Antidepressant Use in the Elderly Is Associated With an Increased Risk of Dementia.

A retrospective cohort study was conducted including 3688 patients age 60 years or older without dementia enrolled in a depression screening study in primary care clinics. Information on antidepressant use and incident dementia during follow-up was retrieved from electronic medical records. The Cox proportional hazard models were used to compare the risk for incident dementia among 5 participant groups: selective serotonin re-uptake inhibitors (SSRI) only, non-SSRI only (non-SSRI), mixed group of SSRI and non-SSRI, not on antidepressants but depressed, and not on antidepressants and not depressed. SSRI and non-SSRI users had significantly higher dementia risk than the nondepressed nonusers (hazard ratio [HR]=1.83, P=0.0025 for SSRI users and HR=1.50, P=0.004 for non-SSRI users). In addition, SSRIs users had significantly higher dementia risk than non-users with severe depression (HR=2.26, P=0.0005). Future research is needed to confirm our results in other populations and to explore potential mechanism underlying the observed association.

Morphine-induced fever: a case report and review of the literature.

BACKGROUND: Morphine is widely used to treat moderate-to-severe cancer pain. However, it causes various adverse effects, with morphine-induced fever being an extremely rare and poorly understood symptom. CASE PRESENTATION: We report the case of a 58-year-old Chinese woman with advanced lung cancer. Due to the ineffectiveness of tramadol for pain relief, her treatment regimen was switched to morphine. Following the change, she developed nausea, vomiting, dizziness, and elevated body temperature. A similar episode occurred subsequently. After a drug review, the pharmacist speculated that morphine was the most likely causative agent. Upon discontinuation of morphine, her body temperature returned to baseline levels. CONCLUSIONS: This case highlights the need for healthcare providers to consider morphine as a potential cause of unexplained fever in patients. The fever may be caused by a hypersensitive response, as there was a significant increase in eosinophils during the fever episodes.

The Discovery of GIT1/ß-Pix Inhibitors: Virtual Screening and Biological Evaluation of New Small-molecule Compounds with Anti-invasion Effect in Gastrointestinal Neoplasms.

Background and Objective: GIT1 (G-protein-coupled receptor kinase interacting protein-1) has been found to be highly related with cancer cell invasion and metastasis in many cancer types. ß-Pix (p21-activated kinase-interacting exchange factor) is one of the proteins that interact with GIT1. Targeting GIT1/ß-Pix complex might be a potential therapeutic strategy for interfering cancer metastasis. However, at present, no well-recognized small-molecule inhibitor targeting GIT1/ß-Pix is available. Thus, we aim to discover novel GIT1/ß-Pix inhibitors with simple scaffold, high activity and low toxicity to develop new therapeutic strategies to restrain cancer metastasis. Methods: GIT1/ß-Pix inhibitors were identified from ChemBridge by virtual screening. Briefly, the modeling of GIT1 was performed and the establishment of GIT1/ß-Pix binding pocket enabled the virtual screening to identify the inhibitor. In addition, direct binding of the candidate molecules to GIT1 was detected by biolayer interferometry (BLI) to discover the hit compound. Furthermore, the inhibitory effect on invasion of stomach and colon cancer cells in vitro was carried out by the transwell assay and detection of epithelial-mesenchymal transition (EMT)-related proteins. Finally, the binding mode of hit compound to GIT1 was estimated by molecular dynamics simulation to analyze the key amino residues to guide further optimization. Results: We selected the top 50 compounds from the ChemBridge library by virtual screening. Then, by skeleton similarity analysis nine compounds were selected for further study. Furthermore, the direct interaction of nine compounds to GIT1 was detected by BLI to obtain the best affinitive compound. Finally, 17302836 was successfully identified (KD = 84.1±2.0 µM). In vitro tests on 17302836 showed significant anti-invasion effect on gastric cancer and colorectal cancer. Conclusion: We discovered a new GIT1/ß-Pix inhibitor (17302836) against gastrointestinal cancer invasion and metastasis. This study provides a promising candidate for developing new GIT1/ß-Pix inhibitors for tumor treatment.

Decentralized clinical trials and rare diseases: a Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) perspective.

BACKGROUND: Traditional clinical trials require tests and procedures that are administered in centralized clinical research sites, which are beyond the standard of care that patients receive for their rare and chronic diseases. The limited number of rare disease patients scattered around the world makes it particularly challenging to recruit participants and conduct these traditional clinical trials. MAIN BODY: Participating in clinical research can be burdensome, especially for children, the elderly, physically and cognitively impaired individuals who require transportation and caregiver assistance, or patients who live in remote locations or cannot afford transportation. In recent years, there is an increasing need to consider Decentralized Clinical Trials (DCT) as a participant-centric approach that uses new technologies and innovative procedures for interaction with participants in the comfort of their home. CONCLUSION: This paper discusses the planning and conduct of DCTs, which can increase the quality of trials with a specific focus on rare diseases.

Treatment for chemotherapy-induced peripheral neuropathy: A systematic review of randomized control trials.

Purpose: Treatment of chemotherapy-induced peripheral neuropathy (CIPN) is challenging for clinicians, and many clinical trials and meta-analyses on CIPN are controversial. There are also few comparisons of the efficacy among drugs used to treat CIPN. Therefore, this systematic review aimed to study the efficacy of drugs in treating CIPN using existing randomized controlled trials. Methods: Electronic databases were searched for randomized controlled trials (RCTs) involving any pharmaceutical intervention and/or combination therapy of treating CIPN. Results: Seventeen RCTs investigating 16 drug categories, duloxetine, pregabalin, crocin, tetrodotoxin, venlafaxine, monosialotetrahexosyl ganglioside (GM1), lamotrigine, KA (ketamine and amitriptyline) cream, nortriptyline, amitriptyline, topical Citrullus colocynthis (bitter apple) oil, BAK (baclofen, amitriptyline hydrochloride, and ketamine) pluronic lecithin organogel, gabapentin, and acetyl l-carnitine (ALC), in the treatment of CIPN were retrieved. Many of the included RCTs consisted of small sample sizes and short follow-up periods. It was difficult to quantify due to the highly variable nature of outcome indicators. Conclusion: Duloxetine, venlafaxine, pregabalin, crocin, tetrodotoxin, and monosialotetrahexosyl ganglioside exhibited some beneficial effects in treating CIPN. Duloxetine, GM1, and crocin showed moderate benefits based on the evidence review, while lamotrigine, KA cream, nortriptyline, amitriptyline, and topical Citrullus colocynthis (bitter apple) oil were not beneficial. Further studies were necessary to confirm the efficacy of gabapentin in the treatment of CIPN because of the controversy of efficacy of gabapentin. Furthermore, BAK topicalcompound analgesic gel only had a tendency to improve the CIPN symptoms, but the difference was not statistically significant. ALC might result in worsening CIPN. Most studies were not of good quality because of small sample sizes. Therefore, standardized randomized controlled trials with large samples were needed to critically assess the effectiveness of these drugs in treating CIPN in the future.

A roadmap to using historical controls in clinical trials - by Drug Information Association Adaptive Design Scientific Working Group (DIA-ADSWG).

Historical controls (HCs) can be used for model parameter estimation at the study design phase, adaptation within a study, or supplementation or replacement of a control arm. Currently on the latter, there is no practical roadmap from design to analysis of a clinical trial to address selection and inclusion of HCs, while maintaining scientific validity. This paper provides a comprehensive roadmap for planning, conducting, analyzing and reporting of studies using HCs, mainly when a randomized clinical trial is not possible. We review recent applications of HC in clinical trials, in which either predominantly a large treatment effect overcame concerns about bias, or the trial targeted a life-threatening disease with no treatment options. In contrast, we address how the evidentiary standard of a trial can be strengthened with optimized study designs and analysis strategies, emphasizing rare and pediatric indications. We highlight the importance of simulation and sensitivity analyses for estimating the range of uncertainties in the estimation of treatment effect when traditional randomization is not possible. Overall, the paper provides a roadmap for using HCs.

Comparison of matrix frequency-doubling technology perimetry and standard automated perimetry in monitoring the development of visual field defects for glaucoma suspect eyes.

BACKGROUND: Perimetry is indispensable for the clinical management of glaucoma suspects. Our goal is to compare the performance of standard automated perimetry (SAP) and Matrix frequency-doubling technology (FDT) perimetry in monitoring the development of visual field (VF) defects in glaucoma suspect eyes. METHODS: Longitudinal data of paired SAP and FDT from 221 eyes of 155 glaucoma suspects enrolled in the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study were included. All eyes had glaucomatous optic neuropathy or ocular hypertension, but normal SAP and FDT results at baseline. The development of glaucomatous VF defects was defined as the presence of a cluster of ≥ 3 (less conservative) or ≥ 4 (more conservative) locations confirmed on ≥ 2 additional consecutive tests. Risk factors for the development of VF defects were analyzed by COX proportional hazard models. After conversion into common logarithmic units, the rates of change of global VF indices were fitted with linear mixed models. RESULTS: FDT detected more eyes that developed VF defects than SAP using the less conservative criterion, and no significant difference was observed using the more conservative criterion. For those eyes detected by both SAP and FDT, FDT detected the development of VF defects either earlier than SAP or simultaneously in most cases. Baseline structural measurements were not significantly associated with an increased risk for the development of glaucomatous VF defects on either SAP or FDT. Older age was significantly associated with the development of VF defects on FDT but not on SAP. Both SAP and FDT detected a progressing worsening trend of pattern standard deviation over time with a similar rate of change between these test types. CONCLUSIONS: Matrix FDT would be useful to monitor the onset of VF defects in glaucoma suspects and may outperform SAP in the early stage of glaucomatous VF damage.

Comparison of Standard Automated Perimetry, Short-Wavelength Automated Perimetry, and Frequency-Doubling Technology Perimetry to Monitor Glaucoma Progression.

Detection of progression is paramount to the clinical management of glaucoma. Our goal is to compare the performance of standard automated perimetry (SAP), short-wavelength automated perimetry (SWAP), and frequency-doubling technology (FDT) perimetry in monitoring glaucoma progression.Longitudinal data of paired SAP, SWAP, and FDT from 113 eyes with primary open-angle glaucoma enrolled in the Diagnostic Innovations in Glaucoma Study or the African Descent and Glaucoma Evaluation Study were included. Data from all tests were expressed in comparable units by converting the sensitivity from decibels to unitless contrast sensitivity and by expressing sensitivity values in percent of mean normal based on an independent dataset of 207 healthy eyes with aging deterioration taken into consideration. Pointwise linear regression analysis was performed and 3 criteria (conservative, moderate, and liberal) were used to define progression and improvement. Global mean sensitivity (MS) was fitted with linear mixed models.No statistically significant difference in the proportion of progressing and improving eyes was observed across tests using the conservative criterion. Fewer eyes showed improvement on SAP compared to SWAP and FDT using the moderate criterion; and FDT detected less progressing eyes than SAP and SWAP using the liberal criterion. The agreement between these test types was poor. The linear mixed model showed a progressing trend of global MS overtime for SAP and SWAP, but not for FDT. The baseline estimate of SWAP MS was significantly lower than SAP MS by 21.59% of mean normal. FDT showed comparable estimation of baseline MS with SAP.SWAP and FDT do not appear to have significant benefits over SAP in monitoring glaucoma progression. SAP, SWAP, and FDT may, however, detect progression in different glaucoma eyes.

Overexpression of PP2A inhibitor SET oncoprotein is associated with tumor progression and poor prognosis in human non-small cell lung cancer.

SET oncoprotein is an endogenous inhibitor of protein phosphatase 2A (PP2A), and SET-mediated PP2A inhibition is an important regulatory mechanism for promoting cancer initiation and progression of several types of human leukemia disease. However, its potential relevance in solid tumors as non-small cell lung cancer (NSCLC) remains mostly unknown. In this study, we showed that SET was evidently overexpressed in human NSCLC cell lines and NSCLC tissues. Clinicopathologic analysis showed that SET expression was significantly correlated with clinical stage (p < 0.001), and lymph node metastasis (p < 0.05). Kaplan-Meier analysis revealed that patients with high SET expression had poorer overall survival rates than those with low SET expression. Moreover, knockdown of SET in NSCLC cells resulted in attenuated proliferative and invasive abilities. The biological effect of SET on proliferation and invasion was mediated by the inhibition of the PP2A, which in turn, activation of AKT and ERK, increased the expression of cyclin D1 and MMP9, and decreased the expression of p27. Furthermore, we observed that restoration of PP2A using SET antagonist FTY720 impaired proliferative and invasive potential in vitro, as well as inhibited tumor growth in vivo of NSCLC cells. Taken together, SET oncoprotein plays an important role in NSCLC progression, which could serve as a potential prognosis marker and a novel therapeutic target for NSCLC patients.

SET-mediated NDRG1 inhibition is involved in acquisition of epithelial-to-mesenchymal transition phenotype and cisplatin resistance in human lung cancer cell.

Development of resistance to therapy continues to be a serious clinical problem in lung cancer management. Cancer cells undergoing epithelial-to-mesenchymal transition (EMT) have been shown to play roles in resistance to chemotherapy. Here, we utilized a proteomics-based method and identified a significant downregulation of the metastasis suppressor NDRG1 in drug resistant lung cancer cells. We showed that downregulation of DNRG1 constitutes a mechanism for acquisition of EMT phenotype and endows lung cancer cells with an increased resistance to cisplatin. We also identified a signal cascade, namely, SET--| PP2A--| c-myc--| NDRG1, in which upregulation of SET is critical for inhibition of NDRG1. We also found that blockade of SET (or reactivation of PP2A) by FTY720 reverted EMT, restored drug sensitivity, and inhibited invasiveness and growth of lung tumor xenografts. Together, our results indicated a functional link between SET-mediated NDRG1 regulation and acquisition of EMT phenotype and drug resistance, and provided an evidence that blockade of SET-driven EMT can overcome drug resistance and inhibit tumor progression.

Redefined blood pressure variability measure and its association with mortality in elderly primary care patients.

Visit-to-visit blood pressure (BP) variability has received considerable attention recently. The objective of our study is to define a variability measure that is independent of change over time and determine the association between longitudinal summary measures of BP measurements and mortality risk. Data for the study came from a prospective cohort of 2906 adults, aged ≥60 years, in an urban primary care system with ≤15 years of follow-up. Dates of death for deceased participants were retrieved from the National Death Index. Systolic and diastolic BP measurements from outpatient clinic visits were extracted from the Regenstrief Medical Record System. For each patient, the intercept, regression slope, and root mean square error for visit-to-visit variability were derived using linear regression models and used as independent variables in Cox proportional hazards models for both all-cause mortality and mortality attributable to coronary heart disease or stroke. Rate of change was associated with mortality risk in a U-shaped relationship and that participants with little or no change in BP had the lowest mortality risk. BP variability was not an independent predictor of mortality risk. By separating change over time from visit-to-visit variability in studies with relatively long follow-up, we demonstrated in this elderly primary care patient population that BP changes over time, not variability, were associated with greater mortality risk. Future research is needed to confirm our findings in other populations.

Cognitive function, body mass index and mortality in a rural elderly Chinese cohort.

BACKGROUND: Previous studies have shown that poor cognition and low body mass index were associated with increased mortality. But few studies have investigated the association between cognition and mortality across the entire cognitive spectrum while adjusting for BMI. The objective of this study is to examine the associations between cognitive function, BMI and 7-year mortality in a rural elderly Chinese cohort. METHODS: A prospective cohort of 2,000 Chinese age 65 and over from four rural counties in China were followed for 7-years. Cognitive function, BMI and other covariate information were obtained at baseline. Cox's proportional hazard models were used to determine the effects of cognitive function and BMI on mortality risk. RESULTS: Of participants enrolled, 473 (23.7%) died during follow-up. Both lower cognitive function (HR = 1.48, p = 0.0049) and lower BMI (HR = 1.6, p < 0.0001) were independently associated with increased mortality risk compared to individuals with average cognitive function and normal weight. Higher cognitive function was associated with lower mortality risk (HR = 0.69, p = 0.0312). We found no significant difference in mortality risk between overweight/obese participants and those with normal weight. CONCLUSIONS: Cognitive function and BMI were independent predictors of mortality risk. Intervention strategies for increasing cognitive function and maintaining adequate BMI may be important in reducing morality risk in the elderly population.