Effect of neuronavigated repetitive Transcranial Magnetic Stimulation on pain, cognition and cortical excitability in fibromyalgia syndrome.

BACKGROUND: Fibromyalgia syndrome is a widespread chronic pain condition identified by body-wide pain, fatigue, cognitive fogginess, and sleep issues. In the past decade, repetitive transcranial magnetic stimulation has emerged as a potential management tool.. In the present study, we enquired whether repetitive transcranial magnetic stimulation could modify pain, corticomotor excitability, cognition, and sleep. METHODS: Study is a randomized, sham-controlled, double-blind, clinical trial; wherein after randomizing thirty-four fibromyalgia patients into active or sham therapy (n = 17 each), each participant received repetitive transcranial magnetic stimulation therapy. In active therapy was given at 1 Hz for 20 sessions were delivered on dorsolateral prefrontal cortex (1200 pulses, 150 pulses per train for 8 trains); while in sham therapy coil was placed at right angle to the scalp with same frequency. Functional magnetic resonance imaging was used to identify the therapeutic site. Pain intensity, corticomotor excitability, cognition, and sleep were examined before and after therapy. RESULTS: Baseline demographic and clinical parameters for both active and sham groups were comparable. In comparison to sham, active repetitive transcranial magnetic stimulation showed significant difference in pain intensity (P < 0.001, effect size = 0.29, large effect) after intervention. Other parameters of pain perception, cognition, and sleep quality also showed a significant improvement after the therapy in active therapy group only, as compared to sham. CONCLUSIONS: Findings suggest that repetitive transcranial magnetic stimulation intervention is effective in managing pain alongside cognition and sleep disturbances in patients of fibromyalgia. It may prove to be an important tool in relieving fibromyalgia-associated morbidity.

Patient-reported cognitive impairments and objective neuropsychological deficits in young sarcoma patients undergoing chemotherapy and its comparison to healthy controls: A tertiary health care study from India.

The study aims to investigate the patient-reported cognitive deficits and objective neuropsychological functions in younger adult (YA) sarcoma patients (16-40 years of age). Ninety patients and 30 age-matched healthy controls from a single tertiary healthcare hospital, were recruited into four groups: Pre-chemotherapy (Pre Cx), During chemotherapy (During Cx), Post-chemotherapy (Post Cx) and Controls. Neurocognitive functions were assessed subjectively using FACT-Cog v3 questionnaire; objectively using ACE-III and neuropsychological tests (NPT). FACT-Cog scores of During Cx (P = .041) and Post Cx (P = .008) groups were significantly lower than Pre Cx group. ACE-III scores of During Cx (P = .048) and Post Cx (P = .043) groups were lower as compared to Pre Cx group. In addition, reaction times and accuracies of the NPT (Flanker's, Sternberg's and Emotional Stroop tests) were worse (P < .05) in During Cx and Post Cx groups as compared to either Pre Cx or control groups. In the Post Cx group, the dose of chemotherapy showed significant negative correlation with the Sternberg reaction time (P = .040) as well as the scores of language (P = .047), and attention (P = .044) domains of ACE-III. Observations demonstrate that cancer/chemotherapy-related neurocognitive deficits fail to improve even after cessation of treatment, and high dosage of chemotherapy used, could be an underlying factor. This emphasizes the need for developing 'model of care' in these patients for monitoring the side effects, and possible titration in the therapeutic regimen for sarcoma in YA.

In vitro activity of cefiderocol against comparators (ceftazidime-avibactam, ceftazidime-avibactam/ aztreonam combination, and colistin) against clinical isolates of meropenem-resistant Klebsiella pneumoniae from India.

Cefiderocol (FDC), a novel siderophore drug, is active against Gram-negative bacteria producing carbapenemases, including metallo-beta-lactamases. The objective of this study is to compare the in vitro activity of FDC with ceftazidime-avibactam (CZA), CZA/aztreonam (AT) combination, and colistin (CST), in clinical isolates of meropenem-resistant (MER-R) Klebsiella pneumoniae. From the 2,052 clinical specimens submitted for culture testing, 245 K. pneumoniae isolates were recovered within a 6-month period in 2021. One hundred three non-duplicate, non-outbreak, MER-R (minimum inhibitory concentration, MIC >4 µg/mL) strains were included in the study. Identification and susceptibility were performed using VITEK-2 (bioMérieux). Meropenem-susceptible isolates (n = 10) served as controls. For FDC, broth microdilution (BMD) was performed after in-house standardization. Disk diffusion (Liofilchem, Italy) and broth microdilution (ComASP, STC, Liofilchem, Italy) were used for susceptibility testing of CZA and CST, respectively. Synergy testing for CZA and AT was performed using disk approximation method. CLSI breakpoints were used for the interpretation of the results. For FDC, MIC50 and MIC90 were 2 and 8 µg/mL, respectively. A total of 80% of isolates were susceptible to FDC, 26.2% of isolates were susceptible to CZA, synergy testing with CZA/AT was positive for 74 (72%) of the isolates, and 89.3% were intermediate to CST. Nine (8.7%) were susceptible only to FDC. FDC is active in vitro against MER-R K. pneumoniae >CZA/AT > CZA > CST, as observed in this study, applying CLSI criteria. Clinico-microbiological studies should be performed to assess the clinical efficacy of this novel drug in this region with a high prevalence of carbapenem resistance among Gram-negative organisms. IMPORTANCE Management of infections with multi-drug resistant Klebsiella pneumoniae is a major challenge in hospital settings, with few treatment options. In this study, the authors aim to assess the in vitro susceptibility of these clinical isolates to cefiderocol, a novel siderophore. Comparators are colistin, ceftazidime-avibactam, and ceftazidime-avibactam/aztreonam synergy, which are currently available options for treatment in this region. Baseline-resistance rates against cefiderocol are higher than those in the previously published studies, with MIC50 and MIC90 at 2 and 8 µg/mL, respectively.

A Clinical Conundrum with Diagnostic and Therapeutic Challenge: a Tale of Two Disorders in One Case.

Living organisms are exposed to exogenous and endogenous agents that affect genomic integrity by creating DNA double strand breaks (DSBs). These breaks are repaired by DNA repair proteins to maintain homeostasis. Defects in DNA repair pathways also affect lymphocyte development and maturation, as DSB sites are critical intermediates for rearrangements required for V(D)J recombination. Recent classifications for inborn errors of immunity (IEIs) have listed DNA repair defect genes in a separate group, which suggests the importance of these genes for adaptive and innate immunity. We report an interesting case of a young female (index P1) with mutations in two different genes, DCLRE1C and FANCA, involved in DNA repair pathways. She presented with clinical manifestations attributed to both defects. With the advent of NGS, more than one defect is increasingly identified in patients with IEIs. Familial segregation studies and appropriate functional assays help ascertain the pathogenicity of these mutations and provide appropriate management and genetic counseling.

Antibiotic Susceptibility Testing (AST) Practices in India: Need for a National AST Forum.

Background Accurate interpretation of antibiotic susceptibility testing (AST) is one of the most crucial functions of the microbiology laboratory. However, its performance depends on a number of critical factors. We conducted a status survey to understand the existing practices in Indian laboratories that have a potential to influence performance of AST. Method We developed a 22-point online survey questionnaire on information about respondent's specifications, use of AST consumables, existing quality control protocols, and matters of contention in AST practices, and sent it by Google forms to 362 clinical microbiologists (holding MD or DNB certification). Participation was voluntary. Results were analyzed using descriptive statistics. Results Among 362, a total of 103 returned the questionnaire. The first 100 responses that were complete (all 22 questions answered) were analyzed. Respondents were from medical colleges (61%), private hospitals (26%), and stand-alone laboratories (13%). Analysis revealed that the Clinical & Laboratory Standards Institute (CLSI) guidelines were followed by all. Overall, 54% used disc diffusion as the primary method for performing AST. For the internal quality control testing of media and AST, 24% and 16% had adequate testing components and frequency, respectively. For performing AST of colistin, broth microdilution was used by 19%. Also, 86% participated in external quality control programs, and 54% respondents were dissatisfied or unsure about the development of competencies in AST methodology during their postgraduate training. Conclusion This survey reveals that potential gaps exist in the performance parameters and internal quality control of AST. There is an urgent need for harmonization in AST performance and postgraduate training in clinical microbiology in India.

Altered functional connectivity: A possible reason for reduced performance during visual cognition involving scene incongruence and negative affect.

Object-context associations and valence are two unavoidable stimulus characteristics when it comes to the processing of natural visual scenes. In line with our previous studies exploring the parallel processing of context-congruity and valence, in the current study, we investigated the valence-specific differences in functional connectivity between congruent-incongruent picture pairs during binocular rivalry using high-density EEG. The functional connectivity measure was calculated using sLORETA during the perceptual dominance of congruent and incongruent stimuli in a time window of 400 ms before the response and compared within and between positive, negative, and neutral valence categories (84 Brodmann's areas across 7 frequency bands) using t-tests. A significant difference in functional connectivity between congruent-incongruent picture pairs was seen only when associated with negative valence and a maximum number of area pairs showed differences in lower alpha 1 (7.1-9 Hz), upper alpha (11.1-13 Hz), and beta (13.1-30 Hz) frequency bands. The functional connectivity was significantly lower during incongruent perception between the area pairs which process mainly emotion, attention, memory, and semantic relations compared to their corresponding congruent stimuli. Similarly, negative incongruent percepts were found to have significantly lower connectivity between areas processing attention, emotion, and incongruence in the lower alpha 2 (9.1 -11 Hz) band when compared to positive incongruent percepts. Together, these results suggest that the perception of negative incongruence is associated with lower functional connectivity and this could be a possible reason for the increased error rates when faced with incongruity and negative affect during visual tasks.

Diagnosis, Treatment and Prevention of Nutritional Anemia in Children: Recommendations of the Joint Committee of Pediatric Hematology-Oncology Chapter and Pediatric and Adolescent Nutrition Society of the Indian Academy of Pediatrics.

JUSTIFICATION: Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia. OBJECTIVE: To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children. PROCESS: These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members. RECOMMENDATIONS: We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

Spectral perturbations of cortical dipoles during a dynamic visuo-spatial working memory task in schizophrenia.

Altered neural oscillations during prestimulus-task conditions have been reported to be associated with aberrant information processing in schizophrenia. Spectral perturbations induced by visuo-spatial working memory (VSWM) task were investigated in patients and their first-degree relatives in order to study the biomarkers in schizophrenia. EEG was recorded using 128-channel during VSWM task in 28 patients, 27 first-degree relatives and 25 controls. After pre-processing and ICA, current dipole was estimated for each IC. Total of 1609 independent and localizable EEG components across all groups were used to compute ERSP during different events of task. Patients deactivated DMN, RSN, auditory cortex more compared to controls during search period to perform VSWM task. Relatives showed altered activation of right medial and inferior frontal gyri during different events and loads of task in lower frequencies compared to controls. Relatives also showed hyperactivity in right cingulate and parahippocampal gyri compared to controls. This is suggestive of genetic predisposition in schizophrenia and could act as vulnerability markers, further strengthened by no significant differences between patients and relatives. Altered processing of simultaneous ongoing events in patients and relatives can serve as state and trait-specific features of schizophrenia.

Multi-domain Cognitive Testing: A Biomarker for Classifying the Cognitive Status of Mild Cognitive Impairment and Alzheimer's Disease.

Context: Cognition is impaired in Alzheimer's disease (AD) and patients with mild cognitive impairment (MCI) with varying levels of magnitude. Aim: The present study aimed to identify a biomarker for classifying MCI and AD using multi-domain cognitive testing. Settings and Design: This was a cross-sectional study. Methods and Materials: 26 AD patients, 28 MCI patients and 25 controls were recruited. Cognitive assessment of different domains was done using standard questionnaires and cognitive function tests. Statistical Analysis Used: Cognitive task scores were compared between the groups using multivariate analysis of variance (MANOVA). Results: Patients with AD had significantly lower MMSE, CDR, cognitive task scores compared to controls and MCI. Cognitive scores of all tasks for MCI were significantly less than controls, except MMSE and digits forward score. ROC analysis showed that picture memory had 100% sensitivity, 91.6% specificity for AD and 88.4% sensitivity, 92.5% specificity for MCI. Word memory had 92.3% specificity, 100% specificity for AD and 80.7% specificity, 84.6% specificity for MCI. Conclusions: The global cognitive tools are less specific in bringing out the differences especially between MCI and control. Limitation of MMSE, heterogeneity of MCI and differential impairment of various domains of cognition, demands the inclusion of multi-domain cognitive evaluation especially picture and word memory tasks with high sensitivity and specificity into the existing diagnostic protocol. ROC results also suggested the continuum of cognitive impairment and MCI as a transitional stage leaving more scope on the quantum of research required for intervention to halt the structural and functional decline.

Placebo-Related Adverse Events in Rheumatoid Arthritis.

Prospective, double-blind, randomized, placebo-controlled studies are considered to provide the highest quality of interventional evidence. This meta-analysis summarizes the frequencies of adverse events according to the Medical Dictionary for Regulatory Activities (MedDRA) in the placebo arms of 101 such studies in rheumatoid arthritis, including a total of 17,150 patients in the placebo arms and 37,819 patients in the verum arms. Placebo-treated patients reported more than one adverse event in a median of 55.0%, 65.5%, and 72.5% (compared to 72.3% in the verum arms), and a serious adverse event in 2.5%, 5.8%, and 8.6% (compared to 5.9% in the verum arms), with stable doses of corticosteroids, conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and biological DMARDs as background therapies, respectively. Odds ratios were comparable between placebo and verum arms for nausea (1.00 with 95% confidence interval (CI) 0.86-1.17), for hepatobiliary disorders (1.08 with CI 0.85-1.36), for abnormal hepatic functions (1.09 with CI 0.83-1.44), and general disorders and administration site conditions (1.39 with CI 0.95-2.03). A publication bias has to be assumed for nausea (p = 0.018; Egger's test), diarrhoea (p = 0.022), and serious infections and infestations (p = 0.009). In conclusion, patients should be aware that "adverse events" may occur even with placebo medication, independent from an additional verum medication added to the background therapy. Further studies are warranted to respect and overcome the psychological and other issues related to these placebo-related "adverse events".

Reduced Resting-State Cortical Alpha Connectivity Reflects Distinct Functional Brain Dysconnectivity in Alzheimer's Disease and Mild Cognitive Impairment.

Background: Emerging evidence suggests distinct abnormal activity patterns during resting state in intrinsic functional brain networks in patients with neurodegenerative diseases, including Alzheimer's disease (AD) and mild cognitive impairment (MCI). This study aimed to identify the changes in the resting-state intracortical lagged phase synchronization derived from dense array electroencephalography (EEG) in AD and MCI. Methods: Resting-state current source density (CSD) and lagged phase synchronization between 84 regions of interest defined by Brodmann areas (BAs) for seven EEG frequency bands were investigated between the study groups (AD, MCI, and age-matched controls) using 128-channel EEG. Results: Reduced CSD and connectivity (large effect size, Cohen's d > 0.8) were found in AD and MCI compared with controls at alpha frequency. However, a positive correlation (r = 0.433; p = 0.044) of mini-mental state examination scores was found with BA 32-33 connectivity values in AD only. Conclusion: Reduced resting-state alpha 1 source connectivity in patient groups and correlation between attenuation of resting-state alpha 1 connectivity with cognitive decline in AD could indicate the disruption of inhibitory function of alpha rhythm leading to tonic unselective cortical excitation that affects attention and controlled access to stored information.

Multicenter Epidemiologic Study of Coronavirus Disease-Associated Mucormycosis, India.

During September-December 2020, we conducted a multicenter retrospective study across India to evaluate epidemiology and outcomes among cases of coronavirus disease (COVID-19)-associated mucormycosis (CAM). Among 287 mucormycosis patients, 187 (65.2%) had CAM; CAM prevalence was 0.27% among hospitalized COVID-19 patients. We noted a 2.1-fold rise in mucormycosis during the study period compared with September-December 2019. Uncontrolled diabetes mellitus was the most common underlying disease among CAM and non-CAM patients. COVID-19 was the only underlying disease in 32.6% of CAM patients. COVID-19-related hypoxemia and improper glucocorticoid use independently were associated with CAM. The mucormycosis case-fatality rate at 12 weeks was 45.7% but was similar for CAM and non-CAM patients. Age, rhino-orbital-cerebral involvement, and intensive care unit admission were associated with increased mortality rates; sequential antifungal drug treatment improved mucormycosis survival. The COVID-19 pandemic has led to increases in mucormycosis in India, partly from inappropriate glucocorticoid use.

Altered spontaneous cortical activity in mild glaucoma: A quantitative EEG study.

Functional neuroimaging studies have reported alterations in cortical activity indicating glaucoma as a progressive neurodegenerative disease. Hence the current study aimed to assess the cortical activity using high-density EEG in patients with mild glaucoma during resting state. Treatment-naive 37 patients with primary open angle glaucoma (POAG), 34 patients with primary angle closure glaucoma (PACG), and 32 healthy controls were included in the study. Resting state EEG i.e., eyes closed (EC) and eyes open conditions (EO) were acquired using 128-channel for 3 min. After preprocessing, the current density of 6239 voxels of the data was estimated using sLORETA. In comparison to healthy controls, PACG had higher activity at cingulate gyri, medial and superior frontal gyri during EO only. POAG had significantly higher activity at precentral gyrus and middle frontal gyrus during EC, whereas at cingulate gyri, frontal gyri, precentral gyri, paracentral lobule, sub-gyral region, postcentral gyrus, and precuneus during EO. POAG had significantly higher activity at precuneus and cuneus compared to PACG during EO. Intraocular pressure and mean-deviation of visual fields had a positive correlation with cortical activity. Results of the study indicate physiological alterations not only at the level of retina but also at brain even in the early stages of the disease. These alterations in the cortical activity were more in POAG than PACG. Controlling the IOP alone might be insufficient in glaucoma because of widespread alterations in cortical activity. These findings might enhance the current understanding of cortical involvement in glaucoma.

Study of EEG microstates in Parkinson's disease: a potential biomarker?

The spontaneous activity of the brain is dynamic even at rest and the deviation from this normal pattern of dynamics can lead to different pathological states. EEG microstate analysis of resting-state neuronal activity in Parkinson's disease (PD) could provide insight into altered brain dynamics of patients exhibiting dementia. Resting-state EEG microstate maps were derived from 128 channel EEG data in 20 PD without dementia (PDND), 18 PD with dementia (PDD) and 20 Healthy controls (CON) using Cartool and sLORETA softwares. Microstate map parameters including global explained variance, mean duration, frequency of occurrence (TF) and time coverage were compared statistically among the groups. Eight maps that explained 72% of the topographic variance were identified and only three maps differed significantly across the groups. TF of Map1 was lower in both PDND and PDD (p < 0.001) and that of Map3 (p = 0.02) in PDND compared to control. Cortical sources showed higher activation in precuneus, cuneus and superior parietal lobe (Threshold: Log-F = 1.74, p < 0.05) with maximum activity in the precuneus region (MNI co-ordinates: - 25, - 75, - 40; Log-F = 1.9) in PDND compared to control only for Map1. Lower TF of Map1 (prototypical microstate D) may potentially serve as a biomarker for PD with or without dementia whereas higher activation of precuneus, cuneus and superior parietal lobe at resting-state could favour signal processing, lack of which could be associated with dementia in Parkinson's disorder.

Frontal activation as a key for deciphering context congruity and valence during visual perception: An electrical neuroimaging study.

The object-context associations and the valence are two important stimulus attributes that influence visual perception. The current study investigates the neural sources associated with schema congruent and incongruent object-context associations within positive, negative, and neutral valence during an intermittent binocular rivalry task with simultaneous high-density EEG recording. Cortical sourceswere calculated using the sLORETA algorithm in 150 ms after stimulus onset (Stim + 150) and 400 ms before response (Resp-400) time windows. No significant difference in source activity was found between congruent and incongruent associations in any of the valence categories in the Stim + 150 ms window indicating that immediately after stimulus presentation the basic visual processing remains the same for both. In the Resp-400 ms window, different frontal regions showed higher activity for incongruent associations with different valence such as the superior frontal gyrus showed significantly higher activations for negative while the middle and medial frontal gyrus showed higher activations for neutral and finally, the inferior frontal gyrus showed higher activations for positive valence. Besides replicating the previous knowledge of frontal activations in response to context congruity, the current study provides further evidence for the sensitivity of the frontal lobe to the valence associated with the incongruent stimuli.

Vitamin C Deficiency and Oxidant Levels in Children With Transfusion-Dependent b-Thalassemia.

OBJECTIVES: To study vitamin C levels in children with transfusion-dependent b-thalassemia and correlate with age, transfusions received and iron overload; and to study the effect of administering vitamin C on its levels and Malondialdehyde (MDA) in deficient patients. METHODS: This case-control study enrolled 100 children with transfusion-dependent b-thalassemia and 30 healthy controls. MDA levels before and after administration of vitamin C were performed randomly in 36 children with low vitamin C levels. RESULTS: 81/95 (85.3%) study subjects vs none in control group, had low plasma vitamin C levels (P<0.001). Vitamin C levels were low in 64 of 71 (74.7%) subjects with dietary deficiency, while none of the 19 (63.3%) controls with dietary deficiency had low levels (P=0.04). Increasing serum ferritin values correlated with vitamin C deficiency (P=0.02). The mean level of MDA reduced (P<0.001) with vitamin C supplementation. CONCLUSIONS: Low levels of vitamin C are common in children with thalassemia. Dietary counseling along with supplementation with vitamin C, in those with low levels may prevent oxidative stress.

The Spectrum of Clinical, Immunological, and Molecular Findings in Familial Hemophagocytic Lymphohistiocytosis: Experience From India.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of immune dysregulation characterized by hyperactivation of the immune system, excessive cytokine secretion and severe systemic inflammation. HLH is classified as familial (FHL) when associated with mutations in PRF1, UNC13D, STX11, and STXBP2 genes. There is limited information available about the clinical and mutational spectrum of FHL patients in Indian population. This study is a retrospective analysis of 101 molecularly characterized FHL patients over the last 10 years from 20 different referral centers in India. FHL2 and FHL3 together accounted for 84% of cases of FHL in our cohort. Patients belonging to different FHL subtypes were indistinguishable based on clinical and biochemical parameters. However, flow cytometry-based assays viz. perforin expression and degranulation assay were found to be specific and sensitive in diagnosis and classification of FHL patients. Molecular characterization of respective genes revealed 76 different disease-causing mutations including 39 (51%) novel mutations in PRF1, UNC13D, STX11, and STXBP2 genes. Overall, survival was poor (28%) irrespective of the age of onset or the type of mutation in our cohort. Altogether, this article sheds light on the current scenario of FHL in India. Our data reveal a wide genetic heterogeneity of FHL in the Indian population and confirms the poor prognosis of FHL. This study also emphasizes that though mutational analysis is important for diagnostic confirmation of FHL, flow cytometry based assays help significantly in rapid diagnosis and functional validation of novel variants identified.

Correlating cognition and cortical excitability with pain in fibromyalgia: a case control study.

BACKGROUND: Fibromyalgia is a chronic pain disorder characterized by widespread musculoskeletal symptoms, primarily attributed to sensitization of somatosensory system carrying pain. Few reports have investigated the impact of fibromyalgia symptoms on cognition, corticomotor excitability, sleepiness, and the sleep quality - all of which can deteriorate the quality of life in fibromyalgia. However, the existing reports are underpowered and have conflicting directions of findings, limiting their generalizability. Therefore, the present study was designed to compare measures of cognition, corticomotor excitability, sleepiness, and sleep quality using standardized instruments in the recruited patients of fibromyalgia with pain-free controls. METHODS: Diagnosed cases of fibromyalgia were recruited from the Rheumatology department for the cross-sectional, case-control study. Cognition (Mini-Mental State Examination, Stroop color-word task), corticomotor excitability (Resting motor threshold, Motor evoked potential amplitude), daytime sleepiness (Epworth sleepiness scale), and sleep quality (Pittsburgh sleep quality index) were studied according to the standard procedure. RESULTS: Thirty-four patients of fibromyalgia and 30 pain-free controls were recruited for the study. Patients of fibromyalgia showed decreased cognitive scores (p = 0.05), lowered accuracy in Stroop color-word task (for color: 0.02, for word: 0.01), and prolonged reaction time (< 0.01, < 0.01). Excessive daytime sleepiness in patients were found (< 0.01) and worsened sleep quality (< 0.01) were found. Parameters of corticomotor excitability were comparable between patients of fibromyalgia and pain-free controls. CONCLUSIONS: Patients of fibromyalgia made more errors, had significantly increased reaction time for cognitive tasks, marked daytime sleepiness, and impaired quality of sleep. Future treatment strategies may include cognitive deficits and sleep disturbances as an integral part of fibromyalgia management.

Electroencephalography-based cortical sources of working memory in the subjects with opioid addiction: A pilot study.

Background & objectives: Working memory impairments in the subjects of opioid addiction may stem from an aberrant cortical activity in the executive areas, and may help in early identification of individuals with addictive tendencies and may also be used as a neurofeedback mechanism in adjunct to the existing therapeutics. Methods: Electrical neuroimaging via 128-channel electroencephalography (EEG) recording was done in 15 male subjects with opioid addiction (29.45±5.6 yr) during the performance of Sternberg Working Memory Task. EEG data were acquired and analyzed for cortical sources during task as compared to resting (baseline) condition. Results: Working memory deficits were manifested as decrease in accuracy percentage in the subjects with opioid addiction, while no significant difference was seen in reaction time, on comparison with laboratory-acquired matched controls. Standardized low-resolution brain electromagnetic tomography (sLORETA)-based EEG source analysis revealed higher cortical activity in the anterior cingulate cortex, inferior, middle and superior temporal gyri, inferior frontal gyrus, superior parietal lobule, inferior parietal lobule and precuneus, whereas significant lower activity was seen in superior and middle frontal gyri, parietal lobule, cingulate cortex and pre- and postcentral gyri when the task was compared to baseline in the subjects with opioid addiction. Further, a negative correlation was seen between the accuracy of task performance and activation ratio for the significant gyri in the subjects with opioid addiction. Interpretation & conclusions: EEG cortical sources revealed the failure of deactivation of default-mode network (DMN) during the task amongst the subjects with opioid addiction. In addition, there was a decrease in the executive function areas in the subjects with opioid addiction. This lack of sufficiently active executive network and persistence of DMN during the task (as compared to baseline) may potentially form the basis of functional impairments in the subjects with opioid addiction.