (AR) pathway-associated gene nuclear receptor coactivator 2 (NCOA2) has an established oncogenic role in early prostate cancer and likewise is a driver of metastatic disease and castration-resistant prostate cancer. However, its significance as a biomarker in metastatic castration-resistant prostate cancer (mCRPC), both alone and in conjunction with co-occurring AR alterations using a liquid biopsy approach has not been investigated. METHODS: Ninety-one patients were included in this study, (n = 68 receiving an androgen receptor pathway inhibitor and n = 23 receiving taxane chemotherapy). Up to 30 ml of peripheral blood was collected before commencing treatment from each patient. Plasma cell-free DNA, along with a matched germline sample, underwent targeted next-generation sequencing using a validated, highly sensitive in-house prostate cancer panel. Variants in AR and NCOA2 were identified and correlated with clinical outcomes. RESULTS: Plasma AR and NCOA2 aberrations were identified in 35% and 13% of the cohort, respectively, whilst 8% had concurrent AR and NCOA2 alterations. NCOA2 copy number gain and any NCOA2 aberration predicted for lower prostate-specific antigen (PSA) response rates. Likewise, median overall survival was shorter for NCOA2 gain (10.1 vs. 18.3 months; p = .004), remaining significant after adjusting for covariates including circulating tumor DNA fraction and tumor suppressor gene alterations. Importantly, dual AR and NCOA2 aberrations were also associated with inferior outcomes, including no PSA responses in patients treated with AR pathway inhibitors (0% vs. 64%; p = .02). CONCLUSIONS: These data highlight the importance of identifying multiple markers of AR pathway modulation in mCRPC and represent the first instance of the assessment of plasma NCOA2 status as a prognostic biomarker for standard-of-care therapies. Further assessment is warranted to determine if NCOA2 aberrations are a marker of primary resistance to AR pathway inhibitors.
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Coactivador 2 del Receptor Nuclear/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Receptores Androgénicos/sangre , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores Androgénicos/uso terapéutico , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Tasa de Supervivencia , Taxoides/uso terapéuticoRESUMEN
Multiple myeloma (MM) tumour cells evade host immunity through a variety of mechanisms, which may potentially include the programmed cell death ligand-1 (PD-L1):programmed cell death protein-1 (PD-1) axis. This interaction contributes to the immunosuppressive bone marrow (BM) microenvironment, ultimately leading to reduced effector cell function. PD-L1 is overexpressed in MMBM and is associated with the resistance to immune-based approaches for treating MM. Ruxolitinib (RUX), an inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases, is approved for myeloproliferative diseases. We investigated the effects of RUX alone or in combination with anti-MM agents on the expression of PD-L1 and T-cell cytotoxicity in MM. We showed that the expression of the PD-L1 gene was markedly increased in BM mononuclear cells from patients with MM with progressive disease versus those in complete remission. Furthermore, RUX treatment resulted in a concentration-dependent reduction of PD-L1 gene expression in the MM tumour cells cultured alone or co-cultured with stromal cells compared with untreated cells. The results also demonstrated that RUX increased MM cell apoptosis in the presence of interleukin-2-stimulated T cells to a similar degree as the treatment with anti-PD-1 or anti-PD-L1 antibodies. In summary, these results indicate that RUX can block PD-L1 expression resulting in augmentation of anti-MM effects of T cells.
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Antineoplásicos/uso terapéutico , Antígeno B7-H1/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Humanos , Quinasas Janus/antagonistas & inhibidores , Masculino , Ratones SCID , Mieloma Múltiple/genética , Nitrilos , Pirimidinas , Microambiente Tumoral/efectos de los fármacosRESUMEN
Monocytes polarize into pro-inflammatory macrophage-1 (M1) or alternative macrophage-2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti-tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co-cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.
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Quimiocinas CXC/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Quinasas Janus/metabolismo , Lenalidomida/farmacología , Mucina-1/biosíntesis , Mieloma Múltiple/tratamiento farmacológico , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Estudios de Casos y Controles , Quimiocina CXCL12/biosíntesis , Quimiocina CXCL12/metabolismo , Quimiocinas CXC/metabolismo , Xenoinjertos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Janus Quinasa 1/metabolismo , Janus Quinasa 2/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Ratones SCID , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Mucina-1/metabolismo , Mieloma Múltiple/sangre , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/biosíntesis , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores CXCR4/biosíntesis , Receptores CXCR4/metabolismo , Transducción de Señal , Células THP-1RESUMEN
BACKGROUND: Emergence coughing can harm the patient following completion of surgery, but it is unclear which medication is most effective at reducing this event. We conducted a systematic review and network meta-analysis of RCTs to determine the medications' relative efficacies on decreasing moderate to severe emergence coughing after general anaesthesia. Medications studied were lidocaine (i.v., intracuff, topical, or tracheal application), dexmedetomidine, remifentanil, and fentanyl. METHODS: We searched eight different medical literature databases, conference abstracts, and article references. After screening, included citations were evaluated for bias and had their data extracted. Pooled odds ratios and 95% confidence intervals for each treatment comparison were calculated. A surface under the cumulative ranking curve analysis (SUCRA) determined the relative rank of each intervention to decrease moderate to severe emergence coughing. Subgroup analyses included severe coughing only, extubation times, type of maintenance anaesthetic, and dosages. RESULTS: The network meta-analysis included 70 studies and 5286 patients. All study medications had favourable odds in reducing moderate and severe peri-extubation coughing compared with either no medication or placebo. No single medication was favoured over another. Dexmedetomidine had the highest SUCRA rank, followed in order by remifentanil, fentanyl, and lidocaine via intracuff, tracheal/topical, and i.v. routes. Remifentanil was ranked highest for decreasing severe coughing only. Intracuff lidocaine had higher odds of prolonging extubation times compared with placebo, dexmedetomidine, fentanyl, and remifentanil. CONCLUSION: All study medications were better than placebo or no medication in reducing moderate to severe emergence cough, with dexmedetomidine ranked the most effective. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42018102870.
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OBJECTIVE: This study sought to identify factors independently associated with a negative impression of the medical profession in patients with endometriosis who were presenting to a tertiary referral centre. METHODS: A cross-sectional analysis was conducted on a prospective data registry between December 2013 and June 2017 at a tertiary referral centre for pelvic pain and endometriosis. The main outcome variable, negative impression about the medical profession, was measured with the four-item subscale of the Endometriosis Health Profile-30 and divided into three groups: no (0), some (1-8), and many (9-16) negative impressions. Patients with a surgical and histological diagnosis of endometriosis were included. Postmenopausal women were excluded. Bivariate analyses determined significant associations (P < 0.05) between variables from the registry and the main outcome. Variables with a significant association were put into ordinal logistic regression with sequential backwards elimination. RESULTS: Negative impression of the medical profession was independently associated with previous surgery that did not help symptoms (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI] 1.09-2.87; Pâ¯=â¯0.021), presentation to an emergency room in the past 3 months (aOR 1.90; 95% CI 1.17-3.07; Pâ¯=â¯0.009), and previous visits to a complementary health care provider (aOR 2.16; 95% CI 1.42-3.29; P < 0.0005), while controlling for an endometriosis pain-related morbidity composite variable. CONCLUSION: Negative perception of the medical profession in women with endometriosis was associated with surgical treatment failure, emergency room use, and accessing complementary health care. Each identified factor offers an opportunity for intervention to improve the perception of the medical profession among women with endometriosis.
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Endometriosis/terapia , Satisfacción del Paciente , Dolor Pélvico/fisiopatología , Relaciones Médico-Paciente , Médicos/psicología , Adulto , Actitud del Personal de Salud , Estudios Transversales , Femenino , Humanos , Percepción , Estudios Prospectivos , Calidad de la Atención de SaludAsunto(s)
Asma , Enfermedades Cardiovasculares , Humanos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/genética , Análisis de la Aleatorización Mendeliana , Asma/epidemiología , Asma/genética , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Estudio de Asociación del Genoma CompletoRESUMEN
Successful selection of modified DNAzymes depends on the potential for modified nucleoside triphosphates (dNTPs) to replace their unmodified counterparts in enzyme catalyzed primer extension reactions and, once incorporated, to serve as template bases for information transfer prior to PCR amplification. To date, the most densely modified DNAzymes have been selected from three modified dNTPs: 8-histaminyl-deoxyadenosine (dAimTP), 5-guanidinoallyl-deoxyuridine (dUgaTP), and 5-aminoallyl-deoxycytidine (dCaaTP) to provide several RNA-cleaving DNAzymes with greatly enhanced rate constants compared to unmodified counterparts. Here we report biophysical and enzymatic properties of these three modified nucleosides in the context of specific oligonucleotide sequences to understand how these three modified nucleobases function in combinatorial selection. The base-pairing abilities of oligonucleotides bearing one or three modified nucleosides were investigated by thermal denaturation studies and as templates for enzymatic polymerization with both modified and unmodified dNTPs. While we address certain shortcomings in the use of modified dNTPs, we also provide key evidence of faithful incorporation and enzymatic read-out, which strongly supports their continued use in in vitro selection.
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ADN Catalítico/metabolismo , Nucleósidos/metabolismo , Polifosfatos/metabolismo , Biocatálisis , ADN Catalítico/química , Nucleósidos/química , Polifosfatos/químicaRESUMEN
BACKGROUND: Recent evidence validates the effectiveness of neoadjuvant chemotherapy in the treatment of gastric adenocarcinoma. Endoscopic ultrasonographic (EUS) staging has been proposed as a useful adjunct in this setting. METHODS: We performed a retrospective review of patients treated at our institution for gastric adenocarcinoma between July 2005 and January 2014. We identified patients referred for EUS before surgery as part of a prospective treatment plan. Histopathologic staging was compared to EUS staging, with a focus on T- and N-stage. Agreement between the two modalities was examined using kappa-statistics. RESULTS: We identified 614 patients with biopsy-proven gastric adenocarcinoma; 145 underwent curative-intent surgery. Surgical pathology and EUS results were available from 69 patients. The accuracy of EUS for the evaluation of T- and N-stage was 44.9% and 56.5%, respectively. EUS demonstrated greater concordance with histopathology at evaluating T-stage (κ = 0.3469) than N-stage (κ = 0.1316). EUS underestimated T- and N-stage in 40.8% and 30.4% of patients, respectively. CONCLUSION: EUS seems to correlate poorly with pathology in the preoperative staging of gastric adenocarcinoma. In the majority of inaccurate cases, EUS underestimates T-stage and N-stage, limiting its utility in the neoadjuvant setting.
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Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Endosonografía , Gastrectomía , Terapia Neoadyuvante , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Periodo Preoperatorio , Estudios Retrospectivos , Sensibilidad y Especificidad , Neoplasias Gástricas/cirugíaRESUMEN
BACKGROUND: The value of FDG-PET in the staging of gastric adenocarcinoma (GA) has been subject to debate. METHODS: We performed a retrospective review of GA patients between 2006 and 2014 and identified those who had a CT and FDG-PET before initiating treatment. CT and FDG-PET images were analyzed by a blinded body radiologist and nuclear physician, respectively. Disease stage was assessed, looking at primary tumor (PT), locoregional (LLN) and distant lymph node disease (DLN), and metastasis (M). RESULTS: We identified 608 patients who had biopsy-proven GA and 207 (34.0%) had a CT and FDG-PET as part of their staging work-up. Of these, imaging from 166 (27.3%) patients was available for review. CT identified PT, LLN, DLN, and M in 120 (72.3%), 84 (50.6%), 25 (15.1%), and 32 (19.3%) patients, respectively; while FDG-PET identified PT, LLN, DLN, and M in 125 (75.3%), 78 (47.0%), 41 (24.7%), and 27 (16.3%) of patients, respectively. FDG-PET up-staged 31 (18.7%) patients while it down-staged 17 (10.2%) patients. Of patients who were up-staged, 20 (64.5%) developed progressive disease. CONCLUSIONS: Our findings support the use of FDG-PET as a valuable adjunct to CT in the staging of GA, as it changed the stage in 48 (28.9%) patients. J. Surg. Oncol. 2016;113:640-646. © 2016 Wiley Periodicals, Inc.
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Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Radiofármacos , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Variaciones Dependientes del Observador , Evaluación de Resultado en la Atención de Salud , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Método Simple Ciego , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: In healthy people, the "fight-or-flight" sympathetic system is counterbalanced by the "rest-and-digest" parasympathetic system. As we grow older, the parasympathetic system declines as the sympathetic system becomes hyperactive. In our prior heart rate variability biofeedback and emotion regulation (HRV-ER) clinical trial, we found that increasing parasympathetic activity through daily practice of slow-paced breathing significantly decreased plasma amyloid-ß (Aß) in healthy younger and older adults. In healthy adults, higher plasma Aß is associated with greater risk of Alzheimer's disease (AD). Our primary goal of this trial is to reproduce and extend our initial findings regarding effects of slow-paced breathing on Aß. Our secondary objectives are to examine the effects of daily slow-paced breathing on brain structure and the rate of learning. METHODS: Adults aged 50-70 have been randomized to practice one of two breathing protocols twice daily for 9 weeks: (1) "slow-paced breathing condition" involving daily cognitive training followed by slow-paced breathing designed to maximize heart rate oscillations or (2) "random-paced breathing condition" involving daily cognitive training followed by random-paced breathing to avoid increasing heart rate oscillations. The primary outcomes are plasma Aß40 and Aß42 levels and plasma Aß42/40 ratio. The secondary outcomes are brain perivascular space volume, hippocampal volume, and learning rates measured by cognitive training performance. Other pre-registered outcomes include plasma pTau-181/tTau ratio and urine Aß42. Recruitment began in January 2023. Interventions are ongoing and will be completed by the end of 2023. DISCUSSION: Our HRV-ER trial was groundbreaking in demonstrating that a behavioral intervention can reduce plasma Aß levels relative to a randomized control group. We aim to reproduce these findings while testing effects on brain clearance pathways and cognition. TRIAL REGISTRATION: ClinicalTrials.gov NCT05602220. Registered on January 12, 2023.
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Cognición , Respiración , Anciano , Humanos , Atención , Biorretroalimentación Psicológica/métodos , Frecuencia Cardíaca/fisiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Persona de Mediana EdadRESUMEN
Drug-induced interstitial lung disease (DI-ILD) is an increasingly common cause of morbidity and mortality as the list of culprit drugs continues to grow. Unfortunately, DI-ILD is difficult to study, diagnose, prove, and manage. This article attempts to raise awareness of the challenges in DI-ILD and discusses the current clinical landscape.
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Enfermedades Pulmonares Intersticiales , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/etiología , Enfermedades Pulmonares Intersticiales/terapia , PulmónRESUMEN
Fundamental to the efficacy of cognitive training (CT) is its dose. Here we used the power and breadth afforded by a large dataset to measure precisely dose-response (D-R) functions for CT and to examine the generality of their magnitude and form. The present observational study involved 107,000 users of Lumosity, a commercial program comprising computer games designed to provide CT over the internet. In addition to training with Lumosity games, these users took an online battery of cognitive assessments (NeuroCognitive Performance Test, NCPT) on two or more occasions separated by at least 10 weeks. Changes in performance on the NCPT between the first and second assessments were examined as a function of the amount of intervening gameplay. The resulting D-R functions were obtained both for overall performance on the NCPT and performance on its eight subtests. Also examined were differences between D-R functions from demographic groups defined by age, gender, and education. Monotonically increasing D-R functions, well fit by an exponential approach to an asymptote, were found consistently for overall performance on the NCPT, performance on seven of the eight subtests, and at each level of age, education, and gender. By examining how individual parameters of the D-R functions varied across subtests and groups, it was possible to measure separately changes in the effects on NCPT performance of 1) transfer from CT and 2) direct practice due to repeated testing. The impact of both transfer and direct practice varied across subtests. In contrast, while the effects of direct practice diminished with age, those of transfer remained constant. Besides its implications for CT by older adults, this latter finding suggests that direct practice and transfer do not involve identical learning processes, with transfer being limited to learning processes that remain constant across the adult lifespan.
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Entrenamiento Cognitivo , Transferencia de Experiencia en Psicología , Humanos , Anciano , Aprendizaje/fisiologíaRESUMEN
Introduction: The current ordinal fibrosis staging system for nonalcoholic steatohepatitis (NASH) has a limited dynamic range. The goal of this study was to determine if second-harmonic generated (SHG) quantifiable collagen fibrillar properties (qFP) and their derived qFibrosis score capture changes in disease progression and regression in a murine model of NASH, in which disease progression can be induced by a high fat sugar water (HFSW) diet and regression by reversal to chow diet (CD). Methods: DIAMOND mice were fed a CD or HFSW diet for 40 to 52 weeks. Regression related changes were studied in mice with diet reversal for 4 weeks after 48 to 60 weeks of a HFSW diet. Results: As expected, mice on HFSW developed steatohepatitis with stage 2 to 3 fibrosis between weeks 40 and 44. Both the collagen proportionate area and the qFibrosis score based on 15 SHG-quantified collagen fibrillar properties in humans were significantly higher in mice on HFSW for 40 to 44 weeks compared to CD fed mice. These changes were greatest in the sinusoids (Zone 2) with further increase in septal and portal fibrosis related scores between weeks 44 and 48. Diet reversal led to decrease in qFibrosis, septal thickness, and cellularity with greatest changes in Zone 2. Specific qFPs associated with progression only, regression only, or both processes were identified and categorized based on direction of fibrosis change. Conclusion: Complementing recent human studies, these findings support the concept that changes of disease progression and regression can be assessed using SHG-based image quantification of fibrosis related parameters.