Bioavailability of three novel oral, sustained-release pellets, relative to an immediate-release tablet containing 500 mg flucytosine: A randomized, open-label, crossover study in healthy volunteers.

The opportunistic fungal infection cryptococcal meningoencephalitis is a major cause of death among people living with HIV in sub-Saharan Africa. We report pharmacokinetic (PK) and safety data from a randomized, four-period crossover phase I trial of three sustained-release (SR) oral pellet formulations of 5-flucytosine conducted in South Africa. These formulations were developed to require less frequent administration, to provide a convenient alternative to the current immediate release (IR) formulation, A. Formulations B, C, and D were designed to release 5-flucytosine as a percentage of the nominal dose in vitro. We assessed their safety and PK profiles in a single dose (1 × 3000 mg at 0 h), relative to commercial IR tablets (Ancotil 500 mg tablets; 3 × 500 mg at 0 h and 3 × 500 mg at 6 h) in healthy, fasted participants. Forty-two healthy participants were included. All treatments were well-tolerated. The primary PK parameters, maximum observed plasma concentration (Cmax ) and area under the concentration-time profiles, were significantly lower for the SR formulations than for the IR tablets, and the geometric mean ratios fell outside the conventional bioequivalence limits. The median maximum time to Cmax was delayed for the SR pellets. Physiologically-based PK modeling indicated a twice-daily 6400 mg dose of SR formulation D in fasted condition would be optimal for further clinical development. This regimen is predicted to result in a rapid steady-state plasma exposure with effective and safe trough plasma concentration and Cmax values, within the therapeutic boundaries relative to plasma exposure after four times per day administration of IR tablets (PACTR202201760181404).

Techno-economic optimization and Nox emission reduction through steam injection in gas turbine combustion chamber for waste heat recovery and water production.

Considering the persistent human need for electricity and fresh water, cogeneration systems based on the production of these two products have attracted the attention of researchers. This study investigates a cogeneration system of electricity and fresh water based on gas turbine (GT) as the prime mover. The wasted energy of the GT exhaust gases is absorbed by a heat recovery steam generator (HRSG) and supplies the superheat steam required by the steam turbine (ST). In order to produce fresh water, a multi-effect desalination (MED) system is applied. The motive steam required is provided by extracting steam from the ST. In order to reduce the environmental pollution of this cogeneration system, the steam injection method is proposed in the GT's combustion chamber (CC). This system is optimized by a multi-objective optimization tool based on the Genetic Algorithm (GA). The design variables include pressure ratio of compressor (CPR), inlet temperature of gas turbine (TIT), steam injection mass flow rate in the CC, HRSG operating pressure, HRSG evaporator pinch point temperature difference (PPTD), steam pressure of the MED ejector, ejector motive steam flow rate, number of MED effects, and return effect. The goals are to minimize the total cost rate (TCR), which includes the cost of initial investment and maintenance of the system, the cost of consumed fuel, and the cost of disposing of CO and NO pollutants, as well as maximizing the exergy efficiency. In the end, it is observed that the steam injection in the CC leads to the reduction of the mentioned pollutant index, and it is proposed as a suitable solution to reduce the pollution of the proposed cogeneration system.

A constructive non-local means algorithm for low-dose computed tomography denoising with morphological residual processing.

Low-dose computed tomography (LDCT) has attracted significant attention in the domain of medical imaging due to the inherent risks of normal-dose computed tomography (NDCT) based X-ray radiations to patients. However, reducing radiation dose in CT imaging produces noise and artifacts that degrade image quality and subsequently hinders medical disease diagnostic performance. In order to address these problems, this research article presents a competent low-dose computed tomography image denoising algorithm based on a constructive non-local means algorithm with morphological residual processing to achieve the task of removing noise from the LDCT images. We propose an innovative constructive non-local image filtering algorithm by means of applications in low-dose computed tomography technology. The nonlocal mean filter that was recently proposed was modified to construct our denoising algorithm. It constructs the discrete property of neighboring filtering to enable rapid vectorized and parallel implantation in contemporary shared memory computer platforms while simultaneously decreases computing complexity. Subsequently, the proposed method performs faster computation compared to a non-vectorized and serial implementation in terms of speed and scales linearly with image dimension. In addition, the morphological residual processing is employed for the purpose of edge-preserving image processing. It combines linear lowpass filtering with a nonlinear technique that enables the extraction of meaningful regions where edges could be preserved while removing residual artifacts from the images. Experimental results demonstrate that the proposed algorithm preserves more textural and structural features while reducing noise, enhances edges and significantly improves image quality more effectively. The proposed research article obtains better results both qualitatively and quantitively when compared to other comparative algorithms on publicly accessible datasets.

Machine learning-based automatic detection of novel coronavirus (COVID-19) disease.

The pandemic was announced by the world health organization coronavirus (COVID-19) universal health dilemma. Any scientific appliance which contributes expeditious detection of coronavirus with a huge recognition rate may be excessively fruitful to doctors. In this environment, innovative automation like deep learning, machine learning, image processing and medical image like chest radiography (CXR), computed tomography (CT) has been refined promising solution contrary to COVID-19. Currently, a reverse transcription-polymerase chain reaction (RT-PCR) test has been used to detect the coronavirus. Due to the moratorium period is high on results tested and huge false negative estimates, substitute solutions are desired. Thus, an automated machine learning-based algorithm is proposed for the detection of COVID-19 and the grading of nine different datasets. This research impacts the grant of image processing and machine learning to expeditious and definite coronavirus detection using CXR and CT medical imaging. This results in early detection, diagnosis, and cure for the accomplishment of COVID-19 as early as possible. Firstly, images are preprocessed by normalization to enhance the quality of the image and removing of noise. Secondly, segmentation of images is done by fuzzy c-means clustering. Then various features namely, statistical, textural, histogram of gradients, and discrete wavelet transform are extracted (92) and selected from the feature vector by principle component analysis. Lastly, k-NN, SRC, ANN, and SVM are used to make decisions for normal, pneumonia, COVID-19 positive patients. The performance of the system has been validated by the k (5) fold cross-validation technique. The proposed algorithm achieves 91.70% (k-Nearest Neighbor), 94.40% (Sparse Representation Classifier), 96.16% (Artificial Neural Network), and 99.14% (Support Vector Machine) for COVID detection. The proposed results show feature combination and selection improves the performance in 14.34 s with machine learning and image processing techniques. Among k-NN, SRC, ANN, and SVM classifiers, SVM shows more efficient results that are promising and comparable with the literature. The proposed approach results in an improved recognition rate as compared to the literature review. Therefore, the algorithm proposed shows immense potential to benefit the radiologist for their findings. Also, fruitful in prior virus diagnosis and discriminate pneumonia between COVID-19 and other pandemics.

AmBisome Monotherapy and Combination AmBisome-Miltefosine Therapy for the Treatment of Visceral Leishmaniasis in Patients Coinfected With Human Immunodeficiency Virus in India: A Randomized Open-Label, Parallel-Arm, Phase 3 Trial.

BACKGROUND: Visceral leishmaniasis (VL) in patients with human immunodeficiency virus (HIV) presents an increasingly important patient cohort in areas where both infections are endemic. Evidence for treatment is sparce, with no high-quality studies from the Indian subcontinent. METHODS: This is a randomized, open-label, parallel-arm, phase 3 trial conducted within a single hospital in Patna, India. One hundred and fifty patients aged ≥18 years with serologically confirmed HIV and parasitologically confirmed VL were randomly allocated to 1 of 2 treatment arms, either a total 40 mg/kg intravenous liposomal amphotericin B (AmBisome; Gilead Pharmaceuticals) administered in 8 equal doses over 24 days or a total 30 mg/kg intravenous AmBisome administered in 6 equal doses given concomitantly with a total 1.4 g oral miltefosine administered through 2 daily doses of 50 mg over 14 days. The primary outcome was intention-to-treat relapse-free survival at day 210, defined as absence of signs and symptoms of VL or, if symptomatic, negative parasitological investigations. RESULTS: Among 243 patients assessed for eligibility, 150 were recruited between 2 January 2017 and 5 April 2018, with no loss to follow-up. Relapse-free survival at day 210 was 85% (64/75; 95% CI, 77-100%) in the monotherapy arm, and 96%, (72/75; 90-100%) in the combination arm. Nineteen percent (28/150) were infected with concurrent tuberculosis, divided equally between arms. Excluding those with concurrent tuberculosis, relapse-free survival at day 210 was 90% (55/61; 82-100%) in the monotherapy and 97% (59/61; 91-100%) in the combination therapy arm. Serious adverse events were uncommon and similar in each arm. CONCLUSIONS: Combination therapy appears to be safe, well tolerated, and effective, and halves treatment duration of current recommendations. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry India (CTRI/2015/05/005807; the protocol is available online at https://osf.io/avz7r).

Efficacy and safety of ravidasvir plus sofosbuvir in patients with chronic hepatitis C infection without cirrhosis or with compensated cirrhosis (STORM-C-1): interim analysis of a two-stage, open-label, multicentre, single arm, phase 2/3 trial.

BACKGROUND: In low-income and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic non-structural protein 5A (NS5A) inhibitor, and sofosbuvir has shown efficacy and safety in patients with chronic HCV genotype 4 infection. STORM-C-1 trial aimed to assess the efficacy and safety of ravidasvir plus sofosbuvir in a diverse population of adults chronically infected with HCV. METHODS: STORM-C-1 is a two-stage, open-label, phase 2/3 single-arm clinical trial in six public academic and non-academic centres in Malaysia and four public academic and non-academic centres in Thailand. Patients with HCV with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-3) aged 18-69 years were eligible to participate, regardless of HCV genotype, HIV infection status, previous interferon-based HCV treatment, or source of HCV infection. Once daily ravidasvir (200 mg) and sofosbuvir (400 mg) were prescribed for 12 weeks for patients without cirrhosis and for 24 weeks for those with cirrhosis. The primary endpoint was sustained virological response at 12 weeks after treatment (SVR12; defined as HCV RNA <12 IU/mL in Thailand and HCV RNA <15 IU/mL in Malaysia at 12 weeks after the end of treatment). This trial is registered with ClinicalTrials.gov, number NCT02961426, and the National Medical Research Register of Malaysia, NMRR-16-747-29183. FINDINGS: Between Sept 14, 2016, and June 5, 2017, 301 patients were enrolled in stage one of STORM-C-1. 98 (33%) patients had genotype 1a infection, 27 (9%) had genotype 1b infection, two (1%) had genotype 2 infection, 158 (52%) had genotype 3 infection, and 16 (5%) had genotype 6 infection. 81 (27%) patients had compensated cirrhosis, 90 (30%) had HIV co-infection, and 99 (33%) had received previous interferon-based treatment. The most common treatment-emergent adverse events were pyrexia (35 [12%]), cough (26 [9%]), upper respiratory tract infection (23 [8%]), and headache (20 [7%]). There were no deaths or treatment discontinuations due to serious adverse events related to study drugs. Of the 300 patients included in the full analysis set, 291 (97%; 95% CI 94-99) had SVR12. Of note, SVR12 was reported in 78 (96%) of 81 patients with cirrhosis and 153 (97%) of 158 patients with genotype 3 infection, including 51 (96%) of 53 patients with cirrhosis. There was no difference in SVR12 rates by HIV co-infection or previous interferon treatment. INTERPRETATION: In this first stage, ravidasvir plus sofosbuvir was effective and well tolerated in this diverse adult population of patients with chronic HCV infection. Ravidasvir plus sofosbuvir has the potential to provide an additional affordable, simple, and efficacious public health tool for large-scale implementation to eliminate HCV as a cause of morbidity and mortality. FUNDING: National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia; UK Aid; Médecins Sans Frontières (MSF); MSF Transformational Investment Capacity; FIND; Pharmaniaga; Starr International Foundation; Foundation for Art, Research, Partnership and Education; and the Swiss Agency for Development and Cooperation.

Reflection of Epidemiological Impact on Burden of Injury in Tertiary Care Centre, Pre-COVID and COVID Era: "Lockdown, a Good Fortune for Saving Life and Limb".

Road traffic injuries continue to be a major public health concern and are a leading cause of death and injury across the world. Road transport remains the most favoured mode of transport for both freight and passenger movement in India. As per the World Health Organization, approximately 1.35 million people die annually on the world's roads, and another 20 to 50 million sustain nonfatal injuries as a result of road traffic crashes. These injuries and deaths have an immeasurable impact on the families affected, whose lives are often changed irrevocably by these tragedies, and on the communities in which these people lived and worked. India ranks 1 in the total number of traffic-related deaths across the 199 countries reported in the World Road Statistics, 2018, followed by China and the USA due to its large population (India, 21.7, and China, 18.6, fatalities per 100,000), although several Central American and African countries have higher fatality rates. During COVID-19 (coronavirus disease-19) pandemic, a national lockdown was implemented by Government of India from 24 March to 31 May 2020, in four phases to control the spread of SARS CoV-2 (severe acute respiratory syndrome coronavirus-2) infection. In our observational study, we compared the epidemiology of trauma patients of two periods from 1 April to 31 May 2019 and 24 March to 31 May 2020 and found out that unique concept of lockdown with stringent implementation of discipline, alcohol ban, behavioural change in visiting family and friends as minimum as possible, promoting work from home and digital classes for school and colleges lead to phenomenal decrease in traffic-related injuries and fatality. The lockdown has grossly decreased 'disability-adjusted life year'(DALY), an outcome indicator for cost-effective analysis, which is calculated as the value of future years of healthy life lost to morbidity/disability and future years of life lost to premature mortality.

Long-term incidence of relapse and post-kala-azar dermal leishmaniasis after three different visceral leishmaniasis treatment regimens in Bihar, India.

BACKGROUND: Few prospective data exist on incidence of post kala-azar dermal leishmaniasis (PKDL) and visceral leishmaniasis (VL) relapse after different treatment regimens. METHODOLOGY/PRINCIPAL FINDINGS: A Phase IV trial included 1761 VL patients treated between 2012-2014 with single dose AmBisome (SDA; N = 891), miltefosine-paromomycin (Milt-PM; n = 512), or AmBisome-miltefosine (AmB-Milt; n = 358). Follow-up for PKDL and VL relapse was scheduled for 6, 12 and 24 months after treatment, lasting until 2017. Patients with lesions consistent with PKDL were tested by rK39 rapid test, and if positive, underwent skin-snip sampling, smear microscopy and PCR. Probable PKDL was defined by consistent lesions and positive rK39; confirmed PKDL required additional positive microscopy or PCR. PKDL and relapse incidence density were calculated by VL treatment and risk factors evaluated in Cox proportional hazards models. Among 1,750 patients who completed treatment, 79 had relapse and 104 PKDL. Relapse incidence density was 1.58, 2.08 and 0.40 per 1000 person-months for SDA, AmB-Milt and Milt-PM, respectively. PKDL incidence density was 1.29, 1.45 and 2.65 per 1000 person-months for SDA, AmB-Milt and Milt-PM. In multivariable models, patients treated with Milt-PM had lower relapse but higher PKDL incidence than those treated with SDA; AmB-Milt rates were not significantly different from those for SDA. Children <12 years were at higher risk for both outcomes; females had a higher risk of PKDL but not relapse. CONCLUSIONS/SIGNIFICANCE: Active surveillance for PKDL and relapse, followed by timely treatment, is essential to sustain the achievements of VL elimination programs in the Indian sub-continent.

Similar biologics in India: A story of access or potential for compromise?

Biosimilars or similar biotherapeutic products are the biological products approved by regulatory agencies based on the demonstration of similarity in quality, safety and efficacy with reference biologics (or original biologics). Though biosimilars could be considered as interchangeable therapeutic alternatives over original biologics, there are concerns regarding their similarity in effectiveness and safety with reference product along with the level of evidence of similarity required for approval. The biosimilars, particularly, monoclonal antibodies that are developed based on the complex manufacturing processes, require stringent comparative evaluations. The Indian Regulatory Authorities in July 2012 developed the first guidelines for approval of similar biologics, which comprised requirements for the manufacturing process, quality evaluation, preclinical and clinical studies, as well as post-marketing studies. The 2016 guidelines, an update to previous guidelines, were released with the intent to provide a well-defined pathway at par with international regulations for the approval of similar biologics in India. This article highlights the key attributes of the 2016 Regulatory Guidelines and also describes the aspects such as interchangeability, nomenclature and labelling of similar biologics in India. Rigorous consideration is imperative for highly complex similar biologics of monoclonal antibodies on a case-to-case basis.

Field effectiveness of new visceral leishmaniasis regimens after 1 year following treatment within public health facilities in Bihar, India.

BACKGROUND: An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. METHODS: The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. RESULTS: Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. CONCLUSION: Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL.

High-power, low-flow, short-ablation duration-the key to avoid collateral injury?

BACKGROUND: A common approach to ablating along the posterior wall of the left atrium in atrial fibrillation ablation is to use low power with longer duration for durable lesions and reducing thermal injury. We hypothesize that similar lesions can be safely obtained at high power with low open-irrigation flow and low duration. METHODS: Twenty-two porcine ventricles were placed in a tissue bath with circulating 0.45% NaCl at a maintained temperature of 37 °C. Bipolar radiofrequency ablation (RFA) with a 4-mm-tip irrigated, force-sensing catheter was performed with various combinations of irrigation, power, and duration at 20g of contact force. Fiber optic temperature probes were placed at depths of 3 mm and 5 mm. Temperature was measured during and 30 s after each ablation. RESULTS: Two hundred sixty-eight lesions were made. At a fixed power and flow rate, lesion surface diameter, maximum lesion width, and lesion depth all increased with longer ablation duration. At fixed duration and irrigation flow rate, increased power led to increased lesion dimensions. At a lower flow rate (2 ml/min), surface lesion diameter and maximum width were significantly larger compared to a higher flow rate (17 ml/min), but lesion depth was not significantly different. The maximum temperature and the rate of temperature rise at a depth of 5 mm with different power settings and ablation durations were lower as compared to a depth of 3 mm at both flow rates (2 ml/min and 17 ml/min). CONCLUSIONS: Effective lesions can be performed with high-power and short-ablation durations, thereby reducing RFA procedure time. Higher power, shorter duration lesions result in adequate temperature for myocardial lesion formation at 3 mm, but do not result in excessive temperature at 5 mm depth, potentially reducing the risk of collateral injury. Compared to higher irrigation flow rate, larger surface lesions and comparable maximum lesion width are achieved with lower irrigation flow rate, thus resulting in better lesion contiguity.

Field safety and effectiveness of new visceral leishmaniasis treatment regimens within public health facilities in Bihar, India.

BACKGROUND: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions. METHODS: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891. RESULTS: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related. CONCLUSION: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India. TRIAL REGISTRATION: Clinical trial is registered at Clinical trial registry of India (CTRI/2012/08/002891, Registered on 16/08/2012, Trial Registered Prospectively).

Recent Development of Visceral Leishmaniasis Treatments: Successes, Pitfalls, and Perspectives.

Research in visceral leishmaniasis in the last decade has been focused on how better to use the existing medicines as monotherapy or in combination. Systematic research by geographical regions has shown that a universal treatment is far from today's reality. Substantial progress has been made in the elimination of kala-azar in South Asia, with a clear strategy on first- and second-line therapy options of single-dose liposomal amphotericin B and a combination of paromomycin and miltefosine, respectively, among other interventions. In Eastern Africa, sodium stibogluconate (SSG) and paromomycin in combination offer an advantage compared to the previous SSG monotherapy, although not exempted of limitations, as this therapy requires 17 days of painful double injections and bears the risk of SSG-related cardiotoxicity. In this region, attempts to improve the combination therapy have been unsuccessful. However, pharmacokinetic studies have led to a better understanding of underlying mechanisms, like the underexposure of children to miltefosine treatment, and an improved regimen using an allometric dosage. Given this global scenario of progress and pitfalls, we here review what steps need to be taken with existing medicines and highlight the urgent need for oral drugs. Furthermore, it should be noted that six candidates belonging to five new chemical classes are reaching phase I, ensuring an optimistic near future.

Accreditation in India: Pathways and Mechanisms.

Continuing medical education (CME) is a valuable mechanism to update physicians' knowledge with ever-increasing plethora of contemporary advances within medical fraternity. Over time, scope of CME has seen change from simple clinical updates to comprehensive continuing professional development (CPD), which is accomplished with help of accredited CME programmes. The Medical Council of India, in 2011, made a mandatory resolution for doctors to attend minimum of 30 hours of CME/5 years to ensure recertification. Authorised accreditation councils and licensing authorities award CME credits for maintenance of physicians' licensures. To date, in India, only 9 of 26 State Medical Councils have made re-registration mandatory. Although CME events benefit healthcare professionals by improving their proficiency and awareness, costs even to attend such interventions may be prohibitive. Despite financial help being received through grants and sponsorships, ethics of industry-sponsored CME remains a matter of debate. However, over past 10 years, pharmaceutical companies have started going beyond basic product information in order to focus on building physicians' knowledge in various therapeutic areas. Though CME credit system and criteria for re-licensure for medical practice in India are evolving at a rapid pace, there is a need for harmonisation and robust implementation across all states in India.

Impact of atrial fibrillation on outcomes with motor vehicle accidents.

BACKGROUND: We examined the effect of AF a commonly encountered arrhythmia with significant morbidity on mortality following a motor vehicle accident (MVA) related hospitalization. METHODS: The Nationwide Inpatient Sample (NIS) was queried to identify patients with AF (ICD-9 CM 427.31) and MVA (ICD-9 CM E810.0-E819.9), considered separately and together, from 2003 through 2012. Baseline characteristics were identified and multilevel mixed model multivariate analysis was employed to verify the impact of AF on in-patient mortality in survivors. RESULTS: Of an estimated 2,978,630 MVA admissions reported, 79,687 (2.6%) hospitalizations also had a diagnosis of AF. The in-hospital mortality was 2.6% in MVA alone and 7.6% in MVA and AF. In multivariate analysis, after adjustment for age, gender, Charlson Comorbidity Index (CCI), the Trauma Mortality Prediction Model (TMPM), and hospital characteristics, AF was independently associated with in-hospital mortality [Odds ratio (OR) 1.52, confidence interval (CI) 1.41-1.69, P value<0.0001]. In patients with MVA and AF, increasing age, CCI, and TMPM were associated with higher mortality. Female gender is associated with lower mortality (OR 0.84, CI 0.81-0.88, P -0.0016). Most patients with MVA and AF had a CHADS2 score of 2 (34.6%). Mortality and transfusion rates were higher in MVA and AF patients compared to patients with MVA alone across all CHADS2 scores. CONCLUSION: In patients with a MVA, the presence of AF is an independent risk factor for in-hospital mortality.

Prevalence of drug-resistant pulmonary tuberculosis in India: systematic review and meta-analysis.

BACKGROUND: Drug-resistant pulmonary tuberculosis (DR-TB) is a significant public health issue that considerably deters the ongoing TB control efforts in India. The purpose of this review was to investigate the prevalence of DR-TB and understand the regional variation in resistance pattern across India from 1995 to 2015, based on a large body of published epidemiological studies. METHODS: A systematic review of published studies reporting prevalence of DR-TB from biomedical databases (PubMed and IndMed) was conducted. Meta-analysis was performed using random effects model and the pooled prevalence estimate (95% confidence interval [CI]) of DR-TB, multidrug resistant (MDR-) TB, pre-extensively drug-resistant (pre-XDR) TB and XDR-TB were calculated across two study periods (decade 1: 1995 to 2005; decade 2: 2006 to 2015), countrywide and in different regions. Heterogeneity in this meta-analysis was assessed using I2 statistic. RESULTS: A total of 75 of 635 screened studies that fulfilled the inclusion criteria were selected. Over 40% of 45,076 isolates suspected for resistance to any first-line anti-TB drugs tested positive. Comparative analysis revealed a worsening trend in DR-TB between the two study decades (decade 1: 37.7% [95% CI = 29.0; 46.4], n = 25 vs decade 2: 46.1% [95% CI = 39.0; 53.2], n = 36). The pooled estimate of MDR-TB resistance was higher in previously treated patients (decade 1: 29.8% [95% CI = 20.7; 39.0], n = 13; decade 2: 35.8% [95% CI = 29.2; 42.4], n = 24) as compared with the newly diagnosed cases (decade 1: 4.1% [95% CI = 2.7; 5.6], n = 13; decade 2: 5.6% [95% CI = 3.8; 7.4], n = 17). Overall, studies from Western states of India reported highest prevalence of DR-TB (57.8% [95% CI = 37.4; 78.2], n = 6) and MDR-TB (39.9% [95% CI = 21.7; 58.0], n = 6) during decade 2. Prevalence of pre-XDR TB was 7.9% (95% CI = 4.4; 11.4, n = 5) with resistance to fluoroquinolone (66.3% [95% CI = 58.2; 74.4], n = 5) being the highest. The prevalence of XDR-TB was 1.9% (95% CI = 1.2; 2.6, n = 14) over the 20-year period. CONCLUSION: The alarming increase in the trend of anti-TB drug resistance in India warrants the need for a structured nationwide surveillance to assist the National TB Control Program in strengthening treatment strategies for improved outcomes.

Tuberculosis and biologics in rheumatology: A special situation.

India has a huge patient burden of rheumatic diseases (RDs) including rheumatoid arthritis. The use of biologics has transformed the treatment paradigm for RD; however, biologic treatment-related infections (especially tuberculosis [TB]) are an area of potential concern for TB-endemic nations like India. Anti-tumor necrosis factor (TNF) therapy impairs the physiological TNF-mediated signaling and may cause reactivation and dissemination of latent TB infection (LTBI). Careful screening is, thus, crucial in RD patients who are about to commence anti-TNF treatment. To date, there is no consensus available for the screening, evaluation and treatment of LTBI as well as on the drug dosage and duration regimen (monotherapy or combination therapy) in the Indian population. An evidence-based algorithm for LTBI screening and management in RD patients undergoing biologic disease-modifying anti-rheumatic drug therapy is suggested in this review for Indian rheumatologists. The proposed algorithm guides physicians through a step-wise screening approach, including medical history, tuberculin skin test, interferon gamma release assay, chest radiograph and management of LTBI with isoniazid therapy or its combination with rifampicin. Further, the provided algorithm can aid the national bodies (such as National TB Control Program) in formulating recommendations for LTBI in this high-risk population.

Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh.

BACKGROUND: AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh. METHODS: The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment. RESULTS: 601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0-100) for AmBisome monotherapy, 99.4% (95%CI 98.2-100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6-98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5-100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved. CONCLUSION: None of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi). TRIAL REGISTRATION: ClinicalTrials.gov NCT01122771.

Effects of Transendocardial Stem Cell Injection on Ventricular Proarrhythmia in Patients with Ischemic Cardiomyopathy: Results from the POSEIDON and TAC-HFT Trials.

Transendocardial stem cell injection in patients with ischemic cardiomyopathy (ICM) improves left ventricular function and structure but has ill-defined effects on ventricular arrhythmias. We hypothesized that mesenchymal stem cell (MSC) implantation is not proarrhythmic. Post hoc analyses were performed on ambulatory ECGs collected from the POSEIDON and TAC-HFT trials. Eighty-eight subjects (mean age 61 ± 10 years) with ICM (mean EF 32.2% ± 9.8%) received treatment with MSC (n = 48), Placebo (n = 21), or bone marrow mononuclear cells (BMC) (n = 19). Heart rate variability (HRV) and ventricular ectopy (VE) were evaluated over 12 months. VE did not change in any group following MSC implantation. However, in patients with ≥ 1 VE run (defined as ≥ 3 consecutive premature ventricular complexes in 24 hours) at baseline, there was a decrease in VE runs at 12 months in the MSC group (p = .01), but not in the placebo group (p = .07; intergroup comparison: p = .18). In a subset of the MSC group, HRV measures of standard deviation of normal intervals was 75 ± 30 msec at baseline and increased to 87 ± 32 msec (p =.02) at 12 months, and root mean square of intervals between successive complexes was 36 ± 30 msec and increased to 58.2 ± 50 msec (p = .01) at 12 months. In patients receiving MSCs, there was no evidence for ventricular proarrhythmia, manifested by sustained or nonsustained ventricular ectopy or worsened HRV. Signals of improvement in ventricular arrhythmias and HRV in the MSC group suggest a need for further studies of the antiarrhythmic potential of MSCs. Stem Cells Translational Medicine 2017;6:1366-1372.