Publications by authors named "Sanjay Sarin"

27 Publications

  • Page 1 of 1

Feasibility, effectiveness and cost of a decentralized HCV care model among the general population in Delhi, India.

Liver Int 2021 Nov 24. Epub 2021 Nov 24.

FIND, Geneva, Switzerland.

Background And Aims: India has a significant burden of hepatitis C virus (HCV) infection and has committed to achieving national elimination by 2030. This will require a substantial scale-up in testing and treatment. The "HEAD-Start Project Delhi" aimed to enhance HCV diagnosis and treatment pathways among the general population.

Methods: A prospective study was conducted at 5 district hospitals (Arm 1: one-stop shop), 15 polyclinics (Arm 2: referral for viral load (VL) testing and treatment) and 62 screening camps (Arm 3: referral for treatment). HCV prevalence, retention in the HCV care cascade, and turn-around time were measured.

Results: Between January and September 2019, 37 425 participants were screened for HCV. The median (IQR) age of participants was 35 (26-48) years, with 50.4% male and 49.6% female. A significantly higher proportion of participants in Arm 1 (93.7%) and Arm 3 (90.3%) received a VL test compared with Arm 2 (52.5%, P < .001). Of those confirmed positive, treatment was initiated at significantly higher rates for participants in both Arms 1 (85.6%) and 2 (73.7%) compared to Arm 3 (41.8%, P < .001). Arm 1 was found to be a cost-saving strategy compared to Arm 2, Arm 3, and no action.

Conclusions: Delivery of all services at a single site (district hospitals) resulted in a higher yield of HCV seropositive cases and retention compared with sites where participants were referred elsewhere for VL testing and/or treatment. The highest level of retention in the care cascade was also associated with the shortest turn-around times.
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http://dx.doi.org/10.1111/liv.15112DOI Listing
November 2021

Pathways to diagnosis of pediatric TB patients: A mixed methods study from India.

Indian J Tuberc 2021 Jul 31;68(3):363-373. Epub 2020 Dec 31.

Foundation for Innovative New Diagnostics, New Delhi, India. Electronic address:

Background: A significant proportion of pediatric tuberculosis (TB) patients go unnotified due to the challenges in diagnosis of TB among children. The experiences of this vulnerable group while going through the TB care cascade remain largely undocumented. The aim of this study was to explore the experiences of pediatric TB patients and families along the pathway to TB diagnosis and appropriate treatment in four cities of India.

Methods: The study used a mixed methods, single phased, embedded design. The primary qualitative and secondary quantitative data were collected simultaneously by interviewing families of 100 randomly selected Xpert MTB/RIF positive pediatric TB patients, under the pediatric TB project, in 4 Indian cities using a semi-structured questionnaire. The qualitative component was analyzed to deduce patterns and themes on the patient and family experiences. Descriptive statistics were used to quantify various events along the TB care pathway including various delays (patient, diagnosis and total) and number of providers visited by patients during the diagnostic process.

Results: The median patient, diagnostic and total delays were 3 (IQR: 2,5), 39 (IQR: 23, 91) and 43 days (IQR: 28.5, 98.5), respectively. Patients visited a median of 3 (IQR: 2,4) providers before accessing Xpert MTB/RIF testing. On an average, 68.4% of physicians ordered any test most of them being irrelevant for TB diagnosis. Qualitative data showed considerable suffering for children and their families before and after TB diagnosis including serious concerns of stigma, disruption in education and social life and recurrence of the disease.

Conclusion: Our study highlights the significant physical and social distress that the children with TB and their families undergo along the TB care pathway. It also shows diagnostic delay in excess of a month during which multiple providers were met and the patients underwent several diagnostic tests, most of them being inappropriate. Efforts to make Xpert MTB/RIF testing more accessible and part of physicians' toolkit will be of considerable value to ease the complexity of TB diagnosis in children. In addition, communication strategy needs to be developed and implemented to generate awareness among general population around pediatric TB and its management.
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http://dx.doi.org/10.1016/j.ijtb.2020.12.011DOI Listing
July 2021

A prospective multicentre diagnostic accuracy study for the Truenat tuberculosis assays.

Eur Respir J 2021 10 4;58(5). Epub 2021 Nov 4.

FIND, Geneva, Switzerland.

Background: Bringing reliable and accurate tuberculosis (TB) diagnosis closer to patients is a key priority for global TB control. Molbio Diagnostics have developed the Truenat point-of-care molecular assays for detection of TB and rifampicin (RIF) resistance.

Methods: We conducted a prospective multicentre diagnostic accuracy study at 19 primary healthcare centres and seven reference laboratories in Peru, India, Ethiopia and Papua New Guinea to estimate the diagnostic accuracy of the point-of-care Truenat MTB, MTB Plus and MTB-RIF Dx assays for pulmonary TB using culture and phenotypic drug susceptibility testing as the reference standard, compared with Xpert MTB/RIF or Ultra.

Results: Of 1807 enrolled participants with TB signs/symptoms, 24% were culture-positive for , of which 15% were RIF-resistant. In microscopy centres, the pooled sensitivity of Truenat MTB and Truenat MTB Plus was 73% (95% CI 67-78%) and 80% (95% CI 75-84%), respectively. Among smear-negative specimens, sensitivities were 36% (95% CI 27-47%) and 47% (95% CI 37-58%), respectively. Sensitivity of Truenat MTB-RIF was 84% (95% CI 62-95%). Truenat assays showed high specificity. Head-to-head comparison in the central reference laboratories suggested that the Truenat assays have similar performance to Xpert MTB/RIF.

Conclusion: We found the performance of Molbio's Truenat MTB, MTB Plus and MTB-RIF Dx assays to be comparable to that of the Xpert MTB/RIF assay. Performing the Truenat tests in primary healthcare centres with very limited infrastructure was feasible. These data supported the development of a World Health Organization policy recommendation of the Molbio assays.
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http://dx.doi.org/10.1183/13993003.00526-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8607906PMC
October 2021

Evaluation of genotype MTBDRplus V2 and genotype MTBDRsl V2 for the diagnosis of extrapulmonary tuberculosis in India.

Tuberculosis (Edinb) 2020 12 23;125:102014. Epub 2020 Oct 23.

World Health Organization, New Delhi, India.

Microbiological diagnosis of extra-pulmonary tuberculosis (EPTB) has been one of the most difficult aspects of tuberculosis (TB) management. Availability of better imaging and diagnostic modalities has led to an increase in the number of diagnosed cases. The current upsurge in multidrug-resistant tuberculosis warrants routine testing of EPTB samples for resistance at baseline with shorter turn-around time. A total of 369 EPTB specimens were subjected to Ziehl-Neelsen (ZN) stain, liquid culture (LC) with phenotypic drug susceptibility testing, MTBDRplus V.2 and MTBDRsl V.2. The molecular categorisation of resistant specimens was further reconfirmed with sequencing. The sensitivity and specificity of MTBDRplus V.2 to detect Mycobacterium tuberculosis (MTB) when compared to ZN stain was 97.9% and 89.2%, respectively while it was 73.4% and 83.8%, respectively when compared to LC. Similarly, for MTBDRsl V.2, the sensitivity and specificity for detection of MTB when compared with ZN was 95.6% and 91.9%, respectively and 75% and 89.2%, respectively when compared to LC. In smear-positive specimens, 94% (141/150) and 86% (129/150) valid results were observed in MTBDRplus V.2 and MTBDRsl V.2, respectively. The utilisation of both MTBDRplus V.2 and MTBDRsl V.2 for the diagnosis of smear-positive EPTB specimens would be useful in programmatic management of TB in high-burden settings.
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http://dx.doi.org/10.1016/j.tube.2020.102014DOI Listing
December 2020

Upfront Xpert MTB/RIF for diagnosis of pediatric TB-Does it work? Experience from India.

PLoS One 2020 5;15(8):e0236057. Epub 2020 Aug 5.

Foundation for Innovative New Diagnostics, New Delhi, India.

Background: Diagnosis of TB in pediatric population poses several challenges. A novel initiative was implemented in several major cities of India aimed at providing upfront access to free-of-cost Xpert MTB/RIF to presumptive pediatric TB cases. This paper aims to describe the experience of implementing this large initiative and assess feasibility of the intervention in high TB burden settings.

Methods: Data were drawn from the pediatric TB project implemented in 10 major cities of India between April 2014 and March 2018. In each city, providers, both public and private, were engaged and linked with a high throughput Xpert MTB/RIF lab (established in that city) through rapid specimen transportation and electronic reporting system. Rates and proportions were estimated to describe the characteristics of this cohort.

Results: Of the total 94,415 presumptive pediatric TB cases tested in the project, 6,270 were diagnosed positive for MTB (6.6%) on Xpert MTB/RIF (vs 2% on smear microscopy). Among MTB positives, 545 cases were rifampicin resistant (8.7%). The median duration between collection of specimens and reporting of results was 0 days (same day) and >89% cases were initiated on treatment. Approximately 50% of the specimens tested were non-sputum. The number of providers/facilities engaged under the project increased >10-fold (from 124 in Q2'14 to 1416 in Q1'18).

Conclusion: This project, which was one of the largest initiatives globally among pediatric population, demonstrated the feasibility of sustaining rapid and upfront access to free-of-cost Xpert MTB/RIF testing. The project underscores the efficiency of this rapid diagnostic assay in tackling several challenges in pediatric TB diagnosis, identifies opportunities for further interventions as well as brings to light scope for effective engagement with healthcare providers. The findings have facilitated a policy decision by National TB Programme mandating the use of Xpert MTB/RIF as a primary diagnostic tool for TB diagnosis in children, which is being scaled-up.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0236057PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406076PMC
September 2020

Diagnostic Evaluation of Non-Interpretable Results Associated with rpoB Gene in Genotype MTBDRplus Ver 2.0.

Tuberc Respir Dis (Seoul) 2020 Oct 5;83(4):289-294. Epub 2020 Aug 5.

Department of Medicine, All India Institute of Medical Sciences, New Delhi, India.

Background: Line probe assay (LPA) is standard diagnostic tool to detect multidrug resistant tuberculosis. Noninterpretable (NI) results in LPA (complete missing or light wild-type 3 and 8 bands with no mutation band in rpoB gene region) poses a diagnostic challenge.

Methods: Sputum samples obtained between October 2016 and July 2017 at the Intermediate Reference Laboratory, All India Institute of Medical Sciences Hospital, New Delhi, India were screened. Smear-positive and smear-negative culturepositive specimens were subjected to LPA Genotype MTBDRplus Ver 2.0. Smear-negative with culture-negative and culture contamination were excluded. LPA NI samples were subjected to phenotypic drug susceptibility testing (pDST) using MGIT-960 and sequencing.

Results: A total of 1,614 sputum specimens were screened and 1,340 were included for the study (smear-positive [n=1,188] and smear-negative culture-positive [n=152]). LPA demonstrated 1,306 (97.5%) valid results with TUB (Mycobacterium tuberculosis) band, 24 (1.8%) NI, three (0.2%) valid results without TUB band, and seven (0.5%) invalid results. Among the NI results, 22 isolates (91.7%) were found to be rifampicin (RIF) resistant and two (8.3%) were RIF sensitive in the pDST. Sequencing revealed that rpoB mutations were noted in all 22 cases with RIF resistance, whereas the remaining two cases had wild-type strains. Of the 22 cases with rpoB mutations, the most frequent mutation was S531W (n=10, 45.5%), followed by S531F (n=6, 27.2%), L530P (n=2, 9.1%), A532V (n=2, 9.1%), and L533P (n=2, 9.1%).

Conclusion: The present study showed that the results of the Genotype MTBDRplus assay were NI in a small proportion of isolates. pDST and rpoB sequencing were useful in elucidating the cause and clinical meaning of the NI results.
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http://dx.doi.org/10.4046/trd.2020.0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515679PMC
October 2020

Diagnostic tools used in the evaluation of acute febrile illness in South India: a scoping review.

BMC Infect Dis 2019 Nov 13;19(1):970. Epub 2019 Nov 13.

Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland.

Background: Acute febrile illness (AFI) is characterized by malaise, myalgia and a raised temperature that is a nonspecific manifestation of infectious diseases in the tropics. The lack of appropriate diagnostics for the evaluation of AFI leads to increased morbidity and mortality in resource-limited settings, specifically low-income countries like India. The review aimed to identify the number, type and quality of diagnostics used for AFI evaluation during passive case detection at health care centres in South India.

Methods: A scoping review of peer-reviewed English language original research articles published between 1946-July 2018 from four databases was undertaken to assess the type and number of diagnostics used in AFI evaluation in South India. Results were stratified according to types of pathogen-specific tests used in AFI management.

Results: The review included a total of 40 studies, all conducted in tertiary care centres (80% in private settings). The studies demonstrated the use of 5-22 tests per patient for the evaluation of AFI. Among 25 studies evaluating possible causes of AFI, 96% tested for malaria followed by 80% for dengue, 72% for scrub typhus, 68% for typhoid and 60% for leptospirosis identifying these as commonly suspected causes of AFI. 54% studies diagnosed malaria with smear microscopy while others diagnosed dengue, scrub typhus, typhoid and leptospirosis using antibody or antigen detection assays. 39% studies used the Weil-Felix test (WFT) for scrub typhus diagnosis and 82% studies used the Widal test for diagnosing typhoid.

Conclusions: The review demonstrated the use of five or more pathogen-specific tests in evaluating AFI as well as described the widespread use of suboptimal tests like the WFT and Widal in fever evaluation. It identified the need for the development of better-quality tests for aetiological diagnosis and improved standardised testing guidelines for AFI.
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http://dx.doi.org/10.1186/s12879-019-4589-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854686PMC
November 2019

Cost and operational impact of promoting upfront GeneXpert MTB/RIF test referrals for presumptive pediatric tuberculosis patients in India.

PLoS One 2019 1;14(4):e0214675. Epub 2019 Apr 1.

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.

Background: Outreach and promotion programs are essential to ensuring uptake of new public health interventions and guidelines. We assessed the costs and operation dynamics of outreach and promotion efforts for up front Xpert MTB/RIF (Xpert) testing for pediatric presumptive tuberculosis (TB) patients in four major Indian cities.

Methods: Xpert test costs were assessed as weighted average per-test costs based on the daily workload dynamics matched by test volume specific Xpert unit cost at each study site. Costs of outreach programs to recruit health providers to refer pediatric patients for Xpert testing were assessed as cost per referral for each quarter based on total program costs and referral data. All costs were assessed in the health service provider's perspective and expressed in 2015 USD.

Results: Weighted average per-test costs ranged from $14.71 to $17.81 at the four laboratories assessed. Differences between laboratories were associated with unused testing capacity and/or frequencies of overtime work to cope with increasing demand and same-day testing requirements. Outreach activities generated between 825 and 2,065 Xpert testing referrals on average each quarter across the four study sites, translating into $0.63 to $2.55 per patient referred. Overall outreach costs per referral decreased with time, stabilizing at an average cost of $1.10, and demonstrated a clear association with increased referrals.

Conclusions: Xpert test and outreach program costs within and across study sites were mainly driven by the dynamics of Xpert testing demand resulting from the combined outreach activities. However, these increases in demand required considerable overtime work resulting in additional costs and operational challenges at the study laboratories. Therefore, careful laboratory operational adjustment should be evaluated at target areas in parallel to the anticipated demand from the Xpert referral outreach program scale-up in other Indian regions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214675PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443160PMC
January 2020

Tuberculosis preventive treatment: the next chapter of tuberculosis elimination in India.

BMJ Glob Health 2018 8;3(5):e001135. Epub 2018 Oct 8.

Revised National Tuberculosis Control Programme, India Ministry of Health and Family Welfare, New Delhi, India.

The End TB Strategy envisions a world free of tuberculosis-zero deaths, disease and suffering due to tuberculosis by 2035. This requires reducing the global tuberculosis incidence from >1250 cases per million people to <100 cases per million people within the next two decades. Expanding testing and treatment of tuberculosis infection is critical to achieving this goal. In high-burden countries, like India, the implementation of tuberculosis preventive treatment (TPT) remains a low priority. In this analysis article, we explore potential challenges and solutions of implementing TPT in India. The next chapter in tuberculosis elimination in India will require cost-effective and sustainable interventions aimed at tuberculosis infection. This will require constant innovation, locally driven solutions to address the diverse and dynamic tuberculosis epidemiology and persistent programme monitoring and evaluation. As new tools, regimens and approaches emerge, midcourse adjustments to policy and practice must be adopted. The development and implementation of new tools and strategies will call for close collaboration between local, national and international partners-both public and private-national health authorities, non-governmental organisations, research community and the diagnostic and pharmaceutical industry. Leading by example, India can contribute to global knowledge through operational research and programmatic implementation for combating tuberculosis infection.
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http://dx.doi.org/10.1136/bmjgh-2018-001135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195150PMC
October 2018

Upfront Xpert MTB/RIF testing on various specimen types for presumptive infant TB cases for early and appropriate treatment initiation.

PLoS One 2018 30;13(8):e0202085. Epub 2018 Aug 30.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Background: Diagnosis of tuberculosis (TB) in infants is challenging due to non-specific clinical presentations of the disease in this age-group and low sensitivity of widely available TB diagnostic tools, which in turn delays prompt access to TB treatment. Upfront access to Xpert/MTB RIF (Xpert) testing, a highly sensitive and specific rapid diagnostic tool, could potentially address some of these challenges. Under the current project, we assessed the utility and feasibility of applying upfront Xpert for diagnosis of tuberculosis in infants, including for testing of non-sputum specimens.

Methods: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city, through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all infant (<2 years of age) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities.

Results: A total of 7,994 presumptive infant TB cases were enrolled in the project from April 2014 to October 2016, detecting 465 (5.8%, CI: 5.3-6.4) TB cases. The majority (93.9%; CI: 93.4-94.4) of patient specimens were non-sputum and TB positivity was higher amongst non-sputum specimens. Further, a high proportion (5.6% CI 3.8-8.1) of infant TB cases were found to be rifampicin resistant. Covering large cities with a single lab per city over more than two years, the project demonstrated the feasibility of same-day diagnosis with upfront Xpert testing. This in turn led to prompt treatment initiation, with a two-day median turnaround time to treatment initiation. Case mortality observed in the project cohort of diagnosed TB cases was 11.0% (CI 8.4-14.1), the majority of which was pre- or early treatment mortality, in spite of prompt access to treatment for most diagnosed cases.

Conclusion: The current project demonstrated the feasibility of applying rapid and upfront Xpert testing for presumptive infant TB cases. Rapid TB diagnosis in turn facilitates prompt and appropriate treatment initiation. Further, levels of rifampicin resistance observed in infants TB cases highlight the additional benefit of upfront resistance testing. However, high rates of early case mortality, in spite of prompt diagnosis and treatment initiation, highlight the need for further research in infant patient pathways for overall improvement in TB care for infant populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202085PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116934PMC
February 2019

"Before Xpert I only had my expertise": A qualitative study on the utilization and effects of Xpert technology among pediatricians in 4 Indian cities.

PLoS One 2018 16;13(3):e0193656. Epub 2018 Mar 16.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Background: Diagnosing tuberculosis (TB) in children presents considerable challenges. Upfront testing on Xpert® MTB/RIF ('Xpert')-a rapid molecular assay with high sensitivity and specificity-for pediatric presumptive TB patients, as recommended by India's Revised National Tuberculosis Control Program (RNTCP), can pave the way for early TB diagnosis. As part of an ongoing project implemented by Foundation for Innovative New Diagnostics (FIND) dedicated to providing upfront free-of-cost (FOC) Xpert testing to children seeking care in the public and private sectors, a qualitative assessment was designed to understand how national guidelines on TB diagnosis and Xpert technology have been integrated into the pediatric TB care practices of different health providers.

Methods: We conducted semi-structured interviews with a sample of health providers from public and private sectors engaged in the ongoing pediatric project in 4 major cities of India. Providers were sampled from intervention data based on sector of practice, number of Xpert referrals, and TB detection rates amongst referrals. A total of 55 providers were interviewed with different levels of FOC Xpert testing uptake. Data were transcribed and analyzed inductively by a medical anthropologist using thematic content analysis and narrative analysis.

Results: It was observed that despite guidance from RNTCP on the use of Xpert and significant efforts by FIND and state authorities to disseminate these guidelines, there was notable diversity in their implementation by different health care providers. Xpert, apart from being utilized as intended, i.e. as a first diagnostic test for children, was utilized variably-as an initial screening test (to rule out TB), confirmatory test (once TB diagnosis is established based on antibiotic trial or clinically) and/or only for drug susceptibility testing after TB diagnosis was confirmed. Most providers who used Xpert frequently reported that Xpert was an important tool for managing pediatric TB cases, by reducing the proportion of cases diagnosed only on clinical suspicion and by providing upfront information on drug resistance, which is seldom suspected in children. Despite non-standard use, these results showed that Xpert access helped raise awareness, aided in antibiotic stewardship, and reduced dependence on clinical diagnosis among those who diagnose and treat TB in children.

Conclusion: Access to free and rapid Xpert testing for all presumptive pediatric TB patients has had multiple positive effects on pediatricians' diagnosis and treatment of TB. It has important effects on speed of diagnosis, empirical treatment, and awareness of drug resistance among TB treatment naive children. In addition, our study shows that access to public sector Xpert machines may be an important way to encourage Public-Private integration and facilitate the movement of patients from the private to public sector for anti-TB treatment. Despite availability of rapid and free Xpert testing, our study showed an alarming diversity of Xpert utilization strategies across different providers who may be moving toward suggested practice over time. The degree of diversity in TB diagnostic approaches in children reported here highlights the urgent need for concerted efforts to place Xpert early in diagnostic algorithms to positively impact the pediatric TB care pathway. A positive change in diagnostic algorithms may be possible with continued advocacy, time, and increased access.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193656PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856339PMC
June 2018

Catalysing progressive uptake of newer diagnostics by health care providers through outreach and education in four major cities of India.

PLoS One 2018 6;13(3):e0193341. Epub 2018 Mar 6.

Foundation for Innovative New Diagnostics, Geneva, Switzerland.

Background: Unlike in adults, diagnosis of TB can be challenging in children, as signs and symptoms of paediatric TB can be very non-specific and similar to other common childhood chest infections, which may lead to under or delayed diagnosis of TB disease. In spite of the increasing availability of rapid high-sensitivity diagnostics in public and private sectors, majority of paediatric TB cases are empirically diagnosed, without laboratory confirmation. To address these diagnostic challenges, World Health Organization (WHO) has recommended upfront Xpert MTB/RIF (Xpert) testing for the diagnosis of TB in paediatric presumptive pulmonary and extra-pulmonary TB (EPTB) cases. However, in spite of the increasing availability of rapid high-sensitivity diagnostics, a significant gap exists in its application with Xpert being rarely used as an upfront diagnostic among patients presumed to have TB. Under an ongoing paediatric project since April 2014, which provided free-of-cost upfront Xpert testing, several low-cost outreach and education interventions were undertaken to increase the diagnostic uptake by different providers catering to the paediatric population, thereby increasing adherence to global guidance.

Methods: Providers catering to paediatric population in the project cities were systematically mapped and contacted using different outreach strategies. The focus of outreach efforts was to increase provider literacy and increase their awareness of the availability of free rapid diagnostic services with the goal of changing their diagnostic approaches.

Results: From April 2014 to June 2016, more than 5,700 providers/facilities were mapped and 3,670 of them were approached. The number of providers/facilities engaged under the project increased more than 10-fold (43 in April, 2014 to 466 in June, 2016), with significant increase in project uptake, both from public and private sector. Overall 42,238 paediatric presumptive TB cases were enrolled in the project, across the four cities. Over the project period, quarterly diagnostic uptake and paediatric TB cases detection rates increased more than two-fold. TB detection rates were similar in patients from public and private sectors.

Conclusions: Ongoing efforts in scaling up new rapid diagnostics involves significant investments. These efforts need to be complemented with proactive provider engagement to ensure provider-literacy and awareness, for maximizing impact of this scale-up. The current project demonstrated the usefulness of outreach and education interventions for the effective uptake of newer diagnostics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193341PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839557PMC
June 2018

Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India.

PLoS One 2018 28;13(2):e0193194. Epub 2018 Feb 28.

Foundation for Innovative New Diagnostics, New Delhi, India.

Background: Diagnosis of TB in children is challenging, and is largely based on positive history of contact with a TB case, clinical and radiological findings, often without microbiological confirmation. Diagnostic efforts are also undermined by challenges in specimen collection and the limited availability of high sensitivity, rapid diagnostic tests that can be applied with a quick turnaround time. The current project was undertaken in four major cities of India to address TB diagnostic challenges in pediatric population, by offering free of cost Xpert testing to pediatric presumptive TB cases, thereby paving the way for better TB care.

Methods: A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all pediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities.

Results: The current project enrolled 42,238 pediatric presumptive TB cases from April, 2014 to June, 2016. A total of 3,340 (7.91%, CI 7.65-8.17) bacteriologically confirmed TB cases were detected, of which 295 (8.83%, CI 7.9-9.86) were rifampicin-resistant. The level of rifampicin resistance in the project cohort was high. Overall Xpert yielded a high proportion of valid results and TB detection rates were more than three-fold higher than smear microscopy. The project provided same-day testing and early availability of results led to rapid treatment initiation and success rates and very low rates of treatment failure and loss to follow-up.

Conclusion: The current project demonstrated the feasibility of rolling out rapid and upfront Xpert testing for pediatric presumptive TB cases through a single Xpert lab per city in an efficient manner. Rapid turnaround testing time facilitated prompt and appropriate treatment initiation. These results suggest that the upfront Xpert assay is a promising solution to address TB diagnosis in children. The high levels of rifampicin resistance detected in presumptive pediatric TB patients tested under the project are a major cause of concern from a public health perspective which underscores the need to further prioritize upfront Xpert access to this vulnerable population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193194PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830996PMC
May 2018

Diagnostic utility of a line probe assay for multidrug resistant-TB in smear-negative pulmonary tuberculosis.

PLoS One 2017 22;12(8):e0182988. Epub 2017 Aug 22.

Foundation for Innovative New Diagnostics, New Delhi, India.

Objective: To evaluate the performance of Genotype MTBDRplus VER 2.0 in the diagnosis of Mycobacterium tuberculosis (MTB) in sputum smear-negative pulmonary TB cases.

Methods: A total of 572 Ziehl-Neelsen sputum smear-negative samples were selected and subjected to line probe assay (Genotype MTBDRplus VER 2.0), and culture in mycobacterial growth indicator tube (MGIT-960). Immunochromatographic test was used to confirm the MTB-complex (MTBC) in culture-positive samples and phenotypic drug-susceptibility testing was done using MGIT-960.

Results: The line probe assay was able to diagnose MTBC in 38.2% (213/558) of specimens after excluding 14 nontuberculous mycobacteria. Sensitivity and specificity of the assay were 68.4% and 89.3% respectively, considering MGIT-960 culture as gold standard after excluding contaminated and invalid results. On comparing with composite reference standard, the assay had 71.5% sensitivity and 100% specificity in the diagnosis of tuberculosis. The sensitivity and specificity for detecting resistance to rifampicin (RMP) were 100% and 99.24% respectively and for resistance to isoniazid (INH) were 97.62% and 98.55%, respectively.

Conclusion: Genotype MTBDRplus VER 2.0 is a rapid and precise diagnostic tool for detection of MTB in sputum smear-negative samples. It also facilitates accurate diagnosis of RMP and INH resistance within turn around-time.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182988PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568731PMC
October 2017

Stromal β-catenin overexpression contributes to the pathogenesis of renal dysplasia.

J Pathol 2016 06 23;239(2):174-85. Epub 2016 Apr 23.

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.

Renal dysplasia, the leading cause of renal failure in children, is characterized by disrupted branching of the collecting ducts and primitive tubules, with an expansion of the stroma, yet a role for the renal stroma in the genesis of renal dysplasia is not known. Here, we demonstrate that expression of β-catenin, a key transcriptional co-activator in renal development, is markedly increased in the expanded stroma in human dysplastic tissue. To understand its contribution to the genesis of renal dysplasia, we generated a mouse model that overexpresses β-catenin specifically in stromal progenitors, termed β-cat(GOF-S) . Histopathological analysis of β-cat(GOF) (-S) mice revealed a marked expansion of fibroblast cells surrounding primitive ducts and tubules, similar to defects observed in human dysplastic kidneys. Characterization of the renal stroma in β-cat(GOF) (-S) mice revealed altered stromal cell differentiation in the expanded renal stroma demonstrating that this is not renal stroma but instead a population of stroma-like cells. These cells overexpress ectopic Wnt4 and Bmp4, factors necessary for endothelial cell migration and blood vessel formation. Characterization of the renal vasculature demonstrated disrupted endothelial cell migration, organization, and vascular morphogenesis in β-cat(GOF) (-S) mice. Analysis of human dysplastic tissue demonstrated a remarkably similar phenotype to that observed in our mouse model, including altered stromal cell differentiation, ectopic Wnt4 expression in the stroma-like cells, and disrupted endothelial cell migration and vessel formation. Our findings demonstrate that the overexpression of β-catenin in stromal cells is sufficient to cause renal dysplasia. Further, the pathogenesis of renal dysplasia is one of disrupted stromal differentiation and vascular morphogenesis. Taken together, this study demonstrates for the first time the contribution of stromal β-catenin overexpression to the genesis of renal dysplasia. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4713DOI Listing
June 2016

Developmental Origins for Kidney Disease Due to Shroom3 Deficiency.

J Am Soc Nephrol 2016 Oct 3;27(10):2965-2973. Epub 2016 Mar 3.

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Hamilton Center for Kidney Research, St. Josephs Healthcare, Hamilton, Ontario, Canada

CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroom family member 3 (SHROOM3) gene, which encodes an actin-associated protein important in epithelial morphogenesis. However, the role of SHROOM3 in kidney development and function is virtually unknown. Studies in zebrafish and rat showed that alterations in Shroom3 can result in glomerular dysfunction. Furthermore, human SHROOM3 variants can induce impaired kidney function in animal models. Here, we examined the temporal and spatial expression of Shroom3 in the mammalian kidney. We detected Shroom3 expression in the condensing mesenchyme, Bowman's capsule, and developing and mature podocytes in mice. Shroom3 null (Shroom3) mice showed marked glomerular abnormalities, including cystic and collapsing/degenerating glomeruli, and marked disruptions in podocyte arrangement and morphology. These podocyte-specific abnormalities are associated with altered Rho-kinase/myosin II signaling and loss of apically distributed actin. Additionally, Shroom3 heterozygous (Shroom3) mice showed developmental irregularities that manifested as adult-onset glomerulosclerosis and proteinuria. Taken together, our results establish the significance of Shroom3 in mammalian kidney development and progression of kidney disease. Specifically, Shroom3 maintains normal podocyte architecture in mice via modulation of the actomyosin network, which is essential for podocyte function. Furthermore, our findings strongly support the GWASs that suggest a role for SHROOM3 in human kidney disease.
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http://dx.doi.org/10.1681/ASN.2015060621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5042660PMC
October 2016

The Good and Bad of β-Catenin in Kidney Development and Renal Dysplasia.

Front Cell Dev Biol 2015 22;3:81. Epub 2015 Dec 22.

Department of Pathology and Molecular Medicine, McMaster University Hamilton, ON, Canada.

Congenital renal malformations are a major cause of childhood and adult onset chronic kidney disease. Identifying the etiology of these renal defects is often challenging since disruptions in the processes that drive kidney development can result from disruptions in environmental, genetic, or epigenetic cues. β-catenin is an intracellular molecule involved in cell adhesion, cell signaling, and regulation of gene transcription. It plays essential roles in kidney development and in the pathogenesis of renal dysplasia. Here, we review the function of β-catenin during kidney development and in the genesis of renal dysplasia.
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http://dx.doi.org/10.3389/fcell.2015.00081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686587PMC
January 2016

Prevalence of diabetes and pre-diabetes and assessments of their risk factors in urban slums of Bangalore.

J Family Med Prim Care 2015 Jul-Sep;4(3):399-404

Global Health (Asia Pacific) - Becton, Dickinson and Company, Gurgaon, Haryana, India.

Background: To determine the prevalence of diabetes and pre-diabetes and to assess the risk factors associated with diabetes and pre-diabetes in the urban slums of Bangalore.

Materials And Methods: A cross-sectional study was conducted in four slums of Bangalore in the age group of 35 years and above comprising of total 2013 subjects. Risk factors like age, sex, family history, behavior, physical activity, BMI, waist hip ration, diet habits were assessed to find their association with diabetes.

Results: Prevalence of diabetes was 12.33% and of pre-diabetes was 11.57%. Prevalence was more among the females compared to males. Increasing age, over weight and obesity, sedentary life style, tobacco consumption, diet habits showed statistically significant association with prevalence of diabetes and pre-diabetes.

Conclusion: Physical activity like regular exercises both at the office and at home, fibers-rich diet, blood sugar estimation after 35 years are some of the recommendations which can control diabetes.
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http://dx.doi.org/10.4103/2249-4863.161336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4535103PMC
August 2015

Stromally expressed β-catenin modulates Wnt9b signaling in the ureteric epithelium.

PLoS One 2015 24;10(3):e0120347. Epub 2015 Mar 24.

Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.

The mammalian kidney undergoes cell interactions between the epithelium and mesenchyme to form the essential filtration unit of the kidney, termed the nephron. A third cell type, the kidney stroma, is a population of fibroblasts located in the kidney capsule, cortex and medulla and is ideally located to affect kidney formation. We found β-catenin, a transcriptional co-activator, is strongly expressed in distinctive intracellular patterns in the capsular, cortical, and medullary renal stroma. We investigated β-catenin function in the renal stroma using a conditional knockout strategy that genetically deleted β-catenin specifically in the renal stroma cell lineage (β-cats-/-). β-cats-/- mutant mice demonstrate marked kidney abnormalities, and surprisingly we show β-catenin in the renal stroma is essential for regulating the condensing mesenchyme cell population. We show that the population of induced mesenchyme cells is significantly reduced in β-cats-/- mutants and exhibited decreased cell proliferation and a specific loss of Cited 1, while maintaining the expression of other essential nephron progenitor proteins. Wnt9b, the key signal for the induction of nephron progenitors, was markedly reduced in adjacent ureteric epithelial cells in β-cats-/-. Analysis of Wnt9b-dependent genes in the neighboring nephron progenitors was significantly reduced while Wnt9b-independent genes remained unchanged. In contrast mice overexpressing β-catenin exclusively in the renal stroma demonstrated massive increases in the condensing mesenchyme population and Wnt9b was markedly elevated. We propose that β-catenin in the renal stroma modulates a genetic program in ureteric epithelium that is required for the induction of nephron progenitors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372213PMC
February 2016

Insights into the renal pathogenesis in Schimke immuno-osseous dysplasia: A renal histological characterization and expression analysis.

J Histochem Cytochem 2015 01 15;63(1):32-44. Epub 2014 Oct 15.

Program in Pathology and Molecular Medicine, McMaster University, Hamilton, Canada (SS, AJ, FB, IA, BS, SC, DL, DB)

Schimke immuno-osseous dysplasia (SIOD) is a pleiotropic disorder caused by mutations in the SWI/SNF2-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like-1 (SMARCAL1) gene, with multiple clinical features, notably end-stage renal disease. Here we characterize the renal pathology in SIOD patients. Our analysis of SIOD patient renal biopsies demonstrates the tip and collapsing variants of focal segmental glomerulosclerosis (FSGS). Additionally, electron microscopy revealed numerous glomerular abnormalities most notably in the podocyte and Bowman's capsule. To better understand the role of SMARCAL1 in the pathogenesis of FSGS, we defined SMARCAL1 expression in the developing and mature kidney. In the developing fetal kidney, SMARCAL1 is expressed in the ureteric epithelium, stroma, metanephric mesenchyme, and in all stages of the developing nephron, including the maturing glomerulus. In postnatal kidneys, SMARCAL1 expression is localized to epithelial tubules of the nephron, collecting ducts, and glomerulus (podocytes and endothelial cells). Interestingly, not all cells within the same lineage expressed SMARCAL1. In renal biopsies from SIOD patients, TUNEL analysis detected marked increases in DNA fragmentation. Our results highlight the cells that may contribute to the renal pathogenesis in SIOD. Further, we suggest that disruptions in genomic integrity during fetal kidney development contribute to the pathogenesis of FSGS in SIOD patients.
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http://dx.doi.org/10.1369/0022155414558335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395996PMC
January 2015

β-Catenin overexpression in the metanephric mesenchyme leads to renal dysplasia genesis via cell-autonomous and non-cell-autonomous mechanisms.

Am J Pathol 2014 May 15;184(5):1395-410. Epub 2014 Mar 15.

Program in Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address:

Renal dysplasia, a developmental disorder characterized by defective ureteric branching morphogenesis and nephrogenesis, ranks as one of the major causes of renal failure among the pediatric population. Herein, we demonstrate that the levels of activated β-catenin are elevated in the nuclei of ureteric, stromal, and mesenchymal cells within dysplastic human kidney tissue. By using a conditional mouse model of mesenchymal β-catenin overexpression, we identify two novel signaling pathways mediated by β-catenin in the development of renal dysplasia. First, the overexpression of β-catenin within the metanephric mesenchyme leads to ectopic and disorganized branching morphogenesis caused by β-catenin directly binding Tcf/lef consensus binding sites in the Gdnf promoter and up-regulating Gdnf transcription. Second, β-catenin overexpression in the metanephric mesenchyme leads to elevated levels of transcriptionally active β-catenin in the ureteric epithelium. Interestingly, this increase of β-catenin-mediated transcription results from a novel Ret/β-catenin signaling pathway. Consistent with these findings, analysis of human dysplastic renal tissue demonstrates that undifferentiated mesenchymal cells expressing high levels of β-catenin also express increased GDNF. Furthermore, dysplastic ureteric tubules that were surrounded by high levels of GDNF also exhibited increased levels of activated β-catenin. Together, these data support a model in which the elevation of β-catenin in the metanephric mesenchyme results in cell-autonomous and non-cell-autonomous events that lead to the genesis of renal dysplasia.
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http://dx.doi.org/10.1016/j.ajpath.2014.01.018DOI Listing
May 2014

Turcot syndrome (glioma polyposis): a case report.

South Med J 2008 Dec;101(12):1273-4

Department of Internal Medicine, Geisinger Medical Center, Danville, PA 17822-2160, USA.

Turcot's syndrome (glioma-polyposis) is a rare hereditary disorder characterized by association of colonic polyposis with primary tumors of the central nervous system. We report a case of a 27-year-old male diagnosed with Turcot's syndrome after an autopsy. The patient survived for more than two decades after his initial presentation with medulloblastoma at the age of five years. Such a long survival is exceptional in patients with this syndrome. Based on the genetic mutations, the patients with Turcot's syndrome are classified into adenomatous polyposis coli (APC) group or hereditary non-polyposis colon cancer (HNPCC) group. The article highlights the contrasting features of the two groups.
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http://dx.doi.org/10.1097/SMJ.0b013e3181883853DOI Listing
December 2008

Clinical significance of epicardial fat measured using cardiac multislice computed tomography.

Am J Cardiol 2008 Sep 2;102(6):767-71. Epub 2008 Jul 2.

Department of Cardiology, Geisinger Medical Center, Danville, Pennsylvania, USA.

Cardiac adiposity defined as increased epicardial adipose tissue and massive deposits of fat within the atrial septum (lipomatous hypertrophy) is seen in overweight persons and is associated with coronary artery disease (CAD), atrial arrhythmias, and increased risk of left ventricular free wall rupture after acute myocardial infarction. Unlike subcutaneous fat, epicardial fat is metabollically active and produces hormones, cytokines, and other vasoactive substances that work systemically or locally to alter vascular endothelial function and may be implicated in the pathogenesis of CAD. The aim of the study was to assess the feasibility of measuring epicardial fat volume (EFV) and identify its clinical correlates using (64-slice) multislice computed tomography (MSCT). A protocol was devised to measure EFV using MSCT in 151 adults (age 26 to 83 years, mean 51 +/- 12; 55% men). Cross-sectional tomographic cardiac slices (2.5-mm thick) from base to apex (range 28 to 40 per heart) were traced semiautomatically using an off-line workstation, and EFV was measured by assigning Hounsfield units ranging from -30 to -250 to fat. Coronary computed tomographic angiography was performed using a standard protocol. EFV ranged from 25 to 274 ml (mean 121 +/- 47), corresponding to 2.4% to 30.5% (mean 15 +/- 5%) of total cardiac volume and correlated with age, atrial septum thickness, body weight, and body mass index. Coronary calcium score was significantly higher in patients with EFV >100 ml (67 +/- 155 vs 216 +/- 639; p = 0.03), and a higher percentage of patients with increased EFV had CAD (46% vs 31%; p <0.05) or metabolic syndrome (44% vs 29%; p <0.05). In conclusion, quantification of EFV was feasible using MSCT. Large deposits of fat around the heart and within the atrial septum were associated with obesity, coronary calcium, metabolic syndrome, and CAD. Measurement of EFV may provide another useful noninvasive indicator of heightened risk of CAD in addition to calcium score and coronary angiography.
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http://dx.doi.org/10.1016/j.amjcard.2008.04.058DOI Listing
September 2008

Images in cardiovascular medicine. Apicoaortic double-valved conduit in a 40-year-old woman.

Circulation 2007 Feb;115(7):e197-9

Department of Cardiology, Geisinger Medical Center, 100 North Academy Ave, Danville, PA 17822-2160, USA.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.106.654632DOI Listing
February 2007

Inverted T waves on electrocardiogram: myocardial ischemia versus pulmonary embolism.

J Electrocardiol 2005 Oct;38(4):361-3

Department of Internal Medicine, Geisinger Medical Center, Danville, PA 17822, USA.

Electrocardiogram (ECG) is of limited diagnostic value in patients suspected with pulmonary embolism (PE). However, recent studies suggest that inverted T waves in the precordial leads are the most frequent ECG sign of massive PE (Chest 1997;11:537). Besides, this ECG sign was also associated with the best sensitivity, specificity, and positive and negative predictive values for diagnosing PE. We report 2 cases with similar ECG findings that were referred to us as unstable angina. Both were hemodynamically stable and had moderate-size pulmonary emboli. The ECG findings reverted to normal within a week of anticoagulation treatment. Our observation suggests that even a moderate-size PE can cause these ECG changes.
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http://dx.doi.org/10.1016/j.jelectrocard.2005.05.008DOI Listing
October 2005
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