Search

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. PATIENTS AND METHODS: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.

IntroductionCoronavirus disease 2019 (COVID-19) has caused >3.5 million deaths worldwide and affected >160 million people. At least twice as many have been infected but remained asymptomatic or minimally symptomatic. COVID-19 includes central nervous system manifestations mediated by inflammation and cerebrovascular, anoxic, and/or viral neurotoxicity mechanisms. More than one third of patients with COVID-19 develop neurologic problems during the acute phase of the illness, including loss of sense of smell or taste, seizures, and stroke. Damage or functional changes to the brain may result in chronic sequelae. The risk of incident cognitive and neuropsychiatric complications appears independent from the severity of the original pulmonary illness. It behooves the scientific and medical community to attempt to understand the molecular and/or systemic factors linking COVID-19 to neurologic illness, both short and long term.MethodsThis article describes what is known so far in terms of links among COVID-19, the brain, neurological symptoms, and Alzheimer's disease (AD) and related dementias. We focus on risk factors and possible molecular, inflammatory, and viral mechanisms underlying neurological injury. We also provide a comprehensive description of the Alzheimer's Association Consortium on Chronic Neuropsychiatric Sequelae of SARS-CoV-2 infection (CNS SC2) harmonized methodology to address these questions using a worldwide network of researchers and institutions.ResultsSuccessful harmonization of designs and methods was achieved through a consensus process initially fragmented by specific interest groups (epidemiology, clinical assessments, cognitive evaluation, biomarkers, and neuroimaging). Conclusions from subcommittees were presented to the whole group and discussed extensively. Presently data collection is ongoing at 19 sites in 12 countries representing Asia, Africa, the Americas, and Europe.DiscussionThe Alzheimer's Association Global Consortium harmonized methodology is proposed as a model to study long-term neurocognitive sequelae of SARS-CoV-2 infection.Key pointsThe following review describes what is known so far in terms of molecular and epidemiological links among COVID-19, the brain, neurological symptoms, and AD and related dementias (ADRD)The primary objective of this large-scale collaboration is to clarify the pathogenesis of ADRD and to advance our understanding of the impact of a neurotropic virus on the long-term risk of cognitive decline and other CNS sequelae. No available evidence supports the notion that cognitive impairment after SARS-CoV-2 infection is a form of dementia (ADRD or otherwise). The longitudinal methodologies espoused by the consortium are intended to provide data to answer this question as clearly as possible controlling for possible confounders. Our specific hypothesis is that SARS-CoV-2 triggers ADRD-like pathology following the extended olfactory cortical network (EOCN) in older individuals with specific genetic susceptibility.The proposed harmonization strategies and flexible study designs offer the possibility to include large samples of under-represented racial and ethnic groups, creating a rich set of harmonized cohorts for future studies of the pathophysiology, determinants, long-term consequences, and trends in cognitive aging, ADRD, and vascular disease.We provide a framework for current and future studies to be carried out within the Consortium. and offers a "green paper" to the research community with a very broad, global base of support, on tools suitable for low- and middle-income countries aimed to compare and combine future longitudinal data on the topic.The Consortium proposes a combination of design and statistical methods as a means of approaching causal inference of the COVID-19 neuropsychiatric sequelae. We expect that deep phenotyping of neuropsychiatric sequelae may provide a series of candidate syndromes with phenomenological and biological characterization that can be further explored. By generating high-quality harmonized data across sites we aim to capture both descriptive and, where possible, causal associations.

IntroductionNumerous studies have reported brain alterations in behavioral variant frontotemporal dementia (bvFTD). However, they pointed to inconsistent findings.MethodsWe used a meta-analytic approach to identify the convergent structural and functional brain abnormalities in bvFTD. Following current best-practice neuroimaging meta-analysis guidelines, we searched PubMed and Embase databases and performed reference tracking. Then, the coordinates of group comparisons between bvFTD and controls from 73 studies were extracted and tested for convergence using activation likelihood estimation.ResultsWe identified convergent abnormalities in the anterior cingulate cortices, anterior insula, amygdala, paracingulate, striatum, and hippocampus. Task-based and resting-state functional connectivity pointed to the networks that are connected to the obtained consistent regions. Functional decoding analyses suggested associated dysfunction of emotional processing, interoception, reward processing, higher-order cognitive functions, and olfactory and gustatory perceptions in bvFTD.DiscussionOur findings highlighted the key role of the salience network and subcortical regions in the pathophysiology of bvFTD.

We examined the effect of increased levels of plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in patients with type 2 diabetes (T2DM) with heart failure. Three groups of patients with T2DM (n = 12 per group) with an LV ejection fraction (EF) ≤50% received incremental infusions of β-hydroxybutyrate (β-OH-B) for 3–6 h to increase the plasma β-OH-B concentration throughout the physiologic (groups I and II) and pharmacologic (group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, group II also received a sodium bicarbonate (NaHCO3) infusion, thus serving as their own control for time, volume, and pH. Additionally, group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, and III achieved plasma β-OH-B levels (mean ± SEM) of 0.7 ± 0.3, 1.6 ± 0.2, 3.2 ± 0.2 mmol/L, respectively. Cardiac output (CO), LVEF, and stroke volume (SV) increased significantly during β-OH-B infusion in groups II (CO, from 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, from 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4), and did not change with NaHCO3 infusion in group II. The increase in LVEF was greatest in group III (P < 0.001 vs. group II). MGU and MBF were not altered by β-OH-B. In patients with T2DM and LVEF ≤50%, increased plasma β-OH-B level significantly increased LV function dose dependently. Because MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU. Article Highlights: Sodium–glucose cotransporter 2 inhibitor (SGLT2i) therapy is associated with an increase in plasma ketone concentration. In patients with type 2 diabetes and heart failure with reduced ejection fraction, we examined the effect of β-hydroxybutyrate (β-OH-B) infusion, spanning the physiologic and pharmacologic ranges of plasma β-OH-B concentrations (0.7, 1.6, and 3.2 mmol/L) on myocardial function (using MRI), myocardial blood flow (measured with positron emission tomography [PET]/15O-labeled water), and myocardial glucose uptake (PET/18F-FDG). β-OH-B caused a dose-response increase in left ventricular ejection fraction and myocardial blood flow without altering myocardial glucose uptake. These results suggest that the SGLT2i-induced increase in plasma ketone concentration may contribute to its beneficial effects on myocardial function. [ABSTRACT FROM AUTHOR]

We disclose herein our evaluation of competitive (hetero)aryl‐X (X: Br>Cl>OTf) reactivity preferences in bisphosphine/Ni‐catalyzed C−N cross‐coupling catalysis, using furfurylamine as a prototypical nucleophile, and employing DalPhos and DPPF as representative ancillary ligands with established efficacy. Beyond this general (pseudo)halide ranking, other intriguing structure‐reactivity trends were noted experimentally, including the unexpected observation that bulky alkyl (e. g. R=tBu) substitution in para‐R‐aryl‐X electrophiles strongly discourages (pseudo)halide reactivity relative to smaller substituents (e. g. nBu, Et, Me), despite being both remote from, and having a similar electronic influence on, the reacting C−X bond; such effects on nickel oxidative addition have not been documented previously and were not observed in our comparator reactions presented herein involving palladium. Density functional theory modeling of such PhPAd‐DalPhos/Ni‐catalyzed C−N cross‐couplings revealed the origins of competitive turnover of C−Br over C−Cl, and possible ways in which bulky para‐alkyl substitution might discourage net electrophile uptake/turnover, leading to inversion of halide selectivity. [ABSTRACT FROM AUTHOR]

Neutralizing monoclonal antibodies hold great potential for prevention of human immunodeficiency virus (HIV) acquisition. IgG is the most abundant antibody in human serum, has a long half-life, and potent effector functions, making it a prime candidate for an HIV prevention therapeutic. We combined Positron Emission Tomography imaging and fluorescent microscopy of 64Cu-labeled, photoactivatable-green fluorescent protein HIV (PA-GFP-BaL) and fluorescently labeled HGN194 IgG1 to determine whether intravenously instilled IgG influences viral interaction with mucosal barriers and viral penetration in colorectal tissue 2 h after rectal viral challenge. Our results show that IgG1 did not alter the number of virions found throughout the colon or viral penetration into the epithelium of the rectum or descending colon. A minor increase in virions was observed in the transverse colon of IgG1 treated animals. Overall, the number of viral particles found in the mesenteric lymph nodes was low. However, IgG1 administration resulted in a significant reduction of virions found in mesenteric lymph nodes. Taken together, our results show that HGN194 IgG1 does not prevent virions from penetrating into the colorectal mucosa but may perturb HIV virion access to the lymphatic system. [ABSTRACT FROM AUTHOR]

Coordinate-based meta-analyses (CBMA) allow researchers to combine the results from multiple functional magnetic resonance imaging experiments with the goal of obtaining results that are more likely to generalize. However, the interpretation of CBMA findings can be impaired by the file drawer problem, a type of publication bias that refers to experiments that are carried out but are not published. Using foci per contrast count data from the BrainMap database, we propose a zero-truncated modeling approach that allows us to estimate the prevalence of nonsignificant experiments. We validate our method with simulations and real coordinate data generated from the Human Connectome Project. Application of our method to the data from BrainMap provides evidence for the existence of a file drawer effect, with the rate of missing experiments estimated as at least 6 per 100 reported. The R code that we used is available at https://osf.io/ayhfv/.