Assessing cognition in people with severe mental disorders in low- and middle-income countries: a systematic review of assessment measures

Background

Cognitive difficulties are common in people with severe mental disorders (SMDs) and various measures of cognition are of proven validity. However, there is a lack of systematic evidence regarding the psychometric properties of these measures in low- and middle-income countries (LMICs).

Objective

To systematically review the psychometric properties of cognitive measures validated in people with SMDs in LMICs.

Methods

We conducted a systematic review of the literature by searching from four electronic databases. Two authors independently screened studies for their eligibility. Measurement properties of measures in all included studies were extracted. All eligible measures were assessed against criteria set for clinical and research recommendations. Results are summarized narratively and measures were grouped by measurement type and population.

Results

We identified 23 unique measures from 28 studies. None of these was from low-income settings. Seventeen of the measures were performance-based. The majority (n = 16/23) of the measures were validated in people with schizophrenia. The most commonly reported measurement properties were: known group, convergent, and divergent validity (n = 25/28). For most psychometric property, studies of methodological qualities were found to be doubtful. Among measures evaluated in people with schizophrenia, Brief Assessment of Cognition in Schizophrenia, Cognitive Assessment Interview, MATRICS Consensus Cognitive Battery, and CogState Schizophrenia Battery were with the highest scores for clinical and research recommendation.

Conclusions

Studies included in our review provide only limited quality evidence and future studies should consider adapting and validating measures using stronger designs and methods. Nonetheless, validated assessments of cognition could help in the management and allocating therapy in people with SMDs in LMICs.

     

The subcellular localisation of trypanosome RRP6 and its association with the exosome

The exosome, a complex of 3'-exoribonucleases and associated proteins, is involved in the degradation of eukaryotic mRNAs in the cytoplasm, and has RNA processing and quality control functions in the nucleus. In yeast, the nuclear exosome differs from the cytoplasmic one in that it contains an additional non-essential component, Rrp6p. In contrast, a small proportion of human RRP6 has been shown to localise to the cytoplasm as well. When we purified the Trypanosoma brucei exosome from cytosolic extracts we found RRP6, apparently in stoichiometric amounts. We here confirm that RRP6 is in the trypanosome cytoplasm and nucleus. The level of RRP6 was unaffected by depletion of core exosome subunits by RNA interference and over-expression of tagged RRP6 was possible, indicating that RRP6 can be present independent of exosome association.     

Detection of QTc interval prolongation using jacket telemetry in conscious non-human primates: comparison with implanted telemetry

Background and Purpose: During repeat-dose toxicity studies, ECGs are collected from chemically or physically-restrained animals over a short timeframe. This is problematic due to cardiovascular changes caused by manual restraint stress and anesthesia, and limited ECG sampling. These factors confound data interpretation, but may be overcome by using a non-invasive jacket-based ECG collection (JET). The current study investigated whether a jacketed external telemetry system could detect changes in cardiac intervals and heart rate in non-human primates (NHPs), previously implanted with a PCT transmitter.Experimental Approach: Twelve male cynomolgus monkeys were treated weekly with vehicle or sotalol (8, 16, 32 mg kg⁻¹) p.o. ECGs were collected continuously for 24 hours, following treatment, over 4 weeks. A satellite group of six NHPs was used for sotalol toxicokinetics.Key Results: Sotalol attained C_max values 1–3 hours after dosing, and exhibited dose-proportional exposure. In jacketed NHPs, sotalol dose-dependently increased QT/QTc intervals, prolonged PR interval, and reduced heart rate. Significant QTc prolongation of 27, 54 and 76 msec was detected by JET after 8, 16, and 32 mg kg⁻¹ sotalol, respectively, compared with time-matched vehicle-treated animals. Overall, JET-derived PR, QT, QTc intervals, QRS duration, and heart rate correlated well with those derived from PCT.Conclusions and Implications: The current findings clearly support the use of JET to quantify cardiac interval and rhythm changes, capable of detecting QTc prolongation caused by sotalol. JET may be a preferred method compared to restraint-based ECG because high-density ECG sampling can be collected in unstressed conscious monkeys, over several weeks.     

P66shc regulates endothelial NO production and endothelium-dependent vasorelaxation: implications for age-associated vascular dysfunction

The p66shc adaptor protein mediates age-associated oxidative stress. We examined the role of p66shc in endothelial nitric oxide synthase (eNOS) signaling. Overexpression of p66shc inhibited eNOS-dependent NO production. RNAi-mediated down-regulation of endogenous p66shc led to activation of the proto-oncogene ras, and Akt kinase, with a corresponding increase in phosphorylation of eNOS at S1177 (S1179 on bovine eNOS). In rat aortic rings, down-regulation of p66shc suppressed the vasoconstrictor response to phenyephrine that was abrogated by treatment with the NOS inhibitor l-NAME, and enhanced vasodilation induced by sub-maximal doses of acetylcholine. These findings highlight a pivotal role for p66shc in inhibiting endothelial NO production, and endothelium-dependent vasorelaxation, that may provide important mechanistic information about endothelial dysfunction seen with aging.     

Interleukin-3 treatment of rhesus monkeys leads to increased production of histamine-releasing cells that express interleukin-3 receptors at high levels

To understand the hematopoietic and nonhematopoietic responses to interleukin-3 (IL-3), expression of cell-surface IL-3 receptors (IL-3R) was examined on bone marrow (BM) cells and peripheral blood (PB) cells of rhesus monkeys during the course of in vivo IL-3 treatment. Whereas IL-3R expression is low in untreated monkeys, IL-3 administration led to a gradual increase in both low- and high-affinity binding sites for IL-3. This increase reflected the total number of cells expressing IL- 3Rs, as detected by flow cytometry using biotinylated IL-3. Most of these IL-3R+ cells in both BM and PB could be characterized as basophilic granulocytes that contained high levels of histamine. In contrast to the effect on these differentiated cells, IL-3 administration did not significantly alter the low level IL-3R expression on immature, CD34+ cells. Further flow cytometric analysis using biotinylated growth factors showed that the IL-3R+ basophils also expressed receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF), but not for IL-6 or Kit ligand. These findings indicated that the IL-3R+ cells included neither monocytes, which express GM-CSFRs and IL-6Rs abundantly, nor mast cells, which express c- kit. By combining flow cytometric and Scatchard data, it was calculated that the basophils contain as many as 1 to 2 x 10(3) high-affinity IL- 3Rs and 15 to 30 x 10(3) low-affinity sites. The finding that in vivo IL-3 treatment leads to the production of large numbers of cells that express high levels of IL-3R and are capable of producing histamine provides an explanation for the often severe allergic reactions that occur during prolonged IL-3 administration. It also indicates that IL- 3, in addition to its direct effects on hematopoietic cells, may also stimulate hematopoiesis through the release of secondary mediators such as histamine by IL-3-responsive mature cells.     

Can source reduction of mosquito larval habitat reduce malaria transmission in Tigray,Ethiopia?

The development of irrigation schemes by dam construction has led to an increased risk of malaria in Tigray, Ethiopia. We carried out a pilot study near a microdam to assess whether environmental management could reduce malaria transmission by Anopheles arabiensis, the main vector in Ethiopia. The study took place in Deba village, close to a dam; Maisheru village, situated 3-4 km away from the dam, acted as a control. Baseline entomological and clinical data were collected in both villages during the first 12 months. Source reduction, involving filling, draining and shading of potential mosquito-breeding habitats was carried out by the community of Deba in the second year and routine surveillance continued in both villages during the second year. Anopheles arabiensis was highly anthropophilic (Human Blood Index=0.73), biting early in the night before people went to bed. The major breeding habitats associated with the dam were areas of seepage at the dam base (28%), leaking irrigation canals (16%), pools that formed along the bed of streams from the dam (13%), and man-made pools (12%). In the pre-intervention year, 5.9-7.2 times more adult vectors were found in the dam village compared with the control village. There was a 3.1% higher prevalence of an enlarged spleen in children under 10 years in the dam village than in the control village during the pre-intervention period, but no statistically significant difference was found in the incidence of falciparum malaria between the two villages during the same period. Source reduction was associated with a 49% (95% CI=46.6-50.0) relative reduction in An. arabiensis adults in the dam village compared with the pre-intervention period. There were very few cases of malaria during the intervention period in both villages making it impossible to judge whether malaria incidence had been reduced. These preliminary findings suggest that in areas of low intensity transmission community-led larval control may be a cheap and effective method of controlling malaria. Further, large-scale studies are needed to confirm these findings.     

The Relationship between Stress and Symptoms of Gastroesophageal Reflux: The Influence of Psychological Factors

This paper describes the first controlled study of the relationships among stress, psychological traits associated with chronic anxiety, acid reflux parameters, and perceptions of reflux symptoms. Seventeen subjects with symptomatic reflux disease were studied using a 2 (high vs. low gastrointestinal susceptibility score) × 2 (stress vs. neutral tasks) × 3 (periods 1, 2, or 3) experimental design. It was found that the stress tasks produced significant increases in systolic and diastolic blood pressure, pulse rates, and subjective ratings of anxiety and reflux symptoms. The stress tasks, however, did not influence objective parameters of acid reflux (total acid exposure, number of reflux episodes, duration of longest reflux episode). Moreover, the effect of stress on reflux ratings was due primarily to the responses of the subjects with high gastrointestinal susceptibility scale scores. These subjects reflux ratings remained at high levels during all stress periods, whereas subjects in all other experimental conditions reported decreased reflux symptoms across periods. These results suggest that reflux patients who are chronically anxious and exposed to prolonged stress may perceive low intensity esophageal stimuli as painful reflux symptoms. Future effort should be devoted to examining the efficacy of anxiolytic and behavioral therapies with these reflux patients.     

In vivo release and turnover of secreted platelet antiheparin proteins in rhesus monkey (Macaca mulatta)

Human and rhesus monkey platelets secrete at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4). Neither of these proteins showed species-related antigenic differences. As determined by radioimmunoassay, the levels of PF4 and LA-PF4 antigen per 10(9) monkey platelets amounted to 10.7 and 20.3 microgram, respectively. One milliliter of monkey plasma prepared from blood collected into an anticoagulant composed of EDTA, prostaglandin E1, and theophylline solution contained 22.4 ng LA-PF4 and 8.0 ng PF4. Concentrations of these two platelet-specific proteins in monkeys closely resembled levels found in human platelets and plasma. Infusion of prostacyclin (PGI2) (100 or 300 ng/kg/min) into monkeys for 15 min resulted in a significant decrease of plasma levels of LA-PF4 antigen and of PF4 by 40%--60% (p < 0.0001). This decrease was related to the inhibitory effect of PGI2 on the secretion of platelets stimulated by a catheter or by venipuncture. Longer infusion of PGI2 did not produce further significant change. The supernate obtained after aggregation of human platelets stimulated by thrombin was injected into monkeys receiving PGI2 infusion. The disappearance of LA-PF4 antigen in monkey plasma followed a biphasic exponential curve with half-lives for the fast and slow components of 8.4 and 63 min. PF4 disappeared faster but followed the same pattern (half-lives for the fast and slow component of 2.1 and 70 min). Analysis of the experimental data suggests that the low levels of secreted platelet proteins in monkey plasma are related to their minimal in vivo release and to their rapid clearance.     

Risk factors for avascular bone necrosis in systemic lupus erythematosus

OBJECTIVE: To study the predictive factors for avascular necrosis (AVN) of bone in patients with systemic lupus erythematosus (SLE). METHOD: The records of 38 SLE patients who developed clinically apparent AVN during the course of their disease were reviewed. Information on clinical presentation, corticosteroid usage and autoantibody profiles was obtained, and comparison was made between these patients and 143 consecutive control SLE patients who did not have AVN. RESULTS: The point prevalence of AVN in our SLE population was 12%. Patients with AVN, when compared with controls, had a significantly higher incidence of neurological disease (39% vs 14%; P < 0.001) and Cushingoid body habitus after steroid treatment (79% vs 53%; P = 0.004). The highest cumulative prednisolone dose in 1 and 4 months was significantly higher in the AVN group than the controls (1.8 vs 1.1 and 4.5 vs 2.8 g, respectively; P < 0.01 in both) and showed a linear trend with the incidence of AVN (chi2 test for trend, P < 0.01 in both). Lupus anticoagulant was associated with AVN (P = 0.02, odds ratio 2.88 [1.14- 7.28]). Logistic regression analysis revealed that the highest cumulative prednisolone dose administered in 4 months, the maximum and mean daily prednisolone dosage, and the lupus anticoagulant were independent risk factors for AVN. CONCLUSIONS: Corticosteroid remains the major predisposing factor for AVN in SLE. Patients who require an initial high-dose steroid for disease control are at risk of AVN, especially if they are positive for the lupus anticoagulant or develop Cushingoid habitus after steroid treatment. High-risk patients should be closely monitored so that early AVN can be diagnosed by sensitive techniques such as magnetic resonance imaging and radioisotope bone scanning.