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1.
Clin Breast Cancer ; 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34824002

RESUMO

BACKGROUND: AR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC). METHODS: Male/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint. RESULTS: Seventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%). CONCLUSIONS: Orteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.

2.
Arch Osteoporos ; 16(1): 163, 2021 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-34719754

RESUMO

Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants. PURPOSE: Autonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans. METHODS: Participants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI). RESULTS: There were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men. CONCLUSIONS: In older women, increased heart rate variation is associated with hip fracture risk.


Assuntos
Fraturas do Quadril , Osteoporose , Idoso , Sistema Nervoso Autônomo , Feminino , Frequência Cardíaca , Fraturas do Quadril/epidemiologia , Humanos , Modelos de Riscos Proporcionais
3.
J Nutr ; 2021 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-34751787

RESUMO

BACKGROUND: Postmenopausal women with higher visceral adipose tissue (VAT) present with suppressed bone resorption (lower c-terminal cross-linking telopeptide of type I collagen, CTX-1) and turnover (lower osteocalcin) but whether this blunts the effect of calcium is unknown. OBJECTIVE: The primary outcome of this study was the effect of VAT on changes in CTX-1 after intake of two forms of calcium. Secondary outcomes included changes in parathyroid hormone (PTH), serum calcium, phosphorus, and alkaline phosphatase (ALP). DESIGN: Randomized open three period crossover trial conducted between 2017-2019 at the University of South Australia among 77 lean and overweight postmenopausal women (53-79 y) with body mass index (BMI) less than 25 kg/m2 and greater than 27 kg/m2, respectively. Participants received a single dose of milk (1000 mg calcium), calcium carbonate tablet (1000 mg calcium), and fruit juice (no calcium) in random order with a seven-day washout period. Blood samples were collected at baseline and hourly for 5h. Data was analysed by repeated measures analysis of variance (ANOVA) of log-transformed data. RESULTS: At baseline, women with higher VAT had significantly lower CTX-1 and higher PTH (44% lower and 30% higher, respectively between Q4 and Q1, P < 0.0001). VAT had no influence on the acute changes in CTX-1 or PTH with calcium or juice. A suppression of 44% in CTX-1 was seen with calcium carbonate and milk and a suppression of 18% with juice. PTH was suppressed more with calcium carbonate (47%) compared to milk (22%). Milk calcium reduced PTH and CTX-1 at 2-hour while calcium carbonate reduced PTH in 1 hour. The suppression in CTX-1 was slower with lowest levels at 4-5 hour. CONCLUSIONS: 1000 mg calcium obtained from milk or from calcium carbonate is effective in acutely suppressing bone resorption in postmenopausal women irrespective of visceral fat.This trial is registered with the Australian New Zealand Clinical Trials Registry http://www.ANZCTR.org.au/ACTRN12617000779370.aspx (ACTRN 12617000779370).

4.
Cancer Res ; 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642183

RESUMO

The relationship between cancer and autoimmunity is complex. However, the incidence of solid tumors such as melanoma has increased significantly among patients with previous or newly diagnosed systemic autoimmune disease (AID). At the same time, immune checkpoint blockade (ICB) therapy of cancer induces de novo autoinflammation and exacerbates underlying AID, even without evident anti-tumor responses. Recently, systemic lupus erythematosus (SLE) activity was found to drive myeloid-derived suppressor cell (MDSC) formation in patients, a known barrier to healthy immune surveillance and successful cancer immunotherapy. Crosstalk between MDSCs and macrophages generally drives immune suppressive activity in the tumor microenvironment. However, it remains unclear how peripheral pre-generated MDSC under chronic inflammatory conditions modulates global macrophage immune functions and the impact it could have on existing tumors and underlying lupus nephritis. Here we show that pathogenic expansion of SLE-generated MDSCs by melanoma drives global macrophage polarization and simultaneously impacts the severity of lupus nephritis and tumor progression in SLE-prone mice. Molecular and functional data showed that MDSCs interact with autoimmune macrophages and inhibit cell surface expression of CD40 and the production of IL-27. Moreover, low CD40/IL-27 signaling in tumors correlated with high TAM infiltration and ICB therapy resistance both in murine and human melanoma exhibiting active IFNγ signatures. These results suggest that preventing global macrophage reprogramming induced by MDSC-mediated inhibition of CD40/IL-27 signaling provides a precision melanoma immunotherapy strategy, supporting an original and advantageous approach to treat solid tumors within established autoimmune landscapes.

5.
J Neurosurg ; : 1-2, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598163
6.
Curr Oncol ; 28(5): 4184-4202, 2021 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-34677273

RESUMO

Colorectal cancer (CRC) can be demanding for primary caregivers; yet, there is insufficient evidence describing the caregiver-reported outcomes (CROs) that matter most to caregivers. CROs refer to caregivers' assessments of their own health status as a result of supporting a patient. The study purpose was to describe the emotions that were most impactful to caregivers of patients with CRC, and how the importance caregivers attribute to these emotions changed from diagnosis throughout treatment. Guided by qualitative Interpretive Description, we analyzed 25 caregiver and 37 CRC patient interviews, either as individuals or as caregiver-patient dyads (six interviews), using inductive coding and constant comparative techniques. We found that the emotional aspect of caring for a patient with CRC was at the heart of caregiving. Caregiver experiences that engendered emotions of consequence included: (1) facing the patient's life-changing diagnosis and an uncertain future, (2) needing to be with the patient throughout the never-ending nightmare of treatment, (3) bearing witness to patient suffering, (4) being worn down by unrelenting caregiver responsibilities, (5) navigating their relationship, and (6) enduring unwanted change. The broad range of emotions important to caregivers contributes to comprehensive foundational evidence for future conceptualization and the use of CROs.


Assuntos
Cuidadores , Neoplasias Colorretais , Neoplasias Colorretais/terapia , Formação de Conceito , Emoções , Humanos , Medidas de Resultados Relatados pelo Paciente
7.
Drug Des Devel Ther ; 15: 4371-4382, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34703212

RESUMO

Introduction: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment. Methods: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized. Results: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16-1.34], 1.17 [1.08-1.27], and 1.25 [1.16-1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone. Conclusion: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.

8.
Soft Matter ; 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34705007

RESUMO

We report an experimental study of the shear-induced migration of flexible fibers in suspensions confined between two parallel plates. Non-Brownian fiber suspensions are imaged in a rheo-microscopy setup, where the top and the bottom plates counter-rotate and create a Couette flow. Initially, the fibers are near the bottom plate due to sedimentation. Under shear, the fibers move with the flow and migrate towards the center plane between the two walls. Statistical properties of the fibers, such as the mean values of the positions, orientations, and end-to-end lengths of the fibers, are used to characterize the behaviors of the fibers. A dimensionless parameter Λeff, which compares the hydrodynamic shear stress and the fiber stiffness, is used to analyze the effective flexibility of the fibers. The observations show that the fibers that are more likely to bend exhibit faster migration. As Λeff increases (softer fibers and stronger shear stresses), the fibers tend to align in the flow direction and the motions of the fibers transition from tumbling and rolling to bending. The bending fibers drift away from the walls to the center plane. Further increasing Λeff leads to more coiled fiber shapes, and the bending is more frequent and with larger magnitudes, which leads to more rapid migration towards the center. Different behaviors of the fibers are quantified with Λeff, and the structures and the dynamics of the fibers are correlated with the migration.

9.
Nat Commun ; 12(1): 5937, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642345

RESUMO

Development of sustainable processes for hydrocarbons synthesis is a fundamental challenge in chemistry since these are of unquestionable importance for the production of many essential synthetic chemicals, materials and carbon-based fuels. Current industrial processes rely on non-abundant metal catalysts, temperatures of hundreds of Celsius and pressures of tens of bars. We propose an alternative gas phase process under mild reaction conditions using only atomic carbon, molecular hydrogen and an inert carrier gas. We demonstrate that the presence of CH2 and H radicals leads to efficient C-C chain growth, producing micron-length fibres of unbranched alkanes with an average length distribution between C23-C33. Ab-initio calculations uncover a thermodynamically favourable methylene coupling process on the surface of carbonaceous nanoparticles, which is kinematically facilitated by a trap-and-release mechanism of the reactants and nanoparticles that is confirmed by a steady incompressible flow simulation. This work could lead to future alternative sustainable synthetic routes to critical alkane-based chemicals or fuels.

10.
Gynecol Oncol ; 163(3): 490-497, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34602290

RESUMO

OBJECTIVE: To describe molecular and clinical characteristics of patients with high-grade recurrent ovarian carcinoma (HGOC) who had long-term responses to the poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib. METHODS: This post hoc analysis pooled patients from Study 10 (NCT01482715; Parts 2A and 2B; n = 54) and ARIEL2 (NCT01891344; Parts 1 and 2; n = 491). Patients with investigator-assessed complete or partial response per RECIST were classified based on duration of response (DOR): long (≥1 year), intermediate (6 months to <1 year), or short (<6 months). Next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. RESULTS: Overall, 25.3% (138/545) of enrolled patients were responders. Of these, 27.5% (38/138) had long-term responses; 28.3% (39/138) were intermediate- and 34.8% (48/138) were short-term responders. Most of the long-term responders harbored a BRCA1 or BRCA2 (BRCA) mutation (71.1%, 27/38), and BRCA structural variants were most frequent among long-term responders (14.8%; 4/27). Responders with HGOC harboring a BRCA structural variant (n = 5) had significantly longer DOR than patients with other mutation types (n = 81; median not reached vs 0.62 years; HR, 0.21; 95% CI, 0.10-0.43; unadjusted p = 0.014). Among responders with BRCA wild-type HGOC, most long- and intermediate-term responders had high genome-wide LOH: 81.8% (9/11) and 76.9% (10/13), respectively, including 7 with deleterious RAD51C, RAD51D, or CDK12 mutations. CONCLUSION: Among patients who responded to rucaparib, a substantial proportion achieved responses lasting ≥1 year. These analyses demonstrate the relationship between DOR to PARP inhibitor treatment and molecular characteristics in HGOC, such as presence of reversion-resistant BRCA structural variants.

11.
Exp Gerontol ; 155: 111585, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34634413

RESUMO

Parkinson's disease (PD) is a progressive, age-associated neurodegenerative disorder that affects an estimated 10 million people worldwide. PD is characterized by proteinaceous, cytoplasmic inclusions containing α-synuclein, called Lewy Bodies, which form in dopaminergic neurons in an age-dependent manner, and are associated with the emergence of characteristic PD symptoms such as resting tremor, rigidity, slow movements and postural instability. Although considerable progress has been made in recent years in identifying genetic and environmental factors that are associated with PD, early diagnosis and therapeutic options remain severely lacking. Recently, microRNAs (miRNAs) have emerged as novel therapeutic targets in various diseases, such as cancer and neurodegenerative diseases. MiRNAs have been shown to play roles in various aging and neurodegenerative disease models across phyla. More recently, studies have identified specific roles for miRNAs and their targets in the pathogenesis and progression of PD in several model organisms. Here, we discuss the evolving field of miRNAs, their association with PD, and the outlook for the future.

12.
J Neurosurg ; : 1-2, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34560649
13.
Res Pract Thromb Haemost ; 5(6): e12592, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34466771

RESUMO

Corticosteroids remain a crucial component of first-line therapy for immune thrombocytopenia (ITP) due to low cost, high initial response rates, and acceptable short-term tolerability. However, extended and recurrent use of corticosteroids is associated with substantial toxicity. Survey studies indicate that >95% of patients with ITP treated with corticosteroids report adverse effects, more than one-third of whom require reduction or discontinuation of treatment. In light of the heavy treatment burden of prolonged corticosteroid exposure, clinical practice guidelines recommend limiting corticosteroid treatment to no more than 6 weeks in adults with ITP receiving initial therapy. For patients who require subsequent therapy, clinical practice guidelines recommend treatments more suitable for long-term disease control such as thrombopoietin receptor agonists, rituximab, other immune-modulating medications, or splenectomy, rather than repeated courses of corticosteroids. Despite these recommendations, real-world evidence suggests that corticosteroids remain the most frequently used treatment for adults with ITP, not only in the first line, but also in the second and third line. In this review, we summarize evidence on the efficacy, safety, and tolerability of corticosteroids; discuss the problem of overuse; and suggest strategies for curtailing the excessive use of corticosteroids in adults with ITP.

15.
N Engl J Med ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34551224

RESUMO

BACKGROUND: The prioritization of U.S. health care personnel for early receipt of messenger RNA (mRNA) vaccines against severe acute respiratory disease coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), allowed for the evaluation of the effectiveness of these new vaccines in a real-world setting. METHODS: We conducted a test-negative case-control study involving health care personnel across 25 U.S. states. Cases were defined on the basis of a positive polymerase-chain-reaction (PCR) or antigen-based test for SARS-CoV-2 and at least one Covid-19-like symptom. Controls were defined on the basis of a negative PCR test for SARS-CoV-2, regardless of symptoms, and were matched to cases according to the week of the test date and site. Using conditional logistic regression with adjustment for age, race and ethnic group, underlying conditions, and exposures to persons with Covid-19, we estimated vaccine effectiveness for partial vaccination (assessed 14 days after receipt of the first dose through 6 days after receipt of the second dose) and complete vaccination (assessed ≥7 days after receipt of the second dose). RESULTS: The study included 1482 case participants and 3449 control participants. Vaccine effectiveness for partial vaccination was 77.6% (95% confidence interval [CI], 70.9 to 82.7) with the BNT162b2 vaccine (Pfizer-BioNTech) and 88.9% (95% CI, 78.7 to 94.2) with the mRNA-1273 vaccine (Moderna); for complete vaccination, vaccine effectiveness was 88.8% (95% CI, 84.6 to 91.8) and 96.3% (95% CI, 91.3 to 98.4), respectively. Vaccine effectiveness was similar in subgroups defined according to age (<50 years or ≥50 years), race and ethnic group, presence of underlying conditions, and level of patient contact. Estimates of vaccine effectiveness were lower during weeks 9 through 14 than during weeks 3 through 8 after receipt of the second dose, but confidence intervals overlapped widely. CONCLUSIONS: The BNT162b2 and mRNA-1273 vaccines were highly effective under real-world conditions in preventing symptomatic Covid-19 in health care personnel, including those at risk for severe Covid-19 and those in racial and ethnic groups that have been disproportionately affected by the pandemic. (Funded by the Centers for Disease Control and Prevention.).

17.
MMWR Morb Mortal Wkly Rep ; 70(37): 1306-1311, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34529645

RESUMO

Data from randomized clinical trials and real-world observational studies show that all three COVID-19 vaccines currently authorized for emergency use by the Food and Drug Administration* are safe and highly effective for preventing COVID-19-related serious illness, hospitalization, and death (1,2). Studies of vaccine effectiveness (VE) for preventing new infections and hospitalizations attributable to SARS-CoV-2, the virus that causes COVID-19), particularly as the B.1.617.2 (Delta) variant has become predominant, are limited in the United States (3). In this study, the New York State Department of Health linked statewide immunization, laboratory testing, and hospitalization databases for New York to estimate rates of new laboratory-confirmed COVID-19 cases and hospitalizations by vaccination status among adults, as well as corresponding VE for full vaccination in the population, across all three authorized vaccine products. During May 3-July 25, 2021, the overall age-adjusted VE against new COVID-19 cases for all adults declined from 91.8% to 75.0%. During the same period, the overall age-adjusted VE against hospitalization was relatively stable, ranging from 89.5% to 95.1%. Currently authorized vaccines have high effectiveness against COVID-19 hospitalization, but effectiveness against new cases appears to have declined in recent months, coinciding with the Delta variant's increase from <2% to >80% in the U.S. region that includes New York and relaxation of masking and physical distancing recommendations. To reduce new COVID-19 cases and hospitalizations, these findings support the implementation of a layered approach centered on vaccination, as well as other prevention strategies such as masking and physical distancing.


Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/diagnóstico , COVID-19/terapia , Hospitalização/estatística & dados numéricos , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Idoso , COVID-19/epidemiologia , COVID-19/prevenção & controle , Técnicas de Laboratório Clínico , Humanos , Pessoa de Meia-Idade , New York/epidemiologia , SARS-CoV-2/isolamento & purificação , Adulto Jovem
18.
Proc Natl Acad Sci U S A ; 118(38)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34531326

RESUMO

The spread of pathogenic bacteria in unsaturated porous media, where air and liquid coexist in pore spaces, is the major cause of soil contamination by pathogens, soft rot in plants, food spoilage, and many pulmonary diseases. However, visualization and fundamental understanding of bacterial transport in unsaturated porous media are currently lacking, limiting the ability to address the above contamination- and disease-related issues. Here, we demonstrate a previously unreported mechanism by which bacterial cells are transported in unsaturated porous media. We discover that surfactant-producing bacteria can generate flows along corners through surfactant production that changes the wettability of the solid surface. The corner flow velocity is on the order of several millimeters per hour, which is the same order of magnitude as bacterial swarming, one of the fastest known modes of bacterial surface translocation. We successfully predict the critical corner angle for bacterial corner flow to occur based on the biosurfactant-induced change in the contact angle of the bacterial solution on the solid surface. Furthermore, we demonstrate that bacteria can indeed spread by producing biosurfactants in a model soil, which consists of packed angular grains. In addition, we demonstrate that bacterial corner flow is controlled by quorum sensing, the cell-cell communication process that regulates biosurfactant production. Understanding this previously unappreciated bacterial transport mechanism will enable more accurate predictions of bacterial spreading in soil and other unsaturated porous media.

19.
JAMA Intern Med ; 181(11): 1440-1450, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34491268

RESUMO

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

20.
Mol Pharmacol ; 100(6): 568-579, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34561298

RESUMO

ß 1 adrenergic receptors (ß 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, ß 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate adenylyl cyclase, cAMP-dependent pathways, and the multifunctional adaptor-transducer protein ß-arrestin. Carvedilol, a traditional ß-blocker widely used in treating high blood pressure and heart failure by blocking ß adrenergic receptor-mediated G protein activation, can selectively stimulate Gs-independent ß-arrestin signaling of ß adrenergic receptors, a process known as ß-arrestin-biased agonism. Recently, a DNA-encoded small-molecule library screen against agonist-occupied ß 2 adrenergic receptors (ß 2ARs) identified Compound-6 (Cmpd-6) to be a positive allosteric modulator for agonists on ß 2ARs. Intriguingly, it was further discovered that Cmpd-6 is positively cooperative with the ß-arrestin-biased ligand carvedilol at ß 2ARs. Here we describe the surprising finding that at ß 1ARs unlike ß 2ARs, Cmpd-6 is cooperative only with carvedilol and not agonists. Cmpd-6 increases the binding affinity of carvedilol for ß 1ARs and potentiates carvedilol-stimulated, ß-arrestin-dependent ß 1AR signaling, such as epidermal growth factor receptor transactivation and extracellular signal-regulated kinase activation, whereas it does not have an effect on Gs-mediated cAMP generation. In vivo, Cmpd-6 enhances the antiapoptotic, cardioprotective effect of carvedilol in response to myocardial ischemia/reperfusion injury. This antiapoptotic role of carvedilol is dependent on ß-arrestins since it is lost in mice with myocyte-specific deletion of ß-arrestins. Our findings demonstrate that Cmpd-6 is a selective ß-arrestin-biased allosteric modulator of ß 1ARs and highlight its potential clinical utility in enhancing carvedilol-mediated cardioprotection against ischemic injury. SIGNIFICANCE STATEMENT: This study demonstrates the positive cooperativity of Cmpd-6 on ß1ARs as a ß-arrestin-biased positive allosteric modulator. Cmpd-6 selectively enhances the affinity and cellular signaling of carvedilol, a known ß-arrestin-biased ß-blocker for ß1ARs, whereas it has minimal effect on other ligands tested. Importantly, Cmpd-6 enhances the ß-arrestin-dependent in vivo cardioprotective effect of carvedilol during ischemia/reperfusion injury-induced apoptosis. The data support the potential therapeutic application of Cmpd-6 to enhance the clinical benefits of carvedilol in the treatment of cardiac disease.

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