Key message
Genomic prediction models for multi-year dry matter yield, via genotyping-by-sequencing in a composite training set, demonstrate potential for genetic gain improvement through within-half ...sibling family selection.
Perennial ryegrass (
Lolium perenne
L.) is a key source of nutrition for ruminant livestock in temperate environments worldwide. Higher seasonal and annual yield of herbage dry matter (DMY) is a principal breeding objective but the historical realised rate of genetic gain for DMY is modest. Genomic selection was investigated as a tool to enhance the rate of genetic gain. Genotyping-by-sequencing (GBS) was undertaken in a multi-population (MP) training set of five populations, phenotyped as half-sibling (HS) families in five environments over 2 years for mean herbage accumulation (HA), a measure of DMY potential. GBS using the ApeKI enzyme yielded 1.02 million single-nucleotide polymorphism (SNP) markers from a training set of
n
= 517. MP-based genomic prediction models for HA were effective in all five populations, cross-validation-predictive ability (PA) ranging from 0.07 to 0.43, by trait and target population, and 0.40–0.52 for days-to-heading. Best linear unbiased predictor (BLUP)-based prediction methods, including GBLUP with either a standard or a recently developed (KGD) relatedness estimation, were marginally superior or equal to ridge regression and random forest computational approaches. PA was principally an outcome of SNP modelling genetic relationships between training and validation sets, which may limit application for long-term genomic selection, due to PA decay. However, simulation using data from the training experiment indicated a twofold increase in genetic gain for HA, when applying a prediction model with moderate PA in a single selection cycle, by combining among-HS family selection, based on phenotype, with within-HS family selection using genomic prediction.
CONTEXT.— Gulf War (GW) veterans report nonspecific symptoms significantly more
often than their nondeployed peers. However, no specific disorder has been
identified, and the etiologic basis and ...clinical significance of their symptoms
remain unclear. OBJECTIVES.— To organize symptoms reported by US Air Force GW veterans into a case
definition, to characterize clinical features, and to evaluate risk factors. DESIGN.— Cross-sectional population survey of individual characteristics and
symptoms and clinical evaluation (including a structured interview, the Medical
Outcomes Study Short Form 36, psychiatric screening, physical examination,
clinical laboratory tests, and serologic assays for antibodies against viruses,
rickettsia, parasites, and bacteria) conducted in 1995. PARTICIPANTS AND SETTING.— The cross-sectional questionnaire survey included 3723 currently active
volunteers, irrespective of health status or GW participation, from 4 air
force populations.The cross-sectional clinical evaluation included 158 GW
veterans from one unit, irrespective of health status. MAIN OUTCOME MEASURES.— Symptom-based case definition; case prevalence rate for GW veterans
and nondeployed personnel; clinical and laboratory findings among veterans
who met the case definition. RESULTS.— We defined a case as having 1 or more chronic symptoms from at least
2 of 3 categories (fatigue, mood-cognition, and musculoskeletal). The prevalence
of mild-to-moderate and severe cases was 39% and 6%, respectively, among 1155
GW veterans compared with 14% and 0.7% among 2520 nondeployed personnel. Illness
was not associated with time or place of deployment or with duties during
the war. Fifty-nine clinically evaluated GW veterans (37%) were noncases,
86 (54%) mild-to-moderate cases, and 13 (8%) severe cases. Although no physical
examination, laboratory, or serologic findings identified cases, veterans
who met the case definition had significantly diminished functioning and well-being. CONCLUSIONS.— Among currently active members of 4 Air Force populations, a chronic
multisymptom condition was significantly associated with deployment to the
GW. The condition was not associated with specific GW exposures and also affected
nondeployed personnel.
Background:
Fibroblast growth factor 21 (FGF21) can regulate glucose and lipid metabolism. The placenta actively synthesizes and secretes many hormones, but it is unknown whether this includes FGF21. ...This study aimed to analyze the placental expression of FGF21 in women with or without gestational diabetes mellitus (GDM).
Methods:
FGF21 and peroxisome proliferator-activated receptor (PPAR)-α mRNA and protein expression were measured in the placentae of 20 women with and 18 without GDM. mRNA expression of PPARα, FGF receptors 1–4, the coreceptor β-klotho, and glucose transporter (GLUT)-1, -3, and -4 was investigated. Maternal and fetal circulating FGF21 levels were assessed in 10 mother-baby dyads per condition.
Results:
FGF21 was expressed in the placenta and its mRNA expression increased in women with GDM 10.75 (interquartile range 3.28–125.6 AU) vs control 0.83 (0.22–4.78), P < .001, as is its protein expression GDM 2.89 (1.44–5.10) vs control 0.42 (0.05–1.98), P < .05. PPARα mRNA but not protein expression was increased in GDM 2.94 (0.70–7.26) vs control 0.99 (0.43–2.17), P < .05 and was positively correlated to FGF21 mRNA expression (ρ = 0.43, P < .01). Placental mRNA expression of FGF receptors and GLUT1 was unchanged, and β-klotho, GLUT3, and GLUT4 showed increased expression in GDM. Maternal circulating FGF21 levels were similar GDM 323 (75–921) vs control 269 (49–731) pg/mL, P = .81. FGF21 was undetected in fetal cord blood.
Conclusions:
FGF21 is expressed in the placenta and its expression is increased in GDM. The absence of FGF21 in fetal cord blood suggests that neither placental FGF21 nor maternal circulating FGF21 is secreted into the fetal circulation. Placental FGF21 may be a regulator of placental metabolism.
Half of the mortality in diabetes is seen in individuals <50 years of age and commonly predicted by the early onset of diabetic kidney disease (DKD). In type 1 diabetes, increased urinary ...albumin-to-creatinine ratio (uACR) during adolescence defines this risk, but the pathological factors responsible remain unknown. We postulated that early in diabetes, glucose variations contribute to kidney injury molecule-1 (KIM-1) release from circulating T cells, elevating uACR and DKD risk. DKD risk was assigned in youth with type 1 diabetes (
= 100; 20.0 ± 2.8 years; males/females, 54:46; HbA
66.1 12.3 mmol/mol; diabetes duration 10.7 ± 5.2 years; and BMI 24.5 5.3 kg/m
) and 10-year historical uACR, HbA
, and random blood glucose concentrations collected retrospectively. Glucose fluctuations in the absence of diabetes were also compared with streptozotocin diabetes in
mice. Kidney biopsies were used to examine infiltration of KIM-1-expressing T cells in DKD and compared with other chronic kidney disease. Individuals at high risk for DKD had persistent elevations in uACR defined by area under the curve (AUC; uACR
, 29.7 ± 8.8 vs. 4.5 ± 0.5;
< 0.01 vs. low risk) and early kidney dysfunction, including ∼8.3 mL/min/1.73 m
higher estimated glomerular filtration rates (modified Schwartz equation;
< 0.031 vs. low risk) and plasma KIM-1 concentrations (∼15% higher vs. low risk;
< 0.034). High-risk individuals had greater glycemic variability and increased peripheral blood T-cell KIM-1 expression, particularly on CD8
T cells. These findings were confirmed in a murine model of glycemic variability both in the presence and absence of diabetes. KIM-1
T cells were also infiltrating kidney biopsies from individuals with DKD. Healthy primary human proximal tubule epithelial cells exposed to plasma from high-risk youth with diabetes showed elevated collagen IV and sodium-glucose cotransporter 2 expression, alleviated with KIM-1 blockade. Taken together, these studies suggest that glycemic variations confer risk for DKD in diabetes via increased CD8
T-cell production of KIM-1.
The effect of fractures other than hip and spine on HRQoL in younger and older women has not been extensively studied. In a cohort of 86,128 postmenopausal women, we found the impact of recent ...osteoporosis‐related fractures on HRQoL to be similar between women <65 compared with those ≥65 years of age. The impact of spine, hip, or rib fractures was greater than that of wrist fractures in both age groups.
Introduction: Health‐related quality of life (HRQoL) after vertebral and hip fractures has been well studied. Less is known about HRQoL after fractures at other sites. We studied the effect of recent clinical fractures on HRQoL, using Short Form‐12 (SF‐12).
Materials and Methods: This study included 86,128 postmenopausal participants in the National Osteoporosis Risk Assessment (NORA) who responded to two follow‐up surveys during a 2‐year interval. At each survey, they completed the SF‐12 HRQoL questionnaire and reported new fractures of the hip, spine, wrist, and rib. The effect of recent fracture on HRQoL was assessed by comparing Physical Component Score (PCS) and Mental Component Score (MCS) means for women with and without new fractures at the second survey. Analyses were by fracture type and by age group (50–64 and 65–99) and were adjusted for PCS and MCS at the first survey.
Results: New fractures (320 hip, 445 vertebral, 657 rib, 835 wrist) occurring during the interval between the first and second follow‐up surveys were reported by 2257 women. The PCS was poorer in both older and younger women who had fractured the hip, spine, or rib (p ≤ 0.001). Wrist fractures had an impact on PCS in women ≤65 years of age (p < 0.001), but not older women (p > 0.10). These differences in PCS by fracture status were similar to those reported for other chronic diseases such as asthma, chronic obstructive pulmonary disease (COPD), and osteoarthritis. MCS was less consistently changed by fracture status, but younger and older women with vertebral fracture (p < 0.004), older women with hip fracture (p < 0.004), and younger women with rib fracture (p < 0.004) had poorer MCS compared with those who did not fracture within their age cohort.
Conclusions: Recent osteoporosis‐related fractures have significant impact on HRQoL as measured by SF‐12. The impact of recent fracture on HRQoL was similar for older and younger postmenopausal women. Fracture prevention and postfracture interventions that target the subsequent symptoms are needed for postmenopausal women of any age.
Macronutrients, Diet Quality, and Frailty in Older Men Shikany, James M; Barrett-Connor, Elizabeth; Ensrud, Kristine E ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
06/2014, Volume:
69, Issue:
6
Journal Article
Peer reviewed
Open access
Background.
Frailty, a phenotype of multisystem impairment and expanding vulnerability, is associated with higher risk of adverse health outcomes not entirely explained by advancing age. We ...investigated associations of macronutrients, dietary fiber, and overall diet quality with frailty status in older community-dwelling men.
Methods.
Participants were 5,925 men aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) study at six U.S. centers. Diet was assessed at baseline with a food frequency questionnaire. We assessed frailty status (robust, intermediate, or frail) at baseline and at a second clinic visit (a mean of 4.6 years later) using a slightly modified Cardiovascular Health Study frailty index. We used multinomial logistic regression to assess associations between macronutrient intake, dietary fiber, and the Diet Quality Index Revised with frailty status at baseline and at the second clinic visit.
Results.
At baseline, 2,748 (46.4%) participants were robust, 2,681 (45.2%) were intermediate, and 496 (8.4%) were frail. Carbohydrate, fat, protein, and dietary fiber showed no consistent associations with frailty status. Overall diet quality exhibited fairly consistent associations with frailty status. The Diet Quality Index Revised was inversely associated with frail status relative to robust status at the baseline visit (odds ratio for Q5 vs Q1 = 0.44, 95% confidence interval: 0.30, 0.63; p for trend < .0001) and at the second clinic visit (odds ratio for Q5 vs Q1 = 0.18, 95% confidence interval: 0.03, 0.97; p for trend = .0180).
Conclusions.
Overall diet quality was inversely associated with prevalent and future frailty status in this cohort of older men.
Background
Current literature indicates that direct‐acting antivirals (DAAs) are cost‐effective to treat compensated cirrhotic patients with hepatitis C. Although already funded by public payers, it ...is unknown whether it is economical to reimburse DAAs within the more advanced decompensated cirrhosis population.
Methods
A state‐transition model was developed to conduct a cost‐utility analysis of sofosbuvir‐velpatasvir (SOF/VEL) plus ribavirin regimen for 12 weeks. The evaluated cohort had a mean age of 58 years and Child‐Turcotte‐Pugh (CTP) class B cirrhosis with decompensated symptoms. A scenario analysis was performed on CTP C patients. We used a payer perspective, a lifetime time horizon and a 1.5% annual discount rate.
Results
While SOF/VEL plus ribavirin treatment for 12 weeks increased costs by $156 676, it provided an extra 4.00 quality‐adjusted life years (QALYs) compared to best supportive care (no DAA therapy). With an incremental cost‐effectiveness ratio of $39 169 per QALY, SOF/VEL plus ribavirin was determined to be cost‐effective at a willingness to pay of $50 000 per QALY. SOF/VEL reduced liver‐related deaths and reduced progression to CTP C cirrhosis by 20.4% and 21.9%, respectively. On the contrary, SOF/VEL regimen resulted in increases in liver transplants and hepatocellular carcinoma (HCC) by 54.0% and 42.5%, respectively. Similar results were found for CTP C patients.
Conclusion
This analysis informs payers that SOF/VEL should continue to be reimbursed in decompensated hepatitis C patients. It also supports the recommendations by the American Association for the Study of Liver Diseases to continue screening for HCC in decompensated cirrhotic patients who have achieved sustained virologic response.
Most platforms used for the molecular reconstruction of the tumor-immune microenvironment (TIME) of a solid tumor fail to explore the spatial context of the three-dimensional (3D) space of the tumor ...at a single-cell resolution, and thus lack information about cell-cell or cell-extracellular matrix (ECM) interactions. To address this issue, a pipeline which integrated multiplex spatially resolved multi-omics platforms was developed to identify crosstalk signaling networks among various cell types and the ECM in the 3D TIME of two FFPE (formalin-fixed paraffin embedded) gynecologic tumor samples. These platforms include non-targeted mass spectrometry imaging (glycans, metabolites, and peptides) and Stereo-seq (spatial transcriptomics) and targeted seqIF (IHC proteomics). The spatially resolved imaging data in a two- and three-dimensional space demonstrated various cellular neighborhoods in both samples. The collection of spatially resolved analytes in a voxel (3D pixel) across serial sections of the tissue was also demonstrated. Data collected from this analytical pipeline were used to construct spatial 3D maps with single-cell resolution, which revealed cell identity, activation, and energized status. These maps will provide not only insights into the molecular basis of spatial cell heterogeneity in the TIME, but also novel predictive biomarkers and therapeutic targets, which can improve patient survival rates.
The ID32 Soft X-ray Beamline line is an ESRF upgrade beamline for X-ray absorption (XAS) and Resonant Inelastic X-ray Scattering (RIXS) spectroscopic studies. It was opened to Users in October 2014 ...and provides polarised soft X-rays in the 400–1600 eV energy range. It has two branches: One branch has been designed for X-ray magnetic dichroism experiments, both linear (XMLD) and circular (XMCD), with high sensitivity, reproducibility, flexibility, user friendliness and the capability for fast energy scanning. The X-ray beam is available in two experimental areas, one with a dedicated superconducting high field magnet and a sample preparation facility, the second area being open for User instruments. The other branch is dedicated to very high energy resolution Resonant Inelastic X-ray Scattering experiments with a combined resolving power up to 30 000 around 930 eV. A scattering arm which is continuously variable under UHV vacuum over 100 degrees and a four-circle sample goniometer allows accurate positioning of the sample to enable 3D mapping of q space. Combined with the possibility of polarisation analysis of the outgoing photons the beamline provides a state-of-the-art soft X-ray RIXS facility.
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