Use of the linear regression method to evaluate population accuracy of predictions from non-linear models.

Background: To address the limitations of commonly used cross-validation methods, the linear regression method (LR) was proposed to estimate population accuracy of predictions based on the implicit assumption that the fitted model is correct. This method also provides two statistics to determine the adequacy of the fitted model. The validity and behavior of the LR method have been provided and studied for linear predictions but not for nonlinear predictions. The objectives of this study were to 1) provide a mathematical proof for the validity of the LR method when predictions are based on conditional means, regardless of whether the predictions are linear or non-linear 2) investigate the ability of the LR method to detect whether the fitted model is adequate or inadequate, and 3) provide guidelines on how to appropriately partition the data into training and validation such that the LR method can identify an inadequate model. Results: We present a mathematical proof for the validity of the LR method to estimate population accuracy and to determine whether the fitted model is adequate or inadequate when the predictor is the conditional mean, which may be a non-linear function of the phenotype. Using three partitioning scenarios of simulated data, we show that the one of the LR statistics can detect an inadequate model only when the data are partitioned such that the values of relevant predictor variables differ between the training and validation sets. In contrast, we observed that the other LR statistic was able to detect an inadequate model for all three scenarios. Conclusion: The LR method has been proposed to address some limitations of the traditional approach of cross-validation in genetic evaluation. In this paper, we showed that the LR method is valid when the model is adequate and the conditional mean is the predictor, even when it is a non-linear function of the phenotype. We found one of the two LR statistics is superior because it was able to detect an inadequate model for all three partitioning scenarios (i.e., between animals, by age within animals, and between animals and by age) that were studied.

Peutz-Jeghers Syndrome: A Comprehensive Review of Genetics, Clinical Features, and Management Approaches.

A relatively rare inherited condition known as Peutz-Jeghers syndrome (PJS) causes mucocutaneous pigmentation and gastrointestinal hamartomatous polyps. These polyps are non-cancerous, but the presence of PJS significantly increases the chances of developing various types of cancers, such as colorectal, pancreatic, gastric, and breast cancer. The purpose of this review article is to give an abbreviated summary of what is currently known about this syndrome, covering its clinical symptoms, pathophysiology, genetics, and management. PJS also raises the risk of getting many malignancies, especially gastrointestinal and pelvic cancers. Symptoms of the gastrointestinal tract brought on by hamartomatous polyps are frequent and include stool blockage, bleeding, and stomach pain. The pigmentation commonly appears as prominent bluish-black macules and frequently affects the skin and mucous membranes. Small macules and large regions of lentiginous pigmentation are both possible. Numerous areas, including the perioral area, buccal mucosa, fingers, and lips, exhibit pigmentation. Bowel obstruction and intussusception risk can be decreased by early identification and routine surveillance of gastrointestinal polyps. The gene serine/threonine kinase 11 (STK11) controls several biological functions, including cell polarity, growth, and proliferation. Genetic counseling is recommended for the affected individuals and their families. This can help assess the risk of passing on the condition to future generations and provide information about available reproductive options. Regular surveillance is crucial for managing the syndrome and reducing the risk of cancer development. Other syndromes and extra-gastrointestinal characteristics, such as somatic tumor polyps outside the gastrointestinal tract, are also linked to this syndrome.

Boswellia serrata Enhances Passive Range-of-Motion Exercises in Radiation-Induced Trismus: A Case Report.

Trismus is a common, extremely detrimental side effect following definitive radiotherapy for head and neck malignancies. Existing therapeutic modalities (active and passive range-of-motion exercises and systemic therapies) offer only modest, slow improvements in jaw opening; thus, there is a need for additional treatment options. Boswellia serrata (BS) ("Indian frankincense") is a tree native to West Asia and North Africa that produces resin-containing "boswellic" acids. These have been shown to have in vitro and in vivo anti-inflammatory effects and have previously been found to be an effective treatment for asthma, colitis, arthritis, and post-radiation edema. Herein we report the case of a 54-year-old male with severe post-radiation trismus who experienced a dramatic resolution with BS/Therabite® combination therapy. His trismus improved from 6 mm to 45 mm over 10 weeks (0.46 mm/day), far exceeding previous rates of improvement documented in the literature. There were no ill effects. Given the dearth of effective treatments for post-radiation trismus, BS is a promising agent deserving of further study.

Long-Term Outcomes Following Definitive or Adjuvant Proton Radiotherapy for Adenoid Cystic Carcinoma.

Purpose: Adenoid cystic carcinoma (ACC) is a rare malignancy accounting for 1% of all head and neck cancers. Treatment for ACC has its challenges and risks, yet few outcomes studies exist. We present long-term outcomes of patients with ACC of the head and neck treated with proton therapy (PT). Materials and Methods: Under an institutional review board-approved, single-institutional prospective outcomes registry, we reviewed the records of 56 patients with de novo, nonmetastatic ACC of the head and neck treated with PT with definitive (n = 9) or adjuvant PT (n = 47) from June 2007 to December 2021. The median dose to the primary site was 72.6 gray relative biological equivalent (range, 64-74.4) delivered as either once (n = 19) or twice (n = 37) daily treatments. Thirty patients received concurrent chemotherapy. Thirty-one patients received nodal radiation, 30 electively and 1 for nodal involvement. Results: With a median follow-up of 6.2 years (range, 0.9-14.7), the 5-year local-regional control (LRC), disease-free survival, cause-specific survival, and overall survival rates were 88%, 85%, 89%, and 89%, respectively. Intracranial extension (P = .003) and gross residual tumor (P = .0388) were factors associated with LRC rates. While the LRC rate for those with a gross total resection was 96%, those with subtotal resection or biopsy alone were 81% and 76%, respectively. The 5-year cumulative incidence of clinically significant grade ≥3 toxicity was 15%, and the crude incidence at the most recent follow-up was 23% (n = 13). Conclusion: This is the largest sample size with the longest median follow-up to date of patients with ACC treated with PT. PT can provide excellent disease control for ACC of the head and neck with acceptable toxicity. T4 disease, intracranial involvement, and gross residual disease at the time of PT following either biopsy or subtotal resection were significant prognostic features for worse outcomes.

University staff perspectives on determinants of high-quality health professions student placements in regional, rural and remote Australia: protocol for a mixed-method study.

INTRODUCTION: In rural areas, work-integrated learning in the form of health student placements has several potential benefits, including contributing to student learning, enhancing rural health service capacity and attracting future rural health workforce. Understanding what constitutes a high-quality rural placement experience is important for enhancing these outcomes. There is no current standardised definition of quality in the context of rural health placements, nor is there understanding of how this can be achieved across different rural contexts. This study is guided by one broad research question: what do university staff believe are the determinants of high-quality health professions student placements in regional, rural and remote Australia? METHODS AND ANALYSIS: This study will adopt a convergent mixed-method design with two components. Component A will use explanatory sequential mixed methods. The first phase of component A will use a survey to explore determinants that contribute to the development of high-quality health student placements from the perspective of university staff who are not employed in University Departments of Rural Health and are involved in the delivery of health student education. The second phase will use semistructured interviews with the same stakeholder group (non-University Department of Rural Health university staff) to identify the determinants of high-quality health student placements. Component B will use a case study Employing COnceptUal schema for policy and Translation Engagement in Research mind mapping method to capture determinants that contribute to the development of high-quality health student placements from the perspective of University Department of Rural Health university staff. ETHICS AND DISSEMINATION: The University of Melbourne Human Ethics Committee approved the study (2022-23201-33373-5). Following this, seven other Australian university human research ethics committees provided external approval to conduct the study. The results of the study will be presented in several peer-review publications and summary reports to key stakeholder groups.

Low contralateral failure rate with unilateral proton beam radiotherapy for oropharyngeal squamous cell carcinoma: A multi-institutional prospective study from the proton collaborative group.

INTRODUCTION: Unilateral radiation therapy is appropriate for select patients with oropharyngeal squamous cell carcinoma (OPSCC). The use of proton beam therapy (PBT) in the unilateral setting decreases the dose to the contralateral neck and organs at risk. This study aims to evaluate contralateral recurrences in patients who received ipsilateral PBT. METHODS: We evaluated the Proton Collaborative Group database for patients treated with PBT for head and neck squamous cell carcinoma between the years 2015-2020 at 12 institutions. Dosimetric analysis was performed in five cases. RESULTS: Our analysis included 41 patients that received ipsilateral PBT with a mean follow-up of 14.7 months. 37% patients (n = 15) were treated for recurrent disease, and 63% (n = 26) were treated for de novo disease. Oropharyngeal sites included tonsillar fossa (n = 30) and base of tongue (n = 11). The median dose and BED delivered were 69.96 CGE and 84 Gy, respectively. Eight (20%) patients experienced at least one grade 3 dysphagia (n = 4) or esophagitis (n = 4) toxicity. No grade ≥ 4 toxicities were reported. There was one (2.4%) failure in the contralateral neck. The 1-year locoregional control was 88.9% and the freedom from distant metastasis was 95.5% (n = 2). The dosimetric analysis demonstrated similar ipsilateral level II cervical nodal region doses, whereas contralateral doses were higher with photon plans, mean: 15.5 Gy and 0.7CGE, D5%: 25.1 Gy and 6.6CGE. CONCLUSIONS: Our series is the first to report outcomes for patients with OPSCC receiving unilateral PBT. The contralateral neck failure rate was excellent and comparable to failure rates with photon irradiation.

Rebels with a cause? How norm violations shape dominance, prestige, and influence granting.

Norms play an important role in upholding orderly and well-functioning societies. Indeed, violations of norms can undermine social coordination and stability. Much is known about the antecedents of norm violations, but their social consequences are poorly understood. In particular, it remains unclear when and how norm violators gain or lose influence in groups. Some studies found that norm violators elicit negative responses that curtail their influence in groups, whereas other studies documented positive consequences that enhance violators' influence. We propose that the complex relationship between norm violation and influence can be understood by considering that norm violations differentially shape perceptions of dominance and prestige, which tend to have opposite effects on voluntary influence granting, depending on the type of norm that is violated. We first provide correlational (Study 1) and causal (Study 2) evidence that norm violations are associated with dominance, and norm abidance with prestige. We then examine how dominance, prestige, and resultant influence granting are shaped by whether local group norms and/or global community norms are violated. In Study 3, protagonists who violated global (university) norms but followed local (sorority/fraternity) norms were more strongly endorsed as leaders than protagonists who followed global norms but violated local norms, because the former were perceived not only as high on dominance but also on prestige. In Study 4, popular high-school students were remembered as violating global (school) norms while abiding by local (peer) norms. In Study 5, individuals who violated global (organizational) norms while abiding by local (team) norms were assigned more leadership tasks when global and local norms conflicted (making violators "rebels with a cause") than when norms did not conflict, because the former situation inspired greater prestige. We discuss implications for the social dynamics of norms, hierarchy development, and leader emergence.

Inference about quantitative traits under selection: a Bayesian revisitation for the post-genomic era.

BACKGROUND: Selection schemes distort inference when estimating differences between treatments or genetic associations between traits, and may degrade prediction of outcomes, e.g., the expected performance of the progeny of an individual with a certain genotype. If input and output measurements are not collected on random samples, inferences and predictions must be biased to some degree. Our paper revisits inference in quantitative genetics when using samples stemming from some selection process. The approach used integrates the classical notion of fitness with that of missing data. Treatment is fully Bayesian, with inference and prediction dealt with, in an unified manner. While focus is on animal and plant breeding, concepts apply to natural selection as well. Examples based on real data and stylized models illustrate how selection can be accounted for in four different situations, and sometimes without success. RESULTS: Our flexible "soft selection" setting helps to diagnose the extent to which selection can be ignored. The clear connection between probability of missingness and the concept of fitness in stylized selection scenarios is highlighted. It is not realistic to assume that a fixed selection threshold t holds in conceptual replication, as the chance of selection depends on observed and unobserved data, and on unequal amounts of information over individuals, aspects that a "soft" selection representation addresses explicitly. There does not seem to be a general prescription to accommodate potential distortions due to selection. In structures that combine cross-sectional, longitudinal and multi-trait data such as in animal breeding, balance is the exception rather than the rule. The Bayesian approach provides an integrated answer to inference, prediction and model choice under selection that goes beyond the likelihood-based approach, where breeding values are inferred indirectly. CONCLUSIONS: The approach used here for inference and prediction under selection may or may not yield the best possible answers. One may believe that selection has been accounted for diligently, but the central problem of whether statistical inferences are good or bad does not have an unambiguous solution. On the other hand, the quality of predictions can be gauged empirically via appropriate training-testing of competing methods.

A method to obtain exact single-step GBLUP for non-genotyped descendants when the genomic relationship matrix of ancestors is not available.

BACKGROUND: Single-step genomic best linear unbiased prediction (GBLUP) involves a joint analysis of individuals with genotype information, and their ancestors, descendants, or contemporaries, without recorded genotypes. Livestock applications typically represent populations with fewer individuals with genotypes relative to the number not genotyped. Most breeding programmes are structured, consisting of a nucleus tier in which selection drives genetic gains that are propagated through descendants that represent parents in multiplier and commercial tiers. In some cases, the genotypes in the nucleus tier are proprietary to a breeding company, and not publicly available for a whole industry analysis. Bayesian inference involves combining a defined description of prior information with new information to generate a posterior distribution that contains all available information on parameters of interest. A natural extension of Bayesian analysis would be to use information from the posterior distribution to define the prior distribution in a subsequent analysis. METHODS: We derive the mixed model equations for inference on breeding values for non genotyped individuals in that subset of the population that is of current interest, using only data on the performance of current individuals and their immediate pedigree, along with prior information defined from the posterior distribution of an external BLUP or single-step GBLUP analysis of the ancestors of the current population. DISCUSSION: Identical estimates of breeding values and their prediction error covariances for current animals of interest in the multiplier or commercial tier can be obtained without requiring neither the genomic relationship matrix nor genotypes of any of their ancestors in the nucleus tier, as can be obtained from a single analysis using pedigree, performance, and genomic information from all tiers. The Bayesian analysis of the current population does not require explicit information on unselected genotyped animals in the external population.

Identifying features of quality in rural placements for health students: scoping review.

OBJECTIVES: To explore and synthesise the evidence relating to features of quality in rural health student placements. DESIGN: Scoping review. DATA SOURCES: MEDLINE, CINAHL, Embase, ProQuest, Informit, Scopus, ERIC and several grey literature data sources (1 January 2005 to 13 October 2020). STUDY SELECTION: The review included peer-reviewed and grey literature from Organisation for Economic Co-operation and Development listed countries that focused on quality of health student placements in regional, rural and remote areas. DATA EXTRACTION: Data were extracted regarding the methodological and design characteristics of each data source, and the features suggested to contribute to student placement quality under five categories based on a work-integrated learning framework. RESULTS: Of 2866 resulting papers, 101 were included for data charting and content analysis. The literature was dominated by medicine and nursing student placement research. No literature explicitly defined quality in rural health student placements, although proxy indicators for quality such as satisfaction, positive experiences, overall effectiveness and perceived value were identified. Content analysis resulted in four overarching domains pertaining to features of rural health student placement quality: (1) learning and teaching in a rural context, (2) rural student placement characteristics, (3) key relationships and (4) required infrastructure. CONCLUSION: The findings suggest that quality in rural health student placements hinges on contextually specific features. Further research is required to explore these findings and ways in which these features can be measured during rural health student placements.

Comparison of linkage disequilibrium estimated from genotypes versus haplotypes for crossbred populations.

BACKGROUND: Linkage disequilibrium (LD) is commonly measured based on the squared coefficient of correlation [Formula: see text] between the alleles at two loci that are carried by haplotypes. LD can also be estimated as the [Formula: see text] between unphased genotype dosage at two loci when the allele frequencies and inbreeding coefficients at both loci are identical for the parental lines. Here, we investigated whether [Formula: see text] for a crossbred population (F1) can be estimated using genotype data. The parental lines of the crossbred (F1) can be purebred or crossbred. METHODS: We approached this by first showing that inbreeding coefficients for an F1 crossbred population are negative, and typically differ in size between loci. Then, we proved that the expected [Formula: see text] computed from unphased genotype data is expected to be identical to the [Formula: see text] computed from haplotype data for an F1 crossbred population, regardless of the inbreeding coefficients at the two loci. Finally, we investigated the bias and precision of the [Formula: see text] estimated using unphased genotype versus haplotype data in stochastic simulation. RESULTS: Our findings show that estimates of [Formula: see text] based on haplotype and unphased genotype data are both unbiased for different combinations of allele frequencies, sample sizes (900, 1800, and 2700), and levels of LD. In general, for any allele frequency combination and [Formula: see text] value scenarios considered, and for both methods to estimate [Formula: see text], the precision of the estimates increased, and the bias of the estimates decreased as sample size increased, indicating that both estimators are consistent. For a given scenario, the [Formula: see text] estimates using haplotype data were more precise and less biased using haplotype data than using unphased genotype data. As sample size increased, the difference in precision and biasedness between the [Formula: see text] estimates using haplotype data and unphased genotype data decreased. CONCLUSIONS: Our theoretical derivations showed that estimates of LD between loci based on unphased genotypes and haplotypes in F1 crossbreds have identical expectations. Based on our simulation results, we conclude that the LD for an F1 crossbred population can be accurately estimated from unphased genotype data. The results also apply for other crosses (F2, F3, Fn, BC1, BC2, and BCn), as long as (selected) individuals from the two parental lines mate randomly.

Further host-genomic characterization of total antibody response to PRRSV vaccination and its relationship with reproductive performance in commercial sows: genome-wide haplotype and zygosity analyses.

BACKGROUND: The possibility of using antibody response (S/P ratio) to PRRSV vaccination measured in crossbred commercial gilts as a genetic indicator for reproductive performance in vaccinated crossbred sows has motivated further studies of the genomic basis of this trait. In this study, we investigated the association of haplotypes and runs of homozygosity (ROH) and heterozygosity (ROHet) with S/P ratio and their impact on reproductive performance. RESULTS: There was no association (P-value ≥ 0.18) of S/P ratio with the percentage of ROH or ROHet, or with the percentage of heterozygosity across the whole genome or in the major histocompatibility complex (MHC) region. However, specific ROH and ROHet regions were significantly associated (P-value ≤ 0.01) with S/P ratio on chromosomes 1, 4, 5, 7, 10, 11, 13, and 17 but not (P-value ≥ 0.10) with reproductive performance. With the haplotype-based genome-wide association study (GWAS), additional genomic regions associated with S/P ratio were identified on chromosomes 4, 7, and 9. These regions harbor immune-related genes, such as SLA-DOB, TAP2, TAPBP, TMIGD3, and ADORA. Four haplotypes at the identified region on chromosome 7 were also associated with multiple reproductive traits. A haplotype significantly associated with S/P ratio that is located in the MHC region may be in stronger linkage disequilibrium (LD) with the quantitative trait loci (QTL) than the previously identified single nucleotide polymorphism (SNP) (H3GA0020505) given the larger estimate of genetic variance explained by the haplotype than by the SNP. CONCLUSIONS: Specific ROH and ROHet regions were significantly associated with S/P ratio. The haplotype-based GWAS identified novel QTL for S/P ratio on chromosomes 4, 7, and 9 and confirmed the presence of at least one QTL in the MHC region. The chromosome 7 region was also associated with reproductive performance. These results narrow the search for causal genes in this region and suggest SLA-DOB and TAP2 as potential candidate genes associated with S/P ratio on chromosome 7. These results provide additional opportunities for marker-assisted selection and genomic selection for S/P ratio as genetic indicator for litter size in commercial pig populations.

The role of chemotherapy in the management of olfactory neuroblastoma: A 40-year surveillance, epidemiology, and end results registry study.

BACKGROUND: In this retrospective surveillance, epidemiology, and end results (SEER) registry analysis, we investigated the role of chemotherapy (CT) in the treatment of olfactory neuroblastoma (ON), an exceedingly rare sino-nasal tumor typically treated with surgery and/or radiation therapy (RT). METHODS: We analyzed all patients in the SEER registry diagnosed with a single primary malignancy of ON, a primary tumor site within the nasal cavity or surrounding sinuses, sufficient staging information to derive Kadish staging, and >0 days of survival, ensuring follow-up data. Receipt of CT in the SEER registry was documented as either Yes or No/Unknown. RESULTS: Six hundred and thirty-six patients were identified. One hundred and ninety-five patients received CT as part of their treatment for ON. Following propensity score matching and inverse probability of treatment weighting, there was inferior overall survival (OS) (HR 1.7, 95% CI: 1.3-2.2, P = .001) and cancer-specific survival (CSS) (HR 1.8, 95% CI: 1.3-2.4, P < .001) for patients who received CT compared to those who were not treated with CT or had unknown CT status. On subgroup analysis, the only patient population that derived benefit from CT were patients who did not receive surgery and were treated with CT and/or RT (HR 0.3, 95% CI: 0.14-0.61, P < .001). CONCLUSIONS: Based on this retrospective SEER registry analysis, the use of CT in the management of ON is associated with decreased OS. Our analysis suggests that patients who are considered nonsurgical candidates may benefit from the addition of CT.

Genomics of response to porcine reproductive and respiratory syndrome virus in purebred and crossbred sows: antibody response and performance following natural infection vs. vaccination.

Antibody response, measured as sample-to-positive (S/P) ratio, to porcine reproductive and respiratory syndrome virus (PRRSV) following a PRRSV-outbreak (S/POutbreak) in a purebred nucleus and following a PRRSV-vaccination (S/PVx) in commercial crossbred herds have been proposed as genetic indicator traits for improved reproductive performance in PRRSV-infected purebred and PRRSV-vaccinated crossbred sows, respectively. In this study, we investigated the genetic relationships of S/POutbreak and S/PVx with performance at the commercial (vaccinated crossbred sows) and nucleus level (non-infected and PRRSV-infected purebred sows), respectively, and tested the effect of previously identified SNP for these indicator traits. Antibody response was measured on 541 Landrace sows ~54 d after the start of a PRRSV outbreak, and on 906 F1 (Landrace × Large White) gilts ~50 d after vaccination with a commercial PRRSV vaccine. Reproductive performance was recorded for 711 and 428 Landrace sows before and during the PRRSV outbreak, respectively, and for 811 vaccinated F1 animals. The estimate of the genetic correlation (rg) of S/POutbreak with S/PVx was 0.72 ± 0.18. The estimates of rg of S/POutbreak with reproductive performance in vaccinated crossbred sows were low to moderate, ranging from 0.05 ± 0.23 to 0.30 ± 0.20. The estimate of rg of S/PVx with reproductive performance in non-infected purebred sows was moderate and favorable with number born alive (0.50 ± 0.23) but low (0 ± 0.23 to -0.11 ± 0.23) with piglet mortality traits. The estimates of rg of S/PVx were moderate and negative (-0.38 ± 0.21) with number of mummies in PRRSV-infected purebred sows and low with other traits (-0.30 ± 0.18 to 0.05 ± 0.18). Several significant associations (P0 > 0.90) of previously reported SNP for S/P ratio (ASGA0032063 and H3GA0020505) were identified for S/P ratio and performance in non-infected purebred and PRRSV-exposed purebred and crossbred sows. Genomic regions harboring the major histocompatibility complex class II region significantly contributed to the genetic correlation of antibody response to PRRSV with most of the traits analyzed. These results indicate that selection for antibody response in purebred sows following a PRRSV outbreak in the nucleus and for antibody response to PRRSV vaccination measured in commercial crossbred sows are expected to increase litter size in purebred and commercial sows.

Cross-validation of best linear unbiased predictions of breeding values using an efficient leave-one-out strategy.

Empirical estimates of the accuracy of estimates of breeding values (EBV) can be obtained by cross-validation. Leave-one-out cross-validation (LOOCV) is an extreme case of k-fold cross-validation. Efficient strategies for LOOCV of predictions of phenotypes have been developed for a simple model with an overall mean and random marker or animal genetic effects. The objective here was to develop and evaluate an efficient LOOCV method for prediction of breeding values and other random effects under a general mixed linear model with multiple random effects. Conventional LOOCV of EBV requires inverting an (n-1)×(n-1) covariance matrix for each of n (= number of observations) data sets. Our efficient LOOCV obtains the required inverses from the inverse of the covariance matrix for all n observations. The efficient method can be applied to complex models with multiple fixed and random effects, but requires fixed effects to be treated as random, with large variances. An alternative is to precorrect observations using estimates of fixed effects obtained from the complete data, but this can lead to biases. The efficient LOOCV method was compared to conventional LOOCV of predictions of breeding values in terms of computational demands and accuracy. For a data set with 3,205 observations and a model with multiple random and fixed effects, the efficient LOOCV method was 962 times faster than the conventional LOOCV with precorrection for fixed effects based on each training data set but resulted in identical EBV. A computationally efficient LOOCV for prediction of breeding values for single- and multiple-trait mixed models with multiple fixed and random effects was successfully developed. The method enables cross-validation of predictions of breeding values and of any linear combination of random and/or fixed effects, along with leave-one-out precorrection of validation phenotypes.

Considerations in Planning Physical Activity for Older Adults in Hot Climates: A Narrative Review.

Regular physical activity has multiple health benefits for both the prevention and management of disease, including for older adults. However, additional precautions are needed with ageing given physiological changes and the increasing prevalence of comorbidities. Hot ambient temperatures increase the risks of exercise at any age, but are particularly important given thermoregulatory changes in older people. This narrative review informs planning of physical activity programs for older people living in rural areas with very hot climates for a period of the year. A multi-database search of peer-reviewed literature was undertaken with attention to its relevance to Australia, starting with definitions and standard advice in relation to physical activity programming and the incremental limitations imposed by age, rurality, and extreme heat. The enablers of and barriers to increasing physical activities in older adults and how they can be modified for those living in extreme hot climates is described. We describe multiple considerations in program design to improve safety, adherence and sustaining physical activity, including supervision, simple instructions, provision of reminders, social support, encouraging self-efficacy. Group-based activities may be preferred by some and can accommodate special populations, cultural considerations. Risk management is an important consideration and recommendations are provided to assist program planning.

Automated identification of urban substructure for comparative analysis.

Neighborhoods are the building blocks of cities, and thus significantly impact urban planning from infrastructure deployment to service provisioning. However, existing definitions of neighborhoods are often ill suited for planning in both scale and pattern of aggregation. Here, we propose a generalized, scalable approach using topological data analysis to identify barrier-enclosed neighborhoods on multiple scales with implications for understanding social mixing within cities and the design of urban infrastructure. Our method requires no prior domain knowledge and uses only readily available building parcel information. Results from three American cities (Houston, New York, San Francisco) indicate that our method identifies neighborhoods consistent with historical approaches. Additionally, we uncover a consistent scale in all three cities at which physical isolation drives neighborhood emergence. However, our methods also reveal differences between these cities: Houston, although more disconnected on larger spatial scales than New York and San Francisco, is less disconnected at smaller scales.

Harnessing the power of electrophoresis and chromatography: Offline coupling of reverse phase liquid chromatography-capillary zone electrophoresis-tandem mass spectrometry for analysis of host cell proteins in monoclonal antibody producing CHO cell line.

Host cell proteins (HCPs) are widely regarded as a critical quality attribute for a biotherapeutic product. Bottom up MS is the present gold standard for HCP analysis but suffers from incomplete protein identification due to complex nature of the HCP mixture and limited separation efficiency of the preceding LC-based systems. In this paper, we present for the first time an application involving use of LC-CE-MS/MS platform for analysis of HCPs. It has been demonstrated that the proposed platform has been able to successfully identify 397 HCPs from the supernatants of recombinant Chinese hamster ovary cells, twice and thrice the number of proteins identified by the state-of-the-art LC-MS/MS (189 HCPs) and CE-MS/MS (128 HCPs) analyses, respectively. Of these, 225 HCPs were unique to the LC-CE-MS/MS approach and were not identified by either LC-MS/MS or CE-MS/MS. It is observed that the LC-CE-MS/MS platform combines the benefits of LC-MS/MS and CE-MS/MS techniques and identifies peptides in a wider range of size, pI, and hydrophobicity. Additionally, LC-CE-MS/MS also identified more HCPs associated with cellular components, molecular functions, biological processes, peptidases, and secretory proteins. The proposed approach would thus be a useful addition in HCP analysis and secretome studies of mAb-producing Chinese hamster ovary cells.

Genetic Analysis of Antibody Response to Porcine Reproductive and Respiratory Syndrome Vaccination as an Indicator Trait for Reproductive Performance in Commercial Sows.

We proposed to investigate the genomic basis of antibody response to porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) vaccination and its relationship to reproductive performance in non-PRRSV-infected commercial sows. Nine hundred and six F1 replacement gilts (139 ± 17 days old) from two commercial farms were vaccinated with a commercial modified live PRRSV vaccine. Blood samples were collected about 52 days after vaccination to measure antibody response to PRRSV as sample-to-positive (S/P) ratio and for single-nucleotide polymorphism (SNP) genotyping. Reproductive performance was recorded for up to 807 sows for number born alive (NBA), number of piglets weaned, number born mummified (MUM), number of stillborn (NSB), and number of pre-weaning mortality (PWM) at parities (P) 1-3 and per sow per year (PSY). Fertility traits such as farrowing rate and age at first service were also analyzed. BayesC0 was used to estimate heritability and genetic correlations of S/P ratio with reproductive performance. Genome-wide association study (GWAS) and genomic prediction were performed using BayesB. The heritability estimate of S/P ratio was 0.34 ± 0.05. High genetic correlations (r g) of S/P ratio with farrowing performance were identified for NBA P1 (0.61), PWM P2 (-0.70), NSB P3 (-0.83), MUM P3 (-0.84), and NSB PSY (-0.90), indicating that genetic selection for increased S/P ratio would result in improved performance of these traits. A quantitative trait locus was identified on chromosome 7 (∼25 Mb), at the major histocompatibility complex (MHC) region, explaining ∼30% of the genetic variance for S/P ratio, mainly by SNPs ASGA0032113, H3GA0020505, and M1GA0009777. This same region was identified in the bivariate GWAS of S/P ratio and reproductive traits, with SNP H3GA0020505 explaining up to 10% (for NBA P1) of the genetic variance of reproductive performance. The heterozygote genotype at H3GA0020505 was associated with greater S/P ratio and NBA P1 (P = 0.06), and lower MUM P3 and NSB P3 (P = 0.07). Genomic prediction accuracy for S/P ratio was high when using all SNPs (0.67) and when using only those in the MHC region (0.59) and moderate to low when using all SNPs excluding those in the MHC region (0.39). These results suggest that there is great potential to use antibody response to PRRSV vaccination as an indicator trait to improve reproductive performance in commercial pigs.

Corrigendum: Exact Distribution of Linkage Disequilibrium in the Presence of Mutation, Selection, or Minor Allele Frequency Filtering.

[This corrects the article DOI: 10.3389/fgene.2020.00362.].