Optimizing the kidney donor pool: transplanting donor kidneys after partial nephrectomy of masses or cysts.

Background: A limiting factor in expanding the kidney donor pool is donor kidneys with renal tumors or cysts. Partial nephrectomy (PN) to remove these lesions prior to transplantation may help optimize organ usage without recurrence of malignancy or increased risk of complications. Methods: We retrospectively analyzed all recipients of a living or deceased donor graft between February 2009 and October 2022 in which a PN was performed prior to transplant due to the presence of one or more concerning growths. Donor and recipient demographics, perioperative data, donor allograft pathology, and recipient outcomes were obtained. Results: Thirty-six recipients received a graft in which a PN was performed to remove suspicious masses or cysts prior to transplant. Majority of pathologies turned out to be a simple renal cyst (65%), followed by renal cell carcinoma (15%), benign multilocular cystic renal neoplasm (7.5%), angiomyolipoma (5%), benign renal tissue (5%), and papillary adenoma (2.5%). No renal malignancy recurrences were observed during the study period (median follow-up: 67.2 months). Fourteen complications occurred among 11 patients (30.6% overall) during the first 6mo post-transplant. Mean eGFR (± standard error) at 36 months post-transplant was 51.9 ± 4.2 ml/min/1.73 m2 (N = 23). Three death-censored graft losses and four deaths with a functioning graft and were observed. Conclusion: PN of renal grafts with suspicious looking masses or cysts is a safe option to optimize organ usage and decrease the kidney non-use rate, with no observed recurrence of malignancy or increased risk of complications.

Myths and Methodologies: Standardisation in human physiology research-should we control the controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

Myths and Methodologies: Standardisation in Human Physiology Research-Should We Control the Controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries.

Malaria and Human Immunodeficiency Virus infections are among the top 10 causes of death in low income countries. Furthermore, many medicines used in these treatment areas are substandard, which contributes to the high death rate. Using a monitoring system to identify substandard and falsified medicines, the study aims to evaluate the quality of antimalarial and antiretroviral medicines in Sahel countries, assessing site conditions, compliance of medicines with pharmacopoeia tests, formulation equivalence with a reference medicine, and the influence of climate on quality attributes. Ultra Performance Liquid Chromatography methods for eight active pharmaceutical ingredients were validated following the International Conference for Harmonization guideline for its detection and quantification. Quality control consists of visual inspections to detect any misinformation or imperfections and pharmacopeial testing to determine the quality of pharmaceutical products. Medicines which complied with uniformity dosage units and dissolution tests were stored under accelerated conditions for 6 months. Artemether/Lumefantrine and Lopinavir/Ritonavir formulations failed uniformity dosage units and disintegration tests respectively, detecting a total of 28.6% substandard medicines. After 6 months stored under accelerated conditions (40 °C // 75% relative humidity) simulating climatic conditions in Sahel countries, some medicines failed pharmacopeia tests. It demonstrated the influence of these two factors in their quality attributes. This study emphasizes the need of certified quality control laboratories as well as the need for regulatory systems to maintain standards in pharmaceutical manufacturing and distribution in these countries, especially when medicines are transported to rural areas where these climatic conditions are harsher.

Elevated shear stress modulates heterogenous cellular subpopulations to induce vascular remodeling.

RATIONALE: Elevated shear stress induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arterio-venous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with single cell resolution before. OBJECTIVE: Using an in vivo animal mode, single-cell RNA-sequencing (scRNA-seq), and histopathology, we precisely manipulate blood flow to comprehensively characterize all cell subpopulations important during vascular remodeling. METHODS: AV loops were created in saphenous vessels of rats using a contralateral saphenous vein interposition graft to promote elevated shear stress (ESS). Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls. FINDINGS: ESS promoted transcriptional homogeneity, and NSS cells promoted considerable heterogeneity. Specifically, ESS ECs showed a more homogeneous transcriptional response promoting angiogenesis and upregulating Endothelial-to-Mesenchymal-Transition (EndMT) inhibiting genes (Klf2). NSS ECs upregulated anti-proliferation genes such as Cav1, Cst3 and Btg1. In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated pro-inflammatory M1-like, thus pro-angiogenic myeloid phenotype, while NSS myeloid cells expressed the anti-inflammatory and anti-angiogenetic marker Mrc1. CONCLUSION: ESS activates unified gene expression profiles to induce adaption of the vessel wall to hemodynamic alterations. Targeted depletion of the identified cellular subpopulations may lead to novel therapies to prevent excessive venous remodeling, intimal hyperplasia, and AV fistula failure.

Influence of the External Workload on Calf Muscle Strain Injuries in Professional Football Players: A Pilot Study.

BACKGROUND: The influence of external workload variables on the development of calf muscle strainsin football players has not been previously explored. HYPOTHESIS: Overloaded players would have an increased risk of calf muscle strain injury. STUDY DESIGN: Prospective observational study. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 41 professional football players from 1 team were monitored for 2 consecutive seasons. Total distance covered (TD), and distances covered at high-intensity running, high sprint running, low (LACC) and high (HACC) acceleration, low (LDEC) and high (HDEC) deceleration, and at high metabolic load distance (HMLD) were monitored with GPS units. Accumulated players' external workload in the week before injury was compared with the weekly mean value of the 6 weeks before injury occurred for each player. RESULTS: Ten players (24.3%) suffered 16 calf muscle strain injuries (3.1 injuries per 1000 hours of match play; 0.5 injuries per 1000 hours of training exposure). Players with a calf muscle injury were older (p = 0.03), with higher body weight (p = 0.01) and height (p = 0.03). Injured players displayed substantially higher total training volume (p < 0.01), TD (p < 0.01), LACC (p < 0.01), LDEC (p < 0.01), HACC (p < 0.01), HDEC (p < 0.01), and HMLD (p = 0.03) in the week before injury, in comparison with the mean values of these variables in the 6 weeks before injury. CONCLUSION: A week with a higher-than-habitual external workload might increase the risk of calf muscle strain injury in professional football players. Calf muscle injuries were preceded by a week with unusually high workloads associated with accelerating and decelerating distances and higher training volumes. CLINICAL RELEVANCE: Monitoring external workload indicators may be helpful in determine players with a higher risk of calf muscle strain injury due to excessive workload during training/competition.

Inequality on the frontline: A multi-country study on gender differences in mental health among healthcare workers during the COVID-19 pandemic.

Healthcare workers (HCWs) were at increased risk for mental health problems during the COVID-19 pandemic, with prior data suggesting women may be particularly vulnerable. Our global mental health study aimed to examine factors associated with gender differences in psychological distress and depressive symptoms among HCWs during COVID-19. Across 22 countries in South America, Europe, Asia and Africa, 32,410 HCWs participated in the COVID-19 HEalth caRe wOrkErS (HEROES) study between March 2020 and February 2021. They completed the General Health Questionnaire-12, the Patient Health Questionnaire-9 and questions about pandemic-relevant exposures. Consistently across countries, women reported elevated mental health problems compared to men. Women also reported increased COVID-19-relevant stressors, including insufficient personal protective equipment and less support from colleagues, while men reported increased contact with COVID-19 patients. At the country level, HCWs in countries with higher gender inequality reported less mental health problems. Higher COVID-19 mortality rates were associated with increased psychological distress merely among women. Our findings suggest that among HCWs, women may have been disproportionately exposed to COVID-19-relevant stressors at the individual and country level. This highlights the importance of considering gender in emergency response efforts to safeguard women's well-being and ensure healthcare system preparedness during future public health crises.

Surgical modifications to the conventional kidney transplant technique - the miami transplant institute approach: a retrospective cohort study.

BACKGROUND: At our center, surgical modifications to the conventional kidney transplant technique were developed with two goals in mind: to minimize the risk of developing post-transplant urologic/vascular/other surgical complications, and to simultaneously eliminate the need for initial ureteral stent placement and surgical drainage. METHODS: Here, we describe these modifications along with(what we believe are) their advantages over the conventional technique: creating an abdominal flap for easier abdominal closure(reflecting the parietal peritoneum from the abdominal wall), mobilizing the bladder before transplant(creating more space for bladder dissection, allowing it to move upward during abdominal wall closure), minimizing the dissection of iliac vessels to only anterior lymphatic tissue(attempting to minimize the incidence of fluid collections), using plastic arterial vascular bulldog clamps(causing less trauma to the iliac artery), performing vascular anastomosis of the renal artery first(making it easier for the surgeon to perform this anastomoses), creating longer ureteral spatulation, and inclusion of bladder mucosa along with some detrusor muscle layer in performing the ureteral anastomosis(attempting to minimize the incidence of urologic complications). Of note, no initial ureteral stent placement or surgical drainage was used. We report our experience during the first 12mo post-transplant of a single transplant surgeon who used each of these modifications among 707 consecutive recipients of kidney-alone transplants at our center since 2014. RESULTS: During the first 12mo post-transplant, 2.3%(16/707) of patients developed a urologic complication; only 1.0%(7/707) required surgical repair of their original ureteroneocystostomy. Additionally, 2.7%(19/707) developed a vascular complication; 8.8%(62/707) developed some other type of surgical complication(wound complication, lymphocele development, or development of a peri-renal hematoma or peri-renal collection). These overall results were clearly advantageous when compared with other studies. CONCLUSION: We believe that this modified kidney transplant technique clearly helped in reducing post-transplant risks of developing urologic/vascular/other surgical complications. Importantly, these results were achieved without initial ureteral stent placement or surgical drainage.

Are there sex differences in the variability of fasting metabolism?

There is evidence across species and across many traits that males display greater between-individual variance. In contrast, (premenopausal) females display large within-individual variance in sex hormone concentrations, which can increase within-individual variance in many other parameters. The latter may contribute to the lower representation of females in metabolic research. This study is a pooled secondary analysis of data from 7 crossover studies to investigate the between-individual and the within-individual variance in fasting plasma metabolites, resting metabolic rate (RMR) and body mass. Females demonstrated higher within-individual variability of plasma 17ß-estradiol (CV 15±15 % for males vs 38±34 % for females, p<0.001) and progesterone concentrations (CV 13±11 % for males vs 52±51 % for females, p<0.001) but there were no meaningful differences in the variability of plasma glucose (CV 4±3 % for males vs 5 ± 5 % for females), insulin, lactate, triglycerides (CV 15±9 % for males vs 15 ± 10 % for females), and non-esterified fatty acid concentrations, nor in RMR and body mass (CV 0.43±0.34 % for males vs for 0.42±0.33 % females; p>0.05 for all outcomes). Males displayed higher between-individual variance in RMR compared to females (SD 224 kcal×day-1 for males vs 151 kcal×day-1 for females). In conclusion, these data do not provide evidence that females show greater within-individual variability in many fasting metabolic variables, RMR or body mass compared to males. We conclude that including females in metabolic research is unlikely to introduce greater within-individual variance when using the recruitment and control procedures described in these studies.

Force Production and Electromyographic Activity during Different Flywheel Deadlift Exercises.

This study aimed to characterize and compare force production and muscle activity during four flywheel deadlift exercises (bilateral [Bi] vs. unilateral [Uni]) with different loading conditions (vertical [Ver] vs. horizontal [Hor]). Twenty-three team-sport athletes underwent assessments for exercise kinetics (hand-grip force), along with surface electromyography (sEMG) of the proximal (BFProx) and medial biceps femoris (BFMed), semitendinosus (ST), and gluteus medius (GM). Mean and peak force were highest (p < 0.001) in Bi + Ver compared with Bi + Hor, Uni + Ver, and Uni + Hor. Although no significant differences were observed between Bi + Hor and Uni + Ver, both variants showed higher (p < 0.001) average force and peak eccentric force when compared with Uni + Hor. The presence of eccentric overload was only observed in the vertically loaded variants. Bi + Ver and Uni + Ver showed higher (p < 0.05) sEMG levels in BFProx and BFMed compared with the Uni + Hor variant. In addition, Uni + Ver registered the largest GM and ST sEMG values. In conclusion, the vertical variants of the flywheel deadlift exercise led to higher muscle force production and sEMG compared with their horizontal counterparts. Both Bi + Ver and Uni + Ver may be effective in promoting an increase in hamstring muscles activity and muscle force at long muscle length, while the Uni + Ver variant may be more effective in promoting GM and ST involvement.

Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

The role of Patient and public involvement (PPI) in pre-clinical spinal cord research: An interview study.

BACKGROUND: Patient and public involvement in research (PPI) has many benefits including increasing relevance and impact. While using PPI in clinical research is now an established practice, the involvement of patients and the public in pre-clinical research, which takes place in a laboratory setting, has been less frequently described and presents specific challenges. This study aimed to explore the perspectives of seriously injured rugby players' who live with a spinal cord injury on PPI in pre-clinical research. METHODS: Semi-structured interviews were conducted via telephone with 11 seriously injured rugby players living with spinal cord injury on the island of Ireland. A purposive sampling approach was used to identify participants. Selected individuals were invited to take part via gatekeeper in a charitable organisation that supports seriously injured rugby players. Interviews were transcribed verbatim and analysed thematically. FINDINGS: Six themes were identified during analysis: 'appreciating potential benefits of PPI despite limited knowledge', 'the informed perspectives of people living with spinal cord injury can improve pre-clinical research relevance', 'making pre-clinical research more accessible reduces the potential for misunderstandings to occur', 'barriers to involvement include disinterest, accessibility issues, and fear of losing hope if results are negative', 'personal contact and dialogue helps people feel valued in pre-clinical research, and 'PPI can facilitate effective dissemination of pre-clinical research as desired by people living with spinal cord injury.' CONCLUSION: People affected by spinal cord injury in this study desire further involvement in pre-clinical spinal cord injury research through dialogue and contact with researchers. Sharing experiences of spinal cord injury can form the basis of PPI for pre-clinical spinal cord injury research.

One-Tip enables comprehensive proteome coverage in minimal cells and single zygotes.

Mass spectrometry (MS)-based proteomics workflows typically involve complex, multi-step processes, presenting challenges with sample losses, reproducibility, requiring substantial time and financial investments, and specialized skills. Here we introduce One-Tip, a proteomics methodology that seamlessly integrates efficient, one-pot sample preparation with precise, narrow-window data-independent acquisition (nDIA) analysis. One-Tip substantially simplifies sample processing, enabling the reproducible identification of >9000 proteins from ~1000 HeLa cells. The versatility of One-Tip is highlighted by nDIA identification of ~6000 proteins in single cells from early mouse embryos. Additionally, the study incorporates the Uno Single Cell Dispenser™, demonstrating the capability of One-Tip in single-cell proteomics with >3000 proteins identified per HeLa cell. We also extend One-Tip workflow to analysis of extracellular vesicles (EVs) extracted from blood plasma, demonstrating its high sensitivity by identifying >3000 proteins from 16 ng EV preparation. One-Tip expands capabilities of proteomics, offering greater depth and throughput across a range of sample types.

Maximizing efficiency in sunflower breeding through historical data optimization.

Genomic selection (GS) has become an increasingly popular tool in plant breeding programs, propelled by declining genotyping costs, an increase in computational power, and rediscovery of the best linear unbiased prediction methodology over the past two decades. This development has led to an accumulation of extensive historical datasets with genotypic and phenotypic information, triggering the question of how to best utilize these datasets. Here, we investigate whether all available data or a subset should be used to calibrate GS models for across-year predictions in a 7-year dataset of a commercial hybrid sunflower breeding program. We employed a multi-objective optimization approach to determine the ideal years to include in the training set (TRS). Next, for a given combination of TRS years, we further optimized the TRS size and its genetic composition. We developed the Min_GRM size optimization method which consistently found the optimal TRS size, reducing dimensionality by 20% with an approximately 1% loss in predictive ability. Additionally, the Tails_GEGVs algorithm displayed potential, outperforming the use of all data by using just 60% of it for grain yield, a high-complexity, low-heritability trait. Moreover, maximizing the genetic diversity of the TRS resulted in a consistent predictive ability across the entire range of genotypic values in the test set. Interestingly, the Tails_GEGVs algorithm, due to its ability to leverage heterogeneity, enhanced predictive performance for key hybrids with extreme genotypic values. Our study provides new insights into the optimal utilization of historical data in plant breeding programs, resulting in improved GS model predictive ability.

A new updated prognostic index for patients with brain metastases (BMs) treated with palliative whole brain radiotherapy (WBRT) in the era of precision oncology. METASNCore project.

INTRODUCTION: Palliative WBRT is the main treatment for multiple BMs. Recent studies report no benefit in survival after WBRT compared to palliative supportive care in patients (pts) with poor prognosis. A new era of systemic treatment strategies based on targeted therapies are improving the prognosis of patients with BMs. The purpose of this study is to develop a prognostic score in palliative pts with BMs who undergo WBRT in this new setting. METHODS: 239 pts with BMs who received palliative WBRT between 2013-2022 in our center were analyzed retrospectively. The score was designed according to the value of the ß coefficient of each variable with statistical significance in the multivariate model using Cox regression. Once the score was established, a comparison was performed according to Kaplan-Meier and was analyzed by log-rank test. RESULTS: 149 pts (62.3%) were male and median (m) age was 60 years. 139 (58,2%) were lung cancer and 35 (14,6%) breast cancer. All patients received 30Gys in 10 sessions. m overall survival (OS) was 3,74 months (ms). 37 pts (15,5%) had a specific target mutation. We found that 62 pts were in group < 4 points with mOS 6,89 ms (CI 95% 3,18-10,62), 84 in group 4-7 points with mOS 4,01 ms (CI 95% 3,40-4,62) and 92 pts in group > 7 points with mOS 2,72 ms (CI 95% 1,93-3,52) (p < 0,001). CONCLUSIONS: METASNCore items are associated with OS and they could be useful to select palliative pts to receive WBRT. More studies are necessary to corroborate our findings.

Survey on the Situation of Medical Departments in the Pharmaceutical Industry in Spain.

INTRODUCTION: Medical departments have evolved from a position of support to one of strategic leadership. The number of tasks and the complexity of interactions in which they are involved is increasing. However, the spectrum of their activity in the sector differs significantly from one company to another. Therefore, the aim of this study was to describe their situation within the pharmaceutical industry, analyzing the positions, functions, and profiles of their professionals. METHODS: This study consisted of an online survey containing 25 questions grouped into four blocks (structure, medical direction, training, and activities and responsibilities). Medical departments in the Spanish pharmaceutical industry of different sizes and scope were invited to participate. The survey took place in 2021, with a designated response period of three months. It is important to note that all responses collected during this time were treated as anonymous. RESULTS: Thirty companies participated. A total of 93.3% of respondents worked for an international laboratory, with a size of 0-5 or 11-20 people (20.7%). For 27.6% of the companies, the number of medical advisors per medical department was 1 or 4, with varying numbers of medical scientific liaisons (1, 6-10, and > 20). A total of 56.7%, 33.3%, and 6.7% indicated that the country manager, head of regional medical affairs, and head of global medical affairs, respectively, had a solid-line reporting relationship with the medical directorate. Medical directors were mostly graduates in medicine (86.2%) with a doctorate (34.5%), and medical managers were mainly graduates in medicine (77.8%) and pharmacy (66.7%). CONCLUSIONS: This study reveals that respondents predominantly work in internationally focused laboratories, with professionals ranging from experienced medical directors to managers with 6-20 years of experience, each with distinct roles.

Genomic selection in plant breeding: Key factors shaping two decades of progress.

Genomic selection, the application of genomic prediction (GP) models to select candidate individuals, has significantly advanced in the past two decades, effectively accelerating genetic gains in plant breeding. This article provides a holistic overview of key factors that have influenced GP in plant breeding during this period. We delved into the pivotal roles of training population size and genetic diversity, and their relationship with the breeding population, in determining GP accuracy. Special emphasis was placed on optimizing training population size. We explored its benefits and the associated diminishing returns beyond an optimum size. This was done while considering the balance between resource allocation and maximizing prediction accuracy through current optimization algorithms. The density and distribution of single-nucleotide polymorphisms, level of linkage disequilibrium, genetic complexity, trait heritability, statistical machine-learning methods, and non-additive effects are the other vital factors. Using wheat, maize, and potato as examples, we summarize the effect of these factors on the accuracy of GP for various traits. The search for high accuracy in GP-theoretically reaching one when using the Pearson's correlation as a metric-is an active research area as yet far from optimal for various traits. We hypothesize that with ultra-high sizes of genotypic and phenotypic datasets, effective training population optimization methods and support from other omics approaches (transcriptomics, metabolomics and proteomics) coupled with deep-learning algorithms could overcome the boundaries of current limitations to achieve the highest possible prediction accuracy, making genomic selection an effective tool in plant breeding.