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.

Purpose To review the current literature for the nonoperative and operative treatment for adult spinal deformity. Recent Findings With more than 11 million baby boomers joining the population of over 60 years of age in the United States, the incidence of lumbar deformity is greatly increasing. Recent literature suggests that a lack of evidence exists to support the effectiveness of nonoperative treatment for adult scoliosis. In regards to operative treatment, current literature reports a varying range of improved clinical outcomes, curve correction, and complication rates. The extension of fusion to S1 compared with L5 and lower thoracic levels compared with L1 remains a highly controversial topic among literature. Summary Most adult deformity patients never seek nonoperative or operative treatment. Of the few that seek treatment, many can benefit from nonoperative treatment. However, in selected patients who have failed nonoperative treatment and who are candidates for surgical intervention, the literature reflects positive outcomes related to surgical intervention as compared with nonoperative treatment despite varying associated ranges in morbidity and mortality rates. If nonoperative therapy fails in addressing a patients complaints, then an appropriate surgical procedure that relieves neural compression, corrects excessive sagittal or coronal imbalance, and results in a solidly fused, pain-free spine is warranted.

Background: Women and men have diverse responses to many infectious diseases. These differences are amplified following menopause. However, despite extensive information regarding the effects of sex hormones on immune cells, our knowledge is limited regarding the effects of sex and gender on the function of the mucosal immune system. Sex differences also manifest in the prevalence of gut associated inflammatory and autoimmune disorders, including Crohn's disease, ulcerative colitis and Celiac disease. It is thus hypothesized that a baseline sex-associated difference in immune activation may predispose women to inflammation-associated disease. Methods: Peripheral blood samples and small intestinal biopsies were obtained from 34 healthy men and women. Immunophenotypic analysis of isolated lymphocytes was performed by flow cytometry. Oligonucleotide analysis was used to study the transcriptional profile in the gut mucosal microenvironment while real-time PCR analysis was utilized to identify differential gene expression in isolated CD4+ T cells. Transcriptional analysis was confirmed by protein expression levels for genes of interest using fluorescent immunohistochemistry. Data was analyzed using the GraphPad software package. Results: Women had higher levels of immune activation and inflammation-associated gene expression in gut mucosal samples. CD4+ and CD8+ T cells had a significantly higher level of immune activation-associated phenotype in peripheral blood as well as in gut associated lymphoid tissue along with higher levels of proliferating T cells. CD4+ T cells that showed upregulation of IL1β as well as the TH17 pathway-associated genes contributed a large part of the inflammatory profile. Conclusion: In this study, we demonstrated an upregulation in gene expression related to immune function in the gut microenvironment of women compared to men, in the absence of disease or pathology. Upon closer investigation, CD4+ T cell activation levels were higher in the LPLs in women than in men. Sex differences in the mucosal immune system may predispose women to inflammation-associated diseases that are exacerbated following menopause. Our study highlights the need for more detailed analysis of the effects of sex differences in immune responses at mucosal effector sites. © 2013 Sankaran-Walters et al.; licensee BioMed Central Ltd.

Background

Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%.

Methods

We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation-positive, advanced NSCLC and PD-L1-positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab.

Results

Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty-two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD-L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient's tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment-related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern.

Conclusions

Pembrolizumab's lack of efficacy in TKI naïve, PD-L1+, EGFR-mutant patients with advanced NSCLC, including those with PD-L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

© 2014 Macmillan Publishers Limited. All rights reserved. The Pliocene and Early Pleistocene, between 5.3 and 0.8 million years ago, span a transition from a global climate state that was 2-3 °C warmer than present with limited ice sheets in the Northern Hemisphere to one that was characterized by continental-scale glaciations at both poles. Growth and decay of these ice sheets was paced by variations in the Earth's orbit around the Sun. However, the nature of the influence of orbital forcing on the ice sheets is unclear, particularly in light of the absence of a strong 20,000-year precession signal in geologic records of global ice volume and sea level. Here we present a record of the rate of accumulation of iceberg-rafted debris oshore from the East Antarctic ice sheet, adjacent to the Wilkes Subglacial Basin, between 4.3 and 2.2 million years ago. We infer that maximum iceberg debris accumulation is associated with the enhanced calving of icebergs during ice-sheet margin retreat. In the warmer part of the record, between 4.3 and 3.5 million years ago, spectral analyses show a dominant periodicity of about 40,000 years. Subsequently, the powers of the 100,000-year and 20,000-year signals strengthen. We suggest that, as the Southern Ocean cooled between 3.5 and 2.5 million years ago, the development of a perennial sea-ice field limited the oceanic forcing of the ice sheet. After this threshold was crossed, substantial retreat of the East Antarctic ice sheet occurred only during austral summer insolation maxima, as controlled by the precession cycle.

Warm intervals within the Pliocene epoch (5.33-2.58 million years ago) were characterized by global temperatures comparable to those predicted for the end of this century and atmospheric CO 2 concentrations similar to today. Estimates for global sea level highstands during these times imply possible retreat of the East Antarctic ice sheet, but ice-proximal evidence from the Antarctic margin is scarce. Here we present new data from Pliocene marine sediments recovered offshore of Adélie Land, East Antarctica, that reveal dynamic behaviour of the East Antarctic ice sheet in the vicinity of the low-lying Wilkes Subglacial Basin during times of past climatic warmth. Sedimentary sequences deposited between 5.3 and 3.3 million years ago indicate increases in Southern Ocean surface water productivity, associated with elevated circum-Antarctic temperatures. The geochemical provenance of detrital material deposited during these warm intervals suggests active erosion of continental bedrock from within the Wilkes Subglacial Basin, an area today buried beneath the East Antarctic ice sheet. We interpret this erosion to be associated with retreat of the ice sheet margin several hundreds of kilometres inland and conclude that the East Antarctic ice sheet was sensitive to climatic warmth during the Pliocene. © 2013 Macmillan Publishers Limited. All rights reserved.

The Majorana Demonstrator will search for the neutrinoless double-beta (β β 0 ) decay of the isotope Ge with a mixed array of enriched and natural germanium detectors. The observation of this rare decay would indicate that the neutrino is its own antiparticle, demonstrate that lepton number is not conserved, and provide information on the absolute mass scale of the neutrino. The Demonstrator is being assembled at the 4850-foot level of the Sanford Underground Research Facility in Lead, South Dakota. The array will be situated in a low-background environment and surrounded by passive and active shielding. Here we describe the science goals of the Demonstrator and the details of its design. © 2014 N. Abgrall et al.