Myopia progression risk assessment score (MPRAS): a promising new tool for risk stratification.

Timely identification of individuals "at-risk" for myopia progression is the leading requisite for myopia practice as it aids in the decision of appropriate management. This study aimed to develop 'myopia progression risk assessment score' (MPRAS) based on multiple risk factors (10) to determine whether a myope is "at-risk" or "low-risk" for myopia progression. Two risk-score models (model-1: non-weightage, model-2: weightage) were developed. Ability of MPRAS to diagnose individual "at-risk" for myopia progression was compared against decision of five clinicians in 149 myopes, aged 6-29 years. Using model-1 (no-weightage), further 7 sub-models were created with varying number of risk factors in decreasing step-wise manner (1a: 10 factors to 1g: 4 factors). In random eye analysis for model-1, the highest Youden's J-index (0.63-0.65) led to the MPRAS cut-off score of 41.50-43.50 for 5 clinicians with a sensitivity ranging from 78 to 85% and specificity ranging from 79 to 87%. For this cut-off score, the mean area under the curve (AUC) between clinicians and the MPRAS model ranged from 0.89 to 0.90. Model-2 (weighted for few risk-factors) provided similar sensitivity, specificity, and AUC. Sub-model analysis revealed greater AUC with high sensitivity (89%) and specificity (94%) in model-1g that has 4 risk factors compared to other sub-models (1a-1f). All the MPRAS models showed good agreement with the clinician's decision in identifying individuals "at-risk" for myopia progression.

Hematopoietic Stem Cell Transplantation is a cost-effective alternative to enzyme replacement therapy in Gaucher Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a feasible treatment option for Gaucher disease (GD). Among 60 patients diagnosed with GD over 15 years (2004-2019), three children who underwent HSCT (January-November 2017) were analyzed. Two boys (cases 1 and 2) and one girl (case 3) received HSCT at 3, 7, and 10 years of age, respectively. Cases 1 and 3 received haplo-HSCT, while case 2 received HLA-identical related-donor transplantation. The CD 34 cell dose was 5-10×106/kg. Neutrophil and platelet engraftment were between days +14 to +21 and days +15 to +76. Post-HSCT chimerism was a 100% donor. None of the patients developed acute or significant chronic graft versus host disease (GVHD). All patients had febrile episodes with negative blood cultures. Major post-HSCT complications included EBV-viremia and recurrent lobar pneumonia in case 1, delayed engraftment and pure red cell aplasia (PRCA) in case 2, and pericardial effusion with tamponade in case 3. At a median of 49 months post-HSCT, all patients were stable with improved growth, absent organomegaly, and had completed immunization. The median cost of treatment was $23,038.96, which is 10.7%-13% of the yearly enzyme replacement therapy (ERT) cost. In a resource-limited setting like India, ERT is a financial burden and not a sustainable option. With improved treatment outcomes, haplo-HSCT is now a possible option for almost every patient, even if no HLA-identical donor is identified.

Neighborhood poverty and pediatric allogeneic hematopoietic cell transplantation outcomes: a CIBMTR analysis.

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.

Towards a global multidisciplinary consensus framework on haemophilia gene therapy: Report of the 2nd World Federation of Haemophilia Gene Therapy Round Table.

INTRODUCTION: With approval of gene therapy for haemophilia likely in the near future, policy frameworks are needed to guide the path forward for this disruptive and novel therapeutic advance. AIM: The WFH has initiated a series of multi-stakeholder Gene Therapy Round Tables (GTRT) to better understand where guidance is needed and develop initial consensus statements to inform policy. METHODS: The first day of the 2nd GTRT was devoted to didactic presentations on models of access to gene therapy, payment and health technology assessment considerations, regulatory issues and the generation of evidence on safety and durable efficacy of gene therapy products. On the second day, participants were tasked with developing and voting on consensus statements that reflected the information presented and multi-stakeholder views expressed during discussions in the 1st and 2nd WFH GTRTs. The statements covered global access to gene therapy for all people with haemophilia (PWH), collection of long-term safety and efficacy data, ensuring gene therapy is available for all subgroups of PWH including those who have been largely excluded from clinical trials and characterizing acceptable and ideal factor expression levels for gene therapy products. RESULTS: The first 3 statements achieved consensus (at least 80% agreement) by this group of experts. The statement on identifying an ideal and an acceptable factor level expression elicited a lively discussion but failed to achieve consensus by this group. CONCLUSIONS: This issue of ideal and acceptable factor level expression and other unresolved issues will be brought to the 3rd WFH GTRT in 2020.

Worldwide Network for Blood and Marrow Transplantation Recommendations for Establishing a Hematopoietic Stem Cell Transplantation Program in Countries with Limited Resources, Part II: Clinical, Technical, and Socioeconomic Considerations.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. Although this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state-of-the-art treatments, including transplantation, by providing financial, technological, legal, ethical, and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population and potentially provide long-term cost savings by circumventing the need for their citizens to seek care abroad. The costs of establishing an HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. In addition, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT, and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation for establishing HSCT programs, with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in resource-constrained settings.

Adult Acute Lymphoblastic Leukemia: Limitations of Intensification of Therapy in a Developing Country.

Purpose Limited data exist on intensifying chemotherapy regimens in the treatment of adult acute lymphoblastic leukemia (ALL) outside the setting of a clinical trial. Materials and Methods Retrospectively, data from 507 consecutive adults (age ≥ 15 years) with a diagnosis of ALL treated at our center were analyzed. Standard-risk (SR) patients were offered treatment with a modified German Multicenter ALL (GMALL) regimen, whereas high-risk (HR) patients were offered intensification of therapy with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD). Because of resource constraints, a proportion of HR patients opted to receive the same treatment regimen as used for SR patients. Results There were 344 SR patients (67.8%) and 163 HR patients (32.2%) at diagnosis. Among the HR patients, 53 (32.5%) opted to receive intensification with the HCVAD regimen. The SR cohort showed a superior 5-year event-free survival rate compared with the HR cohort (47.3% v 23.6%, respectively; P < .001). Within the HR subgroup, there was no statistically significant difference in overall survival or event-free survival between patients who received the modified GMALL regimen (n = 59) and patients who received HCVAD (n = 53). Conclusion Intensified therapy in the HR subset was associated with a significant increase in early treatment-related mortality and cost of treatment. A modified GMALL regimen was found to be cost-effective with clinical outcomes comparable to those achieved with more intensive regimens.

Standardizing evaluation process: Necessary for achieving SDGs - A case study of India.

A set of 17 Sustainable Development Goals (SDGs) adopted by the United Nations General Assembly in September 2015 are to be implemented and achieved in every country from the year 2016 to 2030. In Indian context, all these goals are very relevant and critical, as India missed the target on many components of the Millennium Development Goals (MDGs). The author strongly feels that one of the key reasons was lack of an in-built robust system for measuring the progress and achievements of MDGs. Monitoring and Evaluation of programmes and schemes, aiming at different SDGs, in a robust and regular manner is therefore need of the hour. A National evaluation policy (NEP) would set the tone in the right direction from the very beginning for achieving SDGs. The paper taking India as a case study discusses different critical factors pertinent for having a well laid down national level policy towards standardizing evaluation. Using real examples under different components of an evaluation policy, the paper discusses and questions the credibility and acceptance of the present evaluation system in place. The paper identifies five core mantras or pre-requisites of a national evaluation guideline. The paper emphasizes the importance of an evaluation policy in India and other countries as well, to provide authentic data gathered through a well-designed evaluation process and take corrective measures well on time to achieve SDGs.

Comparison of Safety, Efficacy and Cost Effectiveness of Photoselective Vaporization with Bipolar Vaporization of Prostate in Benign Prostatic Hyperplasia.

OBJECTIVES: To compare bipolar vaporization of prostate (BPVP) with photoselective vaporization (PVP) of prostate in the surgical management of benign prostatic hyperplasia in terms of safety, efficacy and cost effectiveness. METHODS: Data was analyzed retrospectively for patients who underwent either PVP or BPVP between August 2012 to July 2014 for prostate size ≤ 80 ml. Preoperative and postoperative period values along with details like operative time, blood loss, hospitalization days, catheter removal time, blood transfusion and etc., were noted down. International prostatic symptom score, quality of life scores, post void residue, and maximum flow rate were recorded preoperatively and postoperatively at each follow-up visit. Follow-up was performed at 1, 3, 6, 12 and 18 months. RESULTS: Similar preoperative characteristics were observed in all the study arms. Hemoglobin drop, transfusion rate, catheter time and hospital days were similar in both the groups. The follow-up data indicates sustainable significant improvement in international prostatic symptom score, quality of life, post void residue and maximum flow rate in both the groups. As expected the cost of the procedure was significantly more in PVP group as compared to BPVP group (p < 0.01). Neither group had severe perioperative complications and no blood transfusion was required in both the groups. CONCLUSION: Both PVP and BPVP were safe and effective alternatives in men requiring surgery for benign prostatic hyperplasia including patients who were on anticoagulants. Additionally, BPVP has the advantage of being significantly cheaper and therefore it can be more useful in developing countries.

Lack of grading agreement among international hemostasis external quality assessment programs.

: Laboratory quality programs rely on internal quality control and external quality assessment (EQA). EQA programs provide unknown specimens for the laboratory to test. The laboratory's result is compared with other (peer) laboratories performing the same test. EQA programs assign target values using a variety of methods statistical tools and performance assessment of 'pass' or 'fail' is made. EQA provider members of the international organization, external quality assurance in thrombosis and hemostasis, took part in a study to compare outcome of performance analysis using the same data set of laboratory results. Eleven EQA organizations using eight different analytical approaches participated. Data for a normal and prolonged activated partial thromboplastin time (aPTT) and a normal and reduced factor VIII (FVIII) from 218 laboratories were sent to the EQA providers who analyzed the data set using their method of evaluation for aPTT and FVIII, determining the performance for each laboratory record in the data set. Providers also summarized their statistical approach to assignment of target values and laboratory performance. Each laboratory record in the data set was graded pass/fail by all EQA providers for each of the four analytes. There was a lack of agreement of pass/fail grading among EQA programs. Discordance in the grading was 17.9 and 11% of normal and prolonged aPTT results, respectively, and 20.2 and 17.4% of normal and reduced FVIII results, respectively. All EQA programs in this study employed statistical methods compliant with the International Standardization Organization (ISO), ISO 13528, yet the evaluation of laboratory results for all four analytes showed remarkable grading discordance.

Cost and quality issues in establishing hematopoietic cell transplant program in developing countries.

The hematopoietic cell transplant (HCT) activity has grown significantly over the past two decades in both developing and developed countries. Many challenges arise in establishing new HCT programs in developing countries, due to scarcity of resources and manpower in expertise in HCT. While cost issues can potentially hinder establishment of new HCT programs in certain regions, the focus on quality and value should be included in the general vision of leadership before establishing an HCT program. The main challenge in most developing countries is the lack of trained/qualified personnel, enormous start-up costs for a tertiary care center, and quality maintenance. Herein, we discuss the main challenges from a cost and quality perspective which occur at initiation of a new HCT program. We give real world examples of two developing countries that have recently started new HCT programs despite significant financial constraints. We also portray recommendations from the Worldwide Network of Blood and Marrow Transplantation for levels of requirements for a new HCT program. We hope that this review will serve as a general guide for new transplant program leadership with respect to the concerns of balancing high quality with concurrently lowering costs.

Factor VIII/factor IX prophylaxis for severe hemophilia.

Experience with clotting factor concentrate (CFC) replacement products over several decades has shown that regular replacement (prophylaxis) is the only way to prevent musculoskeletal damage in hemophilia and impact the natural history of hemophilia. Yet there is a lack of data on the optimal age to start such replacement therapy and the regimens to be used. While very early administration of high doses is certainly more effective in preventing bleeding, cost and compliance are major constraints all over the world. Starting prophylaxis with even lower doses comparable to that used in episodic therapies leads to major reduction in bleeding. Recognition of the clinical heterogeneity of hemophilia even among patients with a label of severe hemophilia in terms of their spontaneous bleeding has led to efforts aimed at individualizing CFC replacement, based on clinical responses or pharmacokinetic data of the CFC. The importance of long-term outcome assessment being combined with CFC replacement therapy cannot be overemphasized.

Comparative analysis of microsatellites in five different antagonistic Trichoderma species for diversity assessment.

Microsatellites provide an ideal molecular markers system to screen, characterize and evaluate genetic diversity of several fungal species. Currently, there is very limited information on the genetic diversity of antagonistic Trichoderma species as determined using a range of molecular markers. In this study, expressed and whole genome sequences available in public database were used to investigate the occurrence, relative abundance and relative density of SSRs in five different antagonistic Trichoderma species: Trichoderma atroviride, T. harzianum, T. reesei, T. virens and T. asperellum. Fifteen SSRs loci were used to evaluate genetic diversity of twenty isolates of Trichoderma spp. from different geographical regions of India. Results indicated that relative abundance and relative density of SSRs were higher in T. asperellum followed by T. reesei and T. atroviride. Tri-nucleotide repeats (80.2%) were invariably the most abundant in all species. The abundance and relative density of SSRs were not influenced by the genome sizes and GC content. Out of eighteen primer sets, only 15 primer pairs showed successful amplification in all the test species. A total of 24 alleles were detected and five loci were highly informative with polymorphism information content values greater than 0.40, these markers provide useful information on genetic diversity and population genetic structure, which, in turn, can exploit for establishing conservation strategy for antagonistic Trichoderma isolates.

Acute myeloid leukaemia: challenges and real world data from India.

The management of acute myeloid leukaemia (AML) in India remains a challenge. In a two-year prospective study at our centre there were 380 newly diagnosed AML (excluding acute promyelocytic leukaemia, AML-M3) patients. The median age of newly diagnosed patients was 40 years (range: 1-79; 12.3% were ≤ 15 years, 16.3% were ≥ 60 years old) and there were 244 (64.2%) males. The median duration of symptoms prior to first presentation at our hospital was 4 weeks (range: 1-52). The median distance from home to hospital was 580 km (range: 6-3200 km). 109 (29%) opted for standard of care and were admitted for induction chemotherapy. Of the 271 that did not take treatment the major reason was lack of financial resources in 219 (81%). There were 27 (24.7%) inductions deaths and of these, 12 (44.5%) were due to multidrug-resistant gram-negative bacilli and 12 (44.5%) showed evidence of a fungal infection. The overall survival at 1 year was 70.4% ± 10.7%, 55.6% ± 6.8% and 42.4% ± 15.6% in patients aged ≤ 15 years, 15 - 60 years and ≥ 60 years, respectively. In conclusion, the biggest constraint is the cost of treatment and the absence of a health security net to treat all patients with this diagnosis.

Diagnostic accuracy of ultrasound for assessment of hemophilic arthropathy: MRI correlation.

OBJECTIVE. The purpose of this article is to assess the reliability of interpretation of ultrasound findings according to data blinding in maturing hemophilic joints and to determine the diagnostic accuracy of ultrasound compared with MRI for assessing joint components. SUBJECTS AND METHODS. Ankles (n = 34) or knees (n = 25) of boys with hemophilia or von Willebrand disease (median age, 13 years; range, 5-17 years) were imaged by ultrasound, MRI, and radiography in two centers (Toronto, Canada, and Vellore, India). Ultrasound scans were performed by two operators (one blinded and one unblinded to MRI data) and were reviewed by four reviewers who were unblinded to corresponding MRI findings according to a proposed 0- to 14-item scale that matches 14 of 17 items of the corresponding MRI scale. MRI examinations were independently reviewed by two readers. RESULTS. When data were acquired by radiologists, ultrasound was highly reliable for assessing soft-tissue changes (intraclass correlation coefficient [ICC], 0.98 for ankles and 0.97 for knees) and substantially to highly reliable for assessing osteochondral changes (ICC, 0.61 for ankles and 0.89 for knees). Ultrasound was highly sensitive (> 92%) for assessing synovial hypertrophy and hemosiderin in both ankles and knees but had borderline sensitivity for detecting small amounts of fluid in ankles (70%) in contrast to knees (93%) and variable sensitivity for evaluating osteochondral abnormalities (sensitivity range, 86-100% for ankles and 12-100% for knees). CONCLUSION. If it is performed by experienced radiologists using a standardized protocol, ultrasound is highly reliable for assessing soft-tissue abnormalities of ankles and knees and substantially to highly reliable for assessing osteochondral changes in these joints.

A stepwise α-thalassemia screening strategy in high-prevalence areas.

INTRODUCTION: Coinheritance of α-thalassemia influences the clinical and hematological phenotypes of ß-hemoglobinopathies (ß-thalassemia and sickle cell disease) and when present together in significant frequency within a population, a spectrum of clinical forms is observed. Precise molecular characterization of α-thalassemia is important in understanding their disease-modifying role in ß-hemoglobinopathies and for diagnostic purposes. PATIENTS AND METHODS: Because currently used approaches are labor/cost-intensive, time-consuming, error-prone in certain genotype combinations and not applicable for large epidemiological screening, we developed a systematic stepwise strategy to overcome these difficulties. We successfully applied this to characterize the α-globin gene status in 150 Omani cord blood samples with Hb Barts and 32 patients with HbH disease. RESULTS: We observed a good correlation between α-globin genotypes and level of Hb Bart's with the Hb Bart's levels significantly higher in both deletional and non-deletional α-globin genotypes. The most common α-globin genotype in HbH cases was α(TSaudi) α/α(TSaudi) α (n = 16; 50%) followed by -α(3.7) /-(MED) (n = 10; 31%). This approach detects also the α-globin gene triplication as exemplified by the study of a family where the ß-globin gene defect failed to explain the ß-thalassemia intermedia phenotype. CONCLUSION: Molecular characterization of α-thalassemia is complex due to high sequence homology between the duplicated α-globin genes and to the existence of a variety of gene rearrangements (small and large deletions of various sizes) and punctual substitutions (non-deletional alleles). The novelty of our strategy resides, not in the individual technical steps per se but in the reasoned sequential order of their use taking into consideration the hematological phenotype as well.

Standardizing minimal residual disease by flow cytometry for precursor B lineage acute lymphoblastic leukemia in a developing country.

BACKGROUND: In addition to standard risk criteria at diagnosis, minimal residual disease (MRD) following initiation of therapy is a well-recognized risk factor to predict relapse. Literature from developing countries addressing therapeutic or laboratory practices related to MRD, is largely lacking. In a first paper from India, we describe our experience in establishing a flow cytometry-based MRD assay for precursor B lineage ALL (BCP-ALL) with emphasis on the assay standardization and cost. METHODS: Normal templates for B cell development were established in 10 control patients using CD45, CD11a, CD38, CD20, CD10, CD19, CD58, CD34, CD123, and CD22. BCP-ALL samples (n = 42) were characterized at diagnosis to identify a suitable marker for follow-up during mid (D+21) and end of induction (D+33). Both, multiparametric immunophenotyping and single marker detection of LAIP were used for data analysis. RESULTS: In 95.2% of BCP-ALL at least two informative markers could be obtained when a minimum of four cocktail combinations were used. The combination CD20, CD10, CD45, and CD19 was the most useful (71.4%) followed by combinations containing CD38 (66.7%), CD22 (57.1%), CD11a (52.4%), and CD58 (33.3%). Using our approach, 60 and 47% of patients had detectable MRD at mid and end induction time points, respectively. CONCLUSION: We have described a relatively cost effective MRD panel which is applicable to over 90% of patients. We hope that this data would encourage more centers in India and other resource constrained health delivery systems to develop MRD assays.

Bone densitometric assessment and management of fracture risk in Indian men of prostate cancer on androgen deprivation therapy: Does practice pattern match the guidelines?

OBJECTIVE: Estimation of baseline bone mineral density (BMD) at the time of instituting androgen deprivation therapy (ADT) for metastatic prostate cancer is recommended by several specialty groups and expert panels. The present study was carried out to analyze the practice pattern of Indian urologists with regard to bone densitometric assessment and management of fracture risk in men of prostate cancer on ADT, and their degree of adherence to currently available guidelines. MATERIALS AND METHODS: Telephonic interviews of 108 qualified urologists, randomly selected from the member database of Urological Society of India was carried out with a predefined questionnaire. The responses were analyzed and compared with the available evidences and recommendations. RESULTS: Only 19.4% urologists routinely perform a baseline BMD before starting ADT. Although majority of them prescribe calcium and vitamin D supplementation, only few tell regarding fracture risk and life-style modification to their patients. While 59.6% of the respondents use Zoledronic acid (ZA) in their patients on ADT, half of them prescribe it without knowing the BMD status, which may lead to overuse of ZA. CONCLUSION: Majority of the urologists in India do not follow the guidelines for BMD measurement in prostate cancer. A baseline BMD may help in reducing the unnecessary use of ZA.