To assess whether a dementia care coordination intervention delays time to transition from home and reduces unmet needs in elders with memory disorders.
18-month randomized controlled trial of 303 ...community-living elders.
28 postal code areas of Baltimore, MD.
Age 70+ years, with a cognitive disorder, community-living, English-speaking, and having a study partner available.
18-month care coordination intervention to systematically identify and address dementia-related care needs through individualized care planning; referral and linkage to services; provision of dementia education and skill-building strategies; and care monitoring by an interdisciplinary team.
Primary outcomes were time to transfer from home and total percent of unmet care needs at 18 months.
Intervention participants had a significant delay in time to all-cause transition from home and the adjusted hazard of leaving the home was decreased by 37% (Hazard ratio: 0.63, 95% Confidence Interval: 0.42-0.94) compared with control participants. Although there was no significant group difference in reduction of total percent of unmet needs from baseline to 18 months, the intervention group had significant reductions in the proportion of unmet needs in safety and legal/advance care domains relative to controls. Intervention participants had a significant improvement in self-reported quality of life (QOL) relative to control participants. No group differences were found in proxy-rated QOL, neuropsychiatric symptoms, or depression.
A home-based dementia care coordination intervention delivered by non-clinical community workers trained and overseen by geriatric clinicians led to delays in transition from home, reduced unmet needs, and improved self-reported QOL.
Anhedonia is a core symptom of several psychiatric disorders but its biological underpinnings are poorly understood. We performed a genome-wide association study of state anhedonia in 375,275 UK ...Biobank participants and assessed for genetic correlation between anhedonia and neuropsychiatric conditions (major depressive disorder, schizophrenia, bipolar disorder, obsessive compulsive disorder and Parkinson's Disease). We then used a polygenic risk score approach to test for association between genetic loading for anhedonia and both brain structure and brain function. This included: magnetic resonance imaging (MRI) assessments of total grey matter volume, white matter volume, cerebrospinal fluid volume, and 15 cortical/subcortical regions of interest; diffusion tensor imaging (DTI) measures of white matter tract integrity; and functional MRI activity during an emotion processing task. We identified 11 novel loci associated at genome-wide significance with anhedonia, with a SNP heritability estimate (h
SNP) of 5.6%. Strong positive genetic correlations were found between anhedonia and major depressive disorder, schizophrenia and bipolar disorder; but not with obsessive compulsive disorder or Parkinson's Disease. Polygenic risk for anhedonia was associated with poorer brain white matter integrity, smaller total grey matter volume, and smaller volumes of brain regions linked to reward and pleasure processing, including orbito-frontal cortex. In summary, the identification of novel anhedonia-associated loci substantially expands our current understanding of the biological basis of state anhedonia and genetic correlations with several psychiatric disorders confirm the utility of this phenotype as a transdiagnostic marker of vulnerability to mental illness. We also provide the first evidence that genetic risk for state anhedonia influences brain structure, including in regions associated with reward and pleasure processing.
Chimeric antigen receptor (CAR)-modified T cells have revealed promising results in the treatment of cancer, but they still need to overcome various hurdles, including a complicated manufacturing ...process. Receptor-targeted lentiviral vectors (LVs) delivering genes selectively to T cell subtypes may facilitate and improve CAR T cell generation, but so far they have resulted in lower gene delivery rates than conventional LVs (vesicular stomatitis virus VSV-LV). To overcome this limitation, we studied the effect of the transduction enhancer Vectofusin-1 on gene delivery to human T cells with CD4- and CD8-targeted LVs, respectively, encoding a second-generation CD19-CAR in conjunction with a truncated version of the low-affinity nerve growth factor receptor (ΔLNGFR) as reporter. Vectofusin-1 significantly enhanced the gene delivery of CD4- and CD8-LVs without a loss in target cell selectivity and killing capability of the generated CAR T cells. Notably, delivery rates mediated by VSV-LV were substantially reduced by Vectofusin-1. Interestingly, a transient off-target signal in samples treated with Vectofusin-1 was observed early after transduction. However, this effect was not caused by uptake and expression of the transgene in off-target cells, but rather it resulted from cell-bound LV particles having ΔLNGFR incorporated into their surface. The data demonstrate that gene transfer rates in the range of those mediated by VSV-LVs can be achieved with receptor-targeted LVs.
Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model ...systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition.
Metal halide perovskites have proven to be excellent light-harvesting materials in photovoltaic devices whose efficiencies are rapidly improving. Here, we examine the temperature-dependent photon ...absorption, exciton binding energy, and band gap of FAPbI3 (thin film) and find remarkably different behavior across the β–γ phase transition compared with MAPbI3. While MAPbI3 has shown abrupt changes in the band gap and exciton binding energy, values for FAPbI3 vary smoothly over a range of 100–160 K in accordance with a more gradual transition. In addition, we find that the charge-carrier mobility in FAPbI3 exhibits a clear T –0.5 trend with temperature, in excellent agreement with theoretical predictions that assume electron–phonon interactions to be governed by the Fröhlich mechanism but in contrast to the T –1.5 dependence previously observed for MAPbI3. Finally, we directly observe intraexcitonic transitions in FAPbI3 at low temperature, from which we determine a low exciton binding energy of only 5.3 meV at 10 K.
The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia and that ...antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss although having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild-type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the etiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.
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•Tumors expressing Fn14 cause cachexia in mice•Fn14 antibodies extend lifespan by inhibiting tumor-induced cachexia•Fn14- and TWEAK-deficient mice succumb to cancer cachexia•Tumor Fn14 signaling, rather than host, is responsible for inducing cachexia
Antibodies against the TWEAK receptor Fn14 prevent tumor-induced cachexia and extend lifespan by inhibiting weight loss and inflammation, although having only moderate effects on tumor growth.
Bare unpassivated GaAs nanowires feature relatively high electron mobilities (400-2100 cm2 V−1 s−1) and ultrashort charge carrier lifetimes (1-5 ps) at room temperature. These two properties are ...highly desirable for high speed optoelectronic devices, including photoreceivers, modulators and switches operating at microwave and terahertz frequencies. When engineering these GaAs nanowire-based devices, it is important to have a quantitative understanding of how the charge carrier mobility and lifetime can be tuned. Here we use optical-pump-terahertz-probe spectroscopy to quantify how mobility and lifetime depend on the nanowire surfaces and on carrier density in unpassivated GaAs nanowires. We also present two alternative frameworks for the analysis of nanowire photoconductivity: one based on plasmon resonance and the other based on Maxwell-Garnett effective medium theory with the nanowires modelled as prolate ellipsoids. We find the electron mobility decreases significantly with decreasing nanowire diameter, as charge carriers experience increased scattering at nanowire surfaces. Reducing the diameter from 50 nm to 30 nm degrades the electron mobility by up to 47%. Photoconductivity dynamics were dominated by trapping at saturable states existing at the nanowire surface, and the trapping rate was highest for the nanowires of narrowest diameter. The maximum surface recombination velocity, which occurs in the limit of all traps being empty, was calculated as 1.3 × 106 cm s−1. We note that when selecting the optimum nanowire diameter for an ultrafast device, there is a trade-off between achieving a short lifetime and a high carrier mobility. To achieve high speed GaAs nanowire devices featuring the highest charge carrier mobilities and shortest lifetimes, we recommend operating the devices at low charge carrier densities.
Summary Background Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac ...myosin activator, omecamtiv mecarbil. Methods In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov , number NCT01786512. Findings From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18–32, p<0·0001), stroke volume 3·6 mL (0·5–6·7, p=0·0217), left ventricular end-systolic diameter −1·8 mm (−2·9 to −0·6, p=0·0027), left ventricular end-diastolic diameter −1·3 mm, (−2·3 to 0·3, p=0·0128), heart rate −3·0 beats per min (−5·1 to −0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma −970 pg/mL (−1672 to −268, p=0·0069). The frequency of adverse clinical events did not differ between groups. Interpretation Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. Funding Amgen.
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