Interactions between patterns of multimorbidity and functional status among hospitalized older patients: a novel approach using cluster analysis and association rule mining.

BACKGROUND: Multimorbidity (MM) is generally defined as the presence of 2 or more chronic diseases in the same patient and seems to be frequently associated with frailty and poor quality of life. However, the complex interplay between MM and functional status in hospitalized older patients has not been fully elucidated so far. Here, we implemented a 2-step approach, combining cluster analysis and association rule mining to explore how patterns of MM and disease associations change as a function of disability. METHODS: This retrospective cohort study included 3366 hospitalized older patients discharged from acute care units of Ancona and Cosenza sites of Italian National Institute on Aging (INRCA-IRCCS) between 2011 and 2017. Cluster analysis and association rule mining (ARM) were used to explore patterns of MM and disease associations in the whole population and after stratifying by dependency in activities of daily living (ADL) at discharge. Sensitivity analyses in men and women were conducted to test for robustness of study findings. RESULTS: Out of 3366 included patients, 78% were multimorbid. According to functional status, 22.2% of patients had no disability in ADL (functionally independent group), 22.7% had 1 ADL dependency (mildly dependent group), and 57.4% 2 or more ADL impaired (moderately-severely dependent group). Two main MM clusters were identified in the whole general population and in single ADL groups. ARM revealed interesting within-cluster disease associations, characterized by high lift and confidence. Specifically, in the functionally independent group, the most significant ones involved atrial fibrillation (AF)-anemia and chronic kidney disease (CKD) (lift = 2.32), followed by coronary artery disease (CAD)-AF and heart failure (HF) (lift = 2.29); in patients with moderate-severe ADL disability, the most significant ARM involved CAD-HF and AF (lift = 1.97), thyroid dysfunction and AF (lift = 1.75), cerebrovascular disease (CVD)-CAD and AF (lift = 1.55), and hypertension-anemia and CKD (lift = 1.43). CONCLUSIONS: Hospitalized older patients have high rates of MM and functional impairment. Combining cluster analysis to ARM may assist physicians in discovering unexpected disease associations in patients with different ADL status. This could be relevant in the view of individuating personalized diagnostic and therapeutic approaches, according to the modern principles of precision medicine.

DNA Methylation-derived biological age and long-term mortality risk in subjects with type 2 diabetes.

BACKGROUND: Individuals with type 2 diabetes (T2D) face an increased mortality risk, not fully captured by canonical risk factors. Biological age estimation through DNA methylation (DNAm), i.e. the epigenetic clocks, is emerging as a possible tool to improve risk stratification for multiple outcomes. However, whether these tools predict mortality independently of canonical risk factors in subjects with T2D is unknown. METHODS: Among a cohort of 568 T2D patients followed for 16.8 years, we selected a subgroup of 50 subjects, 27 survived and 23 deceased at present, passing the quality check and balanced for all risk factors after propensity score matching. We analyzed DNAm from peripheral blood leukocytes using the Infinium Human MethylationEPIC BeadChip (Illumina) to evaluate biological aging through previously validated epigenetic clocks and assess the DNAm-estimated levels of selected inflammatory proteins and blood cell counts. We tested the associations of these estimates with mortality using two-stage residual-outcome regression analysis, creating a reference model on data from the group of survived patients. RESULTS: Deceased subjects had higher median epigenetic age expressed with DNAmPhenoAge algorithm (57.49 [54.72; 60.58] years. vs. 53.40 [49.73; 56.75] years; p = 0.012), and accelerated DunedinPoAm pace of aging (1.05 [1.02; 1.11] vs. 1.02 [0.98; 1.06]; p = 0.012). DNAm PhenoAge (HR 1.16, 95% CI 1.05-1.28; p = 0.004) and DunedinPoAm (HR 3.65, 95% CI 1.43-9.35; p = 0.007) showed an association with mortality independently of canonical risk factors. The epigenetic predictors of 3 chronic inflammation-related proteins, i.e. CXCL10, CXCL11 and enRAGE, C-reactive protein methylation risk score and DNAm-based estimates of exhausted CD8 + T cell counts were higher in deceased subjects when compared to survived. CONCLUSIONS: These findings suggest that biological aging, as estimated through existing epigenetic tools, is associated with mortality risk in individuals with T2D, independently of common risk factors and that increased DNAm-surrogates of inflammatory protein levels characterize deceased T2D patients. Replication in larger cohorts is needed to assess the potential of this approach to refine mortality risk in T2D.

Association between low values of mean arterial pressure and impaired cognitive performance in older patients with mild cognitive impairment: cross-sectional preliminary findings from the STRENGTH Project.

BACKGROUND: Uncontrolled blood pressure (BP) is a risk factor for Mild Cognitive Impairment (MCI) and dementia. AIMS: This study examined the relationship between BP and clinical/cognitive/neuropsychological aspects in MCI individuals. METHODS: MCI patients underwent clinical, functional, cognitive and metacognitive, as well as psychological assessments. Social network, lifestyle characteristics, and medication prescriptions were also evaluated. Each patient underwent BP measurements. RESULTS: Lower values of systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were associated with poorer cognitive performance. Notably, MAP showed greater capability in detecting impairments in attention and visuospatial abilities compared to SBP and DBP. DISCUSSION: These findings support the notion that in older individuals with MCI excessively low BP values, particularly MAP, might represent a risk and suggest that cerebral hypoperfusion may play a key role. CONCLUSIONS: Routine assessment of MAP could aid clinicians in adjusting antihypertensive treatment and closely monitoring cognitive function in MCI patients.

Endurance-dependent urinary extracellular vesicle signature: shape, metabolic miRNAs, and purine content distinguish triathletes from inactive people.

Extracellular vesicles (EVs) enriched with bioactive molecules have gained considerable attention in nanotechnology because they are critical to intercellular communication while maintaining low immunological impact. Among biological matrices, urine has emerged as a noninvasive source of extracellular-contained liquid biopsy, currently of interest as a readout for physiological adaptations. Therefore, we aimed to evaluate chronic adaptations of endurance sport practice in terms of urinary EV parameters and evaluated by food consumption assessment. Two balanced groups of 13 inactive controls vs. triathlon athletes were enrolled; their urinary EVs were obtained by differential ultracentrifugation and analyzed by dynamic light scattering and transmission electron and atomic force microscopy. The cargo was analyzed by means of purine and miRNA content through HPLC-UV and qRT-PCR. Specific urinary EV signatures differentiated inactive versus endurance-trained in terms of peculiar shape. Particularly, a spheroid shape, smaller size, and lower roughness characterize EVs from triathletes. Metabolic and regulatory miRNAs often associated with skeletal muscle (i.e., miR378a-5p, miR27a-3p, miR133a, and miR206) also accounted for a differential signature. These miRNAs and guanosine in urinary EVs can be used as a readout for metabolic status along with the shape and roughness of EVs, novel informative parameters that are rarely considered. The network models allow scholars to entangle nutritional and exercise factors related to EVs' miRNA and purine content to depict metabolic signatures. All in all, multiplex biophysical and molecular analyses of urinary EVs may serve as promising prospects for research in exercise physiology.

Association of Torquetenovirus Viremia with Physical Frailty and Cognitive Impairment in Three Independent European Cohorts.

INTRODUCTION: Immunosenescence and inflammaging have been implicated in the pathophysiology of frailty. Torquetenovirus (TTV), a single-stranded DNA anellovirus, the major component of the human blood virome, shows an increased replication rate with advancing age. An elevated TTV viremia has been associated with an impaired immune function and an increased risk of mortality in the older population. The objective of this study was to analyze the relation between TTV viremia, physical frailty, and cognitive impairment. METHODS: TTV viremia was measured in 1,131 nonfrail, 45 physically frail, and 113 cognitively impaired older adults recruited in the MARK-AGE study (overall mean age 64.7 ± 5.9 years), and then the results were checked in two other independent cohorts from Spain and Portugal, including 126 frail, 252 prefrail, and 141 nonfrail individuals (overall mean age: 77.5 ± 8.3 years). RESULTS: TTV viremia ≥4log was associated with physical frailty (OR: 4.69; 95% CI: 2.06-10.67, p < 0.0001) and cognitive impairment (OR: 3.49, 95% CI: 2.14-5.69, p < 0.0001) in the MARK-AGE population. The association between TTV DNA load and frailty status was confirmed in the Spanish cohort, while a slight association with cognitive impairment was observed (OR: 1.33; 95% CI: 1.000-1.773), only in the unadjusted model. No association between TTV load and frailty or cognitive impairment was found in the Portuguese sample, although a negative association between TTV viremia and MMSE score was observed in Spanish and Portuguese females. CONCLUSIONS: These findings demonstrate an association between TTV viremia and physical frailty, while the association with cognitive impairment was observed only in the younger population from the MARK-AGE study. Further research is necessary to clarify TTV's clinical relevance in the onset and progression of frailty and cognitive decline in older individuals.

Blood circulating bacterial DNA in hospitalized old COVID-19 patients.

BACKGROUND: Coronavirus disease COVID-19 is a heterogeneous condition caused by SARS-CoV-2 infection. Generally, it is characterized by interstitial pneumonia that can lead to impaired gas-exchange, acute respiratory failure, and death, although a complex disorder of multi-organ dysfunction has also been described. The pathogenesis is complex, and a variable combination of factors has been described in critically ill patients. COVID-19 is a particular risk for older persons, particularly those with frailty and comorbidities. Blood bacterial DNA has been reported in both physiological and pathological conditions and has been associated with some haematological and laboratory parameters but, to date, no study has characterized it in hospitalized old COVID-19 patients The present study aimed to establish an association between blood bacterial DNA (BB-DNA) and clinical severity in old COVID-19 patients. RESULTS: BB-DNA levels were determined, by quantitative real-time PCRs targeting the 16S rRNA gene, in 149 hospitalized older patients (age range 65-99 years) with COVID-19. Clinical data, including symptoms and signs of infection, frailty status, and comorbidities, were assessed. BB-DNA was increased in deceased patients compared to discharged ones, and Cox regression analysis confirmed an association between BB-DNA and in-hospital mortality. Furthermore, BB-DNA was positively associated with the neutrophil count and negatively associated with plasma IFN-alpha. Additionally, BB-DNA was associated with diabetes. CONCLUSIONS: The association of BB-DNA with mortality, immune-inflammatory parameters and diabetes in hospitalized COVID-19 patients suggests its potential role as a biomarker of unfavourable outcomes of the disease, thus it could be proposed as a novel prognostic marker in the assessment of acute COVID-19 disease.

Effects of Human LAV-BPIFB4 Gene Therapy on the Epigenetic Clock and Health of Aged Mice.

The homozygous genotype of the Longevity-Associated Variant (LAV) in Bactericidal/Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) is enriched in long-living individuals of three independent populations and its genetic transfer in C57BL/6J mice showed a delay in frailty progression and improvement of several biomarkers of aging and multiple aspects of health. The C57BL/6J strain is a suitable model for studying therapies aimed at extending healthy aging and longevity due to its relatively short lifespan and the availability of aging biomarkers. Epigenetic clocks based on DNA methylation profiles are reliable molecular biomarkers of aging, while frailty measurement tools are used to evaluate overall health during aging. In this study, we show that the systemic gene transfer of LAV-BPIFB4 in aged C57BL/6J mice was associated with a significant reduction in the epigenetic clock-based biological age, as measured by a three CpG clock method. Furthermore, LAV-BPIFB4 gene transfer resulted in an improvement of the Vitality Score with a reduction in the Frailty Index. These findings further support the use of LAV-BPIFB4 gene therapy to induce beneficial effects on epigenetic mechanisms associated with aging and frailty in aged mice, with potential implications for future therapies to prevent frailty in humans.

Effect of Cytomegalovirus Reactivation on Inflammatory Status and Mortality of Older COVID-19 Patients.

Herpesviridae reactivation such as cytomegalovirus (CMV) has been described in severe COVID-19 (COronaVIrusDisease-2019). This study aimed to understand if CMV reactivation in older COVID-19 patients is associated with increased inflammation and in-hospital mortality. In an observational single-center cohort study, 156 geriatric COVID-19 patients were screened for CMV reactivation by RT-PCR. Participants underwent a comprehensive clinical investigation that included medical history, functional evaluation, laboratory tests and cytokine assays (TNF-α, IFN-α, IL-6, IL-10) at hospital admission. In 19 (12.2%) of 156 COVID-19 patients, CMV reactivation was detected. Multivariate Cox regression models showed that in-hospital mortality significantly increased among CMV positive patients younger than 87 years (HR: 9.94, 95% CI: 1.66-59.50). Other factors associated with in-hospital mortality were C-reactive protein (HR: 1.17, 95% CI: 1.05-1.30), neutrophil count (HR: 1.20, 95% CI: 1.01-1.42) and clinical frailty scale (HR:1.54, 95% CI: 1.04-2.28). In patients older than 87 years, neutrophil count (HR: 1.13, 95% CI: 1.05-1.21) and age (HR: 1.15, 95% CI: 1.01-1.31) were independently associated with in-hospital mortality. CMV reactivation was also correlated with increased IFN-α and TNF-α serum levels, but not with IL-6 and IL-10 serum changes. In conclusion, CMV reactivation was an independent risk factor for in-hospital mortality in COVID-19 patients younger than 87 years old, but not in nonagenarians.

Bacterial DNAemia in Alzheimer's Disease and Mild Cognitive Impairment: Association with Cognitive Decline, Plasma BDNF Levels, and Inflammatory Response.

Microbial dysbiosis (MD) provokes gut barrier alterations and bacterial translocation in the bloodstream. The increased blood bacterial DNA (BB-DNA) may promote peripheral- and neuro-inflammation, contributing to cognitive impairment. MD also influences brain-derived neurotrophic factor (BDNF) production, whose alterations contribute to the etiopathogenesis of Alzheimer's disease (AD). The purpose of this study is to measure BB-DNA in healthy elderly controls (EC), and in patients with mild cognitive impairment (MCI) and AD to explore the effect on plasma BDNF levels (pBDNF), the inflammatory response, and the association with cognitive decline during a two-year follow-up. Baseline BB-DNA and pBDNF were significantly higher in MCI and AD than in EC. BB-DNA was positively correlated with pBDNF in AD, plasma Tumor necrosis factor-alpha (TNF-α), and Interleukin-10 (IL-10) levels in MCI. AD patients with BB-DNA values above the 50th percentile had lower baseline Mini-Mental State Examination (MMSE). After a two-year follow-up, AD patients with the highest BB-DNA tertile had a worse cognitive decline, while higher BB-DNA levels were associated with higher TNF-α and lower IL-10 in MCI. Our study demonstrates that, in early AD, the higher the BB-DNA levels, the higher the pBDNF levels, suggesting a defensive attempt; BB-DNA seems to play a role in the AD severity/progression; in MCI, higher BB-DNA may trigger an increased inflammatory response.

Antimetastatic and Antitumor Activities of Orally Administered NAX014 Compound in a Murine Model of HER2-Positive Breast Cancer.

The natural isoquinoline alkaloid Berberine (BBR) has been shown to possess several therapeutic effects, including anticancer activity. Different BBR derivatives have been designed and synthesized in order to obtain new compounds with enhanced anticancer efficacy. We previously showed that intraperitoneal (IP) administration of the BBR-derived NAX014 compound was able to counteract HER-2 overexpressing mammary tumors onset and progression in transgenic mice. However, the IP administration was found to induce organ toxicity at doses higher than 2.5 mg/Kg. In this study, we evaluated the effect of intragastric (IG) administration of 20 mg/kg of NAX014 on both safety and anticancer efficacy in HER-2/neu transgenic mice. Furthermore, cancer cell dissemination and migration, tumor cell senescence and immunological changes were examined. Our results demonstrated that IG NAX014 administration delayed the onset of mammary tumors with no negative effects on health and survival. NAX014 reduced HER-2 overexpressing BC cells migration in vitro and the frequency of lung metastasis in HER-2/neu transgenic mice. A statistically significant increase of senescence-associated p16 expression was observed in tumors from NAX014-treated mice, and the induction of cell senescence was observed in HER-2 overexpressing BC cells after in vitro treatment with NAX014. Although NAX014 did not modulate the presence of tumor-infiltrating lymphocytes, the level of circulating TNF-α and VEGF was found to be reduced in NAX014-treated mice. The overall results address the NAX014 compound as potential tool for therapeutic strategies against HER-2 overexpressing breast cancer.

Study of the effects of adapted Tango and multidimensional intervention in pREvention of dementia in agiNG: developing healTHy lifestyle programs (STRENGTH Project)-the experimental protocol of a prospective randomised controlled trial.

BACKGROUND: Dementia represents a key health issue for older adults, with negative consequences on psycho-social and functional status. Treatments that counteract cognitive deficits in mild cognitive impairment (MCI) are needed to prevent or delay it. AIM: To describe the experimental protocol of the STRENGTH Project. This study investigates a multimodal intervention in older adults with MCI to improve cognitive, functional, biochemical and psycho-social aspects. METHODS: The prospective randomised controlled trial will enrol 300 subjects with MCI (age ≥ 60 years). Participants will be randomly assigned to: (a) the experimental group, which will undergo sessions of adapted tango, music therapy, engagement in social activities, cognitive intervention and psycho-education for 6 months or (b) the control group, which will receive psycho-education and advice on healthy lifestyle for 6 months. All outcomes will be analysed before intervention (baseline), immediately after termination (follow-up 1), after 6 months (follow-up 2) and after 2 years (follow-up 3). DISCUSSION: We expect that the findings of this multidisciplinary study will be useful to optimize clinical and psycho-social interventions for improving cognitive and functional status of subjects with MCI. CONCLUSIONS: This project could have a meaningful impact on National Health Systems by providing clues on multidisciplinary management of older adults affected by cognitive decline to prevent dementia.

Is cellular senescence involved in cystic fibrosis?

Pulmonary disease is the main cause of the morbidity and mortality of patients affected by cystic fibrosis (CF). The lung pathology is dominated by excessive recruitment of neutrophils followed by an exaggerated inflammatory process that has also been reported to occur in the absence of apparent pathogenic infections. Airway surface dehydration and mucus accumulation are the driving forces of this process. The continuous release of reactive oxygen species and proteases by neutrophils contributes to tissue damage, which eventually leads to respiratory insufficiency. CF has been considered a paediatric problem for several decades. Nevertheless, during the last 40 years, therapeutic options for CF have been greatly improved, turning CF into a chronic disease and extending the life expectancy of patients. Unfortunately, chronic inflammatory processes, which are characterized by a substantial release of cytokines and chemokines, along with ROS and proteases, can accelerate cellular senescence, leading to further complications in adulthood. The alterations and mechanisms downstream of CFTR functional defects that can stimulate cellular senescence remain unclear. However, while there are correlative data suggesting that cellular senescence may be implicated in CF, a causal or consequential relationship between cellular senescence and CF is still far from being established. Senescence can be both beneficial and detrimental. Senescence may suppress bacterial infections and cooperate with tissue repair. Additionally, it may act as an effective anticancer mechanism. However, it may also promote a pro-inflammatory environment, thereby damaging tissues and leading to chronic age-related diseases. In this review, we present the most current knowledge on cellular senescence and contextualize its possible involvement in CF.

Anti-inflammatory Activity of Tocotrienols in Age-related Pathologies: A SASPected Involvement of Cellular Senescence.

Tocotrienols (T3) have been shown to represent a very important part of the vitamin E family since they have opened new opportunities to prevent or treat a multitude of age-related chronic diseases. The beneficial effects of T3 include the amelioration of lipid profile, the promotion of Nrf2 mediated cytoprotective activity and the suppression of inflammation. All these effects may be the consequence of the ability of T3 to target multiple pathways. We here propose that these effects may be the result of a single target of T3, namely senescent cells. Indeed, T3 may act by a direct suppression of the senescence-associated secretory phenotype (SASP) produced by senescent cells, mediated by inhibition of NF-kB and mTOR, or may potentially remove the origin of the SASP trough senolysis (selective death of senescent cells). Further studies addressed to investigate the impact of T3 on cellular senescence "in vitro" as well as in experimental models of age-related diseases "in vivo" are clearly encouraged.

Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy.

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

Different transcriptional profiling between senescent and non-senescent human coronary artery endothelial cells (HCAECs) by Omeprazole and Lansoprazole treatment.

Recent evidence suggests that high dose and/or long term use of proton pump inhibitors (PPIs) may increase the risk of adverse cardiovascular events in older patients, but mechanisms underlying these detrimental effects are not known. Taking into account that the senescent endothelial cells have been implicated in the genesis or promotion of age-related cardiovascular disease, we hypothesized an active role of PPIs in senescent cells. The aim of this study is to investigate the changes in gene expression occurring in senescent and non-senescent human coronary artery endothelial cells (HCAECs) following Omeprazole (OPZ) or Lansoprazole (LPZ) treatment. Here, we show that atherogenic response is among the most regulated processes in PPI-treated HCAECs. PPIs induced down-regulation of anti-atherogenic chemokines (CXCL11, CXCL12 and CX3CL1) in senescent but not in non-senescent cells, while the same chemokines were up-regulated in untreated senescent cells. These findings support the hypothesis that up-regulated anti-atherogenic chemokines may represent a defensive mechanism against atherosclerosis during cellular senescence, and suggest that PPIs could activate pro-atherogenic pathways by changing the secretory phenotype of senescent HCAECs. Moreover, the genes coding for fatty acid binding protein 4 (FABP4) and piezo-type mechanosensitive ion channel component 2 (PIEZO2) were modulated by PPIs treatment with respect to untreated cells. In conclusions, our results show that long-term and high dose use of PPI could change the secretory phenotype of senescent cells, suggesting one of the potential mechanisms by which use of PPI can increase adverse outcomes in older subjects.

Gene Expression, Oxidative Stress, and Senescence of Primary Coronary Endothelial Cells Exposed to Postprandial Serum of Healthy Adult and Elderly Volunteers after Oven-Cooked Meat Meals.

Epidemiological studies have linked high consumption of meat with major age-related diseases including cardiovascular diseases. Abnormal postprandial increases in plasma lipids after a meat meal have been hypothesized among the pathogenetic mechanisms. However, it is still unknown if the postprandial serum derived after a normal meat meal is able to affect endothelial function, and if the type of meat and the age of the donors are critical factors. Here, we show the effects of postprandial sera derived from healthy adults and elderly volunteers who consumed meat meals on human coronary artery endothelial cell (HCAEC) oxidative stress, gene expression, DNA damage, and cellular senescence. We observed that a single exposure to postprandial serum induces a slight increase in ROS that is associated with modulation of gene expression pathways related to oxidative stress response and metabolism. The postprandial-induced increase in ROS is not associated with a measurable DNA oxidative damage. However, repeated exposure to postprandial serum induces an acceleration of cellular senescence. Taking into account the deleterious role of cellular senescence in age-related vascular diseases, the results suggest a new mechanism by which excessive meat consumption and time spent in postprandial state may affect health status during aging.

Circadian rhythms of body temperature and locomotor activity in aging BALB/c mice: early and late life span predictors.

Impairment of one or more parameters of circadian rhythms (CR) of body temperature (BT) and locomotor activity (LMA) are considered among the hallmarks of mammalian aging. These alterations are frequently used as markers for imminent death in laboratory mice. However, there are still contradictory data for particular strains and it is also uncertain which changes might predict senescence changes later in life, including the force of mortality. In the present paper we use telemetry to study LMA and CR of BT during aging of BALB/c mice. At our knowledge this is the first time that CR of BT and LMA are investigated in this strain in a range of age covering the whole lifespan, from young adult up to very old age. CR of BT was analyzed with a cosine model using a cross sectional approach and follow-up measurements. The results show that BT, LMA, amplitude, goodness-of-fit (GoF) to circadian cycle of temperature decrease with different shapes during chronological age. Moreover, we found that the % change of amplitude and BT in early life (5-19 months) can predict the remaining lifespan of the mice. Later in life (22-32 months), best predictors are single measurements of LMA and GoF. The results of this study also offer potential measures to rapidly identifying freely unrestrained mice with the worst longitudinal outcome and against which existing or novel biomarkers and treatments may be assessed.

Response rates to sequential trials of antipsychotic medications according to algorithms or treatment guidelines in psychotic disorders. A systematic review and meta-analysis.

BACKGROUND: There is a relative lack of research evaluating the outcomes when treatment guidelines or algorithms for psychotic disorders are followed. This systematic review and meta-analysis determined the response rates to antipsychotic medications at different stages of these algorithms and whether these response rates differ in first episode cohorts. METHODS: Data sources: A systematic search strategy was conducted across four databases PubMed, EMBASE, PsycINFO (Ovid) and CINAHL. Studies that had sequential trials of different antipsychotic medications were included. A meta-analysis of proportions was performed using random effects models and sub-group analysis in first episode psychosis studies. RESULTS: Of the 4078 unique articles screened, fourteen articles, from nine unique studies, were eligible and included 2522 participants. The proportion who experienced a response to any antipsychotic in the first stage of an algorithm was 0.53 (95 % C.I.:0.38,0.68) and this decreased to 0.26 (95 % C.I.:0.15,0.39) in the second stage. When clozapine was used in the third stage, the proportion that achieved a response was 0.43 (95 % C.I. 0.19, 0.69) compared to 0.26 (95 % C.I.:0.05,0.54) if a different antipsychotic was used. Four studies included 907 participants with a first episode of psychosis and the proportions that achieved a response were: 1st stage: 0.63 (95 % C.I.: 0.45, 0.79); 2nd stage: 0.34 (95 % C.I.:0.16,0.55); clozapine 3rd stage: 0.45 (95 % C.I.:0.0,0.97), different antipsychotic 3rd stage: 0.15 (95 % C.I.,0.01,0.37). DISCUSSION: These findings support the recommendation to have a trial of clozapine after two other antipsychotic medications have been found to be ineffective.