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Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome and presents with cytopenias, characteristic physical features, increased chromosomal breaks, and a higher risk of malignancy. Genetic features of this disease vary among different ethnic groups. We aimed to identify the incidence, outcome, overall condition, and genetic features of patients affected with FA in Lebanon to optimize management, identify the most common genes, describe new mutations, and offer prenatal diagnosis and counseling to the affected families. Over a period of 17 years, 40 patients with FA were identified in 2 major diagnostic laboratories in Lebanon. Information was obtained on their clinical course and outcome from their primary physician. DNA was available in 20 patients and was studied for underlying mutations. FANCA seemed to be the most frequent genetic alteration and 2 novel mutations, one each in FANCA and FANCG, were identified. Nine patients developed various malignancies and died. This is the first study looking at clinical and genetic features of FA in Lebanon, and points to the need for establishing a national and regional registry for this condition.
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Proteína del Grupo de Complementación A de la Anemia de Fanconi/genética , Proteína del Grupo de Complementación G de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Adolescente , Adulto , Niño , Preescolar , Anemia de Fanconi/epidemiología , Femenino , Humanos , Líbano/epidemiología , Masculino , Mutación , Adulto JovenRESUMEN
Congenital disorders of glycosylation (CDG) represent an expanding group of conditions that result from defects in protein and lipid glycosylation. Different subgroups of CDG display considerable clinical and genetic heterogeneity due to the highly complex nature of cellular glycosylation. This is further complicated by ethno-geographic differences in the mutational landscape of each of these subgroups. Ten Arab CDG patients from Latifa Hospital in Dubai, United Arab Emirates, were assessed using biochemical (glycosylation status of transferrin) and molecular approaches (next-generation sequencing [NGS] and Sanger sequencing). In silico tools including CADD and PolyPhen-2 were used to predict the functional consequences of uncovered mutations. In our sample of patients, five novel mutations were uncovered in the genes: MPDU1, PMM2, MAN1B1, and RFT1. In total, 9 mutations were harbored by the 10 patients in 7 genes. These are missense and nonsense mutations with deleterious functional consequences. This article integrates a single-center experience within a list of reported CDG mutations in the Arab world, accompanied by full molecular and clinical details pertaining to the studied cases. It also sheds light on potential ethnic differences that were not noted before in regards to CDG in the Arab world.
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Trastornos Congénitos de Glicosilación/genética , Árabes , Niño , Codón sin Sentido , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Mutación Missense , Emiratos Árabes UnidosRESUMEN
The UNC80 gene encodes for a large component of the NALCN sodium-leak channel complex that regulates the basal excitability of the nervous system. In this study, we report on a novel homozygous mutation in UNC80 in a Palestinian-Emirati patient suffering infantile hypotonia with psychomotor retardation and characteristic facies. This mutation was detected by whole exome sequencing and confirmed using Sanger sequencing in the patient-parents trio. Numerous elements in the patient's phenotype were in agreement with the few reported cases of UNC80 mutations; however there are some notable differences. We present comprehensive clinical and molecular accounts of this mutation in addition to a full review of previously reported patients of UNC80 mutations.
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Proteínas Portadoras/genética , Discapacidad Intelectual/genética , Proteínas de la Membrana/genética , Hipotonía Muscular/genética , Mutación/genética , Adolescente , Epilepsia/genética , Facies , Femenino , Homocigoto , Humanos , Hipotonía Muscular/diagnóstico , Linaje , FenotipoRESUMEN
BACKGROUND: Autosomal dominant mental retardation 21 (MRD21) is a very rare condition, characterized by short stature, microcephaly, mild facial dysmorphisms and intellectual disability that ranged from mild to severe. MRD21 is caused by mutations in CCCTC-binding factor (CTCF) and this was established through only four unrelated cases, two of which had frameshift mutations. CTCF is a master transcriptional regulator that controls chromatin structure and may serve as insulator and transcriptional activator and repressor. CASE PRESENTATION: This study presents, clinically and molecularly, an Emirati patient with de novo frameshift mutation in CTCF. This novel mutation was uncovered using whole exome sequencing and was confirmed by Sanger sequencing in the trio. In silico analysis, using SIFT Indel, indicates that this frameshift; p.Lys206Profs*13 is functionally damaging with the likely involvement of nonsense-mediated mRNA decay. CONCLUSIONS: Upon comparing the clinical picture of the herewith-reported individual with previously reported cases of MRD21, there seems to be many common symptoms, and few new ones that were not observed before. This helps to further define this rare condition and its molecular underpinnings.
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Mutación del Sistema de Lectura , Discapacidad Intelectual/genética , Proteínas Represoras/genética , Factor de Unión a CCCTC , Análisis Mutacional de ADN , Femenino , Humanos , Lactante , Discapacidad Intelectual/patología , SíndromeRESUMEN
BACKGROUND: The X-linked condition "Aarskog-Scott syndrome (AAS)" causes a characteristic combination of short stature, facial, genital and skeletal anomalies. Studies elucidated a causative link between AAS and mutations in the FGD1 gene, which encodes a Rho/Rac guanine exchange factor. FGD1 is involved in regulating signaling pathways that control cytoskeleton organization and embryogenesis. CASE PRESENTATION: FGD1 was studied in an Emirati family with two cases of AAS using PCR amplification and direct sequencing of the entire coding region of the gene. Various in silico tools were also used to predict the functional consequences of FGD1 mutations. In the reported family, two brothers harbor a novel hemizygous mutation in FGD1 c.53del (p.Pro18Argfs*106) for which the mother is heterozygous. This frameshift deletion, being close to N-terminus of FGD1, is predicted to shift the reading frame in a way that it translates to 105 erroneous amino acids followed by a premature stop codon at position 106. Full molecular and clinical accounts about the variant are given so as to expand molecular and phenotypical knowledge about this disorder. CONCLUSIONS: A novel variant in FGD1 was found in an Emirati family with two brothers suffering from AAS. The variant is predicted to be a null mutation, and this is the first report of its kind from the United Arab Emirates.
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Secuencia de Bases , Enanismo/genética , Cara/anomalías , Mutación del Sistema de Lectura , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Genitales Masculinos/anomalías , Factores de Intercambio de Guanina Nucleótido/genética , Deformidades Congénitas de la Mano/genética , Cardiopatías Congénitas/genética , Eliminación de Secuencia , Niño , Preescolar , Enanismo/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Marcadores Genéticos , Deformidades Congénitas de la Mano/diagnóstico , Cardiopatías Congénitas/diagnóstico , Humanos , Masculino , Emiratos Árabes UnidosRESUMEN
OBJECTIVE: The aim of this work was to report a case of an Emirati child who presented with developmental delay and multiple congenital abnormalities that are consistent with distal arthrogryposis type 5D. CLINICAL PRESENTATION AND INTERVENTION: The clinical presentation comprised contractures of the shoulders, elbows, and knees in addition to camptodactyly and neck pterygium. The facial dysmorphic features noted include ptosis and microretrognathia. Importantly, left orchidopexy was also observed and corrected surgically. Whole exome sequencing revealed that the patient is homozygous for the novel c.1184+1G>T variant in endothelin-converting enzyme-like 1 (ECEL1). CONCLUSION: This is a case of a novel homozygous splice site mutation in the ECEL1 gene in a child with a phenotype consistent with distal arthrogryposis type 5D. The child was born to consanguineous Emirati parents heterozygous for the novel ECEL1 mutation.
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Anomalías Múltiples/genética , Metaloendopeptidasas/genética , Preescolar , Consanguinidad , Humanos , Masculino , FenotipoRESUMEN
The 6th Pan Arab Human Genetics Conference (PAHGC), "Genetics of Multifactorial Disorders" was organized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in Dubai, United Arab Emirates from 21 to 23 January, 2016. The PAHGCs are held biennially to provide a common platform to bring together regional and international geneticists to share their knowledge and to discuss common issues. Over 800 delegates attended the first 2 days of the conference and these came from various medical and scientific backgrounds. They consisted of geneticists, molecular biologists, medical practitioners, postdoctoral researchers, technical staff (e.g., nurses and lab technicians) and medical students from 35 countries around the world. On the 3rd day, a one-day workshop on "Genetic Counseling" was delivered to 26 participants. The conference focused on four major topics, namely, diabetes, genetics of neurodevelopmental disorders, congenital anomalies and cancer genetics. Personalized medicine was a recurrent theme in most of the research presented at the conference, as was the application of novel molecular findings in clinical settings. This report discusses a summary of the presentations from the meeting.
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Predisposición Genética a la Enfermedad , Genética Médica , Herencia Multifactorial/genética , Asesoramiento Genético , Genoma Humano , Estudio de Asociación del Genoma Completo , Humanos , Investigación Biomédica Traslacional , Emiratos Árabes UnidosRESUMEN
Microcephaly is a rare neurological condition, both in isolation and when it occurs as part of a syndrome. One of the syndromic forms of microcephaly is microcephaly, seizures and developmental delay (MCSZ) (OMIM #613402), a rare autosomal recessive neurodevelopmental disorder with a range of phenotypic severity, and known to be caused by mutations in the polynucleotide kinase 3' phosphatase (PNKP) gene. The PNK protein is a key enzyme involved in the repair of single and double stranded DNA breaks, a process which is particularly important in the nervous system. We describe an Emirati patient who presented with microcephaly, short stature, uncontrollable tonic-clonic seizures, facial dysmorphism, and developmental delay, while at the same time showing evidence of brain atrophy and agenesis of the corpus callosum. We used whole exome sequencing to identify homozygosity for a missense c.1385G > C (p.Arg462Pro) mutation in PNKP in the patient and heterozygosity for this mutation in her consanguineous parents. The Arg 462 residue forms a part of the lid subdomain helix of the P-loop Kinase domain. Although our patient's phenotype resembled that of MCSZ, the short stature and evidence of brain atrophy distinguished it from other classic cases of the condition. The report raises the question of whether to consider this case as an atypical variant of MCSZ or as a novel form of microcephalic primordial dwarfism. © 2016 Wiley Periodicals, Inc.
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Enzimas Reparadoras del ADN/genética , Enanismo/genética , Estudios de Asociación Genética , Microcefalia/genética , Mutación , Fenotipo , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Secuencia de Aminoácidos , Encéfalo/anomalías , Análisis Mutacional de ADN , Enanismo/diagnóstico , Exoma , Facies , Femenino , Gráficos de Crecimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Humanos , Imagen por Resonancia Magnética , Microcefalia/diagnóstico , Mutación Missense , LinajeRESUMEN
The SOX18 gene encodes a transcription factor that plays a notable role in certain developmental contexts such as lymphangiogenesis, hair follicle development and vasculogenesis. SOX18 mutations are linked to recessive and dominant hypotrichosis-lymphedema-telangiectasia syndrome (HLTS). In this study we report on a novel heterozygous mutation in SOX18 in a Jordanian patient suffering from HLTS that was revealed by Whole Exome Sequencing. In this case, a frameshift caused by 14-nucleotide duplication in SOX18 appeared de novo resulting in a premature translational stop at the N-terminal region of the central trans-activation domain. Here we present the clinical manifestations of the above mentioned molecular lesion in the light of what is known from published SOX18 mutations.
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Análisis Mutacional de ADN/métodos , Exoma/genética , Hipotricosis , Linfedema , Mutación , Factores de Transcripción SOXF/genética , Telangiectasia , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Secuencia de Bases , Humanos , Recién Nacido , Jordania , Masculino , Datos de Secuencia Molecular , SíndromeRESUMEN
ECHS1 is a mitochondrial matrix enzyme that catalyzes an important step in the ß-oxidation spiral of fatty acid catabolism, and individuals with mutations in the ECHS1 gene suffer from an autosomal recessive condition typified by delayed psychomotor development, mitochondrial encephalopathy, hypotonia, and cardiomyopathy. Here we report the first Arab case of ECHS1 Deficiency. The patient was born to consanguineous parents with all growth parameters being low for gestational age, and was persistently desaturated. Cord blood gas and later blood analysis showed severe metabolic acidosis. Tandem MS revealed increased levels of valine, and Leucine/Isoleucine and decreased level of Glutamine. There was also a large patent ductus arteriosus with right to left shunt and a possible small muscular ventricular septal defect. Whole Exome Sequencing revealed a novel homozygous missense mutation in the ECHS1 gene; c.842 A > G (p.Glu281Gly). In-silico analysis suggests that the residue affected by this mutation may be involved in an important functional or structural role.
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Acidosis/diagnóstico , Acidosis/genética , Enoil-CoA Hidratasa/genética , Mutación/genética , Índice de Severidad de la Enfermedad , Secuencia de Aminoácidos , Femenino , Humanos , Recién Nacido , Emiratos Árabes UnidosRESUMEN
OBJECTIVE: The aim of this study was to report clinical and molecular findings in an Emirati child with Marinesco-Sjögren syndrome born to consanguineous parents. CLINICAL PRESENTATION AND INTERVENTION: The child presented with developmental delay, ataxia, bilateral cataracts, and dysmorphic craniofacial features, along with cerebellar atrophy. Sequencing of the SIL1 gene revealed a novel homozygous large indel mutation that was predicted to abrogate part of the 5' untranslated region (UTR) and the first 30 amino acids of the protein. CONCLUSION: This was a case of mutation in SIL1 that affected the 5' UTR, translation initiation site and the endoplasmic reticulum-targeting signal sequence. Further studies will be needed on the functional delineation of the mutation.
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Mutación/genética , Degeneraciones Espinocerebelosas/genética , Regiones no Traducidas 5'/genética , Encéfalo/patología , Niño , Consanguinidad , Humanos , Masculino , Reacción en Cadena de la Polimerasa , Análisis de Secuencia , Emiratos Árabes UnidosRESUMEN
The joint 5th Pan Arab Human Genetics conference and 2013 Golden Helix Symposium, "Genomics into Healthcare" was coorganized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in collaboration with the Golden Helix Foundation (http://www.goldenhelix.org) in Dubai, United Arab Emirates from 17 to 19 November, 2013. The meeting was attended by over 900 participants, doctors and biomedical students from over 50 countries and was organized into a series of nine themed sessions that covered cancer genomics and epigenetics, genomic and epigenetic studies, genomics of blood and metabolic disorders, cytogenetic diagnosis and molecular profiling, next-generation sequencing, consanguinity and hereditary diseases, clinical genomics, clinical applications of pharmacogenomics, and genomics in public health.
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Atención a la Salud , Epigénesis Genética , Genética Médica , Genómica , Citogenética , Bases de Datos Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Emiratos Árabes UnidosRESUMEN
Precision in personalized medicine is a crucial subject that needs comprehensive discussion and scientific validation. Traditional healthcare approaches like the Ayurvedic Sciences are often contextually linked with personalized medicine. However, it is unfortunate that this knowledge concerning Ayurveda and personalized medicine is restricted to applying systems biology techniques to 'prakriti' the phenotypic expression and characterization detailed in the literature. There are other significant constructs besides prakruti that interest an Ayurvedic physician, which accounts for crafting precision in evidence-based medicinal practices. There is this influential model of Ayurvedic healthcare practice wherein the physician maps specific personalized characters in addition to prakruti to deduce the host responses to endogenous and exposome conditions. Subsequently, tailored protocols are administered that bring about holistic, personalized outcomes. The review aimed to determine the effective methods for integrating Systems Biology, Ayurvedic Sciences, and Personalized Medicine (precision medicinebased). Ayurveda adopts a holistic approach, considering multiple variables and their interconnections, while the modern reductionist approach focuses on understanding complex details of smaller parts through rigorous experimentation. Despite seeming extremes, ongoing research on lifestyle, gut health, and spiritual well-being highlights the evolving intersection between traditional Ayurvedic practices and modern science. The current focus is on developing the fundamental concept of Ayurveda Biology by incorporating Systems Biology techniques. Challenges in this integration include understanding diverse data types, bridging interdisciplinary knowledge gaps, and addressing technological limitations and ethical concerns. Overcoming these challenges will require interdisciplinary collaboration, innovative methodologies, substantial investment in technology, and cultural sensitivity to preserve Ayurveda's core principles while leveraging modern scientific advancements. The focus of discussions and debates on such collaborations should be breakthrough clinical models, such as chronic inflammation, which can be objectively related to specific stages of disease manifestations described in Ayurveda. Validating patient characteristics with systems biology approaches, particularly in shared pathologies like chronic inflammation, is crucial for bringing prediction and precision to personalized medicine.
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Like many other Arab countries, the United Arab Emirates (UAE) has a relatively high prevalence of genetic disorders. Here we present the first review and analysis of all genetic disorders and gene variants reported in Emirati nationals and hosted on the Catalogue for Transmission Genetics in Arabs (CTGA), an open-access database hosting bibliographic data on human gene variants associated with inherited or heritable phenotypes in Arabs. To date, CTGA hosts 665 distinct genetic conditions that have been described in Emiratis, 621 of which follow a clear Mendelian inheritance. Strikingly, over half of these are extremely rare according to global prevalence rates, predominantly with an autosomal recessive mode of inheritance. This is likely due to the relatively high consanguinity rates within the Emirati population. The 665 conditions include disorders that are unique to the Emirati population, as well as clearly monogenic disorders that have not yet been mapped to a causal genetic locus. We also describe 1,365 gene variants reported in Emiratis, most of which are substitutions and over half are classified as likely pathogenic or pathogenic. Of these, 235 had not been reported on the international databases dbSNP and Clinvar, as of December 2022. Further analysis of this Emirati variant dataset allows a comparison of clinical significance as reported by Clinvar and CTGA, where the latter is derived from the study cited. A total of 307 pathogenic/likely pathogenic variants from CTGA's Emirati dataset, were classified as benign, variants of uncertain significance, or were missing a clinical significance or had not been reported by Clinvar. In conclusion, we present here the spectrum of genetic disorders and gene variants reported in Emiratis. This review emphasizes the importance of ethnic databases such as CTGA in addressing the underrepresentation of Arab variant data in international databases and documenting population-specific discrepancies in variant interpretation, reiterating the value of such repositories for clinicians and researchers, especially when dealing with rare disorders.
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Anomalías Múltiples/diagnóstico por imagen , Anomalías Múltiples/genética , Cerebelo/anomalías , Anomalías del Ojo/diagnóstico por imagen , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/diagnóstico por imagen , Enfermedades Renales Quísticas/genética , Proteínas de la Membrana/genética , Sitios de Empalme de ARN , Retina/anomalías , Cerebelo/diagnóstico por imagen , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Mutación , Retina/diagnóstico por imagen , Emiratos Árabes UnidosRESUMEN
The current COVID-19 pandemic brought about by the SARS-CoV-2, a novel ß coronavirus is creating intense health havoc globally. Researchers suspect the situation to stay for long in the community, considering this virus's pathogenesis, high rate transmission and tendency to provoke uncontrolled immune response activation. Immune mechanisms are highly individualistic. We put forward a hypothetical model of prakruti (Ayurvedic body phenotyping character) based personalized prophylactic-therapeutic strategies aiming at a better immunomodulation and quicker resolution of host immune mechanisms. We propose this model in symptomatic, mild to moderate, COVID-19 diagnosed cases and in cases quarantined for high to low risk primary contact with a positive case. We also suggest a community level personalized Ayurvedic prophylactic-therapeutic strategy based on the DOTS model. Person-centered body purificatory measures (panchakarma procedures) like therapeutic purgation (virechana) and medicated enema (basti) are suggested in this hypothetical protocol with justification on evidence-based links between immune responses and prakruti along with specific jwara (fevers of varied origin as per Ayurvedic sciences) and COVID-19 symptomatology. The paper also appraises the importance of pitta dosha/ama dosha in the manifestation of inflammation driven destructive phase of immune responses along with its stage-wise intervention. This hypothetical model intends to open up discussions on significance of prakruti assessment as a predictive marker to screen people who are at risk of succumbing into deteriorating states if infected with COVID-19. It also intends to discuss the predictive personalized medicine measures based on prakruti in yielding individual host immune homeostasis which may positively reduce the chances of untoward events of an aggravated immune responsiveness and subsequent inflammation driven tissue destruction - the candidate causes for COVID-19 related casualties. Testing this model may give insight towards emphasizing personalized host immune coping mechanisms that may prove crucial in any infectious outbreaks in near future too.
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A 62 year old woman diagnosed with Ménière's disease, who underwent vairechanika nasya (VN) with shadbindu taila presented with short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) like phenomena immediately after the procedure. Rescue measures of abhyanga (local oil massage) and nadi sweda (local fomentation) were administered. Within half an hour the symptoms considerably declined and after 1 hour got completely relieved. The exact symptom disclosure by the patient who herself was a doctor helped in detecting the classic pattern of 'saw tooth phenomena' giving leads into a rare manifestation of probable SUNCT. Naranjo scale yielded zero score and thus the probable causality of VN with shadbindu taila could not be established so as to cause probable SUNCT as an adverse drug reaction (ADR). This case study is not put up for reporting an ADR of VN with shadbindu taila; rather this illustrates an uncommon, yet imperative adverse event of probable SUNCT while undergoing nasya procedure probably due to judgment error while fixing the VN dose in a patient with Ménière's disease. Transparent reporting of such unusual events during panchakarma procedures is necessary so that clinicians can understand, evaluate and take appropriate initiatives to manage them.
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Lebanon has a high annual incidence of birth defects at 63 per 1000 live births, most of which are due to genetic factors. The Catalogue for Transmission Genetics in Arabs (CTGA) database, currently holds data on 642 genetic diseases and 676 related genes, described in Lebanese subjects. A subset of disorders (14/642) has exclusively been described in the Lebanese population, while 24 have only been reported in CTGA and not on OMIM. An analysis of all disorders highlights a preponderance of congenital malformations, deformations and chromosomal abnormalities and demonstrates that 65% of reported disorders follow an autosomal recessive inheritance pattern. In addition, our analysis reveals that at least 58 known genetic disorders were first mapped in Lebanese families. CTGA also hosts 1316 variant records described in Lebanese subjects, 150 of which were not reported on ClinVar or dbSNP. Most variants involved substitutions, followed by deletions, duplications, as well as in-del and insertion variants. This review of genetic data from the CTGA database highlights the need for screening programs, and is, to the best of our knowledge, the most comprehensive report on the status of genetic disorders in Lebanon to date.
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Árabes , Bases de Datos Genéticas , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/epidemiología , Humanos , Líbano/epidemiologíaRESUMEN
BACKGROUND: There is limited understanding on the impact of the multidose medication packaging service (MDMPS). OBJECTIVES: The main objective of this study was to evaluate changes in medication adherence in patients using MDMPS compared to patients receiving standard medication packaging (control group). The other objectives were to determine the association between medication adherence and clinical outcomes, and to assess patients'/caregivers' perceptions toward MDMPS. METHODS: A retrospective cohort study was conducted among primary care patients in Singapore enrolled into MDMPS between 2012 and 2017. Eligible patients were taking at least five chronic medications, diagnosed with Hypertension, Hyperlipidemia and/or Type 2 Diabetes, with prescription records for at least six months before and after the index period. They were matched to control patients based on the type of comorbidities and medication adherence status. Medication Possession Ratio (MPR), glycated hemoglobin (HbA1c), blood pressure and low-density lipoprotein-cholesterol (LDL-C) of both groups were compared between baseline and at least six months post-index period. Interviewer-administered questionnaires were also conducted for MDMPS patients. RESULTS: The MPR of MDMPS patients (n = 100) increased by 0.37% (P < .001) compared to the control group (n = 100). MDMPS patients with diabetes had reduced HbA1c by 0.1% after six months (P = .022) but was not significant after 12 months. No significant changes were seen in blood pressure and LDL-C between both groups. At least 50% of patients were highly satisfied with MDMPS. CONCLUSION: MDMPS can improve medication adherence. Further studies are needed to understand its clinical impact.