Systematic review of appropriate cognitive assessment instruments used in clinical trials of schizophrenia,major depressive disorder and bipolar disorder

Cognitive dysfunction is increasingly recognized as a symptom in mental conditions including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BPD). Despite the many available cognitive assessment instruments, consensus is lacking on their appropriate use in clinical trials. We conducted a systematic literature review in Embase, PubMed/Medline and PsychINFO to identify appropriate cognitive function instruments for use in clinical trials of schizophrenia, MDD, and BPD. Instruments were identified from the articles. Instruments and articles were excluded if they did not address schizophrenia, MDD, or BPD. Instrument appropriateness was further assessed by the criteria of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative: test–retest reliability, utility, relationship to functional status, potential changeability to pharmacological agents, and tolerability and practicality for clinical trials. The database search yielded 173 articles describing 150 instruments used to assess cognitive function. Seventeen additional instruments were identified through Google and clinicaltrials.gov. Among all these, only 30 (18%) were deemed appropriate for use in the diseases of interest. Of these, 27 were studied in schizophrenia, one in MDD and two in BPD. These findings suggest the need for careful selection of appropriate cognitive assessment instruments, as not all may be valid in these disorders.     

Antimalarial drug efficacy and resistance in malaria-endemic countries in HANMAT-PIAM_net countries of the Eastern Mediterranean Region 2016–2020: Clinical and genetic studies

Introduction

The World Health Organization recommends regular monitoring of the efficacy of nationally recommended antimalarial drugs. We present the results of studies on the efficacy of recommended antimalarials and molecular markers of artemisinin and partner resistance in Afghanistan, Pakistan, Somalia, Sudan and Yemen.

Methods

Single-arm prospective studies were conducted to evaluate the efficacy of artesunate-sulfadoxine-pyrimethamine (ASSP) in Afghanistan and Pakistan, artemether-lumefantrine (AL) in all countries, or dihydroartemisinin-piperaquine (DP) in Sudan for the treatment of Plasmodium falciparum. The efficacy of chloroquine (CQ) and AL for the treatment of Plasmodium vivax was evaluated in Afghanistan and Somalia, respectively. Patients were treated and monitored for 28 (CQ, ASSP and AL) or 42 (DP) days. Polymerase chain reaction (PCR)-corrected cure rate and parasite positivity rate at Day 3 were estimated. Mutations in the P. falciparum kelch 13 (Pfk13) gene and amplifications of plasmepsin (Pfpm2) and multidrug resistance-1 (Pfmdr-1) genes were also studied.

Results

A total of 1680 (249 for ASSP, 1079 for AL and 352 for DP) falciparum cases were successfully assessed. A PCR-adjusted ASSP cure rate of 100% was observed in Afghanistan and Pakistan. For AL, the cure rate was 100% in all but four sites in Sudan, where cure rates ranged from 92.1% to 98.8%. All but one patient were parasite-free at Day 3. For P. vivax, cure rates were 98.2% for CQ and 100% for AL. None of the samples from Afghanistan, Pakistan and Yemen had a Pfk13 mutation known to be associated with artemisinin resistance. In Sudan, the validated Pfk13 R622I mutation accounted for 53.8% (14/26) of the detected non-synonymous Pfk13 mutations, most of which were repeatedly detected in Gadaref. A prevalence of 2.7% and 9.3% of Pfmdr1 amplification was observed in Pakistan and Yemen, respectively.

Conclusion

High efficacy of ASSP, AL and DP in the treatment of uncomplicated falciparum infection and of CQ and AL in the treatment of P. vivax was observed in the respective countries. The repeated detection of a relatively high rate of Pfk13 R622I mutation in Sudan underscores the need for close monitoring of the efficacy of recommended ACTs, parasite clearance rates and Pfk13 mutations in Sudan and beyond. Registration numbers of the trials: ACTRN12622000944730 and ACTRN12622000873729 for Afghanistan, ACTRN12620000426987 and ACTRN12617001025325 for Pakistan, ACTRN12618001224213 for Somalia, ACTRN12617000276358, ACTRN12622000930785 and ACTRN12618001800213 for Sudan and ACTRN12617000283370 for Yemen.     

Macular cystoid spaces in patients with retinal dystrophy

Background: Non leaking macular cystoid spaces (MCS) are seen in some retinal dystrophies. Carbonic anhydrase inhibitor (CAI) treatment may reduce the size of MSC and improve vision.

Methods: A retrospective study of patients with retinal dystrophy with MCS seen between 2009 and 2013 at two sites. Patients had ophthalmic examination, optical coherence tomography (OCT) and genetic testing. Patients with vision worse than 20/30 were treated with CAI. Post treatment visual acuity (VA), central foveal zone (CFZ) thickness, and qualitative estimation of MCS size were assessed.

Results: Eighteen patients, 6–47 years old, were included. IVFA was performed in 15 (83%) patients. Of the 26 eyes in 13 patients who were treated and followed, VA improved in 15 eyes (58%) of 10 patients. Ten of these 15 eyes had decreased CFZ thickness and 9/10 showed qualitative MCS improvement. Regression analysis showed that change in CFZ thickness was not significantly predictive of change in final visual acuity (p = 0.405). Five of 15 eyes with improved VA had paradoxically increased CFZ thickness and 2/5 had enlarged MCS. Three of the treated eyes (11%) in two patients had decreased VA with decreased CFZ thickness and improved MCS in 2/3 eyes. Eight eyes (31%) in six patients showed no change in VA with decreased CFZ thickness in 6/8 eyes with improved MCS. Genetic testing showed mutations of NR2E3, XLRS, CRB1, GPR98 and CNGB1.

Conclusion: Non-leaking MCS occur in a variety of retinal dystrophies. Therapy with topical or systemic CAI has variable efficacy and may result in VA improvement with or without qualitative improvement in MCS and CFZ thickness.     

TOPORS, implicated in retinal degeneration, is a cilia-centrosomal protein

We recently reported that mutations in the widely expressed nuclear protein TOPORS (topoisomerase I-binding arginine/serine rich) are associated with autosomal dominant retinal degeneration. However, the precise localization and a functional role of TOPORS in the retina remain unknown. Here, we demonstrate that TOPORS is a novel component of the photoreceptor sensory cilium, which is a modified primary cilium involved with polarized trafficking of proteins. In photoreceptors, TOPORS localizes primarily to the basal bodies of connecting cilium and in the centrosomes of cultured cells. Morpholino-mediated silencing of topors in zebrafish embryos demonstrates in another species a comparable retinal problem as seen in humans, resulting in defective retinal development and failure to form outer segments. These defects can be rescued by mRNA encoding human TOPORS. Taken together, our data suggest that TOPORS may play a key role in regulating primary cilia-dependent photoreceptor development and function. Additionally, it is well known that mutations in other ciliary proteins cause retinal degeneration, which may explain why mutations in TOPORS result in the same phenotype.     

Neonatal Hyperbilirubinemia in infants with G6PD c.563C > T Variant

ABSTRACT: BACKGROUND: There is a strong correlation between glucose-6-phosphate dehydrogenase (G6PD) deficiency and neonatal hyperbilirubinemia with a rare but potential threat of devastating acute bilirubin encephalopathy. G6PD deficiency was observed in 4-14% of hospitalized icteric neonates in Pakistan. G6PD c.563C > T is the most frequently reported variant in this population. The present study was aimed at evaluating the time to onset of hyperbilirubinemia and the postnatal bilirubin trajectory in infants having G6PD c.563C > T. METHODS: This was a case-control study conducted at The Aga Khan University, Pakistan during the year 2008. We studied 216 icteric male neonates who were re-admitted for phototherapy during the study period. No selection was exercised. Medical records showed that 32 were G6PD deficient while 184 were G6PD normal. Each infant was studied for birth weight, gestational age, age at the time of presentation, presence of cephalhematoma, sepsis and neurological signs, peak bilirubin level, age at peak bilirubin level, days of hospitalization, whether phototherapy or exchange blood transfusion was initiated, and the outcome. During hospital stay, each baby was tested for complete blood count, reticulocyte count, ABO and Rh blood type, direct antiglobulin test and quantitative G6PD estimation [by kinetic determination of G6PDH]. G6PDgenotype was analyzed in 32 deficient infants through PCRRFLP analysis and gene sequencing. RESULTS: G6PD variants c.563C > T and c.131 C > G were observed in 21 (65%) and three (9%) of the 32 G6PD deficient infants, respectively. DNA of eight (25%) newborns remained uncharacterized. In contrast to G6PD normal neonates, infants with c.563C > T variant had significantly lower enzyme activity (mean +/- 1SD; 0.3 +/- 0.2 U/gHb vs. 14.0 +/- 4.5 U/gHb, p < 0.001) experienced higher peak levels of total serum bilirubin (mean +/- 1SD; 16.8 +/- 5.4 mg/dl vs. 13.8 +/- 4.6 mg/dl, p = 0.008) which peaked earlier after birth (mean +/- 1SD 2.9 +/- 1.6 vs. 4.3 +/- 2.3 days, p = 0.007). No statistically significant difference was observed in mean weight, age at presentation, hemoglobin, reticulocyte count, TSH level, hospital stay or in the frequency of initiation of phototherapy or blood exchange between the two groups. CONCLUSIONS: We concluded that infants with G6PD c.563C > T variant developed jaundice earlier than infants with normal G6PD enzyme levels. Compared to G6PD normal infants, G6PD c.563C > T carrying infants had significantly low G6PD activity.     

Effectiveness and Safety of Ketamine for Unipolar Depression: a Systematic Review

Major Depressive Disorder (MDD) is a common psychiatric disorder with major implications for healthcare system and socioeconomic burden. For chronic and treatment-resistant depression, Ketamine has emerged as a possible treatment option. This systematic review explores the evidence for the effectiveness and tolerability of Ketamine in patients with MDD. This systematic review was conducted following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. Eight electronic databases were searched by using search terms: (ketamine) AND (trial OR RCT OR clinical-trial) AND (depressive OR depression OR “depressive-disorder”). After a rigorous screening process against the predetermined eligibility criteria, 35 randomized controlled trials (RCTs) were included. Quality assessment of included studies was done by using the Cochrane risk-of-bias tool for RCTs. Thirty-five RCTs are included in this review article with majority of studies from United States, Iran, and China. Intravenous (IV) Ketamine was effective in 70% (21/30) of the included studies whereas oral and Intranasal (IN) Ketamine were effective in two and three studies, respectively. The majority of studies (6/8) using Ketamine as anesthetic agent during electroconvulsive therapy (ECT) failed to show an improvement compared to the participants receiving ECT and placebo. The most common reported side effects were nausea, vomiting, dizziness, diplopia, drowsiness, dysphoria, hallucinations, and confusion. Ketamine is an effective treatment option for patients with MDD with undesirable effects when administered via oral, IV and IN routes. Ketamine agumentation of ECT requires further exploration in well-designed studies with adequate sample size. The short-lived antidepressant effect of Ketamine is a potential limitation, therefore, further studies administering multiple infusions for acute treatment and maintenance are necessary.