Iranian Journal of Public Health
Volume:49 Issue: 5, May 2020

The evidence of transcranial direct current stimulation (tDCS) treatment effects on dementia is still insufficient. This study aimed to prove the scientific basis of tDCS by conducting a meta-analysis of previous studies that examined the effects of tDCS on the naming of patients with dementia.

The literature search was conducted for publications published from Jan 2000 to Jun 2019 using four academic databases (PubMed, Web of Science, MEDLINE, and Cochrane Library). This study found 129 publications by searching academic databases according to the PRISMA protocol. Among them, irrelevant studies were excluded, and finally, 4 studies were meta-analyzed.

The score of the quality assessment on five studies ranged from 21 to 26 points, rated good or better. Meta-analysis results, tDCS had no significant effect on the improvement of naming ability of dementia. On the other hand, the effect size of the tDCS intervention + language/cognitive training was significant ‘large effect (SMD=0.72, 95% CI: 0.05, 1.39)’.

This combination of tDCS and language/cognitive training significantly improved the naming ability of dementia patients.

The gene polymorphisms in microRNA might relate to susceptibility of type 2 diabetes mellitus (T2DM). However, the results of existing studies were inconsistent and obscure. To investigate the precise associations between microRNA gene polymorphisms and T2DM risk, the present meta-analysis was performed.

The literatures were searched from four electronic databases, PubMed, Embase, CNKI and Wanfang. Subsequently, odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were both used to evaluate the associations between two single nucleotide polymorphisms (SNPs) (microRNA146a rs2910164 (G>C), microRNA124a rs531564 (C>G)) and risk of T2DM in Asian population.

Totally, there were 4 studies included in our present analysis in the language of English and Chinese. There were partly significant associations between susceptibility of T2DM and SNPs (microRNA146a rs2910164 (G>C), microRNA124a rs531564 (C>G)). The G allele in microRNA146a rs2910164 (G>C) and C allele in microRNA124a rs531564 (C>G) both presented remarkably reduced risk of T2DM when compared with the healthy population.

The microRNA146a rs2910164 (G allele) and microRNA124a rs531564 (C allele) might function as protective factors in the pathogenetic process of T2DM in Asian population.

Disasters are increasing all over the world. Iran, is one of the high-risk countries in this regard; so it is unavoidable to prepare hospitals as vital centers when disasters happen. This study aimed to evaluation the hospital preparedness based on previous studies in Iran.

A systematic review and meta-analysis by browsing through all articles published since 2006 to 2017, in English and Persian both languages were designed. Databases that we searched to, include Google Scholar, PubMed, Web of Science, Scopus, Medlib, Cochrane Library, Science Direct, Internationally and SID, Irandoc and Magiran, domestically. Two expert researchers investigated separately. Researchers used random and fixed effect models in the meta-analysis. Moreover, random and fixed effects model and meta-regression tests were applied by using STATA ver. 11. The P<0.05 was considered statistically significant.

Twenty-five studies with a sample size of 181 hospitals were introduced to the process of meta-analysis. Iranian hospital preparedness is 53%, totally, that is moderate. Preparedness in different categories is as follows: emergency services 62%, communication 57%, security 54%, education 57%, logistic 65%, human resources 52%, Management and command 64%, reception 43%, transfer and evacuation 44%, traffic 47%, non-structural safety 57%, and structural safety 49%.

Hospital preparedness is moderate in Iran. Optimal management of existing resources and the use of Update technologies in the field of hospital services be directed towards improving the preparedness of hospitals for disasters.

One of the ways for cost-sharing in health system that has been taken into consideration in recent years in some developed countries is paying deductibles. In case of using deductibles, the insured people more carefully and accurately will use health care services, and potentially many unnecessary costs will be avoided.

To investigate the evidence of deductibles in health systems across the world, a literature review was conducted by searching the materials published in databases including ISI web of science, PubMed, Scopus and also Google scholar search engine from 2000 to 2017. Besides the related websites including WHO and the World Bank were searched. Inclusion criteria were studies carried out only in health insurance, English language, and the year of the study.

The most important positive impacts of deductibles were decrease in utilization of different services, high profitability for the young and healthy people, lower health benefit claims by the insured people, and increase in financial profitability of health insurance organization. Besides, the most negative impacts increase in out of pocket burdens and also higher hospitalization over time.

Deductible plans have their own advantages and disadvantages for the insured and insurance organizations in terms of financial dimensions as well as utilization of health services, and explicitly none of these plans can be flawless. Given the increasing costs of health systems and the potential moral hazard of insured persons, it seems these systems sooner or later should inevitably move towards new cost-sharing plans, including deductibles.

Inadequate health literacy (HL) is associated with poorer health outcomes and worse health care. Up to one-half of Iranian women have difficulty in interpreting medical information, and national HL assessment has been limited in Iran. We have undertaken a systematic review of the literature and used a meta-analysis to examine the situation of HL status in Iranian women, and determine the relationship between HL and self-efficacy, and self-care behaviors.

Six databases (PubMed, Web of Science, Scopus, Google Scholar, Scientific Information Database) and other non-indexed citations were searched using a variety of keywords regarding HL and Iranian women. The bias risk was decreased by the involvement of two independent reviewers assessing study quality and eligibility of included articles.

The average HL scores were in the range of marginal or limited (63.08; 95% CI, 59.83–66.32) in the Iranian women. The HL score was significantly higher among pregnant women (67.55; 95% CI, 32.54– 82.57) and was lower in women with chronic disease (57.79; CI, 48.34-67.24). There was a significant association between HL and self-efficacy and self-care behaviors.

The average level of HL in the period of the review was marginal among Iranian women. The relationship of HL with self-efficacy and self-care behaviors was statistically significant but moderate.

We aimed to demonstrate the effect of 8 wk of scapular kinetic-chain exercise on muscle activity in collegiate baseball players diagnosed with scapular dyskinesis.

The subjects were career baseball players with at least a 7-year career assigned into either a SICK (S; scapular malposition, I; inferior border prominence, C; coracoid process pain, K; scapular dyskinesis; n=7) group or a normal group (n=16), respectively. The groups were further divided into SICK-Dominant, SICK-Non-Dominant, Normal-Dominant, and Normal-Non-Dominant to examine the dominant and non-dominant deviation of each group. Twenty-three subjects finally recruited through the Sports Science Institute of Korea National Sport University, Seoul, Korea in Sep 2014. Subjects were only allowed drug treatment for acute injuries during matches or training, and matches, training, and diet were controlled by university dormitory life.

There was a significant increase in maximal muscular activation (MA) in elevation motion of Normal-Dominant upper trapezii (UT), mean MA of SICK-Dominant UT, and mean MA of SICK-Dominant lower trapezii (LT) (P<0.05). In depression motion, the mean MAs of SICK-Dominant, Normal-Dominant, and Normal-Non-Dominant UT were significantly increased (P<0.05). The maximal MA of Normal-Dominant LT was significantly increased (P=0.029), and the SICK-Dominant and Normal-Dominant groups showed significantly higher maximal and mean MAs after exercise compared with the Normal-Non-Dominant group (P<0.05). The maximal MA of SICK-Dominant musculi serratus anterior was significantly lower than Normal-Dominant at pre-test (P=0.034), and the mean MA of SICK-Dominant musculi serratus anterior differed from Normal-Dominant and Normal-Non-Dominant (P<0.05) before testing, but only from Normal-Non-Dominant after testing (P=0.031).

Scapular kinetic-chain exercise improved muscle activation in both overhead-pitching players with scapular dyskinesis and normal players.

To explore IFN-γ (interferon-γ) and IL-4 (interleukin-4) expressions before and after the treatment of LN (lupus nephritis) and their values for efficacy prediction and evaluation.

Altogether 107 patients with LN treated in the First Hospital of Qiqihaer City, Qiqihar, China from March 2017 to September 2018 were enrolled. Sixty-two patients were treated with cyclophosphamide and prednisolone (control group), while another 45 patients were treated with Qing Shen Fang based on the control group (observation group). Their clinical efficacy and changes in immune indices after treatment were observed.

Compared with those in the control group, clinical efficacy, IFN-γ, IL-4, hemoglobin, complements C3 and C4, ESR (erythrocyte sedimentation rate), serum IgG, SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score, and TCMSSS (Traditional Chinese Medicine Syndrome Score Scale) score were significantly improved after treatment in the study group. Based on the observation, IFN-γ and IL-4 could be used as potential indicators for evaluating clinical efficacy.

The combination of cyclophosphamide, prednisolone, and Qing Shen Fang improves conditions of patients with LN and significantly reduces their IFN-γ and IL-4 levels in serum. IFN-γ and IL-4 can be used as potential indicators for the efficacy prediction and evaluation of the disease.

Knee disease is prevalent in the post middle-aged and associated with lower quality of life. Knee disease (i.e., anterior cruciate ligament, ACL) related injury preventive program should be supported. We examined the significant effect of different age, gender, and exercise modalities on measureable nine dependent markers in National Health Insurance Sharing Service database (NHISS DB) registered ACL patients using big data analysis.

The 1755 ACL patients from 514,866 in NHISS DB have been randomly selected by retrospective cohort study using big data from 2002 to 2013. Six independent and 9 dependent variables were used for analyzing patients with ACL injuries by T-test and Two-way analysis of variance (ANOVA).

Mean (SD) (men vs. women) of BMI, high blood pressure (BP), serum glutamic oxaloacetic transaminase (SGOT), and total cholesterol were 24.38±2.72 vs. 24.86±3.12 (P<0.01, 95% C.I., -0.763 ~ -0.194), 126.64±14.70 vs. 125.02±16.62 (P<0.05, 95% C.I., 0.104 ~ 3.151), 27.63±12.18 vs. 24.27±8.48 (P<0.01, 95% C.I., 2.393 ~ 4.331), 197.77±37.60 vs. 205.72±36.72 (P<0.01, 95% C.I., -11.533 ~ -4.378), respectively. Age and the frequency of 20 min severe exercise per week (Move20_Freq) intensive exercise had a significant association with BMI (P<0.05). Gender and Move20_Freq had a significant association with BP (P<0.05).

Age-dependent Move20_Freq is associated with BMI in ACL patients. Women with ACL have higher BMI and cholesterol levels than men. These gender-specific differences can be relieved by exercise.

Although the concept of the Balanced Scorecard (BSC) was designed for profit-based organisations, the application of the BSC in public and nonprofit organisations (NPOs) could be performed within the NPOs and public health sector, as the conceptual foundation of this system was developed from community hospitals performance.

This study used the BSC concept to analyse the 16 key performance indicators and trends of performance during the last five years of 52 community hospitals located in upper southern Thailand in 2017 and tendency of 2013-2017. The instruments included an annual report and a questionnaire. A statistical analysis to determine percentages, means and standard deviations was performed.

The major findings of the community hospitals performance were as follows: Customer perspective: 1. Patient complaint rate of 0.0097% and 2. Outpatient waiting time of 91.89 minutes, Financial perspective: 1. Ratio of total revenue to total expense at 0.9949 and 2. Cost of drugs and materials to total expense at 13.32%, Internal process perspective: 1. Bed turnover at 88.16 and 2. Hospital infection rate of 0.379 times:1,000 patient days, Learning and growth perspective: 1. Staff turnover rate of 4.69% and 2. Number of research studies at 3.77 articles. Trends and performance of hospitals in every perspective of the BSC in the last 5 years showed no differences.

  The community hospitals offer services such as treatment of common diseases. If the community hospitals could not assist, they will go to referral system by referring patients to secondary and tertiary care respectively.

To explore the effect of different doses of Gamma Globulin (GG) on the condition of children with Hemolytic Disease of Newborn (HDN) and the influence of immune factors in serum.

Overall, 180 infants with hemolytic disease of newborn in the People’s Hospital of Zhangqiu Area, Jinan, China from April 2016 to August 2018 were divided into group A (88 cases) and group B (92 cases). Group A was given intravenous low-dose GG on the basis of phototherapy, and group B was given intravenous high-dose GG on the basis of phototherapy. The level of serum total bilirubin of the infants, the levels of CD3+, CD4+, CD8+, of the infants, the time of jaundice disappearance and the length of hospital stay, hemoglobin and reticulocyte levels were recorded before treatment and after treatment. The number and condition of adverse reactions were recorded.

After treatment, the levels of TBiL, hemoglobin and reticulocyte, the time of jaundice disappearance and hospital stay in group B were significantly lower than those in group A. The level of immune cells in group B was significantly higher than that in group A after 7 days of treatment, and the levels of IgA / IgG / IgM in group B were significantly higher than those in group A after 28 days of treatment.

Intravenous high-dose GG has a better effect on the condition of neonatal hemolytic disease patients, and more effectively improve the immune function of children.

The prevalence of Acute Myocardial Infarction (AMI) varies from region to region caused by seasonal climate changes and temperature variation. This study aimed to assess the relationship between changing meteorological conditions and incidence of AMI in Iran.

This retrospective prevalence study was based on medical records of the heart center of Mazandaran Province on all patients diagnosed with AMI in Mazandaran, northern Iran between 2013 and 2015. Patients’ sex and the day, month, year and time of hospital admission were extracted from patients’ records. Moreover, the meteorological reports were gathered.

A statistically significant difference was found between the distributions of AMI cases across 12 months of the year (P < 0.01). Fuzzy clustering analysis using 16 different climatic variables showed that March, April, and May were in the same cluster together. The other 9 months were in different clusters.

Significant increase in AMI was seen in March, April and May (cold to hot weather).

Serratiopeptidase is a bacterial metalloprotease, which is useful for the treatment of pain and inflammation. It breaks down fibrin, thins the fluids formed during inflammation and acts as an anti-biofilm agent. Because of medicinally important role of the enzyme, we aimed to study the cloning and the expression optimization of serratiopeptidase.

The heat-stable serratiopeptidase (5d7w) was selected as the template. Cloning into pET28a expression vector was performed and confirmed by colony PCR and double restriction enzyme digestion. The recombinant protein was expressed in Esherichia coli BL21 and confirmed by SDS-PAGE and Western blot analysis. Different parameters such as expression vector, culture media, post-induction incubation temperature, inducer concentration, and post-induction incubation time were altered to obtain the highest amount of the recombinant protein.

Serratiopeptidase was successfully cloned and expressed under optimized conditions in E. coli which confirmed by western blot analysis. The optimal conditions of expression were determined using pQE30 as vector, cultivating the host bacteria in Terrific Broth (TB) medium, at 37º C, induction by IPTG concentration equal to 0.5 mM, and cells were harvested 4 h after induction.

As serratiopeptidase is a multi-potent enzyme, the expressed recombinant protein can be considered as a valuable agent for pharmaceutical applications in further studies.

This study aimed to identify the public preference in health services, the principles that Iranian people consider important, and the aspects of trade-offs between different values in resource allocation practices.

This quantitative study was conducted to investigate public preferences on Health Insurance Benefit Package (HIBP) in 2017. A structured questionnaire was used for data collection, including the preferences of the people who live in Tehran, were above 18 year, and were covered by basic insurance for the HIBP contents and premium. The sample size was calculated 430 subjects and SPSS Statistics was used for data analyzing.

81.6% of the sample population agreed with government allocating more money to the health sector compared to other sectors and organizations and 55% were willing to pay higher premiums for expanding the HIBP coverage. The highest and lowest score regarding prioritization of budget allocation between health services was related to hospitalization services (28.6%) and rehabilitation services (1.6%), respectively. The first priority of respondents regarding health care and life cycle, was "prevention in newborns" (15.9%), the second priority was "prevention in children" (14.6%), the third priority was "prevention in adults" (9.5%), and the last priority was "short-term care in newborns" (0.9%).

Iranian people believe that not only the principle of health maximization but also equal opportunities to access health care and a fair allocation of resources should be considered by authorities for effective health insurance policymaking. In this case, given the scarcity of resources, setting priorities for alternative resources is inevitable.

The present study aimed to estimate the survival of HIV-positive patients and compare the accuracy of two commonly used models, Shared Random-Effect Model (SREM) and Joint Latent Class Model (JLCM) for the analysis of time to death among these patients.

Data on a retrospective survey among HIV-positive patients diagnosed during 1989-2014 who referred to the Behavioral Diseases Consultation Center of Mashhad University of Medical Sciences was used in this study. Participants consisted of HIV-positive high-risk volunteers, referrals of new HIV cases from prisons, blood transfusion organization and hospitals. Subjects were followed from diagnosis until death or the end of study. SREM and JLCM were used to predict the survival of HIV/AIDS patients. In both models age, sex and addiction were included as covariates. To compare the accuracy of these alternative models, dynamic predictions were calculated at specific time points. The receiver operating characteristic (ROC) curve was used to select the more accurate model.

Overall, 213 patients were eligible that met entry conditions for the present analysis. Based on BIC criteria, three heterogeneous sub-populations of patients were identified by JLCM and individuals were categorized in these classes (“High Risk”, “Moderate Risk” and “Low Risk”) according to their health status. JLCM had a better predictive accuracy than SREM. The average area under ROC curve for JLCM and SREM was 0.75 and 0.64 respectively. In both models CD4 count decreased with time. Based on the result of JLCM, men had higher hazard rate than women and the CD4 counts levels of patients decreased with increasing age.

Predicting risk of death (or survival) is vital for patients care in most medical research. In a heterogeneous population, such as HIV-positive patients fitting JLCM can significantly improve the accuracy of the risk prediction. Therefore, this model is preferred for these populations.

New Delhi metallo-beta-lactamase-1 (NDM-1) is one of the most important emerging antibiotic resistance. Co-harboring three or four carbapenemases is rare and only a few reports exist in the literature. We described the characteristics of the large epidemic outbreaks and reports co-producing blaNDM-1 with the other carbapenemase genes in P. aeruginosa isolates.

This present cross-sectional research was conducted on 369 P. aeruginosa isolates obtained from burn and general hospitals within years 2013 to 2016. Beta-lactamase classes A, B and D genes were identified by PCR method. Modified hodge test (MHT), double-disk potentiation tests (DDPT) and double disk synergy test (DDST) were performed for detection carbapenemase and metallo beta-lactamase (MBL) production of blaNDM-1 positive P. aeruginos isolates.

From 236 carbapenem-resistant P. aeruginosa (CRPA), 116 isolates have had MBL genes and twenty-nine isolates were found positive for blaNDM-1. In CRPA isolates, blaIMP-1, blaVIM-2 and blaOXA-10 were identified in 27.5%, 21.1% and 32.2% of isolates respectively, while co-producing blaNDM-1, blaIMP-1, blaOXA-10, co-producing blaNDM-1, blaVIM-2, blaOXA-10 and co-producing blaIMP-1, blaVIM-2 were determined in 11 (4.6%), 8 (3.4%) and 27 (11.4%) of isolates respectively.

The finding of this co-existence of multiple carbapenemase resistance genes is threating for public health. Dipicolinic acid is a superior MBL inhibitor in DDPT antique than EDTA in DDST method for the detection of MBL-blaNDM-1 producing P. aeruginosa.

Salmonella enteritidis causes infections in humans and animals. Antibiotics are used to eliminate bacterial infections, which become resistant to antibiotics after a while. This study aimed to isolate S. enteritidis from cattle feces samples and also to evaluate the frequency of genes associated with multi-drug resistance (MDR).

One hundred ten fecal samples of cattle were collected from Jul to Dec, 2017 in Khuzestan Province, southern Iran. Bacterial culture and molecular methods were used to isolate and identify S. enteritidis. Disk diffusion method was used to assess antibiotic susceptibility. Then Polymerase chain reaction (PCR), assay was used for definitive diagnosis of S. enteritidis and resistance genes.

Overall, 101 (91.81%) samples were detected to be contaminated with Salmonella genus and 86 samples (85.14%) were identified as S. enteritidis. The highest and lowest antibiotic resistance were belonged to gentamicin (n=70, 81.39%), and tetracycline (n=6, 6.97%). Besides, 64 samples (74.42%) had 2-10 drugs resistance patterns. Moreover, the highest and the least resistance were related to blaIMP-1 (n=73, 84.88%) and tet(B) (n=49, 56.97%) genes respectively.

The drug-induced genes in S. enteritidis have a high frequency. Therefore, antibiotic resistance and high MDR to antibiotics can be due to the incorrect use of antibiotics and the lack of health monitoring in Cattle farms.

Cutaneous Leishmaniasis (CL) is a major health problem in many parts of Iran. Many methods have been introduced for detection and identification of Cutaneous Leishmaniasis. The purpose of this study was isolation and molecular identification of Leishmania spp. agents in patients with CL from endemic region of central Iran. In this study, one of the main loci of central Iran named Yazd will be assessed CL identification using PCR-RFLP.

For this cross-sectional study, sampling was done from 372 suspicious patients with CL who referred to Health Centers of Yazd Province from 2016 to 2017. After collection samples of patients, DNA extraction was done from samples on slides. Genus detection was done using specific primers by PCR. RFLP analysis was done for species identification.

Out of 372 samples, 159 samples were positive using PCR based method. Out of 159 samples, 87 (54.7%) L. major and 72 (45.3%) L. tropica were identified using RFLP analysis. The number of lesions in each patient was different but 119 (74.8%) patients showed the number of 1-3 lesions, and more lesions (more than 10 lesions) was showed in 4 (2.5%) person.

The CL found in Yazd province resulted from L. major and L. tropica as the agents of rural and urban types, respectively. The prevalence of L. major and L. tropica was almost the same. This indicated that control programs could be designed for treatment and vector and reservoir control.

Circumsporozoite protein (CSP) is one of the most important surface sporozoite antigens in malaria, recently considered as a candidate for vaccination. Considering the importance of CSP, this study was conducted to investigate the polymorphism and genetic diversity of Plasmodium vivax Circumsporozoite Protein (Pvcsp) in the southeastern region of Iran during 2015-2016.

To investigate polymorphism and genetic diversity, 20 blood samples were collected from patients with P. vivax, then DNA was extracted and amplified using partial sequence of CSP gene. Polymerase chain reaction (PCR) products were sequenced and compared to sequences from genomic databases using BLAST. Genetic evaluation and phylogenic analysis were performed using MEGA7 and DnaSP5 software’s on 38 sequences include 20 sequences of our study and 18 sequences of Gene Bank.

Eleven isolates were VK210 genotype and 9 isolates contained VK247. The result of variable segregation nucleotide site indicated that the differentiation of sequences in CSP were 25.67% in our 20 samples which are less than the 38 samples with a value of 26.67%. Comparing the ratio of dN/dS regions in the CSP gene indicates that the CSP varies more synonymously and amino acid has lower variation. Out of 38 samples, 35 unique haplotypes were identified based on 1042 nucleotide sequences in CSP, showing a variation percentage of 99.4%.

The Tajima D analyses showed that CSP gene in P. vivax had a positive number in the total analyzed sequences, which means that the P. vivax mutations are in order to select positive evolution.

Congenital hypothyroidism is one of the most common endocrine disrupters and metabolism, and is one of the most important preventable causes of physical and mental disabilities.

Overall, 111 cases were diagnosed with hypothyroidism, which made the prevalence value equal to 2 cases per 1000 births. The prevalence in females and males was 1.9 and 2.2 per 1,000 birth, respectively. The odds ratio for this disorder was 4.47(2.42-9.28) for the neonates with a family history of hypothyroidism and 1.72(1.05-2.82) for those born through cesarean.

The incidence of this disorder is similar in males and females, and the incidence of this disease in people with a family history is far more than others.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness (CSNB) characterized by specific features such as golden-brown discoloration of the fundus called Mizuo-Nakamura phenomenon which is distinguishable by fundoscopy, and retinography. Clinical diagnosis is confirmed through genetic test. Two known genes in pathogenesis of Oguchi disease are SAG and GRK1. A 35-year-old Iranian male exhibiting the clinical features of congenital stationary night blindness, was referred to the genetic clinic of Dr. Farhud, Tehran, Iran in 2012 and examined. Ophthalmic examination including slit-lamp biomicroscopy, perimetry and funduscopy was performed. Additionally, the full-field electroretinography and molecular testing for congenital stationary night blindness were performed. Molecular genetic tests, including the analysis of GSK1 and SAG genes exon-intron boundaries were performed for this patient and his family. According to the sequencing results, we did not find any mutation in GSK1 gene. However, a new homozygote mutation at location chr2:233320735, c.517delC, p.P96LfsX28 was identified in exon four of SAG gene. This deletion causes a frame shift mutation, and premature stop codon that results in deletion of about 281 amino acid residues of S-antigen visual arrestin protein (from entire C-terminal). This mutation was also found in patient’s parents and one of his sister as heterozygote form. This is the first molecular evidence for SAG gene mutation in an Iranian family affected with Oguchi disease type 1. The identification of the new c.517delC, p.P96LfsX28 mutation in this family with Oguchi disease can confirm the pathogenicity of this variant.