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Radiation enteritis remains a major challenge for radiotherapy against abdominal and pelvic malignancies. Nevertheless, there is no approved effective therapy to alleviate irradiation (IR)-induced gastrointestinal (GI) toxicity. In the current study, Cannabidiol (CBD) was found to mitigate intestinal injury by GPX4-mediated ferroptosis resistance upon IR exposure. RNA-sequencing was employed to investigate the underlying mechanism involved in the radio-protective effect of CBD, wherein runt-related transcription factor 3 (RUNX3) and its target genes were changed significantly. Further experiment showed that the transactivation of GPX4 triggered by the direct binding of RUNX3 to its promoter region, or by stimulating the transcriptional activity of NF-κB via RUNX3-mediated LILRB3 upregulation was critical for the anti-ferroptotic effect of CBD upon IR injury. Specially, CBD was demonstrated to be a molecular glue skeleton facilitating the heterodimerization of RUNX3 with its transcriptional chaperone core-biding factor ß (CBFß) thereby promoting their nuclear localization and the subsequent transactivation of GPX4 and LILRB3. In short, our study provides an alternative strategy to counteract IR-induced enteritis during the radiotherapy on abdominal/pelvic neoplasms.
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BACKGROUND: Robot-assisted total knee arthroplasty (TKA) has been shown to facilitate high-precision bone resection, which is an important goal in TKA. The aim of this cadaveric study was to analyze the accuracy of the target angle and bone resection thickness of a recently introduced robotic TKA system. METHODS: This study used 4 frozen cadaveric specimens (8 knees), 2 different implant designs, navigation, and a robotic system. The 4 surgeons who participated in this study were trained and familiar with the basic principles and operating procedures of this system. The angle of the bone cuts performed using the robotic system was compared with the target angles from the intraoperative plan. For each bone cut, the resection thickness was recorded and compared with the planned resection thickness. RESULTS: The mean angular difference for all specimens was less than 1°, and the standard deviation was less than 2°. The mean difference between the planned and measured angles was close to 0 and not significantly different from 0 except for the difference in the frontal tibial component angle, which was 0.88°. The mean difference in the hip-knee-ankle axis angle was - 0.21°± 1.06°. The mean bone resection difference for all specimens was less than 1 mm, and the standard deviation was less than 0.5 mm. CONCLUSIONS: The results of the cadaveric experimental study showed that the new TKA system can realize highly accurate bone cuts and achieve planned angles and resection thicknesses. Despite the limitations of small sample sizes and large differences between cadaveric and clinical patients, the accuracy of cadaveric experiments provides strong support for subsequent clinical trials.
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Artroplastia do Joelho , Cadáver , Procedimentos Cirúrgicos Robóticos , Humanos , Artroplastia do Joelho/métodos , Artroplastia do Joelho/instrumentação , Procedimentos Cirúrgicos Robóticos/métodos , Procedimentos Cirúrgicos Robóticos/instrumentação , Idoso , Masculino , FemininoRESUMO
BACKGROUND: Longitudinal records of automatically-recorded vaginal temperature (TV) could be a key source of data for deriving novel indicators of climatic resilience (CR) for breeding more resilient pigs, especially during lactation when sows are at an increased risk of suffering from heat stress (HS). Therefore, we derived 15 CR indicators based on the variability in TV in lactating sows and estimated their genetic parameters. We also investigated their genetic relationship with sows' key reproductive traits. RESULTS: The heritability estimates of the CR traits ranged from 0.000 ± 0.000 for slope for decreased rate of TV (SlopeDe) to 0.291 ± 0.047 for sum of TV values below the HS threshold (HSUB). Moderate to high genetic correlations (from 0.508 ± 0.056 to 0.998 ± 0.137) and Spearman rank correlations (from 0.431 to 1.000) between genomic estimated breeding values (GEBV) were observed for five CR indicators, i.e. HS duration (HSD), the normalized median multiplied by normalized variance (Nor_medvar), the highest TV value of each measurement day for each individual (MaxTv), and the sum of the TV values above (HSUA) and below (HSUB) the HS threshold. These five CR indicators were lowly to moderately genetically correlated with shoulder skin surface temperature (from 0.139 ± 0.008 to 0.478 ± 0.048) and respiration rate (from 0.079 ± 0.011 to 0.502 ± 0.098). The genetic correlations between these five selected CR indicators and sow reproductive performance traits ranged from - 0.733 to - 0.175 for total number of piglets born alive, from - 0.733 to - 0.175 for total number of piglets born, and from - 0.434 to - 0.169 for number of pigs weaned. The individuals with the highest GEBV (most climate-sensitive) had higher mean skin surface temperature, respiration rate (RR), panting score (PS), and hair density, but had lower mean body condition scores compared to those with the lowest GEBV (most climate-resilient). CONCLUSIONS: Most of the CR indicators evaluated are heritable with substantial additive genetic variance. Five of them, i.e. HSD, MaxTv, HSUA, HSUB, and Nor_medvar share similar underlying genetic mechanisms. In addition, individuals with higher CR indicators are more likely to exhibit better HS-related physiological responses, higher body condition scores, and improved reproductive performance under hot conditions. These findings highlight the potential benefits of genetically selecting more heat-tolerant individuals based on CR indicators.
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Resposta ao Choque Térmico , Lactação , Animais , Feminino , Lactação/genética , Suínos/genética , Suínos/fisiologia , Resposta ao Choque Térmico/genética , Vagina , Temperatura Corporal , Clima , Cruzamento/métodos , Característica Quantitativa HerdávelRESUMO
BACKGROUND: Heat stress (HS) poses significant threats to the sustainability of livestock production. Genetically improving heat tolerance could enhance animal welfare and minimize production losses during HS events. Measuring phenotypic indicators of HS response and understanding their genetic background are crucial steps to optimize breeding schemes for improved climatic resilience. The identification of genomic regions and candidate genes influencing the traits of interest, including variants with pleiotropic effects, enables the refinement of genotyping panels used to perform genomic prediction of breeding values and contributes to unraveling the biological mechanisms influencing heat stress response. Therefore, the main objectives of this study were to identify genomic regions, candidate genes, and potential pleiotropic variants significantly associated with indicators of HS response in lactating sows using imputed whole-genome sequence (WGS) data. Phenotypic records for 18 traits and genomic information from 1,645 lactating sows were available for the study. The genotypes from the PorcineSNP50K panel containing 50,703 single nucleotide polymorphisms (SNPs) were imputed to WGS and after quality control, 1,622 animals and 7,065,922 SNPs were included in the analyses. RESULTS: A total of 1,388 unique SNPs located on sixteen chromosomes were found to be associated with 11 traits. Twenty gene ontology terms and 11 biological pathways were shown to be associated with variability in ear skin temperature, shoulder skin temperature, rump skin temperature, tail skin temperature, respiration rate, panting score, vaginal temperature automatically measured every 10 min, vaginal temperature measured at 0800 h, hair density score, body condition score, and ear area. Seven, five, six, two, seven, 15, and 14 genes with potential pleiotropic effects were identified for indicators of skin temperature, vaginal temperature, animal temperature, respiration rate, thermoregulatory traits, anatomical traits, and all traits, respectively. CONCLUSIONS: Physiological and anatomical indicators of HS response in lactating sows are heritable but highly polygenic. The candidate genes found are associated with important gene ontology terms and biological pathways related to heat shock protein activities, immune response, and cellular oxidative stress. Many of the candidate genes with pleiotropic effects are involved in catalytic activities to reduce cell damage from oxidative stress and cellular mechanisms related to immune response.
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Resposta ao Choque Térmico , Lactação , Polimorfismo de Nucleotídeo Único , Animais , Feminino , Resposta ao Choque Térmico/genética , Lactação/genética , Suínos/genética , Fenótipo , Locos de Características Quantitativas , Genótipo , GenômicaRESUMO
BACKGROUND: The Fontan operation is used to palliate single ventricle congenital heart defects (CHD) but poses significant morbidity and mortality risks. We present the design, planned analyses, and rationale for a long-term Fontan cohort study aiming to examine the association of patient characteristics at the time of Fontan with post-Fontan morbidity and mortality. METHODS AND RESULTS: We used the Pediatric Cardiac Care Consortium (PCCC), a US-based, multicenter registry of pediatric cardiac surgeries to identify patients who underwent the Fontan procedure for single ventricle CHD between 1 and 21 years of age. The primary outcomes are in-hospital Fontan failure (death or takedown) and post-discharge mortality through 2022. A total of 1461 (males 62.1%) patients met eligibility criteria and were included in the analytical cohort. The median age at Fontan evaluation was 3.1 years (IQR: 2.4-4.3). While 95 patients experienced in-hospital Fontan failure (78 deaths and 17 Fontan takedown), 1366 (93.5%) survived to discharge with Fontan physiology and formed the long-term analysis cohort. Over a median follow-up of 21.2 years (IQR: 18.4-24.5) 184 post-discharge deaths occurred. Thirty-year post Fontan survival was 75.0% (95% CI: 72.3%-77.8%) for all Fontan types with higher rates for current techniques such as lateral tunnel and extracardiac conduit 77.1% (95% CI: 73.5-80.8). CONCLUSION: The PCCC Fontan study aims to identify predictors for post-Fontan morbidity and mortality, enabling risk- stratification and informing surveillance practices. Additionally, the study may guide therapeutic interventions aiming to optimize hemodynamics and enhance Fontan longevity for individual patients.
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Técnica de Fontan , Cardiopatias Congênitas , Sistema de Registros , Humanos , Técnica de Fontan/métodos , Masculino , Feminino , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/mortalidade , Pré-Escolar , Criança , Adolescente , Lactente , Adulto Jovem , Cuidados Paliativos/métodos , Estados Unidos/epidemiologia , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/anormalidades , Ventrículos do Coração/cirurgia , Complicações Pós-Operatórias/epidemiologia , Estudos de Coortes , Fatores de TempoRESUMO
PURPOSE: Pelvic support osteotomy (PSO) is regarded to provide pelvic stability and improve abductor function to delay or even avoid total hip arthroplasty (THA) in young patients with high-riding hip dysplasia. However, some of these patients eventually have to undergo THA. Because of the double-angulation deformity of the femur after PSO, subsequent THA is challenging. This study aimed to analyze whether PSO surgery is suitable for high-riding hip dysplasia and summarize orthopaedic strategy during THA for patients with previous PSO. METHODS: This case-control study included eight cases of THA for high-riding hip dysplasia patients with previous PSO (study group) and 24 cases of high-riding hip dysplasia patients without any hip surgical therapy (control group) by a 1:3 match (from May 2018 to January 2022). We compared demographics and joint function before and after THA between two groups and recorded all patients' preoperative imaging data, surgical procedures, postoperative imaging data, and complications. The surgical techniques for patients with previous PSO were highlighted. RESULTS: There was no statistical difference between the two groups in demographic (p > 0.05). The study group had worse hip Harris score (HHS), range of motion (ROM), visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (p < 0.05) compared with the control group before THA. All patients had concurrent THA and osteotomy at the proximal femur, but the study group experienced longer operation time (p = 0.047) with more blood loss (p = 0.027) and higher complication rate compared with the control group (p = 0.009). At the last follow-up, the study group's HHS, ROM, VAS, and WOMAC were still worse than those in the control group. CONCLUSIONS: PSO did not improve the joint function of high-riding hip dysplasia patients but brought challenges to subsequent THA and affected the surgical outcomes. In short, we suggested that PSO is unsuitable for routine high-riding hip dysplasia patients.
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Artroplastia de Quadril , Osteotomia , Ossos Pélvicos , Humanos , Osteotomia/métodos , Osteotomia/efeitos adversos , Feminino , Masculino , Estudos de Casos e Controles , Artroplastia de Quadril/métodos , Artroplastia de Quadril/efeitos adversos , Adulto , Ossos Pélvicos/cirurgia , Ossos Pélvicos/diagnóstico por imagem , Amplitude de Movimento Articular , Articulação do Quadril/cirurgia , Articulação do Quadril/fisiopatologia , Articulação do Quadril/diagnóstico por imagem , Adulto Jovem , Luxação do Quadril/cirurgia , Luxação do Quadril/etiologia , Adolescente , Resultado do Tratamento , Luxação Congênita de Quadril/cirurgiaRESUMO
BACKGROUND: Accurate preoperative planning is crucial for successful total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH). The aim of this study was to compare the accuracy of an artificial intelligence-assisted three-dimensional (3D) planning system (AIHIP) with two-dimensional templates in predicting acetabular cup size in THA for DDH. METHOD: This study retrospectively analyzed image data from 103 DDH patients who had THA between May 2019 and August 2023. AIHIP was used for 3D planning, and two-dimensional (2D) templates were used by two experienced surgeons. Accuracy was assessed by comparing predicted and actual cup sizes, and potential factors affecting accuracy were analyzed, including gender, side, BMI, and dysplasia classification. RESULTS: AIHIP had higher accuracy in predicting the acetabular cup size compared to the 2D template. Within ± 0 size, AIHIP's accuracy was 84.1%, while the 2D template's was 64.0% (p < 0.05). Within ± 1 size, AIHIP's accuracy was 95.1%, while the 2D template's was 81.1% (p < 0.05). Accuracy was unaffected by gender, side, or BMI but was by DDH classification. In subgroup analysis, AIHIP's mean absolute error (0.21 ± 0.54) was significantly lower than the 2D template's (0.62 ± 0.95) for Crowe II and Crowe III (p < 0.05). CONCLUSION: AIHIP is superior to 2D templates in predicting the acetabular cup size accurately for THA in DDH patients. AIHIP may be especially beneficial for Crowe II and III DDH patients, as 2D templates may not accurately predict cup size in these cases.
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Artroplastia de Quadril , Displasia do Desenvolvimento do Quadril , Luxação Congênita de Quadril , Prótese de Quadril , Humanos , Inteligência Artificial , Estudos Retrospectivos , Displasia do Desenvolvimento do Quadril/cirurgia , Acetábulo/diagnóstico por imagem , Acetábulo/cirurgia , Artroplastia de Quadril/métodos , Luxação Congênita de Quadril/diagnóstico por imagem , Luxação Congênita de Quadril/cirurgia , SoftwareRESUMO
BACKGROUND: Cardiovascular conditions are considered risk factors for poor outcomes associated with COVID-19. However, the effect of the COVID-19 pandemic on the mortality of patients with congenital heart disease (CHD) is unclear. Our study aims to examine the trends in mortality risk of CHD patients during the COVID-19 pandemic. METHODS: This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for CHD. We included patients having US residence and direct identifiers; death events were captured by matching with the National Death Index. The observation window (2017-2022) was divided into pre-COVID-19 and COVID-19 era defined around the national onset of COVID-19 disease in 2020. Stratified Cox model was used to assess all-cause mortality between the pre- and the COVID-19 era. RESULTS: Among 45,130 patients with CHD (median age in 2017: 23.3 years, IQR: 19.0-28.4), 503 deaths occurred during the pandemic with 44 deaths (8.7%) attributed to COVID-19 (COVID-19 mortality rate of 0.09%). The overall risk of death for patients with all types of CHD during the pandemic was significantly higher compared to the pre-COVID-19 era (aHR 1.28, 95%CI: 1.08-1.53), with a differential trend towards increased risk in patients with two-ventricle (aHR 1.44, 95% CI: 1.19-1.76) vs unchanged risk for those with single ventricle CHD (aHR = 0.83, 95% CI: 0.57-1.21). Adjusted subgroup analysis revealed a higher risk of death during the pandemic for CHD patients with male and chromosomal abnormalities. The excess deaths during the pandemic were attributed to COVID-19 itself rather than CHD or cardiovascular conditions. CONCLUSION: In this large CHD cohort study, there was a higher risk of death among CHD patients with male and chromosomal abnormalities. A differential trend towards higher risk for those with two vs. unchanged risk for single ventricle CHD was presented. The excess mortality was attributed to the COVID-19 itself and not to conditions potentially related to deferral of care. These results justify targeted protective measures towards the CHD population and may provide guidance for public health and medical care response in future epidemics.
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COVID-19 , Doenças Cardiovasculares , Cardiopatias Congênitas , Humanos , Masculino , Criança , Adulto Jovem , Adulto , Estudos de Coortes , Pandemias , Estudos Retrospectivos , Aberrações CromossômicasRESUMO
Genetic improvement of livestock productivity has resulted in greater production of metabolic heat and potentially greater susceptibility to heat stress. Various studies have demonstrated that there is genetic variability for heat tolerance and genetic selection for more heat tolerant individuals is possible. The rate of genetic progress tends to be greater when genomic information is incorporated into the analyses as more accurate breeding values can be obtained for young individuals. Therefore, this study aimed (1) to evaluate the predictive ability of genomic breeding values for heat tolerance based on routinely recorded traits, and (2) to investigate the genetic background of heat tolerance based on single-step genome-wide association studies for economically important traits related to body composition, growth and reproduction in Large White pigs. Pedigree information was available for 265,943 animals and genotypes for 8686 animals. The studied traits included ultrasound backfat thickness (BFT), ultrasound muscle depth (MDP), piglet weaning weight (WW), off-test weight (OTW), interval between farrowing (IBF), total number of piglets born (TNB), number of piglets born alive (NBA), number of piglets born dead (NBD), number of piglets weaned (WN) and weaning-to-estrus interval (IWE). The number of phenotypic records ranged from 6059 (WN) to 172,984 (TNB). Single-step genomic reaction norm predictions were used to calculate the genomic estimated breeding values for each individual. Predictions of breeding values for the validation population individuals were compared between datasets containing phenotypic records measured in the whole range of temperatures (WR) and datasets containing only phenotypic records measured when the weather station temperature was above 10°C (10C) or 15°C (15C), to evaluate the usefulness of these datasets that may better reflect the within-barn temperature. The use of homogeneous or heterogeneous residual variance was found to be trait-dependent, where homogeneous variance presented the best fit for MDP, BFT, OTW, TNB, NBA, WN and IBF, while the other traits (WW and IWE) had better fit with heterogeneous variance. The average prediction accuracy, dispersion and bias values considering all traits for WR were 0.36 ± 0.05, -0.07 ± 0.13 and 0.76 ± 0.10, respectively; for 10C were 0.39 ± 0.02, -0.05 ± 0.07 and 0.81 ± 0.05, respectively; and for 15C were 0.32 ± 0.05, -0.05 ± 0.11 and 0.84 ± 0.10, respectively. Based on the studied traits, using phenotypic records collected when the outside temperature (from public weather stations) was above 10°C provided better predictions for most of the traits. Forty-three and 62 candidate genomic regions were associated with the intercept (overall performance level) and slope term (specific biological mechanisms related to environmental sensitivity), respectively. Our results contribute to improve genomic predictions using existing datasets and better understand the genetic background of heat tolerance in pigs. Furthermore, the genomic regions and candidate genes identified will contribute to future genomic studies and breeding applications.
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Estudo de Associação Genômica Ampla , Termotolerância , Humanos , Feminino , Animais , Suínos/genética , Temperatura , Estudo de Associação Genômica Ampla/veterinária , Genótipo , Genômica/métodos , Fenótipo , Tempo (Meteorologia)RESUMO
Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer.
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BACKGROUND: Automatic and continuous recording of vaginal temperature (TV) using wearable sensors causes minimal disruptions to animal behavior and can generate data that enable the evaluation of temporal body temperature variation under heat stress (HS) conditions. However, the genetic basis of TV in lactating sows from a longitudinal perspective is still unknown. The objectives of this study were to define statistical models and estimate genetic parameters for TV in lactating sows using random regression models, and identify genomic regions and candidate genes associated with HS indicators derived from automatically-recorded TV. RESULTS: Heritability estimates for TV ranged from 0.14 to 0.20 over time (throughout the day and measurement period) and from 0.09 to 0.18 along environmental gradients (EG, - 3.5 to 2.2, which correspond to dew point values from 14.87 to 28.19 ËC). Repeatability estimates of TV over time and along EG ranged from 0.57 to 0.66 and from 0.54 to 0.77, respectively. TV measured from 12h00 to 16h00 had moderately high estimates of heritability (0.20) and repeatability (0.64), indicating that this period might be the most suitable for recording TV for genetic selection purposes. Significant genotype-by-environment interactions (GxE) were observed and the moderately high estimates of genetic correlations between pairs of extreme EG indicate potential re-ranking of selection candidates across EG. Two important genomic regions on chromosomes 10 (59.370-59.998 Mb) and16 (21.548-21.966 Mb) were identified. These regions harbor the genes CDC123, CAMK1d, SEC61A2, and NUDT5 that are associated with immunity, protein transport, and energy metabolism. Across the four time-periods, respectively 12, 13, 16, and 10 associated genomic regions across 14 chromosomes were identified for TV. For the three EG classes, respectively 18, 15, and 14 associated genomic windows were identified for TV, respectively. Each time-period and EG class had uniquely enriched genes with identified specific biological functions, including regulation of the nervous system, metabolism and hormone production. CONCLUSIONS: TV is a heritable trait with substantial additive genetic variation and represents a promising indicator trait to select pigs for improved heat tolerance. Moderate GxE for TV exist, indicating potential re-ranking of selection candidates across EG. TV is a highly polygenic trait regulated by a complex interplay of physiological, cellular and behavioral mechanisms.
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Lactação , Termotolerância , Suínos , Animais , Feminino , Lactação/genética , Temperatura , Genoma , GenômicaRESUMO
Synthetic auxotrophy in which cell viability depends on the presence of an unnatural amino acid (unAA) provides a powerful strategy to restrict unwanted propagation of genetically modified organisms (GMOs) in open environments and potentially prevent industrial espionage. Here, we describe a generic approach for robust biocontainment of budding yeast dependent on unAA. By understanding escape mechanisms, we specifically optimize our strategies by introducing designed "immunity" to the generation of amber-suppressor tRNAs and developing the transcriptional- and translational-based biocontainment switch. We further develop a fitness-oriented screening method to easily obtain multiplex safeguard strains that exhibit robust growth and undetectable escape frequency (<~10-9) on solid media for 14 days. Finally, we show that employing our multiplex safeguard system could restrict the proliferation of strains of interest in a real fermentation scenario, highlighting the great potential of our yeast biocontainment strategy to protect the industrial proprietary strains.
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Aminoácidos , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Aminoácidos/metabolismo , Organismos Geneticamente Modificados , RNA de Transferência/metabolismoRESUMO
BACKGROUND: Genetic selection based on direct indicators of heat stress could capture additional mechanisms that are involved in heat stress response and enable more accurate selection for more heat-tolerant individuals. Therefore, the main objectives of this study were to estimate genetic parameters for various heat stress indicators in a commercial population of Landrace × Large White lactating sows measured under heat stress conditions. The main indicators evaluated were: skin surface temperatures (SST), automatically-recorded vaginal temperature (TV), respiration rate (RR), panting score (PS), body condition score (BCS), hair density (HD), body size (BS), ear size, and respiration efficiency (Reff). RESULTS: Traits based on TV presented moderate heritability estimates, ranging from 0.15 ± 0.02 to 0.29 ± 0.05. Low heritability estimates were found for SST traits (from 0.04 ± 0.01 to 0.06 ± 0.01), RR (0.06 ± 0.01), PS (0.05 0.01), and Reff (0.03 ± 0.01). Moderate to high heritability values were estimated for BCS (0.29 ± 0.04 for caliper measurements and 0.25 ± 0.04 for visual assessments), HD (0.25 ± 0.05), BS (0.33 ± 0.05), ear area (EA; 0.40 ± 0.09), and ear length (EL; 0.32 ± 0.07). High genetic correlations were estimated among SST traits (> 0.78) and among TV traits (> 0.75). Similarly, high genetic correlations were also estimated for RR with PS (0.87 ± 0.02), with BCS measures (0.92 ± 0.04), and with ear measures (0.95 ± 0.03). Low to moderate positive genetic correlations were estimated between SST and TV (from 0.25 ± 0.04 to 0.76 ± 0.07). Low genetic correlations were estimated between TV and BCS (from - 0.01 ± 0.08 to 0.06 ± 0.07). Respiration efficiency was estimated to be positively and moderately correlated with RR (0.36 ± 0.04), PS (0.56 ± 0.03), and BCS (0.56 ± 0.05 for caliper measurements and 0.50 ± 0.05 for the visual assessments). All other trait combinations were lowly genetically correlated. CONCLUSIONS: A comprehensive landscape of heritabilities and genetic correlations for various thermotolerance indicators in lactating sows were estimated. All traits evaluated are under genetic control and heritable, with different magnitudes, indicating that genetic progress is possible for all of them. The genetic correlation estimates provide evidence for the complex relationships between these traits and confirm the importance of a sub-index of thermotolerance traits to improve heat tolerance in pigs.
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Transtornos de Estresse por Calor , Termotolerância , Humanos , Animais , Feminino , Suínos , Termotolerância/genética , Temperatura , Lactação/genética , Respiração , Resposta ao Choque Térmico/genéticaRESUMO
The receiver operating characteristic (ROC) curve provides a comprehensive performance assessment of a continuous biomarker over the full threshold spectrum. Nevertheless, a medical test often dictates to operate at a certain high level of sensitivity or specificity. A diagnostic accuracy metric directly targeting the clinical utility is specificity at the controlled sensitivity level, or vice versa. While the empirical point estimation is readily adopted in practice, the nonparametric interval estimation is challenged by the fact that the variance involves density functions due to estimated threshold. In addition, even with a fixed threshold, many standard confidence intervals including the Wald interval for binomial proportion could have erratic behaviors. In this article, we are motivated by the superior performance of the score interval for binomial proportion and propose a novel extension for the biomarker problem. Meanwhile, we develop exact bootstrap and establish consistency of the bootstrap variance estimator. Both single-biomarker evaluation and two-biomarker comparison are investigated. Extensive simulation studies were conducted, demonstrating competitive performance of our proposals. An illustration with aggressive prostate cancer diagnosis is provided.
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An accurate understanding of heat stress (HS) temperatures and phenotypes that indicate HS tolerance is necessary to improve swine HS resilience. Therefore, the study objectives were 1) to identify phenotypes indicative of HS tolerance, and 2) to determine moderate and severe HS threshold temperatures in lactating sows. Multiparous (4.10 ± 1.48) lactating sows and their litters (11.10 ± 2.33 piglets/litter) were housed in naturally ventilated (n = 1,015) or mechanically ventilated (n = 630) barns at a commercial sow farm in Maple Hill, NC, USA between June 9 and July 24, 2021. In-barn dry bulb temperatures (TDB) and relative humidity were continuously recorded for naturally ventilated (26.38 ± 1.21 °C and 83.38 ± 5.40%, respectively) and mechanically ventilated (26.91 ± 1.80 °C and 77.13 ± 7.06%, respectively) barns using data recorders. Sows were phenotyped between lactation days 11.28 ± 3.08 and 14.25 ± 3.26. Thermoregulatory measures were obtained daily at 0800, 1200, 1600, and 2000 h and included respiration rate, and ear, shoulder, rump, and tail skin temperatures. Vaginal temperatures (TV) were recorded in 10 min intervals using data recorders. Anatomical characteristics were recorded, including ear area and length, visual and caliper-assessed body condition scores, and a visually assessed and subjective hair density score. Data were analyzed using PROC MIXED to evaluate the temporal pattern of thermoregulatory responses, phenotype correlations were based on mixed model analyses, and moderate and severe HS inflection points were established by fitting TV as the dependent variable in a cubic function against TDB. Statistical analyses were conducted separately for sows housed in mechanically or naturally ventilated barns because the sow groups were not housed in each facility type simultaneously. The temporal pattern of thermoregulatory responses was similar for naturally and mechanically ventilated barns and several thermoregulatory and anatomical measures were significantly correlated with one another (P < 0.05), including all anatomical measures as well as skin temperatures, respiration rates, and TV. For sows housed in naturally and mechanically ventilated facilities, moderate HS threshold TDB were 27.36 and 26.69 °C, respectively, and severe HS threshold TDB were 29.45 and 30.60 °C, respectively. In summary, this study provides new information on the variability of HS tolerance phenotypes and environmental conditions that constitute HS in commercially housed lactating sows.
Climate change and the associated increase in global temperatures have a well-described negative impact on swine production. Therefore, improving swine heat stress resilience is of utmost importance to reduce the deleterious effects of heat stress on swine health, performance, and welfare. Genomic selection for heat stress resilience may be a viable strategy to improve swine productivity in a changing climate. However, identifying environmental conditions that constitute heat stress and deriving novel traits that can be easily collected on farm and provide accurate and precise predictions of heat stress tolerance is a necessary step. The present study demonstrated that housing conditions had a limited influence on heat stress tolerance phenotypes, several anatomical and thermoregulatory measures were correlated, and housing conditions impacted heat stress threshold temperatures. Results from this study may be applied to large-scale phenotyping initiatives to develop or refine genomic selection indexes for heat stress resilience in pigs.
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Lactação , Termotolerância , Suínos , Animais , Feminino , Lactação/fisiologia , Resposta ao Choque Térmico , Regulação da Temperatura Corporal , Temperatura CorporalRESUMO
Diagnostic tests usually need to operate at a high sensitivity or specificity level in practice. Accordingly, specificity at the controlled sensitivity, or vice versa, is a clinically sensible performance metric for evaluating continuous biomarkers. Meanwhile, the performance of a biomarker may vary across sub-populations as defined by covariates, and covariate-specific evaluation can be informative. In this article, we develop a novel modeling and estimation method for covariate-specific specificity at a controlled sensitivity level. Unlike existing methods which typically adopt elaborate models of covariate effects over the entire biomarker distribution, our approach models covariate effects locally at a specific sensitivity level of interest. We also extend our proposed model to handle the whole continuum of sensitivities via dynamic regression and derive covariate-specific ROC curves. We provide the variance estimation through bootstrapping. The asymptotic properties are established. We conduct extensive simulation studies to evaluate the performance of our proposed methods in comparison with existing methods, and further illustrate the applications in two clinical studies for aggressive prostate cancer.
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Modelos Estatísticos , Neoplasias da Próstata , Masculino , Humanos , Simulação por Computador , Curva ROC , BiomarcadoresRESUMO
Continuous biomarkers are common for disease screening and diagnosis. To reach a dichotomous clinical decision, a threshold would be imposed to distinguish subjects with disease from nondiseased individuals. Among various performance metrics, specificity at a controlled sensitivity level (or vice versa) is often desirable because it directly targets the clinical utility of the intended clinical test. Meanwhile, covariates, such as age, race, as well as sample collection conditions, could impact the biomarker distribution and may also confound the association between biomarker and disease status. Therefore, covariate adjustment is important in such biomarker evaluation. Most existing covariate adjustment methods do not specifically target the desired sensitivity/specificity level, but rather do so for the entire biomarker distribution. As such, they might be more prone to model misspecification. In this paper, we suggest a parsimonious quantile regression model for the diseased population, only locally at the controlled sensitivity level, and assess specificity with covariate-specific control of the sensitivity. Variance estimates are obtained from a sample-based approach and bootstrap. Furthermore, our proposed local model extends readily to a global one for covariate adjustment for the receiver operating characteristic (ROC) curve over the sensitivity continuum. We demonstrate computational efficiency of this proposed method and restore the inherent monotonicity in the estimated covariate-adjusted ROC curve. The asymptotic properties of the proposed estimators are established. Simulation studies show favorable performance of the proposal. Finally, we illustrate our method in biomarker evaluation for aggressive prostate cancer.
Assuntos
Modelos Estatísticos , Masculino , Humanos , Simulação por Computador , Sensibilidade e Especificidade , Curva ROC , BiomarcadoresRESUMO
Multiple biomarkers are often combined to improve disease diagnosis. The uniformly optimal combination, i.e., with respect to all reasonable performance metrics, unfortunately requires excessive distributional modeling, to which the estimation can be sensitive. An alternative strategy is rather to pursue local optimality with respect to a specific performance metric. Nevertheless, existing methods may not target clinical utility of the intended medical test, which usually needs to operate above a certain sensitivity or specificity level, or do not have their statistical properties well studied and understood. In this article, we develop and investigate a linear combination method to maximize the clinical utility empirically for such a constrained classification. The combination coefficient is shown to have cube root asymptotics. The convergence rate and limiting distribution of the predictive performance are subsequently established, exhibiting robustness of the method in comparison with others. An algorithm with sound statistical justification is devised for efficient and high-quality computation. Simulations corroborate the theoretical results, and demonstrate good statistical and computational performance. Illustration with a clinical study on aggressive prostate cancer detection is provided.
RESUMO
The microbial composition resemblance among individuals in a group can be summarized in a square covariance matrix and fitted in linear models. We investigated eight approaches to create the matrix that quantified the resemblance between animals based on the gut microbiota composition. We aimed to compare the performance of different methods in estimating trait microbiability and predicting growth and body composition traits in three pig breeds. This study included 651 purebred boars from either breed: Duroc (n = 205), Landrace (n = 226), and Large White (n = 220). Growth and body composition traits, including body weight (BW), ultrasound backfat thickness (BF), ultrasound loin depth (LD), and ultrasound intramuscular fat (IMF) content, were measured on live animals at the market weight (156 ± 2.5 d of age). Rectal swabs were taken from each animal at 158 ± 4 d of age and subjected to 16S rRNA gene sequencing. Eight methods were used to create the microbial similarity matrices, including 4 kernel functions (Linear Kernel, LK; Polynomial Kernel, PK; Gaussian Kernel, GK; Arc-cosine Kernel with one hidden layer, AK1), 2 dissimilarity methods (Bray-Curtis, BC; Jaccard, JA), and 2 ordination methods (Metric Multidimensional Scaling, MDS; Detrended Correspondence analysis, DCA). Based on the matrix used, microbiability estimates ranged from 0.07 to 0.21 and 0.12 to 0.53 for Duroc, 0.03 to 0.21 and 0.05 to 0.44 for Landrace, and 0.02 to 0.24 and 0.05 to 0.52 for Large White pigs averaged over traits in the model with sire, pen, and microbiome, and model with the only microbiome, respectively. The GK, JA, BC, and AK1 obtained greater microbiability estimates than the remaining methods across traits and breeds. Predictions were made within each breed group using four-fold cross-validation based on the relatedness of sires in each breed group. The prediction accuracy ranged from 0.03 to 0.18 for BW, 0.08 to 0.31 for BF, 0.21 to 0.48 for LD, and 0.04 to 0.16 for IMF when averaged across breeds. The BC, MDS, LK, and JA achieved better accuracy than other methods in most predictions. Overall, the PK and DCA exhibited the worst performance compared to other microbiability estimation and prediction methods. The current study shows how alternative approaches summarized the resemblance of gut microbiota composition among animals and contributed this information to variance component estimation and phenotypic prediction in swine.
Gut microbiota has received significant research attention in farm animals because of its close relationship with host performance. We chose eight approaches to create a square covariance matrix that characterizes the relationship among animals based on their gut microbiota composition. Then, we fitted this information with linear models to evaluate the proportion of phenotypic variance explained by gut microbiota composition and predict host growth and body composition traits in three pig breeds. We found that different matrices had varying performance in predicting host phenotypes, but the results highly depended on the trait and breed considered in the prediction. Our findings highlight possible alternative approaches to incorporate gut microbiome data in regression models and emphasize the value of gut microbiome data in better understanding complex traits in pigs with diverse genetic backgrounds.
Assuntos
Microbioma Gastrointestinal , Animais , Composição Corporal/genética , Masculino , Fenótipo , RNA Ribossômico 16S/genética , SuínosRESUMO
PURPOSE: We assessed whether Prostate Health Index results improve prediction of grade reclassification for men on active surveillance. METHODS AND MATERIALS: We identified men in Canary Prostate Active Surveillance Study with Grade Group 1 cancer. Outcome was grade reclassification to Grade Group 2+ cancer. We considered decision rules to maximize specificity with sensitivity set at 95%. We derived rules based on clinical data (R1) vs clinical data+Prostate Health Index (R3). We considered an "or"-logic rule combining clinical score and Prostate Health Index (R4), and a "2-step" rule using clinical data followed by risk stratification based on Prostate Health Index (R2). Rules were applied to a validation set, where values of R2-R4 vs R1 for specificity and sensitivity were evaluated. RESULTS: We included 1,532 biopsies (n = 610 discovery; n = 922 validation) among 1,142 men. Grade reclassification was seen in 27% of biopsies (23% discovery, 29% validation). Among the discovery set, at 95% sensitivity, R2 yielded highest specificity at 27% vs 17% for R1. In the validation set, R3 had best performance vs R1 with Δsensitivity = -4% and Δspecificity = +6%. There was slight improvement for R3 vs R1 for confirmatory biopsy (AUC 0.745 vs R1 0.724, ΔAUC 0.021, 95% CI 0.002-0.041) but not for subsequent biopsies (ΔAUC -0.012, 95% CI -0.031-0.006). R3 did not have better discrimination vs R1 among the biopsy cohort overall (ΔAUC 0.007, 95% CI -0.007-0.020). CONCLUSIONS: Among active surveillance patients, using Prostate Health Index with clinical data modestly improved prediction of grade reclassification on confirmatory biopsy and did not improve prediction on subsequent biopsies.