Mutations in the X‐linked gene doublecortin, which encodes a protein with no clear structural homologues, are found in pedigrees in which affected females show “double cortex” syndrome (DC; also known as subcortical band heterotopia or laminar heterotopia) and affected males show X‐linked lissencephaly. Mutations in doublecortin also cause sporadic DC in females. To determine the incidence of doublecortin mutations in DC, we investigated a cohort of eight pedigrees and 47 sporadic patients with DC for mutations in the doublecortin open reading frame as assessed by single‐stranded conformational polymorphism analysis. Mutations were identified in each of the eight DC pedigrees (100%), and in 18 of the 47 sporadic DC patients (38%). Identified mutations were of two types, protein truncation mutations and single amino acid substitution mutations. However, pedigrees with DC displayed almost exclusively single amino acid substitution mutations, suggesting that patients with these mutations may have less of a reproductive disadvantage versus those patients with protein truncation mutations. Single amino acid substitution mutations were tightly clustered in two regions of the open reading frame, suggesting that these two regions are critical for the function of the Doublecortin protein. Ann Neurol 1999;45:146–153

Objectives Vaccination for dengue with the live attenuated tetravalent CYD-TDV vaccine (Dengvaxia®) is only recommended in individuals who have had prior dengue virus (DENV) infection. Rapid diagnostic tests (RDT) for past DENV infection would offer a convenient method for pre-vaccination screening at point-of-care. A systematic review was conducted to evaluate the performance of current dengue RDTs for determining dengue serostatus, using IgG antibodies against DENV as a marker of past infection. Methods PubMed and EMBASE databases were searched from 2000 to 2018 to identify studies evaluating dengue RDTs in individuals with known or possible previous DENV infection. Study quality was evaluated using GRADE and QUADAS-2 criteria. Semi-structured interviews were also performed with available dengue RDT manufacturers. Results The performance of four dengue IgG RDTs was determined in 3137 individuals across ten studies conducted in 13 countries, with serum used in most of the studies. No studies reported data for determining dengue serostatus, and limited data were available regarding cross-reactivity with other viruses. The majority of studies demonstrated sensitivities and specificities between 80% and 100% for dengue IgG detection in samples from secondary infection or convalescent time-points after recent infection. Conclusions Although current dengue IgG RDTs have shown reasonable performance compared with laboratory-based tests in secondary infection, additional research is needed to determine how RDTs would perform in relevant populations targeted for vaccination. New RDTs or modifications to current RDTs are feasible and may optimize the performance of these tests for use in a pre-vaccination screening approach.

Mutations in the X‐linked doublecortin gene appear in many sporadic cases of double cortex (DC; also known as subcortical band heterotopia), a neuronal migration disorder causing epilepsy and mental retardation. The purpose of this study was to examine why a significant percentage of sporadic DC patients had been found not to harbor doublecortin mutations and to determine whether clinical features or magnetic resonance imaging scan appearance could distinguish between patients with and without doublecortin mutations. Magnetic resonance imaging scan analysis differentiated patients into the following four groups: anterior biased/global DC with doublecortin mutation (16 of 30; 53%), anterior biased/global DC without mutation (8 of 30; 27%), posterior biased DC without mutation (3 of 30; 10%), and limited/unilateral DC without mutation (3 of 30; 10%). The presence of these atypical phenotypes suggests that other genetic loci or mosaicism at the doublecortin locus may be responsible for this diversity of DC cases. Ann Neurol 2000;47:265–269

Tuberculosis (TB) remains the second leading cause of death from an infectious disease in adults. Extrapulmonary TB (EPTB) accounts for about 25% of all cases of active TB. Pleural TB is the second most common manifestation of EPTB.Existing tests for the diagnosis of pleural TB have major limitations in terms of accuracy, time to diagnosis and drug resistance testing, and require special expertise for sample acquisition and interpretation of the results. Biopsy of the pleural tissue for combined histological examination and culture is considered the diagnostic gold standard, albeit imperfect [1,2].The Xpert MTB/RIF assay (Xpert; Cepheid, Sunnyvale, CA, USA) is a rapid, World Health Organization (WHO) endorsed, automated PCR test optimised for respiratory specimens that can detect both Mycobacterium tuberculosis (MTB) and rifampicin resistance [3,4]. Given the limitations of available tests for the diagnosis of pleural TB, several studies have evaluated the performance of Xpert using pleural fluid as a sample type. Overall, these studies show limited accuracy with sensitivity averaging around 44% [5][6][7]. However, the preferred specimen for the diagnosis of pleural TB is pleural tissue. To date, the evaluation of Xpert performed on pleural tissue has been limited to isolated samples within larger studies [4,6,7].We enrolled consecutive adult patients that were evaluated for pleural TB in the pulmonary clinic and inpatient ward at the Christian Medical College, Vellore, India. Pleural TB was suspected based on clinical symptoms and radiographic evidence of a pleural effusion. Information on demographics, comorbidities, presenting symptoms and results of diagnostic evaluation were collected prospectively. The institutional review boards of the Christian Medical College and McGill University, Montreal, Canada, approved the study.All recruited patients underwent thoracentesis for evaluation of pleural fluid. One specimen was processed with routine diagnostics including fluorescence smear microscopy, adenosine deaminase (ADA; Diazyme Laboratories, San Diego, CA, USA), liquid cultures (Mycobacterium Growth Indicator Tube; Becton Dickinson, Sparks, MD, USA) and solid cultures (Löwenstein-Jensen medium). The second sample was used for Xpert testing. A pleural biopsy was performed, when clinically indicated and safely feasible. Pleural tissue was evaluated with histopathology, smear microscopy and culture. : sensitivity 0% (none out of 17; 95% CI 0-20%) and specificity 97.4% (37 out of 38; 95% CI 86-100%). 1427Pleural fluid was centrifuged (1370 6g for 15 min) and the concentrated sediment, resuspended in 1 mL of the original supernatant, was used for Xpert [5]. Pleural tissue was finely ground and re-suspended in 1 mL of sterile saline [8]. The Xpert ''sample reagent'' was added (2:1 ratio for both pleural fluid and pleural tissue samples) and, after incubation, 2 mL were transferred into a G4 cartridge.We defined two composite reference standards (CRS) for the diagnosis of TB. The first CRS (CRS-1) identified confirme...

Sputum induction, bronchoalveolar lavage, or gastric aspiration are often needed to produce adequate diagnostic respiratory samples from people with HIV in whom tuberculosis is suspected. Since these procedures are rarely appropriate in less-developed countries, we compared the performances of a simple string test and the gold-standard sputum induction. 160 HIV-positive adults under investigation for tuberculosis, and 52 asymptomatic HIV-positive control patients underwent the string test followed by sputum induction. The string test detected tuberculosis in 14 patients in whom this disease was suspected; sputum induction detected only eight of them (McNemar's test, p=0·03). These preliminary data suggest that the string test is safe and effective for retrieval of useful clinical specimens for diagnosis of pulmonary tuberculosis, and is at least as sensitive as sputum induction.Diagnosis of tuberculosis in people with HIV, especially those with a low CD4 count, is complicated by an altered symptom spectrum. Thus, a productive cough, the source of diagnostic sputum samples in HIV-negative people, might not be prominent, necessitating the use of procedures such as sputum induction or gastric aspiration.We postulated that the string test, previously used successfully for retrieval of enteropathogens such as Giardia lamblia1 and Salmonella typhi2 from the upper gastrointestinal tract, might be an effective alternative method to obtain swallowed sputum in such patients. The primary objective of this study was to compare the string test with sputum induction (the gold-standard comparator) for diagnosis of tuberculosis in HIVpositive patients who had proven smear negative for Mycobacterium tuberculosis from a previous sample. The study was approved by the ethics review boards of Asociación Correspondence to: Dr David A J Moore, Wellcome Centre for Clinical Tropical Medicine at Imperial College London (Hammersmith Campus), DuCane Road, London W12 0NN, UK daj.moore@imperial.ac.uk. Contributors R Gilman and E Ticona had the original idea for the protocol, and C Evans oversaw the study. R Gilman, C Evans, C Hong, and E Ticona were responsible for study design. D Vargas, E Ticona, M Ñavincopa, L García, C Hong, and R Luo enrolled patients. L Caviedes was responsible for all laboratory work. R Escombe contributed to data analysis and manuscript preparation. D Moore helped with study design and undertook analysis of results and preparation of the report. Conflict of interest statementWe declare that we have no conflict of interest. Though all previous sputum samples were of poor quality, 90 were sent for mycobacterial culture on Ogawa medium in the hospital microbiology department, all of which proved negative. During the same time, 52 HIV-positive control volunteers with no suspicion of tuberculosis and no previous sputum examination were also enrolled to allow estimation of the string test's specificity. All participants were provided with a study information sheet and gave written informed consent. Europe PMC Funde...