Forensic DNA Phenotyping: Improving the Prediction of Eye, Hair, and Skin Color through Quantitative Measurement

poster abstractWithout a match in the DNA database or a reference profile, current methods in forensic DNA profiling fail to give any leads to further criminal investigations. Forensic DNA Phenotyping bridges that gap in the investigation by providing ‘intelligence’ through the identification of externally visible characteristics of the unknown individual from their biological sample left at the crime scene. Recent work on eye and hair color prediction using a tool called ‘HIrisPlex’ has allowed accurate predictions of blue or brown eye color with a precision greater than 95%, and of hair color with a precision of approximately 75% for blond, brown, black and red categories. DNA phenotyping is a new and exciting area of DNA profiling, however there are areas that still require improvement. These include the prediction of intermediate eye colors such as green, or the mechanisms and/or genes involved in age-dependent hair color changes. At this time, categorical skin color prediction is still being developed and will soon be included in the HIrisPlex system, however it is not until the day that pigmentation measurements move toward a quantitative color scale that accuracy will be at a maximum. Our research hopes to target this area specifically. While the predication of categorical measurements is helpful, the term “light brown” is subjective and leads to the possibility of error in interpretation. In order to circumvent this interpretation issue, understanding quantitative color prediction is key. To achieve this, we are in the midst of a database collection of approximately 5000 individuals in which we will perform genome-wide association studies (GWAS) to locate additional eye, hair and skin color genes associated with a quantitative pigment scale phenotype. This database will help create a world-wide representative statistical panel from which quantitative predictive measures can be ascertained. Furthermore, in conjunction with computer programming techniques, it will allow the creation of a user-friendly software program that will enable the prediction of pigmentation-related externally visible characteristics such as eye, hair and skin color. This software has the capacity to be a revolutionary intelligence tool to aid law enforcement investigations by producing a color-print out biological mugshot

Molecular and Cellular Mechanisms of Aging in Hematopoietic Stem Cells and Their Niches

Aging drives the genetic and epigenetic changes that result in a decline in hematopoietic stem cell (HSC) functioning. Such changes lead to aging-related hematopoietic/immune impairments and hematopoietic disorders. Understanding how such changes are initiated and how they progress will help in the development of medications that could improve the quality life for the elderly and to treat and possibly prevent aging-related hematopoietic diseases. Here, we review the most recent advances in research into HSC aging and discuss the role of HSC-intrinsic events, as well as those that relate to the aging bone marrow niche microenvironment in the overall processes of HSC aging. In addition, we discuss the potential mechanisms by which HSC aging is regulated

TAK1 and TBK1 are Differentially Required by GMP- and LMPP-like Leukemia Stem Cells

Acute myeloid leukemia (AML) encompasses a diverse group of cancers that originate in the blood-forming tissues of the bone marrow. Aside from the M3 subtype (PML-RARA+), AML carries a 5-year survival rate of 28% for patients 20+ years of age. AML is the most common cancer of the hematopoietic system and is slightly more common in biological males; the average age at diagnosis is 68 years. Standard frontline treatment for AML is a 2-phase regimen of intensive chemotherapy (CTx) employing daunorubicin and cytarabine. Despite 60-70% of patients achieving complete remission (CR), at least half of CR-achieving patients experience relapse within 3 years from their diagnosis. Additionally, 30-40% of patients present with refractory AML, experiencing little to no benefit from frontline treatment. AML relapses when a pool of undetectable, CTx-resistant leukemia stem cells (LSCs) survives & proliferates after frontline CTx [1]. Notably, the poor performance status of many AML patients precludes use of the standard CTx regimen; while reduced-intensity CTx still offers therapeutic benefit, it is less effective at killing LSCs and, as a result, relapse is more likely. Goardon, et al. determined that AML patients harbor two types of LSCs: granulocyte-macrophage progenitor (GMP)-like LSCs and FLT3+ lymphoid-primed multipotential progenitor (LMPP)-like LSCs [2]. Eradication of both types of LSCs is necessary to maintain CR in AML. Our group and others have established that ~40% of AML patients express upregulated Toll-like receptor (TLR) signaling (TLR+). TLR+ disease is associated with specific genetic abnormalities, such as MLL rearrangements (MLL-r+), and is inversely associated with prognosis (Figure 1) [3,4]. TLR+ AML represents a challenging, treatment-sparse subset of an already difficult-to-treat disease. To study TLR+ AML, we utilize an MLL-r+ model using the MLL-AF9 oncogene. We have also demonstrated that both GMP- and LMPP-like LSCs require TLR-associated Ser/Thr protein kinases for their survival [5-7]. Specifically, GMP-like LSCs require TAK1 and LMPP-like LSCs require TBK1. The loss of either Tak1 or Tbk1 ablates the corresponding LSC pool and enriches for the opposite LSC pool in vitro and in vivo. Recently, our group determined that the genetic loss of Tak1 sensitizes mouse AML cells to TBK1 blockade in vitro. Strikingly, the loss of Tbk1 also seems to extend overall survival (OS) despite causing extramedullary AML. While mice given Tbk1NULL AML cells develop a subcutaneous tumor of AML cells (chloroma) near the pelvis, they survive longer than mice given control (Tbk1WT) AML cells. The clinical significance is unknown, but these data support our impression that the loss of Tbk1 forces AML cells to differentiate; this should be therapeutically favorable, as inducing the differentiation of AML cells is an effective treatment strategy. Theoretically, chloromas may form in Tbk1NULL AML due to the enrichment of GMP-like LSCs, which express higher levels of chemokine receptors. We hypothesize that the differentiation & eradication of LSCs can be induced by blocking TAK1/TBK1 in combination with standard CTx (and possibly targeted agents like Mylotarg®, Venclexta®, and/or Xospata®). We propose TAK1/TBK1 parallel blockade as augmentation to standard CTx, ideally allowing for a dose-reduction of CTx & promoting improved patient outcomes

Changes in interpersonal violence and utilization of trauma recovery services at an urban trauma center in the United States during the COVID-19 pandemic: a retrospective, comparative study

Purpose This study investigated changes in interpersonal violence and utilization of trauma recovery services during the COVID-19 pandemic. At an urban level I trauma center, trauma recovery services (TRS) provide education, counseling, peer support, and coordination of rehabilitation and recovery to address social and mental health needs. The COVID-19 pandemic prompted considerable changes in hospital services and increases in interpersonal victimization. Methods A retrospective analysis was conducted between September 6, 2018 and December 20, 2020 for 1,908 victim-of-crime patients, including 574 victims of interpersonal violence. Outcomes included length of stay associated with initial TRS presentation, number of subsequent emergency department visits, number of outpatient appointments, and utilization of specific specialties within the year following the initial traumatic event. Results Patients were primarily female (59.4%), single (80.1%), non-Hispanic (86.7%), and Black (59.2%). The mean age was 33.0 years, and 247 patients (49.2%) presented due to physical assault, 132 (26.3%) due to gunshot wounds, and 76 (15.1%) due to sexual assault. The perpetrators were primarily partners (27.9%) or strangers (23.3%). During the study period, 266 patients (mean, 14.9 patients per month) presented before the declaration of COVID-19 as a national emergency on March 13, 2020, while 236 patients (mean, 25.9 patients per month) presented afterward, representing a 74.6% increase in victim-of-crime patients treated. Interactions with TRS decreased during the COVID-19 period, with an average of 3.0 interactions per patient before COVID-19 versus 1.9 after emergency declaration (P<0.01). Similarly, reductions in length of stay were noted; the pre–COVID-19 average was 3.6 days, compared to 2.1 days post–COVID-19 (P=0.01). Conclusions While interpersonal violence increased, TRS interactions decreased during the COVID-19 pandemic, reflecting interruption of services, COVID-19 precautions, and postponement/cancellation of elective visits. Future direction of hospital policy to enable resource and service delivery to this population, despite internal and external challenges, appears warranted

Single or double headed capsules for the investigation of suspected small bowel bleeding: Are two heads better than one

BackgroundCapsule endoscopy is now the accepted first line investigation for suspected small bowel (SB) bleeding. Recent evidence suggests the diagnostic yield for SB pathology may be higher for tailored double headed (DH) SB capsules. Whether other forms of bidirectional capsules offer a similar advantage is less clear.AimTo compare the efficacy of single headed versus bidirectional capsules in detecting pathology in patients with suspected small bowel bleeding.MethodsA single centre prospective comparison study was conducted over an 8 month period in a tertiary care hospital. Patients referred with overt or suspected SB bleeding were assigned to either SB3 Medtronic SB capsule (SH) during the initial four months or PillCam Colon 2 Medtronic capsule (DH) during the subsequent four months. Studies were analysed by trained Capsule Endoscopists and approved by our institutions capsule review board. Findings were compared between SH and DH capsules using a chi2 or t-test as appropriate. A p value of &lt;0.05 was considered significant.Results201 subjects were included, mean age 61.8 years, 90 (45%) male. Majority referred with occult bleeding, 153 (76%). DH and SH capsule used in 100 and 101 cases, respectively. 90% (n=181) capsules were complete and overall diagnostic yield was 57% (n=114). Diagnostic yield was similar between both groups - DH 53% (n=53), SH 60% (n=61). Positive finding in overt bleeding; SH 85% (n=22) versus DH 50% (n=11), p&lt;0.02. SH capsules more frequently detected SB inflammation, 27 (27%) versus 9 (9%), p&lt;0.002. More patients had another diagnosis in the DH (19) than the SH (9), p&lt;0.04, the majority were type 1a vascular lesions, “red spots” or diminutive colonic polyps.ConclusionSingle head and double head capsules perform similary in terms of diagnostic yield overall. This supports the continued use of standard small bowel capsules for investigation of the small bowel

Variance components for bovine tuberculosis infection and multi-breed genome-wide association analysis using imputed whole genome sequence data

peer-reviewedBovine tuberculosis (bTB) is an infectious disease of cattle generally caused by Mycobacterium bovis, a bacterium that can elicit disease humans. Since the 1950s, the objective of the national bTB eradication program in Republic of Ireland was the biological extinction of bTB; that purpose has yet to be achieved. Objectives of the present study were to develop the statistical methodology and variance components to undertake routine genetic evaluations for resistance to bTB; also of interest was the detection of regions of the bovine genome putatively associated with bTB infection in dairy and beef breeds. The novelty of the present study, in terms of research on bTB infection, was the use of beef breeds in the genome-wide association and the utilization of imputed whole genome sequence data. Phenotypic bTB data on 781,270 animals together with imputed whole genome sequence data on 7,346 of these animals’ sires were available. Linear mixed models were used to quantify variance components for bTB and EBVs were validated. Within-breed and multi-breed genome-wide associations were undertaken using a single-SNP regression approach. The estimated genetic standard deviation (0.09), heritability (0.12), and repeatability (0.30) substantiate that genetic selection help to eradicate bTB. The multi-breed genome-wide association analysis identified 38 SNPs and 64 QTL regions associated with bTB infection; two QTL regions (both on BTA23) identified in the multi-breed analysis overlapped with the within-breed analyses of Charolais, Limousin, and Holstein-Friesian. Results from the association analysis, coupled with previous studies, suggest bTB is controlled by an infinitely large number of loci, each having a small effect. The methodology and results from the present study will be used to develop national genetic evaluations for bTB in the Republic of Ireland. In addition, results can also be used to help uncover the biological architecture underlying resistance to bTB infection in cattle

Longitudinal Impact of Childhood Adversity on Early Adolescent Mental Health During the COVID-19 Pandemic in the ABCD Study Cohort: Does Race or Ethnicity Moderate Findings?

Background During the COVID-19 pandemic in the United States, mental health among youth has been negatively affected. Youth with a history of adverse childhood experiences (ACEs), as well as youth from minoritized racial-ethnic backgrounds, may be especially vulnerable to experiencing COVID-19–related distress. The aims of this study are to examine whether exposure to pre-pandemic ACEs predicts mental health during the COVID-19 pandemic in youth and whether racial-ethnic background moderates these effects. Methods From May to August 2020, 7983 youths (mean age, 12.5 years; range, 10.6–14.6 years) in the Adolescent Brain Cognitive Development (ABCD) Study completed at least one of three online surveys measuring the impact of the pandemic on their mental health. Data were evaluated in relation to youths\u27 pre-pandemic mental health and ACEs. Results Pre-pandemic ACE history significantly predicted poorer mental health across all outcomes and greater COVID-19–related stress and impact of fears on well-being. Youths reported improved mental health during the pandemic (from May to August 2020). While reporting similar levels of mental health, youths from minoritized racial-ethnic backgrounds had elevated COVID-19–related worry, stress, and impact on well-being. Race and ethnicity generally did not moderate ACE effects. Older youths, girls, and those with greater pre-pandemic internalizing symptoms also reported greater mental health symptoms. Conclusions Youths who experienced greater childhood adversity reported greater negative affect and COVID-19–related distress during the pandemic. Although they reported generally better mood, Asian American, Black, and multiracial youths reported greater COVID-19–related distress and experienced COVID-19–related discrimination compared with non-Hispanic White youths, highlighting potential health disparities