Large-scale analysis of sheep rumen metagenome profiles captured by reduced representation sequencing reveals individual profiles are influenced by the environment and genetics of the host.

BACKGROUND: Producing animal protein while reducing the animal's impact on the environment, e.g., through improved feed efficiency and lowered methane emissions, has gained interest in recent years. Genetic selection is one possible path to reduce the environmental impact of livestock production, but these traits are difficult and expensive to measure on many animals. The rumen microbiome may serve as a proxy for these traits due to its role in feed digestion. Restriction enzyme-reduced representation sequencing (RE-RRS) is a high-throughput and cost-effective approach to rumen metagenome profiling, but the systematic (e.g., sequencing) and biological factors influencing the resulting reference based (RB) and reference free (RF) profiles need to be explored before widespread industry adoption is possible. RESULTS: Metagenome profiles were generated by RE-RRS of 4,479 rumen samples collected from 1,708 sheep, and assigned to eight groups based on diet, age, time off feed, and country (New Zealand or Australia) at the time of sample collection. Systematic effects were found to have minimal influence on metagenome profiles. Diet was a major driver of differences between samples, followed by time off feed, then age of the sheep. The RF approach resulted in more reads being assigned per sample and afforded greater resolution when distinguishing between groups than the RB approach. Normalizing relative abundances within the sampling Cohort abolished structures related to age, diet, and time off feed, allowing a clear signal based on methane emissions to be elucidated. Genus-level abundances of rumen microbes showed low-to-moderate heritability and repeatability and were consistent between diets. CONCLUSIONS: Variation in rumen metagenomic profiles was influenced by diet, age, time off feed and genetics. Not accounting for environmental factors may limit the ability to associate the profile with traits of interest. However, these differences can be accounted for by adjusting for Cohort effects, revealing robust biological signals. The abundances of some genera were consistently heritable and repeatable across different environments, suggesting that metagenomic profiles could be used to predict an individual's future performance, or performance of its offspring, in a range of environments. These results highlight the potential of using rumen metagenomic profiles for selection purposes in a practical, agricultural setting.

Combining host and rumen metagenome profiling for selection in sheep: prediction of methane, feed efficiency, production, and health traits.

BACKGROUND: Rumen microbes break down complex dietary carbohydrates into energy sources for the host and are increasingly shown to be a key aspect of animal performance. Host genotypes can be combined with microbial DNA sequencing to predict performance traits or traits related to environmental impact, such as enteric methane emissions. Metagenome profiles were generated from 3139 rumen samples, collected from 1200 dual purpose ewes, using restriction enzyme-reduced representation sequencing (RE-RRS). Phenotypes were available for methane (CH4) and carbon dioxide (CO2) emissions, the ratio of CH4 to CH4 plus CO2 (CH4Ratio), feed efficiency (residual feed intake: RFI), liveweight at the time of methane collection (LW), liveweight at 8 months (LW8), fleece weight at 12 months (FW12) and parasite resistance measured by faecal egg count (FEC1). We estimated the proportion of phenotypic variance explained by host genetics and the rumen microbiome, as well as prediction accuracies for each of these traits. RESULTS: Incorporating metagenome profiles increased the variance explained and prediction accuracy compared to fitting only genomics for all traits except for CO2 emissions when animals were on a grass diet. Combining the metagenome profile with host genotype from lambs explained more than 70% of the variation in methane emissions and residual feed intake. Predictions were generally more accurate when incorporating metagenome profiles compared to genetics alone, even when considering profiles collected at different ages (lamb vs adult), or on different feeds (grass vs lucerne pellet). A reference-free approach to metagenome profiling performed better than metagenome profiles that were restricted to capturing genera from a reference database. We hypothesise that our reference-free approach is likely to outperform other reference-based approaches such as 16S rRNA gene sequencing for use in prediction of individual animal performance. CONCLUSIONS: This paper shows the potential of using RE-RRS as a low-cost, high-throughput approach for generating metagenome profiles on thousands of animals for improved prediction of economically and environmentally important traits. A reference-free approach using a microbial relationship matrix from log10 proportions of each tag normalized within cohort (i.e., the group of animals sampled at the same time) is recommended for future predictions using RE-RRS metagenome profiles.

Tralesinidase Alfa Enzyme Replacement Therapy Prevents Disease Manifestations in a Canine Model of Mucopolysaccharidosis Type IIIB.

Mucopolysaccharidosis type IIIB (MPS IIIB; Sanfilippo syndrome B; OMIM #252920) is a lethal, pediatric, neuropathic, autosomal recessive, and lysosomal storage disease with no approved therapy. Patients are deficient in the activity of N-acetyl-alpha-glucosaminidase (NAGLU; EC 3.2.150), necessary for normal lysosomal degradation of the glycosaminoglycan heparan sulfate (HS). Tralesinidase alfa (TA), a fusion protein comprised of recombinant human NAGLU and a modified human insulin-like growth factor 2, is in development as an enzyme replacement therapy that is administered via intracerebroventricular (ICV) infusion, thus circumventing the blood brain barrier. Previous studies have confirmed ICV infusion results in widespread distribution of TA throughout the brains of mice and nonhuman primates. We assessed the long-term tolerability, pharmacology, and clinical efficacy of TA in a canine model of MPS IIIB over a 20-month study. Long-term administration of TA was well tolerated as compared with administration of vehicle. TA was widely distributed across brain regions, which was confirmed in a follow-up 8-week pharmacokinetic/pharmacodynamic study. MPS IIIB dogs treated for up to 20 months had near-normal levels of HS and nonreducing ends of HS in cerebrospinal fluid and central nervous system (CNS) tissues. TA-treated MPS IIIB dogs performed better on cognitive tests and had improved CNS pathology and decreased cerebellar volume loss relative to vehicle-treated MPS IIIB dogs. These findings demonstrate the ability of TA to prevent or limit the biochemical, pathologic, and cognitive manifestations of canine MPS IIIB disease, thus providing support of its potential long-term tolerability and efficacy in MPS IIIB subjects. SIGNIFICANCE STATEMENT: This work illustrates the efficacy and tolerability of tralesinidase alfa as a potential therapeutic for patients with mucopolysaccharidosis type IIIB (MPS IIIB) by documenting that administration to the central nervous system of MPS IIIB dogs prevents the accumulation of disease-associated glycosaminoglycans in lysosomes, hepatomegaly, cerebellar atrophy, and cognitive decline.

Gene expression in tonsils in swine following infection with porcine reproductive and respiratory syndrome virus.

BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is a threat to pig production worldwide. Our objective was to understand mechanisms of persistence of PRRS virus (PRRSV) in tonsil. Transcriptome data from tonsil samples collected at 42 days post infection (dpi) were generated by RNA-seq and NanoString on 51 pigs that were selected to contrast the two PRRSV isolates used, NVSL and KS06, high and low tonsil viral level at 42 dpi, and the favorable and unfavorable genotypes at a genetic marker (WUR) for the putative PRRSV resistance gene GBP5. RESULTS: The number of differentially expressed genes (DEGs) differed markedly between models with and without accounting for cell-type enrichments (CE) in the samples that were predicted from the RNA-seq data. This indicates that differences in cell composition in tissues that consist of multiple cell types, such as tonsil, can have a large impact on observed differences in gene expression. Based on both the NanoString and the RNA-seq data, KS06-infected pigs showed greater activation, or less inhibition, of immune response in tonsils at 42 dpi than NVSL-infected pigs, with and without accounting for CE. This suggests that the NVSL virus may be better than the KS06 virus at evading host immune response and persists in tonsils by weakening, or preventing, host immune responses. Pigs with high viral levels showed larger CE of immune cells than low viral level pigs, potentially to trigger stronger immune responses. Presence of high tonsil virus was associated with a stronger immune response, especially innate immune response through interferon signaling, but these differences were not significant when accounting for CE. Genotype at WUR was associated with different effects on immune response in tonsils of pigs during the persistence stage, depending on viral isolate and tonsil viral level. CONCLUSIONS: Results of this study provide insights into the effects of PRRSV isolate, tonsil viral level, and WUR genotype on host immune response and into potential mechanisms of PRRSV persistence in tonsils that could be targeted to improve strategies to reduce viral rebreaks. Finally, to understand transcriptome responses in tissues that consist of multiple cell types, it is important to consider differences in cell composition.

Chirality-Enhanced Periodic Self-Focusing of Light in Soft Birefringent Media.

We experimentally and numerically show that chirality can play a major role in the nonlinear optical response of soft birefringent materials, by studying the nonlinear propagation of laser beams in frustrated cholesteric liquid crystal samples. Such beams exhibit a periodic nonlinear response associated with a bouncing pattern for the optical fields, as well as a self-focusing effect enhanced by the chirality of the birefringent material. Our results open new possible designs of nonlinear optical devices with low power consumption and tunable interactions with localized topological solitons.

Harnessing longitudinal information to identify genetic variation in tolerance of pigs to Porcine Reproductive and Respiratory Syndrome virus infection.

BACKGROUND: High resistance (the ability of the host to reduce pathogen load) and tolerance (the ability to maintain high performance at a given pathogen load) are two desirable host traits for producing animals that are resilient to infections. For Porcine Reproductive and Respiratory Syndrome (PRRS), one of the most devastating swine diseases worldwide, studies have identified substantial genetic variation in resistance of pigs, but evidence for genetic variation in tolerance has so far been inconclusive. Resistance and tolerance are usually considered as static traits. In this study, we used longitudinal viremia measurements of PRRS virus infected pigs to define discrete stages of infection based on viremia profile characteristics. These were used to investigate host genetic effects on viral load (VL) and growth at different stages of infection, to quantify genetic variation in tolerance at these stages and throughout the entire 42-day observation period, and to assess whether the single nucleotide polymorphism (SNP) WUR10000125 (WUR) with known large effects on resistance confers significant differences in tolerance. RESULTS: Genetic correlations between resistance and growth changed considerably over time. Individuals that expressed high genetic resistance early in infection tended to grow slower during that time-period, but were more likely to experience lower VL and recovery in growth by the later stage. The WUR genotype was most strongly associated with VL at early- to mid-stages of infection, and with growth at mid- to late-stages of infection. Both, single-stage and repeated measurements random regression models identified significant genetic variation in tolerance. The WUR SNP was significantly associated only with the overall tolerance slope fitted through all stages of infection, with the genetically more resistant AB pigs for the WUR SNP being also more tolerant to PRRS. CONCLUSIONS: The results suggest that genetic selection for improved tolerance of pigs to PRRS is possible in principle, but may be feasible only with genomic selection, requiring intense recording schemes that involve repeated measurements to reliably estimate genetic effects. In the absence of such records, consideration of the WUR genotype in current selection schemes appears to be a promising strategy to improve simultaneously resistance and tolerance of growing pigs to PRRS.

Genomic prediction of piglet response to infection with one of two porcine reproductive and respiratory syndrome virus isolates.

BACKGROUND: Genomic prediction of the pig's response to the porcine reproductive and respiratory syndrome (PRRS) virus (PRRSV) would be a useful tool in the swine industry. This study investigated the accuracy of genomic prediction based on porcine SNP60 Beadchip data using training and validation datasets from populations with different genetic backgrounds that were challenged with different PRRSV isolates. RESULTS: Genomic prediction accuracy averaged 0.34 for viral load (VL) and 0.23 for weight gain (WG) following experimental PRRSV challenge, which demonstrates that genomic selection could be used to improve response to PRRSV infection. Training on WG data during infection with a less virulent PRRSV, KS06, resulted in poor accuracy of prediction for WG during infection with a more virulent PRRSV, NVSL. Inclusion of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with a major quantitative trait locus (QTL) on chromosome 4 was vital for accurate prediction of VL. Overall, SNPs that were significantly associated with either trait in single SNP genome-wide association analysis were unable to predict the phenotypes with an accuracy as high as that obtained by using all genotyped SNPs across the genome. Inclusion of data from close relatives into the training population increased whole genome prediction accuracy by 33% for VL and by 37% for WG but did not affect the accuracy of prediction when using only SNPs in the major QTL region. CONCLUSIONS: Results show that genomic prediction of response to PRRSV infection is moderately accurate and, when using all SNPs on the porcine SNP60 Beadchip, is not very sensitive to differences in virulence of the PRRSV in training and validation populations. Including close relatives in the training population increased prediction accuracy when using the whole genome or SNPs other than those near a major QTL.

Different personal propensities among scientists relate to deeper vs. broader knowledge contributions.

Scientific journal publications, and their contributions to knowledge, can be described by their depth (specialized, domain-specific knowledge extensions) and breadth (topical scope, including spanning multiple knowledge domains). Toward generating hypotheses about how scientists' personal dispositions would uniquely predict deeper vs. broader contributions to the literature, we assumed that conducting broader studies is generally viewed as less attractive (e.g., riskier) than conducting deeper studies. Study 1 then supported our assumptions: the scientists surveyed considered a hypothetical broader study, compared with an otherwise-comparable deeper study, to be riskier, a less-significant opportunity, and of lower potential importance; they further reported being less likely to pursue it and, in a forced choice, most chose to work on the deeper study. In Study 2, questionnaire measures of medical researchers' personal dispositions and 10 y of PubMed data indicating their publications' topical coverage revealed how dispositions differentially predict depth vs. breadth. Competitiveness predicted depth positively, whereas conscientiousness predicted breadth negatively. Performance goal orientation predicted depth but not breadth, and learning goal orientation contrastingly predicted breadth but not depth. Openness to experience positively predicted both depth and breadth. Exploratory work behavior (the converse of applying and exploiting one's current knowledge) predicted breadth positively and depth negatively. Thus, this research distinguishes depth and breadth of published knowledge contributions, and provides new insights into how scientists' personal dispositions influence research processes and products.

Fixed-length haplotypes can improve genomic prediction accuracy in an admixed dairy cattle population.

BACKGROUND: Fitting covariates representing the number of haplotype alleles rather than single nucleotide polymorphism (SNP) alleles may increase genomic prediction accuracy if linkage disequilibrium between quantitative trait loci and SNPs is inadequate. The objectives of this study were to evaluate the accuracy, bias and computation time of Bayesian genomic prediction methods that fit fixed-length haplotypes or SNPs. Genotypes at 37,740 SNPs that were common to Illumina BovineSNP50 and high-density panels were phased for ~58,000 New Zealand dairy cattle. Females born before 1 June 2008 were used for training, and genomic predictions for milk fat yield (n = 24,823), liveweight (n = 13,283) and somatic cell score (n = 24,864) were validated within breed (predominantly Holstein-Friesian, predominantly Jersey, or admixed KiwiCross) in later-born females. Covariates for haplotype alleles of five lengths (125, 250, 500 kb, 1 or 2 Mb) were generated and rare haplotypes were removed at four thresholds (1, 2, 5 or 10%), resulting in 20 scenarios tested. Genomic predictions fitting covariates for either SNPs or haplotypes were calculated by using BayesA, BayesB or BayesN. This is the first study to quantify the accuracy of genomic prediction using haplotypes across the whole genome in an admixed population. RESULTS: A correlation of 0.349 ± 0.016 between yield deviation and genomic breeding values was obtained for milk fat yield in Holstein-Friesians using BayesA fitting covariates. Genomic predictions were more accurate with short haplotypes than with SNPs but less accurate with longer haplotypes than with SNPs. Fitting only the most frequent haplotype alleles reduced computation time with little decrease in prediction accuracy for short haplotypes. Trends were similar for all traits and breeds and there was little difference between Bayesian methods. CONCLUSIONS: Fitting covariates for haplotype alleles rather than SNPs can increase prediction accuracy, although it decreased drastically for long (>500 kb) haplotypes. In this population, fitting 250 kb haplotypes with a 1% frequency threshold resulted in the highest genomic prediction accuracy and fitting 125 kb haplotypes with a 10% frequency threshold improved genomic prediction accuracy with comparable computation time to fitting SNPs. This increased accuracy is likely to increase genetic gain by changing the ranking of selection candidates.

Use of multi-trait and random regression models to identify genetic variation in tolerance to porcine reproductive and respiratory syndrome virus.

BACKGROUND: A host can adopt two response strategies to infection: resistance (reduce pathogen load) and tolerance (minimize impact of infection on performance). Both strategies may be under genetic control and could thus be targeted for genetic improvement. Although there is evidence that supports a genetic basis for resistance to porcine reproductive and respiratory syndrome (PRRS), it is not known whether pigs also differ genetically in tolerance. We determined to what extent pigs that have been shown to vary genetically in resistance to PRRS also exhibit genetic variation in tolerance. Multi-trait linear mixed models and random regression sire models were fitted to PRRS Host Genetics Consortium data from 1320 weaned pigs (offspring of 54 sires) that were experimentally infected with a virulent strain of PRRS virus to obtain genetic parameter estimates for resistance and tolerance. Resistance was defined as the inverse of within-host viral load (VL) from 0 to 21 (VL21) or 0 to 42 (VL42) days post-infection and tolerance as the slope of the reaction-norm of average daily gain (ADG21, ADG42) on VL21 or VL42. RESULTS: Multi-trait analysis of ADG associated with either low or high VL was not indicative of genetic variation in tolerance. Similarly, random regression models for ADG21 and ADG42 with a tolerance slope fitted for each sire did not result in a better fit to the data than a model without genetic variation in tolerance. However, the distribution of data around average VL suggested possible confounding between level and slope estimates of the regression lines. Augmenting the data with simulated growth rates of non-infected half-sibs (ADG0) helped resolve this statistical confounding and indicated that genetic variation in tolerance to PRRS may exist if genetic correlations between ADG0 and ADG21 or ADG42 are low to moderate. CONCLUSIONS: Evidence for genetic variation in tolerance of pigs to PRRS was weak when based on data from infected piglets only. However, simulations indicated that genetic variance in tolerance may exist and could be detected if comparable data on uninfected relatives were available. In conclusion, of the two defense strategies, genetics of tolerance is more difficult to elucidate than genetics of resistance.

Comparison of host genetic factors influencing pig response to infection with two North American isolates of porcine reproductive and respiratory syndrome virus.

BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is one of the most important swine diseases in the world and genetic selection of pigs for increased resistance to PRRS is an attractive method to improve the health status of the swine herd. This study compared phenotypic and genetic responses to infection with one of two genetically distinct type 2 PRRS virus (PRRSV) isolates: NVSL-97-7895 (NVSL) and KS-2006-72109 (KS06), and evaluated whether the single nucleotide polymorphism (SNP) WUR10000125 (WUR) on chromosome 4 that was associated with viral load and weight gain under infection with NVSL also has an effect on response to infection across North American PRRSV isolates. Wood's lactation curve was fitted to repeated viremia measurements to derive five curve characteristics that were evaluated. RESULTS: Infection with NVSL was characterized by reaching a 14 ± 2 % higher peak viremia (PV) 2.5 ± 0.6 days earlier (time to peak; TP) than KS06, followed by 36 ± 1 % faster virus clearance, which occurred 3.9 ± 0.7 days sooner. Weight gain from 0 to 42 days post-infection (WG) tended to be higher under infection with KS06 than NVSL (3.7 ± 1.5 kg). Estimates of heritability were moderate for both PRRSV isolates for viral load from 0 to 21 days post-infection (VL) (NVSL: 0.31 ± 0.06; KS06: 0.51 ± 0.09) and WG (NVSL: 0.33 ± 0.06; KS06: 0.31 ± 0.09). Strong negative genetic correlations were observed between VL and WG for both NVSL (-0.74 ± 0.10) and KS06 (-0.52 ± 0.17) infected pigs. Pigs with genotype AB at the WUR SNP had a more desirable phenotype than AA pigs for all traits under infection with NVSL, but only for VL and PV with KS06; effects on other traits were smaller and not significantly different from zero (P > 0.05). Genetic correlations of host response between isolates were strong for VL, WG and PV. Accounting for WUR genotype had little impact on these correlations, suggesting that response to PRRSV infection has a substantial polygenic component that is common between these two isolates. CONCLUSIONS: These results suggest that the KS06 PRRSV isolate is less virulent than NVSL but that genetic selection for increased resistance to either of these genetically distinct isolates is expected to increase resistance to the other isolate.

Field-controlled dynamics of skyrmions and monopoles.

Magnetic monopoles, despite their ongoing experimental search as elementary particles, have inspired the discovery of analogous excitations in condensed matter systems. In chiral condensed matter systems, emergent monopoles are responsible for the onset of transitions between topologically distinct states and phases, such as in the case of transitions from helical and conical phase to A-phase comprising periodic arrays of skyrmions. By combining numerical modeling and optical characterizations, we describe how different geometrical configurations of skyrmions terminating at monopoles can be realized in liquid crystals and liquid crystal ferromagnets. We demonstrate how these complex structures can be effectively manipulated by external magnetic and electric fields. Furthermore, we discuss how our findings may hint at similar dynamics in other physical systems and their potential applications.

Current challenges and future of agricultural genomes to phenomes in the USA.

Dramatic improvements in measuring genetic variation across agriculturally relevant populations (genomics) must be matched by improvements in identifying and measuring relevant trait variation in such populations across many environments (phenomics). Identifying the most critical opportunities and challenges in genome to phenome (G2P) research is the focus of this paper. Previously (Genome Biol, 23(1):1-11, 2022), we laid out how Agricultural Genome to Phenome Initiative (AG2PI) will coordinate activities with USA federal government agencies expand public-private partnerships, and engage with external stakeholders to achieve a shared vision of future the AG2PI. Acting on this latter step, AG2PI organized the "Thinking Big: Visualizing the Future of AG2PI" two-day workshop held September 9-10, 2022, in Ames, Iowa, co-hosted with the United State Department of Agriculture's National Institute of Food and Agriculture (USDA NIFA). During the meeting, attendees were asked to use their experience and curiosity to review the current status of agricultural genome to phenome (AG2P) work and envision the future of the AG2P field. The topic summaries composing this paper are distilled from two 1.5-h small group discussions. Challenges and solutions identified across multiple topics at the workshop were explored. We end our discussion with a vision for the future of agricultural progress, identifying two areas of innovation needed: (1) innovate in genetic improvement methods development and evaluation and (2) innovate in agricultural research processes to solve societal problems. To address these needs, we then provide six specific goals that we recommend be implemented immediately in support of advancing AG2P research.

Sinonasal and Skull Base Metastatic Renal Cell Carcinoma: A Case Series.

Metastatic lesions to the paranasal sinuses and skull base, while rare, carry a poor prognosis. Renal cell carcinoma has been reported in multiple case reports to be one of the most common distant malignancies to spread to the paranasal sinuses; however, it is often unrecognized by physicians, and thus treatment is delayed. To increase awareness of this disease process, we describe three cases of metastatic renal cell carcinoma to the sinonasal cavity, which is the largest case series in the literature to date.

Large Cutaneous Squamous Cell Carcinoma: A Consequence of Elective Surgery Deferment During the COVID-19 Pandemic.

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer that can be treated effectively with limited morbidity if caught and treated early with elective surgical procedures. The COVID-19 pandemic caused most healthcare facilities to delay or defer elective surgeries as they allocated workforce and resources to treating significant increases of critically ill patients. This care delay has increased morbidity and mortality of many conditions treated with surgery. A few case reports exist on delayed elective surgeries' effects on patients and healthcare facilities. We report a case of cSCC enlarging and locally spreading due to elective surgery delay during the COVID-19 pandemic.

The Transverse Turbinate Line: A Reliable Landmark for the Maxillary Sinus Natural Ostium.

OBJECTIVES: Approximating the maxillary sinus natural ostium's (MSNO) natural position during anterograde surgery is challenging, as only a single visual "landmark," the maxillary line, is routinely offered to guide the identification of the MSNO in three-dimensional space. Despite almost 40 years of endoscopic sinus surgery (ESS) experience in North America, maxillary recirculation and discontinuity between the natural and surgical ostia are commonly encountered during revision ESS. Consequently, we feel an additional visual landmark would assist in localizing the MSNO with or without image guidance. In this study, we aim to provide a second reliable landmark in the sinonasal cavity. METHODS: We present a cadaveric anatomical landmark series that provides a second visual landmark for the MSNO, which we have labeled the transverse turbinate line (TTL): a 2-millimeter zone of confidence for the craniocaudal positioning of the MSNO that can be combined with the anteroposterior (AP) landmark of the maxillary line. RESULTS: In our study, 40 cadaveric sinuses were dissected, and the TTL was found to correspond consistently with the zone between the superior and inferior aspects of the MSNO. CONCLUSION: We anticipate that this second relational landmark may decrease the time required for anterograde access to the MSNO in trainees, increase the accuracy of identification, and translate to lower long-term recirculation and maxillary surgery failure rates. LEVEL OF EVIDENCE: NA Laryngoscope, 133:3285-3291, 2023.

Does lymphovascular invasion predict survival in oral cancer? A population-based analysis.

OBJECTIVE: To evaluate lymphovascular invasion as an independent predictor for overall survival in patients with oral cavity squamous cell carcinoma. STUDY DESIGN: Retrospective cohort study. SETTING: Multi-center, population-based facilities reporting to the National Cancer Database registry. METHODS: The database was accessed to collect data on patients with oral cavity squamous cell carcinoma. A multivariate cox proportional hazards model was used to analyze the association between presence of lymphovascular invasion and overall survival. RESULTS: 16,992 patients met inclusion criteria. 3,457 patients had lymphovascular invasion. The mean follow-up was 32 ± 19 months. Lymphovascular invasion predicted reduced 2-year overall survival (relative hazard 1.29, 95% CI: 1.20, 1.38, p < 0.001) and 5-year overall survival (relative hazard 1.30, 95% CI: 1.23, 1.39, p < 0.001). LVI reduced overall survival in patients with squamous cell carcinoma of the oral tongue (HR: 1.27, 95% CI: 1.17, 1.39, p < 0.001), floor of mouth (HR: 1.33, 95% CI: 1.17, 1.52, p < 0.001) and buccal mucosa (HR: 1.44, 95% CI: 1.15, 1.81, p = 0.001). Patients with lymphovascular invasion treated with surgery plus post-operative radiotherapy had significantly improved survival compared to those who underwent surgery alone (relative hazard 1.79, 95% CI: 1.58, 2.03, p < 0.001), and patients treated with surgery + post-operative chemoradiotherapy had improved survival compared to those treated with surgery alone (relative hazard 2.0, 95% CI: 2.26, 1.79, p < 0.001). CONCLUSION: Lymphovascular invasion is an important independent risk factor for decreased overall survival in oral cavity squamous cell carcinoma involving the oral tongue, floor of mouth and buccal mucosa subsites.

Single hair analysis by X-ray fluorescence spectrometry detects small changes in dietary zinc intake: A nested randomized controlled trial.

The aim of this study was to determine whether X-ray fluorescence spectrometry (XRF) could be used to detect changes in hair zinc concentration in response to a modest daily increase in zinc from the consumption of zinc biofortified wheat flour. This study was conducted as part of an effectiveness trial (BiZiFED2) exploring the potential for zinc biofortified wheat to alleviate zinc deficiency in adolescent girls aged 10-16 years in Pakistan (trial registration ID ISRCTN17107812). A randomized controlled design was used. Participants received either control flour or zinc biofortified flour for 6 months. Consumption of biofortified flour resulted in an average daily increase in dietary zinc intake of 1.5 mg per day above that of the control flour. At baseline and at the end of the intervention, individual hair samples (control: n = 59, intervention: n = 64) were analyzed for zinc and sulfur content by XRF. Data were analyzed using linear mixed effects models to contrast between trial groups the changes from baseline to end point and also to compare baseline and end point values within each trial group. Increases from baseline to endpoint in both sulfur and zinc were significantly greater in the intervention group compared to control (sulfur counts. CONTROL: baseline = 119.87 ± 20.33 and endpoint = 121.58 ± 23.58/intervention: baseline = 122.67 ± 24.19 and endpoint = 131.60 ± 21.34); (Zinc counts. CONTROL: baseline = 50.88 ± 14.33 and endpoint = 54.82 ± 14.61/intervention: baseline = 49.61 ± 10.77 and endpoint = 58.79 ± 12.20). For these parameters, there were also significant increases from baseline to endpoint in the intervention group but not in control. Furthermore, for Zn:S count ratio there were no differences in terms of the magnitude of the change from baseline to endpoint in the control group, although significant increases from baseline to endpoint were evident in the intervention group (Zn:S count ratio. CONTROL: baseline = 0.42 ± 0.10 and endpoint = 0.45 ± 0.08/intervention: baseline = 0.41 ± 0.08 and endpoint = 0.45 ± 0.08). A modest increase in dietary zinc over 6 months resulted in a detectable increase in both sulfur and zinc counts in individual hairs measured using XRF. This offers a sensitive, non-invasive method to monitor changes within subjects in response to dietary zinc interventions.

Alpha-Calcitonin Gene Related Peptide: New Therapeutic Strategies for the Treatment and Prevention of Cardiovascular Disease and Migraine.

Alpha-calcitonin gene-related peptide (α-CGRP) is a vasodilator neuropeptide of the calcitonin gene family. Pharmacological and gene knock-out studies have established a significant role of α-CGRP in normal and pathophysiological states, particularly in cardiovascular disease and migraines. α-CGRP knock-out mice with transverse aortic constriction (TAC)-induced pressure-overload heart failure have higher mortality rates and exhibit higher levels of cardiac fibrosis, inflammation, oxidative stress, and cell death compared to the wild-type TAC-mice. However, administration of α-CGRP, either in its native- or modified-form, improves cardiac function at the pathophysiological level, and significantly protects the heart from the adverse effects of heart failure and hypertension. Similar cardioprotective effects of the peptide were demonstrated in pressure-overload heart failure mice when α-CGRP was delivered using an alginate microcapsules-based drug delivery system. In contrast to cardiovascular disease, an elevated level of α-CGRP causes migraine-related headaches, thus the use of α-CGRP antagonists that block the interaction of the peptide to its receptor are beneficial in reducing chronic and episodic migraine headaches. Currently, several α-CGRP antagonists are being used as migraine treatments or in clinical trials for migraine pain management. Overall, agonists and antagonists of α-CGRP are clinically relevant to treat and prevent cardiovascular disease and migraine pain, respectively. This review focuses on the pharmacological and therapeutic significance of α-CGRP-agonists and -antagonists in various diseases, particularly in cardiac diseases and migraine pain.

Sinonasal IgG4-related sclerosing disease: A rare entity and challenging diagnosis.

Objectives: To describe the rare presentation, imaging and histological findings, and treatments in patients with IgG4-related disease (IgG4-RD) and diagnostic pitfalls and difficulties. Methods: Cases of sinonasal IgG4-RD were retrieved, and clinicopathological features were reviewed. Results: Seven cases of sinonasal IgG4-RD were identified over an 11-year period, including four males and three females, with an age range of 19-66 years (median 58 years). Patients presented with symptoms related to the mass effect of the lesions or the destructive nature of the disease including fullness, swelling, obstruction, and pain. Serum IgG and IgG4 levels, IgG/IgG4 ratios, storiform fibrosis, obliterative phlebitis, and plasma cell infiltration were seen in varying proportions. Bony erosion and tissue inflammation were present in some cases. Conclusion: Sinonasal IgG4-RD is exceedingly rare among other IgG4-RD and varied in its clinical presentation thus posing as a clinically difficult disease to diagnosis. Proper clinical, pathological, and immunohistopathological analysis is required for accurate diagnosis. Such disease should be considered in all cases of similar presentation to those in this study.Level of Evidence: 4.