Hereditary retinal degenerations (HRDs) are Mendelian diseases characterized by progressive blindness and caused by ultra-rare mutations. In a genomic screen of 331 unrelated Japanese patients, we identify a disruptive Alu insertion and a nonsense variant (p.Arg1933*) in the ciliary gene RP1 , neither of which are rare alleles in Japan. p.Arg1933* is almost polymorphic (frequency = 0.6%, amongst 12,000 individuals), does not cause disease in homozygosis or heterozygosis, and yet is significantly enriched in HRD patients (frequency = 2.1%, i.e., a 3.5-fold enrichment; p -value = 9.2 × 10 −5 ). Familial co-segregation and association analyses show that p.Arg1933* can act as a Mendelian mutation in trans with the Alu insertion, but might also associate with disease in combination with two alleles in the EYS gene in a non-Mendelian pattern of heredity. Our results suggest that rare conditions such as HRDs can be paradoxically determined by relatively common variants, following a quasi-Mendelian model linking monogenic and complex inheritance.

Summary. The north-western populations of Pakistan in the Federally Administered Tribal Areas (FATA) adjoining the Pakistan-Afghanistan border are an amalgamation of native and migrated Pashtun tribes. These tribal populations are in transition due to war conditions and geo-political turmoil on both sides of the border since the Soviet invasion in 1979. Bio-demographic and epidemiological data for these tribes are scarce. A prospective cross-sectional sample of 967 males was selected from a representative Pashtun population of Bajaur Agency, and information obtained on bio-demographic variables and marital union types. Analysis of these data revealed that consanguinity was 22.34% and the inbreeding coefficient F was calculated to be 0.0134. The inbreeding coefficient was observed to be higher in subjects who were illiterate, had unskilled jobs and who belonged to younger age categories, extended families and the Tarkalani tribe. Further analyses with respect to temporal variables like subject's age, year of marriage and age at marriage revealed that after a transition in marital union types in the early 80s, there has been a declining trend in the rate of consanguineous unions. Further, consanguineous unions in the parental generation were only 5%, but parental marriage types were predictors of subjects' marital union types. The data further establish that, contrary to a general notion about a high consanguinity rate in Pakistan, consanguineous unions are not common in Bajaur Agency and first cousin marriage is not the preferred type. Furthermore, this research shows that there is a great regional variation in the pattern of consanguinity in Pakistan that needs to be documented in order to draw a more comprehensive picture of the inbreeding coefficient in the country.

Citrus yellow vein clearing virus is a newly accepted member of the genus Mandarivirus in the family Alphaflexiviridae. The triple gene block proteins (TGBp1, TGBp2 and TGBp3) encoded by plant viruses in this family function on facilitating virus movement. However, the protein function of citrus yellow vein clearing virus (CYVCV) have never been explored. Here, we showed in both yeast two-hybrid (Y2H) and bimolecular fluorescence (BiFC) assays that the coat protein (CP), TGBp1 and TGBp2 of CYVCV are self-interacting. Its CP also interacts with all three TGB proteins, and TGBp1 and TGBp2 interact with each other but not with TGBp3. Furthermore, the viral CP colocalizes with TGBp1 and TGBp3 at the plasmodesmata (PD) of epidermal cells of Nicotiana benthamiana leaves, and TGBp1 can translocate TGBp2 from granular-like structures embedded within ER networks to the PD. The results suggest that these proteins could coexist at the PD of epidermal cells of N. benthamiana. Using Agrobacterium infiltration-mediated RNA silencing assays, we show that CYVCV CP is a strong RNA silencing suppressor (RSS) triggered by positive-sense green fluorescent protein (GFP) RNA. The presented results provide insights for further revealing the mechanism of the viral movement and suppression of RNA silencing.

Variants in more than 271 different genes have been linked to hereditary retinal diseases, making comprehensive genomic approaches mandatory for accurate diagnosis. We explored the genetic landscape of retinal disorders in consanguineous families from North-Western Pakistan, harboring a population of approximately 35 million inhabitants that remains relatively isolated and highly inbred (~50% consanguinity). We leveraged on the high degree of consanguinity by applying genome-wide high-density single-nucleotide polymorphism (SNP) genotyping followed by targeted Sanger sequencing of candidate gene(s) lying inside autozygous intervals. In addition, we performed whole-exome sequencing (WES) on at least one proband per family. We identified 7 known and 4 novel variants in a total of 10 genes (ABCA4, BBS2, CNGA1, CNGA3, CNGB3, MKKS, NMNAT1, PDE6B, RPE65, and TULP1) previously known to cause inherited retinal diseases. In spite of all families being consanguineous, compound heterozygosity was detected in one family. All homozygous pathogenic variants resided in autozygous intervals ≥2.0 Mb in size. Putative founder variants were observed in the ABCA4 (NM_000350.2:c.214G>A; p.Gly72Arg; ten families) and NMNAT1 genes (NM_022787.3:c.25G>A; p.Val9Met; two families). We conclude that geographic isolation and sociocultural tradition of intrafamilial mating in North-Western Pakistan favor both the clinical manifestation of rare “generic” variants and the prevalence of founder mutations.

This paper intends to explore the level of ICT competencies, and the training needs for updating these competencies among library professionals in Khyber Pakhtunkhwa, Pakistan. It also looks at the various approaches utilized by these professionals for acquiring ICT skills and problems faced by them in this regard. Descriptive survey research method has been used for conducting this study. The population for this study comprised of 105 library professionals working in the 14 public sector universities in Khyber Pakhtunkhwa, Pakistan. The study revealed that the status of ICT competencies among library professionals in the region is unsatisfactory. Self-study is their main avenue of acquiring ICT skills and insufficient staff in the libraries is their main problem. Further training in establishing & maintaining a digital library software and using institutional repository software is their foremost training need for updating their ICT competencies. The results can be utilized by library administrators to organize regular ICT training programs to train library staff in modern ICT resources as per their needs and to eradicate any hurdle in updating staff ICT competencies. This study provides valuable insight into the level of the ICT competencies of library professionals in KPK, and provides a framework for the development of ICT competencies of library professionals in KPK and elsewhere. It would lead to the provision of qualitative and standardized library services to the patrons and would enable library professionals to benefit from modern ICT resources in the field of library and information science.

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BackgroundDespite the high sociocultural preferences in contracting marriages among close relatives in Pakistan, marked regional differences exist in the prevalence of consanguinity. There is great interest to elucidate the sociodemographic variables underlying the heterogeneity in consanguinity prevalence in the various populations. The present study was conducted in the Mardan district of Pakistan, the second largest multiethnic Pashtun metropolis.ObjectiveTo find determinants of consanguineous unions.MethodsIn a cross-sectional study design, a convenience sample of 1,202 ever-married men from 3tehsilsof Mardan district was recruited in an unselected manner and data regarding their marital union types and sociodemographic variables were obtained by a structured interview. Descriptive statistics and multivariable logistic regression analyses were used.ResultsConsanguineous unions accounted for 44% of all marriages, and the inbreeding coefficient was calculated as 0.0258. Regression analyses revealed that 6 variables were significant predictors of consanguinity, namely, tehsil, age, year of marriage, caste (zaat/biradari) system, area of house, and marriage arrangement of the respondent, while 6 other variables, namely, rural/urban origin, literacy, occupation, monthly income, household type, and number of family members, were not found to be significant. Regression analyses showed that there were different combinations of variables predictive of consanguinity among the varioustehsils.ConclusionsThe prevalence of consanguinity in the Mardan district was found to be lower than that in many other districts of Pakistan. National regional differences exist in consanguinity, and the combination of predictive factors varies greatly.

Background Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. MethodsIn this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middleincome countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42•4% vs 44•2%; absolute difference -1•69 [-9•58 to 6•11] p=0•67; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5-8] vs 6 [5-8] cm H 2 O; p=0•0011). ICU mortality was higher in MICs than in HICs (30•5% vs 19•9%; p=0•0004; adjusted effect 16•41% [95% CI 9•52-23•52]; p<0•0001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0•80 [95% CI 0•75-0•86]; p<0•0001).Interpretation Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status.