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This discursive article aims to capture and explore the most pertinent nursing aspects of dementia literacy (DL).Older people constitute a rapidly increasing proportion of the global population, experiencing higher risk of developing chronic disease, including dementia. It is important that older adults receive and understand reliable health-related information, as age-related changes may affect the level of health literacy in an older person. It has been suggested that older adults may have poorer health literacy than younger adults, associated with poorer health outcomes. Health literacy, how people receive, interpret and act on health information, play a significant role in dementia-related disorders, both as a possible predicter of onset of dementia and as a potential modifier of cognitive decline. Dementia literacy constitutes one aspect of health literacy in relation to nursing care, related to knowledge of dementia-related disorders and approaches towards older people with dementia.This discursive article explores the importance of DL for the nursing profession, including dementia-related assessment, education and interventions.This article is informed by analysis of relevant descriptive and empirical literature and policy documents related to DL, an increasingly important aspect of dementia-related nursing care. Valid assessment tools that can accurately assess aspects an individuals' DL are examined; these have the potential to help nurses detect dementia-related symptoms. With early detection and prevention of dementia, older people may have better chance of benefiting from evolving treatment options.Greater attention needs to be given to the issue of DL in older people, especially in terms of nursing assessment and care. Globally, increased DL-related education is urgently required to improve knowledge of this concept; this includes public awareness initiatives to better understanding this chronic condition.Enhancing DL has the potential to empower older people to have greater access to healthcare services and to make more informed decisions about their health care.No patient or public contribution, as this is a discursive article.

Objective To compare predictive validity of the Wilson Sims Fall Risk Assessment Tool (WSFRAT) with that of the Morse Fall Scale (MFS) in psychogeriatric inpatients. Methods Psychogeriatric patients from Shatin Hospital, Tai Po Hospital, Castle Peak Hospital, and United Christian Hospital who had fall incident between April 2019 and April 2020 were identified. Their fall risks were assessed by the WSFRAT and the MFS, and their falls incidents during hospitalisation were recorded. Patients were classified as having high fall risk when their MFS score was ≥45 and when their WSFRAT score was ≥7. Sensitivity, specificity, and positive and negative predictive values of the two scales were calculated. Results We identified 183 (90 male and 93 female) psychogeriatric patients aged ≥65 years who had fall incident and were assessed by both the WSFRAT and the MFS during the study period. Among the 183 patients, four sustained a fall during hospital stay, giving a prevalence of 2.19%. All four patients were classified as having high risk of fall by WSFRAT, but only two of them were classified so by MFS. The sensitivity of WSFRAT was 100%, which was higher than the 50% by MFS, but specificity of MFS was higher than that of WSFRAT (45.81% vs 54.75%). Conclusion WSFRAT is a better fall risk assessment scale for psychiatric inpatients than MFS, because of higher sensitivity (100% vs 50%). It has items specific to psychiatric patients and should replace MFS in psychiatric settings.

Background Late-life depression (LLD) has a poorer long-term prognosis and higher relapse rate than in younger adults with up to one third of patients with LLD showing suboptimal response to antidepressant therapy. Also, LLD has been associated with significant impairment in cognition and daily functioning. Few studies have evaluated the therapeutic effects of high-definition transcranial direct current stimulation (HD-tDCS) on the depressive and cognitive symptoms of LDD. The current randomized controlled trial assesses the efficacy of HD-tDCS as an augmentation therapy with antidepressants compared to sham-control in subjects with LLD. Method Fifty-eight patients with LLD will be recruited and randomly assigned to the active HD-tDCS or sham HD-tDCS group. In both groups, patients will receive the active or sham intervention in addition to their pre-existing antidepressant therapy, for 2 weeks with 5 sessions per week, with each lasting 30 minutes. The primary outcome measures will be the change of depressive symptoms, the clinical response and the remission rate as measured with the HAMD-17 before and after the intervention, and at 4 th and 12 th week after completed intervention. Secondary outcome measures include cognitive symptoms, anxiety symptoms, daily functioning and adverse effects. Discussion Older adults with depression are associated with poorer outcomes with unsatisfactory responses to antidepressant therapy and significant cognitive decline thus a new effective treatment option is needed. This randomized control trial aims at assessing the efficacy of HD-tDCS on ameliorating the depressive, cognitive and anxiety symptoms and improving daily functioning of subjects with LLD. Trial registration : ClinicalTrials.gov ID NCT05322863 released on 11 April 2022 https://clinicaltrials.gov/ct2/show/NCT05322863

Summary Background & aims Mild cognitive impairment (MCI) patients are at risk of cognitive decline, while elevated serum homocysteine is also associated with cognitive impairment. Thus, older people with MCI and hyperhomocysteinemia may be under greater risk of cognitive decline. We therefore performed a randomized trial of homocysteine-lowering by B vitamins supplementation to prevent cognitive decline in older MCI patients with elevated serum homocysteine. Methods 279 MCI outpatients aged ≥65 years with serum homocysteine ≥10.0 μmol/L were randomly assigned to take either methylcobalamin 500 μg and folic acid 400 μg once daily, or two placebo tablets for 24 months. All subjects were followed up at 12 monthly intervals. The primary outcome was cognitive decline as defined by an increase in clinical dementia rating scale (CDR) sum of boxes (CDR_SOB). The secondary outcomes were global CDR, memory Z score, executive function Z score and Hamilton depression rating scale (HDRS) score. Results The clinical characteristics between two groups were well matched, except that the supplement group had better executive function. The supplement effectively lowered serum homocysteine (mean 13.9 ± sd 3.5 μmol at baseline to 9.3 ± 2.4 μmol/L at month 24). At month 24, there was no significant group difference in CDR_SOB or any secondary outcomes (mean changes in CDR_SOB 0.36 versus 0.22 in supplement and placebo groups respectively). At month 12, the supplement group significantly improved in executive function and had lower HDRS score (P = 0.004 and 0.012 respectively). Group difference was significant for HDRS, but borderline significant for executive function. (P = 0.01; 0.06 respectively) These effects were not significant at month 24. Subgroup analysis showed that aspirin use had significant interaction with B supplements in CDR_SOB at month 24 (Beta 0.189, P = 0.005). Conclusions Vitamin B12 and folic acid supplementation did not reduce cognitive decline in older people with MCI and elevated serum homocysteine, though the cognitive decline over two years in placebo group was small. The supplement led to a significant reduction in depressive symptoms at month 12, though this effect was not sustained. Aspirin use had a negative interaction effect on cognitive functioning with B supplements. Clinical trial registration Centre for Clinical Research and Biostatistics (CCRB) Clinical Trials Registry: CUHK_CCT00373.

Performing motion-free imaging is frequently challenging in children. To bridge the gap between examinations performed in children who are awake and in those under general anesthesia, a moderate sedation program was implemented at our institution but was seldom used despite substantial eligibility. In conjunction with a 5-month quality improvement (QI) course, a multidisciplinary team was assembled and, by using an A3 approach, sought to address the most important key drivers of low utilization, namely the need for clear moderate sedation eligibility criteria, reliable protocol routing order, consistent moderate sedation screening performed by registered nurses (RNs), and enhanced visibility of moderate sedation services to ordering providers. Initial steps focused on developing better-defined criteria and protocoling standard work for technologists and RNs, with coaching and audits. Modality-specific forecasting was then implemented to reroute profiles of patients who were awaiting scheduling or already scheduled for an examination with general anesthesia to the moderate sedation queue to identify more eligible patients. These manual efforts were coupled with higher reliability but more protracted electronic health record changes, facilitating automated protocol routing on the basis of moderate sedation eligibility and order entry constraints. As a result, scheduled imaging examinations requiring moderate sedation increased from a mean of 1.2 examinations per week to a sustained 6.1 examinations per week (range, 4-8) over the 5-month period, exceeding the team SMART (specific, measurable, achievable, relevant, and time bound) goal to achieve an average of five examinations per week by the QI course end. By targeting the most high-impact yet modifiable process deficiencies through a multifaceted team approach and initially investing in manual efforts to gain cultural buy-in while awaiting higher-reliability interventions, the project achieved success and may serve as a more general model for workflow change when there is organizational resistance. ©RSNA, 2021.

The incredible variety of proteins associated with immune responses presents a major challenge in immune monitoring. When combinations of these proteins are measured, cell types that influence disease can be precisely identified. Here, we introduce TerraFlow, a novel data analysis tool that performs an exhaustive search of disease-associated cell populations from high-parameter flow cytometry experiments. Using a newly generated dataset, from 24-color immune checkpoint-focused and 18-color immune function-focused experiments, we apply TerraFlow to classical Hodgkin lymphoma (cHL), where systemic T-cell immunity has not been investigated in detail. We reveal novel immune perturbations in newly diagnosed cHL, as well as persistent immune perturbations after treatment. Newly diagnosed patients have elevated levels of activated (CD278+), exhausted (e.g., CD366+ and CD152+ phenotypes), and IL17-expressing cells, along with diminished levels of naïve and central memory (CD127+) T-cells and fewer IFNγ+ and TNF+ T-cells. Exhaustion signatures are reduced with treatment, but compared to healthy individuals, treated patients still exhibit more activated (CD278+ phenotypes), exhausted (CD366+), and IL17-expressing cells. Notably, TerraFlow identifies more phenotypic differences between patient groups than FlowSOM and CellCNN, often with better predictive power. Finally, we introduce a new non-gating approach for data analysis that obviates the need for time-consuming and subjective setting of fluorescence thresholds. Our results benchmark TerraFlow against common methods, provide mechanistic support for past reports of immune deficiency in cHL, and provide a roadmap for future immunotherapy and biomarker studies.

This article describes a dataset that was generated as part of the article: Personalized prediction of transcranial magnetic stimulation clinical response in patients with treatment-refractory depression using neuroimaging biomarkers and machine learning (DOI: 10.1016/j.jad.2021.04.081). We collected resting-state functional Magnetic Resonance Imaging data from 70 medication-refractory depressed subjects before undergoing four weeks of repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex. The data presented here include information about the seed-based analyses such as regions of interest, individual/group functional connectivity maps and contrast maps. The contrast maps are controlled for age, gender, duration of the current depressive episode, duration since the first depressive episode, and symptom scores. Demographics, clinical characteristics, and categorical treatment response variables are reported as well. Further, the individual connectivity values of the identified neuroimaging biomarkers of long-term clinical response were used as features in the support vector machine models are presented in combination with the trained classifiers of the support vector machine models. Post hoc analyses that were not published in the original analyses are presented as well. Finally, the R or MATLAB code scripts for all figures published in the co-submitted paper are included.

Background Although community-level benefits of health system engagement (i.e., health service planning, delivery, and quality improvement, engaged research and evaluation, and collaborative advocacy) are well established, individual-level impacts on the health and well-being of community members are less explored, in particular for people who use or have used illegal drugs (PWUD). Capacity building, personal growth, reduced/safer drug use, and other positive outcomes may or may not be experienced by PWUD involved in engagement activities. Indeed, PWUD may also encounter stigma and harm when interacting with healthcare and academic structures. Our objective is to uncover why, how, and under what circumstances positive and negative health outcomes occur during health system engagement by PWUD. Methods We propose a realist review approach due to its explanatory lens. Through preliminary exploration of literature, lived experience input, and consideration of formal theories, an explanatory model was drafted. The model describes contexts, mechanisms, and health outcomes (e.g., mental health, stable/safer drug use) involved in health system engagement. The explanatory model will be tested against the literature and iteratively refined against formal theories. A participatory lens will also be used, wherein PWUD with lived experience of health system engagement will contribute throughout all stages of the review. Discussion We believe this is the first realist review to explore the contextual factors and underlying mechanisms of health outcomes for PWUD who participate in health system engagement. A thorough understanding of the relevant literature and theoretical underpinnings of this process will offer insights and recommendations to improve the engagement processes of PWUD.

Background Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 (177 Lu-J591) targets prostate cancer with efficacy and dose-response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely. Method Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of 177 Lu-J591 2 weeks apart. 177 Lu-J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment. Results Forty-nine men received fractionated doses of 177 Lu-J591 ranging from 20 to 45 mCi/m2 ×2 two weeks apart. The dose-limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m2 and 45 mCi/m2 ×2. At the highest RP2D (45 mCi/m2 ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate-specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9-64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses. Conclusion Fractionated administration of 177 Lu-J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose-limiting myelosuppression) increased with higher doses.

Background Dementia shows sex difference in its epidemiology. Childbirth, a distinctive experience of women, is associated with the risk for various diseases. However, its association with the risk of dementia in women has rarely been studied. Methods We harmonized and pooled baseline data from 11 population-based cohorts from 11 countries over 3 continents, including 14,792 women aged 60 years or older. We investigated the association between parity and the risk of dementia using logistic regression models that adjusted for age, educational level, hypertension, diabetes mellitus, and cohort, with additional analyses by region and dementia subtype. Results Across all cohorts, grand multiparous (5 or more childbirths) women had a 47% greater risk of dementia than primiparous (1 childbirth) women (odds ratio [OR] = 1.47, 95% confidence interval [CI] = 1.10–1.94), while nulliparous (no childbirth) women and women with 2 to 4 childbirths showed a comparable dementia risk to primiparous women. However, there were differences associated with region and dementia subtype. Compared to women with 1 to 4 childbirths, grand multiparous women showed a higher risk of dementia in Europe (OR = 2.99, 95% CI = 1.38–6.47) and Latin America (OR = 1.49, 95% CI = 1.04–2.12), while nulliparous women showed a higher dementia risk in Asia (OR = 2.15, 95% CI = 1.33–3.47). Grand multiparity was associated with 6.9-fold higher risk of vascular dementia in Europe (OR = 6.86, 95% CI = 1.81–26.08), whereas nulliparity was associated with a higher risk of Alzheimer disease (OR = 1.91, 95% CI 1.07–3.39) and non-Alzheimer non-vascular dementia (OR = 3.47, 95% CI = 1.44–8.35) in Asia. Conclusion Parity is associated with women’s risk of dementia, though this is not uniform across regions and dementia subtypes.

We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54–103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.

Background GABA-deficit characterizes depression (MDD), which is highly comorbid with Functional Dyspepsia (FD). We examined brain GABA concentrations and resting activities in post-prandial distress subtype FD (FD-PDS) patients with and without MDD. Methods 24 female age/education-matched FD-PDS with comorbid MDD (FD-PDS-MDD), non-depressed FD-PDS, and healthy controls each were compared on GABA concentrations, resting fMRI (fALFF) in bilateral pregenual anterior cingulate (pgACC), left dorsolateral prefrontal cortex (DLPFC), insula, and somatosensory cortex (SSC). Results FD-PDS-MDD patients had mild though elevated depressive symptoms. FD-PDS patients had generally mild dyspeptic symptoms. No significant between-group differences in GABA or fALFF were found. No significant correlations were found between GABA and depressive/dyspeptic symptoms after Bonferroni correction. In patients, GABA correlated positively with left insula fALFF (r = 0.38, Bonferroni-corrected p = .03). Conclusion We did not find altered GABA concentrations or brain resting activity in FD-PDS or its MDD comorbidity. The neurochemical link between MDD and FD remains elusive.

BACKGROUND AND OBJECTIVE: There is currently no objective measure of the visual deficits experienced by patients with symptomatic vitreous opacities (SVOs) that would also correlate with the functional improvement they report following vitrectomy. This study aims to determine whether reading speed can be used as a reliable outcome measure to assess objectively the impact of both SVOs and vitrectomy on patients' visual performance. PATIENTS AND METHODS: Twenty adult patients seeking surgery for SVO were included. Measures of visual function were obtained before and after vitrectomy using the Early Treatment Diabetic Retinopathy Study acuity chart, the National Eye Institute Visual Function Questionnaire, and the MNREAD acuity chart. RESULTS: In patients with nonopacified lenses (n = 10), maximum reading speed increased significantly from 138 to 159 words per minute after complete removal of SVOs by vitrectomy (95% confidence interval, 14–29; P < .001). CONCLUSIONS: Reading speed is impaired with SVOs and improves following vitrectomy in phakic and pseudophakic eyes with clear lenses. Reading speed is a valid objective measure to assess the positive effect of vitrectomy for SVOs on near-distance daily life activities. [ Ophthalmic Surg Lasers Imaging Retina . 2020;51:456–466.]

Acute myeloid leukemia carries a dismal prognosis in older patients. The objective of this study was to investigate the safety and efficacy of decitabine combined with the CXCR4 antagonist plerixafor in newly diagnosed older patients with acute myeloid leukemia and to evaluate the effects of plerixafor on leukemia stem cells. Patients were treated with monthly cycles of decitabine 20 mg/m2 days 1–10 and escalating doses of plerixafor (320–810 mcg/kg) days 1–5. Sixty-nine patients were treated, with an overall response rate of 43%. Adverse karyotype did not predict response (P=0.31). Prior hypomethylating agent treatment was the strongest independent predictor of adverse overall survival (hazard ratio 3.1; 95%CI: 1.3–7.3; P=0.008) and response (14% in previously treated patients, 46% in treatment naïve; P=0.002). As expected, the most common toxicities were myelosuppression and infection. Plerixafor induced mobilization of leukemia stem and progenitor cells, but did not cause clinically significant hyperleukocytosis. Reduction in leukemia stem cells appeared to correlate with duration of response. Plerixafor can be safely added to decitabine in poor-prognosis, elderly acute myeloid leukemia patients. The maximum tolerated dose of the combination was 810 mcg/kg. While mobilization of leukemia stem cells was observed in some patients, the clinical benefit of adding plerixafor was uncertain. This trial was registered at clinicaltrials.gov identifier: 01352650.

Acute myelogenous leukemia (AML) is a deadly disease characterized by high relapse rates even in patients who initially achieve complete remission. Standard therapy for AML has remained largely unc...

Patients with metastatic castration-resistant prostate cancer (mCPRC) now have an unprecedented number of approved treatment options, including chemotherapies (docetaxel, cabazitaxel), androgen receptor (AR)-targeted therapies (enzalutamide, abiraterone), a radioisotope (radium-223) and a cancer vaccine (sipuleucel-T). However, the optimal treatment sequencing pathway is unknown, and this problem is exacerbated by the issues of primary and acquired resistance. This review focuses on mechanisms of resistance to AR-targeted therapies and taxane-based chemotherapy. Patients treated with abiraterone, enzalutamide, docetaxel or cabazitaxel may present with primary resistance, or eventually acquire resistance when on treatment. Multiple resistance mechanisms to AR-targeted agents have been proposed, including: intratumoral androgen production, amplification, mutation, or expression of AR splice variants, increased steroidogenesis, upregulation of signals downstream of the AR, and development of androgen-independent tumor cells. Known mechanisms of resistance to chemotherapy are distinct, and include: tubulin alterations, increased expression of multidrug resistance genes, TMPRSS2-ERG fusion genes, kinesins, cytokines, and components of other signaling pathways, and epithelial-mesenchymal transition. Utilizing this information, biomarkers of resistance/response have the potential to direct treatment decisions. Expression of the AR splice variant AR-V7 may predict resistance to AR-targeted agents, but available biomarker assays are yet to be prospectively validated in the clinic. Ongoing prospective trials are evaluating the sequential use of different drugs, or combination regimens, and the results of these studies, combined with a deeper understanding of mechanisms of primary and acquired resistance to treatment, have the potential to drive future treatment decisions in mCRPC.

Progress in the understanding of molecular events of carcinogenesis and cancer evolution as well as the identification of tumor antigens has led to the development of different targeted therapeutic approaches, including the use of monoclonal antibodies (mAbs). Prostate cancer (PC) is highly amenable to mAb targeting given the existence of prostate-specific targets and the natural history and localization of metastatic disease. Areas covered: Several aspects of the PC phenotype, including growth factors, angiogenesis mediators, bone microenvironment signals, and immune evasion pathways, have become areas of ongoing investigation in terms of mAb targeting. These are reviewed. The greatest success so far has been the development of mAbs against prostate-specific tumor antigen (PSMA), which opened an opportunity to improve diagnostic accuracy and simultaneously target metastatic disease. Expert opinion: As mAb use in PC continues to evolve, more accurate imaging of the extent of disease and more effective mAb therapies (naked or conjugated with drugs, toxins or radioactive molecules) are emerging. In addition, the combination of mAbs with other treatment modalities is expected to further improve responses and overall survival. Identification of validated biomarkers is necessary for better recognition of patient subgroups who will derive the greatest benefit from mAb therapy.

Background With no effective treatments for cognitive decline or dementia, improving the evidence base for modifiable risk factors is a research priority. This study investigated associations between risk factors and late-life cognitive decline on a global scale, including comparisons between ethno-regional groups. Methods and findings We harmonized longitudinal data from 20 population-based cohorts from 15 countries over 5 continents, including 48,522 individuals (58.4% women) aged 54–105 (mean = 72.7) years and without dementia at baseline. Studies had 2–15 years of follow-up. The risk factors investigated were age, sex, education, alcohol consumption, anxiety, apolipoprotein E ε4 allele (APOE*4) status, atrial fibrillation, blood pressure and pulse pressure, body mass index, cardiovascular disease, depression, diabetes, self-rated health, high cholesterol, hypertension, peripheral vascular disease, physical activity, smoking, and history of stroke. Associations with risk factors were determined for a global cognitive composite outcome (memory, language, processing speed, and executive functioning tests) and Mini-Mental State Examination score. Individual participant data meta-analyses of multivariable linear mixed model results pooled across cohorts revealed that for at least 1 cognitive outcome, age (B = −0.1, SE = 0.01), APOE*4 carriage (B = −0.31, SE = 0.11), depression (B = −0.11, SE = 0.06), diabetes (B = −0.23, SE = 0.10), current smoking (B = −0.20, SE = 0.08), and history of stroke (B = −0.22, SE = 0.09) were independently associated with poorer cognitive performance (p < 0.05 for all), and higher levels of education (B = 0.12, SE = 0.02) and vigorous physical activity (B = 0.17, SE = 0.06) were associated with better performance (p < 0.01 for both). Age (B = −0.07, SE = 0.01), APOE*4 carriage (B = −0.41, SE = 0.18), and diabetes (B = −0.18, SE = 0.10) were independently associated with faster cognitive decline (p < 0.05 for all). Different effects between Asian people and white people included stronger associations for Asian people between ever smoking and poorer cognition (group by risk factor interaction: B = −0.24, SE = 0.12), and between diabetes and cognitive decline (B = −0.66, SE = 0.27; p < 0.05 for both). Limitations of our study include a loss or distortion of risk factor data with harmonization, and not investigating factors at midlife. Conclusions These results suggest that education, smoking, physical activity, diabetes, and stroke are all modifiable factors associated with cognitive decline. If these factors are determined to be causal, controlling them could minimize worldwide levels of cognitive decline. However, any global prevention strategy may need to consider ethno-regional differences., Darren Lipnicki and the Sydney COSMIC team analysed cognitive performance and risk factor data from older people from 15 countries to assess associations between risk factors and late-life cognition, Author summary Why was this study done? There is a growing global burden associated with cognitive decline and dementia. Evidence for modifiable risk factors that could be targeted to reduce this burden needs to be improved. Risk factors for cognitive decline and dementia might differ between ethno-regional groups. What did the researchers do and find? We analyzed cognitive performance and risk factor data from 48,522 older individuals, provided by 20 studies of aging representing 15 countries (Australia, Brazil, Cuba, France, Germany, Greece, Hong Kong, Italy, Japan, Singapore, Spain, South Korea, The Netherlands, the United Kingdom, and the United States). Cognitive performance was measured as Mini-Mental State Examination (MMSE) and global cognition scores. When controlling for confounding risk factors, the apolipoprotein E ε4 allele (APOE*4), depression, diabetes, current smoking, and history of stroke were associated with poorer cognitive performance, and higher levels of education and vigorous physical activity were associated with better performance. Age, APOE*4, and diabetes were associated with faster cognitive decline. Compared to white people, Asian people showed stronger associations between having ever smoked and cognitive performance, and between diabetes and cognitive decline. What do these findings mean? Modifiable risk factors associated with cognitive decline include education, smoking, physical activity, diabetes, and stroke. If these associations are determined to be causal, interventions targeting these factors may help reduce the global burden of cognitive decline and dementia. Interventions may require tailoring to particular ethno-regional groups.

Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 (Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses ofForty-nine men received fractionated doses ofFractionated administration of

Background: Asia will soon have the majority of demented patients in the world. Objective: To assess dementia using a uniform data system to update the current status of dementia in Asia. Methods: A uniformed data set was administered in Taiwan, China, Hong Kong, Korea, Japan, Philippines, Thailand, Singapore, and Indonesia to gather data with regard to Alzheimer's disease (AD) and its related issues for these countries. Results: In total, 2,370 AD patients and their caregivers were recruited from 2011 to 2014. The demographic characteristics of these patients and the relationships between patients and caregivers were different among individuals in these countries (p < 0.001). Of note, the family history for having dementia was 8.2% for females in contrast to 3.2% for males. Conclusion: Our study highlighted the differences in dementia assessment and care in developing versus developed countries. Greater effort with regard to studying dementia, especially in developing countries, is necessary.

Background: Classical Hodgkin lymphoma (HL) has a unique histopathology, with rare malignant Hodgkin/Reed Sternberg (HRS) cells surrounded by a strong inflammatory cellular component in the tumor microenvironment (TME). Although extensive studies describe the interdependence of the HRS cells and the TME, the impact of HL on systemic immunity has not been well described. Here, we develop a new approach, employing a recently commercialized single cell cytokine secretion platform (IsoLight) to assess, precisely and comprehensively, the function of peripheral blood mononuclear cells (PBMCs) in HL patients. Methods: Cells were selected from 4 HL patients: 2 newly diagnosed who had a complete response (CR) to therapy standard first line therapy, and 2 relapsed patients who progressed on second line chemotherapy (PD). Cryopreserved PBMCs from a pre-treatment and post-treatment time point for each patient were thawed, rested overnight, stimulated with PMA/ionomycin and loaded into the IsoLight single cell cytokine secretion system. IsoLight captures single cells in microwells; as cytokines are secreted, they are bound by antibodies lining the microwell cover. Bound cytokines are then revealed by fluorescent secondary antibodies and photos are taken at various time points to assess fluorescence intensity, which corresponds to the relative amount of each cytokine secreted. Twenty thousand cells can be assayed per sample simultaneously. Results: The percentage of cytokine-secreting cells varied dramatically by donor (12%-48%), with monofunctional cells making only TNFa, MIP1b, or IL-15 dominating the functional landscape. Polyfunctional cells, capable of making three or more cytokines simultaneously represented only 0.1-7% of the cells in each sample, but there were more of these cells, and each secreted higher levels of cytokines, in individuals who responded to therapy with a CR. Responders also secreted higher levels of IL2, Perforin, IL4, IL12, MIP1a, and TNFb (p values ranging from 0.005 to 0.03), and lower levels of IL9 and IL22 (p=0.0028 and 0.021, respectively), compared to non-responders at diagnosis. Responders lost expression of IL4, IL7, and MIP1a over the course of treatment (pre- vs post-treatment, p=0.01 to 0.05), while non-responders gained cells that expressed IL4, IL5, IL10, IL17, and TNFb from diagnosis to end of treatment (p=0.001 to 0.05). Conclusion: This work represents an important methodological advance in immune monitoring for hematologic malignancies. Single cell cytokine secretion technology measures more cytokines simultaneously than flow cytometry, providing a sample-sparing and comprehensive overview of the functional landscape of immune cells in a patient. Moreover, the technology provides cell-by-cell information about cytokine secretion, unlike Luminex. Our work represents the first application of this technology to HL, which we use to define, for the first time, the particular combinations of 32 cytokines that can be secreted by individual immune cells. We also identify candidate cytokines whose frequency at diagnosis may predict treatment outcome, and reveal changes in cytokine levels over treatment time that may distinguish patients destined to relapse. Immunotherapy may impact PBMC function differently, this may partially explain the high efficacy of this therapy in the relapsed population. The impact of immunotherapy on cytokine levels is currently under investigation by our group in a larger study. Other important questions which are under investigation include the impact of prior chemotherapy on cytokine profiles in relapsed patients, and whether certain cytokines which increase during treatment may be a surrogage for tumor bulk in patients with PD. Cytokines elevated in patients with poor responses to treatment include IL9, IL10, IL17, and IL22, which may present attractive drug targets if validated in our larger ongoing follow-up study. Disclosures Diefenbach: Bristol-Myers Squibb: Consultancy, Research Funding; MEI: Research Funding; Denovo: Research Funding; Genentech: Consultancy, Research Funding; Incyte: Research Funding; LAM Therapeutics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Research Funding; Millenium/Takeda: Research Funding. Hymes:Celgene: Consultancy. Martin:Janssen: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy. Ruan:Celgene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie company: Research Funding; Juno: Consultancy; Kite: Consultancy. Leonard:Miltenyi: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; BeiGene: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Nordic Nanovector: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Gilead: Consultancy; Nordic Nanovector: Consultancy; BeiGene: Consultancy; Merck: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; MorphoSys: Consultancy.

Cognition dysfunction may reflect trait characteristics of bipolarity but cognitive effects of medications have confounded previous comparisons of cognitive function between bipolar II and unipolar depression, which are distinct clinical disorders with some overlaps. Therefore, we examined the executive function (WCST), attention, cognitive speed (TMT-A) and memory (CAVLT, WMS-Visual reproduction) of 20 treatment-naïve bipolar II patients (BPII), 35 treatment-naïve unipolar depressed (UD) patients, and 35 age/sex/education matched healthy controls. The subjects were young (aged 18–35), and had no history of psychosis or substance use, currently depressed and meeting either RDC criteria for Bipolar II Disorder or DSM-IV-TR criteria for Major Depressive Disorder. The patients were moderately depressed (MADRS) and anxious(HAM-A), on average within 3.44 years of illness onset. Sociodemographic data and IQ were similar between the groups. UD patients had significantly slower cognitive speed and cognitive flexibility (WCST perseverative error). BPII depressed patients showed relatively intact cognitive function. Verbal memory (CAVLT List A total) correlated with illness chronicity only in BPII depression, but not UD. In conclusion, young and treatment-naïve BPII depressed patients differed from unipolar depression by a relatively intact cognitive profile and a chronicity-cognitive correlation that suggested a stronger resemblance to Bipolar I Disorder than Unipolar Depression.

Background & aims Older diabetic people are at risk of cognitive decline. Vitamin B12 deficiency in older people is associated with cognitive impairment and Alzheimer's disease. Vitamin B12 deficiency may therefore contribute to cognitive decline in older diabetic people. We therefore performed a randomized placebo-controlled trial of vitamin B12 supplementation to prevent cognitive decline in older diabetic people with mild vitamin B12 deficiency. Methods 271 diabetic non-demented outpatients aged 70 years or older with plasma vitamin B12 150–300 pmol/L in outpatient clinics were randomly assigned to take either methylcobalamin 1000 μg or two similar looking placebo tablets once daily for 27 months. All subjects were followed up at 9 monthly intervals. The primary outcome is cognitive decline as defined by an increase in clinical dementia rating scale (CDR) global score. The secondary outcomes included Neuropsychological Test Battery (NTB) z-scores, serum methymalonic acid (MMA) and homocysteine. Results The subjects in the trial groups were well matched in clinical characteristics, except that active intervention group had more smokers. 46.5% and 74.1% had elevated serum methymalonic acid (≥0.21 μmol/L) and homocysteine (≥13 μmol/L) respectively. 44% of the subjects had CDR score of 0.5 suggesting questionable dementia. At month 9 and 27, serum MMA and homocysteine was significantly reduced in the active treatment group, when compared with placebo group. (P < 0.0001, student t test) At month 27, there was no significant group difference in changes in CDR or NTB z-scores. Exclusion of smokers did not alter the results. Subgroup analysis of high MMSE and serum MMA showed similar results. Conclusion Vitamin B12 supplementation did not prevent cognitive decline in older diabetic patients with borderline vitamin B12 status. Clinical trial registration ClinicalTrials.gov: NCT02457507.

AimTo evaluate whether people with age-related macular degeneration (AMD) and a history of amblyopia have equal severity of AMD in both eyes.MethodsBilling records were used to locate all people with a history of amblyopia and AMD evaluated between 1 January 2003 and 1 June 2015 at a single ophthalmology institute. Two ophthalmic graders blinded to amblyopia status determined the severity of AMD in each eye using fundus photos and a validated grading scale.ResultsA total of 14 people were found to have AMD and a documented history of amblyopia. Average patient age was 77.0 years and average best corrected visual acuity was 20/160 in eyes with a history of amblyopia and 20/40 in fellow eyes without amblyopia. Eyes with a history of amblyopia were found to have a lower AMD severity score (mean lower score: −1.38; paired t-test P=0.019). Of the 11 people with asymmetric disease severity, 10 individuals had worse AMD in the non-amblyopic eye while one person had worse AMD in the amblyopic eye (P=0.0067).ConclusionsOur pilot study suggests that eyes with a history of amblyopia may manifest decreased severity of AMD compared with non-ambylopic eyes in the same patient. Further research is warranted to investigate this clinical observation.

Functional Dyspepsia-Post-prandial Distress Syndrome (FD-PDS) was associated with mood-related increases in resting activity and lowered activation threshold in the somatosensory cortex (SSC), insula and perigenual anterior cingulate cortex(pgACC) in functional imaging studies. The underlying cortical neurochemical changes are unknown. We performed proton Magnetic Resonance Spectroscopy (1H-MRS) on 17 consecutive tertiary clinic-recruited psychotropic-naïve Rome III FD-PDS female and 17 age-sex matched healthy controls. Voxels were placed on bilateral pgACC, left insula and SSC. Water-suppressed spectra were acquired using PRESS with short echo time (TE) (T = 24 ms) to separately quantify glutamate (Glu) and glutamine (Gln). Main outcome measure was regional Glu/Cr + PCr. Severity of depression, anxiety, somatization, and dyspepsia were also assessed. We found significantly increased SSC Glu/Cr + PCr in FD-PDS subjects compared to controls. SSC Glu/Cr + PCr correlated significantly with postprandial distress chronicity, dyspeptic symptoms severity and anxiety. The SSC Glu/Cr + PCr - dyspepsia correlations became insignificant after controlling for anxiety but were independent of depression. Gln/Glu ratio, which indicates glial Glu cycling failure, was unchanged. No between-group differences were noted in other regional metabolite concentrations. Our findings suggested enhanced SSC glutamate transmission in FD-PDS that was linked to post-prandial distress chronicity and severity and anxiety.

Inherent or acquired drug resistance is a major contributor to epithelial ovarian cancer (EOC) mortality. Novel drugs or drug combinations that produce EOC cell death or resensitize drug resistant cells to standard chemotherapy may improve patient treatment. After conducting drug tolerability studies for the multikinase inhibitors dorsomorphin (DM) and it is structural analogue LDN-193189 (LDN), these drugs were tested in a mouse intraperitoneal xenograft model of EOC. DM significantly increased survival, whereas LDN showed a trend toward increased survival. In vitro experiments using cisplatin (CP)-resistant EOC cell lines, A2780-cp or SKOV3, we determined that pretreatment or cotreatment with DM or LDN resensitized cells to the killing effect of CP or carboplatin (CB). DM was capable of blocking EOC cell cycle and migration, whereas LDN produced a less pronounced effect on cell cycle and no effect on migration. Subsequent analyses using primary human EOC cell samples or additional established EOC cells lines showed that DM or LDN induced a dose-dependent autophagic or cell death response, respectively. DM induced a characteristic morphological change with the appearance of numerous LC3B-containing acidic vacuoles and an increase in LC3BII levels. This was coincident with a decrease in cell growth and the altered cell cycle consistent with DM-induced cytostasis. By contrast, LDN produced a caspase 3-independent, reactive oxygen species-dependent cell death. Overall, DM and LDN possess drug characteristics suitable for adjuvant agents used to treat chemotherapy-sensitive and -resistant EOC.

Purpose To present the case of a patient with bilateral macular detachments, venous stasis retinopathy, and retinal hemorrhages as the initial manifestation of multiple myeloma. Methods Case report. Results A 59-year-old woman presented with complaints of photopsias and decreased vision and was found to have bilateral macular detachments, venous stasis retinopathy, and retinal hemorrhages. Fluorescein angiography revealed an angiographically silent fundus in both eyes, indicating no fluorescein leakage was found in the macula. Workup revealed multiple myeloma as the cause of the retinal findings. Conclusion Macular detachment or subretinal fluid, retinal venous dilation or congestion, and retinal hemorrhages may be presenting signs of multiple myeloma.

A single centre retrospective cohort study to evaluate the association between implementation of an acute myocardial infarction clinical pathway and clinical outcomes☆ Ka Lam Wong ⁎, Yiu Tung Anthony Wong , See Yue Arthur Yung , Chor Cheung Frankie Tam , Cheung Chi Simon Lam , Siu Han Jojo Hai , Ki Wan Kelvin Chan , Wing Sze Carmen Chan , Yui Ming Lam , Linda Lam , Hon Wah Raymond Chan , Wai Luen Stephen Lee 1

Background.Little is known about the perception of salty taste in obese patients, especially after bariatric surgery. Therefore, the aim of this study was to analyse possible differences in salt detection thresholds and preferences for foods differing in salt content in obese persons before and after bariatric surgery with weight loss compared to non-obese individuals.Methods.Sodium chloride detection thresholds and liking for cream soups with different salt concentrations were studied with established tests. Moreover, a brief salt food questionnaire was assessed to identify the usage and awareness of salt in food.Results.The results showed similar mean sodium chloride detection thresholds between non-obese and obese participants. After bariatric surgery a non-significant increase in the salt detection threshold was observed in the obese patients (mean ± SD: 0.44 ± 0.24 g NaCl/L before OP vs. 0.64 ± 0.47 g NaCl/L after OP,p= 0.069). Cream soup liking between controls and obese patients were not significantly different. However, significant sex specific differences were detected with the tested women not liking the soups (p< 0.001). Results from the food questionnaire were similar between the groups.Conclusion.No differences between non-obese persons and obese patients were regarding. However, due to highly significant differences in soup liking, sex should be taken into consideration when conducting similar sensory studies.

This paper presents a numerical model for the cyclic/seismic behavior of reinforced concrete (RC) columns retrofitted with fiber-reinforced polymer (FRP) confining jackets. Such a column model has previously been unavailable despite the popularity of FRP jacketing as a seismic retrofit method for RC columns. The proposed numerical column model is based on a recent stress-strain model for FRP-confined concrete subjected to cyclic axial compression and a hysteretic moment-rotation model to account for the effect of strain penetration of the longitudinal steel bars in the column footing (i.e., effect of fixed-end rotations). This column model was implemented into OpenSees (Open System for Earthquake Engineering Simulation) using its fiber-section force-based nonlinear beam-column element. Predictions of the numerical column model for three FRP-jacketed RC columns subjected to either double-curvature bending or single-curvature bending are shown to be in close agreement with the test results.

The WPA, within its 2014‐2017 Action Plan1, established a network of Collaborating Centres to develop innovative initiatives on education, policy and research in mental health. The aim of this network is to create repositories of information as well as offer practical advice and guidance on teaching, policy and research.

We report the interim findings of a randomised controlled trial that assessed the efficacy of a home-based exercise programme in alleviating depression among caregivers of persons with dementia. In this single-blind trial, participants were randomly assigned to receive eight sessions of home-based 12-step sitting Tai Chi or a standard non-exercise social contact control, which spanned over 12 weeks. Clinical response was evaluated with Hamilton Rating Scale for Depression (HAM-D-17), Zarit Carer Burden Interview (ZBI), and cognitive assessment. A total of 138 primary caregivers of persons with dementia have been recruited. Sixty-nine caregivers were randomised to the Tai Chi group whereas 69 to the control group. To date, 86 caregivers have completed the study. Using linear mixed models, HAM-D-17 scores were found to decline significantly among Tai Chi participants at both week 6 and 12 (p

Aims To evaluate the effect of switching to bevacizumab or ranibizumab after developing tachyphylaxis during anti-vascular endothelial growth factor (VEGF) therapy for choroidal neovascularisation (CNV). Methods The authors reviewed the records of all patients who received both ranibizumab and bevacizumab for treatment of CNV to identify those who developed tachyphylaxis, defined as optical coherence tomography evidence of initial decreased exudation followed by lack of further reduction or an increase in exudation. Signs of exudation included subreitnal fluid (SRF), pigment epithelial detachment (PED) and/or cystoid macular oedema (CMO). Results 26 eyes were included. 10 were initially treated with bevacizumab and then changed to ranibizumab for persistent SRF, PED and/or CMO. Of these, seven had occult CNV and three had predominantly classic CNV. One eye in the occult CNV group did not respond after being switched to ranibizumab. Six eyes had a positive therapeutic response, after one injection in four eyes, and after two or three injections in one eye each. In the classic group, two responded to ranibizumab and one did not. Sixteen eyes were initially treated with ranibizumab before changing to bevacizumab. Of these, 15 had occult CNV and 1 was predominantly classic. Three of the 16 eyes failed to respond to bevacizumab; 6 improved after one injection and 5 after two injections. Conclusions Patients with CNV who develop tachyphylaxis to ranibizumab or bevacizumab may respond to another anti-VEGF drug. The majority of cases (81%) in this series demonstrated at least some response after switching therapies.

Summary Introduction Whether homocysteine lowering by B vitamins can reduce cognitive decline in Alzheimer disease and vascular dementia patients is unclear. Methods and materials 140 subjects with mild to moderate Alzheimer disease or vascular dementia were randomly assigned to take 1 mg of methylcobalamin and 5 mg of folic acid, or placebo once daily for 24 months. The primary outcome was Mattis dementia rating scale (MDRS). Secondary outcomes were MDRS domain scores, neuropsychiatric inventory and Cornell scale for depression in dementia. Measurements were performed at baseline and every six months during the study. Fasting plasma tHCY concentrations were measured at baseline and month 18. Results Trial groups were well matched in baseline characteristics. The average plasma tHCY concentration of subjects was 14.1 ± 3.8 μmol/L. 80% of subjects completed the trial. The supplement group had average plasma tHCY reduced to 9.3 ± 2.7 μmol/L. There was no significant group difference in changes in any of the neuropsychological scores, but among those with elevated plasma tHCY (>13 μmol/L), the decline in MDRS (construction domain) was significantly smaller in the supplement group (median 0 versus 2 points in placebo group, P = 0.003). Conclusion Homocysteine lowering in dementia patients did not significantly reduce global cognitive decline.