Methods and criteria for the assessment of orphan drugs: a scoping review.

OBJECTIVES: This study aimed to identify different criteria for priority setting of rare diseases to help policy makers in making evidence-informed decisions. METHODS: A scoping review was conducted to comprehensively examine the existing various methods and criteria for prioritizing orphan drugs and rare diseases. We performed searching in Scopus, PubMed, Embase, and websites of health technology assessment (HTA) agencies, 2000-21, and data were extracted. RESULTS: From the 1,580 identified publications, eleven articles were included. Multicriteria decision analysis was the most frequent method (seven out of eleven studies) used for priority setting. The extracted criteria for priority setting of orphan products were analyzed based on six main categories as follows: health outcomes and clinical implications (six subsets which showed clinical implications), economic aspects (four subsets that indicated the economic effects of orphan drugs and rare diseases), disease and population characteristics (six subsets that included the characteristics of the rare diseases), therapeutic alternatives and uniqueness of orphan technologies (two subsets which discussed the alternatives and uniqueness of orphan technologies), evidence (three subsets which regarded the quality and availability of evidence), and other criteria (three subsets dealing with social and organizational criteria). Cost-effectiveness, budget impact, and disease severity were the most frequent criteria in the studies. CONCLUSIONS: Because of the high price of orphan drugs and limitations of using HTA for reimbursement of them, it is critical to explore them by precise technical methods like multiple criteria decision making in priority setting.

Molecular characterization of a large cohort of mucopolysaccharidosis patients: Iran Mucopolysaccharidosis RE-diagnosis study (IMPRESsion).

Mucopolysaccharidoses (MPSs) are rare, heterogeneous inborn errors of metabolism (IEM) diagnosed through a combination of clinical, biochemical, and genetic investigations. The aim of this study was molecular characterization of the largest cohort of Iranian MPS patients (302 patients from 289 unrelated families), along with tracking their ethnicity and geographical origins. 185/289 patients were studied using an IEM-targeted NGS panel followed by complementary Sanger sequencing, which led to the diagnosis of 154 MPS patients and 5 non-MPS IEMs (diagnostic yield: 85.9%). Furthermore, 106/289 patients who were referred with positive findings went through reanalysis and confirmatory tests which confirmed MPS diagnosis in 104. Among the total of 258 MPS patients, 225 were homozygous, 90 harbored novel variants, and 9 had copy number variations. MPS IV was the most common type (34.8%) followed by MPS I (22.7%) and MPS VI (22.5%). Geographical origin analysis unveiled a pattern of distribution for frequent variants in ARSB (c.430G>A, c.962T>C [p.Leu321Pro], c.281C>A [p.Ser94*]), GALNS (c.319G>A [p.Ala107Thr], c.860C>T [p.Ser287Leu], c.1042A>G [p.Thr348Ala]), and IDUA (c.1A>C [p.Met1Leu], c.1598C>G [p.Pro533Arg], c.1562_1563insC [p.Gly522Argfs*50]). Our extensive patient cohort reveals the genetic and geographic landscape of MPS in Iran, which provides insight into genetic epidemiology of MPS and can facilitate a more cost-effective, time-efficient diagnostic approach based on the region-specific variants.

Quality of Life and Related Factors in ß-Thalassemia Patients.

The ß-thalassemias are a group of genetic disorders defined by decreased levels of functional hemoglobin (Hb). In light of pivotal improvements in patient survival, the load of consistent treatment harms patients' quality of life (QOL). This study aimed to determine the QOL in patients with ß-thalassemia (ß-thal) in Iran and identify associated factors. This cross-sectional study was conducted among 1240 patients with ß-thal. Data for this study were obtained from the General, the TranQol (Transfusion-dependent QoL) Standard, and the Multidimensional Scale of Perceived Social Support (MSPSS) questionnaires. The univariate and multivariable linear regression was used in STATA version 14 to identify factors related to QOL. Overall, the QOL score was 103 ± 21.96, and adults had a higher score than children under 15 years old. Emotional health had the highest score (39.96 ± 11.54), and sexual activity in adults (1.87 ± 2.08) and activities related to education in children (10.43 ± 7.46) had the lowest. The multivariable linear regression analysis showed that the age, gender, age of blood transfusion initiation, Hb level, number of underlying diseases, and social support level by family and community significantly impact QOL. In exchange for an increase in comorbidities, patients' QOL decreased by 86.0% [odds ratio (OR) = 0.14, 95% confidence interval (95% CI): 0.04-0.45]. Many factors affecting the QOL can be controlled, so social support, increased Hb levels, regular and timely blood transfusions, and treatment can improve the thalassemia patients' QOL.

Fixation of distal tibia fracture through plating, nailing, and nailing with Poller screws: A comparative biomechanical-based experimental and numerical investigation.

The goal of this study was to investigate two commonly used methods of fixation of distal metaphyseal tibia fractures, plating and nailing as well as the less frequently employed nailing with Poller screws, from a biomechanical perspective. Despite numerous studies, the best method to repair fractures of tibia the remains up for of debate. This study includes an in vitro experimental phase on human cadaveric tibias followed by a finite element analysis. In the experimental phase, under partial weight-bearing axial loading, the axial stiffness of the bone-implant construct and interfragmentary movements for each of the fixation methods, bone-plate, bone-nail, and bone-nail-Poller screw, were measured and compared with each other. Shear interfragmentary movement and stress distribution in the bone-implant construct for the three mentioned fixation methods were also determined from FE models and compared with each other. Results of in vitro experiments, i.e., the exertion of axial loading on the tibia-plate, tibia-nail, and tibia-nail-Poller screw, showed that utilization of tibia-nail and tibia-nail-Poller screw led to a stiffer bone-implant construct, and consequently, lower interfragmentary movement, compared to the tibia-plate construct (p values for tibia-nail and tibia-nail-Poller screw, and for both axial stiffness and interfragmentary movement, compared to those of tibia-plate construct, were less than 0.05). Numerical analyses showed that nailing produced less undesirable shear interfragmentary movement, compared to the plating, and application of a Poller screw decreased the shear movements, compared to tibia-nail. Furthermore, using the finite element analysis, maximum von Mises stress of adding a screw in tibia-nail, tibia-plate, and tibia-nail-Poller screw, was found to be: 51.5, 78.6, and 60.5 MPa, respectively. The results of this study suggested that from a biomechanical standpoint, nailing both with and without a Poller screw is superior to plating for the treatment of distal tibia fractures.

Perspective of 20 Years Hemodialysis Registry in Iran, on the Road to Progress.

End-stage renal disease (ESRD) is a foremost health issue with major consequences in various parts of the world. In Iran, the prevalence/incidence of ESRD has increased during the past decades. The economic burden of ESRD treatment on patients, their families, and the whole healthcare system is huge as well. Hence ESRD is considered emerging public health problem in developing countries, including Iran, requiring short- and longterm changes in healthcare policies. Developing a national registry system for dialysis patients in Iran now enables us to summarize certain clinical characteristics of these patients and compares the present situation with the late 1990s when dialysis services just began to expand in the country. In this paper, the authors provide information regarding the process of establishing dialysis registry in Iran along with the report of the output of such a registry. Focusing on such an important measure in the whole country of around along with the data that it has produced is a gateway to further progress.

A patient specific finite element simulation of intramedullary nailing to predict the displacement of the distal locking hole.

Distal locking is a challenging subtask of intramedullary nailing fracture fixation due to the nail deformation that makes the proximally mounted targeting systems ineffective. A patient specific finite element model was developed, based on the QCT data of a cadaveric femur, to predict the position of the distal hole of the nail postoperatively. The mechanical interactions of femur and nail (of two sizes) during nail insertion was simulated using ABAQUS in two steps of dynamic pushing and static equilibrium, for the intact and distally fractured bone. Experiments were also performed on the same specimen to validate the simulation results. A good agreement was found between the model predictions and the experimental observations. There was a three-point contact pattern between the nail and medullary canal, only on the proximal fragment of the fractured bone. The nail deflection was much larger in the sagittal plane and increased for the larger diameter nail, as well as for more distally fractured or intact femur. The altered position of the distal hole was predicted by the model with an acceptable error (mean: 0.95; max: 1.5 mm, in different tests) to be used as the compensatory information for fine tuning of proximally mounted targeting systems.

Survival probabilities of end stage renal disease patients on renal replacement therapy in Iran.

AIM: To bridge the gap in the current knowledge, the present study was conducted to obtain evidences relating to clinical outcomes of the end-stage renal disease (ESRD) population in Iran over the last two decades. METHODS: The records of 84 652 incident ESRD patients from 1995 up to and including 2014 in the national registry of ESRD patients were analyzed retrospectively. Data were collected from dialysis and transplant centres in Iran from 1995 to 2008 via paper forms and from 2009 to 2014 through web-based records. RESULTS: Mean age (SD) in incident cases of ESRD (57.7% male) was 52.5 (16.6) years. The prevalence of ESRD patients grew on average 14.9% and 5.3% annually in the periods of 1995-2004 and 2005-2014, respectively. Adjusted mortality rate among dialysis patients in 1995, 2005, and 2014 was 145, 154, and 177/ 1000 patient-years, respectively. Median graft half-life (IQR) and median expected remaining life-years (IQR) for dialysis patients in the 2003 incident patient cohort were 4.4 (1.9-8.3) and 4.2 (1.8-8.2) years, respectively. CONCLUSIONS: The overall slightly decreasing, and still comparable, survival trend in dialysis patients, despite the accessible and free dialysis treatment, may be the result of the counterbalance of different contributory factors, including increased age and the higher proportion of patients with co-morbidities resulting from diabetes and hypertension. The half-lives of renal allografts were generally shorter compared to thus far shared evidence, which may be due to tissue incompatibility. The decreasing trend, in this context, can be attributable to the increased number of transplantation from deceased donors with expanded criteria.

Factors Associated With Lumbar and Femoral Bone Mineral Density in Kidney Transplants Candidates.

INTRODUCTION: Data on risk factors associated with low bone mineral density are limited in patients with end-stage renal disease. This study evaluated the factors deemed associated with lumbar and femoral Z and T scores. MATERIALS AND METHODS: Clinical and demographic data of 98 patients waiting for kidney transplantation were collected, as well as lumbar and femoral bone densitometries, before transplantation. Osteoporosis and osteopenia and factors associated with bone mineral density were assessed. RESULTS: According to the femoral T score, 38.8% (95% confidence interval [CI], 29.1% to 48.4%), 44.9% (95% CI, 35.1% to 54.7%), and 16.3% (95% CI, 9.0% to 23.6%) of the patients had normal bone density, osteopenia, and osteoporosis, respectively. According to the lumbar T score, 54.1% (95% CI, 44.2% to 63.9%), 33.7% (95% CI, 24.3% to 44.0%), and 12.2% (95% CI, 5.8% to 18.7%) of the patients had normal density, osteopenia, and osteoporosis, respectively. Age, serum levels of creatinine and parathyroid hormone, and use of calcitriol and calcium carbonate were associated with femoral densitometry scores. Serum total protein level, Rh-negative status, and B blood type were associated with the lumbar scores. CONCLUSIONS: Parathyroid hormone contributed to bone loss in our kidney transplant candidates, and B and Rh-negative blood types were associated with a higher risk of lumbar osteoporosis while total protein was negatively associated with the risk of bone loss. Calcitriol might improve femoral mineral density, but calcium carbonate was negatively associated with femoral bone density. Age and higher creatinine levels were associated with higher femoral bone densities.

Chronic kidney disease management program in Shahreza, Iran.

INTRODUCTION: Chronic kidney disease (CKD) is a public health problem that needs an integrated program to be detected, monitored, and controlled. This study reports the results of a CKD program designed and implemented in Shahreza, Iran. MATERIALS AND METHODS: After initial evaluation of CKD in Shahreza, a CKD management program was developed in the Ministry of Health and the pilot project was started in February 2011 in Shahreza rural areas. The patients at risk, including those with diabetes mellitus and hypertension, were tested with serum creatinine and urine albumin-creatinine ratio. The CKD management program included training, screening, monitoring, and controlling of weight, hypertension, diabetes mellitus, lipids, and vitamin D. RESULTS: This pilot program was organized in the rural population aged over 30 years who were suffering from hypertension, diabetes mellitus, or both, and resulted in the discovery of cases in various stages of CKD. The prevalence of CKD in this high-risk group was 21.5%. Persistent albuminuria and a glomerular filtration rate less than 60 mL/min/1.73 m(2) were 13% and 11%, respectively. The rate of CKD stages 1, 2, 3a, 3b, 4, and 5 were 2.75%, 6.82%, 10.08%, 0.92%, 0.31%, and 0.17% respectively. After 1 year of the program implemented, incidence rate of CKD was 24% and improvement rate was 21%. In diabetic patients, the mean of hemoglobin A1c decreased from 8.5 ± 1.9% to 7.5% ± 1.8%. CONCLUSIONS: Integration of CKD programs in primary health care is possible and results in improvement in management of CKD patients.

Outlook of organ transplantation in Iran: time for quality assessment.

Organ transplantation as an undeniable life-saving therapeutic modality fundamentally requires infrastructure, devoted and trained professionals, and positive public attitude to be set up in a well-organized manner at the national level. In addition to sharing achievements and reviewing the increasing trend of transplanted organs in the past 12 years following legislations in Iran, this report raises some concerns from the point of transplantation outcome view.

Short-term survival in renal transplantation from brain-death donors: focusing on recipients with diabetes background.

PURPOSE: Our aim was to evaluate short term survival rates in renal transplant recipients from deceased donors, while focusing on recipients with diabetes mellitus background. MATERIALS AND METHODS: This is a longitudinal follow-up study based on national registry of recipients in Ministry of Health and Medical Education in Iran from 2010-11. Five hundred fifty-five recipients, 226 (40.8%) females and 328 (59.2%) males, were included in the study. Mean (± SD) age of the recipients was 39 ± 14 years. Of donors 18.4% were females and 81.6% were males. Age of the donors was 33 ± 14 years. All allograft recipients from deceased donors enrolled in the study. Short-term graft survival (1 year) was determined. Data regarding age, gender, background disease and cold ischemic time of recipients and donors were collected from the organ procurement units. RESULTS: Allografts were functioning in 499 (90.1%) of recipients after one year. Of recipients 38 (6.9%) died and rejection of transplanted kidney occurred in 17 (3.1%) cases. So, in 55 (9.9%) cases, allografts were not functioning. There were significant relationships between short term graft survival of donors' gender, age of recipients, cold ischemic time and level of clearance of creatinine of recipients. CONCLUSION: In addition to cold ischemic time, graft survival can be affected by recipients' age. There are some other considerations and implications regarding the short term graft survival in renal transplantation from cadaver donors which are discussed in this paper.

Hemodialysis adequacy and treatment in Iranian patients: a national multicenter study.

INTRODUCTION: Assessment of the hemodialysis adequacy is one of the key factors in evaluating health service system. This would provide a good background for effective future planning by healthcare authorities. In this study, we aimed to evaluate the hemodialysis adequacy in Iran. MATERIALS AND METHODS: One hundred and twenty-seven hemodialysis centers affiliated to 30 medical universities in Iran participated in this cross-sectional multicenter national study. All demographic data as well as hemodialysis prescription data, including blood flow rate, length of the hemodialysis session, hemodialysis membrane type, and composition of the dialysis solution were recorded for each patient. In addition, urea reduction ratio and Kt/V were calculated to determine the hemodialysis adequacy. RESULTS: A total of 4004 patients were included in this study, 2345 men (58.6%) and 1659 women (41.4%). Bicarbonate-based solutions and low-flux membranes were prescribed for 77.0% and 97.6% of the patients, respectively. The mean blood flow rate was 242.9 ± 39.2 mL/min. The mean length of hemodialysis session was 229.2 ± 22.2 minutes. The mean urea reduction ratio and Kt/V were calculated to be 61.0 ± 11.8% and 1.2 ± 0.4, respectively. A Kt/V less than 1.2 and a urea reduction ratio less than 65% were found in 56.7%, and 65.2% of the hemodialysis patients, respectively. CONCLUSIONS: This study showed a substantial inadequate hemodialysis in Iran as compared with the Kidney Disease Outcomes Quality Initiative guidelines. Considering the impact of dialysis adequacy on quality of life and survival rates, as well as healthcare costs, rigorous attempts to achieve the desired goals are necessary.

Haemophilia in the developing countries: the Iranian experience.

INTRODUCTION: Management of haemophilia and inherited bleeding disorders is a major challenge especially in developing countries, because of a shortage or absence of products, the cost and the infrastructural health problems. Development of local expertise which results in an improved outlook and reduction in mortality and morbidity in these countries can be helpful for advocators in other developing countries. However, very little information on demography and organizational models for haemophilia care in developing countries are available in the literature. Our aim is a comprehensive report of haemophilia status and its management in Iran. MATERIAL AND METHODS: THE MANAGEMENT CENTER OF TRANSPLANTATION AND SPECIAL DISEASES (MCTSD) OF THE MINISTRY OF HEALTH OF IRAN DECIDED TO CARRY OUT A COMPLETE REVIEW AND COMPILATION OF ALL OF THE PUBLISHED OR AVAILABLE DATA ABOUT PATIENTS WITH HAEMOPHILIA (PWH) IN IRAN: their health status, their management planning, organizations, treatment products, facilities and care problems during 2007. RESULTS: 6496 patients with congenital bleeding disorders were registered. Most of them had haemophilia A and B and von Willebrand disease (vWD). However, rare bleeding disorders are seen more than expected. Inhibitor development is 14-28%. There are different data about virological status of PWH. Factor products and facilities are fairly available with more than 1.5 units per capita of inhabitant factor consumption. CONCLUSIONS: A national formulary based on facilities of the country should be considered and followed by collaboration among the Ministry Of Health, universities and non-governmental organizations.

Changing epidemiology of end-stage renal disease in last 10 years in Iran.

INTRODUCTION: The rapid increase in the prevalence of end-stage renal disease (ESRD) necessitates putting into practice some strategies to prevent its development and progression, especially in the developing world. Detailed chronological changes in the incidence of ESRD may sharpen the focus on its prevention. We, therefore, determined the detailed epidemiological features of ESRD in Iran. MATERIALS AND METHODS: Data of the national registry of Iran's ESRD provided by the Ministry of Health were used to retrieve the ESRD figures between 1997 and 2006. RESULTS: A total of 35 859 patients who initiated renal replacement therapy (20 633 men and 15 226 women) were registered during the study period from 1997 to 2006. The annual number of patients with ESRD beginning maintenance treatment in Iran increased 130% between 2000 and 2006. During 1997 to 2006, the proportion of new cases of ESRD attributed to diabetes mellitus increased 2-fold from 16% in 1997 to 31% in 2006. The mean age of newly registered men and women increased from 47.0 years and 49.0 years to 52.5 years and 53.0 years, respectively. As for all and major causes of ESRD, age-adjusted incidence rates for men generally were higher than those for women. Male-female ratio was 1.3:1, with no significant changes during this period. CONCLUSIONS: We strongly recommend considering chronic kidney disease prevention with initial focusing on strategies and treatment modalities that slow ESRD progression in order to postpone the need for renal replacement therapy.