Systematic pharmacological analysis of agonistic and antagonistic fibroblast growth factor receptor 1 MAbs reveals a similar unique mode of action.

Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase that plays a major role in developmental processes and metabolism. The dysregulation of FGFR1 through genetic aberrations leads to skeletal and metabolic diseases as well as cancer. For this reason, FGFR1 is a promising therapeutic target, yet a very challenging one due to potential on-target toxicity. More puzzling is that both agonistic and antagonistic FGFR1 antibodies are reported to exhibit similar toxicity profiles in vivo, namely weight loss. In this study, we aimed to assess and compare the mechanism of action of these molecules to better understand this apparent contradiction. By systematically comparing the binding of these antibodies and the activation or the inhibition of the major FGFR1 signaling events, we demonstrated that the molecules displayed similar properties and can behave either as an agonist or antagonist depending on the presence or the absence of the endogenous ligand. We further demonstrated that these findings translated in xenografts mice models. In addition, using time-resolved FRET and mass spectrometry analysis, we showed a functionally distinct FGFR1 active conformation in the presence of an antibody that preferentially activates the FGFR substrate 2 (FRS2)-dependent signaling pathway, demonstrating that modulating the geometry of a FGFR1 dimer can effectively change the signaling outputs and ultimately the activity of the molecule in preclinical studies. Altogether, our results highlighted how bivalent antibodies can exhibit both agonistic and antagonistic activities and have implications for targeting other receptor tyrosine kinases with antibodies.

A case report of multicentric carpotarsal osteolysis syndrome: Depiction of a debilitating disease course.

Multicentric carpotarsal osteolysis syndrome (MCTO) is a rare skeletal disorder characterized by progressive osteolysis involving the carpal and tarsal bones, and often associated with nephropathy. It is caused by heterozygous mutation in the MAF bZIP transcription factor B (MAFB) gene. Heterogeneous clinical manifestation and wide spectrum of disease severity have been observed in patients with MCTO. Here, we report a case of a male patient who presented with kidney failure in childhood with progressive disabling skeletal deformity. He was diagnosed with MCTO at 31-years-old, where a de novo pathogenic heterozygous variant in NM_005461.5:c.212C>A: p.(Pro71His) of the MAFB gene was identified. While there has been little data on the long-term prognosis and life expectancy of this disease, this case report sheds light on the debilitating disease course with multiple significant morbidities of a patient with MCTO throughout his lifetime of 33 years.

Following the COMPASS: Antithrombotic Prescription Trends in Patients with Symptomatic Peripheral Arterial Disease following Revascularization.

BACKGROUND: The Vascular Outcomes Study of aspirin (ASA) Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for peripheral artery disease (PAD) trial demonstrated the superiority of ASA and low-dose rivaroxaban (Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial dosing) compared with ASA alone in reducing major adverse cardiovascular events and major adverse limb events. We studied the COMPASS discharge prescription patterns in patients with symptomatic PAD who have undergone revascularization in our institution, since the time of publication of the Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD trial. METHODS: All patients included in this study had documented lower-extremity atherosclerotic PAD and were eligible for COMPASS dosing. Revascularization strategies included endovascular (n = 299), suprainguinal bypass (n = 18), and infrainguinal bypass (n = 36). RESULTS: COMPASS prescription patterns for the composite of endovascular and surgical strategies demonstrated a consistently low rate over time, without a trend toward increasing use. COMPASS dosing was prescribed as often as antiplatelet monotherapy (33.4% COMPASS vs. 34.6% antiplatelet monotherapy). This low COMPASS prescription rate was driven by significantly lower COMPASS prescriptions following endovascular therapy compared to surgical bypass (28.8% endovascular vs. 59.3% surgical bypass). COMPASS prescriptions following surgical bypass showed better trends; half of suprainguinal bypass patients (50.0%) and two-thirds of infrainguinal bypass patients (63.9%) were discharged on COMPASS. Despite patients with chronic limb-threatening ischemia (CLTI) representing a high-risk limb presentation, COMPASS prescriptions were low (29.8%), as opposed to patients without CLTI, and did not show a trend toward increasing use. In patients who underwent reinterventions throughout the observation period, there was a low conversion rate from ASA alone to COMPASS (3/26, 11.5%). CONCLUSIONS: In this observational study, one-third of patients were undertreated by prescription of antiplatelet monotherapy, indicating that there is significant room for medical optimization. This is especially true of patients undergoing endovascular treatment, including the high-risk subgroup of patients with CLTI. We highlight the importance of dual pathway antithrombotic therapy in patients eligible for COMPASS dosing to optimize best current evidence medical therapy.

Clinical outcomes and complications of laparoscopic sacrocolpopexy with versus without concomitant hysterectomy for pelvic organ prolapse in Hong Kong Chinese patients after median follow-up of 7 years.

INTRODUCTION AND HYPOTHESIS: This retrospective cohort study is aimed at comparing outcomes and complications of laparoscopic sacrocolpopexy (LSC) with or without concomitant hysterectomy in the Hong Kong Chinese population. METHODS: Women with stage II or above uterine or apical vault prolapse who underwent LSC with or without concomitant hysterectomy in a regional referral unit from 2007 to 2019 were included. The primary objectives were to compare the anatomical outcomes by pelvic organ prolapse quantification system (POP-Q) and recurrence of apical vault prolapse (≥stage II). The secondary objective was to compare the functional outcomes and complications. Anatomical recurrence and incidence of mesh exposure were analyzed using the Kaplan-Meier method. Cox proportional hazard regression was performed to identify risk factors of anatomical recurrence. RESULTS: Seventy-six women were included for analysis. The recurrence rate of apical vault prolapse was 3.9% after a median follow-up time of 83 months (20-190 months). A significant reduction of POP-Q scores of three compartments in both groups of women were demonstrated (p<0.001). There was no difference between the two groups in terms of functional outcomes and complications. 6.6% of women developed mesh exposure. The time to recurrence of apical vault prolapse was shorter in women who had LSC with prior hysterectomy (p =0.019). No risk factors were identified for recurrence of apical vault prolapse. CONCLUSIONS: Laparoscopic sacrocolpopexy with concomitant hysterectomy is comparable with LSC alone. The recurrence and complication rates are low. We suggest that LSC with concomitant hysterectomy might be offered to women with pelvic organ prolapse, with women's preference taken into account.

Kaposiform haemangioendothelioma of the spine associated with fixed hyperlordotic deformity and Kasabach-Merritt Syndrome: a case report and literature review.

Kaposiform haemangioendothelioma (KHE) is a rare childhood disease classified by the International Society for the Study of Vascular Anomalies (ISSVA) as a locally aggressive vascular tumor. It has been reported to affect any site, with a predilection for the extremities and trunk. Although it typically manifests as an enlarging cutaneous or soft tissue lesion, less than 10% of cases have no skin involvement, with the retroperitoneum being the most frequently involved extracutaneous site. Approximately twenty cases of KHE with bony involvement have been reported in the literature to date, with only five of those cases involving the spine specifically.We present a, rare case of KHE who presented with progressive fixed hyperlordotic deformity, multiple non-specific spinal lesions, and abnormal blood tests, posing a clinical and radiological diagnostic challenge. Additionally, we conducted a thorough review of the literature to compare and contrast the various multimodality imaging manifestations of KHE involving the spine.

Evaluation of Digital Drawing Tests and Paper-and-Pencil Drawing Tests for the Screening of Mild Cognitive Impairment and Dementia: A Systematic Review and Meta-analysis of Diagnostic Studies.

Digital drawing tests have been proposed for cognitive screening over the past decade. However, the diagnostic performance is still to clarify. The objective of this study was to evaluate the diagnostic performance among different types of digital and paper-and-pencil drawing tests in the screening of mild cognitive impairment (MCI) and dementia. Diagnostic studies evaluating digital or paper-and-pencil drawing tests for the screening of MCI or dementia were identified from OVID databases, included Embase, MEDLINE, CINAHL, and PsycINFO. Studies evaluated any type of drawing tests for the screening of MCI or dementia and compared with healthy controls. This study was performed according to PRISMA and the guidelines proposed by the Cochrane Diagnostic Test Accuracy Working Group. A bivariate random-effects model was used to compare the diagnostic performance of these drawing tests and presented with a summary receiver-operating characteristic curve. The primary outcome was the diagnostic performance of clock drawing test (CDT). Other types of drawing tests were the secondary outcomes. A total of 90 studies with 22,567 participants were included. In the screening of MCI, the pooled sensitivity and specificity of the digital CDT was 0.86 (95% CI = 0.75 to 0.92) and 0.92 (95% CI = 0.69 to 0.98), respectively. For the paper-and-pencil CDT, the pooled sensitivity and specificity of brief scoring method was 0.63 (95% CI = 0.49 to 0.75) and 0.77 (95% CI = 0.68 to 0.84), and detailed scoring method was 0.63 (95% CI = 0.56 to 0.71) and 0.72 (95% CI = 0.65 to 0.78). In the screening of dementia, the pooled sensitivity and specificity of the digital CDT was 0.83 (95% CI = 0.72 to 0.90) and 0.87 (95% CI = 0.79 to 0.92). The performances of the digital and paper-and-pencil pentagon drawing tests were comparable in the screening of dementia. The digital CDT demonstrated better diagnostic performance than paper-and-pencil CDT for MCI. Other types of digital drawing tests showed comparable performance with paper-and-pencil formats. Therefore, digital drawing tests can be used as an alternative tool for the screening of MCI and dementia.

Generation of a Porcine Antibody Fab Fragment Using Protein Engineering to Facilitate the Evaluation of Ocular Sustained Delivery Technology.

Treatment of age-related macular degeneration (AMD) with anti-vascular endothelial growth factor (VEGF) biologic agents has been shown to restore and maintain visual acuity for many patients afflicted with wet AMD. These agents are usually administered via intravitreal injection at a dosing interval of 4-8 weeks. Employment of long-acting delivery (LAD) technologies could improve the therapeutic outcome, ensure timely treatment, and reduce burden on patients, caregivers, and the health care system. Development of LAD approaches requires thorough testing in pre-clinical species; however, therapeutic proteins of human origin may not be well tolerated during testing in non-human species due to immunogenicity. Here, we have engineered a surrogate porcine antibody Fab fragment (pigG6.31) from a human antibody for testing ocular LAD technologies in a porcine model. The engineered Fab retains the VEGF-A-binding and inhibition properties of the parental human Fab and has stability properties suitable for LAD evaluation. Upon intravitreal injection in minipigs, pigG6.31 showed first-order clearance from the ocular compartments with vitreal elimination rates consistent with other molecules of this size. Application of the surrogate molecule in an in vivo evaluation in minipigs of a prototype of the port delivery (PD) platform indicated continuous ocular delivery from the implant, with release kinetics consistent with both the results from in vitro release studies and the efficacy observed in human clinical studies of the PD system with ranibizumab (PDS). Anti-drug antibodies in the serum against pigG6.31 were not detected over exposure durations up to 16 weeks, suggesting that this molecule has low porcine immunogenicity.

Comparing drawing under instructions with image copying for mild cognitive impairment (MCI) or dementia screening: a meta-analysis of 92 diagnostic studies.

OBJECTIVES: Drawing is a major component of cognitive screening for dementia. It can be performed without language restriction. Drawing pictures under instructions and copying images are different screening approaches. The objective of this study was to compare the diagnostic performance between drawing under instructions and image copying for MCI and dementia screening. METHOD: A literature search was carried out in the OVID databases with keywords related to drawing for cognitive screening. Study quality and risk of bias were assessed by QUADAS-2. The level of diagnostic accuracy across different drawing tests was pooled by bivariate analysis in a random effects model. The area under the hierarchical summary receiver-operating characteristic curve (AUC) was constructed to summarize the diagnostic performance. RESULTS: Ninety-two studies with sample size of 22,085 were included. The pooled results for drawing under instructions showed a sensitivity of 79% (95% CI: 76 - 83%) and a specificity of 80% (95% CI: 77 - 83%) with AUC of 0.87 (95% CI: 0.83 - 0.89). The pooled results for image copying showed a sensitivity of 71% (95% CI: 62 - 79%) and a specificity of 83% (95% CI: 72 - 90%) with AUC of 0.83 (95% CI: 0.80 - 0.86). Clock-drawing test was the screening test used in the majority of studies. CONCLUSION: Drawing under instructions showed a similar diagnostic performance when compared with image copying for cognitive screening and the administration of image copying is relatively simpler. Self-screening for dementia is feasible to be done at home in the near future.

Liver complications of haemoglobin H disease in adults.

Haemoglobin H (HbH) disease is a type of non-transfusion-dependent thalassaemia. This cross-sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24-79) years, male 34%, non-deletional HbH disease 24%]. Patients underwent 'observed' T2-weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate-to-severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non-deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52-17·50; P = 0·047] and moderate-to-severe liver iron overload (OR 3·47, 95% CI 1·01-12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.

Development of an ultra-sensitive human IL-33 biomarker assay for age-related macular degeneration and asthma drug development.

BACKGROUND: Over the past decade, human Interleukin 33 (hIL-33) has emerged as a key contributor to the pathogenesis of numerous inflammatory diseases. Despite the existence of several commercial hIL-33 assays spanning multiple platform technologies, their ability to provide accurate hIL-33 concentration measurements and to differentiate between active (reduced) and inactive (oxidized) hIL-33 in various matrices remains uncertain. This is especially true for lower sample volumes, matrices with low hIL-33 concentrations, and matrices with elevated levels of soluble Interleukin 1 Receptor-Like 1 (sST2), an inactive form of ST2 that competes with membrane bound ST2 for hIL-33 binding. RESULTS: We tested the performance of several commercially available hIL-33 detection assays in various human matrices and found that most of these assays lacked the sensitivity to accurately detect reduced hIL-33 at biologically relevant levels (sub-to-low pg/mL), especially in the presence of human sST2 (hsST2), and/or lacked sufficient target specificity. To address this, we developed and validated a sensitive and specific enzyme-linked immunosorbent assay (ELISA) capable of detecting reduced and total hIL-33 levels even in the presence of high concentrations of sST2. By incorporating the immuno-polymerase chain reaction (iPCR) platform, we further increased the sensitivity of this assay for the reduced form of hIL-33 by ~ 52-fold. Using this hIL-33 iPCR assay, we detected hIL-33 in postmortem human vitreous humor (VH) samples from donors with age-related macular degeneration (AMD) and found significantly increased hIL-33 levels when compared to control individuals. No statistically significant difference was observed in aqueous humor (AH) from AMD donors nor in plasma and nasosorption fluid (NF) from asthma patients compared to control individuals. CONCLUSIONS: Unlike existing commercial hIL-33 assays, our hIL-33 bioassays are highly sensitive and specific and can accurately quantify hIL-33 in various human clinical matrices, including those with high levels of hsST2. Our results provide a proof of concept of the utility of these assays in clinical trials targeting the hIL-33/hST2 pathway.

Supporting Informal Caregivers of People With Dementia in Cost-Effective Ways: A Systematic Review and Meta-Analysis.

OBJECTIVES: Caring for persons with dementia is a heavy burden for informal caregivers. This study aimed to appraise the economic evidence of interventions supporting informal caregivers of people with dementia. METHODS: Literature was searched, and trial-based studies evaluating the costs and effects of interventions supporting informal caregivers of people with dementia were included. Cost data were analyzed from both healthcare and societal perspectives. Random-effects models were used to synthesize cost and effect data, based on mean differences (MDs) or standardized MDs. RESULTS: Of 33 eligible studies identified from 48 588 records, 14 (42.4%) showed net savings in total cost regardless of analytical perspectives. Among 22 studies included in meta-analyses, caregiver-focused psychosocial interventions showed improvements in caregivers' psychological health (n = 4; standardized MD 0.240; 95% confidence interval 0.094-0.387); nevertheless, the increases in societal cost were significant (n = 5; MD 3144; 95% confidence interval 922-5366). Psychological intervention and behavioral management engaging patient-caregiver dyads showed positive effects on caregivers' subjective burden, also with increases in total cost. Subgroup analyses indicated that the inclusion of different intervention components, the caregiver characteristics, and the follow-up periods could affect the costs and effects of interventions supporting informal caregivers. CONCLUSIONS: Psychosocial interventions directed at informal caregivers and dyad-based psychological and behavioral interventions are effective but also expensive. The use of these interventions depends on the society's willingness to pay. More comprehensive economic evidence of interventions supporting informal caregivers is required, and the design of intervention should focus more on different intervention components, characteristics of patients and caregivers, and healthcare systems.

Utility of contrast-enhanced ultrasound for solid mass surveillance and characterization in children with tuberous sclerosis complex: an initial experience.

BACKGROUND: Patients with tuberous sclerosis complex (TSC) can develop solid kidney masses from childhood. Imaging surveillance is done to detect renal cell carcinoma (RCC) and angiomyolipomas (AML), including AMLs at risk for hemorrhage. Intravenous contrast-enhanced ultrasound (CEUS) may be useful for screening as ultrasound is well tolerated by children and ultrasound contrast agents (UCA) are not nephrotoxic. METHODS: Retrospective review of kidney CEUS exams of pediatric TSC patients. Qualitative CEUS analysis by consensus of 3 radiologists assessed rate, intensity, and pattern of lesion enhancement. Quantitative CEUS analysis was performed using Vuebox®. Where available, abdominal MRI was analyzed qualitatively for the same features and quantitatively by in-house-developed software. Time-intensity curves were generated from both CEUS and MRI where possible. Appearance of lesions were compared between CEUS and MRI and histology where available. RESULTS: Nine masses in 5 patients included one histologically proven RCC and 8 AMLs diagnosed by imaging. Quantitative CEUS of RCC showed malignant features including increased peak enhancement 162%, rapid wash-in rate 162%, and elevated washout rate 156% compared to normal kidney tissue; versus AML which was 68%, 105%, and 125%, respectively. All masses were hypoenhancing on MRI compared to normal kidney tissue; MR dynamic contrast study offered no distinction between RCC and AML. The only MRI feature differentiating RCC from AML was absence of fat. CONCLUSION: Temporal resolution afforded by CEUS was useful to distinguish malignant from benign kidney masses. CEUS may prove useful for screening, characterizing, and follow-up of kidney lesions in pediatric TSC patients.

Diagnostic accuracy of dementia screening tools in the Chinese population: a systematic review and meta-analysis of 167 diagnostic studies.

BACKGROUND: The rate of undetected dementia is high in China. However, the performance of dementia screening tools may differ in the Chinese population due to the lower education level and cultural diversity. This study aimed to evaluate the diagnostic accuracy of dementia screening tools in the Chinese population. METHODS: Eleven electronic databases were searched for studies evaluating the diagnostic accuracy of dementia screening tools in older Chinese adults. The overall diagnostic accuracy was estimated using bivariate random-effects models, and the area under the summary receiver operating characteristic curve was presented. RESULTS: One hundred sixty-seven studies including 81 screening tools were identified. Only 134 studies qualified for the meta-analysis. The Mini-Mental State Examination (MMSE) was the most commonly studied tool, with a combined sensitivity (SENS) and specificity (SPEC) of 0.87 (95%CI 0.85-0.90) and 0.89 (95%CI 0.86-0.91), respectively. The Addenbrooke's Cognitive Examination-Revised (ACE-R) (SENS: 0.96, 95%CI 0.89-0.99; SPEC: 0.96, 95%CI 0.89-0.98) and Montreal Cognitive Assessment (MoCA) (SENS: 0.93, 95%CI 0.88-0.96; SPEC: 0.90, 95%CI 0.86-0.93) showed the highest performance. The General Practitioner Assessment of Cognition (GPCOG), Hasegawa's Dementia Scale and Cognitive Abilities Screening Instrument had performances comparable to that of the MMSE. The cut-off scores ranged widely across studies, especially for the MMSE (range: 15-27) and MoCA (range: 14-26). CONCLUSIONS: A number of dementia screening tools were validated in the Chinese population after cultural and linguistical adaptations. The ACE-R and MoCA had the best diagnostic accuracy, whereas the GPCOG, with an administration time < 5 minutes, could be considered as a rapid screening tool.

Correction: Electronic Cognitive Screen Technology for Screening Older Adults With Dementia and Mild Cognitive Impairment in a Community Setting: Development and Validation Study.

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Half-life extension of peptidic APJ agonists by N-terminal lipid conjugation.

Agonism of the endothelial receptor APJ (putative receptor protein related to AT1; AT1: angiotensin II receptor type 1) has the potential to ameliorate congestive heart failure by increasing cardiac output without inducing hypertrophy. Although the endogenous agonist, pyr-apelin-13 (1), has shown beneficial APJ-mediated inotropic effects in rats and humans, such effects are short-lived given its extremely short half-life. Here, we report the conjugation of 1 to a fatty acid, providing a lipidated peptide (2) with increased stability that retains inotropic activity in an anesthetized rat myocardial infarction (MI) model. We also report the preparation of a library of 15-mer APJ agonist peptide-lipid conjugates, including adipoyl-γGlu-OEG-OEG-hArg-r-Q-hArg-P-r-NMeLeuSHK-G-Oic-pIPhe-P-DBip-OH (17), a potent APJ agonist with high plasma protein binding and a half-life suitable for once-daily subcutaneous dosing in rats. A correlation between subcutaneous absorption rate and lipid length/type of these conjugates is also reported.

Effects of virtual reality on moods in community older adults. A multicenter randomized controlled trial.

INTRODUCTION: Virtual reality (VR) technology is a potential method to use in cognitive intervention, but the use of VR in cognitive stimulation intervention for older adults has not been investigated. Therefore, the aim of this study was to investigate the mood change of older adults after participating in the VR cognitive stimulation activity. METHODS: This is a multicenter randomized controlled, cross-over trial. The intervention was a VR cognitive stimulation activity, and the control was a paper-and-pencil activity. The participants were older adults with age over 60 and recruited in the elderly community centers. The Positive and Negative Affect Score (PANAS) was used to measure mood change. Mean difference (MD) with 95% confidence interval (95% CI) was calculated. The Simulator sickness questionnaire was used to measure adverse events. RESULTS: A total of 236 participants from 19 community centers were recruited. After the VR activity, the participants had a significant increase in total PANAS positive affect score (MD = 2.09, 95% CI = 0.69 to 3.49), and a significant reduction in total negative affect score (MD = -1.99, 95% CI = -2.55 to -1.43). The reduction in negative affect score was significantly larger in VR activity than paper-and-pencil activity (MD = -0.48, 95% CI = -0.98 to 0.00). Besides, only three participants reported severe advance events after VR activity. CONCLUSIONS: The use of VR technology is well accepted by older adults. Therefore, the use of VR technology through smartphone and a mobile app can be a potential method for future cognitive training interventions.

Cognitive training interventions and depression in mild cognitive impairment and dementia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Depression is common in people with cognitive impairment but the effect of cognitive training in the reduction of depression is still uncertain. AIMS: The purpose of this paper is to evaluate the effect of cognitive training interventions in the reduction of depression rating scale score in people with cognitive impairment. METHODS: Literature searches were conducted via OVID databases. Randomized controlled trials (RCTs) evaluated the effect of cognitive training interventions for the reduction of depression rating scale score in people with mild cognitive impairment (MCI) or dementia were included. Mean difference (MD) with 95% confidence interval (CI) was used to combine the results of Geriatric Depression Scale (GDS). Standardized mean difference (SMD) was used to combine the results of different depression rating scales. Subgroup analyses were conducted according to the types of cognitive training and severity of cognitive impairment, i.e. MCI and dementia. RESULTS: A total of 2551 people with MCI or dementia were extracted from 36 RCTs. The baseline mean score of GDS-15 was 4.83. Participants received cognitive training interventions had a significant decrease in depression rating scale score than the control group (MD of GDS-15 = -1.30, 95% CI = -2.14--0.47; and SMD of eight depression scales was -0.54 (95% CI = -0.77--0.31). In subgroup analyses, the effect size of computerized cognitive training and cognitive stimulation therapy were medium-to-large and statistically significant in the reduction of depression rating scale score. CONCLUSIONS: Cognitive training interventions show to be a potential treatment to ameliorate depression in people with cognitive impairment.

Vascular Quality of Care Assessment: Clinicians' Adherence to Lipid-Lowering Therapy for Patients with Atherosclerotic Cardiovascular Disease.

BACKGROUND: Lipid-lowering medication can considerably lessen the risk for cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD). Despite well-publicized guidelines and the accessibility of effective therapies, many patients do not attain their lipid goals and remain at high cardiovascular risk. Guidelines recommend statins as first-line therapy to reduce cardiovascular morbidity and mortality in ASCVD. We aimed to analyze admission lipid levels in a broad contemporary population of patients with ASCVD attending a vascular clinic or admitted to an inpatient vascular unit. METHODS: Patients with known ASCVD, current cholesterol levels, and lipid-lowering medications were documented and compared with published current Canadian Cardiovascular Society Guidelines recommendations for achieving <2.0 mmol/L or >50% reduction in low-density lipoprotein cholesterol (LDL-C). Cholesterol levels (current and previous), demographic characteristics, cardiovascular risk factors, and medical therapy were assessed from available patient records. RESULTS: Two hundred eight adult patients were identified. The mean age of the patients was 72 (±10) years, and 76% were men. About half had peripheral arterial disease (n = 118, 56.7%), one-third had coronary artery disease (n = 78, 37.5%), and one-third had diabetes (n = 76, 36.5%). Most were hypertensive (n = 140, 67.3%) and half gave a history of dyslipidemia (n = 103, 49.5%). Most patients (n = 183, 88%) were taking a statin and the majority at a moderate-intensity dose (n = 79, 43.2%) or high-intensity dose (n = 101, 55.2%). However, 32.7% of patients (n = 68) did not reach target of LDL-C level of <2.0 mmol/L or had ≤50% reduction from the baseline level. Of the patients who did not reach goals, 7 (10.3%) did not fill their statin prescriptions in the last 3 months. Only 26 patients (12.5%) were also on ezetimibe, a guideline-recommended second-line therapy if targets are not reached with maximally tolerated statin therapy. One patient, who was able to reach target LDL-C, was on evolocumab monotherapy, a PCSK9 inhibitor, a contemporary nonstatin therapy that could be considered in ASCVD in those not at LDL-C goal. Of the 16 patients who were not prescribed any lipid-lowering therapy and did not reach target, 8 (50%) did not have any identified or documented reasons. Of the remaining 8 patients, 7 (87.5%) reported intolerance or side effects to statins only, and could benefit from nonstatin LDL-lowering therapy. CONCLUSIONS: In this observational study, we established suboptimal adherence to guideline recommendations for statin therapy and hesitancy to use nonstatin LDL-lowering agents in high-risk patients with ASCVD. These treatment gaps have an enormous effect on achieving improved cardiovascular clinical outcomes and must be tackled.

Electronic Cognitive Screen Technology for Screening Older Adults With Dementia and Mild Cognitive Impairment in a Community Setting: Development and Validation Study.

BACKGROUND: A digital cognitive test can be a useful and quick tool for the screening of cognitive impairment. Previous studies have shown that the diagnostic performance of digital cognitive tests is comparable with that of conventional paper-and-pencil tests. However, the use of commercially available digital cognitive tests is not common in Hong Kong, which may be due to the high cost of the tests and the language barrier. Thus, we developed a brief and user-friendly digital cognitive test called the Electronic Cognitive Screen (EC-Screen) for the detection of mild cognitive impairment (MCI) and dementia of older adults. OBJECTIVE: The aim of this study was to evaluate the performance of the EC-Screen for the detection of MCI and dementia in older adults. METHODS: The EC-Screen is a brief digital cognitive test that has been adapted from the Rapid Cognitive Screen test. The EC-Screen uses a cloud-based platform and runs on a tablet. Participants with MCI, dementia, and cognitively healthy controls were recruited from research clinics and the community. The outcomes were the performance of the EC-Screen in distinguishing participants with MCI and dementia from controls, and in distinguishing participants with dementia from those with MCI and controls. The cohort was randomly split into derivation and validation cohorts based on the participants' disease group. In the derivation cohort, the regression-derived score of the EC-Screen was calculated using binomial logistic regression. Two predictive models were produced. The first model was used to distinguish participants with MCI and dementia from controls, and the second model was used to distinguish participants with dementia from those with MCI and controls. Receiver operating characteristic curves were constructed and the areas under the curves (AUCs) were calculated. The performances of the two predictive models were tested using the validation cohorts. The relationship between the EC-Screen and paper-and-pencil Montreal Cognitive Assessment-Hong Kong version (HK-MoCA) was evaluated by the Pearson correlation coefficient. RESULTS: A total of 126 controls, 54 participants with MCI, and 63 participants with dementia were included in the study. In differentiating participants with MCI and dementia from controls, the AUC of the EC-Screen in the derivation and validation cohorts was 0.87 and 0.84, respectively. The optimal sensitivity and specificity in the derivation cohorts were 0.81 and 0.80, respectively. In differentiating participants with dementia from those with MCI and controls, the AUC of the derivation and validation cohorts was 0.90 and 0.88, respectively. The optimal sensitivity and specificity in the derivation cohort were 0.83 and 0.83, respectively. There was a significant correlation between the EC-Screen and HK-MoCA (r=-0.67, P<.001). CONCLUSIONS: The EC-Screen is suggested to be a promising tool for the detection of MCI and dementia. This test can be self-administered or assisted by a nonprofessional staff or family member. Therefore, the EC-Screen can be a useful tool for case finding in primary health care and community settings.

Medical student support for vulnerable patients during COVID-19 - a convergent mixed-methods study.

BACKGROUND: The coronavirus pandemic has exerted significant impacts on primary care, causing rapid digital transformation, exacerbating social isolation, and disrupting medical student and General Practice [GP] trainee education. Here we report on a medical student telephone initiative set-up by a final year GP trainee (the equivalent of a family medicine resident), which aimed to support patients at high risk and vulnerable to the Coronavirus Disease of 2019 [Covid-19]. In addition, it was hoped the project would mitigate a digital divide, enable proactive anticipatory planning, and provide an active learning environment to compensate for the pandemic's impact on medical education. METHODS: Thirty-three medical students conducted daily telephone conversations with high risk and vulnerable patients as specified by the initial NHSE published lists. They confirmed public health messages, offered details for voluntary support groups, established need for medication delivery, explored levels of digital connectivity, and prompted discussions around end-of-life choices. Students had access to online reflective resources and daily remote debriefing sessions with the GP trainee. A convergent mixed-methods evaluation was subsequently undertaken, using quantitative process and descriptive data and individual qualitative interviews were conducted according to a maximal variation sampling strategy with students, General Practitioners [GPs], and the GP trainee. Inductive thematic analysis was then applied with cross-validation, respondent validation, and rich evidential illustration aiding integrity. RESULTS: Ninety-seven 'high risk' and 781 'vulnerable' calls were made. Individuals were generally aware of public heath information, but some struggled to interpret and apply it within their own lives. Therefore respondents felt students provided additional practical and psychological benefits, particularly with regard to strengthening the links with the community voluntary groups. The project was widely liked by students who reported high levels of skill development and widened awareness, particularly valuing the active learning environment and reflective feedback sessions. CONCLUSION: This study demonstrates utilization of medical students as wider assets within the primary health care team, with an initiative that enables support for vulnerable patients whilst promoting active medical education. Ongoing integration of students within 'normal' primary health care roles, such as chronic disease or mental health reviews, could provide similar opportunities for supported active and reflective learning.