| 1. |
- Saadi, Saadia Maryam, et al.
(author)
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Genetic Investigation of Consanguineous Pakistani Families Segregating Rare Spinocerebellar Disorders
- 2023
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In: Genes. - : MDPI AG. - 2073-4425. ; 14:7
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Journal article (peer-reviewed)abstract
- Spinocerebellar disorders are a vast group of rare neurogenetic conditions, generally characterized by overlapping clinical symptoms including progressive cerebellar ataxia, spastic paraparesis, cognitive deficiencies, skeletal/muscular and ocular abnormalities. The objective of the present study is to identify the underlying genetic causes of the rare spinocerebellar disorders in the Pakistani population. Herein, nine consanguineous families presenting different spinocerebellar phenotypes have been investigated using whole exome sequencing. Sanger sequencing was performed for segregation analysis in all the available individuals of each family. The molecular analysis of these families identified six novel pathogenic/likely pathogenic variants; ZFYVE26: c.1093del, SACS: c.1201C>T, BICD2: c.2156A>T, ALS2: c.2171-3T>G, ALS2: c.3145T>A, and B4GALNT1: c.334_335dup, and three already reported pathogenic variants; FA2H: c.159_176del, APTX: c.689T>G, and SETX: c.5308_5311del. The clinical features of all patients in each family are concurrent with the already reported cases. Hence, the current study expands the mutation spectrum of rare spinocerebellar disorders and implies the usefulness of next-generation sequencing in combination with clinical investigation for better diagnosis of these overlapping phenotypes.
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| 4. |
- Khatri, C, et al.
(author)
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Outcomes after perioperative SARS-CoV-2 infection in patients with proximal femoral fractures: an international cohort study
- 2021
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In: BMJ open. - : BMJ. - 2044-6055. ; 11:11, s. e050830-
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Journal article (peer-reviewed)abstract
- Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.SettingProspective, international, multicentre, observational cohort study.ParticipantsPatients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.ResultsThis study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p<0.001), age >80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).ConclusionsPatients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration numberNCT04323644
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| 5. |
- Klar, Joakim, 1974-, et al.
(author)
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A missense variant in ITPR1 provides evidence for autosomal recessive SCA29 with asymptomatic cerebellar hypoplasia in carriers.
- 2017
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In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 25:7, s. 848-853
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Journal article (peer-reviewed)abstract
- Spinocerebellar ataxias (SCA) comprise a heterogeneous group of inherited neurological disorders characterized by a range of symptoms from both cerebellar and extra cerebellar structures. We investigated the cause of autosomal recessive, congenital SCA in six affected family members from a large consanguineous family. Using whole-exome sequencing, we identified a homozygous ITPR1 missense variant [c.5360T>C; p.(L1787P)] segregating in all affected individuals. Heterozygous carriers were asymptomatic despite cerebellar hypoplasia. Variants in the ITPTR1 gene have previously been associated exclusively with autosomal dominant SCA15 and SCA29 with slow or no progression. The L1787 residue is highly conserved and the leucine to proline substitution has a predicted destabilizing effect on the protein structure. Additionally, the L1787P variant is located in a domain separated from previously described and dominant-acting missense variants consistent with a distinct effect on IP3R1 tetramer structure and function. Taken together, we show for the first time that a biallelic ITPR1 missense variant may cause an autosomal recessive and infantile onset SCA29, albeit with subclinical cerebellar hypoplasia in carriers. Our findings add to the genetic complexity of SCA29 and broaden the correlations between ITPR1 variants and their clinical expression.
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| 6. |
- Mahmood, Zafar, et al.
(author)
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MHD mixed convective stagnation point flow of nanofluid past a permeable stretching sheet with nanoparticles aggregation and thermal stratification
- 2022
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In: Scientific Reports. - : Springer Nature. - 2045-2322. ; 12
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Journal article (peer-reviewed)abstract
- Using a thermally stratified water-based nanofluid and a permeable stretching sheet as a simulation environment, this research examines the impact of nanoparticle aggregation on MHD mixed convective stagnation point flow. Nanoparticle aggregation is studied using two modified models: the Krieger–Dougherty and the Maxwell–Bruggeman. The present problem's governing equations were transformed into a solvable mathematical model utilizing legitimate similarity transformations, and numerical solutions were then achieved using shooting with Runge–Kutta Fehlberg (RKF) technique in Mathematica. Equilibrium point flow toward permeable stretching surface is important for the extrusion process because it produces required heat and mass transfer patterns and identifies and clarifies fragmented flow phenomena using diagrams. Nanoparticle volume fraction was shown to have an impact on the solutions' existence range, as well. Alumina and copper nanofluids have better heat transfer properties than regular fluids. The skin friction coefficients and Nusselt number, velocity, temperature profiles for many values of the different parameters were obtained. In addition, the solutions were shown in graphs and tables, and they were explained in detail. A comparison of the current study's results with previous results for a specific instance is undertaken to verify the findings, and excellent agreement between them is observed.
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| 7. |
- Zafar, Waqar Ali, et al.
(author)
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Time series subsidence evaluation using NSBAS InSAR: a case study of twin megacities (Rawalpindi and Islamabad) in Pakistan
- 2024
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In: Frontiers in Earth Science. - : Frontiers Media SA. - 2296-6463. ; 12
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Journal article (peer-reviewed)abstract
- Ground deformation associated with natural and anthropogenic activities can be damaging for infrastructure and can cause enormous economic loss, particularly in developing countries which lack measuring instruments. Remote sensing techniques like interferometric synthetic aperture radar (InSAR) can thus play an important role in investigating deformation and mitigating geohazards. Rawalpindi and Islamabad are twin cities in Pakistan with a population of approximately 5.4 million, along with important government and private entities of national and international interest. In this study, we evaluate rapid paced subsidence in this area using a modified small baseline subset technique with Sentinel-1A imagery acquired between 2015 and 2022. Our results show that approximately 50 mm/year subsidence occurs in the older city of Rawalpindi, the most populated zone. We observed that subsidence in the area is controlled by the buried splays of the Main Boundary Thrust, one of the most destructive active faults in the recent past. We suggest that such rapid subsidence is most probably due to aggressive subsurface water extraction. It has been found that, despite provision of alternate water supplies by the district government, a very alarming number of tube wells are being operated in the area to extract ground water. Over 2017–2021, field data showed that near-surface aquifers up to 50–60 m deep are exhausted, and most of the tube wells are currently extracting water from depths of approximately 150–160 m. The dropping water level is proportional to the increasing number of tube wells. Lying downstream of tributaries originating from the Margalla and Murree hills, this area has a good monsoon season, and its topography supports recharge of the aquifers. However, rapid subsidence indicates a deficit between water extraction and recharge, partly due to the limitations inherent in shale and the low porosity near the surface lithology exposed in the area. Other factors amplifying the impacts are fast urbanization, uncontrolled population growth, and non-cultivation of precipitation in the area.
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| 8. |
- Zulfiqar, Shumaila, et al.
(author)
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Identification of a novel variant in GPR56/ADGRG1 gene through whole exome sequencing in a consanguineous Pakistani family
- 2021
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In: Journal of clinical neuroscience. - : Elsevier. - 0967-5868 .- 1532-2653. ; 94, s. 8-12
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Journal article (peer-reviewed)abstract
- GPR56 gene is best known for its pivotal role in cerebral cortical development. Mutations in GPR56 give rise to cobblestone-like brain malformation, white matter changes and cerebellar dysplasia. This study aimed to identify causative variant in a consanguineous family having five individuals affected with developmental delay, mild to severe intellectual disability, speech impairment, strabismus and seizures. Whole exome sequencing was performed to identify mutation in affected individuals. Variants were filtered and further validated by Sanger sequencing and segregation analysis. A novel frameshift variant c.1601dupT leading to p.Ala535GlyfsTer17) was identified in GPR56 gene by whole exome sequencing and subsequent filtering. All five affected individuals were homozygous for the mutant allele while four asymptomatic individuals carried the variant in heterozygous state. Radiological findings of a representative patient presented features of GPR56-associated cobblestone like brain malformation. MRI findings suggested paucity of sulci, dilated ventricular system and brainstem atrophy. The microgyria were observed in a simplified gyral pattern (cobblestone). This single bp insertion, and the consequent frame-shift, results in the truncation of GPR56 protein. This could result in a malformed cortex giving the brain a cobblestone like shape. Our study identified a 7th novel frameshift variant from Pakistani population in GPR56 gene, thus broadening mutation spectrum.
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| 9. |
- Zulfiqar, Shumaila, et al.
(author)
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Whole exome sequencing identifies novel variant underlying hereditary spastic paraplegia in consanguineous Pakistani families
- 2019
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In: Journal of clinical neuroscience. - : Elsevier BV. - 0967-5868 .- 1532-2653. ; 67, s. 19-23
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Journal article (peer-reviewed)abstract
- Hereditary Spastic paraplegias (HSPs) are heterogeneous group of degenerative disorders characterized by progressive weakness and spasticity of the lower limbs, combined with additional neurological features. This study aimed to identify causative gene variants in two nonrelated consanguineous Pakistani families segregating HSP. Whole exome sequencing (WES) was performed on a total of five individuals from two families including four affected and one phenotypically normal individual. The variants were validated by Sanger sequencing and segregation analysis. In family A, a novel homozygous variant c.604G > A (p.Glu202Lys) was identified in the CYP2U1 gene with clinical symptoms of SPG56 in 3 siblings. Whereas, a previously reported variant c.5769delT (p.Ser1923Argfs*28) in the SPG11 gene was identified in family B manifesting clinical features of SPG11 in 3 affected individuals. Our combined findings add to the clinical and genetic variability associated with CYP2U1 and SPG11 variants highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.
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| 10. |
- Bravo, L, et al.
(author)
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- 2021
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| 11. |
- Tabiri, S, et al.
(author)
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- 2021
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