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BACKGROUND/PURPOSE: Locoregional control in breast cancer is a fundamental part of treatment and determinant for survival outcomes. It has been reported that most locoregional recurrence (LRR) events occur in the first 5 years after treatment. However, LRR continue to occur after this timeline, with unclear risk factors and unknown survival impact. METHODS: Retrospective singe-centered cohort of patients treated for primary breast cancer, between January 2002 and December 2004. Primary outcome was LRR; secondary outcomes were overall survival (OS), disease-free survival (DFS), and predictive factors for LRR. RESULTS: This analysis included 1001 patients, of which 959 (95%) had invasive carcinoma. A mastectomy was performed in 501 (50%) and 500 (50%) had breast conservative surgery (BCS). Median follow-up time was 197 [Inter-quartile range (IQR) 96-211] months. Global LRR rate was 7.6%, with median time to recurrence of 45 [IQR 21-91] months. There was no difference in LRR rate after mastectomy vs BCS, adjusted to tumor stage (p > 0.05). The 10-year OS and DFS rates were 68.4 and 77.8%, respectively. Factors associated with LRR were metastatic axillary lymph nodes and high histologic grade (p < 0.05). Estrogen-negative (ER) tumors had higher LRR rates than ER-positive tumors in the first 5 years (p < 0.05); but no difference was observed with longer follow-up (p > 0.05). LRR was associated with OS (p < 0.05). DISCUSSION AND CONCLUSIONS: Global LRR in this cohort was 7.6% (with over 16 years of follow-up). LRR associates with decreased OS. Time to LRR varies significantly with tumor biology, supporting differentiation of follow-up regimens.
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The human kallikrein (KLK) cluster, located at chromosome 19q13.3-13.4, encodes 15 serine proteases, including neighboring genes (KLK3, KLK2, KLK4, and KLK5) with key roles in the cascades of semen liquefaction, tooth enamel maturation, and skin desquamation. KLK2 and KLK3 were previously identified as targets of adaptive evolution in primates through different mechanisms linked to reproductive biology and, in humans, genome-wide scans of positive selection captured, a yet unexplored, evidence for KLK neutrality departure in East Asians. We perform a detailed evaluation of KLK3-KLK5 variability in the 1000 Genomes samples from East Asia, Europe, and Africa, which was sustained by our own sequencing. In East Asians, we singled out a 70-kb region surrounding KLK4 that combined unusual low levels of diversity, high frequency variants with significant levels of population differentiation (FST > 0.5) and fairly homogenous haplotypes given the large local recombination rates. Among these variants, rs1654556_G, rs198968_T, and rs17800874_A stand out for their location on putative regulatory regions and predicted functional effects, namely the introduction of several microRNA binding sites and a repressor motif. Our functional assays carried out in different cellular models showed that rs198968_T and rs17800874_A operate synergistically to reduce KLK4 expression and could be further assisted by rs1654556_G. Considering the previous findings that KLK4 inactivation causes enamel malformations in humans and mice, and that this gene is coexpressed in epidermal layers along with several substrates involved in either cell adhesion or keratinocyte differentiation, we propose KLK4 as another target of selection in East Asians correlated to tooth and epidermal morphological traits.
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Povo Asiático/genética , Regulação para Baixo/genética , Variação Genética/genética , Calicreínas/genética , Evolução Molecular , Ásia Oriental , Humanos , Seleção Genética/genéticaRESUMO
STUDY QUESTION: Are kallikreins (KLKs), the whey-acidic-protein four-disulfide core domain (WFDCs) and their neighbors, semenogelins (SEMGs), known to play a role in the cascade of semen coagulation and liquefaction, associated with male infertility? SUMMARY ANSWER: Several KLK and SEMG variants are overrepresented among hyperviscosity, asthenozoospermia and oligozoospermia, supporting an effect of abnormal semen liquefaction on the loss of semen quality and in lowering male reproductive fitness. WHAT IS KNOWN ALREADY: In the cascade of semen coagulation and liquefaction the spermatozoa coated by EPPIN (a protease inhibitor of the WFDC family) are entrapped in a cross-linked matrix established by SEMGs. After ejaculation, the SEMG matrix is hydrolyzed by KLK3/2 in a fine-tuned process regulated by other KLKs that allows the spermatozoa to increase motility. STUDY DESIGN SIZE, DURATION: This study includes a cohort of 238 infertility-related cases and 91 controls with normal spermiogram analysis. The remaining 126 controls are healthy males with unknown semen parameters. Sample collection was carried out from June 2011 to January 2015 and variant screening from May 2013 to August 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a screening by massive parallel sequencing in a pooled sample (N = 222) covering approximately 93 kb of KLK (19q13.3-13.4) and WFDC (20q13) clusters, followed by the genotyping of most promising variants in the full cohort. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 160 common and 296 low-frequency variants passed the quality control filtering. Statistical tests disclosed an association with hyperviscosity of a KLK7 regulatory variant (P = 0.0035), and unveiled a higher burden of deleterious mutations in KLKs than expected by chance (P = 0.0106). KLK variants found to be overrepresented in cases included two substitutions likely affecting the substrate binding pocket, two nonsynonymous variants overlapping in the three-dimensional structure and two mutations mapping in consecutive N-terminal residues. Other variants identified in SEMGs possibly contributing to hyperviscosity and asthenozoospermia consisted of three replacements predicted to modify targets of proteolysis (P = 0.0442 for SEMG1 p.Gly400Asp) and a copy number variation associated with a reduced risk of oligozoospermia (P = 0.0293). LARGE SCALE DATA: Not applicable. LIMITATIONS REASONS FOR CAUTION: The sampling of a few hundred individuals has limited power to detected associations with low-frequency variants and only a small set of variants was prioritized for genotyping. Other susceptibility variants for male infertility may remain unidentified. WIDER IMPLICATIONS OF THE FINDINGS: We provide important evidence for an effect of KLKs and SEMGs variability on semen quality and for modifications in the process of semen liquefaction as a possible cause for male infertility. STUDY FUNDING/COMPETING INTERESTS: This work was funded through the Portuguese Foundation for Science and Technology (FCT) and FEDER through COMPETE and QREN. The authors have no conflict of interest to declare.
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Infertilidade Masculina/genética , Calicreínas/genética , Proteínas/genética , Sêmen , Genótipo , Humanos , Masculino , Fenótipo , Análise do Sêmen , Proteínas Secretadas pela Vesícula Seminal/genética , Motilidade dos Espermatozoides/genética , Espermatogênese/genética , ViscosidadeRESUMO
Many countries are facing challenges in recruiting and retaining physicians, particularly in regions where the public and private sectors compete for doctors. Understanding the factors influencing physicians' job choices can help inform policies aimed at attracting and retaining this valuable workforce. This study aims to elicit the strength of physicians' preferences regarding various job-related aspects, including earnings, time flexibility, discussion of clinical cases, frequency of facilities and equipment updates, training opportunities and autonomy in decision making. To achieve this, a Discrete Choice Experiment (DCE) was administered to 697 physicians. Each participant completed a series of eight choice tasks, where they had to choose between two hypothetical jobs differing in these attributes with levels mirroring positions in the public and private sectors in Portugal. The resulting choices were analysed using mixed logit, generalized multinomial logit and latent classes models to account for diverse unobserved variations in physicians' preferences and to explore preference heterogeneity across different observable characteristics. Jobs that offered more autonomy and training opportunities were strongly preferred, as physicians would require additional compensation to work with reduced autonomy (equivalent to 28.62% of gross income) or less frequent training (equivalent to 22.75%). This study also shows that the ranking of the job characteristics is similar between physicians working exclusively in the public sector and those engaged in dual practice. Nevertheless, public sector physicians place more emphasis on the availability of frequent training possibilities and frequent updates of facilities and equipment compared to their counterparts in dual practice. These findings contribute to existing knowledge by highlighting the significance of non-monetary attributes and shedding light on the preferences of physicians across various employment scenarios. They offer valuable insights for policy development aimed at influencing physicians' allocation of time between sectors.
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Escolha da Profissão , Médicos , Humanos , Renda , Emprego , Recursos Humanos , Comportamento de EscolhaRESUMO
In developing countries, markets are the main supply of horticultural products to populations, but this can pose a public health challenge due to the risk of the fecal-oral transmission of gut pathogens. This transmission is strongly associated with inadequate public sanitation or low standards of personal and domestic hygiene, and their prevalence can cause gastrointestinal diseases, which are the third leading cause of death in Mozambique. This study aims at assessing the risk for public health of horticultural products supply chain, from the farmers-vendors to the consumers, in municipal markets in Maputo-City, Mozambique. Surveys (75) were conducted on vendors and an observational analysis was performed in the markets under study. The results showed that 62% of the vendors had access to water from boreholes or artisanal sources and the issue "access to water" was significantly different between markets (p = 0.004). Of the vendors who wash their products (53.3%), only 7.5% use tap-water for this purpose, with the difference in attitudes being statistically significant between vendors in the markets (p = 0.035). The majority (60.4%) said that vegetables and fruits can cause diseases due to pesticides and only 31.3% believe that the diseases may be related to poor hygiene. Despite the vendors' low knowledge of Good Hygiene Practices (GHP), we noticed that women have better practical assimilation of GHP when compared to men (p = 0.008). Although Maputo's markets are struggling to achieve quality hygiene standards in a reliable and sustainable manner, their resources are limited and significantly different (p = 0.044) from market to market, and this problem remains a concern for the public-health authorities of the city. In conclusion, the provision of adequate drinking water and sewage disposal systems, together with education for health of vendors, can reduce the risk of contamination of fresh food by the more common organisms causing diarrhea in children, including intestinal parasites.