A systematic review and meta-analysis of miRNAs for the detection of cervical cancer.

Aim: This study aimed to critically appraise the evidence of the diagnostic effectiveness of miRNAs for the detection of cervical cancer. Methods & materials: A systematic review and meta-analysis was performed, searching PubMed, EMBASE and Web of Science. An umbrella meta-analysis of meta-analyses of individual biomarkers was performed. A Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment of evidence was also performed. Results: A total of 52 miRNAs were included. Umbrella meta-analysis revealed significant heterogeneity in terms of sensitivity, specificity, receiver operating characteristic (ROC), positive predictive value and/or negative predictive value. Umbrella effects were 0.76 (95% CI: 0.73-0.78), 0.78 (95% CI: 0.75-0.81), 0.77 (95% CI: 0.75-0.80), 0.75 (95% CI: 0.71-0.79) and 0.76 (95% CI: 0.74-0.79), respectively. Conclusion: Moderate quality evidence suggested miR199a-5p, miR21-5p and miR-141a had excellent diagnostic performance.

miRNAs are small chemical messengers that play a role in the regulation of protein produced inside the cytoplasm of cells, including cancer cells. In cervical cancer cells, miRNAs become dysregulated ­ that is, their levels become increased or decreased ­ and therefore detecting their relative abundance or absence in test samples may enable identification of cervical cancer. This study aimed to systematically collect and appraise the evidence for the diagnostic ability of miRNAs for detection of cervical cancer. A systematic appraisal of the evidence was conducted by searching three research databases (PubMed, EMBASE and Web of Science) to collect evidence published up to 13 November 2022. Results for diagnostic performance of 52 miRNAs were extracted from 20 relevant studies. An assessment of risk of bias for each study was performed using a standardized checklist, which identified one high-quality study, 18 moderate-quality studies and one low-quality study. Results for each individual biomarker were assessed by meta-analytic methods, which generated weighted averages for 38 of 52 miRNAs. All 52 miRNAs were then compared using an umbrella meta-analysis (a weighted average of all miRNA biomarkers), which identified significant differences in diagnostic ability between miRNAs. Sensitivity analyses suggested that these differences were partly explained by differences in grades of cervical cancer and differences in types of sample used for testing. A GRADE assessment of the overall evidence quality suggested that moderate-quality evidence supported further investigation of three miRNA biomarkers (miR-199a-5p, miR-21-5p and miR-141a), which performed excellently (i.e., better than the umbrella weighted average) across five performance parameters, including sensitivity, specificity, receiver operator characteristic, positive predictive value and negative predictive value. In summary, this study suggested miR-199a-5p, miR-21-5p and miR-141a had excellent diagnostic performance for detection of cervical cancer and recommends further investigation of these miRNAs in randomized controlled trials.

A systematic review and meta-analysis of the diagnostic effectiveness of human papillomavirus methylation biomarkers for detection of cervical cancer.

Background: The aim of this systematic review and meta-analysis was to assess the evidence for the diagnostic effectiveness of human papillomavirus (HPV) methylation biomarkers for detection of cervical cancer. Methods: PubMed, Embase and Web of Science were searched. Nine articles focusing on HPV methylation for detection of precancerous and cancerous cervical lesions were included. The QUADAS-2 tool was used for quality assessment. The receiver operating characteristic (ROC) was the main diagnostic performance parameter extracted. Results: Of the nine articles included in this study, seven were of moderate quality and two were of high quality. A meta-analysis of the ROC for 27 HPV methylation biomarkers revealed an overall pooled ROC of 0.770 (95% CI: 0.720-0.819; I2: 98.4%; Q: 1537.4; p < 0.01). Four methylation biomarkers had strong diagnostic ability (ROC > 0.900), 17 were moderate (ROC: 0.7000-0.8999) and six were poor (ROC < 0.700). Conclusion: HPV methylation biomarkers hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

This study reviewed the literature to assess the available evidence for the ability of biomarkers based on human papillomavirus (HPV) methylation (i.e., the detection of methyl groups in HPV DNA in cervical specimens) to screen for cervical precancerous and cancerous lesions. Scientific databases were searched, and abstracts screened for relevance. The quality of the included articles was assessed using a quality assessment tool called QUADAS-2. The main diagnostic performance parameter extracted from the included articles was the receiver operating characteristic (ROC), a measure of the ability of a biomarker to detect all true cases (true positives) while excluding all true non-cases (true negatives). After screening, nine articles were included, of which seven were of moderate quality and two were of high quality. ROC data were extracted for 27 biomarkers, of which four methylation biomarkers had high diagnostic ability (i.e., ROC > 0.900), 17 had moderate diagnostic ability (ROC: 0.7000­0.8999) and six had low diagnostic ability (ROC < 0.700). An umbrella meta-analysis (i.e., a weighted-average ROC for all HPV methylation biomarkers) revealed an ROC consistent with moderate diagnostic ability (0.770). The main conclusion from this study was that HPV methylation biomarkers, especially ones with high diagnostic ability, hold significant promise as independent screening tests for the detection of cervical precancerous and cancerous lesions.

Investigating the pro-cognitive and anti-depressant efficacy of metformin: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The preclinical and clinical data regarding the efficacy of metformin as a pro-cognitive and anti-depressant therapy is mixed. We conducted a systematic review and meta-analysis of randomised controlled trials investigating the effects of metformin on cognition and depressive symptoms. METHODS: The study was conducted in accordance with PRISMA guidelines (PROSPERO identifier: CRD42020184547). PubMed and Web of Science were searched (inception through to May 6, 2020) for trials which measured the effects (change from baseline to end-of-treatment) of metformin on cognition and depressive symptoms, compared to either placebo or other oral antidiabetic therapies. When feasible, pooled meta-analytic estimates were provided using a random-effects model. RESULTS: Eight studies met the inclusion criteria: four assessed only cognition, three assessed only depressive symptoms, and one study assessed both cognition and depressive symptoms. Results suggested that metformin was significantly superior to placebo in improving cognitive function in patients suffering with clinical conditions associated with cognitive impairment (SMD: 0.80; 95%CI: 0.46 to 1.15; p < 0.001; N = 2 studies; I2 = 0.0%). One study reported an association between improved cognition and depressive symptoms in a cohort of patients with type 2 diabetes mellitus and depression. Two studies investigating metformin versus pioglitazone showed a superior, but not significant, effect of pioglitazone on depressive symptoms (SMD: 1.56; 95%CI: -0.52 to 3.56; p = 0.13;I2 = 94.9%; N = 2 studies). LIMITATIONS: Assessment of risk of bias identified two studies as having "some concerns". CONCLUSIONS: Our findings suggest that metformin might be re-purposed for the treatment of cognitive deficits in select clinical conditions.

Fatality Rate and Survival Time of Laboratory-Confirmed COVID-19 for Patients in England During the First Wave of SARS-CoV-2 Infection: A Modelling Study.

Background Fatality rate estimates for coronavirus disease 2019 (COVID-19) have varied widely. A major confounding factor in fatality rate estimates is the survival time (time from diagnosis to death). Predictive models that incorporate the survival time benefit from greater accuracy due to the elimination of sampling bias. This study outlines a survival time-based predictive model that estimates a precise fatality rate for patients with laboratory-confirmed COVID-19. This model was utilised to predict deaths for COVID-19 patients who died during the first wave of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in England. Methodology This study included Public Health England (PHE) data for cumulative laboratory-confirmed COVID-19 cases (n = 143,463) and deaths (n = 30,028) that were reported by PHE between 30 January and 14 May 2020 in England, that is, from the first COVID-19 case in England and the most recently available data at the time of conducting this study. Fatality rate and survival time were estimated by linear regression analysis. This enabled the predicted cumulative COVID-19 deaths to be calculated up to 21 May 2020. Time periods with significantly different rates in daily deaths were identified using Joinpoint trend analysis. Results A fatality rate of 21.9% (95% confidence interval = 21.8% to 22.0%) with a survival time of seven days was determined for patients in England with laboratory-confirmed COVID-19 during the first wave of SARS-CoV-2 infection. Based on these estimates, predicted trends for cumulative and daily laboratory-confirmed COVID-19 deaths were generated with >99% and >96% accuracy with reported data, respectively. This model predicted that the number of cumulative laboratory-confirmed COVID-19 deaths in England was likely to be 31,420 by 21 May 2020. Joinpoint trend analysis identified significant differences in predicted daily laboratory-confirmed COVID-19 deaths during the following periods: 10.5 (6 to 17 March), 111.0 (17 to 27 March), 446.8 (27 March to 4 April), 817.0 (4 to 23 April), 536.3 (23 April to 7 May), and 266.7 (7 to 21 May) daily deaths (P < 0.001). Conclusions During the first wave of SARS-CoV-2 infection in England, the fatality rate of laboratory-confirmed COVID-19 was 21.9%. The survival time of these patients was seven days. The predictive model presented in this study can be adapted for estimating COVID-19 deaths in different geographical regions. As such, this study has utility for clinicians, scientists, and policymakers responding to new waves of SARS-CoV-2 infection because the methodology can be applied to more recent time periods as new data for COVID-19 cases and deaths become available.

Opportunities to diagnose fibrotic lung diseases in routine care: A primary care cohort study.

BACKGROUND AND OBJECTIVE: Temporal trends of healthcare use in the period before a diagnosis of pulmonary fibrosis are poorly understood. We investigated trends in respiratory symptoms and LR HRU in the 10 years prior to diagnosis. METHODS: We analysed a primary care clinical cohort database (UK OPCRD) and assessed patients aged ≥40 years who had an electronically coded diagnosis of pulmonary fibrosis between 2005 and 2015 and a minimum 2 years of continuous medical records prior to diagnosis. Exclusion criteria consisted of electronic codes for recognized causes of pulmonary fibrosis such as CTD, sarcoidosis or EAA. RESULTS: Data for 2223 patients were assessed. Over the 10 years prior to diagnosis of pulmonary fibrosis, there was a progressive increase in HRU across multiple LR-related domains. Five years before diagnosis, 18% of patients had multiple healthcare contacts for LR complaints; this increased to 79% in the year before diagnosis, with 38% of patients having five or more healthcare contacts. CONCLUSION: There are opportunities to diagnose pulmonary fibrosis at an earlier stage; research into case-finding algorithms and strategies to educate primary care physicians is required.

Ultrasound Classification of Thyroid Nodules: A Systematic Review.

Ultrasound (US) based classification systems exist for the stratification of thyroid nodules based on the risk for malignancy. This systematic review aimed to assess the evidence for the performance of US-based thyroid nodule classification systems through correlation with fine needle aspiration biopsy (FNAB). PubMed and Scopus were searched using keywords that included 'ultrasound classification', 'thyroid nodules', 'fine needle aspiration', and 'malignancy'. Inclusion criteria were as follows: studies/reviews reporting on US imaging for the classification of thyroid nodules. Exclusion criteria were as follows: no comparison between US imaging findings and histology reports based on FNAB, no full English text available/accessible. The database searches identified 66 publications. After evaluation, 12 studies met the inclusion criteria. Two US-based classification systems for thyroid nodules were assessed: the Thyroid Imaging Reporting and Data System (TIRADS) and the American Thyroid Association (ATA) guidelines. For TIRADS, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) ranged from 70.6% to 97.4%, 29.3% to 90.4%, 23.3% to 64.3%, and 87.1% to 99.0%, respectively. The median sensitivity, specificity, PPV, and NPV for TIRADS was 90.0%, 57.4%, 49.0%, and 91.0%, respectively. One study comparing TIRADS with the ATA guidelines demonstrated that TIRADS was superior in terms of sensitivity, whereas the ATA guidelines were superior in terms of specificity and PPV. The high sensitivity and NPV of the US-based TIRADS classification system have excellent utility for correctly classifying nodules as positive for malignant disease and for predicting the absence of malignant disease. The paucity of studies assessing the ATA guidelines highlights avenues for further research comparing TIRADS with other systems of thyroid nodule classification.

Psychiatric Sequelae of Guillain-Barré Syndrome: Towards a Multidisciplinary Team Approach.

Guillain-Barré syndrome (GBS) is a post-infectious autoimmune polyneuropathy. Recent research has highlighted that GBS is associated with the onset of psychiatric symptoms which represent a burden for patients and close relatives. However, acute psychiatric sequelae due to GBS may be misinterpreted as 'intensive care unit (ICU) delirium'. This review outlines the existing evidence for the psychiatric symptoms associated with GBS with a view to improving psychoeducation of patients. The main psychiatric symptoms of GBS that have been reported in the literature include, stress, anxiety, depression, fatigue, sleep abnormalities, visual hallucinations, paranoid delusions, disorientation, terror and psychosis. These psychiatric symptoms, which occur during the acute phase of GBS, if not recognised and treated, may progress to long-term psychiatric problems that interfere with improvement of physical symptoms. A multidisciplinary team approach to the management of GBS may improve both physical and psychiatric recovery.

Prevalence and Characteristics of Asthma-Chronic Obstructive Pulmonary Disease Overlap in Routine Primary Care Practices.

Rationale: Adults may exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD), a situation recently described as asthma-COPD overlap (ACO). There is a paucity of information about ACO in primary care.Objectives: To estimate the prevalence and describe characteristics of individuals with ACO in primary care practices among patients currently diagnosed with asthma, COPD, or both; and to compare the prevalence and characteristics of ACO among the three source populations.Methods: The Respiratory Effectiveness Group conducted a cross-sectional study of individuals ≥40 years old and with ≥2 outpatient primary care visits over a 2-year period in the UK Optimum Patient Care Research Database. Patients were classified into one of three source populations based on diagnostic codes: 1) COPD only, 2) both asthma and COPD, or 3) asthma only. ACO was defined as the presence of all of the following 1) age ≥40 years, 2) current or former smoking, 3) post-bronchodilator airflow limitation (forced expiratory volume in 1 second/forced vital capacity <0.7), and 4) ≥12% and ≥200 ml reversibility in post-bronchodilator forced expiratory volume in 1 second.Results: Among 2,165 individuals (1,015 COPD only, 395 with both asthma and COPD, and 755 asthma only), the overall prevalence of ACO was 20% (95% confidence interval, 18-23%). Patients with ACO had a mean age of 70 years (standard deviation, 11 yr), 60% were men, 73% were former smokers (the rest were current smokers), and 66% were overweight or obese. Comorbid conditions were common in patients with ACO, including diabetes (53%), cardiovascular disease (36%), hypertension (30%), eczema (23%), and rhinitis (21%). The prevalence of ACO was higher in patients with a diagnosis of both asthma and COPD (32%) compared with a diagnosis of COPD only (20%; P < 0.001) or asthma only (14%; P < 0.001). Demographic and clinical characteristics of ACO varied across these three source populations.Conclusions: One in five individuals with a diagnosis of COPD, asthma, or both asthma and COPD in primary care settings have ACO based on the Respiratory Effectiveness Group ACO Working group criteria. The prevalence and characteristics of patients with ACO varies across the three source populations.

Changes in Persistent Asthma Care and Outcomes From 2006 to 2016 in France.

BACKGROUND: Changes in asthma care need to be documented at arrival of biotherapies. OBJECTIVES: To characterize changes in asthma care and outcomes in patients with persistent asthma. METHODS: Repeated transversal analyses were conducted on a historical cohort using the French national claims data over 10 years. Patients aged 18 to 40 years with either 1 or more (any-use population) or 4 or more (high-use population) yearly dispensings of controller therapy were selected. Clinical and demographic features were characterized, and comparisons were made between 2006 and 2016 to assess temporal changes in asthma therapy, health care resource utilization, and outcomes. RESULTS: In 2016, prevalent use of controller therapy was 5.2% (any-use population) and 0.8% (high-use population) of the population aged 18 to 40 years. In the any-use population, the use of long-acting ß2-agonists in monotherapy, and inhaled corticosteroids decreased (1.7% and 40.3% in 2016, respectively), whereas the use of fixed-dose combinations increased (56.4%). In both populations, visits to respiratory or hospital physicians and pulmonary function testing increased with time, in parallel to a decreasing number of general practitioner visits; in addition, oral corticosteroid use and incidence of emergency room visits increased. However, asthma hospitalizations and mortality remained low in both populations. CONCLUSIONS: Changes in persistent asthma care included replacement of inhaled corticosteroids by fixed-dose combinations, decreased use of long-acting ß2-agonists as a monotherapy, and increased involvement of secondary care physicians. In parallel, despite low figures for hospital admissions and mortality, overall use of oral corticosteroids and incidence of emergency room visits have increased over the last decade.

Matched cohort study of therapeutic strategies to prevent preschool wheezing/asthma attacks.

Background: An inhaled corticosteroid (ICS) or leukotriene receptor antagonist (LTRA) may prevent wheezing/asthma attacks in preschoolers with recurrent wheeze when added to short-acting ß-agonist (SABA). Objective: The aim of this historical matched cohort study was to assess the effectiveness of these treatments for preventing wheezing/asthma attacks. Methods: Electronic medical records from the Optimum Patient Care Research Database were used to characterize a UK preschool population (1-5 years old) with two or more episodes of wheezing during 1 baseline year before first prescription (index date) of ICS or LTRA, or repeat prescription of SABA. Children initiating ICS or LTRA on the index date were matched 1:4 to those prescribed only SABA for age, sex, year of index prescription, mean baseline SABA dose, baseline attacks, baseline antibiotic prescriptions, and eczema diagnosis. Wheezing/asthma attacks (defined as asthma-related emergency attendance, hospital admission, or acute oral corticosteroid prescription) during 1 outcome year were compared using conditional logistic regression. Results: Matched ICS and SABA cohorts included 990 and 3,960 children, respectively (61% male; mean [SD] age 3.2 [1.3] years), and matched LTRA and SABA cohorts included 259 and 1,036 children, respectively (65% male; mean [SD] age 2.6 [1.2] years). We observed no significant difference between matched cohorts in the odds of a wheezing/asthma attack: ICS vs SABA, OR (95% CI) 1.01 (0.85-1.19) and LTRA vs SABA, OR (95% CI) 1.28 (0.96-1.72). Conclusion: We found no evidence that initiation of ICS or LTRA therapy is associated with fewer attacks during 1 outcome year than SABA alone for a heterogeneous group of preschool children with recurrent wheeze in the real-life clinical setting.

Validating the Concept of COPD Control: A Real-world Cohort Study from the United Kingdom.

The concept of Chronic Obstructive Pulmonary Disease (COPD) control has been developed to inform therapeutic decision-making. We explored the validity of a definition of COPD control in a representative population of patients with COPD in the United Kingdom. Electronic medical records and linked COPD questionnaire data from the Optimum Patient Care Research Database were used to characterize control status. Patients were aged ≥40 years, with spirometry-confirmed COPD, current or ex-smokers, and continuous records throughout the study period. Control was evaluated based on COPD stability and patients' (i) clinical features or (ii) COPD Assessment Test (CAT) score over a three-month baseline period and linked to time to first exacerbation. Of 2788 eligible patients, 2511 (90%) had mild/moderate COPD and 277 (10%) had severe/very severe COPD based on Body Mass Index, Obstruction, Dyspnoea, Exacerbations (BODEx) cut-off of 4. Within the mild/moderate cohort, 4.5% of patients were controlled at baseline according to clinical features and 21.5% according to CAT threshold of 10. Within the severe/very severe cohort, no patients were controlled at baseline according to the proposed clinical features and 8.3% were controlled according to CAT threshold of 20. Compared with uncontrolled patients, time to first exacerbation was longer for controlled patients with mild/moderate COPD but not for those with severe/very severe COPD. Lowering the BODEx threshold for severity classification to 2 increased the number of patients achieving control. CAT scores were not good predictors of the risk of future exacerbation. With the proposed definition, very few patients were defined as controlled.

Pathogenic potential of antibodies to the GABAB receptor.

GABAB receptor (GABABR) autoantibodies have been detected in the serum of immunotherapy-responsive patients with autoimmune encephalitis. This study aimed to investigate the effect of immunoglobulin G (IgG) from a patient with GABABR antibodies on primary neuronal cultures and acute slices of entorhinal cortex. Primary hippocampal neuronal cultures were incubated with serum immunoglobulin from patients with GABABR or AMPA receptor (AMPAR) antibodies for up to 72 h to investigate their effect on receptor surface expression. Whole-cell patch-clamp recordings from layer III pyramidal cells of the medial entorhinal cortex were used to examine the effect on neuronal activity. GABABR surface expression was unaltered by incubation with GABABR antibodies. By contrast, after 24 h application of AMPAR antibodies, AMPARs were undetectable. However, acute application of GABABR IgG decreased both the duration of network UP states and the spike rate of pyramidal cells in the entorhinal cortex. GABABR antibodies do not appear to affect GABABRs by internalization but rather reduce excitability on the medial temporal lobe networks. This unusual mechanism of action may be exploited in rational drug development strategies.

Inappropriate asthma therapy-a tale of two countries: a parallel population-based cohort study.

Against recurrent controversies around the safety of short- and long-acting ß2-agonists (SABA and LABA), and the National Review of Asthma Deaths inquiry in the United Kingdom, we investigated the prevalence of inappropriate therapy in asthma. Our study aimed to determine the prevalence of inappropriate use of asthma therapy in the United Kingdom and in France. Two interval, parallel, population-based cohorts (2007 and 2013) were developed in each country by using the UK OPCRD and the French EGB databases. Patients aged 6-40 years were studied over the 12-month period following inclusion, regarding overuse (⩾12 units) of SABA, use of LABA without inhaled corticosteroids (ICS) and ⩾2-fold higher use of LABA compared with that of ICS. Overall, 39,743 UK and 4,910 French patients were included in 2007, and 14,036 and 5,657 patients, respectively, were included in 2013. UK adults were more frequently exposed to SABA overuse compared with those in France in both periods, with an upward trend in the United Kingdom (P<0.05). In 2013, LABA use without ICS occurred in 0.1% and 1.5% of United Kingdom and French adults, respectively. Unbalanced use of LABA relative to ICS became marginal in both countries in 2013. Inappropriate use of therapy was less marked, but present, in children. Inappropriate therapy remains a common issue in asthma. Based on our figures, it may be estimated that >210,000 British and >190,000 French asthmatics aged 6-40 years were inappropriately treated in 2013.

Antibodies to AMPA receptors in Rasmussen's encephalitis.

Rasmussen's encephalitis is a rare progressive childhood disorder characterized by frequent severe seizures, hemiparesis, encephalitis and mental deterioration, and associated with severe unilateral neuroinflammation. Autoantibodies, particularly to the GluA3 subtype of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propinonic acid receptor (AMPAR) were reported in the 1990s but not always confirmed. To explore further, sera from 52 patients with Rasmussen's encephalitis were tested by cell-based assays for antibodies to AMPAR GluA1/2/3, N-methyl-d-aspartate (NMDA NR1/2b), γ-aminobutyric acid type A and B (GABAAR α1/γ2/ß2 and GABABR b1/b2) receptors, for potassium channel complex proteins, and for binding to live cortical and hippocampal neuronal cultures. Two patients' sera (3.8%) bound to HEK cells co-transfected with the GluA2 and GluA3 subunits. One additional patient had a low level of VGKC-complex antibodies. These three, and seven additional, sera bound to hippocampal cultures. No other antibodies were detected. Thus, despite the rarity of GluA2/3 antibodies, 10 patients (19.2%) had evidence of antibodies to neuronal antigens. Whether these antibodies play a primary role in RE, or appear secondary to the neuro-inflammatory damage in this highly destructive disease, requires further study.

Paraneoplastic neurologic disorders in small cell lung carcinoma: A prospective study.

OBJECTIVE: To determine the frequency and range of paraneoplastic neurologic disorders (PNDs) and neuronal antibodies in small cell lung carcinoma (SCLC). METHODS: Two hundred sixty-four consecutive patients with biopsy-proven SCLC were recruited at the time of tumor diagnosis. All patients underwent full neurologic examination. Serum samples were taken prior to chemotherapy and analyzed for 15 neuronal antibodies. Thirty-eight healthy controls were analyzed in parallel. RESULTS: PNDs were quite prevalent (n = 24, 9.4%), most frequently Lambert-Eaton myasthenic syndrome (3.8%), sensory neuronopathy (1.9%), and limbic encephalitis (1.5%). Eighty-seven percent of all patients with PNDs had antibodies to SOX2 (62.5%), HuD (41.7%), or P/Q VGCC (50%), irrespective of their syndrome. Other neuronal antibodies were found at lower frequencies (GABAb receptor [12.5%] and N-type VGCC [20.8%]) or very rarely (GAD65, amphiphysin, Ri, CRMP5, Ma2, Yo, VGKC complex, CASPR2, LGI1, and NMDA receptor [all <5%]). CONCLUSIONS: The spectrum of PNDs is broader and the frequency is higher than previously appreciated, and selected antibody tests (SOX2, HuD, VGCC) can help determine the presence of an SCLC.

Antibodies to GABAA receptor α1 and γ2 subunits: clinical and serologic characterization.

OBJECTIVE: To search for antibodies against neuronal cell surface proteins. METHODS: Using immunoprecipitation from neuronal cultures and tandem mass spectrometry, we identified antibodies against the α1 subunit of the γ-aminobutyric acid A receptor (GABAAR) in a patient whose immunoglobulin G (IgG) antibodies bound to hippocampal neurons. We searched 2,548 sera for antibodies binding to GABAAR α, ß, and γ subunits on live HEK293 cells and identified the class, subclass, and GABAAR subunit specificities of the positive samples. RESULTS: GABAAR-Abs were identified in 40 of 2,046 (2%) referred sera previously found negative for neuronal antibodies, in 5/502 (1%) previously positive for other neuronal surface antibodies, but not in 92 healthy individuals. The antibodies in 40% bound to either the α1 (9/45, 20%) or the γ2 subunits (9/45, 20%) and were of IgG1 (94%) or IgG3 (6%) subclass. The remaining 60% had lower antibody titers (p = 0.0005), which were mainly immunoglobulin M (IgM) (p = 0.0025), and showed no defined subunit specificity. Incubation of primary hippocampal neurons with GABAAR IgG1 sera reduced surface GABAAR membrane expression. The clinical features of 15 patients (GABAAR α1 n = 6, γ2 n = 5, undefined n = 4) included seizures (47%), memory impairment (47%), hallucinations (33%), or anxiety (20%). Most patients had not been given immunotherapies, but one with new-onset treatment-resistant catatonia made substantial improvement after plasma exchange. CONCLUSIONS: The GABAAR α1 and γ2 are new targets for antibodies in autoimmune neurologic disease. The full spectrum of clinical features, treatment responses, correlation with antibody specificity, and in particular the role of the IgM antibodies will need to be assessed in future studies.

Autoantibodies to neuronal antigens in children with new-onset seizures classified according to the revised ILAE organization of seizures and epilepsies.

PURPOSE: Potentially pathogenic autoantibodies are found increasingly in adults with seizure disorders, including focal seizures and those of unknown cause. In this study, we investigated a cohort of children with new-onset seizures to see whether there were autoantibodies and the relationship to any specific seizure or epilepsy type. METHODS: We prospectively recruited 114 children (2 months to 16 years) with new-onset seizures presenting between September 2009 and November 2011, as well as 65 controls. Patients were clinically assessed and classified according to the new International League Against Epilepsy (ILAE) organization of seizures and epilepsies classification system. Sera were tested for autoantibodies to a range of antigens, blind to the clinical and classification details. KEY FINDINGS: Eleven (9.7%) of 114 patients were positive for one or more autoantibodies compared to 3 of 65 controls (4.6%, p = ns). Patients had antibodies to the voltage-gated potassium channel (VGKC) complex (n = 4), contactin-associated protein-like 2 (CASPR2) (n = 3), N-methyl-d-aspartate receptors (NMDARs) (n = 2), or VGKC-complex and NMDAR (n = 2). None had antibodies to glutamic acid decarboxylase, contactin-2, or to glycine, 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA), or γ-aminobutyric acid B receptors. Ten of these 11 patients were classified as having epilepsy according to the new ILAE organization of seizures and epilepsy. Although, there were no significant differences in the demographic and clinical features between antibody-positive and antibody-negative patients, the classification of "unknown cause" was higher in the antibody positive (7/10; 70%) compared with the antibody negative subjects (23/86; 26.7%; p = 0.0095, Fisher's exact test). Furthermore, four of these seven patients with epilepsy (57.1%) were classified as having predominantly focal seizures compared with 12 of the 86 antibody-negative patients (13.9%; p = 0.015). SIGNIFICANCE: Because autoantibodies were more frequent in pediatric patients with new-onset epilepsy of "unknown cause," often with focal epilepsy features, this group of children may benefit most from autoantibody screening and consideration of immune therapy.

Acute onset of focal seizures, psychiatric features and confusion: a case of autoimmune encephalitis?

An elderly woman presented with disorganised thinking, unusual behaviour and clustered episodes of speech arrest accompanied by right-sided face and arm twitching. The following investigations were normal: interictal electroencephalography, brain MRI, cerebrospinal fluid viral PCR and cell count and voltage-gated potassium channel-complex, N-methyl-d-aspartate receptor, gamma-aminobutyric acid (B) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, glycine receptor, glutamic acid decarboxylase and paraneoplastic antibodies. The syndrome showed partial spontaneous resolution but 1 year later, typical postencephalopathic features persisted including disinhibition and alteration of sleep-wake cycle. The most likely clinical diagnosis was autoimmune encephalitis and the broader differential diagnoses are discussed within the article. This case demonstrates the need to be aware of this under-recognised and potentially treatable entity.

Importance of Arg-599 of ß-galactosidase (Escherichia coli) as an anchor for the open conformations of Phe-601 and the active-site loop.

Structural and kinetic data show that Arg-599 of ß-galactosidase plays an important role in anchoring the "open" conformations of both Phe-601 and an active-site loop (residues 794-803). When alanine was substituted for Arg-599, the conformations of Phe-601 and the loop shifted towards the "closed" positions because interactions with the guanidinium side chain were lost. Also, Phe-601, the loop, and Na+, which is ligated by the backbone carbonyl of Phe-601, lost structural order, as indicated by large B-factors. IPTG, a substrate analog, restored the conformations of Phe-601 and the loop of R599A-ß-galactosidase to the open state found with IPTG-complexed native enzyme and partially reinstated order. ᴅ-Galactonolactone, a transition state analog, restored the closed conformations of R599A-ß-galactosidase to those found with ᴅ-galactonolactone-complexed native enzyme and completely re-established the order. Substrates and substrate analogs bound R599A-ß-galactosidase with less affinity because the closed conformation does not allow substrate binding and extra energy is required for Phe-601 and the loop to open. In contrast, transition state analog binding, which occurs best when the loop is closed, was several-fold better. The higher energy level of the enzyme•substrate complex and the lower energy level of the first transition state means that less activation energy is needed to form the first transition state and thus the rate of the first catalytic step (k2) increased substantially. The rate of the second catalytic step (k3) decreased, likely because the covalent form is more stabilized than the second transition state when Phe-601 and the loop are closed. The importance of the guanidinium group of Arg-599 was confirmed by restoration of conformation, order, and activity by guanidinium ions.