Metastatic pituitary neuroendocrine neoplasms: A case report of a malignant prolactinoma.

We report a rare clinical case of a malignant prolactinoma in which the exponential increase of prolactin levels with minimal tumor growth and no response to treatment led to diagnosis of abdominal, thoracic, and vertebral metastases.

Time-series reconstruction of the molecular architecture of human centriole assembly.

Centriole biogenesis, as in most organelle assemblies, involves the sequential recruitment of sub-structural elements that will support its function. To uncover this process, we correlated the spatial location of 24 centriolar proteins with structural features using expansion microscopy. A time-series reconstruction of protein distributions throughout human procentriole assembly unveiled the molecular architecture of the centriole biogenesis steps. We found that the process initiates with the formation of a naked cartwheel devoid of microtubules. Next, the bloom phase progresses with microtubule blade assembly, concomitantly with radial separation and rapid cartwheel growth. In the subsequent elongation phase, the tubulin backbone grows linearly with the recruitment of the A-C linker, followed by proteins of the inner scaffold (IS). By following six structural modules, we modeled 4D assembly of the human centriole. Collectively, this work provides a framework to investigate the spatial and temporal assembly of large macromolecules.

Age-Related Changes in Clinical and Analytical Variables in Chronic Hemodialyzed Patients.

Worldwide, the number of elderly individuals receiving chronic hemodialysis is rising. The aim of our study was to evaluate several clinical and analytical biomarkers in chronically dialyzed patients and analyze how they change with age. A cross-sectional study was performed by evaluating 289 end-stage renal disease patients undergoing dialysis. We evaluated the hemogram, adipokines, the lipid profile, and several markers related to inflammation, endothelial function/fibrinolysis, nutrition, iron metabolism, and cardiac and renal fibrosis. Clinical data and dialysis efficacy parameters were obtained from all patients. The relationships between studied biomarkers and age were assessed by a statistical comparison between younger (adults with age < 65 years) and older (age ≥ 65 years) patients and by performing regression analysis. Participants presented a mean age of 68.7 years (±13.6), with 66.8% (n = 193) being classified as older. Compared to younger patients, older patients presented the following: (a) significantly lower values of diastolic blood pressure (DBP) and ultrafiltration volume; (b) lower levels of phosphorus, uric acid, creatinine, and albumin; and (c) higher circulating concentrations of tissue-type plasminogen activator (tPA), D-dimer, interleukin-6, leptin, N-terminal pro B-type natriuretic peptide, and tissue inhibitor of metalloproteinase-1. In the multiple linear regression analysis, DBP values, tPA, phosphorus, and D-dimer levels were independently associated with the age of patients (standardized betas: -0.407, 0.272, -0.230, and 0.197, respectively; p < 0.001 for all), demonstrating relevant changes in biomarkers with increasing age at cardiovascular and nutritional levels. These findings seem to result from crosstalk mechanisms between aging and chronic kidney disease.

Cultural Translation and Validation of the Bariatric Quality of Life Index to European Portuguese.

INTRODUCTION: Obesity is a chronic noncommunicable disease, defined by a body mass index over 30 kg/m2. Its impact is not restricted to its association with higher risks of mortality and morbidity from other noncommunicable diseases, but also with a decrease in quality of life (QoL). There are several tools to assess QoL, from generic health-related tools to obesity-related specific ones. However, to assess QoL in patients undergoing bariatric surgery, only the Bariatric Analysis and Reporting Outcome System was available, which presented some significant problems. Therefore, the Bariatric Quality of Life (BQL) Index was developed. The aim of this study was the validation and cultural adaptation of the BQL Index for European Portuguese. METHODS: A cross-sectional study was conducted, with the presentation of two questionnaires to the participants: BQL Index and EQ-5D-3L (European Quality of Life 5 Dimensions and 3 Level) Index. Direct translation followed reviewing, back-translation, comparison, and pilot testing were performed. Retest was done six months after the baseline. The following psychometric properties were assessed: convergent validity using the Spearman r correlation coefficient between BQL Index and EQ-5D-3L Index; internal consistency based on Cronbach alpha coefficient; and reproducibility between test and retest through Spearman r correlation coefficient and intraclass correlation coefficient (ICC). RESULTS: A total of 260 participants were included, the mean age was 45 ± 10 years old, the mean body mass index was 44 ± 6.5 kg/m2 and 78% were females. The most frequent obesity-related comorbidities were osteoarticular disease (69%), anxiety/depression (60%), and hypertension (54%). The most common eating patterns were volume eater (67%) and sweet eater (62%). Quality of Life scores were 41.3 ± 9.3 for the BQL Index, 0.35 ± 0.19 for the EQ-5D-3L Index and 55.7 ± 19.8 for the EQ-5D-3L VAS. The translation yielded good convergent validity (r = 0.62), good internal consistency (alpha = 0.94), and good reproducibility (r = 0.62 and ICC = 0.79). CONCLUSION: Our translation exhibited good parametric properties, with validity within the original BQL values, higher internal consistency, and good reproducibility.

Adrenal Vein Sampling in the Management of Primary Aldosteronism: The Added Value of Intraprocedural Cortisol Assessment.

Introduction: Primary aldosteronism is the most common cause of secondary hypertension. Adrenal vein sampling is the gold standard for subtyping primary aldosteronism. However, this procedure is technically challenging and often has a low success rate. Our center is one of the very few performing this technique in our country with an increasing experience. Objective: The aim of this study was to evaluate the role of the cortisol intraprocedural assay in improving the performance of adrenal vein sampling. Design: We enrolled all of the patients with primary aldosteronism that underwent adrenal vein sampling from February 2016 to April 2023. The cortisol intraprocedural assay was introduced in October 2021. Methods: We enrolled a total of 50 adrenal vein samplings performed on 43 patients with the diagnosis of primary aldosteronism. In this sample, 19 patients and 24 patients underwent adrenal vein sampling before and after intraprocedural cortisol measurement, respectively. The procedure was repeated in seven patients (one before and six after intraprocedural cortisol measurement), given the unsuccess of the first exam. Selectivity of the adrenal vein sampling was assumed if the serum cortisol concentration from the adrenal vein was at least five times higher than that of the inferior vena cava. Lateralization was assumed if the aldosterone to cortisol ratio of one adrenal vein was at least four times the aldosterone to cortisol ratio of the contralateral side. Results: The mean age of the patients that underwent adrenal vein sampling (N = 43) was 55.2 ± 8.9 years, and 53.5% (n = 23) were female. The mean interval between the diagnosis of hypertension and the diagnosis of primary aldosteronism was 9.8 years (±9.9). At diagnosis, 62.8% of the patients (n = 27) had hypokalemia (mean value of 3 mmol/L (±0.34)), 88.4% (n = 38) had adrenal abnormalities on preprocedural CT scan, and 67.4% (n = 29) described as unilateral nodules. There were no statistically significant differences in the patients' baseline characteristics between the two groups (before and after intraprocedural cortisol measurement). Before intraprocedural cortisol measurement, adrenal vein sampling selectivity was achieved in 35% (n = 7) patients. Selectivity increased to 100% (30/30) after intraprocedural cortisol measurement (p < 0.001). With the exception of one patient who refused it, all patients with lateralized disease underwent unilateral adrenalectomy with normalization of the aldosterone to renin ratio postoperatively. Conclusions: The lack of effective alternatives in subtyping primary aldosteronism highlights the need to improve the success rate of adrenal vein sampling. In this study, intraprocedural cortisol measurement allowed a selectivity of 100%. Its addition to this procedure protocol should be considered, especially in centers with a low success rate.

Evaluating the impact of modeling the family effect for clonal selection in potato-breeding programs.

Because of its wide distribution, high yield potential, and short cycle, the potato has become essential for global food security. However, the complexity of tetrasomic inheritance, the high level of heterozygosity of the parents, the low multiplication rate of tubers, and the genotype-by-environment interactions impose severe challenges on tetraploid potato-breeding programs. The initial stages of selection take place in experiments with low selection accuracy for many of the quantitative traits of interest, for example, tuber yield. The goal of this study was to investigate the contribution of incorporating a family effect in the estimation of the total genotypic effect and selection of clones in the initial stage of a potato-breeding program. The evaluation included single trials (STs) and multi-environment trials (METs). A total of 1,280 clones from 67 full-sib families from the potato-breeding program at Universidade Federal de Lavras were evaluated for the traits total tuber yield and specific gravity. These clones were distributed in six evaluated trials that varied according to the heat stress level: without heat stress, moderate heat stress, and high heat stress. To verify the importance of the family effect, models with and without the family effect were compared for the analysis of ST and MET data for both traits. The models that included the family effect were better adjusted in the ST and MET data analyses for both traits, except when the family effect was not significant. Furthermore, the inclusion of the family effect increased the selective efficiency of clones in both ST and MET analyses via an increase in the accuracy of the total genotypic value. These same models also allowed the prediction of clone effects more realistically, as the variance components associated with family and clone effects within a family were not confounded. Thus, clonal selection based on the total genotypic value, combining the effects of family and clones within a family, proved to be a good alternative for potato-breeding programs that can accommodate the logistic and data tracking required in the breeding program.

Use of alternative diluent ACP-Lact® and coconut water powder (ACP) in cryopreservation of goat semen and fixed-time artificial insemination (FTAI) in half-breed goats.

The aim of the present study was to evaluate semen cryopreservation with ACP-Lact® diluent, which consists of coconut water powder (ACP) added to goat milk powder. After thawing, the samples were evaluated for sperm kinetics, membrane evaluation and in vivo insemination. For cryopreservation, a pool was made with the ejaculate of six goats, diluted in four equal aliquots for the respective treatments: T1 (ACP-Lact®); T2 (ACP-Lact® 50%); T3 (ACP + 2.5% egg yolk) and T4 (Tris + 2.5% egg yolk). After dilution of the treatments, the samples were placed in 0.5 ml straws and chilled at a rate of -1.07°C/min. After reaching 4°C and stabilizing for one hour, the straws were placed in nitrogen vapour at -60°C for 15 minutes and then immersed in liquid nitrogen (-196ºC). The straws were thawed in a 37°C water bath and kinetic assessments were performed immediately using a computerized semen analysis program (CSA), viability (EN), membrane functionality (HOST), mitochondrial activity (DAB) and DNA integrity assessment of spermatozoa. For the in vivo experiment, ten goats were inseminated, divided into two groups of five goats each, G1 inseminated with ACP-Lact® and G2 with ACP, by fixed-time artificial insemination (FTAI). Regarding the kinetic parameters, the ACP-Lact® treatment showed higher progressive motility (PM) and sperm velocity than the other treatments (36.77%). In the VSL parameter the ACP-Lact diluent was superior to ACP and Tris. In viability the treatment with ACP-Lact® was superior to the treatment with Tris, 95% and 83% respectively. In FTAI two goats were born out of the 5 goats inseminated with ACP-Lact®. It was concluded that the use of ACP-Lact® for cryopreservation of caprine semen is efficient in maintaining seminal parameters during thawing in vitro and in vivo and proved to be a good alternative extender for the caprine species.

Effects of the Mean Weight of Uniform Litters on Sows and Offspring Performance.

This study aimed to determine the effects of uniform litters of different mean birth weights on colostrum production of sows and piglets performance. The study involved 98 multiparous sows from a commercial lean genotype and their piglets. Simultaneous farrowing were supervised and the piglets were divided into experimental litters of 12 piglets each of heterogenous litters (HET, CV = 23.8%, n = 20), uniform light litters (ULL, CV = 9.8%, n = 27), uniform average litters (UAL, CV = 8.2%, n = 23) or uniform heavy litters (UHL, CV = 8.6%, n = 28) piglets and allowed to suckle. Piglets were re-weighed at 24 h and 21 d of life and deaths registered. Colostrum intake (CI) of the piglets and sow's colostrum yield (CY) was estimated using two prediction equations. Significant differences (p < 0.001) were observed in the CY of sows being higher in UHL, lower in ULL and intermediary in HET and UAL litters. CY was positively related to litter total weight at birth and litter weight gain in the first 24 h (p < 0.001). The CI differ between litter type being higher in UHL litters and lower in ULL litters. The coefficient of variation of CI in HET litters was higher than in uniform litters, regardless of their type. The mortality rate of piglets until 21 d was globally 9.6% and it was significantly higher in HET than in UAL (p = 0.033) and tended to be higher than in UHL litters (p = 0.052). No differences in piglet survival were observed between uniform litters. Results show the beneficial effect of uniformity in piglet survival and that the mean weight of uniform litter influences colostrum intake and piglet performance.

The location and development of Replicon Cluster Domains in early replicating DNA.

Background: It has been known for many years that in metazoan cells, replication origins are organised into clusters where origins within each cluster fire near-synchronously. Despite clusters being a fundamental organising principle of metazoan DNA replication, the genomic location of origin clusters has not been documented. Methods: We synchronised human U2OS by thymidine block and release followed by L-mimosine block and release to create a population of cells progressing into S phase with a high degree of synchrony. At different times after release into S phase, cells were pulsed with EdU; the EdU-labelled DNA was then pulled down, sequenced and mapped onto the human genome. Results: The early replicating DNA showed features at a range of scales. Wavelet analysis showed that the major feature of the early replicating DNA was at a size of 500 kb, consistent with clusters of replication origins. Over the first two hours of S phase, these Replicon Cluster Domains broadened in width, consistent with their being enlarged by the progression of replication forks at their outer boundaries. The total replication signal associated with each Replicon Cluster Domain varied considerably, and this variation was reproducible and conserved over time. We provide evidence that this variability in replication signal was at least in part caused by Replicon Cluster Domains being activated at different times in different cells in the population. We also provide evidence that adjacent clusters had a statistical preference for being activated in sequence across a group, consistent with the 'domino' model of replication focus activation order observed by microscopy. Conclusions: We show that early replicating DNA is organised into Replicon Cluster Domains that behave as expected of replicon clusters observed by DNA fibre analysis. The coordinated activation of different Replicon Cluster Domains can generate the replication timing programme by which the genome is duplicated.

2023 UPDATE: Luso-Brazilian evidence-based guideline for the management of antidiabetic therapy in type 2 diabetes.

BACKGROUND: The management of antidiabetic therapy in people with type 2 diabetes (T2D) has evolved beyond glycemic control. In this context, Brazil and Portugal defined a joint panel of four leading diabetes societies to update the guideline published in 2020. METHODS: The panelists searched MEDLINE (via PubMed) for the best evidence from clinical studies on treating T2D and its cardiorenal complications. The panel searched for evidence on antidiabetic therapy in people with T2D without cardiorenal disease and in patients with T2D and atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), or diabetic kidney disease (DKD). The degree of recommendation and the level of evidence were determined using predefined criteria. RESULTS AND CONCLUSIONS: All people with T2D need to have their cardiovascular (CV) risk status stratified and HbA1c, BMI, and eGFR assessed before defining therapy. An HbA1c target of less than 7% is adequate for most adults, and a more flexible target (up to 8%) should be considered in frail older people. Non-pharmacological approaches are recommended during all phases of treatment. In treatment naïve T2D individuals without cardiorenal complications, metformin is the agent of choice when HbA1c is 7.5% or below. When HbA1c is above 7.5% to 9%, starting with dual therapy is recommended, and triple therapy may be considered. When HbA1c is above 9%, starting with dual therapyt is recommended, and triple therapy should be considered. Antidiabetic drugs with proven CV benefit (AD1) are recommended to reduce CV events if the patient is at high or very high CV risk, and antidiabetic agents with proven efficacy in weight reduction should be considered when obesity is present. If HbA1c remains above target, intensification is recommended with triple, quadruple therapy, or even insulin-based therapy. In people with T2D and established ASCVD, AD1 agents (SGLT2 inhibitors or GLP-1 RA with proven CV benefit) are initially recommended to reduce CV outcomes, and metformin or a second AD1 may be necessary to improve glycemic control if HbA1c is above the target. In T2D with HF, SGLT2 inhibitors are recommended to reduce HF hospitalizations and mortality and to improve HbA1c. In patients with DKD, SGLT2 inhibitors in combination with metformin are recommended when eGFR is above 30 mL/min/1.73 m2. SGLT2 inhibitors can be continued until end-stage kidney disease.

A registry-based population study of the HLA in Québec, Canada.

As part of the worldwide effort to better characterize HLA diversity in populations, we have studied the population of Québec in Canada. This province has been defined by a complex history with multiple founder effects and migration patterns. We analyzed the typing data of 3806 individuals registered in Héma-Québec's Registry, which covered most administrative regions in Québec. Typing information was resolved at the second field level of resolution by next-generation sequencing (NGS) or by Sanger sequencing. We used the HLA-net.eu GENE[RATE] tools to estimate allele and two-locus haplotype frequencies for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1, as well as Hardy-Weinberg equilibrium (HWE), selective neutrality, and linkage disequilibrium. The chord genetic distance was also calculated between administrative regions and was visualized using non-metric multidimensional scaling (NMDS) analysis. While most individual regions were in HWE, HWE was rejected for the province considered as a whole. Some regions exhibited signatures of selection, mostly toward an excess of heterozygotes. Allele and haplotype frequencies revealed outlier regions that strongly differed from the other regions. NMDS plots also showed differences between regions. The administrative regions of the province of Québec displayed heterogeneity in their HLA profiles. This heterogeneity was attributable to differing allele and haplotype specificities by region. In particular, regions 02-Saguenay-Lac-Saint-Jean and 01-Bas-St-Laurent diverged from the rest of the regions. The urban regions 06-Montréal and 13-Laval were very diversified in their HLA profiles. Together, these results will help optimize donor recruitment strategies in Québec.

TADs: Dynamic structures to create stable regulatory functions.

Mammalian chromosomes are organized at different length scales within the cell nucleus. Topologically Associating Domains (TADs) are structural units of 3D genome organization with functions in gene regulation, DNA replication, recombination and repair. Whereas TADs were initially interpreted as insulated domains, recent studies are revealing that these domains should be interpreted as dynamic collections of actively extruding loops. This process of loop extrusion is subsequently blocked at dedicated TAD boundaries, thereby promoting intra-domain interactions over their surroundings. In this review, we discuss how mammalian TAD structure can emerge from this dynamic process and we discuss recent evidence that TAD boundaries can have regulatory functions.

The Association of Leptin with Left Ventricular Hypertrophy in End-Stage Kidney Disease Patients on Dialysis.

Left ventricular hypertrophy (LVH) is a common cardiovascular complication in end-stage kidney disease (ESKD) patients. We aimed at studying the association of LVH with adiponectin and leptin levels, cardiovascular stress/injury biomarkers and nutritional status in these patients. We evaluated the LV mass (LVM) and calculated the LVM index (LVMI) in 196 ESKD patients on dialysis; the levels of hemoglobin, calcium, phosphorus, parathyroid hormone, albumin, adiponectin, leptin, N-terminal pro B-type natriuretic peptide (NT-proBNP) and growth differentiation factor (GDF)-15 were analyzed. ESKD patients with LVH (n = 131) presented higher NT-proBNP and GDF-15, lower hemoglobin and, after adjustment for gender, lower leptin levels compared with non-LVH patients. LVH females also showed lower leptin than the non-LVH female group. In the LVH group, LVMI presented a negative correlation with leptin and a positive correlation with NT-proBNP. Leptin emerged as an independent determinant of LVMI in both groups, and NT-proBNP in the LVH group. Low hemoglobin and leptin and increased calcium, NT-proBNP and dialysis vintage are associated with an increased risk of developing LVH. In ESKD patients on dialysis, LVH is associated with lower leptin values (especially in women), which are negatively correlated with LVMI, and with higher levels of biomarkers of myocardial stress/injury. Leptin and NT-proBNP appear as independent determinants of LVMI; dialysis vintage, hemoglobin, calcium, NT-proBNP and leptin emerged as predicting markers for LVH development. Further studies are needed to better understand the role of leptin in LVH in ESKD patients.

Diagnosis of 17-alpha hydroxylase deficiency performed late in life in a patient with a 46,XY karyotype.

Summary: 17-Alpha-hydroxylase deficiency (17OHD) is a rare autosomal recessive disease, representing 1% of cases of congenital adrenal hyperplasia. A 44-year-old female presented to the emergency department complaining of generalized asthenia and polyarthralgia for about 2 weeks. On examination, she was hypertensive (174/100 mmHg), and laboratory results revealed hypokalemia and hypocortisolism. She had an uncharacteristic morphotype, BMI of 16.7 kg/m2, cutaneous hyperpigmentation, and Tanner stage M1P1, with normal female external genitalia. She reported to have primary amenorrhea. Further analytical evaluations of her hormone levels were performed CT scan revealed adrenal bilateral hyperplasia and absence of female internal genitalia. A nodular lesion was observed in the left inguinal canal with 25 × 10 mm, compatible with a testicular remnant. Genetic analysis identified the c.3G>A p.(Met1?) variant in homozygosity in the CYP17A1 gene, classified as pathogenic, confirming the diagnosis of 17OHD. Karyotype analysis was compatible with 46,XY. The association of severe hypokalemia, hypertension, hypocortisolism, and oligo/amenorrhea and the absence of secondary sexual characteristics favored the diagnosis of 17OHD, confirmed by genetic testing. As in other published clinical cases, diagnosis outside pediatric age is not rare and should be considered when severe hypokalemia occurs in hypertensive adults with a lack of secondary sexual characteristics. Learning points: The association of severe hypokalemia, hypertension, hypocortisolism, and oligo/amenorrhea and the absence of secondary sexual characteristics favor the diagnosis of 17-alpha-hydroxylase deficiency (17OHD). Diagnosis outside pediatric age is not rare. 17OHD should be considered when severe hypokalemia occurs in hypertensive adults with a lack of secondary sexual characteristics.

Phylogenomics and taxon-rich phylogenies of new and historical specimens shed light on the systematics of Hypnea (Cystocloniaceae, Rhodophyta).

Cystocloniacae is a highly diverse family of Rhodophyta, including species of ecological and economic importance, whose phylogeny remains largely unresolved. Species delimitation is unclear, particularly in the most speciose genus, Hypnea, and cryptic diversity has been revealed by recent molecular assessments, especially in the tropics. Here, we carried out the first phylogenomic investigation of Cystocloniaceae, focused on the genus Hypnea, inferred from chloroplast and mitochondrial genomes including taxa sampled from new and historical collections. In this work, molecular synapomorphies (gene losses, InDels and gene inversions) were identified to better characterize clades in our congruent organellar phylogenies. We also present taxon-rich phylogenies based on plastid and mitochondrial markers. Molecular and morphological comparisons of historic collections with contemporary specimens revealed the need for taxonomic updates in Hypnea, the synonymization of H. marchantiae to a later heterotypic synonym of H. cervicornis and the description of three new species: H. davisiana sp. nov., H. djamilae sp. nov. and H. evaristoae sp. nov.

Medium-Term Effects of Sprinkler Irrigation Combined with a Single Compost Application on Water and Rice Productivity and Food Safety.

Traditional rice (Oryza sativa L.) management (tillage and flooding) is unsustainable due to soil degradation and the large amount of irrigation water used, an issue which is exacerbated in the Mediterranean region. Therefore, there is a need to explore rice management strategies in order to improve water-use efficiency and ensure its sustainability. Thus, field experiments were conducted to determine the medium-term effects of different irrigation and tillage methods combined with a single compost application on water and rice productivity, as well as food safety in a semiarid Mediterranean region. The management systems evaluated were: sprinkler irrigation in combination with no-tillage (SNT), sprinkler irrigation in combination with conventional tillage (ST), which were implemented in 2015, and flooding irrigation in combination with conventional tillage (FT), and their homologues (SNT-C, ST-C, and FT-C) with single compost application in 2015. In reference to rice grain yield, the highest values were observed under ST treatment with 10 307 and 11 625 kg ha-1 in 2018 and 2019 respectively; whereas between FT and SNT there were no significant differences, with 8 140 kg ha-1 as mean value through the study. Nevertheless, sprinkler irrigation allowed saving 55% of the total amount of water applied in reference to flooding irrigation. Furthermore, the highest arsenic concentration in grains was found under FT but it decreased with compost application (FT-C) and especially with sprinkler irrigation, regardless of tillage management systems. However, sprinkler irrigation favors the cadmium uptake by plants, although this process was reduced under SNT in reference to ST, and especially under amended compost treatments. Therefore, our results suggested that a combination of sprinkler irrigation and compost application, regardless of the tillage system, could be an excellent strategy for rice management for the Mediterranean environment in terms of water and crop productivity as well as food safety.

Genomic prediction for complex traits across multiples harvests in alfalfa (Medicago sativa L.) is enhanced by enviromics.

Breeding for dry matter yield and persistence in alfalfa (Medicago sativa L.) can take several years as these traits must be evaluated under multiple harvests. Therefore, genotype-by-harvest interaction should be incorporated into genomic prediction models to explore genotypes' adaptability and stability. In this study, we investigated how enviromics could help to predict the genotypic performance under multiharvest alfalfa breeding trials by evaluating 177 families across 11 harvests under four cross-validation scenarios. All scenarios were analyzed using six models in a Bayesian mixed model framework. Our results demonstrate that models accounting to the enviromics information led to an increase of genetic variance and a decrease in the error variance, indicating better biological explanation when the enviromic information was incorporated. Furthermore, models that accounted for enviromic data led to higher predictive ability (PA) in a reduced number of harvests used in the training data set. The best enviromic models (M2 and M3) outperformed the base model (GBLUP model-M0) for predicting adaptability and persistence across all cross-validation scenarios. Incorporating environmental covariates also provided higher PA for persistence compared with the base model, as predictions increased from 0 to 0.16, 0.20, 0.56, and 0.46 for CV00, CV1, CV0, and CV2. The results also demonstrate that GBLUP without enviromics term has low power to predict persistence, thus the adoption of enviromics is a cheap and efficient alternative to increase accuracy and biological meaning.

Maturity-onset diabetes of the young secondary to HNF1B variants (HNF1B-MODY): a series of 10 patients from a single diabetes center.

BACKGROUND: Maturity-Onset Diabetes of the Young (MODY) is an autosomal dominant condition and represents 1-5% of all cases of diabetes mellitus. MODY is often misdiagnosed as type 1 or type 2 diabetes. The rare subtype 5 (HNF1B-MODY) is due to hepatocyte nuclear factor 1ß (HNF1B) molecular alteration and is remarkable for its multisystemic phenotypes characterized by a broad spectrum of pancreatic and extra-pancreatic clinical manifestations. METHODS: Retrospective study of patients with HNF1B-MODY diagnosis followed in the Centro Hospitalar Universitário Lisboa Central (Lisbon, Portugal). Demographic data, medical history, clinical and laboratory data, follow-up and treatment procedures were obtained from electronic medical records. RESULTS: We found 10 patients with HNF1B variants (7 index cases). The median age at diabetes diagnosis was 28 (IQR 24) years and the median age at HNF1B-MODY diagnosis was 40.5 (IQR 23) years. Six patients were initially misclassified as type 1 and 4 as type 2 diabetes. The average time between diabetes diagnosis and the diagnosis of HNF1B-MODY was 16.5 years. Diabetes was the first manifestation in half of the cases. The other half presented with kidney malformations and chronic kidney disease at pediatric age as the first manifestation. All these patients were submitted to kidney transplantation. Long-term diabetes complications included retinopathy (4/10), peripheral neuropathy (2/10) and ischemic cardiomyopathy (1/10). Other extra-pancreatic manifestations included liver test alterations (4/10) and congenital malformation of the female reproductive tract (1/6). History of a first-degree relative with diabetes and/or nephropathy diagnosed at a young age was present in 5 of the 7 index cases. CONCLUSIONS: Despite being a rare disease, HNF1B-MODY is underdiagnosed and often misclassified. It should be suspected in patients with diabetes and CKD, especially when diabetes appears at a young age, a family history is present, and nephropathy appears before/shortly after the diagnosis of diabetes. Presence of unexplained liver disease increases the degree of suspicion for HNF1B-MODY. Early diagnosis is important to minimize complications and to allow familial screening and pre-conception genetic counseling. Trial registration not applicable due to the retrospective nature of the study, non-interventional.