A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24

Meckel-Gruber syndrome (MKS), the most common monogenic cause of neural tube defects, is an autosomal recessive disorder characterised by a combination of renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalcoele), hepatic ductal dysplasia and cysts, and polydactyly. Locus heterogeneity has been demonstrated by the mapping of the MKS1 locus to 17q21-24 in Finnish kindreds, and of MKS2 to 11q13 in North African-Middle Eastern cohorts. In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2. We report the localisation of a third MKS locus (MKS3) to chromosome 8q24 in this cohort by a genome-wide linkage search using autozygosity mapping. We identified a 26-cM region of autozygosity between D8S586 and D8S1108 with a maximum cumulative two-point LOD score at D8S1179 (Z(max)=3.04 at theta=0.06). A heterogeneity test provided evidence of one unlinked family. Exclusion of this family from multipoint analysis maximised the cumulative multipoint LOD score at locus D8S1128 (Z(max)=5.65). Furthermore, a heterozygous SNP in DDEF1, a putative candidate gene, suggested that MKS3 mapped within a 15-cM interval. Comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3-linked families

Indigenous Grasses for Rehabilitating Degraded African Drylands

Drylands provide an important livelihood stream to its inhabitants across the globe through a range of products and ecosystem services. However, these fragile ecosystems are threatened and believed to experience various degrees of land degradation. Estimates of the landmass affected by land degradation in the global drylands range from 10% to 20%, a percentage that is increasing at an annual global rate of 12 million ha of soil lost from desertification and drought. African drylands are especially highly susceptible to severe degradation because of their poor soil structure aggravated by scarce vegetation cover. Causes of degradation in these environments are both natural and anthropogenic in nature. Change in vegetation cover, decline in soil fertility, biodiversity loss and soil erosion demonstrate degradation in African drylands. Grass reseeding using indigenous species is one of the promising sustainable land management strategies to combat degradation in the drylands. Reseeding programmes are aimed at improving vegetation cover and biomass, and they conserve the soil to an extent not possible by grazing and land management alone. Indigenous drought-tolerant grasses notably African foxtail grass (Cenchrus ciliaris), bush rye grass (Enteropogon macrostachyus) and Maasai lovegrass (Eragrostis superba) have produced promising rehabilitation outcomes. Previous studies in African drylands have demonstrated the potential of such indigenous forage grasses in improving both vegetation cover (plant frequency and densities, basal cover) and soil hydrological properties (increased infiltration capacity, reduced runoff and sediment production) as indicators of rehabilitation success. Despite their comparative and widespread success, natural and anthropogenic challenges persist. This makes reseeding programmes a risky and often expensive venture, especially for the resource-poor pastoral communities in African drylands. Despite the risks, grass reseeding using indigenous pastures remains a viable sustainable land management option to combat degradation in African drylands. However, to ensure its continued success in the long term, multifaceted approaches and strategies that will integrate land and water management and seed systems suitable for African drylands need to be developed, strengthened and promoted.Peer reviewe

Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity

Serology based disease status of Pakistani population infected with Hepatitis B virus

<p>Abstract</p> <p>Background</p> <p>The infection rate of hepatitis B virus is continuously increasing in Pakistan. Therefore, a comprehensive study of epidemiological data is the need of time.</p> <p>Methods</p> <p>A total of 1300 individuals were screened for HBV infection markers including HBsAg, anti-HBsAg, HBeAg and anti-HBcAg. The association of these disease indicators was compared with patients' epidemiological characteristics like age, socio-economic status and residential area to analyze and find out the possible correlation among these variables and the patients disease status.</p> <p>Results</p> <p>52 (4%) individuals were found positive for HBsAg with mean age 23.5 ± 3.7 years. 9.30%, 33.47% and 12% individuals had HBeAg, antibodies for HBsAg, and antibodies for HBcAg respectively. HBsAg seropositivity rate was significantly associated (<it>p </it>= 0.03) with the residing locality indicating high infection in rural areas. Antibodies titer against HBsAg decreased with the increasing age reflecting an inverse correlation.</p> <p>Conclusion</p> <p>Our results indicate high prevalence rate of Hepatitis B virus infection and nationwide vaccination campaigns along with public awareness and educational programs are needed to be practiced urgently.</p

Molecular epidemiology of Hepatitis B virus genotypes in Pakistan

<p>Abstract</p> <p>Background</p> <p>Eight genotypes of Hepatitis B virus designated A-H, have been known but in Pakistan, no such data is available on the prevalent HBV genotypes. Therefore, the subject study was conducted to determine HBV genotypes in the indigenous Pakistani population.</p> <p>Methods</p> <p>A total of 690 individuals were enrolled for HBV screening with EIA and nested PCR. Positive samples were further analyzed to determine HBV genotypes (A-F) by multiplex-PCR using type specific primers.</p> <p>Results</p> <p>110 (15.94%) individuals were positive for HBV, including 64% males and 36% females. Out of these, 66 samples (65.34%) were classified into genotype D, 27 (26.73%) were of genotype B while 5(4.95%) had genotype A. In 3 (2.98%) samples, multiple genotypes were detected (genotype A+B; 2(1.99%) and genotypes B+D; 1(0.99%). Nine (8.18%) samples remained untyable.</p> <p>Conclusion</p> <p>In Asia, genotypes B and C are the most prevalent but our study reveals that genotype D is predominant and HBV infection constitutes a significant health problem in Pakistan.</p

Using Intervention Mapping to develop an occupational advice intervention to aid return to work following hip and knee replacement in the United Kingdom

Background There are increasing numbers of total hip replacements (THR) and total knee replacements (TKR) being performed in patients of working age. Providing patients undergoing TKR and THR with return to work advice might facilitate return to work. The aim of this paper is to report on the process used to systematically develop an occupational advice intervention to be delivered in hospital for those undergoing arthroplasty. Methods The six-step Intervention Mapping (IM) approach to development, implementation and evaluation of a theory and evidence-based interventions was followed. This paper reports on the development of the intervention covered by steps 1 to 4 of the IM process. Steps 1-3 gathered data on current practice and barriers to change using a mixed methods approach (cohort study of patients undergoing THR or TKR, stakeholder interviews, survey of practice, evidence synthesis) and provided a theoretical framework for intervention development. Step 4 used information from steps 1-3 in combination with a Delphi consensus process to develop the intervention and the associated tools and materials to facilitate its delivery. Results The final intervention identified included a number of core principles including: early patient identification; delivery of key information to patients and their employers; assessment and support by a member of the orthopaedic team; procedures for escalation based on patient need; mechanisms to support communication; and training and support for the clinical teams delivering care. A total of 13 patient and 20 staff performance objectives as delivery requirements, supported by a range of tools, roles and training resources. The intervention addressed outcomes based at the individual and interpersonal levels of the ecological model. Conclusions Following the IM approach resulted in a structured and justified occupational intervention for delivery in secondary care for patients undergoing total hip and knee replacement. The feasibility of the intervention will subsequently be tested alongside further investigation to establish its effectiveness and cost-effectiveness. Key Words Intervention Mapping Return to Work Occupational advice Arthroplasty Hip Kne

Generation of ribosome imprinted polymers for sensitive detection of translational responses

Whilst the profiling of the transcriptome and proteome even of single-cells becomes feasible, the analysis of the translatome, which refers to all messenger RNAs (mRNAs) engaged with ribosomes for protein synthesis, is still an elaborate procedure requiring millions of cells. Herein, we report the generation and use of “smart materials”, namely molecularly imprinted polymers (MIPs) to facilitate the isolation of ribosomes and translated mRNAs from merely 1,000 cells. In particular, we show that a hydrogel-based ribosome imprinted polymer could recover ribosomes and associated mRNAs from human, simian and mice cellular extracts, but did not selectively enrich yeast ribosomes, thereby demonstrating selectivity. Furthermore, ribosome imprinted polymers enabled the sensitive measurement of an mRNA translational regulatory event, requiring 1,000-fold less cells than current methodologies. These results provide first evidence for the suitability of MIPs to selectively recover ribonucleoprotein complexes such as ribosomes, founding a novel means for sensitive detection of gene regulation

Missed Opportunities for HIV Testing and Late-Stage Diagnosis among HIV-Infected Patients in Uganda

BACKGROUND: Late diagnosis of HIV infection is a major challenge to the scale-up of HIV prevention and treatment. In 2005 Uganda adopted provider-initiated HIV testing in the health care setting to ensure earlier HIV diagnosis and linkage to care. We provided HIV testing to patients at Mulago hospital in Uganda, and performed CD4 tests to assess disease stage at diagnosis. METHODS: Patients who had never tested for HIV or tested negative over one year prior to recruitment were enrolled between May 2008 and March 2010. Participants who tested HIV positive had a blood draw for CD4. Late HIV diagnosis was defined as CD4≤250 cells/mm. Predictors of late HIV diagnosis were analyzed using multi-variable logistic regression. RESULTS: Of 1966 participants, 616 (31.3%) were HIV infected; 47.6% of these (291) had CD4 counts ≤250. Overall, 66.7% (408) of the HIV infected participants had never received care in a medical clinic. Receiving care in a non-medical setting (home, traditional healer and drug stores) had a threefold increase in the odds of late diagnosis (OR = 3.2; 95%CI: 2.1-4.9) compared to receiving no health care. CONCLUSIONS: Late HIV diagnosis remains prevalent five years after introducing provider-initiated HIV testing in Uganda. Many individuals diagnosed with advanced HIV did not have prior exposure to medical clinics and could not have benefitted from the expansion of provider initiated HIV testing within health facilities. In addition to provider-initiated testing, approaches that reach individuals using non-hospital based encounters should be expanded to ensure early HIV diagnosis

RGB2LIDAR: Towards Solving Large-Scale Cross-Modal Visual Localization

We study an important, yet largely unexplored problem of large-scale cross-modal visual localization by matching ground RGB images to a geo-referenced aerial LIDAR 3D point cloud (rendered as depth images). Prior works were demonstrated on small datasets and did not lend themselves to scaling up for large-scale applications. To enable large-scale evaluation, we introduce a new dataset containing over 550K pairs (covering 143 km^2 area) of RGB and aerial LIDAR depth images. We propose a novel joint embedding based method that effectively combines the appearance and semantic cues from both modalities to handle drastic cross-modal variations. Experiments on the proposed dataset show that our model achieves a strong result of a median rank of 5 in matching across a large test set of 50K location pairs collected from a 14km^2 area. This represents a significant advancement over prior works in performance and scale. We conclude with qualitative results to highlight the challenging nature of this task and the benefits of the proposed model. Our work provides a foundation for further research in cross-modal visual localization.Comment: ACM Multimedia 202

Genetic analysis reveals a hierarchy of interactions between polycystin-encoding genes and genes controlling cilia function during left-right determination

During mammalian development, left-right (L-R) asymmetry is established by a cilia-driven leftward fluid flow within a midline embryonic cavity called the node. This ‘nodal flow’ is detected by peripherally-located crown cells that each assemble a primary cilium which contain the putative Ca2+ channel PKD2. The interaction of flow and crown cell cilia promotes left side-specific expression of Nodal in the lateral plate mesoderm (LPM). Whilst the PKD2-interacting protein PKD1L1 has also been implicated in L-R patterning, the underlying mechanism by which flow is detected and the genetic relationship between Polycystin function and asymmetric gene expression remains unknown. Here, we characterize a Pkd1l1 mutant line in which Nodal is activated bilaterally, suggesting that PKD1L1 is not required for LPM Nodal pathway activation per se, but rather to restrict Nodal to the left side downstream of nodal flow. Epistasis analysis shows that Pkd1l1 acts as an upstream genetic repressor of Pkd2. This study therefore provides a genetic pathway for the early stages of L-R determination. Moreover, using a system in which cultured cells are supplied artificial flow, we demonstrate that PKD1L1 is sufficient to mediate a Ca2+ signaling response after flow stimulation. Finally, we show that an extracellular PKD domain within PKD1L1 is crucial for PKD1L1 function; as such, destabilizing the domain causes L-R defects in the mouse. Our demonstration that PKD1L1 protein can mediate a response to flow coheres with a mechanosensation model of flow sensation in which the force of fluid flow drives asymmetric gene expression in the embryo