Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide ...association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.
Modern instant messaging systems facilitate reach-back medical support for Defence Medical Services (DMS) by connecting deployed clinicians to remote specialists. The mobile app Pando (Forward ...Clinical, UK) has been used for this purpose by the DMS via the '
' function. We aimed to investigate the usage statistics for this technology in its first 1000 days to better understand its role in the DMS.
An observational study was undertaken using metadata extracted from the prospective database within the application server for clinical queries between June 2019 and February 2022. These data included details regarding number and name of specialties, timings, active users per day and the number of conversations.
There were 29 specialties, with 298 specialist users and 553 requests for advice. The highest volume of requests were for trauma and orthopaedics (n=116; 21.0%), ear, nose and throat (n=67; 12.1%) and dermatology (n=50; 9.0%). There was a median of 164 (IQR 82-257) users logged in per day (range 2-697). The number of requests during each day correlated with the number of users on that day (r=0.221 (95% CI 0.159 to 0.281); p<0.001). There were more daily users on weekdays than weekends (215 (IQR 123-277) vs 88 (IQR 58-121), respectively; p<0.001). For the top 10 specialties, the median first response time was 9 (IQR 3-42) min and the median time to resolution was 105 (IQR 21-1086) min.
In the first 1000 days of secure app-based reach-back by the DMS there have been over 500 conversations, responded to within minutes by multiple specialists. This represents a maturing reach-back capability that may enhance the force multiplying effect of defence healthcare while minimising the deployed '
'. Further discussions should address how this technology can be used to provide appropriately responsive clinical advice within DMS consultant job-planned time.
The construction and use of recombinant chimeric and later fully humanized (CDR-grafted) antibodies to tumor-associated antigens has reduced the immune response generated to these antibodies in ...clinical studies. However, their long circulating half-life is a disadvantage for tumor imaging and therapy. Fragments such as F(ab')2, Fab', Fv and single chain Fv (scFv) offer faster blood clearance but also lower overall tumor doses. We have examined the tumor targeting of several novel fragments produced by chemical cross-linking of Fab' or scFv to dimeric and trimeric species. To facilitate cross-linking of Fab' fragments, a chimeric B72.3 Fab' fragment has been expressed with a hinge sequence containing a single cysteine residue. B72.3 scFv was also produced with a similar hinge region peptide attached to the COOH terminus to allow cross-linking. These fragments, Fab' delta Cys and scFv' delta Cys were cross-linked with linkers containing two or three maleimide groups to produce dimeric and trimeric molecules with increased avidity for antigen. Cross-linkers were also designed to contain a 12-N-4 macrocycle capable of stable radiolabeling with 90Y. This allowed the production of site-specifically-labeled, fully immunoreactive proteins. Biodistribution studies in the nude mouse LS174T xenograft model with scFv, di-scFv, and tri-scFv demonstrated that these fragments clear extremely rapidly from the circulation and give rise to only low levels of activity accumulated at the tumor. Di-Fab (DFM) and tri-Fab (TFM) however, accumulated relatively high levels of activity at the tumor with high tumor:blood ratios generated, demonstrating improved targeting compared to IgG. cB72.3 90Y-labeled tri-Fab was found not to accumulate in the kidney or the bone, resulting in an attractive antibody fragment for tumor therapy.
Accuracy of evolutionary analysis of populations within a species requires the testing of a large number of genetic polymorphisms belonging to many loci. We report here a reconstruction of human ...differentiation based on 100 DNA polymorphisms tested in five populations from four continents. The results agree with earlier conclusions based on other classes of genetic markers but reveal that Europeans do not fit a simple model of independently evolving populations with equal evolutionary rates. Evolutionary models involving early admixture are compatible with the data. Taking one such model into account, we examined through simulation whether random genetic drift alone might explain the variation among gene frequencies across populations and genes. A measure of variation among populations was calculated for each polymorphism, and its distribution for the 100 polymorphisms was compared with that expected for a drift-only hypothesis. At least two-thirds of the polymorphisms appear to be selectively neutral, but there are significant deviations at the two ends of the observed distribution of the measure of variation: a slight excess of polymorphisms with low variation and a greater excess with high variation. This indicates that a few DNA polymorphisms are affected by natural selection, rarely heterotic, and more often disruptive, while most are selectively neutral.
A humanised IgG1/k version of A33 (hA33) has been constructed and expressed with yields up to 700 mg l-1 in mouse myeloma NS0 cells in suspension culture. The equilibrium dissociation constant of ...hA33 (KD = 1.3 nM) was shown to be equivalent to that of the murine antibody in a cell-binding assay. hA33 labelled with yttrium-90 using the macrocyclic chelator 12N4 (DOTA) was shown to localise very effectively to human colon tumour xenografts in nude mice, with tumour levels increasing as blood concentration fell up to 144 h. A Fab' variant of hA33 with a single hinge thiol group to facilitate chemical cross-linking has also been constructed and expressed with yields of 500 mg l-1. Trimaleimide cross-linkers have been used to produce a trivalent Fab fragment (hA33 TFM) that binds antigen on tumour cells with greater avidity than hA33 IgG. Cross-linkers incorporating 12N4 or 9N3 macrocycles have been used to produce hA33 TFM labelled stably and site specifically with yttrium-90 or indium-111 respectively. These molecules have been used to demonstrate that hA33 TFM is cleared more rapidly than hA33 IgG from the circulation of animals but does not lead to accumulation of these metallic radionuclides in the kidney. 90Y-labelled hA33 TFM therefore appears to be the optimal form of the antibody for radioimmunotherapy of colorectal carcinoma.
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