Sex Influence on Autophagy Markers and miRNAs in Basal and Angiotensin II-Treated Human Umbilical Vein Endothelial Cells.

Cardiovascular diseases (CVD) display many sex and gender differences, and endothelial dysfunction, angiotensin II (Ang II), and autophagy represent key factors in the autophagic process Therefore, we studied whether Ang II modulates the mentioned processes in a sex-specific way in HUVECs obtained from healthy male and female newborns. In basal HUVECs, the Parkin gene and protein were higher in FHUVECs than in MHUVECs, while the Beclin-1 protein was more expressed in MHUVECs, and no other significant differences were detected. Ang II significantly increases LAMP-1 and p62 protein expression and decreases the expression of Parkin protein in comparison to basal in MHUVECs. In FHUVECs, Ang II significantly increases the expression of Beclin-1 gene and protein, and Parkin gene. The LC3 II/I ratio and LAMP-1 protein were significantly higher in MHUVECs than in FHUVECs, while Parkin protein was significantly more expressed in Ang II-treated FHUVECs than in male cells. Ang II affects the single miRNA levels: miR-126-3p and miR-133a-3p are downregulated and upregulated in MHUVECs and FHUVECs, respectively. MiR-223 is downregulated in MHUVEC and FHUVECs. Finally, miR-29b-3p and miR-133b are not affected by Ang II. Ang II effects and the relationship between miRNAs and organelles-specific autophagy is sex-dependent in HUVECs. This could lead to a better understanding of the mechanisms underlying sex differences in endothelial dysfunction, providing useful indications for innovative biomarkers and personalized therapeutic approaches.

Human monocytes respond to lipopolysaccharide (LPS) stimulation in a sex-dependent manner.

Monocytes play a critical role in inflammation and immune response, their activity being sex-dependent. However, the basis of sex differences is not well understood. Therefore, we investigated the lipopolysaccharide (LPS) effects on tumor necrosis factor-α (TNF-α) release, autophagy, and chemotaxis in freshly isolated monocytes from healthy young men and women. In basal conditions, male and female monocytes had similar TNF-α release, chemotaxis, and estrogen receptors (ER-α) and ER-ß expression, while the LC3II/I ratio was significantly higher in males. LPS treatment induced qualitative and quantitative sex differences. It reduced autophagy and increased TNF-α release only in male monocytes, while, chemotaxis was significantly influenced only in female cells. Moreover, it reduced the expression of ER-α only in female cells, while ER-ß expression was reduced in both sexes, but more markedly in female cells. Finally, the interplay between LPS treatment and 17-ß-estradiol (E2 ) was present only in female cells. Globally, these findings expand the concept that sex plays a role in regulating monocytes' functions, being sex differences cell- and parameter-specific.

Smoking and combined oral contraceptives should be considered as an independent variable in sex and gender-oriented studies.

The influence of sex combined with smoking and combined oral contraceptives (COC) use on atherogenic indexes is scarcely studied. Thus, traditional lipid parameters were measured, and non-traditional atherogenic indexes were calculated in a young and healthy population of men, COC-free women, and COC users. Total cholesterol (TChol), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and HDL/LDL ratio were lower in men, while triglycerides (TG)/HDL ratio, atherogenic index of plasma (AIP), Castelli's Risk Index I (CRII) and CRI-II, atherogenic coefficient (AC), creatinine, creatinine clearance, and estimated glomerular filtration rate (eGFR) were higher in men. The use of COC modified TChol, HDL, TG, TG/HDL, and AIP which had significantly higher values in COC users. In addition, TG were also increased in COC users in comparison with men. Smoking reduced sexually divergent parameters: BMI, TG, HDL/LDL, TG/HDL, AIP, CRII, CRI-II, and AC became similar among the three cohorts, losing the reported sex differences. Smoking also reduced differences in TChol, HDL, TG, and AIP between COC-free women and COC users, but it does not affect CRII, CRI-II, creatinine, creatinine clearance, and eGFR, underlining that COC users and COC-free women have to be considered two different populations. Our results represent a complex landscape suggesting that for both sexes smoking should be an independent variable in medical studies. Moreover, in women, the use of COC evidenced two different cohorts. Thus, more variables should be considered during a single study indicating that sex, smoking, and COC should be studied together to get a picture of the real-life context.

Posterior tibial perforators relationship with superficial nerves and veins: A cadaver study.

BACKGROUND: Most authors have evaluated the location of lower leg arterial perforators, but little is still known about the relationship between the arterial network and great saphenous vein (GSV) and saphenous nerve (SN). The aim of this study is to evaluate the relationship between the arterial network of the posterior tibial artery perforators, the cutaneous nerves, and the superficial venous system in the lower one third of the leg. METHODS: Eighteen lower limbs from cadavers were used for this study. The arterial and venous compartment were selectively injected with a mixture of barium sulfate and epoxy. The specimen were CT scanned and the superficial veins, nerves, and the arterial perforators were dissected. RESULTS: A large perforator of the posterior tibial artery was found at a mean distance of 6.23 cm ± 0.88, with a 95% CI: 5.79-6.67, from the medial malleolus. The average diameter was 0.9 mm ± 0.17, with a 95% CI: 0.81-0.99. In 67% the connection of the venae comitantes to the superficial venous system was established with the GSV, in the other cases, with Leonardo's vein. Both dissection and imaging studies showed perineural interperforator connections along the branches of SN in all the specimens examined. CONCLUSIONS: The distribution pattern of posterior tibial artery perforators followed the superficial nerves in this region. There is an interperforator anastomotic network along the SN. The various patterns of the venous drainage system, in relationship to the distribution of the branches of posterior tibial artery perforators, have been clarified.

Epigenetics, Stem Cells, and Autophagy: Exploring a Path Involving miRNA.

MiRNAs, a small family of non-coding RNA, are now emerging as regulators of stem cell pluripotency, differentiation, and autophagy, thus controlling stem cell behavior. Stem cells are undifferentiated elements capable to acquire specific phenotype under different kind of stimuli, being a main tool for regenerative medicine. Within this context, we have previously shown that stem cells isolated from Wharton jelly multipotent stem cells (WJ-MSCs) exhibit gender differences in the expression of the stemness related gene OCT4 and the epigenetic modulator gene DNA-Methyltransferase (DNMT1). Here, we further analyze this gender difference, evaluating adipogenic and osteogenic differentiation potential, autophagic process, and expression of miR-145, miR-148a, and miR-185 in WJ-MSCs derived from males and females. These miRNAs were selected since they are involved in OCT4 and DNMT1 gene expression, and in stem cell differentiation. Our results indicate a difference in the regulatory circuit involving miR-148a/DNMT1/OCT4 autophagy in male WJ-MSCs as compared to female cells. Moreover, no difference was detected in the expression of the two-differentiation regulating miRNA (miR-145 and miR-185). Taken together, our results highlight a different behavior of WJ-MSCs from males and females, disclosing the chance to better understand cellular processes as autophagy and stemness, usable for future clinical applications.

Sex Differences in Estrogen Receptor α and ß Levels and Activation Status in LPS-Stimulated Human Macrophages.

Immune function, inflammation, and atherosclerosis display sex differences and are influenced by 17ß-estradiol through estrogen receptors subtypes ERα and ERß. Male tissues express active ERs, but their possible involvement in inflammation in males has never been assessed. Macrophages express both ERα and ERß and offer the opportunity to evaluate the role of ER levels and activation in inflammation. We assessed the ability of lipopolysaccharide (LPS) to modulate, in a sex-specific way, the expression and the activation status of ERα and ERß in blood monocytes-derived macrophages (MDMs) from men and women. MDMs were incubated with 100 ng/ml LPS for 24 h and used to evaluate ERα, ERß, P-ERα, p38, and P-p38 expression by Western Blotting. In basal conditions, ERα and ERß were significantly higher in female MDMs than in male MDMs. LPS up-regulated ERα and ERα phosphorylation in both sexes, with a significantly higher effect observed in male MDMs, and down-regulated ERß level only in female MDMs. p38 and P-p38 proteins, indicative of ERß activity, did not show sex differences both in basal conditions and after LPS treatment. Finally, ERα/ERß and P-ERα/ERα ratios were significantly higher in male MDMs than in female ones. Our data indicate, for the first time, that LPS affects ERα but not ERß activation status. We identify a significant role of ERα in LPS-mediated inflammatory responses in MDMs, which represents an initial step in understanding the influence of sex in the relationship between LPS and ERα. J. Cell. Physiol. 232: 340-345, 2017. © 2016 Wiley Periodicals, Inc.

Essential trace elements in amyotrophic lateral sclerosis (ALS): Results in a population of a risk area of Italy.

Sardinian (Italy) island population has a uniquely high incidence of amyotrophic lateral sclerosis (ALS). Essential trace element levels in blood, hair, and urine of ALS Sardinian patients were investigated in search of valid biomarkers to recognize and predict ALS. Six elements (Ca, Cu, Fe, Mg, Se, and Zn) were measured in 34 patients compared to 30 age- and sex-matched healthy controls by a validated method. Levels of Ca and Cu in blood and of Se and Zn in hair were significantly higher in ALS than in controls, while urinary excretion of Mg and Se was significantly decreased. The selected cut-off concentrations for these biomarkers may distinguish patients with or without ALS with sufficient sensitivity and specificity. Many positive (as Se-Cu and Se-Zn) and negative associations (as Ca-Mg and Ca-Zn) between elements suggested that multiple metals involved in multiple mechanisms have a role in the ALS degeneration.

Sex-specific pharmacological modulation of autophagic process in human umbilical artery smooth muscle cells.

Sex has largely been neglected in cell studies. Therefore, we investigated the occurrence of sexual dimorphism in human umbilical artery smooth muscle cells (HUASMCs). In particular, we investigated the existence of sex differences in basal and in drug-induced autophagy, a process involved in cardiovascular diseases. HUASMCs were isolated from healthy and normal weight male and female newborns (MHUASMCs and FHUASMCs, respectively). Expression of the primary molecules involved in the autophagic process [beclin-1 and microtubule-associated protein 1 light chain 3 (LC3)], and PmTOR were detected using western blotting in basal conditions, after serum starvation, rapamycin and verapamil treatments. The level of constitutive autophagy, measured as the LC3II/I ratio, was similar in male and female HUASMCs in the basal condition. Serum starvation promoted autophagy in both cell types, but the increase was more pronounced in FHUASMCs, while 250nM rapamycin induced autophagy only in female cells. Moreover, the level of verapamil-induced autophagy was not different between the two sexes. Notably, in the basal condition, Beclin-1 was more elevated in MHUASMCs than in FHUASMCs, and the difference disappeared after serum starvation and exposure to rapamycin. After exposure to verapamil, the differences in Beclin-1 increased, with more elevated expression levels in female cells. PmTor did not differ in basal conditions, but it was significantly down-regulated by starvation only in FHUASMCs and by rapamycin both in male and female cells. Finally, a strong negative correlation was observed between the newborn's weight and basal autophagy in female cells and between the newborn's weight and the LC3II/I ratio in male verapamil-treated cells. These results indicate that sex-differences begin in utero, are parameter-specific and drug specific suggesting that HUASMCs are a suitable model for the screening of drugs and to study the influence of sex. The sex differences in the autophagy suggest sexually different pharmacodynamics effects of verapamil and rapamycin.

Estrogenic Compounds Have Divergent Effects on Human Endothelial Progenitor Cell Migration according to Sex of the Donor.

BACKGROUND: Endothelial progenitor cells (EPCs) are key elements in vascular homeostasis. Their function is regulated by estrogens and estrogen receptors (ERs), but the effect of estrogenic compounds such as bisphenol A (BPA; an agonist of ER-ß and agonist and antagonist of ER-α) and (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC; an agonist of ER-α and antagonist of ER-ß) on human EPCs is unknown. We analyzed whether BPA and THC influence the migration of human EPCs, an essential process in endothelial regeneration, in both male and female EPCs. METHODS: EPCs isolated from healthy adult men and women were assayed for ER expression by Western blotting and chemotaxis assay. RESULTS: Male and female EPCs similarly expressed ERs and did not differ in basal migration. Interestingly, 17-ß-estradiol (10(-9) and 10(-10) M) significantly inhibited migration in female EPCs but not in males. Moreover, both 10(-5) M THC and 10(-8) M BPA blocked migration in female EPCs, allowing us to hypothesize that the effect is mediated by ER-α. CONCLUSIONS: Estrogenic compounds have a sex divergent effect which could help in understanding differences in the pathophysiology of endothelial function observed between men and women.

A scanning electron microscope study and statistical analysis of adipocyte morphology in lipofilling: comparing the effects of harvesting and purification procedures with 2 different techniques.

BACKGROUND: The aim of this study was to evaluate the effects on adipocyte morphology of 2 techniques of fat harvesting and of fat purification in lipofilling, considering that the number of viable healthy adipocytes is important in fat survival in recipient areas of lipofilling. METHODS: Fat harvesting was performed in 10 female patients from flanks, on one side with a 2-mm Coleman cannula and on the other side with a 3-mm Mercedes cannula. Thirty milliliter of fat tissue from each side was collected and divided into three 10 mL syringes: A, B, and C. The fat inside syringe A was left untreated, the fat in syringe B underwent simple sedimentation, and the fat inside syringe C underwent centrifugation at 3000 rpm for 3 minutes. Each fat graft specimen was processed for examination under low-vacuum scanning electron microscope. Diameter (µ) and number of adipocytes per square millimeter and number of altered adipocytes per square millimeter were evaluated. Untreated specimens harvested with the 2 different techniques were first compared, then sedimented versus centrifuged specimens harvested with the same technique were compared. Statistical analysis was performed using Wilcoxon signed rank test. RESULTS: The number of adipocytes per square millimeter was statistically higher in specimens harvested with the 3-mm Mercedes cannula (P = 0.0310). The number of altered cells was statistically higher in centrifuged specimens than in sedimented ones using both methods of fat harvesting (P = 0.0080) with a 2-mm Coleman cannula and (P = 0.0050) with a 3-mm Mercedes cannula. Alterations in adipocyte morphology consisted in wrinkling of the membrane, opening of pore with leakage of oily material, reduction of cellular diameter, and total collapse of the cellular membrane. CONCLUSIONS: Fat harvesting by a 3-mm cannula results in a higher number of adipocytes and centrifugation of the harvested fat results in a higher number of morphologic altered cells than sedimentation.

Objective Non-Invasive Bio-Parametric Evaluation of Regenerated Skin: A Comparison of Two Acellular Dermal Substitutes.

Several dermal substitutes are available on the market, but there is no precise indication that helps surgeons choose the proper one. Few studies have tried to compare different xenogeneic bioengineered products, but no objective bio-parametric comparison has been made yet. Fifteen patients who underwent skin reconstruction with Integra® or Pelnac® were retrospectively evaluated. After at least 12 months of follow-up, an objective and quantitative assessment of several skin biophysical properties, such as color, texture, elasticity, hydration, glossiness and trans-epidermal water loss, were measured with non-invasive skin measurement devices. The grafted skin showed a reduction of the superficial hydration level and a tendency to lower values of trans-epidermal water loss with both dermal substitutes. Melanic and hemoglobin pigmentation were higher in comparison to the donor site in both groups, while a melanic pigmentation increase versus the surrounding skin was seen just with Integra®. Finally, the skin was found to be more elastic when reconstructed with Integra®. The skin barrier appeared to be intact in both groups. Hence, these substitutes are valuable means of skin regeneration. Integra® seems to be more advantageous for reconstructing areas that need more skin flexibility.

Cytoskeletal proteins in the cerebrospinal fluid as biomarker of multiple sclerosis.

The axonal cytoskeleton is a finely organized system, essential for maintaining the integrity of the axon. Axonal degeneration is implicated in the pathogenesis of unremitting disability of multiple sclerosis (MS). Purpose of this study is to evaluate levels of cytoskeletal proteins such as neurofilament light protein (NFL), glial fibrillary acidic protein (GFAP), and ß-tubulin (ß-Tub) isoforms II and III in the cerebrospinal fluid (CSF) of MS patients and their correlation with MS clinical indices. CSF levels of cytoskeletal proteins were determined in 51 patients: 33 with MS and 18 with other neurological diseases (OND). NFL, GFAP and ß-Tub II proteins were significantly higher (p < 0.0001) in MS than in OND group; no significant difference (p > 0.05) was found between MS and OND with regard to ß-Tub III. Interestingly, levels of ß-Tub III and NFL were higher in progressive than in remitting MS forms; on the contrary, higher levels of ß-Tub II and GFAP were found in remitting MS forms. However, with the exception of ß-Tub III, all proteins tend to decrease their CSF levels concomitantly with the increasing disability (EDSS) score. Overall, our results might indicate ß-Tub II as a potential candidate for diagnostic and ß-Tub III as a possible prognostic biomarker of MS. Therefore, further analyses are legitimated and desirable.

Partial trisomy of the long arm of chromosome 1: prenatal diagnosis, clinical evaluation and cytogenetic findings. Case report and review of the literature.

Partial trisomy of the long arm of chromosome 1 is a relatively rare cytogenetic anomaly. Its phenotype has still not been completely defined, because of the cytogenetic heterogeneity of the cases so far described. We report a prenatal case of partial 1q trisomy associated with partial monosomy 4q, secondary to balanced maternal translocation t(1;4). The trisomic segment extended from 1q31.1 to qter and the monosomy 4q was from 4q35.2 to qter. The phenotypic anomalies found by post-mortem and autopsy examinations were compared with those of similar cases reported in the literature. We performed standard cytogenetics and fluorescence in situ hybridization. Cerebral ventriculomegaly, present in our case, seemed to be a constant feature in partial 1q trisomies, so this cerebral malformation could be considered as the main echographic marker for this chromosomal imbalance and trisomy 1q should be added to the list of chromosomal abnormalities associated with ventriculomegaly.

Cadmium modifies the cell cycle and apoptotic profiles of human breast cancer cells treated with 5-fluorouracil.

Industrialisation, the proximity of factories to cities, and human work activities have led to a disproportionate use of substances containing heavy metals, such as cadmium (Cd), which may have deleterious effects on human health. Carcinogenic effects of Cd and its relationship with breast cancer, among other tumours, have been reported. 5-Fluorouracil (5-FU) is a fluoropyrimidine anticancer drug used to treat solid tumours of the colon, breast, stomach, liver, and pancreas. The purpose of this work was to study the effects of Cd on cell cycle, apoptosis, and gene and protein expression in MCF-7 breast cancer cells treated with 5-FU. Cd altered the cell cycle profile, and its effects were greater when used either alone or in combination with 5-FU compared with 5-FU alone. Cd significantly suppressed apoptosis of MCF-7 cells pre-treated with 5-FU. Regarding gene and protein expression, bcl2 expression was mainly upregulated by all treatments involving Cd. The expression of caspase 8 and caspase 9 was decreased by most of the treatments and at all times evaluated. C-myc expression was increased by all treatments involving Cd, especially 5-FU plus Cd at the half time of treatment. Cd plus 5-FU decreased cyclin D1 and increased cyclin A1 expression. In conclusion, our results indicate that exposure to Cd blocks the anticancer effects of 5-FU in MCF-7 cells. These results could have important clinical implications in patients treated with 5-FU-based therapies and who are exposed to high levels of Cd.

Brain perivascular spaces and autism: clinical and pathogenic implications from an innovative volumetric MRI study.

Introduction: Our single-center case-control study aimed to evaluate the unclear glymphatic system alteration in autism spectrum disorder (ASD) through an innovative neuroimaging tool which allows to segment and quantify perivascular spaces in the white matter (WM-PVS) with filtering of non-structured noise and increase of the contrast-ratio between perivascular spaces and the surrounding parenchyma. Methods: Briefly, files of 65 ASD and 71 control patients were studied. We considered: ASD type, diagnosis and severity level and comorbidities (i.e., intellectual disability, attention-deficit hyperactivity disorder, epilepsy, sleep disturbances). We also examined diagnoses other than ASD and their associated comorbidities in the control group. Results: When males and females with ASD are included together, WM-PVS grade and WM-PVS volume do not significantly differ between the ASD group and the control group overall. We found, instead, that WM-PVS volume is significantly associated with male sex: males had higher WM-PVS volume compared to females (p = 0.01). WM-PVS dilation is also non-significantly associated with ASD severity and younger age (< 4 years). In ASD patients, higher WM-PVS volume was related with insomnia whereas no relation was found with epilepsy or IQ. Discussion: We concluded that WM-PVS dilation can be a neuroimaging feature of male ASD patients, particularly the youngest and most severe ones, which may rely on male-specific risk factors acting early during neurodevelopment, such as a transient excess of extra-axial CSF volume. Our findings can corroborate the well-known strong male epidemiological preponderance of autism worldwide.

Stratification of Amniotic Fluid Cells and Amniotic Fluid by Sex Opens Up New Perspectives on Fetal Health.

Amniotic fluid is essential for fetus wellbeing and is used to monitor pregnancy and predict fetal outcomes. Sex affects health and medicine from the beginning of life, but knowledge of its influence on cell-depleted amniotic fluid (AF) and amniotic fluid cells (AFCs) is still neglected. We evaluated sex-related differences in AF and in AFCs to extend personalized medicine to prenatal life. AFCs and AF were obtained from healthy Caucasian pregnant women who underwent amniocentesis at the 16th-18th week of gestation for advanced maternal age. In the AF, inflammation biomarkers (TNFα, IL6, IL8, and IL4), malondialdehyde, nitrites, amino acids, and acylcarnitines were measured. Estrogen receptors and cell fate (autophagy, apoptosis, senescence) were measured in AFCs. TNFα, IL8, and IL4 were higher in female AF, whereas IL6, nitrites, and MDA were similar. Valine was higher in male AF, whereas several acylcarnitines were sexually different, suggesting a mitochondrial involvement in establishing sex differences. Female AFCs displayed higher expression of ERα protein and a higher ERα/ERß ratio. The ratio of LC3II/I, an index of autophagy, was higher in female AFCs, while LC3 gene was similar in both sexes. No significant sex differences were found in the expression of the lysosomal protein LAMP1, while p62 was higher in male AFCs. LAMP1 gene was upregulated in male AFCs, while p62 gene was upregulated in female ones. Finally, caspase 9 activity and senescence linked to telomeres were higher in female AFCs, while caspase 3 and ß-galactosidase activities were similar. This study supports the idea that sex differences start very early in prenatal life and influence specific parameters, suggesting that it may be relevant to appreciate sex differences to cover knowledge gaps. This might lead to improving the diagnosis of risk prediction for pregnancy complications and achieving a more satisfactory monitoring of fetus health, even preventing future diseases in adulthood.

Sex Differences in X-ray-Induced Endothelial Damage: Effect of Taurine and N-Acetylcysteine.

Ionizing radiation (IR) can induce some associated pathological conditions due to numerous cell damages. The influence of sex is scarcely known, and even less known is whether the effect of antioxidants is sex-dependent. Given the increased use of IR, we investigated whether male human umbilical vein endothelial cells (MHUVECs) and female human umbilical vein endothelial cells (FHUVECs) respond differently to IR exposure and whether the antioxidants 10 mM taurine (TAU) and 5 mM N-acetylcysteine (NAC) can prevent IR-induced damage in a sex-dependent way. In untreated cells, sex differences were observed only during autophagy, which was higher in FHUVECs. In non-irradiated cells, preincubation with TAU and NAC did not modify viability, lactate dehydrogenase (LDH) release, migration, or autophagy, whereas only NAC increased malondialdehyde (MDA) levels in FHUVECs. X-ray irradiation increased LDH release and reduced viability and migration in a sex-independent manner. TAU and NAC did not affect viability while reduced LDH release in irradiated cells: they have the same protective effect in FHUVECs, while, TAU was more protective than NAC in male cells.. Moreover, TAU and NAC significantly promoted the closure of wounds in both sexes in irradiated cells, but NAC was more effective at doing this in FHUVECs. In irradiated cells, TAU did not change autophagy, while NAC attenuated the differences between the sexes. Finally, NAC significantly decreased MDA in MHUVECs and increased MDA in FHUVECs. In conclusion, FHUVECs appear to be more susceptible to IR damage, and the effects of the two antioxidants present some sex differences, suggesting the need to study the influence of sex in radiation mitigators.

Low back pain prevalence and risk factors in Italian adolescent male soccer players: results from an online survey.

BACKGROUND: The purpose of this retrospective survey was to analyze the prevalence of low back pain (LBP) among Italian adolescent soccer players, and to identify potential risk factors. METHODS: Participants were requested to answer an online survey based on the standardized Nordic questionnaires for musculoskeletal symptoms. RESULTS: Data were obtained from 204 male soccer players aged 14-17 years competing at the national and regional level. More than half of the players had experienced LBP in their lives. One-way ANOVA revealed that the players with LBP were taller, heavier and with a higher BMI (all P values<0.00001). When considering the playing position, ANOVA revealed that 14-15 years-old strikers displayed higher LBP scores than all other roles (all P values<0.05). Accordingly, strikers were exposed to a higher risk of LBP than midfielders (RR=1.48; 95% CI: 1.10-2.01; P=0.01) and goalkeepers (RR=1.48; 95% CI: 1.02-2.971; P=0.04), but not defenders (RR=1.23; 95% CI: 0.93-1.63; P=0.15). Within the 14-15 age-class, strikers were, again, those most exposed to LBP risk (all P values<0.05). CONCLUSIONS: Anthropometric and soccer-related features should be monitored to ensure early identification of potential risk factors for LBP. This information should be considered along with the specific playing position as strikers emerged as the roles most exposed to LBP risk.

The Person's Care Requires a Sex and Gender Approach.

There is an urgent need to optimize pharmacology therapy with a consideration of high interindividual variability and economic costs. A sex-gender approach (which considers men, women, and people of diverse gender identities) and the assessment of differences in sex and gender promote global health, avoiding systematic errors that generate results with low validity. Care for people should consider the single individual and his or her past and present life experiences, as well as his or her relationship with care providers. Therefore, intersectoral and interdisciplinary studies are urgently required. It is desirable to create teams made up of men and women to meet the needs of both. Finally, it is also necessary to build an alliance among regulatory and ethic authorities, statistics, informatics, the healthcare system and providers, researchers, the pharmaceutical and diagnostic industries, decision makers, and patients to overcome the gender gap in medicine and to take real care of a person in an appropriate manner.