Human Leukocyte Antigen-Allelic Variations May Influence the Age at Cancer Diagnosis in Lynch Syndrome.

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of developing various solid cancers, but mostly colorectal cancer (CRC). Despite having the same germline pathogenic variant (PV) in one of the mis-match repair genes or the EPCAM gene, Lynch syndrome variant heterozygotes (LSVH) exhibit a remarkable phenotypic variability in the risk of developing cancer. The role of human leukocyte antigen (HLA) in modifying cancer development risk prompted our hypothesis into whether HLA variations act as potential genetic modifiers influencing the age at cancer diagnosis in LSVH. To investigate this, we studied a unique cohort of 426 LSVH carrying the same germline PV in the hMLH1 gene (MLH1:c.1528C > T) in South Africa. We intuitively selected 100 LSVH with the greatest diversity in age at cancer diagnosis (N = 80) and the oldest cancer unaffected LSVH (N = 20) for a high-throughput HLA genotyping of 11 HLA class I and class II loci using the shotgun next-generation sequencing (NGS) technique on the Illumina MiSeq platform. Statistical analyses employed Kaplan-Meier survival analyses with log-rank tests, and Cox proportional hazards using binned HLA data to minimize type I error. Significant associations were observed between young age at cancer diagnosis and HLA-DPB1*04:02 (mean age: 37 y (25-50); hazard ratio (HR) = 3.37; corrected p-value (q) = 0.043) as well as HLA-DPB1 binned alleles (including HLA-DPB1*09:01, HLA-DPB1*10:01, HLA-DPB1*106:01, HLA-DPB1*18:01, HLA-DPB1*20:01, HLA-DPB1*26:01, HLA-DPB1*28:01, HLA-DPB1*296:01, and HLA-DPB1*55:01) (mean age: 37 y (17-63); HR = 2.30, q = 0.045). The involvement of HLA-DPB1 alleles in the age at cancer diagnosis may highlight the potential role of HLA class II in the immune response against cancer development in LSVH. When validated in a larger cohort, these high-risk HLA-DPB1 alleles could be factored into cancer risk prediction models for personalized cancer screening in LSVH.

Association of Physical Domain Participation with POTFF Domains in Special Forces Operators.

BACKGROUND: The purpose of this study was to evaluate the effectiveness of the physical domain (PD) to improve performance in all the POTFF domains (physical, psychological, social/family, and spiritual) among Special Forces (SF) Operators. METHODS: This was a cross-sectional study of active SF Operators assigned to the United States Army Special Operations Command (USASOC). Recruitment began in October 2016. Testing began on 1 January 2017, and concluded on 28 February 2020. Participants completed physical testing, blood draws, and questionnaires to determine domain metrics. Means, medians, and proportions were compared by level of participation in the PD. RESULTS: A total of 231 Soldiers participated; n=63 in the control group, n=93 in the <4 days PD/week (PD <4) group, and n=66 in the >4 days PD/week (PD =4) group. The average age was 31 years (range 21-47 y). The average time in the Special Operations Forces (SOF) was 4 years (range 0-19 y). The PD =4 group showed significantly greater overall upper (p=.01) and lower (p=0) body strength, power (p=.01), and positive affect (p=.04). The PD =4 group also had significantly lower anxiety (p=.03), stress (p=.04), and depression (p=.02) than the control group. CONCLUSION: The PD and psychological domain metrics were most associated with PD participation. This finding is consistent with the goals of the PD, which are to increase physical and mental capabilities and decrease injury recovery time.

Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer.

Introduction: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel. Materials and methods: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR. Results: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes. Conclusion: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis.

TMPRSS6 is a serine protease highly expressed in the liver. Its role in iron regulation was first reported in 2008 when mutations in TMPRSS6 were shown to be the cause of iron-refractory iron deficiency anemia (IRIDA) in humans and in mouse models. TMPRSS6 functions as a negative regulator of the expression of the systemic iron-regulatory hormone hepcidin. Over the last decade and a half, growing understanding of TMPRSS6 biology and mechanism of action has enabled development of new therapeutic approaches for patients with diseases of erythropoiesis and iron homeostasis.ClinicalTrials.gov identifier NCT03165864.

A comparative cost analysis of two screening strategies for colorectal cancer in Lynch Syndrome in a South African tertiary hospital.

AIM: Lynch Syndrome (LS) individuals have a 25-75% lifetime risk of developing colorectal cancer. Colonoscopy screening decreases this risk. This study compared the cost of Strategy 1: screening colonoscopy for 1st degree relatives of patients that met the Revised Bethesda Criteria (i.e., probands) to Strategy 2: screening colonoscopy for 1st degree relatives of probands with genetic mutations for Lynch Syndrome based in a resource-constrained health care system. METHOD: A comparative, health care provider perspective, cost analysis was conducted at a tertiary hospital, using a micro-costing, ingredient approach. Forty probands that underwent genetic testing between November 01, 2014 and October 30, 2015 and their first-degree relatives were costed according to Strategy 1 and Strategy 2. Unit costs of colonoscopy and genetic testing were estimated and used to calculate and compare the total costs per strategy in South African rand (R) converted to UK pounds (£). Sensitivity analyses were performed on colonoscopy adherence, relatives' positivity, and variable discount rates. RESULTS: The cost for Strategy 1 amounted to £653 344/R6 161 035 compared to £49 327/R 465 155 for Strategy 2 (Discount rate 3%; Adherence 75%; and Positivity rate of relatives 45%). Base case analysis indicated a difference of 92% less in the total cost for Strategy 2 compared to Strategy 1. Sensitivity analyses showed that the difference in cost between the two strategies was not sensitive to variations in adherence, positivity or discount rates. CONCLUSION: Colonoscopy screening for LS and at-risk family members was tenfold less costly when combined with genetic analysis. The logistics of rolling out this strategy nationally should be investigated.

Does Mental and Visual Skills Training Improve High-Value Target Identification and Marksmanship Among Elite Soldiers?

BACKGROUND: The purpose of this preliminary investigation was to determine the impact of a mental and visual skills training (MVST) program on a high-value target identification and marksmanship (HVTM) task among Special Operations Forces (SOF) Soldiers. METHODS: Deidentified archival data for 52 male SOF Operators (age: 31.06 ± 4.10 years) were assessed to determine if differences in performance existed between MVST program users (n = 15) and nonusers (n = 37) on a HVTM task performed immediately after a Special Forces Advanced Urban Combat (SFAUC) stress shoot. Independent-samples t-tests were utilized to determine if significant mean score differences existed between groups on specific shooting elements within the HVTM task. Effect size calculations were also performed to assess the magnitude of differences between groups in each measure of performance. RESULTS: Statistically significant differences in performance were not discovered between MVST users and nonusers on overall score (Score) or any individual elements of the HVTM task. However, small to medium effect sizes (d = 0.305-0.493) were observed between groups in Score, Positive Identification Accuracy, Shot Accuracy, and Kill Shot Score. CONCLUSION: While inconclusive, these findings suggest the use of a MVST program administered by a trained cognitive performance specialist may have the potential to positively influence HVTM performance. More research using larger sample sizes is required to confirm this supposition.

Microstratigraphic preservation of ancient faunal and hominin DNA in Pleistocene cave sediments.

Ancient DNA recovered from Pleistocene sediments represents a rich resource for the study of past hominin and environmental diversity. However, little is known about how DNA is preserved in sediments and the extent to which it may be translocated between archaeological strata. Here, we investigate DNA preservation in 47 blocks of resin-impregnated archaeological sediment collected over the last four decades for micromorphological analyses at 13 prehistoric sites in Europe, Asia, Africa, and North America and show that such blocks can preserve DNA of hominins and other mammals. Extensive microsampling of sediment blocks from Denisova Cave in the Altai Mountains reveals that the taxonomic composition of mammalian DNA differs drastically at the millimeter-scale and that DNA is concentrated in small particles, especially in fragments of bone and feces (coprolites), suggesting that these are substantial sources of DNA in sediments. Three microsamples taken in close proximity in one of the blocks yielded Neanderthal DNA from at least two male individuals closely related to Denisova 5, a Neanderthal toe bone previously recovered from the same layer. Our work indicates that DNA can remain stably localized in sediments over time and provides a means of linking genetic information to the archaeological and ecological records on a microstratigraphic scale.

The 50 years' war: The history and outcomes of the National Cancer Act of 1971.

The National Cancer Act of 1971 instigated 50 years of momentum that raised the federal investment in cancer research from $500 million in 1972 to $6.5 billion in 2021. This investment has fueled basic, translational, and clinical research that has had a tremendous impact on our understanding of cancer and our ability to prevent, diagnose, and treat it. It has also affected many other diseases.

Lysosomal cholesterol accumulation contributes to the movement phenotypes associated with NUS1 haploinsufficiency.

PURPOSE: Variants in NUS1 are associated with a congenital disorder of glycosylation, developmental and epileptic encephalopathies, and are possible contributors to Parkinson disease pathogenesis. How the diverse functions of the NUS1-encoded Nogo B receptor (NgBR) relate to these different phenotypes is largely unknown. We present three patients with de novo heterozygous variants in NUS1 that cause a complex movement disorder, define pathogenic mechanisms in cells and zebrafish, and identify possible therapy. METHODS: Comprehensive functional studies were performed using patient fibroblasts, and a zebrafish model mimicking NUS1 haploinsufficiency. RESULTS: We show that de novo NUS1 variants reduce NgBR and Niemann-Pick type C2 (NPC2) protein amount, impair dolichol biosynthesis, and cause lysosomal cholesterol accumulation. Reducing nus1 expression 50% in zebrafish embryos causes abnormal swim behaviors, cholesterol accumulation in the nervous system, and impaired turnover of lysosomal membrane proteins. Reduction of cholesterol buildup with 2-hydroxypropyl-ß-cyclodextrin significantly alleviates lysosomal proteolysis and motility defects. CONCLUSION: Our results demonstrate that these NUS1 variants cause multiple lysosomal phenotypes in cells. We show that the movement deficits associated with nus1 reduction in zebrafish arise in part from defective efflux of cholesterol from lysosomes, suggesting that treatments targeting cholesterol accumulation could be therapeutic.

Reconstructing Late Pleistocene paleoclimate at the scale of human behavior: an example from the Neandertal occupation of La Ferrassie (France).

Exploring the role of changing climates in human evolution is currently impeded by a scarcity of climatic information at the same temporal scale as the human behaviors documented in archaeological sites. This is mainly caused by high uncertainties in the chronometric dates used to correlate long-term climatic records with archaeological deposits. One solution is to generate climatic data directly from archaeological materials representing human behavior. Here we use oxygen isotope measurements of Bos/Bison tooth enamel to reconstruct summer and winter temperatures in the Late Pleistocene when Neandertals were using the site of La Ferrassie. Our results indicate that, despite the generally cold conditions of the broader period and despite direct evidence for cold features in certain sediments at the site, Neandertals used the site predominantly when climatic conditions were mild, similar to conditions in modern day France. We suggest that due to millennial scale climate variability, the periods of human activity and their climatic characteristics may not be representative of average conditions inferred from chronological correlations with long-term climatic records. These results highlight the importance of using direct routes, such as the high-resolution archives in tooth enamel from anthropogenically accumulated faunal assemblages, to establish climatic conditions at a human scale.

Issues of theory and method in the analysis of Paleolithic mortuary behavior: A view from Shanidar Cave.

Mortuary behavior (activities concerning dead conspecifics) is one of many traits that were previously widely considered to have been uniquely human, but on which perspectives have changed markedly in recent years. Theoretical approaches to hominin mortuary activity and its evolution have undergone major revision, and advances in diverse archeological and paleoanthropological methods have brought new ways of identifying behaviors such as intentional burial. Despite these advances, debates concerning the nature of hominin mortuary activity, particularly among the Neanderthals, rely heavily on the rereading of old excavations as new finds are relatively rare, limiting the extent to which such debates can benefit from advances in the field. The recent discovery of in situ articulated Neanderthal remains at Shanidar Cave offers a rare opportunity to take full advantage of these methodological and theoretical developments to understand Neanderthal mortuary activity, making a review of these advances relevant and timely.

Named entity recognition in electronic health records using transfer learning bootstrapped Neural Networks.

Neural networks (NNs) have become the state of the art in many machine learning applications, such as image, sound (LeCun et al., 2015) and natural language processing (Young et al., 2017; Linggard et al., 2012). However, the success of NNs remains dependent on the availability of large labelled datasets, such as in the case of electronic health records (EHRs). With scarce data, NNs are unlikely to be able to extract this hidden information with practical accuracy. In this study, we develop an approach that solves these problems for named entity recognition, obtaining 94.6 F1 score in I2B2 2009 Medical Extraction Challenge (Uzuner et al., 2010), 4.3 above the architecture that won the competition. To achieve this, we bootstrap our NN models through transfer learning by pretraining word embeddings on a secondary task performed on a large pool of unannotated EHRs and using the output embeddings as a foundation of a range of NN architectures. Beyond the official I2B2 challenge, we further achieve 82.4 F1 on extracting relationships between medical terms using attention-based seq2seq models bootstrapped in the same manner.

TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.

OBJECTIVE: Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. METHODS: TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers. RESULTS: Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration. INTERPRETATION: Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early-stage clinical trials.

Hominin and animal activities in the microstratigraphic record from Denisova Cave (Altai Mountains, Russia).

Denisova Cave in southern Siberia uniquely contains evidence of occupation by a recently discovered group of archaic hominins, the Denisovans, starting from the middle of the Middle Pleistocene. Artefacts, ancient DNA and a range of animal and plant remains have been recovered from the sedimentary deposits, along with a few fragmentary fossils of Denisovans, Neanderthals and a first-generation Neanderthal-Denisovan offspring. The deposits also contain microscopic traces of hominin and animal activities that can provide insights into the use of the cave over the last 300,000 years. Here we report the results of a micromorphological study of intact sediment blocks collected from the Pleistocene deposits in the Main and East Chambers of Denisova Cave. The presence of charcoal attests to the use of fire by hominins, but other evidence of their activities preserved in the microstratigraphic record are few. The ubiquitous occurrence of coprolites, which we attribute primarily to hyenas, indicates that the site was visited for much of its depositional history by cave-dwelling carnivores. Microscopic traces of post-depositional diagenesis, bioturbation and incipient cryoturbation are observed in only a few regions of the deposit examined here. Micromorphology can help identify areas of sedimentary deposit that are most conducive to ancient DNA preservation and could be usefully integrated with DNA analyses of sediments at archaeological sites to illuminate features of their human and environmental history that are invisible to the naked eye.

Differences in Stress Shoot Performance Among Special Forces Operators Who Participate in a Human Performance Program Versus Those Who Do Not.

BACKGROUND: The purpose of this investigation was to determine if Army Special Operation Forces (ARSOF) Operators who participate in the Tactical Human Optimization, Rapid Rehabilitation and Reconditioning program perform significantly better on a simulated stress shoot scenario than ARSOF Operators who do not participate in the program. METHODS: Deidentified archival data from 64 male ARSOF Operators (mean ± standard deviation: age, 31.1 ± 4.96 years; SOF experience, 3.44 ± 4.10 years) who participated in the Special Forces Advanced Urban Combat stress shoot were assessed to determine if differences in performance existed between program users (n = 25) and nonusers (n = 39). A series of bootstrapped analyses of variance in conjunction with effect-size calculations was conducted to determine if significant mean score differences existed between users and nonusers on raw and total course completion times, high-value target acquisition (positive identification time), and penalties accrued. RESULTS: Small to medium effect sizes were observed between users and nonusers in raw time, penalties, and total time. Although there were no significant differences between users and nonusers, there was less variation in raw time and total time in users compared with nonusers. CONCLUSION: Our findings becomes a question of practical versus statistical significance, because less performance variability while under physical and psychological duress could be life saving for ARSOF Operators.

Perianal synovial sarcoma treated postoperatively with Iodine-125 brachytherapy: Technical details.

PURPOSE: A 23-year-old lady had an incompletely excised perianal sarcoma. Brachytherapy as the sole treatment, rather than further surgery or external beam radiotherapy, was considered to be the best option with the least morbidity. METHODS AND MATERIALS: Although brachytherapy techniques with iridium-192 for anal and rectal carcinoma are well described using a perianal template, the size of the template was not suitable for a two-plane implant that needed to be in situ for about 4 days. An anal canal applicator was designed, which carried three templates about 15 mm apart inside it, to ensure accurate alignment of the tubes, and an inferior template that was 90 mm from the perianal skin. Three inner and three outer tubes of iodine-125 seeds were designed to treat a 2 o'clock h wedge of perianal tissue as a temporary implant. A thin metal shield was placed around a hole to protect the uninvolved anal canal. The tubes were inserted under general anesthetic and delivered a dose of 59 Gy at 0.8 Gy/h over 75 h. A spinal anesthetic was maintained for the duration of the insertion. RESULTS: The treatment was well tolerated, and the patient is well and clear of disease 6 years later with minimal morbidity. CONCLUSIONS: Iodine-125 is a low-energy isotope, readily available in our unit, that can be easily screened to reduce morbidity to surrounding normal tissues. In the form of seeds, it provides a flexible system that can be adapted to different tumor sites as required, as illustrated in this case.

The age of three Middle Palaeolithic sites: Single-grain optically stimulated luminescence chronologies for Pech de l'Azé I, II and IV in France.

Optically stimulated luminescence (OSL) measurements were made on individual, sand-sized grains of quartz from Middle Palaeolithic deposits at three sites (Pech de l'Azé I, II and IV) located close to one another in the Dordogne region of southwest France. We were able to calculate OSL ages for 69 samples collected from these three sites. These ages reveal periods of occupation between about 180 and 50 thousand years ago. Our single-grain OSL chronologies largely support previous age estimates obtained by thermoluminescence dating of burnt flints at Pech IV, electron spin resonance dating of tooth enamel at Pech I, II and IV and radiocarbon dating of bone at Pech I and IV, but provide a more complete picture due to the ubiquitous presence of sand-sized quartz grains used in OSL dating. These complete chronologies for the three sites have allowed us to compare the single-grain ages for similar lithic assemblages among the three sites, to test the correlations among them previously proposed by Bordes in the 1970s, and to construct our own correlative chronological framework for the three sites. This shows that similar lithic assemblages occur at around the same time, and that where a lithic assemblage is unique to one or found at two of the Pech sites, there are no deposits of chronologically equivalent age at the other Pech site(s). We interpret this to mean that, at least for these Pech de l'Azé sites, the Mousterian variants show temporal ordering. Whether or not this conclusion applies to the wider region and beyond, the hypothesis that Mousterian industrial variation is temporally ordered cannot be refuted at this time.

Driving physician adoption of mHeath solutions.

A well-executed mobile health (mHealth) solution can help a hospital with its population health and readmission reduction initiatives. Successful implementation of an mHealth solution requires a campaign to persuade physicians to use it. Orchestrating physician adoption includes educating physicians about benefits such as easy access to lab results, enhanced caregiver communications, and better access to consult requests.