Digenic inheritance in autosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: Assessment of GJB4, GJA1, and GJC3

Objective: Autosomal recessive non-syndromic hearing loss (ARNSHL) can be caused by many genes. However, mutations in the GJB2 gene, which encodes the gap-junction (GJ) protein connexin (Cx) 26, constitute a considerable proportion differing among population. Between 10 and 42 percent of patients with recessive GJB2 mutations carry only one mutant allele. Mutations in GJB4, GJA1, and GJC3 encoding Cx30.3, Cx43, and Cx29, respectively, can lead to HL Combination of different connexins in heteromeric and heterotypic GJ assemblies is possible. This study aims to determine whether variations in any of the genes GJB4, GJA1 or GJC3 can be the second mutant allele causing the disease in the digenic mode of inheritance in the studied GJB2 heterozygous cases. Methods: We examined 34 unrelated GJB2 heterozygous ARNSHL subjects from different geographic and ethnic areas in Iran, using polymerase chain reaction (PCR) followed by direct DNA sequencing to identify any sequence variations in these genes. Restriction fragment length polymorphism (RFLP) assays were performed on 400 normal hearing individuals. Results: Sequence analysis of GJB4 showed five heterozygous variations including cA51C>A, c.219C>T, c.507C>G, c.155_158delTCTG and c.542C>T, with only the latter variation not being detected in any of control samples. There were three heterozygous variations including c.758C>T, c.717G>A and c.3*dupA in GJA1 in four cases. We found no variations in GJC3 gene sequence. Conclusion: Our data suggest that GJB4 c.542C>T variant and less likely some variations of GJB4 and GJA1, but not possibly GJC3, can be assigned to ARNSHL in GJB2 heterozygous mutation carriers providing clues of the digenic pattern. (C) 2012 Elsevier Ireland Ltd. All rights reserved

The Trend of Prescribing Ceftriaxone Injection in the Medical Prescriptions of the Social Security Organization-insured Persons in Kerman during 2006- 2012

Background: Rational drug usage is a main priority in health research, and controlling prescribing Ceftriaxone injection due to its fatal adverse effects is a crucial challenge in Iran. The aim of this study was to assess the trend of prescribing Ceftriaxone injections in the medical prescriptions of the Social Security Organization-insured persons in Kerman during 2006- 2012. Methods: In this Cross-sectional study, using descriptive data mining all data about prescribing the three types of Ceftriaxone injection that were prescribed by the physicians and dentists and dispensed in Kerman pharmacies during 78 months (December 22, 2005 to June 20, 2012), obtained from The Comprehensive Medical Documentation System, in the Medical Documents Audit Office of Social Security Organization in Kerman was extracted by census sampling. Then, the prescribing rate of Ceftriaxone injection (defined daily dose) was analyzed and compared in different groups. Results: About 17 million prescriptions from 3621 physicians and dentists (aged 28-91 years) with male/female ratio as 1.7 were analyzed. About 300 thousands of prescriptions (1.75%) contained Ceftriaxone. The average number of monthly prescriptions; count of monthly prescriptions with the drug; and the ratio of prescribing Ceftriaxone in all prescriptions were significantly different between general practitioners and specialists/sub-specialists (P<0.001). The trend of Ceftriaxone prescribing has slightly decreased during 6.5 years. Conclusion: The studies on drug prescribing in Iran show the inappropriate patterns of drug prescribing and use, and also low adherence to the prescribed medications; therefore, serious interventions should be performed by the responsible organizations to control this challeng

Mutation screening of GJB2 and GJB6 and genetic linkage study of three prevalent DFNB loci in Iranian families with autosomal recessive non-syndromic hearing loss

Background and aim: The incidence of prelingual hearing loss (HL) is about 1 in 1000 neonates of which, more than 60% of cases are inherited. Non-syndromic HL (NSHL) is extremely heterogeneous: more than 100 loci have been identified. The most common form of NSHL is the autosomal recessive form (ARNSHL). Here, we have investigated CX26 (GJB2) and CX30 (GJB6) gene mutation and linkage analysis of 3 known loci in Iranian families. Methods: A cohort of 36 big ARNSHL pedigrees from 7 provinces of Iran was investigated. All of the families were examined for the presence of GJB2 and GJB6 (del D13S1830 and del D13S1854) mutations using direct sequencing and multiplex PCR, respectively. The negative mutations pedigrees for the above- mentioned mutations, were then tested for the linkage to the 3 known loci, including DFNB3(MYO7A), DFNB4(SLC26A4) and DFNB7/11(TMC1), using STR markers and conventional PCR and PAGE. Results: Six families had GJB2 mutations. No GJB6 mutation was found. Totally, 3 families showed linkage to DFNB4 and 1 family was linked to DFNB7/11. Conclusion: DFNB1 (GJB2) and DFNB4 are the main causes of ARNSHL in our study samples and GJB6 mutations are apparently absent in the Iranian populatio

Genetic Linkage Analysis of 15 DFNB Loci in a Group of Iranian Families with Autosomal Recessive Hearing Loss

Background: Hearing loss (HL) is the most frequent sensory birth defect in humans. Autosomal recessive non-syndromic HL (ARNSHL) is the most common type of hereditary HL. It is extremely heterogeneous and over 70 loci (known as DFNB) have been identified. This study was launched to determine the relative contribution of more frequent loci in a cohort of ARNSHL families. Methods: Thirty-seven Iranian families including 36 ARNSHL families and 1 family with Pendred syndrome each with >= 4 affected individuals, from seven provinces of Iran, were ascertained. DFNB1 contribution was initially studied by DNA sequencing of GJB2 and linkage analysis using the relative STR markers. The excluded families were then subjected to homozygosity mapping for fifteen ARNSHL loci. Results: Sixteen families were found to be linked to seven different known loci, including DFNB I (6 families), DFNB4 (3 families +1 family with Pendred syndrome), DFNB63 (2 families), DFNB2 (1 family), DFNB7/11 (1 family), DFNB9 (1 family) and DFNB21 (1 family). DNA sequencing of the corresponding genes is in progress to identify the pathogenic mutations. Conclusion: The genetic causes were clarified in 43.2% of the studied families, giving an overview of the causes of ARNSHL in Iran. DFNB4 is ranked second after DFNB1 in the studied cohort. More genetic and epigenetic investigations will have to be done to reveal the causes in the remaining families

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin

Burden of tracheal, bronchus, and lung cancer in North Africa and Middle East countries, 1990 to 2019: Results from the GBD study 2019

ObjectiveTo provide estimates on the regional and national burden of tracheal, bronchus, and lung (TBL) cancer and its attributable risk factors from 1990 to 2019 in the North Africa and Middle East (NAME) region.Methods and materialsThe Global Burden of Disease (GBD) 2019 data were used. Disability-adjusted life years (DALYs), death, incidence, and prevalence rates were categorized by sex and age groups in the NAME region, in 21 countries, from 1990 to 2019. Decomposition analysis was performed to calculate the proportion of responsible factors in the emergence of new cases. Data are presented as point estimates with their 95% uncertainty intervals (UIs).ResultsIn the NAME region, TBL cancer caused 15,396 and 57,114 deaths in women and men, respectively, in 2019. The age-standardized incidence rate (ASIR) increased by 0.7% (95% UI -20.6 to 24.1) and reached 16.8 per 100,000 (14.9 to 19.0) in 2019. All the age-standardized indices had a decreasing trend in men and an increasing trend in women from 1990 to 2019. Turkey (34.9 per 100,000 [27.6 to 43.5]) and Sudan (8.0 per 100,000 [5.2 to 12.5]) had the highest and lowest age-standardized prevalence rates (ASPRs) in 2019, respectively. The highest and lowest absolute slopes of change in ASPR, from 1990 to 2019, were seen in Bahrain (-50.0% (-63.6 to -31.7)) and the United Arab Emirates (-1.2% (-34.1 to 53.8)), respectively. The number of deaths attributable to risk factors was 58,816 (51,709 to 67,323) in 2019 and increased by 136.5%. Decomposition analysis showed that population growth and age structure change positively contributed to new incident cases. More than 80% of DALYs could be decreased by controlling risk factors, particularly tobacco use.ConclusionThe incidence, prevalence, and DALY rates of TBL cancer increased, and the death rate remained unchanged from 1990 to 2019. All the indices and contribution of risk factors decreased in men but increased in women. Tobacco is still the leading risk factor. Early diagnosis and tobacco cessation policies should be improved

The effect of registry-based performance feedback via short text messages and traditional postal letters on prescribing parenteral steroids by general practitioners--A randomized controlled trial

It is conjectured that providing feedback on physicians' prescribing behavior improves quality of drug prescriptions. However, the effectiveness of feedback provision and mode of feedback delivery is not well understood. The objective of this study was to assess and compare the effect of traditional paper letters (TPL) and short text message (STM) feedback on general practitioners' prescribing behavior of parenteral steroids (PSs). In a single-blind randomized controlled trial, 906 general practitioners (GPs) having at least 10 monthly prescriptions were randomly recruited into two interventions and one control study arms with 1:1 allocation, stratified by percentage of prescriptions. The intervention was the provision of 3 feedback messages containing prescribing indices in TPL and STM (in the first two arms) versus the control arm (CG) with an interval of 3 months between these messages. We calculated the PS Defined Daily Dose (DDD) for every GP, every month, and compared between the 3 arms, before and after the interventions. The expected primary outcome was to reduce prescription of parenteral steroids by participants. The study was performed in the Kerman Social Security Organization in Iran. A total of 906 GPs were selected for the trial, but only 721 of them (TPL=191, STM=228, CG=302) were recruited for the 1st feedback. The mean age of GPs was 44 and 59% of them were male. The prescribed parenteral steroid DDDs at baseline were similar (TPL=121.62, STM=127.49, CG=115.68, P>0.5). At the end of the study, DDDs in the TPL and STM arms were similar (TPL=104.38, STM=101.90, P>0.9) but DDDs in each intervention arm was statistically significantly lower than in CG (CG=156.17, P <0.0001). Being in TPL and STM arms resulted in 36.1 and 41.7 units of decrease in DDD respectively, compared to the control arm (P <0.02 and P <0.005) after the one-year duration of the study. Feedback by TPLs and STMs on prescribing performance effectively reduced prescribing PSs by GPs. STM, being a cheap and fast tool, is potentially powerful and efficient for drug prescription rationalizatio