Micronized natural progesterone (Seidigestan®) vs GnRH antagonists for preventing the LH surge during controlled ovarian stimulation (PRO_NAT study): study protocol of a randomized clinical trial.

Introduction: Progesterone-primed cycles effectively suppress the pituitary LH surge during ovarian stimulation in oocyte donors and in the infertile population. Particularly in oocyte donors, the use of synthetic progesterone (progestins) has been explored in prospective clinical trials, showing mixed results. This trial was designed to determine whether the use of micronized natural progesterone is as effective as the GnRH-antagonist protocol in terms of the number of mature oocytes (MII) retrieved in oocyte donation cycles as a primary outcome, and it also aims to explore the corresponding results in recipients as a secondary outcome. Methods: We propose a prospective, open-label, non-inferiority clinical trial to compare a novel approach for oocyte donors with a control group, which follows the standard ovarian stimulation protocol used in our institution. A total of 150 donors (75 in each group) will be recruited and randomized using a computer algorithm. After obtaining informed consent, participants will be randomly assigned to one of two ovarian stimulation protocols: either the standard GnRH antagonist or the oral micronized natural progesterone protocol. Both groups will receive recombinant gonadotropins tailored to their antral follicle count and prior donation experiences, if any. The primary outcome is the number of mature metaphase II (MII) oocytes. Secondary measures include treatment duration, pregnancy outcomes in recipients, as well as the economic cost per MII oocyte obtained in each treatment regimen. Analyses for the primary outcome will be conducted in both the intention-to-treat (ITT) and per-protocol (PP) populations. Each donor can participate only once during the recruitment period. The estimated duration of the study is six months for the primary outcome and 15 months for the secondary outcomes. Discussion: The outcomes of this trial have the potential to inform evidence-based adjustments in the management of ovarian stimulation protocols for oocyte donors. Clinical trial registration: ClinicalTrials.gov, identifier, NCT05954962.

Prevalencia de anticuerpos neutralizantes frente al SARS-CoV-2 inducidos tras 2 dosis de vacuna BNT162b2 (Pfizer–BioNTech) en trabajadores sanitarios / Prevalence of neutralizing antibodies against SARS-CoV-2 using a rapid serological test in health workers of a Spanish Department of Health in Alicante (Spain) before the booster dose of the vaccine

Fundamento: Estudiar la prevalencia de anticuerpos neutralizantes en el personal sanitario y de apoyo tras la administración de la segunda dosis de vacuna BNT162b2 (Pfizer–BioNTech). Material y métodos: En diciembre 2021 llevamos a cabo un estudio en el Departamento de Salud de Orihuela, Alicante (España), formado por 1.500 trabajadores. En los participantes del estudio, recogimos variables demográficas y realizamos un test «point-of-care» (POC) de inmunocromatografía para medir la presencia de anticuerpos neutralizantes (OJABIO® SARS-CoV-2 Neutralizing Antibody Detection Kit, fabricado por Wenzhou OJA Biotechnology Co., Ltd.- Wenzhou, Zhejiang, China) antes de la administración de la tercera dosis de vacuna. Resultados: Obtuvimos información completa de 964 (64%) trabajadores, siendo 290 varones y 674 mujeres. La edad media fue de 45,8 años (mín: 18, máx: 68) y el tiempo desde la última dosis (TUD) de vacuna fue 40,5 semanas (mín: 1,71; máx: 47,71). Un total de 131 (13,5%) habían padecido infección por SARS-CoV-2 confirmada mediante RT-PCR. La proporción de sujetos con presencia de anticuerpos neutralizantes fue de 38,5%. En el análisis multivariable el TUD de vacuna (razón de probabilidades ajustada [ORa] semana: 1,07; IC 95%: 1,04; 1,09) y la infección previa por SARS-CoV-2 (ORa: 3,7; IC 95%: 2,39; 5,63) mostraron asociación estadísticamente significativa con la presencia de anticuerpos neutralizantes. Conclusiones: El TUD de vacuna y la infección previa por SARS-CoV-2 determinaron la presencia de anticuerpos neutralizantes en 38,5% del personal sanitario y personal de apoyo.(AU)

Aim: To study the prevalence of neutralizing antibodies in healthcare workers and healthcare support personnel after the administration of the second dose of the BNT162b2 vaccine (Pfizer-BioNTech). Materials and methods: In December 2021, we undertook a study in the Health Department in Orihuela, Alicante (Spain), which consists of 1500 workers. We collected demographic variables about the study participants, and we performed a «point-of-care» immunochromatography test to measure the presence of neutralizing antibodies (OJABIO® SARS-CoV-2 Neutralizing Antibody Detection Kit, manufactured by Wenzhou OJA Biotechnology Co., Ltd. Wenzhou, Zhejiang, China) before the administration of the third dose of the vaccine. Results: We obtained complete information about 964 (64%) workers, which consisted of 290 men and 674 women. The average age was 45,8 years (min. 18, max. 68) and the average time since the last dose of the vaccine was 40,5 weeks (min. 1,71, max. 47,71). A total of 131 participants (13,5%) had suffered infection by SARS-CoV-2 confirmed using RT-PCR. The proportion of participants who showed presence of neutralizing antibodies was 38,5%. In the multivariable analysis, the time since the last dose of the vaccine (aOR week: 1,07; 95%CI: 1,04; 1,09) and previous infection by SARS-CoV-2 (aOR: 3,7; 95CI: 2,39; 5,63) showed a statistically significant association with the presence of neutralizing antibodies. Conclusions: The time since the administration of the last dose of the vaccine and the previous infection by SARS-CoV-2 determined the presence of neutralizing antibodies in 38,5% of the healthcare workers and support workers.(AU)

Prevalence of neutralizing antibodies against SARS-CoV-2 using a rapid serological test in health workers of a Spanish Department of Health in Alicante (Spain) before the booster dose of the vaccine.

AIM: To study the prevalence of neutralizing antibodies in healthcare workers and healthcare support personnel after the administration of the second dose of the BNT162b2 vaccine (Pfizer-BioNTech). MATERIALS AND METHODS: In December 2021, we undertook a study in the Health Department in Orihuela, Alicante (Spain), which consists of 1500 workers. We collected demographic variables about the study participants, and we performed a "point-of-care" immunochromatography test to measure the presence of neutralizing antibodies (OJABIO® SARS-CoV-2 Neutralizing Antibody Detection Kit, manufactured by Wenzhou OJA Biotechnology Co., Ltd. Wenzhou, Zhejiang, China) before the administration of the third dose of the vaccine. RESULTS: We obtained complete information about 964 (64%) workers, which consisted of 290 men and 674 women. The average age was 45,8 years (min. 18, max. 68) and the average time since the last dose of the vaccine was 40,5 weeks (min. 1,71, max. 47,71). A total of 131 participants (13,5%) had suffered infection by SARS-CoV-2 confirmed using RT-PCR. The proportion of participants who showed presence of neutralizing antibodies was 38,5%. In the multivariable analysis, the time since the last dose of the vaccine (aOR week: 1,07; 95%CI: 1,04; 1,09) and previous infection by SARS-CoV-2 (aOR: 3,7; 95CI: 2,39; 5,63) showed a statistically significant association with the presence of neutralizing antibodies. CONCLUSIONS: The time since the administration of the last dose of the vaccine and the previous infection by SARS-CoV-2 determined the presence of neutralizing antibodies in 38,5% of the healthcare workers and support workers.

Factors associated with embryo mosaicism: a systematic review and meta-analysis.

PURPOSE: Evaluate which factors are involved in the increased rate of mosaicism in embryos. METHODS: A systematic review and meta-analysis was performed. After an exhaustive search of the literature, a total of seven papers were included in the analysis. In addition, data collected from IVF cycles performed in our fertility clinic were also analysed. Day of biopsy, embryo quality, maternal and paternal age and seminal quality were the chosen factors to be studied. RESULTS: The results of the meta-analysis show that neither embryo quality nor seminal quality were related to mosaic embryo rate (OR: 1.09; 95% CI: 0.94-1.28 and OR: 1.10; 95% CI: 0.87-1.37, respectively). A positive association was observed for the variable "biopsy day" with embryos biopsied at day 6 or 7 having the highest rate of mosaicism (OR: 1.06; 95% CI: 1.01-1.11). In opposite to what happens with aneuploidy rate, which increases with maternal age, embryo mosaicism is higher in younger women (<34 years) rather than in older ones (≥34 years) (OR: 0.95; 95% CI: 0.92-0.98). However, for the "paternal age" factor, no association with mosaicism was found (OR: 1.04; 95% CI: 0.90-1.21). CONCLUSIONS: With the present study, we can conclude that the factors related to the presence of mosaicism in embryos are the embryo biopsy day and maternal age. The rest of the studied factors showed no significant relationship with mosaicism. These results are of great importance as knowing the possible causes leading to mosaicism helps to improve the clinical results of reproductive treatments.

Identification of novel candidate genes associated with meiotic aneuploidy in human embryos by whole-exome sequencing.

PURPOSE: To identify novel genetic variants responsible for meiotic embryonic aneuploidy. METHODS: A prospective observational cohort study that included 29 couples who underwent trophectoderm biopsies from 127 embryos and performed whole-exome sequencing (WES) between November 2019 and March 2022. Patients were divided into two groups according to the expected embryo aneuploidy rate based on maternal age. RESULTS: After variant filtering in the WES analysis of 58 patients/donors, five heterozygous variants were identified in female partners from the study group that had an impact on embryo aneuploidy. Additionally, a slowdown in embryo development and a decrease in the number of blastocysts available for biopsy were observed in the study group embryos. CONCLUSION: This study has identified new candidate genes and variants not previously associated with meiotic embryo aneuploidy, but which are involved in important biological processes related to cell division and chromosome segregation. WES may be an efficient tool to identify patients with a higher-than-expected risk of embryo aneuploidy based on maternal age and allow for individualized genetic counselling prior to treatment.

IL-6/IL-10 and IL-1ß/IL-4 ratios associated with poor ovarian response in women undergoing in-vitro fertilization.

The aim of this work was to evaluate whether serum cytokines levels are associated with ovarian response in IVF. 149 patients were included in a retrospective study. Cytokines IL-2, IL-4, IL- 6, IL-8, IL-10, VEGF, IFNγ, TNFα, IL-1α, IL-1ß, MCP-1 and EGF were measured by sandwich immunoassay previously to ovarian stimulation. Performing hierarchical cluster analysis, we observed that the antral follicle count, the total oocytes recovered and the MII recovered are grouped in the same cluster as the cytokines IL-2-4-6-10-1α-1ß, IFNγ y TNFα. Then, we found that the ratio between IL and 6 and IL-10 was higher in low responder women (2.15 versus 1.55; p = 0.035). If we establish 0.9 as a cut-off for the IL-6/IL-10, we observed that above this value the risk of having a low response to ovarian stimulation was more than 3 times greater than below this value (22.9 % versus 6.0 %; p = 0.007). Also, the ratio IL-1ß/IL-4 was higher in patients with normal or suboptimal response (0.62 versus 0.34; p = 0.034) and any patient with low response had a value greater than 0.7 (p = 0.003). As a conclusion, the IL-6/IL-10 and IL-1ß/IL-4 ratios showed differences between normoresponder women and patients with low ovarian response.

Identification of new variants and candidate genes in women with familial premature ovarian insufficiency using whole-exome sequencing.

PURPOSE: To identify candidate variants in genes possibly associated with premature ovarian insufficiency (POI). METHODS: Fourteen women, from 7 families, affected by idiopathic POI were included. Additionally, 98 oocyte donors of the same ethnicity were enrolled as a control group. Whole-exome sequencing (WES) was performed in 14 women with POI to identify possibly pathogenic variants in genes potentially associated with the ovarian function. The candidate genes selected in POI patients were analysed within the exome results of oocyte donors. RESULTS: After the variant filtering in the WES analysis of 7 POI families, 23 possibly damaging genetic variants were identified in 22 genes related to POI or linked to ovarian physiology. All variants were heterozygous and five of the seven families carried two or more variants in different genes. We have described genes that have never been associated to POI pathology; however, they are involved in important biological processes for ovarian function. In the 98 oocyte donors of the control group, we found no potentially pathogenic variants among the 22 candidate genes. CONCLUSION: WES has previously shown as an efficient tool to identify causative genes for ovarian failure. Although some studies have focused on it, and many genes are identified, this study proposes new candidate genes and variants, having potentially moderate/strong functional effects, associated with POI, and argues for a polygenic etiology of POI in some cases.

Identification of vaginal microbiome associated with IVF pregnancy.

The factors that cause a preterm birth (PTB) are not completely understood up to date. Moreover, PTB is more common in pregnancies achieved by in-vitro fertilization (IVF) than in spontaneous pregnancies. Our aim was to compare the composition of vaginal microbiome at 12 weeks of gestation between women who conceived naturally or through IVF in order to study whether IVF PTB-risk could be related to vaginal microbiome composition. We performed an observational, prospective and multicentre study among two public hospitals and a fertility private clinic in Spain. Vaginal swabs from 64 pregnant women at 12 weeks of gestation were collected to analyse the microbiome composition by sequencing the V3-V4 region of the 16S rRNA. Our results showed that the vaginal microbiome signature at 12 weeks of pregnancy was different from women who conceived naturally or through IVF. The beta diversity and the genus composition were different between both cohorts. Gardnerella, Neisseria, Prevotella, and Staphylococcus genus were enriched genus in the vaginal microbiome from the IVF group, allowing us to create a balance model to predict both cohorts. Moreover, at species level the L. iners abundance was higher and L. gasseri was lower in the IVF group. As a conclusion, our findings were consistent with a proposed framework in which IVF pregnancy are related to risk for preterm birth (PTB) suggesting vaginal microbiome could be the reason to the relation between IVF pregnancy and risk for PTB.

Improving the preparedness against an oil spill: Evaluation of the influence of environmental parameters on the operability of unmanned vehicles.

When an oil spill occurs, a prompt response reduces significantly the impact. The preparedness and contingency plans are essential to identify the most appropriate technologies. Unmanned and autonomous vehicles (UAVs) is emerging as a powerful tool of strategic potential in the observation, oil tracking and damage assessment of an oil spill. The SpilLess project explored the suitability of these devices to be the first-line response to an oil spill. This work analyses the operational requirements related to environmental parameters following a two steps approach: 1) Environmental characterization from long wind and waves time series and modelling; 2) Definition of the optimal periods for operating each UAVs. We have defined the periods in which each of these facilities acts best, confirming that the operational limits of UAVs are not significantly more restrictive than the traditional operations. UAVs should be included in contingency plans as available tools to fight against oil spills.

Characterization of the vaginal and endometrial microbiome in patients with chronic endometritis.

OBJECTIVE: To compare the endometrial and vaginal microbiome of women with and without chronic endometritis. STUDY DESIGN: A cohort study with 60 patients undergoing assisted reproductive treatment with their own or donated gametes was undertaken. Vaginal and endometrial samples were taken in the cycle prior to embryo transfer. The endometrial and vaginal microbiome was analysed by mass sequencing of the V3V4 region of 16S rRNA gene. Bioinformatics analysis was performed using QIIME2 and MicrobiomeAnalyst packages. Alpha diversity, beta diversity and taxonomic characterization were compared between samples that tested positive and negative for chronic endometritis on CD138 immunohistochemistry. RESULTS: Different bacterial communities were detected when vaginal and endometrial samples were analysed in patients with and without endometritis diagnosed using CD138 immunohistochemistry. In patients with endometritis, a higher alpha-diversity index was found in vaginal samples (p = 0.15 for the Shannon index) and significant differences were found in endometrial samples (p = 0.01 for the Shannon index). In the beta-diversity analysis, no significant differences were observed between the groups with and without endometritis. Vaginal and endometrial samples from women with endometritis showed a microbiome pattern that was not dominated by Lactobacillus spp. Relative abundance analysis identified Ralstonia and Gardnerella spp. in endometrial samples, and Streptoccoccus and Ureaplasma spp. in vaginal samples of patients diagnosed with chronic endometritis on CD138 immunohistochemistry. When comparing endometrial and vaginal samples diagnosed with endometritis on CD138 immunohistochemistry, both alpha diversity (p = 0.06 for the Shannon index and p = 0.08 for the Simpson index) and beta diversity (p < 0.001) showed significant differences. Lactobacillus spp. (p = 3.76E-4), Ralstonia spp. (p = 8.19E-4), Delftia spp. (p = 0.004) and Anaerobacillus spp. (p = 0.004) were identified in these sample groups. CONCLUSION: These results demonstrate the existence of a characteristic vaginal and endometrial microbiota in patients with chronic endometritis. Different genera and species were identified in patients with and without chronic endometritis depending on whether the sample was endometrial or vaginal. There is a clear relationship between changes in the vaginal microbiome and chronic endometritis. The microbiota is a continuum throughout the female reproductive tract, so study of the vaginal microbiota could be useful for the diagnosis of diseases of the upper reproductive tract, such as chronic endometritis.

[ADA2 deficit: a case with neurological manifestations as a predominant clinic]. / Déficit de ADA2: caso con manifestaciones neurológicas como clínica predominante.

TITLE: Déficit de ADA2: caso con manifestaciones neurológicas como clínica predominante.

Comprehensive mitochondrial DNA analysis and IVF outcome.

STUDY QUESTION: Do mitochondrial DNA (mtDNA) copy number and heteroplasmy in human embryos affect the ongoing pregnancy rate? SUMMARY ANSWER: Our study suggests that mtDNA copy number above a specific threshold is associated with the ongoing pregnancy rate. WHAT IS KNOWN ALREADY: Mitochondria play a vital role in cell function. Recently, there has been increasing research on mtDNA as a biomarker of embryo implantation. Although reports showed that high levels of mtDNA in the blastocyst are associated with low implantation potential, other publications were unable to confirm this. Confounding factors may influence the mtDNA copy number in euploid embryos. On the other hand it has been speculated that both mtDNA heteroplasmy and copy number contribute to mitochondrial function. Next generation sequencing (NGS) allows us to study in depth mtDNA heteroplasmy and copy number simultaneously. STUDY DESIGN SIZE DURATION: A prospective non-selection study was performed. We included 159 blastocyst biopsies from 142 couples who attended our clinic for preimplantation genetic testing for aneuploidies (PGT-A), from January 2017 to December 2017. All embryos were biopsied on Day 5 or Day 6. The aneuploid testing was performed by NGS. All blastocysts were diagnosed as euploid non-mosaic and were transferred. The mtDNA analysis was performed once the embryo diagnosis was known. PARTICIPANTS/MATERIALS SETTING METHODS: Sequencing reads mapping to the mtDNA genome were extracted from indexed bam files to identify copy number and heteroplasmy. The relative measure of mtDNA copy number was calculated by dividing the mtDNA reads by the nuclear DNA value to normalize for technical variants and the number of cells collected at the biopsy. All the results were subjected to a mathematical correction factor according to the embryo genome. Heteroplasmy was assigned by MitoSeek. MAIN RESULTS AND THE ROLE OF CHANCE: The mean average copy number and SD of mtDNA per genome was 0.0016 ± 0.0012. Regarding heteroplasmy, 40 embryos were heteroplasmy carriers (26.32%). MtDNA variants were detected in coding and non-coding regions and the highest number of variants in an embryo was eight. With respect to IVF outcome for mtDNA copy number analysis, we set a threshold of 0.003 for the following analysis. The vast majority of the embryos were below the threshold (142/159, 89.31%) and 17 embryos were classified as having higher mtDNA levels. We showed a reduction in ongoing pregnancy rate associated with elevated mtDNA copy number (42.96% versus 17.65%, P < 0.05). This result was independent of maternal age and day of the biopsy: these factors were included as confounding factors because mtDNA copy number was negatively correlated with female age (25 -30 y: 0.0017 ± 0.0011, 30 -35 y: 0.0012 ± 0.0007, 35 -40 y: 0.0016 ± 0.0009, over 40 y: 0.0024 + 0.0017, P < 0.05). Embryos biopsied on Day 5 were more likely to have higher quantities of mtDNA compared with those biopsied on Day 6 (0.0017 versus 0.0009, P < 0.001). According to IVF outcome and heteroplasmy, a lower ongoing pregnancy rate was reported for embryos that carried more than two variants. However, this did not reach statistical significance when we compared embryos with a number of variants lower or higher than two (39.15 versus 20.0, P = 0.188). Finally, a clear positive association between the mtDNA variants and copy number was reported when we compare embryos with or without heteroplasmy (0.0013 ± 0.0009 versus 0.0025 ± 0.0014, P < 0.001) and among different numbers of variants (0:0.0013 ± 0.0009, 1-2:0.0023 ± 0.0012, >2:0.0043 ± 0.0014, P < 0.05). LIMITATIONS REASONS FOR CAUTION: A limitation may be the size of the sample and the high-throughput sequencing technology that might not have detected heteroplasmy levels below 2% which requires high sequence depth A clinical randomized trial comparing the clinical outcome after the transfer of embryos selected according to mtDNA levels or only by morphological evaluation will be necessary. More research into the impact of mtDNA heteroplasmy and copy number on IVF outcome is needed. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrate that embryos with elevated mtDNA copy number have a lower chance of producing an ongoing pregnancy. MtDNA copy number is higher in older women and is dependent upon the number of cell divisions that preceded biopsy. Moreover, our data suggest that mitochondrial activity could be a balance between functional capacity and relative mtDNA copy number. STUDY FUNDING/COMPETING INTERESTS: There are no conflicts of interest or sources of funding to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Desensitization Protocol in Recipients of Deceased Kidney Donor With Donor-Specific Antibody-Low Titers.

BACKGROUND: Kidney transplantation is the better option for end-stage renal disease (ESRD), but for patients with human leukocyte antigen (HLA) sensitization, the wait times are significantly longer than for patients without antibodies. Many desensitization protocols have been described involving strong immunosuppression, the use of apheresis, and B-cell-modulating therapies. We have designed a desensitization protocol from day 0 for deceased donor kidney transplantation. Our aim was to present our initial experience with five kidney transplant patients. METHODS: All patients had a negative complement-dependent cytotoxicity cross-match. The desensitization protocol included five to seven doses of thymoglobulin (1.25 mg/kg) and three sessions of plasmapheresis (PP) within the first week after transplantation, with intravenous immunoglobulin (500 mg/kg) after each PP session and one dose of rituximab on day 8. The presence of donor-specific antibodies (DSA) was analyzed by use of Luminex technology; levels between 1000 and 3000 mean fluorescence intensity were considered for desensitization. RESULTS: The median age was 44 years and median renal replacement therapy time was 9 years. All recipients presented 1 to 3 DSA specificities. There were no severe side effects related to PP, infusion of intravenous immunoglobulin, or rituximab. The median follow-up period was 19.3 months. Median serum creatinine level at last follow-up was 1.7 mg/dL. A kidney biopsy was performed in all patients. Graft and patient survival was 100%. CONCLUSIONS: Until now, few data are available concerning whether HLA-incompatible kidney transplantation after desensitization would benefit patients with ERSD. The desensitization strategy using the combination of PP, low doses of intravenous immunoglobulin, and rituximab at our center resulted in a satisfactory clinical outcome.

Safety and efficacy of induction treatment with low thymoglobulin doses in kidney transplantation from expanded-criteria donors.

BACKGROUND: Induction treatment has been recommended as part of the initial immunosuppressive regimen in kidney transplantation, and antithymocyte globulin is one of the drugs used for it, but at usual dosage it has been related to an increase of infectious and neoplastic complications. Our aim was to analyze the safety and efficacy of induction treatment with low doses of antithymocyte globulin, compared to basiliximab. METHODS: In this retrospective cohort study of 321 kidney transplant patients with a minimum follow-up of 2 years, 162 were treated with low doses of antithymocyte globulin (1.25 mg/kg, every other day) and 159 with basiliximab. Mean follow-up was 76.6 ± 37.51 months (range, 24-187 mo) and was similar for the 2 groups. RESULTS: Mean number of antithymocyte globulin doses was 1.89 ± 0.32 mg/kg (range, 1-3). The globulin group received a higher proportion of kidneys from donors >70 years old (25.3% vs 13.8%; P = .010) and donors with higher creatinine levels (1.01 ± 0.62 vs 0.86 ± 0.28 mg/dL; P = .006). The basiliximab group presented a higher incidence of acute rejection (22.1% vs 9.1%; P = .010). Cytomegalovirus disease was more frequent in the globulin group (18.6% vs 8.1%; P = .011) without an increase of infectious hospitalizations. Graft (P = .214) and patient (P = .533) survivals were similar. CONCLUSIONS: Induction with low doses of antithymocyte globulin resulted in a lower incidence of acute rejection with graft and patient survivals similar to that obtained with basiliximab induction, in spite of a worse donor profile. CMV disease was more frequent with antithymocyte globulin, without an increase of infectious hospitalizations or cancer development, in long-term follow-up.

Surgery improves survival in elderly with breast cancer. A study of 465 patients in a single institution.

INTRODUCTION: Breast cancer treatment in elderly patients is controversial. This single-centre study was conducted to review the treatment and outcomes for octogenarian women treated for breast cancer. METHODS: Data from all patients aged 80 years or more with primary breast cancer treated at our institution between 1995 and 2012 were included. Patients with carcinoma in-situ (stage 0) and advanced breast cancer (stage IV) were excluded. RESULTS: The study population consisted of 369 patients (median age 84 years). A total of 277 (75%) patients underwent surgical treatment (PST) and 92 (25%) received primary endocrine treatment (PET). Prognostic factors (HER-2, tumour grade, lymphovascular invasion and subsequent adjuvant therapy) were homogeneously distributed in both groups. PST and PET were stratified according to stage: 273 (66%) patients with early stage disease (I, IIA, IIB) and 96 (34%) with locally advanced disease (IIIA, IIIB, IIIC). Patients were followed-up for a median of 63 months. In patients with early stage disease, the mean breast cancer-specific survival (BCSS) was 109 months (95% CI = 101-115) in PST patients, and 50 months (95% CI = 40-60) in PET patients (P < 0.01). Conversely, for patients with locally advanced breast cancer, there was no significant difference in BCSS between the surgical and non-surgical groups. In the PST group, BCSS and disease-free survival were significantly better among patients who underwent standard surgical treatment than among those who received suboptimal treatment. There were no differences in the Charlson comorbidity index scores between the PST and PET groups. CONCLUSION: In women ≥80 years with early-stage breast cancer, standard surgical treatment was associated with a better BCSS when compared with PET.

Impact of vitamin D insufficiency on insulin homeostasis and beta cell function in nondiabetic male HIV-infected patients.

OBJECTIVES: Vitamin D is thought to play a role in glucose homeostasis and beta cell function. Our aim was to examine the impact of plasma 25-hydroxyvitamin D [25(OH)D] upon in vivo insulin sensitivity and beta cell function in HIV-infected male patients without diabetes. METHODS: A cross-sectional study was carried out involving a cohort of HIV-infected patients undergoing regular assessment in a tertiary hospital. Eighty-nine patients [mean (± standard deviation) age 42 ± 8 years] were included in the study: 14 patients were antiretroviral therapy (ART)-naïve, while 75 were on ART. Vitamin D insufficiency (VDI) was defined as 25(OH)D < 75 nmol/L; insulin sensitivity was determined using a 2-h continuous infusion of glucose model assessment with homeostasis (CIGMA-HOMA), using the trapezoidal model to calculate the incremental insulin and glucose areas under the curve (AUCins and AUGglu, respectively). Beta cell function was assessed using the disposition index (DI). Abdominal visceral adipose tissue (VAT) and hepatic triglyceride content (HTGC) were measured by magnetic resonance imaging (MRI) and 1-H magnetic resonance spectroscopy. Multivariate linear regression analysis was performed. RESULTS: VDI was associated with insulin resistance (IR), as indicated by a higher CIGMA-HOMA index (odds ratio 1.1) [1.01-1.2]. This association was independent of the main confounders, such as age, Centers for Disease Control and Prevention (CDC) stage, ART, lipodystrophy, body mass index, VAT:subcutaneous adipose tissue ratio and HTGC, as confirmed by multivariate analysis (B = 12.3; P = 0.01; r² = 0.7). IR in patients with VDI was compensated by an increase in insulin response. However, beta cell function was lower in the VDI subpopulation (33% decrease in DI). CONCLUSIONS: VDI in nondiabetic HIV-positive male patients is associated with impaired insulin sensitivity and a decrease in pancreatic beta cell function.

Recurrent arrival of oil to Galician coast: the final step of the Prestige deep oil spill.

Yearly monitoring in one of the most affected coastal zones by the Prestige oil spill, namely Nemiña and O Rostro beaches (NW Spain), has been carried out since 2004. Topographic data of beaches revealed seasonal altimetric changes up to 4m that would prevent the on shore persistence of oil. However, surficial and subsurficial oil was detected in the intertidal area of both beaches in all campaigns. The hydrocarbon analysis confirmed that this oil corresponded to the Prestige oil, even nine years after the accident. Tar balls were highly biodegraded suggesting that the oil was accumulated on the subtidal sediments for a long time and transported to the coast by the action of waves. The present work provides new evidence of the long term persistence of deep oil spills from wrecks in marine areas where the hydrodynamic conditions play a twofold key role, in determining the exposed coastal area to recurrent contamination and in burying and resurfacing the oil in the intertidal zone.

Pretransplant donor-specific HLA antibodies detected by single antigen bead flow cytometry: risk factors and outcomes after kidney transplantation.

BACKGROUND: The clinical significance of pretransplant donor-specific antibodies (pre-Tx DSAs) detected by single antigen bead flow cytometry (SAB-FC) remains unclear. Our aim was to investigate the impact that pre-Tx DSAs detected by SAB-FC have on the early and late clinical outcomes. PATIENTS AND METHODS: We retrospectively tested stored frozen pre-Tx sera from 222 deceased-donor kidney transplants performed between November 1997 and November 2006. All patients had a negative complement-dependent cytotoxicity (CDC) cross-match with the donor. Median follow up was 5.1 years. RESULTS: Twenty-two (10%) patients had pre-Tx HLA antibodies detected by CDC. Pre-Tx HLA antibodies were detected using SAB-FC in the sera of 46 (20.7%) patients; 36 (16.2%) of them presented pre-Tx DSAs, 18 had class I antibodies, 9 class II, and 9 patients presented both classes. Mean pre-Tx DSA class I/II was 2360/1972 (MFI) mean fluorescence index in non CDC-sensitized patients. Pre-Tx DSAs were associated with female sex, retransplants, and pretransplant transfusions. Patients with Pre-Tx DSAs more than 1000 MFI and negative CDC screening presented a higher percentage of delayed graft function (61.1% versus 38.9%), more episodes of acute vascular rejection (33.3% versus 13.7%), and chronic rejection as the cause of allograft failure (22.2% versus 9.7%) compared with non-pre-Tx DSAs patients. Five-year allograft survival was significantly worse in patients with pre-Tx DSA (68.5% versus 82%, P = .006) and in patients with pre-Tx DSA class II more than 1000 MFI (43% versus 82%, P = .009). We didn't find differences in patient survival. DISCUSSION: Pre-Tx DSAs detected by SAB-FC were more frequent in female recipients, and they were associated with acute vascular and chronic rejection and a poorer graft outcome.

Donor-specific HLA antibodies: risk factors and outcomes after kidney transplantation.

BACKGROUND: Anti-human leukocyte antigen antibodies (HLA Abs) have been associated with reduced kidney allograft survival. Our aim was to analyze the prevalence and impact on allograft function of donor-specific HLA antibodies (DSA) among a cohort of kidney transplant recipients. PATIENTS AND METHODS: The 321 recipients had received deceased-donor kidneys followed for a median of 70 ± 43 months. We performed a cross-sectional analysis of the presence of HLA Abs with the use of Luminex technology. RESULTS: Fifty patients (15.6%) displayed HLA Abs after transplantation including 21 (6.7%) as de novo HLA Abs. Eight patients (2.5%) developed DSA, and 42 (13%) showed no DSA. We compared 3 groups of patients: with DSA, without DSA, and without HLA sensitization. The DSA patients were younger (P = .03) with a higher percentage of men (P = .00), and having received less frequent induction treatment with basiliximab or thymoglobulin (P = .02). Patients without DSA revealed a higher percentage of pretransplantation HLA sensitization (P = .00), more pretransplantation transfusions (P = .08), and more frequent retransplantations (P = .00). The incidence of acute rejections was higher for DSA patients (P = .02) than for the other 2 groups, behaving as an independent risk factor (relative risk, 4.7; 95% confidence interval, 1.1-18.8; P = .03). Graft survival at 5 years was lower among patients with compared to those without HLA Abs (P = .00). CONCLUSIONS: HLA donor-specific sensitization, an uncommon situation in our study, was associated with younger male recipients and less induction treatment. An acute rejection episode was an independent risk factor for the development of DSA; therefore, we think that monitoring of HLA Abs should be included in evaluation of the early postransplantation period.

Delayed graft function after renal transplantation: an unresolved problem.

Unlike other areas in renal transplantation, delayed graft function (DGF) remains an apparently unavoidable complication owing to the characteristics of current donors. The aim of this study was to analyze risk factors for DGF in relation to graft and patient survivals. We retrospectively analyzed 507 renal transplant recipients with a median follow-up of 74.83 ± 45.06 months. DGF, which occurred among 189 patients (36.8%) was defined as requirement for dialysis within the first week after transplantation. Donor (P = .000) and recipient (P = .000) age were greater in the DGF group without differences in recipient or donor gender, HLA sensitization, or dialysis time before transplantation. Donor factors as the cause of death associated with DGF were secondary cerebrovascular stroke (P = .002) and hypertensive history (P = .000). Recipient characteristics associated therewith were higher body mass index (P = .000), smoking habit (P = .003), ischemic cardiopathy (P = .01), and dyslipidemia (P = .05). Moreover, the DGF group showed longer cold ischemia (P = .01) and vascular anastomosis (P = .02) times. On multivariate analysis, recipient age (P = .00) and smoking habit (P = .01) together with a donor history of hypertension (P = .02) were independent risk factors for DGF. No differences were observed in acute rejection incidence (P = .07) with worse renal function during follow-up (P < .05). Graft (81% vs 88%; P = .00) and patient (89% vs 95%; P = .00) survivals at 5 years were lower among the DGF group. In conclusion, DGF which was associated with factors related to the donor, the recipient, and the surgical times, produced worse graft and patient survivals. Shortening the cold ischemia time seems to be a modifiable variable to reduce DGF.