Utah College of Applied Technology

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Abstract Here, Ruby et al. analyze an unprecedented amount of public family tree data from Ancestry and determine that the heritability of human longevity was well below 10%, lower than the widely-held belief that lifespan... Human life span is a phenotype that integrates many aspects of health and environment into a single ultimate quantity: the elapsed time between birth and death. Though it is widely believed that long life runs in families for genetic reasons, estimates of life span “heritability” are consistently low (∼15–30%). Here, we used pedigree data from Ancestry public trees, including hundreds of millions of historical persons, to estimate the heritability of human longevity. Although “nominal heritability” estimates based on correlations among genetic relatives agreed with prior literature, the majority of that correlation was also captured by correlations among nongenetic (in-law) relatives, suggestive of highly assortative mating around life span-influencing factors (genetic and/or environmental). We used structural equation modeling to account for assortative mating, and concluded that the true heritability of human longevity for birth cohorts across the 1800s and early 1900s was well below 10%, and that it has been generally overestimated due to the effect of assortative mating.

The COVID-19 pandemic continues to pose a major public health threat,\nespecially in countries with low vaccination rates. To better understand\nthe biological underpinnings of SARS-CoV-2 infection and COVID-19\nseverity, we formed the COVID-19 Host Genetics Initiative1\n. Here we\npresent a genome-wide association study meta-analysis of up to 125,584\ncases and over 2.5 million control individuals across 60 studies from\n25 countries, adding 11 genome-wide significant loci compared with\nthose previously identified2\n. Genes at new loci, including SFTPD, MUC5B\nand ACE2, reveal compelling insights regarding disease susceptibility\nand severity

Despite strides in characterizing human history from genetic polymorphism data, progress in identifying genetic signatures of recent demography has been limited. Here we identify very recent fine-scale population structure in North America from a network of over 500 million genetic (identity-by-descent, IBD) connections among 770,000 genotyped individuals of US origin. We detect densely connected clusters within the network and annotate these clusters using a database of over 20 million genealogical records. Recent population patterns captured by IBD clustering include immigrants such as Scandinavians and French Canadians; groups with continental admixture such as Puerto Ricans; settlers such as the Amish and Appalachians who experienced geographic or cultural isolation; and broad historical trends, including reduced north-south gene flow. Our results yield a detailed historical portrait of North America after European settlement and support substantial genetic heterogeneity in the United States beyond that uncovered by previous studies.

Abstract We present a massive investigation into the genetic basis of human lifespan. Beginning with a genome-wide association (GWA) study using a de-identified snapshot of the unique AncestryDNA database – more than 300,000 genotyped individuals linked to pedigrees of over 400,000,000 people – we mapped six genome-wide significant loci associated with parental lifespan. We compared these results to a GWA analysis of the traditional lifespan proxy trait, age, and found only one locus, APOE, to be associated with both age and lifespan. By combining the AncestryDNA results with those of an independent UK Biobank dataset, we conducted a meta-analysis of more than 650,000 individuals and identified fifteen parental lifespan-associated loci. Beyond just those significant loci, our genome-wide set of polymorphisms accounts for up to 8% of the variance in human lifespan; this value represents a large fraction of the heritability estimated from phenotypic correlations between relatives.

Abstract Ultracentrifuged faeces from a variety of species of domestic animals with diarrhoea were examined by electron microscopy. Rotaviruses were detected in faeces of cattle, pigs and horses from neonates to 6 months of age. Infections were most common in the early post-natal period. Rotavirus infection was usually associated with a history of recurrent outbreaks of severe diarrhoea that was unresponsive to conventional antibacterial and symptomatic treatment. Coronaviruses were found in faeces of cattle, sheep, deer and horse, and were associated with sudden out-breaks of profuse, watery diarrhoea. A wide range of ages were represented in the infected group. Direct electron microscopy and immune-electron microscopy of faeces clarified by centrifugation in a microhaematocrit centrifuge, proved to be useful ancillary techniques of examination.

Abstract We conducted a meta‐analysis on the most commonly used forensic polygraph test, the Comparison Question Test. We captured as many studies as possible by using broad inclusion criteria. Data and potential moderators were coded from 138 datasets. The meta‐analytic effect size including inconclusive outcomes was 0.69 [0.66, 0.79]. We found significant moderator effects. Notably, level of motivation had a positive linear relationship with our outcome measures. Information Gain analysis of CQT outcomes representing the median accuracy showed a significant information increase over interpersonal deception detection across almost the complete range of base rates. Our results suggest that the CQT can be accurate, that experimental studies are generalizable, and no publication bias was detected. We discussed the limitations of the field research literature and problems within polygraph profession that lower field accuracy. We suggest some possible solutions.

This study explores the meaning of weaving for Karen refugee women from Burma as they participated in their traditional practice of weaving in Salt Lake City, Utah. Participants included eight Karen refugee women. Data were collected through one focus group and in-depth, semi-structured, open-ended interviews, structured to capture past and present meanings related to weaving. Transcription and analysis of the interviews and focus group were guided by phenomenology. Three themes emerged from structured, qualitative analysis: “I am Karen people”; “When there is nobody I am not happy, but with a lot of people I am happy”; and “If I can sell a lot of things I am happy to weave all the time”. The findings demonstrate how potent one occupation can be for the well-being of a particular group of people in terms of cultural identity construction, empowerment, social support, and economic survival in a new environment.

Abstract A virological survey was carried out on 150 calf faeces from 30 central North Island properties, utilising electron miscroscopic examination of ultracentrifuged faecal pellets. Rotaviruses were detected on three farms, and coronavirus-like particles on two farms. In the same area, three other properties with past histories of rotavirus infection were also studied. Weekly examination of faeces from 10 calves from each property over a period of 5 weeks demonstrated that rotavirus excretion commenced at the same time as the onset of outbreaks of diarrhoea. On two of these rotavirus-positive farms, coronaviruses were also detected. At one farm, this coincided with rotavirus excretion and diarrhoea, and was associated with a more severe clinical disease but, on the other property, the coronavirus was unassociated with clinical disease. A similar study, carried out on a further property with a past history of coronavirus infection, showed that coronavirus excretion commenced simultaneously with the onset of an outbreak of diarrhoea. The virus was, however, detected in small numbers in 1 of 10 calves only. The results of the survey, coupled with previously gathered data, indicate that both viruses may be widespread in the cattle population. On some properties, rotavirus had a clear association with diarrhoea, but the relationship of coronavirus to diarrhoea was less well-established.

Most signal transduction pathways in humans are regulated by protein kinases through phosphorylation of their protein substrates. Typical eukaryotic protein kinases are of two major types: those that phosphorylate-specific sequences containing tyrosine (~90 kinases) and those that phosphorylate either serine or threonine (~395 kinases). The highly conserved catalytic domain of protein kinases comprises a smaller N lobe and a larger C lobe separated by a cleft region lined by the activation loop. Prior studies find that protein tyrosine kinases recognize peptide substrates by binding the polypeptide chain along the C-lobe on one side of the activation loop, while serine/threonine kinases bind their substrates in the cleft and on the side of the activation loop opposite to that of the tyrosine kinases. Substrate binding structural studies have been limited to four families of the tyrosine kinase group, and did not include Src tyrosine kinases. We examined peptide-substrate binding to Src using paramagnetic-relaxation-enhancement NMR combined with molecular dynamics simulations. The results suggest Src tyrosine kinase can bind substrate positioning residues C-terminal to the phosphoacceptor residue in an orientation similar to serine/threonine kinases, and unlike other tyrosine kinases. Mutagenesis corroborates this new perspective on tyrosine kinase substrate recognition. Rather than an evolutionary split between tyrosine and serine/threonine kinases, a change in substrate recognition may have occurred within the TK group of the human kinome. Protein tyrosine kinases have long been therapeutic targets, but many marketed drugs have deleterious off-target effects. More accurate knowledge of substrate interactions of tyrosine kinases has the potential for improving drug selectivity.

In the last decade, many advances have been made in the field of automatic temperature estimation, including wearable sensor technologies (WST), infrared thermography (IRT), and non-contact infrared thermometer (NCIT). In contrast with the WST and IRT, NCIT is inexpensive without the risk of potential skin irritation. Nevertheless, NCIT is limited in short valid estimation distance (<;12 cm), resulting in the non-satisfaction of the surging application requirements nowadays. This paper proposed an algorithm based on Neural Network Regression not only to reduce the error from 0.6° to 0.12°, which is close to the medical instrument level, but as well to lengthen the valid distance to the range between 50 cm and 100 cm. Furthermore, this study developed an embedded automatic body temperature estimation system which could continuously and unconsciously measure the human temperature in real-time. Integrated with face tracking and fuzzy-control of Pan-tilt unit, the system ensures that human face is focused while measuring. With wireless communication techniques, users can review their physiological Information via App and Web, which is beneficial to remote healthcare.

Background: The prevalence of hypothyroidism (HT) has increased over time. To assess the effectiveness of treatment, we (1) studied thyrotropin (TSH) levels among patients receiving levothyroxine (LT4) and (2) determined the percentages of patients switching among LT4 formulations. Methods: Data on patients with HT receiving LT4 from the Optum™ Clinical and Claims Database were analyzed from March 2013 through February 2020. Eligible adult patients had ≥1 medical claim with an HT diagnosis and all patients were observed for ≥12 months. Patients included in Objective 1 were indexed on a randomly selected TSH result and had ≥2 results for TSH 1–15 months apart. Patients included in Objective 2 were indexed on a randomly selected LT4 pharmacy claim and had ≥2 LT4 claims ≥1 month apart and ≥1 claim during follow-up. Outcomes were the proportion of patients with low, normal, or high (&lt;0.45, 0.45–4.5, or &gt;4.5 mIU/L, respectively) TSH levels and the proportion of patients switching LT4 formulations, respectively. Data were stratified by age group, sex, and insurance type. All data reported were analyzed using descriptive statistics. Results: Of patients who were in the indexed TSH group, 81.1% [confidence intervals: 80.4–81.8; n / N = 9130/11,259] achieved normal TSH values. When stratified by age group, sex, and insurance type, ≥70% of patients in each of these subgroups exhibited normal mean TSH values at follow-up. For Objective 2 ( N = 25,076), 24.9% ( N = 6238) of the LT4-indexed group had ≥1 formulation switch in 12 months, of which 67.3% only switched once, and 41.4% ( N = 10,370) had ≥1 formulation switch in up to 24 months. A significantly higher proportion of Medicare vs. commercially insured patients had switched formulations (26.2% vs. 23.1%, p &lt; 0.001). Conclusions: Most LT4-treated patients maintain normal TSH levels, which is an improvement vs. previous reports. Continued physician engagement and patient education are advised to further reduce the number of patients who maintain off-target TSH levels. Contrary to clinical recommendations, about 25% of patients receiving LT4 switched formulations within 1 year, with &gt;40% switching within 2 years; among patients who switched, most only switched once.

PURPOSE: This work seeks to develop exact confidence interval estimators for figures of merit that describe the performance of linear observers, and to demonstrate how these estimators can be used in the context of x-ray computed tomography (CT). The figures of merit are the receiver operating characteristic (ROC) curve and associated summary measures, such as the area under the ROC curve. Linear computerized observers are valuable for optimization of parameters associated with image reconstruction algorithms and data acquisition geometries. They provide a means to perform assessment of image quality with metrics that account not only for shift-variant resolution and nonstationary noise but that are also task-based. METHODS: We suppose that a linear observer with fixed template has been defined and focus on the problem of assessing the performance of this observer for the task of deciding if an unknown lesion is present at a specific location. We introduce a point estimator for the observer signal-to-noise ratio (SNR) and identify its sampling distribution. Then, we show that exact confidence intervals can be constructed from this distribution. The sampling distribution of our SNR estimator is identified under the following hypotheses: (i) the observer ratings are normally distributed for each class of images and (ii) the variance of the observer ratings is the same for each class of images. These assumptions are, for example, appropriate in CT for ratings produced by linear observers applied to low-contrast lesion detection tasks. RESULTS: Unlike existing approaches to the estimation of ROC confidence intervals, the new confidence intervals presented here have exactly known coverage probabilities when our data assumptions are satisfied. Furthermore, they are applicable to the most commonly used ROC summary measures, and they may be easily computed (a computer routine is supplied along with this article on the Medical Physics Website). The utility of our exact interval estimators is demonstrated through an image quality evaluation example using real x-ray CT images. Also, strong robustness is shown to potential deviations from the assumption that the ratings for the two classes of images have equal variance. Another aspect of our interval estimators is the fact that we can calculate their mean length exactly for fixed parameter values, which enables precise investigations of sampling effects. We demonstrate this aspect by exploring the potential reduction in statistical variability that can be gained by using additional images from one class, if such images are readily available. We find that when additional images from one class are used for an ROC study, the mean AUC confidence interval length for our estimator can decrease by as much as 35%. CONCLUSIONS: We have shown that exact confidence intervals can be constructed for ROC curves and for ROC summary measures associated with fixed linear computerized observers applied to binary discrimination tasks at a known location. Although our intervals only apply under specific conditions, we believe that they form a valuable tool for the important problem of optimizing parameters associated with image reconstruction algorithms and data acquisition geometries, particularly in x-ray CT.

Eye health in patients with myeloma. Newer regimens have continued to improve outcomes in multiple myeloma (MM). For many such regimens, dexamethasone (often 20–40 milligrams weekly) is continued alongside other anti-MM agents until progression. A link between systemic dexamethasone and ocular cataracts was first established decades ago, likely due to corticosteroid-related metabolic or oxidative changes within the lens.1-4 Despite the ubiquity of dexamethasone in MM regimens, however, relatively few studies have investigated its association with ocular toxicities in MM. In one claims analysis, the prevalence of ocular comorbidities in MM rose with each subsequent line of therapy (LoT) as compared to newly diagnosed MM.5 Potential mechanisms for this finding include continued dexamethasone, advancing age, and perhaps chronic paraprotein-mediated damage to the lens.6, 7 As a first step toward characterizing the specific impact of dexamethasone on ocular comorbidities, we used patient-reported and Electronic Medical Record (EMR)-derived data to analyze relationships between dexamethasone exposure, patient-reported cataract incidence, and patient-reported cataract severity. We analyzed patient-reported data from users of the HealthTree Cure Hub for MM, an online platform promoted to patients with MM residing in the United States (US) through emails, social media, and community events. As of December 2022, 11 356 patients with MM have created a Cure Hub account. In addition to educational materials and discussion forums, patients can optionally answer questions about previous LoT and what side effects they developed. The platform also optionally allows patients to authorize linkage of their treating center's EMR to their survey responses for use in deidentified research. We conducted a targeted analysis of patients on the Cure Hub platform who had recalled first developing cataracts with any LoT, including their current LoT. All patients who reported cataracts were asked to rate their cataracts at the time of initial presentation on a 1–5 scale of severity: (1) hardly noticeable; (2) uncomfortable but manageable; (3) disruptive; (4) severely disruptive; and (5) unmanageable requiring treatment discontinuation. When patients reported that cataracts had developed with a given LoT, we estimated the number of cycles before cataract onset by calculating the total number of months where the patient had been on any dexamethasone-containing regimen (excluding months without any corticosteroids, for example, lenalidomide maintenance). Within the LoT where cataracts were first reported, we approximated the actual date of cataract incidence as the median date between LoT initiation and discontinuation (or, for patients still on that LoT, the median date between LoT initiation and survey completion). For uniformity, we converted days of dexamethasone exposure into 28-day cycles. For the subset of patients who had authorized EMR linkage at the time of survey completion, we reviewed their dexamethasone prescriptions to identify the total number of dexamethasone-containing cycles, total milligrams (mg) dexamethasone prescribed across all cycles, and median mg dexamethasone per week across all dexamethasone-containing cycles. We conducted time-to-event survival analyses to conduct the cumulative risk of cataracts based on the number of cycles of exposure to dexamethasone. Ordinal logistic regression and correlation analyses were performed to evaluate the association between dexamethasone exposure and cataract severity. The parent protocol for the use of the Cure Hub for de-identified secondary analyses was reviewed and declared exempt by the WCG Institutional Review Board. Of 231 patients who reported having developed cataracts following the initiation of MM therapy, respondents were balanced between genders (43% male, 57% female) but were predominantly White (85%). The median age at cataract onset was 65 years [interquartile range (IQR) 61–68], and most patients were on their first LoT (78%, n = 182) or second LoT (17%, n = 40) at the time of cataract onset. Cataract severity (on a 1–5 Likert scale) was rated as hardly noticeable by 23%, uncomfortable by 29%, disruptive by 36%, severely disruptive by 11%, and requiring treatment discontinuation by 1%. Time-to-event analyses (Figure 1) demonstrated that, of patients who did develop cataracts, 36% (n = 83) did so within 6 cycles of dexamethasone-containing regimens while 48% (n = 111) did so within 12 cycles. We then performed more detailed analyses of the 97 patients (42% of all respondents) who had pre-authorized EMR linkage at the time of survey completion. Compared to the larger population of respondents, this subset of 97 patients had similar demographic characteristics apart from ethnicity (Table S1). Of these 97 patients, the median total dexamethasone dose from first-line treatment initiation to the time of cataract development was 1020 mg (IQR 520–2000 mg), which corresponded to a median dose of 40 mg (IQR 20–40 mg) per week. Ordinal regression analyses demonstrated a significant association between total mg of dexamethasone exposure and cataract severity, with a coefficient estimate (ce) of .255, p = .047. Among patients who rated their cataracts as severely disruptive or unmanageable (4 or higher on a 1–5 Likert scale), median total dexamethasone exposure was 1907 mg versus 788 mg for those who rated their cataract severity as hardly noticeable (1 on a 1–5 Likert scale). However, age at cataract onset (ce .004, p = .817), median dexamethasone dose per cycle (ce −.004, p = .189), and total number of dexamethasone-containing cycles (ce −0.016, p = .155) did not show significant relationships with cataract severity. In summary, we analyzed patient-reported data around cataract timing and reported severity for 231 patients living with MM. Of patients who newly developed cataracts following their MM diagnosis, over a third did so within 6 months of exposure to dexamethasone. We also conducted a more detailed analysis of dexamethasone dosing in patients who had authorized EMR linkage to their responses. In this subset of almost 100 patients, we found that total milligrams of dexamethasone exposure longitudinally—but not milligrams per cycle or total number of cycles—was a significant predictor of cataract severity. Indeed, patients who rated their cataracts as severely disruptive or unmanageable had over twice the total dexamethasone exposure as those who rated their cataracts more mildly. Our findings serve as the starting point for prospective research into the ocular health of patients with MM with an emphasis on dexamethasone dosing. Given the modest nature of our cross-sectional analysis, our study limitations warrant upfront discussion. Due to the ubiquity of corticosteroids in MM treatment regimens, we did not have a control arm of patients who were unexposed to dexamethasone during therapy. Similarly, although patients identified the start and end dates of the LoT during which they first developed cataracts, we were not able to identify precisely when cataracts developed during that LoT. For our second set of analyses involving detailed dexamethasone dosing, other potential confounders for cataract development (for example, lens damage from high paraprotein levels)2 could not be assessed. Compared to the US distribution of patients with MM,8 our respondents were younger, more likely to be female, and less likely to be from racial minorities. Selection bias in terms of patients who were willing to create a Cure Hub account and participate in this survey may also limit the generalizability of our findings. Nevertheless, our study is noteworthy in that total longitudinal dexamethasone dose (but not total time on dexamethasone) was a significant predictor of cataract severity. Cataracts are very prevalent in relapsed MM, a fact underscored by baseline ophthalmological exams in studies of belantamab mafodotin. In a pooled analysis of the DREAMM-2 trial among patients who had received at least three prior LoT (median ages 65–67 at baseline), 60% of patients were found to have cataracts on ophthalmologic exams before their first dose of belantamab.9 This high prevalence is related to several factors, including advancing age itself as a risk factor for cataract development.10 Our research focused more specifically on patient-reported cataracts, almost half of which were rated as uncomfortable or disruptive when they were diagnosed. Visually significant cataracts can impair patient quality of life as well as the practicalities of MM care, for example, one's ability to drive to the clinic for infusions. Future survey-based studies of ocular health in plasma cell disorders, enrolling both patients with MM as well as age-matched controls with MM precursor conditions where weekly dexamethasone is not used, are actively in development. These studies will also investigate the risk of corticosteroid-induced glaucoma, another ophthalmologic complication that carries a potential risk of irreversible vision loss. More broadly, the importance of dexamethasone in MM after its initial role in cytoreduction and infusion reaction prophylaxis remains unclear. Among frailer patients, scheduled discontinuation of dexamethasone during first-line therapy does not compromise efficacy.11 There are already many reasons to consider dexamethasone dose reduction in MM based on toxicities that patients and physicians recognize rapidly, for example, insomnia or hyperglycemia. Our study demonstrates that dexamethasone may also accelerate the development of visually significant cataracts, an adverse event that may develop more insidiously. Given the uncertain long-term contribution of dexamethasone to most MM regimens, our findings suggest that reducing dexamethasone exposure after the first few cycles could be considered in all patients with MM regardless of age or frailty. The authors acknowledge the patients who participated in this study. Jennifer M. Ahlstrom Patient advocacy committee: Pfizer, BMS, Janssen, Takeda Oncology, and Sanofi. JRH receives research funding from Adaptive Biotechnologies, Sanofi, GlaxoSmithKline, Regeneron, Janssen and Takeda. Rahul Banerjee: Consultancy: BMS, Janssen, Pfizer, Genentech/Roche, Sanofi Pasteur, SparkCures; Research Funding: Pack Health. Jennifer M. Ahlstrom: Consultancy: Pfizer, BMS, Janssen, Takeda, and Sanofi. Andrew J. Cowan: Consultancy: BMS, Adaptive Biotechnologies; Research Funding: Adaptive Biotechnologies, Harpoon, Nektar, BMS, Janssen, Sanofi, Abbvie. Data are available upon reasonable request by emailing the corresponding author ([email protected]). Table S1. Baseline demographics. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

OBJECTIVES: The enormous toll of the COVID-19 pandemic has heightened the urgency of collecting and analysing population-scale datasets in real time to monitor and better understand the evolving pandemic. The objectives of this study were to examine the relationship of risk factors to COVID-19 susceptibility and severity and to develop risk models to accurately predict COVID-19 outcomes using rapidly obtained self-reported data. DESIGN: A cross-sectional study. SETTING: AncestryDNA customers in the USA who consented to research. PARTICIPANTS: The AncestryDNA COVID-19 Study collected self-reported survey data on symptoms, outcomes, risk factors and exposures for over 563 000 adult individuals in the USA in just under 4 months, including over 4700 COVID-19 cases as measured by a self-reported positive test. RESULTS: We replicated previously reported associations between several risk factors and COVID-19 susceptibility and severity outcomes, and additionally found that differences in known exposures accounted for many of the susceptibility associations. A notable exception was elevated susceptibility for men even after adjusting for known exposures and age (adjusted OR=1.36, 95% CI=1.19 to 1.55). We also demonstrated that self-reported data can be used to build accurate risk models to predict individualised COVID-19 susceptibility (area under the curve (AUC)=0.84) and severity outcomes including hospitalisation and critical illness (AUC=0.87 and 0.90, respectively). The risk models achieved robust discriminative performance across different age, sex and genetic ancestry groups within the study. CONCLUSIONS: The results highlight the value of self-reported epidemiological data to rapidly provide public health insights into the evolving COVID-19 pandemic.

Abstract Background Androgen receptor (AR) gene alterations, as detected by circulating tumor cell‐free DNA (cfDNA) genomic profiling, have been shown to emerge after a variable duration of androgen signaling inhibition. AR alterations were associated with inferior outcomes on treatment with androgen receptor pathway inhibitors (ARPI) in the first line metastatic castration‐resistant prostate cancer (mCRPC) setting in a phase 2 trial. Here in, we assessed the impact of these AR alterations on survival outcomes in a real‐world patient population of mCRPC experiencing disease progression on an ARPI. Methods In this IRB‐approved retrospective study, consecutively seen patients with a confirmed diagnosis of mCRPC, with disease progression on a treatment with ARPIs in the first line mCRPC setting, with no prior exposure to an ARPI in the castration sensitive setting, and with available cfDNA profiling from a CLIA certified laboratory were included. Patients were categorized based on AR status: wild‐type ( AR wt ) or alteration‐positive ( AR + ). The objective was to correlate overall survival (OS) after disease progression on the first‐line ARPI with the presence or absence of AR alterations. Kaplan–Meier and Cox Regression Tests were used as implemented in R‐Studio (v.4.2). Results A total of 137 mCRPC patients were eligible: 69 with AR wt versus 68 with AR + . The median OS posttreatment with the first ARPI was significantly higher for AR wt than AR + patients (30.1 vs. 15.2 mos; p &lt; 0.001). Of 108 patients who received a subsequent line of therapy, 63 received an alternate ARPI (AR + 39 vs. 24 AR wt ), while 20 received a taxane‐based therapy (11 AR + vs. 9 AR wt ). Among patients receiving an alternate ARPI, AR + had numerically shorter OS (16.8 vs. 30.4 mos, p = 0.1). Among patients receiving taxane‐based regimens, the OS was not significantly different between AR + and AR wt (14.5 vs. 10.1 mos, p = 0.18). Conclusion In this real‐world study, mCRPC patients with AR alterations on cfDNA had inferior OS after disease progression on the first ARPI, compared to those who did not, and may impact outcomes on a subsequent ARPI but not on subsequent taxane‐based therapy received. By providing survival estimates for patients with or without AR alterations, our data may aid in patient counseling, prognostication, treatment decision, and for designing future clinical trials in this setting.

Abstract Pyruvate kinase is a crucial enzyme responsible for the last step of glycolysis. Cancer cells can use the M2 isoform of pyruvate kinase (PKM2), to better balance respiration and biosynthesis due to allosteric switching between the less active dimeric and fully active tetrameric forms. Additionally, the dimeric form of PKM2 can translocate to the nucleus, altering transcription to enhance cancer cells' ability to grow and evade immune detection. Inducing tetramerization presents an opportunity to target PKM2 resulting in the metabolic reprogramming of tumor-immune microenvironment (TME). TP-1454 is a potent PKM2 activator with low nanomolar PKM2 activation in biochemical assays (AC50 = 10 nM) and multiple cell types (AC &amp;lt; 50 nM), tolerated in mice, rats and dogs after repeat doses as high as 1000 mg/kg/day and has recently entered a Phase I clinical trial (NCT04328740). We hypothesize that PKM2 activation may reverse the immune-suppressive TME. To test this hypothesis, we examined the activity of TP-1454 combination with immunotherapy (I/O) in multiple mouse syngeneic tumor models. TP-1454 and anti-PD-1 combination therapy in colorectal cancer models resulted in tumor growth inhibition versus vehicle (53% in CT26; 99% in MC38, P &amp;lt; 0.001). We observed decreases in multiple glycolytic intermediates in TP-1454-treated tumors versus vehicle. We conducted immunophenotyping of the TME in multiple models to identify targets of PKM2 activation. TP-1454 treatment reduced the CD4+ Foxp3+ T-regulatory (Treg) population in MC38, 4T1, RENCA models. Further, we assayed TP-1454 induced PKM2 activation in different immune cell types. To confirm the effect of PKM2 activation on Treg cells we conducted an in vitro assay to explore TP-1454 treatment response on polarization of Tregs and/or toxicity and proliferation. We further utilized LCMS to explore metabolic intermediates that play a critical role in Treg regulation, including regulation of the O-linked β-N-acetylglucosamine (O-GlcNac) post-translational modification, which is reported to stabilize Foxp3 in CD4+ cells. We are currently exploring the effect of TP-1454 treatment on O-GlcNac of Foxp3 and its stability in HEK293 cells, to support the link between PKM2 activation and stabilization of Foxp3. TP-1454 effects on tumor-specific immunity were validated using tumor rechallenge studies. The results of a tumor rechallenge study will be presented using murine MC38 or RENCA xenograft models that are treated with TP-1454 and I/O combination therapies that exhibited a complete response (CR) and were re-implanted. These preclinical studies indicate a unique mechanism modulating tumor metabolism and the TME to improve the response of cancer patients to immunotherapy. Citation Format: Salah Sommakia, Satya Pathi, Yuta Matsumura, Curtis Allred, Ethika Tyagi, Matthew Lalonde, Jason Foulks, Adam Siddiqui, Clifford Whatcott, David Bearss, Steven Warner. Pkm2 activation modulates the tumor-immune microenvironment and enhances response to checkpoint inhibitors in preclinical solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 606.

This paper describes the ICFHR2016 Local Attribute Detection competition held at the 15th International Conference on Frontiers in Handwriting Recognition. This competition uses the ANDoc-Attrib-10K database, which consists of roughly 10,000 image snippets drawn from 30 collections from historical documents and records of various types, each labeled with seven attributes such as the presence of text, text type (handwritten machine-printed, or both), if the text is legible, etc. The objective of this competition is to use the training partition of the database to develop and submit for evaluation a system that detects the seven attributes in the snippets from the test partition. Two teams submitted five systems for scoring, evaluation, and comparison to Ancestry baseline systems. The results of this scoring are reported, along with brief descriptions of each system.

Compilers are a core technology within Computer Science, whether they create a native executable file that runs directly on the hardware or a byte-code file that runs in a Virtual Machine. This paper begins by outlining the primary author's capstone where he implemented an Assembler, Virtual Machine and Compiler all from scratch. No existing code-base or any special purpose libraries could be used in the implementation. The major components for these programs will be discussed and the base approach taken to creating them discussed. Following this overview, a more detailed description of lessons learned by the author while converting part of his capstone project from Python to C++ will be given. The project used in this paper provided for a rather unique perspective on the issue of converting a program from one language to another as the example program was the non-trivial Virtual Machine. The paper will conclude with a brief section describing future work where a Garbage Collector will be implemented.