A founder truncating variant in GDF1 causes autosomal‐recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds

The genetic basis of congenital heart malformations associated with disruption of left–right (L–R) asymmetry is broad and heterogenous, with variants in over 25 genes implicated thus far. Of these, deleterious variants in the Growth/Differentiation Factor 1 (GDF1) gene have been shown to cause heterotaxy with varied complex heart malformations of left–right patterning, in 23 individuals reported to date, either in monoallelic or biallelic state. We report three unrelated individuals exhibiting right isomerism with congenital heart defects, each originating from a consanguineous kindred of Arab‐Muslim descent. Using whole exome sequencing, a shared novel homozygous truncating c.608G > A (p.W203*) variant in the GDF1 gene was revealed as the molecular basis of their disease. Subsequently, targeted sequencing of this variant showed full segregation with the disease in these families, with a total of over 15 reportedly affected individuals, enabling genetic counseling, prenatal diagnosis, and planning of future pregnancies. Our findings further confirm the association of biallelic GDF1 variants, heterotaxy and congenital heart defects of left–right patterning, and expand the previously described phenotypic spectrum and mutational profile. Moreover, we suggest targeted screening for the p.W203* variant in relevant clinical circumstances.     

Is there a correlation between time of delivery and newborn cord pH?

Purpose: Since more senior and attending physicians work in labor wards during morning shifts, we expect a better delivery outcome during that time period.

Materials and methods: A retrospective study was conducted between 1/2005 and 12/2014. Records of 56 428 singleton deliveries from a tertiary hospital in which cord blood pH was routinely measured at birth were analyzed. Time of birth was divided into shifts: 7 AM–3?PM (morning shift), 3?PM–11?PM (afternoon shift), and 11?PM–7 AM (night shift). Additional stratification compared weekdays and weekend deliveries.

Results: 19?601, 18?429, and 18?398 neonates were born during morning, afternoon, and night shifts, respectively. There was no significant difference in maternal age, neonatal weight, or mean 5-min Apgar score among the three shift periods. Furthermore, there was no correlation between shift time of delivery and newborn acidosis with respect to cord pH less than 7 (0.1% in each time periods, p?=?0.67). Despite the above, instrumental deliveries and cesarean sections were more common in the morning shift compared to the afternoon and night shift, respectively (p?=?0.001 each).

Conclusions: Although shift time of delivery was found to be related to mode of delivery it was not related to either 5-min Apgar score or newborn acidosis as reflected by cord pH.     

Automatic Identification of Web-Based Risk Markers for Health Events

Background

The escalating cost of global health care is driving the development of new technologies to identify early indicators of an individual’s risk of disease. Traditionally, epidemiologists have identified such risk factors using medical databases and lengthy clinical studies but these are often limited in size and cost and can fail to take full account of diseases where there are social stigmas or to identify transient acute risk factors.

Objective

Here we report that Web search engine queries coupled with information on Wikipedia access patterns can be used to infer health events associated with an individual user and automatically generate Web-based risk markers for some of the common medical conditions worldwide, from cardiovascular disease to sexually transmitted infections and mental health conditions, as well as pregnancy.

Methods

Using anonymized datasets, we present methods to first distinguish individuals likely to have experienced specific health events, and classify them into distinct categories. We then use the self-controlled case series method to find the incidence of health events in risk periods directly following a user’s search for a query category, and compare to the incidence during other periods for the same individuals.

Results

Searches for pet stores were risk markers for allergy. We also identified some possible new risk markers; for example: searching for fast food and theme restaurants was associated with a transient increase in risk of myocardial infarction, suggesting this exposure goes beyond a long-term risk factor but may also act as an acute trigger of myocardial infarction. Dating and adult content websites were risk markers for sexually transmitted infections, such as human immunodeficiency virus (HIV).

Conclusions

Web-based methods provide a powerful, low-cost approach to automatically identify risk factors, and support more timely and personalized public health efforts to bring human and economic benefits.     

A novel design of injectable porous hydrogels with in situ pore formation

The use of injectable porous hydrogels is of great interest in biomedical applications due to their excellent permeability and ease of integration into sites of surgical intervention. By implementing a method that enables the formation in situ of pores with controllable porosity and pore size, it is possible to synthesize bioactive hydrogels that are tailor-made for specific biomedical applications. An emulsion-templating technique was used to encapsulate oil droplets, which are subsequently leached out of the hydrogel to create the porous structure. Pore size and porosity were manipulated by changing oil-to-water ratios and the surfactant concentrations. Highly swellable porous hydrogels were obtained with control over mechanical strength and diffusive properties. The relationship between porosity, pore size, and the hydrogel’s physical and mechanical characteristics was analyzed, and the potential of this material as a protein drug delivery system was demonstrated.     

Targeting glycosylated antigens on cancer cells using siglec-7/9-based CAR T-cells

Chimeric antigen receptor (CAR) T-cells treatment demonstrate the increasing and powerful potential of immunotherapeutic strategies, as seen mainly for hematological malignancies. Still, efficient CAR-T cell approaches for the treatment of a broader spectrum of tumors are needed. It has been shown that cancer cells can implement strategies to evade immune response that include the expression of inhibitory ligands, such as hypersialylated proteins (sialoglycans) on their surface. These may be recognized by sialic acid-binding immunoglobulin-type lectins (siglecs) which are surface receptors found primarily on immune cells. In this regard, siglec-7 and -9 are found on immune cells, such as natural killer cells, T-cells, and dendritic cells and they can promote immune suppression when binding to sialic acids expressed on target cells. In the present study, we hypothesized that it is possible to use genetically engineered T-cells expressing siglec-based CARs, enabling them to recognize and eliminate tumor cells, in a non-histocompatibility complex molecule restricted way. Thus, we genetically modified human T-cells with different chimeric receptors based on the exodomain of human siglec-7 and -9 molecules and selected optimal receptors. We then assessed their antitumor activity in vitro demonstrating the recognition of cell lines from different histologies. These results were confirmed in a tumor xenograft model exemplifying the potential of the present approach. Overall, this study demonstrates the benefit of targeting cancer-associated glycosylation patterns using CAR based on native immune receptors and expressed in human primary T-cells.     

Indirect flight of an African bat to Israel: an example of the potential for zoonotic pathogens to move between continents

The transmission of harmful pathogens during commercial air flights is an increasing health concern. A potential, yet relatively overlooked source of zoonotic infectious diseases involves collisions of birds and bats with aircraft and long distance transport of their carcasses. We report a case of aerial transportation of the remains of an African fruit bat over three continents, following a collision with an aircraft, and demonstrate the relative ease with which zoonotic pathogens, such as rabies virus or other viruses associated with bats, may cross national boundaries and continents even. Improper handling and disposal of animal remains by airport personnel, may lead to exposure of both humans and local fauna to exotic pathogens. This in turn may trigger an epidemic with potentially devastating results.