Factors associated with the discrepancy between objective and subjective cognitive impairment in bipolar disorder.

OBJECTIVE: The aim of this study is to evaluate the discrepancy between objective cognitive measures and cognitive subjective complaints in a sample of euthymic patients with bipolar disorder (BD). METHODS: One hundred and sixteen participants (83 euthymic patients with BD and 33 healthy controls) were enrolled for this study. Patients were assessed with a comprehensive neuropsychological battery and they also reported their subjective cognitive complaints with the Cognitive Complaints in Bipolar Disorder Rating Scale (COBRA). The discrepancy between objective and subjective data was calculated using a novel methodology proposed in a previous study (Miskowiak, 2016). Statistical analyses included Pearson correlations and multiple linear regression. RESULTS: Higher number of previous depressive episodes was identified as one variable associated with the global sensitivity composite score (Beta = 0.25; t = 2.1; p = 0.04) and with the verbal learning and memory sensitivity score (Beta = 0.26; t = 2.16; p = 0.03). That is, patients with more previous depressive episodes tend to over-report cognitive complaints. In contrast, higher number of previous hospitalizations was associated with stoicism in the global total score (Beta = -0.27; t = -2.24: p = 0.029) and in the domain of attention/processing speed (Beta = -0.34; t = -2.52; p = 0.016), indicating patients with more hospitalizations tend to report less cognitive complaints. DISCUSSION: Our study identified some factors that might help to explain the discrepancy between objective and subjective cognitive measures in BD, including number of previous depressive episodes and number of previous hospitalizations. This highlights the need of the combined use of both types of cognitive measures to make an accurate assessment of cognitive dysfunctions and their effective treatment.

Do people with knee osteoarthritis use guideline-consistent treatments after an orthopaedic surgeon recommends nonsurgical care? A cross-sectional survey with long-term follow-up.

Objective: Describe "usual care" patterns of education, exercise, weight management, pain medication and other nonsurgical treatments for knee osteoarthritis (OA) in people recommended for nonsurgical care by an orthopaedic surgeon. Methods: We used a telephone-administered questionnaire to capture treatments people with knee OA used over the three to six years after an orthopaedic surgeon recommended nonsurgical care. The primary outcome, guideline-consistent nonsurgical treatments, was an aggregate measure defined as using education, exercise, weight management, and at least one recommended medication. Secondary outcomes were first-line (education, exercise, and weight management) and guideline-inconsistent treatments (orthoses, opioids, hyaluronic acid, platelet rich plasma, and stem cell therapy). Multivariable robust Poisson regression assessed the association between participant characteristics and use of guideline-consistent, first-line and guideline-inconsistent treatments. Results: 479 people were invited and 250 participated (52%). Participants were 58% female with a mean age 66.2 years. Participants received education by a healthcare professional (64%), exercised regularly (74%), used weight management (38%), and used recommended pain medications (91%). All guideline-consistent nonsurgical treatments were used by 19% of participants, 19% of participants used first-line treatments, and 42% used guideline-inconsistent treatments. Over six years, 34% had another consult then underwent arthroplasty. Older participants were less likely to use any treatment. People without post-secondary education were less likely to use first-line treatments (RR 0.54, 95% CI: 0.30-0.96), and females were less likely to use guideline-inconsistent treatments (RR 0.62, 95% CI:0.47-0.81). Conclusions: Nonsurgical usual care for people with knee OA was not consistent with international clinical guidelines.

Are education, exercise and diet interventions a cost-effective treatment to manage hip and knee osteoarthritis? A systematic review.

OBJECTIVE: To identify research gaps and inform implementation we systematically reviewed the literature evaluating cost-effectiveness of recommended treatments (education, exercise and diet) for the management of hip and/or knee OA. METHODS: We searched Medline, Embase, Cochrane Central Register of Controlled Trials, National Health Services Economic Evaluation Database, and EconLit from inception to November 2019 for trial-based economic evaluations investigating hip and/or knee OA core treatments. Two investigators screened relevant publications, extracted data and synthesized results. Risk of bias was assessed using the Consensus on Health Economic Criteria list. RESULTS: Two cost-minimization, five cost-effectiveness and 16 cost-utility analyses evaluated core treatments in six health systems. Exercise therapy with and without education or diet was cost-effective or cost-saving compared to education or physician-delivered usual care at conventional willingness to pay (WTP) thresholds in 15 out of 16 publications. Exercise interventions were cost-effective compared to physiotherapist-delivered usual care in three studies at conventional WTP thresholds. Education interventions were not cost-effective compared to usual care or placebo at conventional WTP thresholds in three out of four publications. CONCLUSIONS: Structured core treatment programs were clinically effective and cost-effective, compared to physician-delivered usual care, in five health care systems. Providing education about core treatments was not consistently cost-effective. Implementing structured core treatment programs into funded clinical pathways would likely be an efficient use of health system resources and enhance physician-delivered usual primary care.

Mixed states in bipolar and major depressive disorders: systematic review and quality appraisal of guidelines.

OBJECTIVE: This systematic review provided a critical synthesis and a comprehensive overview of guidelines on the treatment of mixed states. METHOD: The MEDLINE/PubMed and EMBASE databases were systematically searched from inception to March 21st, 2018. International guidelines covering the treatment of mixed episodes, manic/hypomanic, or depressive episodes with mixed features were considered for inclusion. A methodological quality assessment was conducted with the Appraisal of Guidelines for Research and Evaluation-AGREE II. RESULTS: The final selection yielded six articles. Despite their heterogeneity, all guidelines agreed in interrupting an antidepressant monotherapy or adding mood-stabilizing medications. Olanzapine seemed to have the best evidence for acute mixed hypo/manic/depressive states and maintenance treatment. Aripiprazole and paliperidone were possible alternatives for acute hypo/manic mixed states. Lurasidone and ziprasidone were useful in acute mixed depression. Valproate was recommended for the prevention of new mixed episodes while lithium and quetiapine in preventing affective episodes of all polarities. Clozapine and electroconvulsive therapy were effective in refractory mixed episodes. The AGREE II overall assessment rate ranged between 42% and 92%, indicating different quality level of included guidelines. CONCLUSION: The unmet needs for the mixed symptoms treatment were associated with diagnostic issues and limitations of previous research, particularly for maintenance treatment.

Psychometric properties of the well-being index (WHO-5) spanish version in a sample of euthymic patients with bipolar disorder.

BACKGROUND: The concept of well-being which focuses on positive emotions has received increased research attention. However, a consensus definition of this term is lacking. The Well-Being Index scale (WHO-5) is a generic, self-report scale that contains five Likert-type items to evaluate psychological well-being. This construct may provide a relevant outcome in bipolar disorder (BD) research and care beyond the rating of mood symptoms. Thus, in the current study, the psychometric properties of the WHO-5 Spanish version were assessed in a sample of euthymic patients with BD. METHODS: Patients with BD- I and BD-II and healthy controls completed the Well-Being Index (WHO-5) together with an assessment of depressive (Hamilton Depression Rating Scale-17; HAM-D) and manic symptoms (Young Mania Rating Scale; YMRS); and a measure of psychosocial functioning (Functioning Assessment Short Test; FAST). Internal consistency reliability was measured through Cronbach's alpha. Test-retest reliability was calculated comparing the WHO-5 total score at baseline and after 10 days of the first administration. To assess the structure of the scale, a principal component analysis (PCA) was carried out. Correlations between the WHO-5, HAM-D, YMRS and FAST were calculated. Finally, a t-test for independent samples was applied to compare the WHO-5 total score in the patient and control groups. RESULTS: A total of 104 patients with BD and 40 healthy controls were included in this study. A Chronbach's alpha of 0.83 indicated acceptable internal consistency. A paired sample t-test revealed no significant differences between WHO-5 total score at baseline and at follow-up (tn = - 0.72; df = 15; p = 0.48). The PCA provided a single factor solution that accounted for 59.74% of the variation in WHO-5. Test-retest reliability was high (r = 0.83; p < 0.001). Moderate negative correlations were observed between the WHO-5 total score, the FAST (r = - 0.46.; p < 0.001) and the HAM-D (r = - 0.68; p < 0.001), but not with the YMRS (r = - 0.07; p = 0.42). Finally, significant differences were found when comparing the WHO-5 total score between patient and healthy controls (t = 5.1; df = 147; p < 0.001). LIMITATIONS: some limitations include the lack of a comparator scale to test for validity construct and the small sample size in the test-retest reliability CONCLUSIONS: The WHO-5 shows an acceptable reliability index and measures a unitary construct in a Spanish population of euthymic patients with BD.

Treatment of neurocognitive symptoms in unipolar depression: A systematic review and future perspectives.

BACKGROUND: Cognitive symptoms in Major Depressive Disorder (MDD) are persistent and commonly entail neurocognitive impairment and a decline in quality of life. This systematic review gathers the current scientific evidence on therapeutic strategies for neuropsychological impairment in MDD. METHOD: A systematic search on PubMed, PsycINFO and Clinicaltrials.gov was carried out on December 2016 according to PRISMA using Boolean terms to identify interventions for the treatment of cognitive dysfunction in MDD. Only English-written articles providing original data and focusing in adults with MDD were included with no time restrictions. RESULTS: A total of 95 studies reporting data on 40 pharmacological and non-pharmacological interventions were included. Interventions were grouped into the following categories: 1) Pharmacological Therapies (antidepressants, stimulants, compounds acting on NMDA receptors, compounds acting on the cholinergic system, compounds showing anti-inflammatory or antioxidant properties, other mechanisms of action), 2) Physical Therapies and 3) Psychological Therapies, 4) Exercise. There are some promising compounds showing a positive impact on cognitive symptoms including vortioxetine, lisdexamfetamine or erythropoietin. LIMITATIONS: The studies included showed significant methodological differences in heterogeneous samples. The lack of a standardized neuropsychological battery makes comparisons between studies difficult. CONCLUSION: Current evidence is not sufficient to widely recommend the use of procognitive treatments in MDD although promising results are coming to light.

Vasopressin receptor antagonists in patients with chronic heart failure.

In this brief review, the pathophysiology of hyponatremia and its clinical significance in the course of chronic heart failure (CHF) are illustrated. Moreover, issues concerning the optimal treatment for hyponatremia during CHF are addressed and discussed. In addition, advantages and limitations resulting from the use of vasopressin receptor antagonists, drugs that have recently emerged as the best available resource against hyponatremia, are highlighted.

Course of residual symptoms according to the duration of euthymia in remitted bipolar patients.

OBJECTIVE: Although many studies showed the negative impact of residual symptoms on the course of bipolar disorder (BD), there is a need to examine potential differences in residual symptoms according to the duration of euthymia in remitted BD patients. METHOD: This was a large cross-sectional study of 525 euthymic BD out-patients. A multivariate analysis of covariance was conducted to compare depressive and manic residual symptoms, sleep disturbances and cognitive complaints among three patient groups on the basis of duration of euthymia (A. 6 months to <1 year; B. 1 year to <3 years; C. 3 years to ≤5 years). RESULTS: A significant difference between the three groups was found in residual symptoms [Pillai's Trace: F(8942) = 4.659, P < 0.001]. Tukey post hoc analysis indicated that patients from Group C presented lower residual depressive symptoms, higher sleep quality and better perceived cognitive performance compared with Group A. Group B also presented better sleep and cognitive outcomes than Group A. In addition, Group C showed the lowest incidence of functional impairment. CONCLUSION: This study suggests that the intensity of residual symptoms and functional impairment in remitted BD patients is negatively related to the duration of euthymia.

The role of family interventions in bipolar disorder: A systematic review.

The reciprocal relationship between bipolar disorder (BD) and the family system highlights the importance of adjunctive family intervention. However, its implementation in clinical practice is not widespread. To update the knowledge in this field and identify areas of uncertainty this manuscript present a comprehensive overview of the bidirectional relationship between BD and family variables, and a systematic review of the evidence-based studies published up to March 2015 on the efficacy of adjunctive family intervention in BD. Findings show that not only specific family's attitudes/interactions affect the course of BD but that equally the illness itself has a strong impact on family functioning, caregivers' burden and health. Regarding family intervention, there are methodological differences between studies and variability in the sample characteristics and the intervention used. Most evidence-based studies support the efficacy of adjunctive family treatment in the illness outcomes, both in youth and adult population, as well as benefits for caregivers. The results emphasize the need to involve caregivers in the therapeutic management of BD through tailored interventions based on patients' characteristics and family needs.

Asenapine prescribing patterns in the treatment of manic in- and outpatients: Results from the MANACOR study.

BACKGROUND: Asenapine is the most recent compound that has been FDA- and EMA-approved for treatment of mania. Its efficacy and safety have been assessed in placebo-controlled trials, but little is known about its performance in routine clinical conditions. In this study, we compared features of patients treated with adjunctive asenapine or other adjunctive antipsychotics and the costs of the treatment. METHODS: A combined prospective and retrospective data collection and analysis was conducted from January 2011 to December 2013 following a clinical interview and assessment of manic and depressive symptoms (YMRS, HDRS-17), clinical state (CGI-BP-M), psychosocial functioning (FAST), sexual dysfunction (PRSexDQ) and health resource costs associated with treatment with adjunctive asenapine versus other adjunctive antipsychotics. RESULTS: Hundred and fifty-two patients from different university hospitals were included. Fifty-three patients received adjunctive asenapine and 99 received other adjunctive antipsychotics concomitantly to mood stabilizers. Considering inpatients, those treated with adjunctive asenapine presented a significantly less severe manic episode (P=0.001), less psychotic symptoms (P=0.030) and more comorbid personality disorder (P=0.002). Regarding outpatients, those treated with adjunctive asenapine showed significantly less severe manic episode (P=0.046), more previous mixed episodes (P=0.013) and more sexual dysfunction at baseline (P=0.036). No significant differences were found in mean total costs per day. CONCLUSION: Clinicians tended to use adjunctive asenapine in patients with less severe manic symptoms but more complex clinical profile, including more mixed episodes in the past, concomitant personality disorder, and sexual problems. Treatment with adjunctive asenapine was not associated with higher costs when compared to other options.

Suitability of partly destoned exhausted olive cake as by-product feed ingredient for lamb production.

The effect of diets with different levels of partly destoned exhausted olive cake (PDEOC) on growth performance and carcass traits of Gentile di Puglia breed lambs was studied. Sixty lambs (16.5 ± 0.5 kg) at weaning were randomly allocated to 3 isocaloric and isonitrogenous diets for 50 d. Pelleted total mixed rations (TMR) were formulated to provide olive by-product at 3 different levels: 1) a control diet without olive by-product (PDEOC-0), 2) an experimental corn-based diet containing 10% by-product (PDEOC-10) replacing part of the oat hay and sunflower meal, and 3) an experimental corn-based diet containing 20% PDEOC (PDEOC-20) replacing part of the oat hay and soybean meal. To evaluate in vivo digestibility of the diets, adult rams (n = 3) were placed in metabolic cages, their individual feces and urine were collected, and differences were observed for DM and fiber fractions. Results from the growth trial of the lambs showed that performance was influenced by olive by-product inclusion in diet (P < 0.05). At the end of the feeding period, lambs were slaughtered, and none of the variables studied were influenced by dietary treatment except for cold carcass dressing (P = 0.027) and half-carcass weight (P = 0.019), which were improved in lambs fed the PDEOC-20 diet. As a result, the current study confirms that olive by-product can be used in lamb finishing rations, resulting in a valuable ingredient as replacement for conventional feeds, which could reduce feeding costs because of the lower cost of the olive by-product. Use of olive by-products as animal feed may become economically feasible for producers where the olive oil industries play an important economic role.

Prevalence of sleep disturbances in mild cognitive impairment and dementing disorders: a multicenter Italian clinical cross-sectional study on 431 patients.

BACKGROUND/AIMS: Sleep disturbances are common in the elderly and in persons with cognitive decline. The aim of this study was to describe frequency and characteristics of insomnia, excessive daytime sleepiness, sleep-disordered breathing, REM behavior disorder and restless legs syndrome in a large cohort of persons with mild cognitive impairment or dementia. METHODS: 431 consecutive patients were enrolled in 10 Italian neurological centers: 204 had Alzheimer's disease, 138 mild cognitive impairment, 43 vascular dementia, 25 frontotemporal dementia and 21 Lewy body dementia or Parkinson's disease dementia. Sleep disorders were investigated with a battery of standardized questions and questionnaires. RESULTS: Over 60% of persons had one or more sleep disturbances almost invariably associated one to another without any evident and specific pattern of co-occurrence. Persons with Alzheimer's disease and those with mild cognitive impairment had the same frequency of any sleep disorder. Sleep-disordered breathing was more frequent in vascular dementia. REM behavior disorder was more represented in Lewy body or Parkinson's disease dementia. CONCLUSION: A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. Instrumental supports should be used only in selected patients.

The reversed clock drawing test phenomenon in Alzheimer's disease: A perfusion SPECT study.

AIM: To unveil a brain single photon emission computed tomography (SPECT) pattern in Alzheimer's disease (AD) patients, showing a reversed clock drawing test (CDT) phenomenon. PATIENTS AND METHODS: Among 1,005 consecutive subjects, 9 AD patients who drew a reversed CDT (AD-R) underwent SPECT, which was analysed (SPM2) versus a group of 10 AD patients performing the CDT correctly (AD+) and versus 15 controls (CTR). Brain SPECT in 11 AD patients who mistook the CDT in a common way (AD-) was compared with AD+ and CTR groups. RESULTS: Relative hypoperfusion was found in AD-R versus CTR in right medial frontal, parahippocampal and subcallosal gyri, and in left insula and superior temporal gyrus. Hypoperfusion was found in AD-R versus AD+ in the right uncus, superior temporal and parahippocampal gyri. In the AD- versus CTR comparison, hypoperfusion was found in left hippocampus, parahippocampal gyrus and superior parietal lobule. In AD-R versus AD+ and CTR merged together, the analysis showed hypoperfusion in the right parahippocampus, medial frontal gyrus, superior temporal gyrus and uncus, in the left insula and superior temporal gyrus. CONCLUSION: Fronto-temporal dysfunction, especially in the right hemisphere, plays a role in the reversed CDT phenomenon in AD patients, whereas matched AD patients mistaking the CDT in a common way show left posterior temporo-parietal hypoperfusion.

A low shear stress modular bioreactor for connected cell culture under high flow rates.

A generic "system on a plate" modular multicompartmental bioreactor array which enables microwell protocols to be transferred directly to the bioreactor modules, without redesign of cell culture experiments or protocols is described. The modular bioreactors are simple to assemble and use and can be easily compared with standard controls since cell numbers and medium volumes are quite similar. Starting from fluid dynamic and mass transport considerations, a modular bioreactor chamber was first modeled and then fabricated using "milli-molding," a technique adapted from soft lithography. After confirming that the shear stress was extremely low in the system in the range of useful flow rates, the bioreactor chambers were tested using hepatocytes. The results show that the bioreactor chambers can increase or maintain cell viability and function when the flow rates are below 500 microL/min, corresponding to wall shear stresses of 10(-5) Pa or less at the cell culture surface.

MCI patients declining and not-declining at mid-term follow-up: FDG-PET findings.

Patients with Mild Cognitive Impairment (MCI) not converted to dementia at one to three years follow-up represent a heterogeneous group across studies, by including 'late converters' but also patients without any neurodegenerative disease. We tested the hypothesis that the combination of memory and brain metabolic assessment could identify subgroups of memory decliners (MCI/Decl) and non-decliners (MCI/noDecl) before a long follow-up time is available. From twenty-nine patients with amnestic MCI (aMCI) at baseline, three groups were identified at follow-up: 10 patients who converted to AD (MCI/AD); 10 patients either showing episodic memory worsening or reaching the floor effect on memory and declining in other key tests (MCI/Decl) and 9 patients showing no memory worsening or even improvement (MCI/noDecl). They were compared with a group of fourteen elderly controls (CTR) by means of basal FDG-PET voxel-based analysis (SPM2). Two hypometabolic clusters were found in MCI/AD versus CTR, including the bilateral posterior cingulate cortex, the left parietal precuneus and the left fusiform gyrus. MCI/AD showed also a large hypometabolic region, mainly including the left medium and superior temporal gyri and inferior parietal lobule, when compared to MCI/noDecl. The MCI/Decl showed a hypometabolic region in the left medial temporal lobe versus both CTR (hippocampus) and MCI/noDecl (parahippocampal gyrus and hippocampus). No significant difference was found in the comparison between CTR and MCI/noDecl, neither in the comparison between MCI/Decl and MCI/AD. Thus, non converter MCI patients comprised a sub-group of 'decliners' with AD-like metabolic and cognitive patterns, likely including 'late converters', and a sub-group lacking this pattern, with stable or improving memory function and a brain metabolic picture similar to that in healthy controls. Combining neuropsychological and FDG-PET information could be used for prognostic purposes in aMCI patients at medium-term follow-up.

The factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease.

Our aim was to evaluate the factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease (AD). Five hundred and twenty-four consecutive outpatients at their first diagnostic work-up (age 78.02+/-6.07 years, education 6.62+/-3.48 years, mean MMSE score 20.23+/-4.89) (+/-S.D.) with probable AD (based on DSM-IV and NINCDS-ADRDA criteria) were enrolled in a multicenter, cross-sectional, regional-based study. For the purpose of the present study, the 11 subtests composing the MMSE and the global MMSE score (ranging from 10 to 29, included) were considered. Factor analysis with Varimax rotation method identified two factors that explained about the 85% of total variance. The first factor explained the 65% of variance and mainly included temporal orientation, delayed recall, attention/concentration, and constructional praxia. The second factor explained the 20% of variance and included reading a sentence, writing a sentence, naming, verbal repetition and immediate memory. The first factor was a reliable index of cognitive deterioration along the MMSE score interval between 29 and 10, whereas the second factor was not a suitable marker in this range. The two-factor structure of the MMSE in AD is shown in a large series of patients. The first factor expresses the ability to use new information and is related with working memory. The second factor is related with a more consolidated knowledge, namely verbal abilities, and is essentially useless in mild to moderate AD.

A renal abnormality as a possible cause of "essential" hypertension.

The renal abnormality which causes hypertension in the Milan hypertensive strain of rats disappears as hypertension develops. Because of the many analogies between the condition in these rats and "essential" hypertension in man, the same pattern of change may occur if a renal abnormality is the cause of essential hypertension in man. This hypothesis was tested in two groups of young normotensive subjects matched for age, sex, and body-surface area; in the first group both parents were hypertensive, and in the second group both parents were normotensive. Renal plasma-flow, glomerular filtration-rate, plasma-volume, plasma-renin activity, plasma-concentrations of Na+, K+, and catecholamines, 24 h urinary excretion of Na+, K+, and aldosterone, and the cardiac index were measured so that renal function and the role of factors affecting blood-pressure regulation could be assessed. Renal plasma-flow was significantly higher (p less than 0.01) in the first group, whereas results of tests for all the other factors were almost the same in both groups. The hypothesis that a primary kidney abnormality causes hypertension in a proportion of patients with essential hypertension is proposed.