Exome sequencing identifies homozygous variants in MBOAT7 associated with neurodevelopmental disorder.

Intellectual disability (ID) is a large group of neurodevelopmental disorders characterized by a congenital limitation in intellectual functioning (reasoning, learning, and problem solving), adaptive behavior (conceptual, social, and practical skills), originated at birth and manifested before the age of 18. By whole exome sequencing of five consanguineous Pakistani families presenting hallmark features of ID, global developmental delay, aggressive and self-injurious behaviors, microcephaly, febrile seizures and facial dysmorphic features, we identified three novel homozygous missense variants (NM_024298.5: c.588G > T; p.Trp196Cys, c.736 T > C; p.Tyr246His and c.524A > C; p. Asp175Ala) and one rare homozygous in-frame deletion variant (c.758_778del;p.Glu253_Ala259del) in membrane-bound O-acyltransferase family member 7 (MBOAT7) gene previously associated with autosomal recessive neurodevelopmental disorder. The segregation of the variants was validated by Sanger sequencing in all family members. In silico homology modeling of wild-type and mutated proteins revealed substantial changes in the structure of both proteins, indicating a possible effect on function. The identification and validation of new pathogenic MBOAT7 variants in five cases of autosomal recessive ID further highlight the importance of this genes in proper brain function and development.

Orbital Lesions: A bird's eye view of series of 2068 cases in 27 years in a tertiary care hospital in Pakistan.

Objective: To determine the relative frequency of orbital lesions based on the site of origin and histopathology at a Tertiary care hospital (Mayo Hospital, Lahore Pakistan) from 1996 till 2022 (27 years). Methods: This descriptive case series included 2651 patients of all age groups presenting with orbital lesions who initially got enrolled at Institute of Ophthalmology Mayo Hospital, Lahore from 1996 till 2022. Of these, 583 patients left against medical advice. So, clinical data of 2068 patients were completely analyzed. Lesions were managed medically and/ or surgically. Final clinical diagnosis, with the help of histopathology, was used to classify the lesions. Results: There were 1258 (60.9%) adults and 810 (39.1%) children, 1358 (65.66%) were neoplastic while 710 (34.33%) non-neoplastic lesions. Amongst the neoplastic lesions, 405 (29.8 %) were benign and 953 (70.2%) malignant. Primary orbital lesions were 1676 (81.04%), Secondary orbital lesions were 300 (14.51%), Endocrine/ hematopoietic reticulo-endothelial system lesions were 84 (4.06%) and Metastatic lesions from distant organs were 08 (0.39%). Conclusion: Retinoblastoma, rhabdomyosarcoma, optic nerve gliomata were common in children. Pleomorphic adenoma & adenocystic carcinoma of lacrimal gland, cavernous hemangioma, optic nerve meningioma, neurofibroma, schwannoma, squamous cell carcinoma of eyelid, carcinoma of maxillary antrum and lymphomas were more common in adults.

Tunable metalensing based on plasmonic resonators embedded on thermosresponsive hydrogel.

Metalenses of adjustable power and ultrathin flat zoom lens system have emerged as a promising and key photonic device for integrated optics and advanced reconfigurable optical systems. Nevertheless, realizing an active metasurface retaining lensing functionality in the visible frequency regime has not been fully explored to design reconfigurable optical devices. Here, we present a focal tunable metalens and intensity tunable metalens in the visible frequency regime through the control of the hydrophilic and hydrophobic behavior of freestanding thermoresponsive hydrogel. The metasurface is comprised of plasmonic resonators embedded on the top of hydrogel which serves as dynamically reconfigurable metalens. It is shown that the focal length can be continuously tuned by adjusting the phase transition of hydrogel, the results reveal that the device is diffraction limited in different states of hydrogel. In addition, the versatility of hydrogel-based metasurfaces is further explored to design intensity tunable metalens, that can dynamically tailor the transmission intensity and confined it into the same focal spot under different states, i.e., swollen and collapsed. It is anticipated that the non-toxicity and biocompatibility make the hydrogel-based active metasurfaces suitable for active plasmonic devices with ubiquitous roles in biomedical imaging, sensing, and encryption systems.

Rainwater harvesting for agriculture development using multi-influence factor and fuzzy overlay techniques.

Rainwater harvesting (RWH) is an essential technique for enhancing agricultural development, particularly in regions facing water scarcity or unreliable rainfall patterns. Water shortage, however, is one of the key causes of low crop production especially in mountainous regions like the Khyber Pakhtunkhwa province where most rainwater is lost by runoff. Therefore, rainwater harvesting could be a suitable to make better use of runoff and increase crop production. The study focuses on selecting suitable rainwater harvesting sites in District Karak to enhance agriculture by utilizing multi-influence factor (MIF) and fuzzy overlay techniques. We considered seven factors, i.e., land use land cover (LULC), slope, geology, soil, rainfall, lineament, drainage density, to create a ranking system to understand its application in site selection analysis. The results were combined into one overlay process to produce a rainwater harvesting suitability map. The weighted overlay analysis of the MIF model results reveals that 167.96 km2 area has a very high potential for rainwater harvesting, 874.17 km2 has a high potential, 1182.92 km2 has a moderate and 354.50 km2 has a poor potential for rainwater harvesting. The fuzzy overlay analysis revealed that 257.53 km2 has a very high potential for rainwater harvesting, 896.56 km2 area is classified as high, 1018.30 km2 moderate, and 407.7 km2 has poor potential for rainwater harvesting. The findings of this research work will help the policymakers and decision-makers construct various rainwater harvesting structures in the study area to overcome the water shortage problems.

Multifunctional and switchable metamaterial for terahertz polarization modulation in the reflection mode.

In this paper, a broadband multi-layered active metamaterial design is investigated, which can achieve a high polarization conversion efficiency over a wide band of frequencies in the terahertz regime. The design can be switched to an efficient metamaterial absorber using the phase transition property of vanadium dioxide (V O 2). Additionally, the designed structure can convert the linear polarization of the incoming wavefronts to its cross-polarization and linear polarization to circular polarization in the reflection mode. The broadband characteristic is achieved due to the strong anisotropic behavior of the metasurface. The structure is robust to a wide range of incident angles as well. The proposed switchable multifunctional design can contribute to the development of active plasmonic polarization devices and metamaterial absorbers.

All-dielectric metasurface designs for spin-tunable beam splitting via simultaneous manipulation of propagation and geometric phases.

Metasurfaces offer diverse wavefront control by manipulating amplitude, phase, and polarization of light which is beneficial to design subwavelength scaled integrated photonic devices. Metasurfaces based tunable circular polarization (CP) beam splitting is one functionality of interest in polarization control. Here, we propose and numerically realize metasurface based spin tunable beam splitter which splits the incoming CP beam into two different directions and tune the splitting angles by switching the handedness of incident light polarization. The proposed design approach has potential in applications such as optical communication, multiplexing, and imaging.

Whole exome sequencing identifies a novel compound heterozygous GFM1 variant underlying developmental delay, dystonia, polymicrogyria, and severe intellectual disability in a Pakhtun family.

Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as "likely-pathogenic" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.

Effect of Cypermethrin on Blood Hematology and Biochemical Parameters in Fresh Water Fish Ctenopharyngodon idella (Grass Carp).

The insecticide, cypermethrin, adversely affects biochemical parameters in blood and behavior in grass carp (Ctenopharyngodon idella). Fish were obtained from hatchery, reared in the laboratory. Different concentration of cypermethrin were applied. Blood was collected and hematological and biochemical parameters were measured. Biochemical parameters such as, protein levels, cholesterol, phosphorous and calcium in both acute and chronically cypermethrin treated groups decreased, with increasing exposure time from 24h to 15 days with more pronounced effects in the acute groups. Increased glucose, urea, serum glutamic pyruvic transaminase (SGPT), creatinine, and lactate dehydrogenase (LDH) levels were found in both acute and chronic groups with the increasing exposure time. Hematological parameters, such as red blood cell (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MHCH), and red cell distribution width (RDW) were significantly reduced in both groups as the exposure time increases. However, the numbers of white blood cells (WBC) and platelets were increased. This study established both the acute and chronic toxicity of cypermethrin in grass carp, which likely occurs secondary to altered biochemical and blood parameters.

Whole exome sequencing identified a novel missense alteration in CC2D2A causing Joubert syndrome 9 in a Pakhtun family.

BACKGROUND: Joubert syndrome (JBTS) is a heterogenous disorder characterized by intellectual disability, developmental delays, molar tooth sign in brain imaging, hypotonia, ocular motor apraxia and overlapping features of ciliopathies. There are 36 clinical subtypes of JBTS, with an equal number of genes known so far for this phenotype. METHODS: Whole exome sequencing (WES) and Sanger sequencing were performed for the molecular diagnosis of a Pakhtun family affected with Joubert syndrome type 9 (JBTS9). RESULTS: A novel homozygous missense variant (c.4417C>G; Pro1473Ala) in exon 34 was identified in coiled-coil and C2 domains-containing the protein 2A (CC2D2A; NM_001080522) gene. The variant co-segregated in autosomal recessive fashion within the family and was not found in 200 ethnically matched unaffected individuals. In silico analyses supported the pathogenic effect of the altered CC2D2A protein. CONCLUSIONS: To the best of our knowledge, this is the first report of CC2D2A alteration co-segragating with a JBTS9 phenotype in a Pakhtun family from Pakistan. Our findings broaden the pathogenic spectrum of JBTS9, adding a novel variant to CC2D2A variation pool. WES analysis is a successful molecular diagnostic tool for rare genetic disorders, especially in those populations where the marriage of cousins is more frequent. Efficient and accurate genetic testing and counselling of the affected families are helpful for patient management and for reducing the disease burden in future generations.

Absence of CD74 Isoform at 41kDa Prevents the Heterotypic Associations between CD74 and CD44 in Human Lung Adenocarcinoma-derived Cells.

Lung cancer is a leading cause of cancer-associated death in all over the globe. This study was undertaken to determine the expression and interaction of membrane-bound receptors CD74 and CD44 in human lung adenocarcinoma cells and their associated signaling was also attempted. Levels of CD74 and CD44 were studied in human lung adenocarcinoma-evolved cells A549 and H460. CD74-mediated downstream signaling was studied by the nuclear-transcription-factor NF-κB and prostaglandin E2 (PGE2) production. Flow-cytometric analysis showed that both CD74 and CD44 were perfectly expressed in A549 cells. Importantly, Western immunoblotting showed that A549 cells expressed only two isoforms of CD74 at 33 and 35 kDa but isoform at 41 kDa was absent. These results were verified in H460 cells. Confocal microscopy showed CD74 and CD44 was colocalized but heterotypic interaction between them was missing in both A549 and H460 cells. Activation of NF-κB and production of PGE2 in human lung cancer cells were comparable with other cancer cells. In conclusion, this is the first study that shows A549 and H460 cells expressed two distinctive isoforms of CD74 but isoform at 41 kDa was absent. Due to the absence of this isoform, the direct physical interaction between them CD74 and CD44 was lacking. Furthermore, the data also demonstrated that lacking of direct physical interaction between CD74 and CD44 had no effect on NF-κB activation and PGE2 production indicating that CD74-mediated downstream signaling occurs either through coreceptors or indirect interaction with CD44 in human lung cancer cells.Abbreviation: CD: cluster of differentiation; SCLC: small cell lung cancer; NSCLC: nonsmall cell lung cancer; SCC: squamous cell carcinoma; ADC: adenocarcinoma; LCC: large cell carcinoma.

A novel approach for high-level expression and purification of GST-fused highly thermostable Taq DNA polymerase in Escherichia coli.

Polymerases are enzymes that synthesize long chains or polymers of nucleic acids including DNA or RNA from nucleotides. They assemble nucleic acids by copying a DNA or RNA template strand using base-pairing interactions. One of the polymerase enzymes, Taq DNA polymerase, originally isolated from Thermus aquaticus (Taq) is a widely used enzyme in molecular biology so far. The thermostable properties of this enzyme have contributed majorly to the specificity, automation, and efficacy of the polymerase chain reaction (PCR), making it a powerful tool for today's molecular biology researches across the globe. The purification of Taq DNA polymerase from the native host results in low yield, more labor and time consumption. Therefore, many studies have been previously conducted to obtain this enzyme using alternative hosts. So far, all the existing methodologies are more laborious, time-consuming and require heavy expense. We used a novel approach to purify the enzyme with relatively high efficiency, yield and minimum time consumption using Escherichia coli (E. coli) as an alternative host. We cloned a 2500 base pair Taq DNA polymerase gene into pGEX-4T-1 vector, containing a GST-tag, downstream of tac promoter and overexpressed it using isopropyl ß-d-1-thiogalactopyranoside (IPTG) as an inducer. The enzyme was efficiently purified using novel chromatography approaches and was used in routine PCR assays in our laboratory. Our findings suggest a novel approach to facilitate the availability of polymerases for molecular and diagnostic studies. In the future, it may be used for the purification of other recombinant peptides or proteins used in structural biology and proteomics-based researches.

A mutation in the major autophagy gene, WIPI2, associated with global developmental abnormalities.

We describe a large consanguineous pedigree from a remote area of Northern Pakistan, with a complex developmental disorder associated with wide-ranging symptoms, including mental retardation, speech and language impairment and other neurological, psychiatric, skeletal and cardiac abnormalities. We initially carried out a genetic study using the HumanCytoSNP-12 v2.1 Illumina gene chip on nine family members and identified a single region of homozygosity shared amongst four affected individuals on chromosome 7p22 (positions 3059377-5478971). We performed whole-exome sequencing on two affected individuals from two separate branches of the extended pedigree and identified a novel nonsynonymous homozygous mutation in exon 9 of the WIPI2 (WD-repeat protein interacting with phosphoinositide 2) gene at position 5265458 (c.G745A;pV249M). WIPI2 plays a critical role in autophagy, an evolutionary conserved cellular pathway implicated in a growing number of medical conditions. The mutation is situated in a highly conserved and critically important region of WIPI2, responsible for binding PI(3)P and PI(3,5)P2, an essential requirement for autophagy to proceed. The mutation is absent in all public databases, is predicted to be damaging and segregates with the disease phenotype. We performed functional studies in vitro to determine the potential effects of the mutation on downstream pathways leading to autophagosome assembly. Binding of the V231M mutant of WIPI2b to ATG16L1 (as well as ATG5-12) is significantly reduced in GFP pull-down experiments, and fibroblasts derived from the patients show reduced WIPI2 puncta, reduced LC3 lipidation and reduced autophagic flux.

Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10.

BACKGROUND: Limb-girdle muscular dystrophies (LGMDs) are large group of heterogeneous genetic diseases, having a hallmark feature of muscle weakness. Pathogenic mutations in the gene encoding the giant skeletal muscle protein titin (TTN) are associated with several muscle disorders, including cardiomyopathy, recessive congenital myopathies and limb-girdle muscular dystrophy (LGMD) type10. The phenotypic spectrum of titinopathies is expanding, as next generation sequencing (NGS) technology makes screening of this large gene possible. AIM: This study aimed to identify the pathogenic variant in a consanguineous Pakistani family with autosomal recessive LGMD type 10. METHODS: DNA from peripheral blood samples were obtained, whole exome sequencing (WES) was performed and several molecular and bioinformatics analysis were conducted to identify the pathogenic variant. TTN coding and near coding regions were further amplified using PCR and sequenced via Sanger sequencing. RESULTS: Whole exome sequencing analysis revealed a novel homozygous missense variant (c.98807G > A; p.Arg32936His) in the TTN gene in the index patients. No heterozygous individuals in the family presented LGMD features. The variant p.Arg32936His leads to a substitution of the arginine amino acid at position 32,936 into histidine possibly causing LGMD type 10. CONCLUSION: We identified a homozygous missense variant in TTN, which likely explains LGMD type 10 in this family in line with similar previously reported data. Our study concludes that WES is a successful molecular diagnostic tool to identify pathogenic variants in large genes such as TTN in highly inbred population.

Correction to: Homozygous missense variant in the TTN gene causing autosomal recessive limb-girdle muscular dystrophy type 10.

Please be advised that following publication of the original article [1], the authors have identified the following errors with the scientific content.

Comet Assay and Micronucleus Test in Circulating Erythrocytes of Ctenopharyngodon idella Exposed to Nickel Oxide Nanoparticles.

The number of pollutants released into freshwater and marine environments has increased due to the widespread use of nanoparticles. Nickel oxide nanoparticles (NiO-NPs) were tested for genotoxicity in fish fingerlings of the species Ctenopharyngodon idella. For 7, 14, and 21 days, fingerlings were exposed to NiO-NPs with each increasing concentrations of 2.25 mg/L, 4.50 mg/L, and 6.75 mg/L, respectively. The micronuclei assay and comet assay were used to evaluate the DNA damage. The experiment revealed that with the increase in nanoparticle concentration and exposure duration, the level of DNA damage also increased. The experiment resulted to be time and dose dependent, and the damage was found as follows: 6.75 mg/L > 4.50 mg/L > 2.25 mg/L against each exposure period. In terms of comet assay, the results showed that after 7 days, the level of DNA damage in all the concentrations was highly significant (P < 0.001). Increased DNA damage was calculated at the higher administered dose of 6.75 mg/L for 21 days of exposition, followed by 14 and 7 days, respectively. The second high toxic effect was observed in the fish blood at the exposure concentration of 4.50 mg/L for 21 days, followed by 14 and 7 days, respectively. The micronuclei induction in the nanoparticle's administered blood could be detected only for a 7-day exposition period. Whereas for the exposed duration of 14 and 21 days, the entire red blood cells of the grass carp were completely destroyed demonstrating the ability of the nanoparticles to cause anomalies in aquatic life.

Identification and mapping of groundwater recharge zones using multi influencing factor and analytical hierarchy process.

The management of groundwater systems is essential for nations that rely on groundwater as the principal source of communal water supply (e.g., Mohmand District of Pakistan). The work employed Remote Sensing and GIS datasets to ascertain the groundwater recharge zones (GWRZ) in the Mohmand District of Pakistan. Subsequently, a sensitivity analysis was conducted to examine the impact of geology and hydrologic factors on the variability of the GWRZ. The GWRZ was determined by employing weighted overlay analysis on thematic maps derived from datasets about drainage density, slope, geology, rainfall, lineament density, land use/land cover, and soil types. The use of multi-criteria decision analysis (MCDA) involves the utilization of the multi-influencing factor (MIF) and analytical hierarchy procedure (AHP) to allocate weights to the selected influencing factors. The MIF data found that very high groundwater recharge spanned 1.20%, high zones covered 40.44%, moderate zones covered 50.81%, and low zones covered 7.54%. In comparison, the AHP technique results suggest that 1.81% of the whole area is very high, 33.26 is high, 55.01% is moderate, and 9.92% has low groundwater potential. The geospatial-assisted multi-influencing factor approach helps increase conceptual knowledge of groundwater resources and evaluate possible groundwater zones.

Spatially explicit estimation of freshwater fish stock biomass with limited data: A case study of an endangered endemic fish on the Tibetan Plateau, China.

Accurate evaluation of fish stock biomass is essential for effective conservation management and targeted species enhancement efforts. However, this remains challenging owing to limited data availability. Therefore, we present an integrated modeling framework combining catch per unit effort with ensemble species distribution modeling called CPUESDM, which explicitly assesses and validates the spatial distribution of stock biomass for freshwater fish species with limited data, applied to Herzensteinia microcephalus. The core algorithm incorporates the Leslie regression model, ensemble species distribution modeling, and exploratory spatial interpolation techniques. We found that H. microcephalus biomass in the Yangtze River source area yielded an initial estimate of 113.52 tons. Our validation results demonstrate high accuracy with a Cohen's kappa coefficient of 0.78 and root mean square error of 0.05. Furthermore, our spatially-explicit, global, absolute biomass density map effectively identified areas with high and low concentrations of biomass distribution centers. Additionally, this study offers access to the source code, example raw data, and a step-by-step instruction manual for other researchers using field data to explore the application of this model. Our findings can help inform for future conservation efforts around fish stock biomass estimation, especially for endangered species.

Novel mutation in alpha-spectrin gene in Saudi patients with hereditary spherocytosis.

Hereditary spherocytosis (HS) is the most common hereditary hemolytic disorder induced by red blood cell (RBC) membrane defect. This study was undertaken to determine mutations in genes associated with RBC membrane defect in patients with HS such as α-spectrin gene (SPTA1), ß-spectrin gene (SPTB), ankyrin gene (ANK1), band 3 anion transport gene (SLC4A1) and erythrocyte membrane protein band 4.1 gene (EPB41). Blood samples were collected from 23 unrelated patients with HS. Patients were diagnosed according to the guidelines from the British Society for Hematology. All hematological examinations for the determination of RBC abnormalities and osmotic fragility tests were conducted. Genomic DNA were extracted from peripheral blood cells and coding exons of known genes for hereditary spherocytosis were enriched using Roche/KAPA sequence capture technology and sequenced on an Illumina system via next-generation sequencing (NGS). The data showed that most of the HS patients confirmed splenomegaly and showed elevated reticulocytes and abnormal bilirubin values. NGS analysis identified the heterozygous variant c.5501G > A in the exon 39 of SPTA1 gene, resulted in a Trp1834*, which leads to a premature stop codon and subsequent mRNA degradation (nonsense- mediated decay) or truncation in α spectrin. Moreover, our data also revealed conventional mutations in genes SPTB, ANK, SLC4A1 and EBP41 in severe patients of HS. In short, this is the first report that determined a novel mutation c.5501G > A in SPTA1 gene in the Saudi population. To the best of our knowledge, this variant c.5501G > A has not been described in global literature so far. This novel mutation in SPTA1 gene is unique in the Saudi population.

Unveiling genetics of non-syndromic albinism using whole exome sequencing: A comprehensive study of TYR, TYRP1, OCA2 and MC1R genes in 17 families.

BACKGROUND: Oculocutaneous albinism (OCA) is a group of skin depigmentation disorders. Clinical presentation of OCA includes defects in melanocyte differentiation, melanin biosynthesis, and melanosome maturation and transport. OBJECTIVES: A molecular diagnostics study of families presenting oculocutaneous albinism. METHODS: In this study, 17 consanguineous OCA families consisting of 93 patients were investigated. Whole Exome Sequencing (WES) of the index patient in each family were performed. Short listed variants of WES were Sanger validated for Mendelian segregation in obligate carriers and other available family members. Variant prioritization and pathogenicity were classified as per the criteria of American College Medical Genetics and Genomics (ACMG). Comparative computational modelling was performed to predict the potential damaging effect of the altered proteins. RESULTS: 15 pathogenic variations: c.132 T > A, c.346C > T, c.488C > G, c.1037G > A in TYR, c.1211C > T, c.1441G > A, c.1706_1707insT, c.2020C > G, c.2402G > C, c.2430del, in OCA2, c.1067G > A in TYRP1 and c.451C > T, c.515G > T, c.766C > T, c.917G > A in MC1R genes were identified. Three variants in OCA2 gene were characterized: c.1706_1707insT, c.2430del, and c.2402G > C, all of which were not reported before in OCA families. CONCLUSION: A few studies focusing on mutation screening of OCA patients have been reported before; however, this study has uniquely presents the Pakhtun ethnic population residing on the North-Western boarder. It explains that TYR, OCA2, TYRP1, and MC1R variations lead to non-syndromic OCA phenotype The overlapping phenotypes of OCA can precisely be diagnosed for its molecular pathogenicity using WES. This study recommends WES as a first-line molecular diagnostic tool, and provides a basis for developing customized genetic tests i.e. pre-marital screening to reduce the disease burden in the future generations.

Ambient Temperature and Cardiac Biomarkers: A Meta-Analysis.

This study quantified the effect of cold or heat exposure of ambient temperature on the alteration of well-known cardiac markers. A meta-analysis was performed using the PRISMA guidelines. Peer-reviewed studies on ambient temperature and cardiac biomarkers were retrieved from MEDLINE, ScienceDirect and Google Scholar from January 2000 to February 2022. The pooled effect sizes of ambient temperature on cardiac biomarkers c-reactive protein, soluble-cell adhesion-molecule-1, soluble-intercellular-adhesion-molecule-1, total cholesterol, low-densitylipoprotein, interleukin-6, B-type-Natriuretic-Peptide; systolic/diastolic blood pressure were quantified using a random-effects meta-analysis. A total of 26 articles were included in the metaanalysis after screening the titles, abstracts and full texts. The pooled results for a 1°C decrease of ambient temperature showed an increase of 0.31% (95% CI= 0.26 to 0.38) in cardiac biomarkers (p=0.00; I-squared=99.2%; Cochran's Q=5636.8). In contrast, the pooled results for a 1°C increase in ambient temperature showed an increase of 2.03% (95% CI= 1.08 to 3.82) in cardiac biomarkers (p=0.00; I-squared=95.7%; Cochran's Q=235.2). In the cardiovascular (CV) population, the percent increase in cardiac biomarkers levels due to a decrease/increase in ambient temperature was greater. This study showed the decrease/increase in ambient temperature has a direct correlation with the alterations in cardiac biomarkers. These findings are useful for managing temperatureassociated cardiovascular mortality.