Association between socioeconomic factors, race, and use of a specialty memory clinic

BACKGROUND AND OBJECTIVES: The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use of memory clinics, this could exacerbate health care disparities, especially if more effective treatments of Alzheimer disease become available. We aimed to understand how use of a memory clinic is associated with neighborhood-level measures of socioeconomic factors and the intersectionality of race. METHODS: We conducted an observational cross-sectional study using electronic health record data to compare the neighborhood advantage of patients seen at the Washington University Memory Diagnostic Center with the catchment area using a geographical information system. Furthermore, we compared the severity of dementia at the initial visit between patients who self-identified as Black or White. We used a multinomial logistic regression model to assess the Clinical Dementia Rating at the initial visit and RESULTS: A total of 4,824 patients seen at the memory clinic between 2008 and 2018 were included in this study (mean age 72.7 [SD 11.0] years, 2,712 [56%] female, 543 [11%] Black). Most of the memory clinic patients lived in more advantaged neighborhoods within the overall catchment area. The percentage of patients self-identifying as Black (11%) was lower than the average percentage of Black individuals by census tract in the catchment area (16%) ( DISCUSSION: This study demonstrates that patients living in less affluent neighborhoods were less likely to be seen in one large memory clinic. Black patients were under-represented in the clinic, and Black patients had more severe dementia at their initial visit. These findings suggest that patients with a lower socioeconomic status and who identify as Black are less likely to be seen in memory clinics, which are likely to be a major point of access for any new Alzheimer disease treatments that may become available

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells.

The two major intracellular protein degradation systems, the ubiquitin-proteasome system (UPS) and autophagy, work collaboratively in many biological processes including development, apoptosis, aging, and countering oxidative injuries. We report here that, in human retinal pigment epithelial cells (RPE), ARPE-19 cells, proteasome inhibitors, clasto-lactacystinβ-lactone (LA) or epoxomicin (Epo), at non-lethal doses, increased the protein levels of autophagy-specific genes Atg5 and Atg7 and enhanced the conversion of microtubule-associated protein light chain (LC3) from LC3-I to its lipidative form, LC3-II, which was enhanced by co-addition of the saturated concentration of Bafilomycin A1 (Baf). Detection of co-localization for LC3 staining and labeled-lysosome further confirmed autophagic flux induced by LA or Epo. LA or Epo reduced the phosphorylation of the protein kinase B (Akt), a downstream target of phosphatidylinositol-3-kinases (PI3K), and mammalian target of rapamycin (mTOR) in ARPE-19 cells; by contrast, the induced changes of autophagy substrate, p62, showed biphasic pattern. The autophagy inhibitor, Baf, attenuated the reduction in oxidative injury conferred by treatment with low doses of LA and Epo in ARPE-19 cells exposed to menadione (VK3) or 4-hydroxynonenal (4-HNE). Knockdown of Atg7 with siRNA in ARPE-19 cells reduced the protective effects of LA or Epo against VK3. Overall, our results suggest that treatment with low levels of proteasome inhibitors confers resistance to oxidative injury by a pathway involving inhibition of the PI3K-Akt-mTOR pathway and activation of autophagy

LA or Epo decreased phospho-AKT and phospho-mTOR protein levels.

<p>ARPE-19 cells were treated with Epo (0.3∼10 nM) (<b>A</b>) or LA (100–1000 nM) (<b>B</b>) for 18–24 h, and proteins were harvested and subjected to immunoblotting for mTOR, phospho-mTOR(p-mTOR), AKT, phospho-AKT(p-AKT), p62. The optical density ratios (mTOR/GAPDH, AKT/GAPDH, p-mTOR/GAPDH, p-AKT/GAPDH, p62/GAPDH) for Epo (<b>C</b>) or LA treatment (<b>D</b>) were averaged from at least triplicate experiments and the ratios for the mTOR/GAPDH, AKT/GAPDH were not shown. The values for control were set as 100%; the values for treatment condition were normalized to the control values. *P <0.05 <i>vs</i> control.</p

Bafilomycin A1 (Baf) reversed the protective effect of LA against HNE or VK3 in ARPE-19 cells.

<p>Cultures were pre-treated with LA and the indicated concentrations of Baf (30∼300 nM) for 18 h before 18 h exposure to HNE (15 µM) (<b>A</b>) or VK3 (20 µM) (<b>B</b>). MTS assay was used to measure cell viability (<b>A</b>, <b>B</b>) and caspase-3 activity assay to measure apoptosis (<b>C</b>) at the end of the 18 h HNE or VK3 treatment. In MTS assay, *P<0.05 <i>vs</i>. control, ** P<0.05 indicated that the three combinatorial treatment including HNE or VK3, LA, and Baf differed significantly from cultures treated by HNE plus LA or VK3 plus LA; in caspase-3 assay, ** P<0.05 <i>vs</i>. control, ***P, *P <0.05 indicated that the three combinatorial treatment including VK3, LA, and Baf differed significantly from either VK3 or VK3 plus LA treatment respectively. <b>D</b>, ARPE-19 cells were treated by Baf (300 nM), LA (1 µM), Epo (10 nM), LA plus Baf, or Epo plus Baf for 18 h, and then subjected to chymotrypsin-like proteasome activity assay as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103364#s2" target="_blank">Methods</a>. *P<0.05 indicated significant difference between LA and LA plus Baf or between Epo and Epo plus Baf treatment; **P<0.05 indicated significant difference between control and treatment conditions except by Baf. All the values in control cultures (<b>A</b>, <b>B</b>,<b>C</b>,<b>D</b>) were set at 100% and the values in treated cultures were normalized to the control values. All the results shown are mean (± SEM) of at least triplicate experiments in quadruplicate cultures.</p

Knockdown of Atg7 attenuated the protective effect of LA or Epo.

<p>ARPE-19 cells were transfected with scramble siRNA (SCR), or Atg7-specific siRNA (SiATG7), continued to be cultured for 24 h, followed by pre-treatments with Epo (10 nM, <b>C</b>) or LA (1 µM, <b>D</b>), or sham treatment for 18–24 h, and then subjected to VK3 (20 µM) treatment for 18 h. After the 18 h VK3 treatment, the cultures were subjected to western blot analyses (<b>A</b>) or MTS assay (<b>C</b>, <b>D</b>). The knockdown effects by siRNA were quantified in <b>B</b>, *P<0.05 indicated significant difference between the knockdown effect of SiATG7 and SCR. In <b>C</b>, <b>D</b>, *P<0.05 indicated significant differences between LA or Epo treatment and LA or Epo plus VK3 treatments; ** P<0.05 indicated significant differences between the protective effects of LA or Epo treatment in SCR group and those in SiATG7 group. All the results were averaged from at least triplicate experiments and the values in control were set as 100% and the values in treated conditions were normalized to the control values.</p

Bafilomycin A1 (Baf) reversed the protection of Epo against HNE or VK3.

<p>Cultures were pre-treated with the indicated concentrations of Epo for 18 h before 18 h exposure to HNE (15 µM) (<b>A</b>) or VK3 (20 µM) (<b>B</b>); or the cultures were pre-treated with Epo (10 nM) and the indicated concentrations of Baf (30∼300 nM) for 18 h before 18 h exposure to HNE (15 µM) (<b>C</b>) or VK3 (20 µM) (<b>D</b>). MTS assay was used to measure cell viability at the end of the 18 h HNE or VK3 treatment. The results shown in A, B, C, and D are mean (± SEM) of at least three independent experiments in quadruplicate cultures. The values in the control cultures were set at 100% and the survivals in treated cultures were normalized to the control values. * P<0.05 vs. control, ** P<0.05 indicated that the three combinatorial treatment including HNE or VK3, Epo, Baf differed from either Epo plus VK3 or Epo plus HNE treatment.</p

LA or Epo increased protein levels of ATG5, ATG7, and the conversion of LC3-I to LC3-II.

<p><b>A</b>, ARPE-19 cells were treated with Epo (0.3∼10 nM, left panel) or LA (100-1000 nM, right panel) for 18-24 h, and proteins were harvested and subjected to immunoblotting for ATG5, ATG7, LC3 and GAPDH. The blots shown were typical of at least triplicate experiments. The ratios of ATG5/GAPDH, ATG7/GAPHH, and LC3-II/GAPDH for Epo (<b>B</b>) or LA treatment (<b>C</b>) were mean (<u>+</u> SEM) of at least triplicate experiments. The ratios for control were set as 100% and the values from treatment conditions were normalized to the control values. P<0.05 <i>vs</i> control.</p

LA or Epo induced autophagic flux.

<p><b>A</b>, ARPE-19 cells were treated with DMSO, Epo (10 nM), or LA (1 µM) for 18 h and Baf (400 nM) was added to the cultures for the final 4 h. Proteins were harvested and subjected to immunoblotting against LC3. The blots shown are typical of at least triplicate experiments. The optic densities were averaged and quantified in <b>B</b>, the values in control were set as 100% and the values in treated conditions were normalized to the control values. * P<0.05 <i>vs</i> control; **P<0.05 indicated that Epo or LA plus Baf differed significantly from Epo or LA treatments. <b>C</b>, ARPE-19 cells were treated with DMSO, Epo (10 nM), or LA (1 µM) for 18 h, and labeled with fluorescence as described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0103364#s2" target="_blank">Methods</a>, and imaged by confocal laser microscope. The images shown were typical of the images from five non-contiguous fields in each dish from triplicate experiments. Scale bar, 20 µM. The LC3-positive puncta overlaying labeled lysosome for Epo, or LA treatment, and sham condition were averaged from 20 cells and quantified in <b>D</b>. * P<0.05 <i>vs</i> control. Blue, DAPI-labeled nuclei; Red, lyso tracker-labeled lysosome; Green, FITC-labeled LC3. The merged images were shown in the most right column and the orange-stained cells indicated LC3, co-localized with lysosome.</p

A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease

International audienceDominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses