Comparative efficacy of family mediated intervention versus early intensive behavioural intervention on symptom domains in children with autism spectrum disorder: A randomized controlled trial.

BACKGROUND: Family Mediated Intervention (FMI) and Early Intensive Behavioural Intervention (EIBI) are found to be standard of care for children with Autism Spectrum Disorder (ASD). Comparison of their efficacy were assessed using ISAA as primary outcome measure. METHODS: This study was a parallel arm, open label, randomized active- controlled non-inferiority clinical trial. 50 Children diagnosed with ASD were randomized into FMI and EIBI groups. Clinical status was checked by using Indian scale for assessment of autism (ISAA), Oro- motor and sensory profile at baseline, after three and six months. RESULTS: Difference between change in mean ISAA score between FMI and EIBI group at the end of 6 months as per protocol (PP) analysis was -7.23 (CI=-18.41, 3.94), which was within pre-defined clinically relevant non-inferiority (NI) margin of - 24. FMI was found to be non-inferior to EIBI at the end of 6 months as the lower bound of 95% CI (-18.41) for ISAA score was higher than NI margin. ISAA scores were found to be statistically lower in both FMI and EIBI groups at the end point compared to baseline which indicated improvement in symptom severity. CONCLUSION: FMI was non-inferior to EIBI as therapy for children with ASD at the end of six months. Finding also indicated longer duration of treatment is required for FMI to be superior. FMI can be recommended for children with ASD in view of improved ISAA scores reported in our study. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2020/08/027099 (Registered with Clinical Trials Registry- India).

Effect of cannabinoids in mild-to-moderate cases of Crohn's disease as compared to placebo: a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: In view of limited treatment options (those too may fail) for Crohn's disease, cannabinoids have been tried as a therapeutic. However, their efficacy is not unequivocally established. This systematic review and meta-analysis was planned to pool data from randomised controlled trials (RCTs) evaluating effect of cannabinoids in Crohn's disease with an intention to take this uncertainty away. CONTENT: Following literature search in Medline, EMBASE, Scopus and Google Scholar databases, RCTs assessing the effect of cannabinoids on mild-to-moderate Crohn's disease in adults were included. Crohns' disease activity index (CDAI), QoL (Quality of life), number participants achieving full remission and serum CRP at eight weeks of treatment were the outcomes considered for meta-analysis. Quality of studies was assessed using Cochrane's RoB2 tool. Random effect model was applied for meta-analysis. Heterogeneity was assessed by Cochrane 'Q' statistics and I2 test. Sensitivity analysis was performed to identify the major contributor(s) to heterogeneity and assess robustness of the results. SUMMARY: Risk of bias for the four included studies varied from 'low' to 'some concern'. Overall effect estimate (SMD -0.92; 95 % CI -1.80, -0.03) indicated a statistically significant effect of cannabinoids as compared to control (p<0.05) on CDAI score. Effect of cannabinoids on rest of the outcome parameters was comparable to that of placebo. Magnitude of heterogeneity for different outcome parameters ranged from 'low' to 'substantial'. OUTLOOK: Cannabinoids were superior to placebo for favourably affecting the disease severity in terms of CDAI score. However, no statistically significant difference was found between the two for improving QoL, causing full disease-remission and reducing inflammatory markers. The results must be interpreted with caution in view of relatively high heterogeneity among the studies.

HIV cure: Are we going to make history?

BACKGROUND: At present, combination antiretroviral therapy (cART) is the mainstay for the treatment of people living with HIV/AIDS. cART can suppress the viral load to a minimal level; however, the possibility of the emergence of full-blown AIDS is always there. In the latter part of the first decade of the 21st century, an HIV-positive person received stem cell transplantation (SCT) for treatment of his haematological malignancy. The patient was able to achieve remission of the haematological condition as well as of HIV following SCT. Thorough investigations of various samples including blood and biopsy could not detect the virus in the person's body. The person was declared to be the first cured case of HIV. LITERATURE SEARCH: Over the next decade, a few more similar cases were observed and have recently been declared cured of the infection. A comprehensive search was performed in PubMed, Cochrane library and Google Scholar. Four such additional cases were found in literature. DESCRIPTION & DISCUSSION: These cases all share a common proposed mechanism for the HIV cure, that is, transplantation of stem cells from donors carrying a homozygous mutation in a gene encoding for CCR5 (receptor utilized by HIV for entry into the host cell), denoted as CCR5△32. This mutation makes the host immune cells devoid of CCR5, causing the host to acquire resistance against HIV. To the best of our knowledge, this is the first review to look at relevant and updated information of all cured cases of HIV as well as the related landmarks in history and discusses the underlying mechanism(s).

Efficacy of COVID-19 vaccines: a systematic review and network meta-analysis of phase 3 randomized controlled trials.

Several vaccines have been approved for the prevention of COVID-19. However, no head-to-head trials comparing their clinical efficacy have been performed. This network meta-analysis aims to identify those, among the competing existing vaccines, conferring the maximum protection against COVID-19. A literature search was done in Medline (via PubMed), Embase and Cochrane Library databases for phase 3 randomized controlled trials evaluating the efficacy of different COVID-19 vaccines. Search results were screened and eligible studies were included to perform a network meta-analysis in software 'R' version 4.1.2 using a random effect model. Cochrane's 'Risk of Bias tool (RoB2)' was used for quality assessment. Raw data from the included studies was used for network meta-analysis. Assessment of inconsistency was not possible as no study compared two or more vaccines directly. A forest plot for indirect comparison of various COVID-19 vaccines was obtained. Rankogram and 'P' scores were obtained to rank the vaccines based on the indirect evidence of their comparative efficacy. A total of 17 randomized controlled trials evaluating the efficacy of 16 COVID-19 vaccines, were included in the network meta-analysis. A total of 361,386 participants was included in this network meta-analysis. Overall risk of bias among included studies was of 'some concern'. All the COVID-19 vaccines had a statistically significant reduction of risk for contracting symptomatic SARS-CoV-2 in comparison to the placebo, however, the maximum protection (RR 0.05) was with BNT126b2. The indirect comparison also revealed BNT126b2 vaccine confers the highest protection against symptomatic SARS-CoV-2 infection in comparison to all others included, with a 'P' score of 0.9771 followed by mRNA-1273, rAD26 & rAD5 and NVX-CoV2373. The evidence generated from this network meta-analysis indicates the good efficacy of all the included vaccines in preventing symptomatic COVID-19 as compared to placebo. The BNT126b2 vaccine was found to provide the highest protection against symptomatic SARS-CoV-2 among all included followed by mRNA-1273, rAD26 & rAD5, NVX-CoV2373 and others.

Quality Assessment of Pre-Clinical Studies of Chimeric Antigen Receptor T-Cell Therapy Products: A Point of Focus on Safety.

BACKGROUND: Serious adverse reactions have been reported with the use of Chimeric Antigen Receptor (CAR) T-cell therapy in a clinical setting despite the success of these products in pre- clinical stages of development. OBJECTIVE: We evaluated the quality of available pre-clinical safety data of CAR T-cell therapy products. METHODS: A 21 items safety checklist was designed specifically for CAR T-cell. Literature was searched using search/MeSH terms in PubMed (October 2019 - February 2020). Studies were screened from title and abstract. Original pre-clinical researches related to CAR T-cell anti-cancer therapy were included. RESULTS: Of the search results, 152 studies (3 in vivo, 39 in vitro, and 110 combined) were included. Only 7.9% of studies were specifically designed to evaluate/ improve product safety. Eleven studies included target antigen(s), and no study included co-stimulatory molecule(s) expressed exclusively by the tumor tissue and/or CAR T-cells. One study used CRISPR-Cas9 for CAR gene insertion. The use of switch-off mechanism and purity assessment of CAR T-cell products were reported in 13.2% and 8.6% studies, respectively. Of the 113 studies with in vivo components, immuno- competent animal models were used in 24.8%. Measurements of blood pressure, temperature, body weight, and serum cytokines were reported in 0, 2.7, 29.2, and 27.4% studies, respectively. The tissue distribution and CAR T-cells persistence were reported in 26.5% of studies. The surface expression level of CAR, functional characterization of the product, and use of control were reported in >90% of studies. CONCLUSION: The majority of the checklist parameters were not reported in the pre-clinical publications to be adequately predictive of the safety of CAR T-cells in a clinical setting.

Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study.

OBJECTIVES: The fact that oxidative stress plays an important role in the pathogenesis of various pulmonary diseases is supported by the beneficial effect of antioxidants. It is also well known that an altered oxidant-antioxidant balance after the age of 35 years increases the susceptibility to develop obstructive lung diseases later in life. Given this, the present study was designed to evaluate the effect of antioxidant supplementation on lung functions in healthy adults after the age of 35 years. METHODS: Persons of age ≥35 years (n=45) were randomized into three arms (each comprising 15 participants) to receive either no intervention (NI arm), ascorbic acid 250 mg daily (AA250 arm), or ascorbic acid 500 mg daily (AA500 arm) for 6 weeks. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, and peak expiratory flow (PEF) were measured at baseline and 6 weeks. Persons of age group (20-30 years) were also enrolled in the study to compare their lung functions and cardiovascular parameters at baseline with those ≥35 years of age. All the adverse events experienced by participants were recorded. RESULTS: Baseline pulmonary functions were found to be comparable among the three study arms and compared to ≥35 years age group, these parameters were found to be better in the younger age group (20-30 years). Most of the pulmonary functions were comparable among the three study arms at 6 weeks. A significant improvement in PEF and % predicted PEF was noted in AA250 arm when compared to baseline values (p=0.049 and 0.026, respectively) and in participants with normal pulmonary functions when compared to those with reduced functions at baseline (p=0.059 and p=0.037). CONCLUSIONS: Although ascorbic acid did not affect most of the pulmonary functions in healthy adults, it improved PEF and % predicted PEF at a daily dose of 250 mg. In this regard, it was found effective in individuals with normal pulmonary indices at baseline.

Efficacy of Interferon-ß in Moderate-to-Severe Hospitalised Cases of COVID-19: A Systematic Review and Meta-analysis.

BACKGROUND AND OBJECTIVE: Interferon-ß, as with several other anti-viral agents, has been investigated as a treatment option for COVID-19 as a repurposed drug. The present study is a systematic review and meta-analysis of interferon-ß to determine its efficacy among moderate-to-severe COVID-19 patients. METHODS: A systematic literature search was done using relevant terms for 'COVID-19' and 'interferon-ß'. Randomised controlled trials (RCT) evaluating the efficacy of interferon-ß in COVID-19 were included. Data were extracted for outcome measures, namely mortality, time to clinical improvement and length of hospital stay. Random effects meta-analysis was performed using RevMan V.5.4.1 to calculate overall effect estimate as odds ratio/hazard ratio for categorical variables and mean difference for continuous variable. RESULT: Eight RCTs were eligible for qualitative synthesis and seven for meta-analysis. The overall effect estimate (odds ratio [OR] 0.59; 95 % CI 0.91, 1.12) and (mean difference [MD] - 1.41; 95 % CI - 2.84, 0.02) indicated no statistically significant difference between effect of IFN-ß and that of control on mortality and length of hospital stay, respectively. However, the overall effect estimate (hazard ratio [HR] 1.95; 95 % CI 1.36, 2.79) denoted a favourable effect of INF-ß on reducing the time to clinical improvement in moderate-to-severe COVID-19 patients. CONCLUSION: Addition of interferon-ß to standard of care resulted in significant reduction in time to clinical improvement but no significant benefit in terms of reduction in mortality and length of hospital stay in moderate-to-severe cases of COVID-19.

A Narrative Review of Antiviral Drugs Used for COVID-19 Pharmacotherapy.

PURPOSE: A number of research articles has been published evaluating safety and efficacy of drugs against COVID-19. This study was undertaken to collate and review the information regarding common proposed anti- viral drugs for easy reference. METHODS: The literature was search was done using terms like severe acute respiratory syndrome or SARS-CoV-2 or 2019-nCoV or SARS-CoV or COVID-19 in combination with drugs or treatment or pharmaco-therapy using PubMed and google scholar to identify relevant articles. RESULTS: Despite showing good early results, hydroxychloroquine and lopinavir-ritonavir has not shown clinical benefit in randomized controlled trials. However lopinavir in combination with other drugs specially interferon is being investigated. Remdesivir has shown positive effect in terms of clinical improvement and continued to being investigated alone or in combination with other drugs. Favipiravir has shown mixed results and more data from adequately powered study is needed to prove its efficacy. CONCLUSIONS: Many drugs which showed positive effect in initial studies could not replicate the same benefit in large randomized controlled trials. There is need to evaluate efficacy and safety of drugs based on high quality evidence before allowing it to be used in general population.

Efficacy and safety of potential vaccine candidates against coronavirus disease 2019: A systematic review.

Search for an effective and safe vaccine to prevent transmission of current pandemic is an unmet need. This study reviews and compares the available early phase clinical data of vaccine candidates which have reached phase 3 of clinical development. The latest update of "DRAFT landscape of coronavirus (CoV) disease 2019 candidate vaccines (October 2, 2020)" released by the World Health Organization was accessed to identify the potential vaccine candidates. The full text articles (published and/or preprint) of data of early clinical trials of the selected vaccines were accessed from the links provided in the same document, PubMed and/or medRxiv.com. After extraction and synthesis, the data were critically evaluated for the study efficacy and safety outcomes. Of the total 193 candidate vaccines 10 were found to reach phase 3 of the clinical development. Nine of these were included in the evaluation process. In all of the included studies, immunogenicity and serious adverse events/local or systemic adverse events/laboratory parameters abnormality was considered as efficacy and safety outcomes respectively. Immunogenicity response with most of the vaccines was either higher than or similar to the respective controls except one (recombinant adenovirus type 26 COV2 [Ad26.COV2.S]) for which it was less than that in control. Overall adverse events (related and/or unrelated) were more with vaccines than those with respective control(s) in three studies, in other two, these were similar whereas in one study, the events were less in the vaccine group than in control group and in the rest, data described were descriptive only without any mention for the same for the control. In conclusion all studies showed immunogenic response to target protein of severe acute respiratory syndrome CoV-2 and which was higher than the respective control except for Ad26.CoV2.S. Many of the vaccines caused more adverse events than the controls, however most were mild and transient and/or manageable.

Effect of Helicobacter pylori-eradication therapy on hepatic steatosis in patients with non-alcoholic fatty liver disease: a randomized-controlled pilot study.

BACKGROUND: Helicobacter pylori infection has been associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD). This study was done to evaluate the effect of H. pylori-eradication therapy (HPET) in patients with NAFLD compared to standard management therapy (SMT). METHODS: Eighty NAFLD patients with H. pylori co-infection were randomized into SMT (diet and exercise, n = 36) and HPET (SMT plus amoxicillin, clarithromycin, and pantoprazole, n = 44) groups. The controlled attenuation parameter (CAP), anthropometric parameters, liver enzymes, lipid profile, and glycemic parameters including homeostasis model assessment-insulin resistance (HOMA-IR) were measured and compared between two groups at the baseline and 24 weeks. RESULTS: Sixty-four participants (SMT group [n = 28] and HPET group [n = 36]) were included in a modified intention-to-treat analysis. Both the SMT group and the HPET group had a significant reduction in CAP scores at 24 weeks (P = 0.002 and P < 0.001, respectively), but the change between the groups was insignificant (P = 0.213). Successful eradication of H. pylori occurred in 68% of the HPET group and led to greater improvement in HOMA-IR at 24 weeks compared to SMT or non-responder patients (P = 0.007). The liver enzymes reduced significantly at 24 weeks in both groups, but the changes between the groups were similar. The lipid parameters remained unchanged within the groups and between the groups at 24 weeks. A significant increase in the levels of reduced glutathione was noted in the HPET group, but the change between the two groups was not statistically different. CONCLUSIONS: HPET was found to be comparable to SMT alone in reducing hepatic steatosis and liver enzymes at 24 weeks in NAFLD patients. However, successful eradication of H. pylori led to greater improvement in HOMA-IR (Trial registration CTRI/2017/05/008608).

Nusinersen: The First Option Beyond Supportive Care for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal motor neurons and poses significant adverse outcome in affected population. Survival motor neuron 1 (SMN1) protein encoded by SMN1 gene located on 5q13 is critical for survival and functioning of motor neurons. Almost identical gene SMN2, present on the same chromosome, produces a small truncated protein (SMN2) because of skipping of exon 7 from translation due to translation silent C6U substitution in exon 7 of SMN2 pre-mRNA transcript. Only 10% of the SMN2 mRNAs produce full length SMN2 protein by including exon 7 in healthy individuals. A large deletion or sometimes a point mutation in SMN1 gene is responsible for SMA. In this case the number of copies of SMN2 genes in an individual determines the severity of disease (the more the number of copies the less severe the disease). Nusinersen (ISIS 396443) binds to intron splicing silencer-N1 (ISS-N1; a site present ten nucleotides down to the junction of exon 7 and intron 7), modulating the splicing of SMN2 pre-mRNA transcript to increase the inclusion of exon 7, thereby increasing the production of full length SMN2 protein. Major evidence of its efficacy came from a sham controlled phase 3 clinical study ENDEAR. The study was stopped early based on significantly favorable results in interim analysis and all the patients were transitioned to receive nusinersen in an ongoing open-label, phase 3 study, SHINE, which will evaluate the long-term efficacy, safety and tolerability of the drug. Nusinersen is globally the first drug approved (by the US FDA) for treatment of SMA in children and adults.

Chronic administration of phenytoin and pleomorphic adenoma: A case report and review of literature.

Adverse drug effects that are uncommon or appear only on chronic administration of a drug may not be detected in clinical trials. This explains the need of strict post-marketing vigilance on drug use. Phenytoin administration has been shown in the literature to be associated with development of neoplasia (benign/malignant). In our knowledge current work represents the first case of pleomorphic-adenoma of sub-mandibular salivary gland developed following chronic phenytoin use. A 40 year old male having a history of head trauma twenty years back, had been on tablet phenytoin 100 mg thrice daily since then. One year back he noticed a small swelling in left sub-mandibular region and gradually increasing in size. FNAC and CECT revealed the diagnosis of pleomorphic-adenoma of sub-mandibular salivary gland. Other causes were ruled out. Surgical excision was performed successfully and continuing follow-up with no recurrence at the end of 6 months. Histo-pathogical examination of the tissue did not show any malignant changes.

Tracheo-Esophageal Fistula (TEF) in a Newborn Following Maternal Antenatal Exposure to Olanzapine.

There is a dearth of evidence on the safety of the use of antipsychotics during pregnancy. Olanzapine, a pregnancy category C drug, has no unequivocal evidence of harm to the fetus. Against this backdrop, we report the first case of a tracheo-esophageal fistula (TEF) in a newborn following maternal antenatal exposure to olanzapine. A 29-year-old woman with acute psychotic disorder had been treated with olanzapine for the last 7 years. Her first pregnancy, while taking olanzapine, resulted in a miscarriage at 4 months' gestation, following which she discontinued olanzapine. She reconceived after a few months and delivered a full-term normal child. However, due to the recurrence of psychiatric illness after her second pregnancy, she was prescribed olanzapine again, which was continued throughout her third pregnancy. The outcome of the third pregnancy was a full-term female baby with a TEF. The baby was managed surgically and discharged with satisfactory vital signs. Unfortunately, however, the baby did not survive beyond 11 months of age. Causality between antenatal maternal olanzapine exposure and TEF in the newborn was determined to be 'probable' (score +5) as per the Naranjo causality assessment scale. Greater knowledge of this potential teratogenicity caused by olanzapine is needed to reduce morbidity and mortality in newborns.

Blepharospasm: an uncommon adverse effect caused by long-term administration of olanzapine.

BACKGROUND: Blepharospasm is one of the components of drug-induced Meige's syndrome which is reported to be caused by typical antipsychotics. Reports of blepharospasm or Meige's syndrome caused by atypical antipsychotics are rare. CASE: A 30-year-old female patient presented to psychiatry out patient department (OPD) with chief complaints of inability to keep her eyes open for long and excessive blinking for 2 months, irritation of eyes, watery discharge from eyes and photophobia for last 1 month. The patient had been taking olanzapine 10 mg, sertraline 100 mg and divalproex sodium 500 mg per orally on once a day basis for the management of major depressive disorder with psychotic features for last 6 months. Routine blood analysis, thyroid function, EEG, MRI, lipid profile did not reveal any abnormality. Ocular examination was also within normal limits. Olanzapine was suspected as a culprit for the above symptoms of patient, so it was replaced with quetiapine 25 mg/day. Patient showed partial recovery of symptoms within 1 week and complete recovery within 2 months of stopping olanzapine. Causality of olanzapine-induced blepharospasm as per WHO-UMC scale was probable. CONCLUSIONS: Olanzapine (atypical antipsychotics) should also be kept in the list of suspected drugs causing blepharospasm in psychotic patients on treatment although further similar evidences from observational studies and/or reports are needed to establish the causal relationship.

Comparison of online reporting systems and their compatibility check with respective adverse drug reaction reporting forms.

AIM: Different forms and online tools are available in different countries for spontaneous reporting, one of the most widely used methods of pharmacovigilance. Capturing sufficient information and adequate compatibility of online systems with respective reporting form is highly desirable for appropriate reporting of adverse drug reactions (ADRs). This study was aimed to compare three major online reporting systems (US, UK, and WHO) of the world and also to check their compatibility with the respective ADR reporting form. MATERIALS AND METHODS: A total of 89 data elements to provide relevant information were found out from above three online reporting systems. All three online systems were compared regarding magnitude of information captured by each of them and scoring was done by providing a score of "1" to each element. Compatibility of ADR reporting forms of India (Red form), US (Form 3500), and UK (Yellow card form) was assessed by comparing the information gathered by them with that can be entered into their respective online reporting systems, namely, "VigiFlow," "US online reporting," and "Yellow card online reporting." Each unmatching item was given a score of "-1". RESULTS: VigiFlow scored "74" points, whereas online reporting systems of the US and UK scored "56" and "49," respectively, regarding magnitude of the information gathered by them. Compatibility score was found to be "0," "-9," and "-26" in case of ADR reporting systems of US, UK, and India, respectively. CONCLUSION: Our study reveals that "VigiFlow" is capable of capturing the maximum amount of information but "Form 3500" and "Online reporting system of US" are maximally compatible to each other among ADR reporting systems of all three countries.

Comparison of Effect of Enalapril and Losartan Monotherapy on Quality of Life and Safety of Stage 1 Hypertensive Patients.

An open label randomized controlled study was conducted to compare the quality of life (QoL) and safety of newly diagnosed stage I hypertensive patients randomized into two groups of 30 receiving either enalapril 5 mg or losartan 50 mg per-oral once daily for three months. QoL was assessed at the baseline and at the end of study using SF-36v2 health care questionnaire. Adverse drug reactions (ADRs) were monitored. Investigations at baseline were compared with those after intervention. Pre & post-intervention QoL transformed scores within each group and change in the same between two groups were analyzed using paired and unpaired t-test respectively. Transformed scores of role limitation due to energy/fatigue, emotional well being and general health domains improved significantly in both treatment groups. Scores of bodily pain improved significantly (p=0.0008) in losartan group only. Results were not significantly different between two groups (except for bodily pain). No serious ADR was reported.