Improving the quality of systematic reviews of neurological conditions: an assessment of current practice and the development and validation of six new search strategies.

BACKGROUND AND PURPOSE: Our aim was to study the quality of the literature search strategies used in recent systematic reviews and to develop and assess the diagnostic accuracy of six new search strategies (i.e. hedges). METHODS: Six neurological conditions were studied: migraine, stroke, dementia, epileptic seizures, Parkinson's disease and multiple sclerosis. Two reviewers independently assessed the quality of the search strategies used in systematic reviews published in 2015-2016. Complex hedges pertaining to the six conditions for use in Ovid MEDLINE were developed. Their diagnostic accuracy was compared to simple, single-term keyword searches. RESULTS: Almost 60% of quality criteria for the overall literature search strategy used in 182 systematic reviews were not respected. Over 30% of search strategies relied on a single keyword to identify the neurological condition. The sensitivities of our complex hedges amongst 10 311 articles were between 83% and 95%, significantly higher than the simple keyword searches (as low as 48%). The specificities were greater than 97%. CONCLUSIONS: There is great room for improvement in the search strategies used in systematic reviews of neurological conditions. Complex hedges were developed and validated to improve the accuracy of such searches. It is expected that this will lead to higher quality systematic reviews and meta-analyses.

Safety and effectiveness of neuraminidase inhibitors for influenza treatment, prophylaxis, and outbreak control: a systematic review of systematic reviews and/or meta-analyses.

OBJECTIVES: To review evidence from systematic reviews and/or meta-analyses (SR/MAs) regarding neuraminidase inhibitor (NI) safety and effectiveness. METHODS: We conducted an SR of SR/MAs of randomized control and/or observational studies. We searched eight electronic databases for SR/MAs that examined the effectiveness or safety of NIs administered for influenza (i.e. influenza-like illness or lab-confirmed) treatment or prophylaxis. RESULTS: We identified 27 (0.7%) eligible SR/MAs of 3723 articles reviewed. NI (n = 2) or oseltamivir (n = 1) versus no treatment were consistently associated with a decrease in mortality odds among the hospitalized, general population (OR range 0.2 - 0.8). Oseltamivir versus no treatment was associated with a decrease in hospitalization and pneumonia risk/odds in 2/4 SR/MAs. Oseltamivir (n = 4) and zanamivir (n = 3) were consistently associated with a 0.5 - 1 day decrease in symptom duration. Oseltamivir (n = 4) or zanamivir (n = 4) versus no prophylaxis were consistently associated with a decrease in the odds/risk of symptomatic secondary transmission (OR/RR range 0.1 - 0.5). Oseltamivir versus no treatment was consistently associated with a 1.5- to 2.5-fold increase in the odds/risk of nausea (n = 4) and vomiting (n = 5). CONCLUSIONS: NI treatment is likely to be effective at reducing mortality among hospitalized patients, and symptom duration by up to 1 day in the general population. Oseltamivir or zanamivir prophylaxis are likely to be effective at reducing secondary symptomatic influenza transmission. Increased nausea and vomiting are likely associated with oseltamivir use. We recommend that decisions regarding NI use are made in consideration of potential adverse events, particularly for the general population at low risk of complications. Among hospitalized patients, NI administration seems warranted to reduce mortality risk.

Safety and effectiveness of neuraminidase inhibitors in situations of pandemic and/or novel/variant influenza: a systematic review of the literature, 2009-15.

Objectives: To review systematically the published literature evaluating neuraminidase inhibitor (NI) safety and effectiveness in situations of pandemic and novel/variant influenza. Methods: We searched six online databases using comprehensive search criteria for observational studies and randomized controlled trials investigating the effects of NI treatment, prophylaxis or outbreak control in patients of all ages. Results: Overall, 165 studies were included (95% observational), which were generally of low methodological quality due to lack of adjustment for confounding variables. In studies reporting adjusted estimates in general populations, NI treatment appeared likely to be effective against mortality (primarily if administered within 48 h of symptom onset) and potentially effective in reducing pneumonia. NIs appeared effective in reducing secondary transmission when indicated for prophylaxis. Limited, low-quality data suggest NIs are likely safe in general populations and may be safe in pregnant women and children. Data are scarce regarding safety of NIs in adults and high-risk individuals. Conclusions: Most included studies were observational, statistically underpowered and at high risk of reporting biased and/or confounded effect estimates. NI treatment appeared likely effective in reducing mortality (cause unspecified) and pneumonia in general populations, with increasing benefit when administered with 48 h of symptom onset. NI pre- or post-exposure prophylaxis is likely effective in reducing secondary transmission of influenza in a general population. Our evidence suggests NIs are likely safe to use in the general population; however, data for children and pregnant women are limited. Knowledge gaps persist in specific populations such as Aboriginals, high-risk individuals and the elderly.

The diagnostic accuracy of routine electroencephalography after a first unprovoked seizure.

The clinical utility of routine electroencephalography (EEG) after a first unprovoked seizure remains uncertain. Its diagnostic accuracy in identifying adults and children with new onset epilepsy was examined. A systematic review and meta-analysis of studies examining individuals who underwent routine EEG after a first unprovoked seizure and were followed for seizure recurrence for at least 1 year was performed. A 'positive' test was defined by the presence of epileptiform discharges (ED). Pooled sensitivity and specificity estimates were calculated using a bivariate random effects regression model. In all, 3096 records were reviewed, from which 15 studies were extracted with a total of 1799 participants. Amongst adult studies, the sensitivity and specificity (95% confidence interval) of routine EEG were 17.3% (7.9, 33.8) and 94.7% (73.7, 99.1), respectively. Amongst child studies, the pooled sensitivity and specificity were 57.8% (49.7, 65.6) and 69.6% (57.5, 79.5), respectively. Based upon our positive likelihood ratios, and assuming a pre-test probability of 50%, an adult with ED on routine EEG after a first unprovoked seizure has a 77% probability of having a second seizure, whilst a child with similar findings has a 66% probability. Further studies are required to examine the impact of patient characteristics and EEG features on the diagnostic accuracy of routine EEG for new onset epilepsy.

Quality of tuberculosis care in India: a systematic review.

BACKGROUND: While Indian studies have assessed care providers' knowledge and practices, there is no systematic review on the quality of tuberculosis (TB) care. METHODS: We searched multiple sources to identify studies (2000-2014) on providers' knowledge and practices. We used the International Standards for TB Care to benchmark quality of care. RESULTS: Of the 47 studies included, 35 were questionnaire surveys and 12 used chart abstraction. None assessed actual practice using standardised patients. Heterogeneity in the findings precluded meta-analysis. Of 22 studies evaluating provider knowledge about using sputum smears for diagnosis, 10 found that less than half of providers had correct knowledge; 3 of 4 studies assessing self-reported practices by providers found that less than a quarter reported ordering smears for patients with chest symptoms. In 11 of 14 studies that assessed treatment, less than one third of providers knew the standard regimen for drug-susceptible TB. Adherence to standards in practice was generally lower than correct knowledge of those standards. Eleven studies with both public and private providers found higher levels of appropriate knowledge/practice in the public sector. CONCLUSIONS: Available evidence suggests suboptimal quality of TB care, particularly in the private sector. Improvement of quality of care should be a priority for India.

Theoretical studies on the structure and detonation properties of amino-, methyl-, and nitro-substituted 3,4,5-trinitro-1H-pyrazoles.

In this study, 3,4,5-trinitro-1H-pyrazole (R20), 3,4,5-trinitro-1H-pyrazol-1-amine (R21), 1-methyl-3,4,5-trinitro-1H-pyrazole (R22), and 1,3,4,5-tetranitro-1H-pyrazole (R23) have been considered as potential candidates for high-energy density materials by quantum chemical treatment. The geometric and electronic structures, band gap, thermodynamic properties, crystal density and detonation properties were studied using density functional theory at the B3LYP/aug-cc-pVDZ level. The calculated energy of explosion, density, and detonation performance of model compounds are comparable to 1,3,5-trinitro-1,3,5-triazinane (RDX), and 1,3,5,7-tetranitro-1,3,5,7-tetrazocane (HMX). Atoms-in-molecules (AIM) analyses have also been carried to understand the nature of intramolecular interactions and the strength of trigger bonds.

Effectiveness of voice therapy in reflux-related voice disorders.

Gastroesophageal reflux (GER) with laryngopharyngeal reflux plays a significant role in voice disorders. A significant proportion of patients attending ear, nose, and throat clinics with voice disorders may have gastroesophageal reflux disease (GERD). There is no controlled study of the effect of voice therapy on GERD. We assessed the effect of voice therapy in patients with dysphonia and GERD. Thirty-two patients with dysphonia and GERD underwent indirect laryngoscopy and voice analysis. Esophageal and laryngeal symptoms were assessed using the reflux symptom index (RSI). At endoscopy, esophagitis was graded according to Los Angeles classification. Patients were randomized to receive either voice therapy and omeprazole (20 mg bid) (n=16, mean [SD] age 36.1 [9.6] y; 5 men; Gp A) or omeprazole alone (n=16, age 31.8 [11.7] y; 9 men; Gp B). During voice analysis, jitter, shimmer, harmonic-to-noise ratio (HNR) and normalized noise energy (NNE) were assessed using the Dr. Speech software (version 4 1998; Tigers DRS, Inc). Hoarseness and breathiness of voice were assessed using a perceptual rating scale of 0-3. Parameters were reassessed after 6 weeks, and analyzed using parametric or nonparametric tests as applicable. In Group A, 9 patients had Grade A, 3 had Grade B, and 1 had Grade C esophagitis; 3 had normal study. In Group B, 8 patients had Grade A, 2 had Grade B esophagitis, and 6 had normal study. Baseline findings: median RSI scores were comparable (Group A 20.0 [range 14-27], Group B 19.0 [15-24]). Median rating was 2.0 for hoarseness and breathiness for both groups. Values in Groups A and B for jitter 0.5 (0.6) versus 0.5 (0.8), shimmer 3.1 (2.5) versus 2.8 (2.0), HNR 23.0 (5.6) versus 23.1 (4.2), and NNE -7.3 (3.2) versus -7.2 (3.4) were similar. Post-therapy values for Groups A and B: RSI scores were 9.0 (5-13; P<0.01 as compared with baseline) and 13.0 (10-17; P<0.01), respectively. Ratings for hoarseness and breathiness were 0.5 (P<0.01) and 1.0 (P<0.01) and 2.0. Values for jitter were 0.2 (0.0; P=0.02) versus 0.4 (0.7), shimmer 1.3 (0.7; P<0.01) versus 2.3 (1.2), HNR 26.7 (2.3; P<0.01) versus 23.7 (3.2), and NNE -12.3 (3.0, P<0.01) versus -9.2 (3.4; P<0.01). Improvement in the voice therapy group was significantly better than in patients who received omeprazole alone. Dysphonia is a significant problem in GER. Treatment for GER improves dysphonia, but in addition, voice therapy enhances the improvement.

Synthesis and characterization of 3,6-bis(1H-1,2,3,4-tetrazol-5-ylamino)-1,2,4,5-tetrazine (BTATz): novel high-nitrogen content insensitive high energy material.

This paper reports the synthesis, characterization and thermolysis studies of 3,6-bis(1H-1,2,3,4-tetrazol-5-ylamino)-1,2,4,5-tetrazine (BTATz) and 3-(1H-1,2,3,4-tetrazol-5-ylamino)-6-(3,5-dimethyl-pyrazol-1-yl)-s-tetrazine monohydrate (TADPTz). The synthesized BTATz and TADPTz have been characterized by spectroscopic techniques and the data obtained confirm their structure. TGA and DSC results suggested that BTATz decomposes in the range 265-350 degrees C and TADPTz in the range 245-275 degrees C respectively. The calculated energy of activation of BTATz and TADPTz is 212.69 and 257.29kJ/mol respectively. The experimentally determined DeltaH(f) value matches with theoretically computed heat of explosion. The computed volume of gases indicates that they can find application in gas generating compositions.

Studies on thermal decomposition mechanism of CL-20 by pyrolysis gas chromatography-mass spectrometry (Py-GC/MS).

The thermal decomposition study of CL-20 (hexanitrohexaazaisowurtzitane) using pyrolysis GC/MS was carried out mainly by electron impact (EI) mode. Chemical ionization (CI) mode was used for further confirmation of identified species. Mass spectrum of CL-20 decomposition products predominantly revealed fragments with m/z 81 and 96 corresponding to C(4)H(5)N(2)(+) and C(4)H(4)N(2)O(+) ions, respectively. The total ion chromatogram (TIC) of CL-20 pyrolysis shows peak within first 2 min due to the presence of low molecular weight gases. Peaks corresponding to several other products were also observed including the atmospheric gases. Cyanogen formation (C(2)N(2), m/z 52) observed to be enriched at the scan number 300-500. The low molecular mass range decomposition products formed by cleavage of C-N ring structure were found in majority. Additional structural information was sought by employing chemical ionization mode. The data generated during this study was instrumented in determining decomposition pathways of CL-20.

Ultrasonically controlled particle size distribution of explosives: a safe method.

Size reduction of the high energy materials (HEM's) by conventional methods (mechanical means) is not safe as they are very sensitive to friction and impact. Modified crystallization techniques can be used for the same purpose. The solute is dissolved in the solvent and crystallized via cooling or is precipitated out using an antisolvent. The various crystallization parameters such as temperature, antisolvent addition rate and agitation are adjusted to get the required final crystal size and morphology. The solvent-antisolvent ratio, time of crystallization and yield of the product are the key factors for controlling antisolvent based precipitation process. The advantages of cavitationally induced nucleation can be coupled with the conventional crystallization process. This study includes the effect of the ultrasonically generated acoustic cavitation phenomenon on the solvent antisolvent based precipitation process. CL20, a high-energy explosive compound, is a polyazapolycyclic caged polynitramine. CL-20 has greater energy output than existing (in-use) energetic ingredients while having an acceptable level of insensitivity to shock and other external stimuli. The size control and size distribution manipulation of the high energy material (CL20) has been successfully carried out safely and quickly along with an increase in the final mass yield, compared to the conventional antisolvent based precipitation process.

Electro-analysis of energetic materials.

Cyclic voltammetric studies of triaminoguanidine nitrate (TAGN), 3,3'-hydrazino bis(bis[6,6'-(3,5-dimethylpyrazol-lyl])-1,2,4,5-tetrazine (HBPT), 4,6-dinitrobenzofuroxan (DNBF) and 3,3'-diamino-4,4'-azoxyfurazan (DAAF) were carried out at different pH conditions in 50% aqueous acetonitrile using glassy carbon electrode. Optimum pH was selected for individual compounds. Influence of scan rate and concentration on the voltammetric response were studied in optimum pH. The number of electron transferred was determined by controlled potential coulometry. All compounds undergo diffusion controlled electrochemical reaction. Based on cyclic voltammetric results, differential pulse and square wave voltammetric methods have been developed for the analytical determination. Instrumental parameters such as initial scan potential, amplitude, pulse increment, pulse period, pulse width and frequency were studied. Optimum experimental conditions for each compound were obtained. After fixing optimum conditions, the effect of concentration was studied and calibration plot was arrived. These plots can be used to determine the traces of the above said four energetic materials.

Study on ultrasound assisted precipitation of CL-20 and its effect on morphology and sensitivity.

Applying ultrasound to crystallizing systems offers significant advantages for modifying and improving the processes as well as quality of products. This paper reports on ultrasound assisted reprecipitation of CL-20 to obtain fine particles as well as to achieve desired morphology, which will improve insensitivity characteristics. In this study, CL-20 has been reprecipitated by sonication process and has been characterized by DSC, SEM and particle size analysis. The results are compared with control CL-20 sample (unsonicated). SEM photographs revealed that sonication process offer uniform crystalline morphology without any agglomeration. The particle size of sonicated CL-20 sample obtained is around 5+/-1 microm with a narrow particle size distribution. The DSC thermogram of sonicated and unsonicated sample is identical. CL-20 samples were subjected to impact and friction sensitivity experiments, the results indicate the sensitivity characteristics reduced considerably. Ultrasonic assisted crystallization technique reduces the time of reprecipitation considerably with an enhanced recovery of CL-20 with a very narrow particle size distribution.

Preparation and thermal studies on tetranitrodibenzo tetraazapentalene (TACOT): a thermally stable high explosive.

Thermally stable high explosive, tetranitro-2,3,5,6-dibenzo-1,3a,4,6a-tetraazapentalene (TACOT) was synthesized and characterized during this work. Thermo analytical techniques (TG and DSC) were applied to study the thermal decomposition behaviour of TACOT in comparison with benchmark thermally stable high explosive 1,3,5-triamino-2,4,6-trinitrobenzene (TATB). Kinetic parameters such as reaction order, activation energy and pre-exponential factors were computed from the thermal data. The activation energy for TACOT (292 kJ/mol) was found 1.5 times to that of TATB (200 kJ/mol), which can account for its higher thermal stability and can be attributed to pentalene moiety in the former.

Method for preparation of fine TATB (2-5 microm) and its evaluation in plastic bonded explosive (PBX) formulations.

There is a need of fine 1,3,5-triamino-2,4,6-trinitrobenzene (TATB) (2-5 microm) for various high explosive formulations to achieve desired mechanical strength, ease in processing and finally, provide better performance of end product. The reprecipitation method for TATB has been developed using concentrated sulfuric acid as a solvent. The reprecipitation parameters of TATB were optimized to achieve required fine TATB of particle size approximately 2-5 microm. The characteristic properties of fine TATB thus obtained have been confirmed by FTIR, DSC and TG-FTIR. The spectroscopic and thermal data obtained for fine TATB were compared with standard coarse TATB and found chemically unchanged during particle size reduction. In the present study, the preparation of fine TATB was also attempted using ultrasonication method. The fine (2-5 microm) TATB has been introduced to study in the bimodal high explosive formulations. High explosive formulations based on coarse (55 microm) and fine TATB ( approximately 2-5 microm) with 10% polyurethane were studied. It was observed that properties like bulk density (1.70 g/cm(3)), mechanical strength/compressed strength (115.9 mg/cm(2)), %elongation (6.36) were improved for fine TATB in comparison with coarse TATB ( approximately 55 microm) alone in high explosive formulations.

Synthesis, characterization and thermolysis studies on triazole and tetrazole based high nitrogen content high energy materials.

This paper reports the synthesis, characterisation and thermolysis studies of hydrazinium azotetrazolate (HAZ) and 1,1'-dinitro-3,3'-azo-1,2,4-triazole (N-DNAT). TGA and DSC results suggested that HAZ decomposes in the range of 150-180 degrees C and N-DNAT in the range of 160-170 degrees C, respectively. The pattern of decomposition of HAZ dihydrate and N-DNAT has been predicted with the help of pyrolysis GC/MS technique and a probable decomposition mechanism has been proposed. The theoretically predicted performance data suggests the potential nature of HAZ and N-DNAT for their use in propellant/explosive as well as in gas generator formulations.

Primary explosives: electrostatic discharge initiation, additive effect and its relation to thermal and explosive characteristics.

All explosives, under all conditions must be considered vulnerable to generation, accumulation and discharge of static charge. The low energy static hazards of the order as low as 2-3 mJ need to be guarded against in case of highly sensitive compounds namely primary explosives. The hazard is normally associated with manufacturing and filling operations due to discharge of static charge accumulated on a person supplying energy up to 20 mJ. To reduce the risk associated with static initiation hazard in the processing and handling of the explosives, the electrostatic sensitivity tests can provide an important input regarding electrostatic hazards. This paper presents electrostatic sensitivity data in terms of zero ignition probability data (E(SE0)) of some of the initiatory explosives such as nickel/cobalt hydrazinium nitrate, silver azide, lead azide and mercury salt of 5-nitro tetrazole. Similar data has also been presented for samples coated with polyvinyl pyrrolidone to study its effect on electrostatic sensitivity. The electrostatic spark sensitivity of some conventional and novel made to explain the increased spark sensitivity behavior on the basis of the possible primary explosives has been studied. The electrostatic spark sensitivity of primary explosives decreased in the order of AgN3 = NHN > PbN6 > MNT > CoHN > BNCP. A possible correlation of spark energy with approximation and assumption has been drawn with thermal, detonation and mechanical properties. The polyvinyl pyrrolidone coated samples followed the same order but interestingly with increased spark sensitivity. An attempt has been reasoning of dielectric nature of the materials or exothermic effects of decomposition products of PVP. The present work also reports the electrostatic spark sensitivity of cap compositions.

Synthesis, characterization and thermolysis of 1,1-diamino-2,2-dinitroethylene (FOX-7) and its salts.

The present paper discusses the efforts made in HEMRL to establish the synthesis of FOX-7 at 100 g/batch level. In the present study, 1,1-diamino-2,2-dinitroethylene has been synthesised by treatment of acetamidinium chloride with diethylmalonate to obtain 2-methyl-pyrimidine-4,6-dione which on nitration followed by hydrolysis gave FOX-7. The synthesised FOX-7 has been characterized by spectroscopic and thermal techniques. The data obtained confirms the structure of FOX-7. The sensitivity of FOX-7 towards mechanical stimuli indicated its insensitive nature. The theoretically computed explosive and ballistic parameters are close to that of RDX. The synthesised FOX-7 has been used as a precursor for the synthesis of potassium and guanidinium salts and the thermal analysis of these salts indicate their exothermic nature.

Effect of organic additives on the mitigation of volatility of 1-nitro-3,3'-dinitroazetidine (TNAZ): next generation powerful melt cast able high energy material.

1-Nitro-3,3'-dinitroazetidine (TNAZ) was synthesized based on the lines of reported method. Thermolysis studies on synthesized and characterized TNAZ using differential scanning calorimetry (DSC) and hyphenated TG-FT-IR techniques were undertaken to generate data on decomposition pattern. FT-IR of decomposition products of TNAZ revealed the evolution of oxides of nitrogen and HCN containing species suggesting the cleavage of C/N-NO(2) bond accompanied with the collapse of ring structure. The effect of incorporation of 15% additives namely, 3-amino-1,2,4-triazole (AT), 3,5-diamino-1,2,4-triazole (DAT), carbohydrazide (CHZ), 5,7-dinitrobenzofuroxan (DNBF), bis (2,2-dinitropropyl) succinate (BNPS), triaminoguanidinium nitrate (TAGN), 2,4,6-trinitrobenzoic acid (TNBA) and nitroguanidine (NQ) on the volatility of TNAZ was investigated by undertaking thermogravimetric analysis. The TG pattern brings out the potential of BNPS and TAGN as additives to mitigate the volatility of TNAZ. The influence of additives on thermal decomposition of pattern of TNAZ was also investigated by DSC. The DSC results indicated that the additives did not have appreciable effect on the melting point of TNAZ. Scanning electron microscopic (SEM) studies were carried out to investigate the effect of additives on morphology of TNAZ. This paper also discusses the possible mechanism involved in between the TNAZ and TAGN and BNPS. It appears that the formation of charge transfer complex formation between the TNAZ and TAGN/BNPS. The effect of addition of high explosives such as CL-20, HMX and RDX on thermo-physical characteristics of TNAZ is also reported in this paper.

Establishment of process technology for the manufacture of dinitrogen pentoxide and its utility for the synthesis of most powerful explosive of today--CL-20.

This paper reviews the recent work done on the synthesis as well as characterization of dinitrogen pentoxide (DNPO). The physico-chemical characteristics of DNPO are also discussed. The review brings out the key aspects of N2O5 technology with relevance to realize modern and novel HEMs. The paper also includes the aspects related with establishing the synthesis facility of dinitrogen pentoxide at HEMRL by gas phase interaction of N2O4 with O3. The process parameters for the synthesis of N2O5 at 50 g/batch have been optimized. The synthesized dinitrogen pentoxide has been characterized by UV [204, 213, 258 nm (pi-->pi*) 378 and 384 nm (n-->pi*)] and IR (1428, 1266, 1249, 1206, 1044, 822, 750, 546 and 454 cm(-1)) spectroscopy. The DSC clearly showed the sublimation of N2O5 at 32 degrees C. The nitration studies on 2,6,8,12-tetraacetylhexaaza tetracyclo[5,5,0,0(3,11)0(5,9)]dodecane (TAIW) proved its viability in 2,4,6,8,10,12-hexanitro-2,4,6,8(10,12))-hexaazatetracyclo [5,5,0,0(3,11)0(5,9)]dodecane (CL-20) synthesis. The synthesized CL-20 and its precursors have also been subjected to hyphenated TG-FTIR studies to understand decomposition pattern.