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Background Research has implicated hypofrontality in the pathogenesis of Negative symptoms of schizophrenia.These symptoms are often resistant to treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to reverse this hypofrontality. Higher frequency rTMS has shown better promise, but so far there has been very little research in this area. Objective We aimed to evaluate the efficacy of high-frequency (20 Hz) unilateral rTMS over the left Dorso-Lateral Pre-frontal Cortex (DLPFC) in the improvement of Negative symptoms in Schizophrenia. Methods:100 patients of schizophrenia with predominantly negative symptoms, were enrolled for this randomized, sham-controlled, double-blind trial.Each participant received 20 sessions of rTMS at 20 Hz frequency and 100% motor threshold, via either the active or the sham coil, over 4 weeks. A total of 2000 pulses were imparted in 10 trains per session. Negative symptoms were assessed with the SANS and PANSS. CDSS was used to rule out depressive symptoms. Assessments were carried out at baseline, post-intervention, and 1-month, 2-months, 3-months and 4-months follow ups. Results The improvement in the negative symptoms (Anhedonia, Alogia, Avolition, Attention impairment) in active group was statistically significant at 0.01 and 0.05 (p-value) as compared to sham group. Conclusions These results suggest that high-frequency rTMS may lead to improvement in negative symptoms of schizophrenia. It may be worth considering its use as an adjunct to pharmacological treatment of negative symptoms.

Introduction Present study has compared methods of synthesizing the pooled effect estimate under meta-analysis, namely Fixed Effect Method (FEM), Random Effects Method (REM) and a recently proposed Weighted Least Square (WLS) method. Methods Three methods of estimating pooled effect estimates under meta-analysis were compared on the basis of coverage probability and width of confidence interval. These methods were compared for seven outcomes with varying heterogeneity and sample size using real data of systematic review comparing neo-adjuvant chemotherapy with adjuvant chemotherapy involving ‘hazard ratio' and ‘risk ratio' as effect size. Results WLS method was found to be superior to FEM having higher coverage probability in case of heterogeneity. Further, WLS with similar coverage probability was found to be superior to REM with more precise confidence interval. Conclusion Unrestricted WLS method needs to be preferred unconditionally over fixed effect method and random effects method.

Background The purpose of our study was to evaluate the clinical, cytogenetic, and molecular features, and survival outcomes in patients with acute myeloid leukemia (AML) with myeloid sarcoma (MS) and compare them with patients with AML without MS. Patients and Methods This was a retrospective analysis of de novo pediatric AML patients with or without MS diagnosed at our cancer center between June 2003 and June 2016. Results MS was present in 121 of 570 (21.2%), the most frequent site being the orbit. Patients with MS had a younger median age (6 years vs. 10 years) and presented with higher hemoglobin and platelet but lower white blood cell count compared with patients without MS. Further, t (8; 21) ( P P P = .03) were significantly higher in patients with AML with MS. Event-free survival (EFS; P = .003) and overall survival (OS; P = .001) were better among patients with AML with MS (median EFS 21.0 months and median OS 37.1 months) compared with those with AML without MS (median EFS 11.2 months and median OS 16.2 months). The t (8; 21) was significantly associated with MS (odds ratio, 3.92). In a comparison of the 4 groups divided according to the presence or absence of MS and t (8; 21), the subgroup of patients having MS without concomitant t (8; 21) was the only group to have a significantly better OS (hazard ratio, 0.53; 95% confidence interval, 0.34-0.82; P = .005). Conclusion Although t (8; 21) was more frequently associated with MS, it did not appear to be the reason for better outcome.

Investigations such as EEG and brain imaging are often difficult to obtain in primary care settings of resource-limited regions impacting millions of epilepsy patients. We wanted to test the hypothesis that classification of chronic epilepsy into focal and generalized based on clinical history and examination alone would be comparable to making such a classification with additional inputs from EEG and brain imaging.Two investigators independently classified consecutive chronic epilepsy patients into focal, generalized and unclassified epilepsy. Investigator 1 made this determination using clinical history and examination alone whereas Investigator II additionally used EEG and brain imaging too. We calculated inter observer agreement between the two investigators and also looked at the predictors of focal and generalized epilepsy.Five hundred and twelve patients were recruited. Inter observer agreement between the two investigators in making the focal versus generalized classification was 96.8%, kappa 0.91 (p0.0001). When EEG and neuroimaging findings were added to clinical information, there was a change in classification in 3.2% patients. Several predictors of focal and generalized epilepsy were identified.Classification of chronic epilepsy into focal and generalized can be done reliably in most patients using clinical information alone. Investigating chronic epilepsy patients with EEG and brain imaging may not be necessary in every patient. The results of our study are especially significant for epilepsy patients living in resource-limited regions where such investigations may not always be available.

Purpose Our objective was to assess how telephonic review of outpatients with stable epilepsy compared with conventional face-to-face clinic management. Methods We constructed a randomized parallel group study of suitable patients attending our Epilepsy Clinic and compared telephonic review with conventional clinic visit based management. Primary outcomes were the percentage of patients with breakthrough seizures and total number of breakthrough seizures. We also compared cost, patient satisfaction and numbers defaulting. Results A total of 465 patients were randomized and 429 were included in the final analysis. There was no significant difference in breakthrough seizures between the two groups. Mean time spent in the consultation was 10min in the telephone group (FT) and 22h in the face-to-face group (FC) and cost was INR 865 more expensive on an average in the FC group. Satisfaction was over 90% in the FT group. Significantly more people in the FC group were lost to follow-up. Conclusion This study provides Class I evidence that the number of stable epilepsy patients who have breakthrough seizures and the total number of breakthrough seizures remain the same irrespective of whether patients are reviewed telephonically or face-to-face in the clinic. Clinicians managing epilepsy patients should consider using telephonic review for selected patients. Telephonic reviews have the potential of effectively reducing the secondary treatment gap in millions of patients who do not have easy access to doctors.

Objectives Stroke constitutes a significant public health problem in developing countries. Caregivers provide an important support system for patient care but usually lack knowledge and skill to attend their stroke patients. We assessed whether a caregiver-directed educational intervention would reduce hospital-acquired complications and improve stroke patients’ outcomes. Materials and methods We randomly assigned two Neurology inpatient wards to receive either standard care or an educational intervention. The coprimary outcomes included incidence of hospital-acquired complications and in-hospital mortality. Secondary outcomes included the modified Rankin Scale and mortality at three months. Results Among 164 patients recruited, 82 received intervention, and standard care each. The mean (Standard deviation) Glasgow coma scale of patients was 11.01 (3.4), and National Institute of Health Stroke Scale was 19.17 (8.54). The incidence of complications (72 in the intervention versus 81 in the control group; p=0.56) was not different. Ten patients (12.2%) in the intervention group and 16 (19.5%) in the control group (p=0.20) died in-hospital. Twenty patients (27.8%) in the intervention and twelve (18.2%) in the control group attained modified Rankin Scale 0-2 at three months (p=0.12). The mortality at three months (20 [24.4%] in the intervention versus 25 [30.5%] in the control group) was not different (p=0.38). The intervention group had fewer complications (42 versus 68 in the control group; p=0.01) during the initial ten days of hospital stay, but adjusted analysis revealed no difference. Conclusion A structured educational intervention did not reduce the incidence of hospital-acquired complications, mortality, or morbidity. However, there was a trend towards fewer complications in the initial days of hospital stay. Extended hospital stay, caregiver fatigue, and dilution of the intervention over time might be reasons for the apparent lack of effect. Clinical trial registration-URL http://www.ctri.nic.in . Unique identifier: CTRI/2018/11/016312.

Context: Absolute lymphocyte count has been evaluated as a prognostic factor in pediatric B-ALL. However, few prospective studies are available with BFM-90 protocols in a uniform group of patients, and there is a lack of consensus regarding the optimum cutoff for ALC as a prognostic factor. Objective: This study was done to evaluate the association of ALC with EFS and OS in pediatric B-ALL. Outcomes: Association of ALC at baseline, day 8, day 15, and the end of induction with EFS and OS was evaluated in pediatric B- ALL. Designs: It was a prospective study conducted from July 2015–June 2017. Setting: The study was done in a tertiary cancer institute in India. Patients: De novo B-ALL patients between age 1 and 18 years were included. 20 May 2021 was the cutoff date for EFS and OS data analysis. Total leukocyte count was done on MS95s (MeletSchloesing Laboratories, Osny, France) at baseline, day 8, day 15, and the end of induction. Simultaneously, a peripheral smear was made, and a manual differential count was done to determine the percentage of lymphocytes. ALC was calculated as a percentage of lymphocytes multiplied by total leukocyte count. ALC was categorized into two categories taking cutoffs at 0.5×109 cells/l, 0.75×109 cells/l, 1×109 cells/l, and 1.5×109 cells/l. EFS and OS for these categories were evaluated by Kaplan–Meier method. Results: For the two-year duration, 197 B-ALL patients were recruited, of which 150 were analyzed. We found that day 8 ALC >1.5×109 cells/l was associated with poor OS (HR: 2, CI: 1.24–3.24, P=0.004), whereas ALC >1.5×109 cells/l at the end of induction was associated with significantly better OS (HR: 0.51, CI: 0.30–0.86, P=0.01) and better EFS (HR:0.49, CI: 0.30–0.80, P=0.004). ALC cutoffs at baseline and day 15 were not associated with EFS and OS. Conclusions: In our prospective study, we found that ALC >1.5×109 cells/l predicted better EFS and OS in pediatric B-ALL. A larger sample size is needed to establish ALC as a predictor of EFS and OS.

Context ABVD is a standard therapy in adult Hodgkin lymphoma (HL); in children, ABVD is not the standard of care due to concerns regarding long-term toxicities. However, no studies have evaluated long-term toxicities of ABVD in this population. Objective To study long-term toxicities of ABVD in paediatric HL survivors. Setting and Design One hundred fifty-seven paediatric HL survivors ( 2 years) treated with ABVD at a tertiary care centre between January 2003–December 2013 were clinically evaluated at each follow-up visit, single time assessment by MUGA scan, spirometry with DLCO, and TSH and total T4 measurement. Binary logistic regression analysis was used to identify risk factors for long-term toxicities and ordinal logistic regression analysis to study predictors for multiple late adverse effects. Patients Median age: 10 years (3–18); 88%: males, 54%: advanced HL, and 50%: B symptoms. Median of four chemotherapy cycles delivered (1–8), and the median doxorubicin and bleomycin doses were 300 mg/m2 (range 150–400) and 80 IU/m2 (range 50–160), respectively. One hundred ten patients received radiation: 93 (59.2%) neck and 12 (7.6%) mediastinal. Median follow-up at time of toxicity evaluation was 67 months with 56% and 36% patients having completed 10 and 12 year of clinical follow-up, respectively. Results No secondary malignancies or symptomatic cardiac or pulmonary toxicity were seen. Twenty-eight patients (18.1%) had asymptomatic LVEF reduction ( 10 years (OR 4.2 95% CI 1.81–9.73, p=0.001) and male sex (OR 4.16 95% CI 1.09–16.66, p=0.03). Development of subclinical (44.8%) and overt (12.7%) hypothyroidism was related to neck RT (OR 35.1, 95% CI 13.8–89.3, p 10 years and neck radiation predicted for development of multiple late effects. Number of chemotherapy cycles or dose of doxorubicin/bleomycin did not correlate with development of any toxicity. Conclusions ABVD remains safe in children 10 years of age are more susceptible to multiple late effects and should be followed up closely.

Traumatic spinal cord injury (SCI) is a devastating condition of CNS which leads to loss of sensory as well as motor functions. Secondary damage after SCI initiates cascade of events that creates an inhibitory milieu for axonal growth and repair. Combinatorial therapies are the hope to attenuate secondary injury progression and make the microenvironment growth and repair friendly for the neurons. We fabricated gelatin- genipin hydrogel system which was impregnated with IONPs and injected at the lesion site in a clinically relevant contusion rat model of SCI. 24 h later, the rats were exposed to magnetic fields (17.96 μT, 50 Hz uniform EMF) for 2 h/day for 5 weeks. A significant (P < 0.001) improvement in Basso, Beattie and Bresnahan (BBB) locomotor score, amplitude and threshold of spinally mediated reflexes and motor and somatosensory evoked potentials (MEP & SSEP) was observed following IONPs implantation and EMF exposure. Moreover, retrograde tracing showed a higher level of neuronal connectivity and survival after the intervention. There was also a reduction in activated microglia and lesion volume which attenuate secondary damage as evident by reduction in the scaring following intervention for 5 weeks. Moreover, we observed increase in the neuronal growth cone marker, GAP-43, growth promoting neurotrophins (GDNF, BDNF & NT-3) and reduction in the inhibitory molecule (Nogo-A) after this combinatorial therapy. We obsrvered that a significant improvement in behavioral, electrophysiological and morphological parameters was due to an alteration in neurotrophin levels, reduction in activated microglia and increase in GAP-43 expression after the combinatorial therapy. We propose that implantation of IONPs embedded gelatin-genipin hydrogel system along with MF exposure modulated the microenvironment, making it conducive for neural repair and regeneration.

High-risk hospital-associated multidrug-resistant (MDR) Enterococcus faecalis clonal complexes (CCs) such as CC2 and CC87 are enriched with virulence determinants that help to accumulate, colonize, and cause serious nosocomial infections. The aim of this study was to establish the epidemiology and clonal composition of 134 clinical E. faecalis isolates and to link molecular typing data with antimicrobial resistance and virulence determinants. All isolates were identified by conventional methods and confirmed by polymerase chain reaction (PCR) (16srRNA gene and ddl genes of E. faecalis/ E. faecium) in 5-years. Disc diffusion test was performed on all strains. We screened all E. faecalis for aac(6′)-aph(2″), vanA, and vanB resistance genes, and aggregation substance-asa1, cytolysin-cylA, collagen-binding protein-ace, enterococcal surface protein-esp, gelatinase-gelE, and hyaluronidase-hyl virulence genes by PCR. Representative isolates of E. faecalis were characterized by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing (MLST). Out of 539 patients with enterococcal infections, 134 (24.9%) had E. faecalis infections, 366 (67.9%) had E. faecium infections, and 39 (7.2%) had infections due to other enterococcal species. Of the 134 isolates, 79.1% and 61.9% isolates were high-level gentamicin resistant (HLGR) and MDR. In multivariate analysis, independent predictor for infection due to MDR E. faecalis strains was a surgical intervention (OR 2.41, 95% CI 1.17–4.96, P = 0·017). Overall, the observed rate of in-hospital mortality was 11.9%. The gelE, asa1, ace, cylA, esp and hyl genes were detected in 87.3%, 78.4%, 54.5%, 53.7%, 36.6% and 3.0%, respectively in E. faecalis isolates. The asaI, cylA, and gelE genes were significantly correlated with MDR E. faecalis. The PFGE analysis showed 28 clones with four major clones. MLST analysis revealed two sequence types-ST28 (CC87) and ST181 (CC2). This is the first Indian report on the emergence of the high-risk hospital-associated worldwide-disseminated ST28 (CC87) and ST181 (CC2), which have enriched with multiple virulence determinants and resistance to antibiotics, paticularly ampicillin. This report indicates serious health concern and calls for on-going surveillance, close monitoring, and improved infection control procedures to stop further spread of these isolates.

Background: Sepsis is one of the most common causes of neonatal deaths globally. Most sepsis-related deaths occur in low-income and middle-income countries, where the epidemiology of neonatal sepsis remains poorly understood. Most of these countries lack proper surveillance networks, hampering accurate assessment of the burden of sepsis, implementation of preventive measures, and investment in research. We report results of neonates born in hospital from a multicentre collaboration on neonatal sepsis. Methods: In this cohort study, dedicated research teams prospectively followed up neonates born in one of three tertiary care centres in Delhi, India (Vardhaman Mahavir Medical College, Maulana Azad Medical College, and All India Institute of Medical Sciences [coordinating centre]) and subsequently admitted to the intensive care unit. Neonates were followed up daily until discharge or death. On clinical suspicion, neonates underwent sepsis work-up including blood cultures. The isolated organisms were identified and tested for antimicrobial susceptibility. We defined Gram-negative isolates resistant to any three of five antibiotic classes (extended-spectrum cephalosporins, carbapenems, aminoglycosides, fluoroquinolones, and piperacillin-tazobactam) as multidrug resistant. Findings: 13 530 neonates of 88 636 livebirths were enrolled between July 18, 2011, and Feb 28, 2014. The incidence of total sepsis was 14·3% (95% CI 13·8–14·9) and of culture-positive sepsis was 6·2% (5·8–6·6). Nearly two-thirds of total episodes occurred at or before 72 h of life (defined as early onset; 1351 [83%] of 1980). Two-thirds (645 [64%]) of 1005 isolates were Gram-negative including, Acinetobacter spp (22%), Klebsiella spp (17%), and Escherichia coli (14%). The pathogen mix in early-onset sepsis did not differ from that of late-onset sepsis (ie, after 72 h). High rates of multidrug resistance were observed in Acinetobacter spp (181/222, 82%), Klebsiella spp (91/169, 54%), and Escherichia coli (52/137, 38%) isolates. Meticillin resistance prevailed in 61% (85/140) of coagulase-negative staphylococci and 38% (43/114) of Staphylococcus aureus isolates. Nearly a quarter of the deaths were attributable to sepsis. The population-attributable risks of mortality were 8·6% in culture-negative sepsis, 15·7% in culture-positive sepsis by multidrug-resistant organisms, and 12·0% in culture-positive sepsis by non-multidrug-resistant organisms. Interpretation: The high incidence of sepsis and alarming degree of antimicrobial resistance among pathogens in neonates born in tertiary hospitals underscore the need to understand the pathogenesis of early-onset sepsis and to devise measures to prevent it in low-income and middle-income countries. Funding: Indian Council of Medical Research

Background Treatment of unresectable HNSCC is not well defined and has a poor outcome. This study has been designed to address the unmet needs of such groups of patients with primary end points of (a) proportion of patients eligible for radical treatment in each arm (b) loco-regional disease control at 6months between two arms. Materials and methods Locally advanced and unresectable HNSCC patients (except Nasopharynx and Larynx) unfit for radical treatment were randomized to arm A [short course RT alone (4Gy/#/day for 5days)] or arm B [RT as arm A+concurrent cisplatin at 6mg/m 2 /day IV bolus for 5days]. Those with at least PR were taken for further RT to complete biological equivalent dose of 70Gy, in both the arms. In arm B, concurrent CDDP at a dose of 40mg/m 2 /week was administered. Results 114 patients (57 in each arm) were randomized but 111 were analyzable. 15 (27.27%) patients in arm A and 28 (50%) patients in arm B had ⩾PR ( p =0.01) however patients taken for FRT were 14 (25.45%) and 26 (46.42%) in arms A and B respectively ( p =0.02). Locoregional control i.e. (CR+PR) at 6months was 16.36% in arm A versus 32.14% in arm B ( p =0.15). Median PFS (arm A – 3.2months, arm B – 6.2months; p =0.02) and OS (arm A – 5.9months, arm B – 10.1months; p =0.03) was significantly more in arm B. There was relative improvement in quality of life for most parameters in arm B. Conclusion Concurrent low dose CTRT can be an effective treatment modality in advanced and incurable HNSCC. However, a larger phase III trial is required.

India is a subtropical country with clear seasonal variations in weather conditions. Seasonal and circadian variation in occurrence of subtypes of cerebrovascular disease has been of interest in several studies from different countries and climate zones, but discrepant results have made the conclusions unclear. The aim of the present study was to observe the seasonal and circadian variation in the occurrence of stroke and its subtypes among our population.This was a cross-sectional observational study based on new cases and past cases of stroke on follow-up, conducted between January 2011 and December 2012 in the Department of Neurology, at the All India Institute of Medical Sciences, New Delhi, India. The date and time of onset of the stroke was recorded. The categorization of months into season was in accordance with the Indian Meteorological Department guidelines. The time of onset was distributed into 6 hourly intervals. Statistical calculations were performed using Stata version 12.1 and SPSS version 20.A total of 583 patients were included for the study. The rate of occurrence of stroke was highest in the late morning 0600-1159 hours (P value.001) compared with other times of the day, regardless of gender or age for both ischemic and hemorrhagic strokes. It was lowest in late evening (1800-2359 hours) quadrant compared with other quadrants. Although there was no significant difference found by dichotomizing the groups into two 6-month periods, there was an increasing trend in number of patients with stroke during the months November-February. There was no difference in stroke occurrence between the types of stroke or within each type among different seasons with different temperatures. Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification of ischemic strokes also did not show any association with season or circadian rhythm.There is a significant increase in occurrence of strokes between 0600 and 1159 hours and lowest between 1800-2359 hours. No significant variation in stroke occurrence or subtype for any of the seasons was observed.

In acute myeloid leukemia (AML), simultaneous expression of proliferative (FLT3, KIT) and anti-apoptotic genes (BCL2) is unknown. The aim of the study was to prospectively evaluate proliferative and anti-apoptotic gene transcripts, their interrelationship and impact on the outcome in pediatric AML patients.We assessed proliferative and anti-apoptotic gene transcripts by Q-polymerase chain reaction (TaqMan probe) in 64 consecutive pediatric AML patients. Survival data was analyzed by Kaplan-Meier curves followed by log rank test to compare statistical significance between groups. Stepwise multivariable Cox regression method was used to evaluate independent prognostic factors.In univariate analysis, transcript ratio of FLT3/BCL2 and FLT3+KIT/BCL2 significantly predicted event free survival (EFS) (0.01 and0.01 respectively) and overall survival (OS) (0.01 and0.01 respectively). In stepwise Cox-regression model, high white blood cell count and high FLT3+KIT/BCL2 ratio predicted EFS (HR: 2.2 and 2.3); high hemoglobin and high FLT3+KIT/BCL2 ratio predicted OS (HR: 0.45 and 3.85). Prognostic index (PI) was calculated using the hazard coefficient of independent prognostic factors; at 57.3 months, predicted OS of patients with the highest PI of 1.8 was 8% versus 73% for the lowest PI of -0.3. The mean PI of patients who died was 1.8±0.72 versus 0.54±0.70 for those who are alive, P=0.004.This first study showed that individual expression of proliferative and anti-apoptotic transcripts is not as important in AML patients, rather their interrelationship and relative level probably determines the outcome.

Purpose The present study prospectively evaluated outcome, pathologic findings, and compliance in orbital retinoblastoma patients (International Retinoblastoma Staging System [IRSS] stage III). Design Prospective study and case series. Participants Twenty-eight consecutive IRSS stage III retinoblastoma patients were enrolled prospectively in the study after ethics committee approval and written informed consent. Methods Planned therapy for patients included treatment with a uniform protocol consisting of neoadjuvant chemotherapy followed by enucleation, adjuvant radiotherapy, and chemotherapy. Prospective computerized data entry and telephone contact were undertaken to improve compliance, a major issue in treatment of orbital retinoblastoma. Main Outcome Measures Event-free survival (EFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis. The difference between groups was analyzed using the log-rank test. Results Median follow-up was 14.75 months (range, 2.23–26.3 months). The OS for all patients was 40.4% and the EFS was 33.33% at a follow-up of 26.3 months. The median EFS and OS were 10.37 months and 15.73 months, respectively. At baseline, bilateral retinoblastoma predicted inferior EFS ( P = 0.0006) and OS ( P = 0.0081). Twenty-two of 28 patients underwent enucleation, and viable tumor was present in 21 of 22 enucleated specimens (95%). Neoadjuvant chemotherapy prevented orbital exenterations. Presence of tumor in the cut end of the optic nerve significantly correlated with inferior EFS ( P = 0.012) and OS ( P = 0.0098). Central nervous system metastasis was the most common site of relapse and death. The overall rate of compliance with treatment was 67.8% (19/28), which was twice the compliance rate at the authors' center before initiation of the present study. Conclusions There is a paucity of information in the literature on outcomes and pathologic findings after neoadjuvant chemotherapy in IRSS stage III retinoblastoma treated with a uniform treatment protocol, and as far as the authors are aware, there has been no prospective study. Neoadjuvant chemotherapy was able to avoid exenteration in all operated patients; however, residual viable tumor was present in 95% of enucleated specimens. Bilaterality and tumor in the optic nerve cut end after neoadjuvant chemotherapy were associated with inferior outcome. Compliance could be improved with computerized data entry and regular telephone contact. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.