Search

Background: To date, there is a lack of a structured national plan of sexual education in Italy, with large interregional differences and poor uniformity in the promotion and learning of sexual health., Aim: The aim of this study was to evaluate the level of knowledge on sexuality and reproductive function among adolescents before and after a sexual education program, considering gender differences in the results., Methods: A longitudinal and interventional study was conducted on high school students. Six sessions for each class were carried out by a multidisciplinary team. Anonymous questionnaires were administered to investigate basic knowledge of human sexuality and reproduction before and after intervention., Outcomes: Participants were high school students who completed the questionnaires. Outcomes included pre and posttest answers on the knowledge questionnaire in study population., Results: We obtained data from 842 high school students (mean ± SD age, 16.11 ± 1.74 years). The main informative sources on sexuality were social media in 37.9% of participants; family, school, and scientific material were the main source in 15.1%, 5.2%, and 4.4%, respectively. A total score of 12.6 ± 3.4 (range, 1-20) was obtained on the knowledge questionnaire; specifically, the score was higher in females than males (12.8 ± 3.4 vs 11.9 ± 3.4, P = .0001). In males and females, a statistically significant increase in level of knowledge was found after the multidisciplinary intervention (14.5 ± 3.6, P = .0001)., Clinical Implications: The lack of sexual education programs in schools in Italy compels adolescents to refer to frequently unreliable sources, such as social media and peers, contributing to misinformation and adoption of risky sexual behaviors., Strengths and Limitations: This study is based on a large sample size and highlights the importance of sexual education programs. The main limitations are a greater representation of the female population and the inclusive nature of the school (ie, an artistic school), attracting students who identify with sexual minorities., Conclusions: Adolescents have limited knowledge about sexuality and reproduction, with a notable gender disparity; sexual education programs in schools, providing information from sexuality experts, led to a substantial increase in knowledge and a reduction in the gender gap., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism., Methods: This retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients with available tOCN levels before and 3 months after TRT commencement., Results: The tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3 months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031)., Conclusion: In KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutely reduced tOCN levels in adults., (© 2024. The Author(s).)

Background: Bilateral testicular germ cell tumours (B-GCT) are rare, with an incidence of 2-5%, and can be classified as synchronous (sB-GCT) or metachronous (mB-GCT). Our study aimed to identify clinical, biochemical, and radiological risk factors for mB-GCT in a cohort of patients with GCT at a single tertiary referral centre., Methods: This retrospective case-control study included patients with GCT referred to Policlinico Umberto I-Sapienza University of Rome, from 2005 to 2023. We evaluated clinical history, testicular ultrasound features, hormone levels, semen analysis, histological characteristics, staging, and treatments. mB-GCTs were compared with unilateral GCT patients with a follow-up longer than the median time-to-onset of the second tumour., Results: Of 319 patients, 52 experienced B-GCT, with a median time-to-onset of the second tumour of 62 months (range: 8-229). The mB-GCT group showed higher gonadotropin levels (FSH 13.6mUI/mL vs. 7.4mUI/mL, p < 0.001; LH 6.6mUI/mL vs. 3.9mUI/mL, p = 0.004), lower sperm concentration (27 × 10 6 /ejaculate vs. 78 × 10 6 /ejaculate, p = 0.009), smaller residual testis volume (10.4 mL vs. 16.3 mL, p < 0.001), more inhomogeneous echotexture [57.5% vs. 14%, p < 0.001], and presence of microlithiasis (75% vs. 19.5%, p < 0.001). Kaplan-Meier curves confirmed that ultrasound features of the residual testis increased the cumulative risk of developing a second tumour. Microlithiasis was a strong independent predictor (OR 30.712, 95% CI 3.357-280.942, p = 0.002)., Conclusions: Histological features of the first tumour or its treatment do not influence the onset of a second tumour. However, low residual testis volume, inhomogeneous echotexture, and microlithiasis significantly increase this risk. A comprehensive evaluation of the residual testis at baseline is essential for developing a personalised surveillance programme in GCT survivors, with regular ultrasound follow-up recommended beyond the conventional 5-year limit., (© 2024 The Author(s). Andrology published by John Wiley & Sons Ltd on behalf of American Society of Andrology and European Academy of Andrology.)

Hemochromatosis (HC) is characterized by the progressive accumulation of iron in the body, resulting in organ damage. Endocrine complications are particularly common, especially when the condition manifests in childhood or adolescence, when HC can adversely affect linear growth or pubertal development, with significant repercussions on quality of life even into adulthood. Therefore, a timely and accurate diagnosis of these disorders is mandatory, but sometimes complex for hematologists without endocrinological support. This is a narrative review focused on puberty and growth disorders during infancy and adolescence aiming to offer guidance for diagnosis, treatment, and proper follow-up. Additionally, it aims to highlight gaps in the existing literature and emphasizes the importance of collaboration among specialists, which is essential in the era of precision medicine., (© 2024 Wiley Periodicals LLC.)

Introduction: Hypertension (HTN) represents the primary individual risk factor, contributing significantly to the global burden of cardiovascular diseases (CVD). In our country, epidemiological research has highlighted substantial variations in the prevalence of these risk factors across different populations. However, there is a lack of epidemiological studies assessing exclusive cardiovascular risk factors within vulnerable neighborhoods characterized by extremely limited economic resources, sociocultural challenges, and inadequate healthcare access., Methods: A multicenter cross-sectional observational study was conducted among individuals residing in economically deprived and marginalized communities, including informal settlements and underprivileged neighborhoods. Simple random sampling of households was employed. Blood pressure measurements, anthropometric assessments, and epidemiological, economic, and sociocultural questionnaires were administered. Results encompass prevalence rates, awareness levels, and blood pressure control across diverse regions. Logistic regression was utilized to identify independent variables influencing primary outcomes., Results: A total of 989 participants were analyzed. The overall prevalence of hypertension was 48.2%. About 82% had a body mass index (BMI) >25. Approximately 45.3% had less than 6 years of formal education. Independent association was established between education levels below 6 years and higher hypertension prevalence. Among hypertensive individuals, 44% were unaware of their condition, with only 17.2% achieving control, correlated with having health insurance and a higher educational background. Merely 24% were receiving combined therapy., Conclusion: The prevalence of hypertension within vulnerable neighborhoods is alarmingly high, surpassing rates in other social strata. Knowledge, treatment, and control levels of hypertension are suboptimal, comparable to other populations. Inadequate use of combination therapy was observed. This study underscores the urgent need for targeted interventions addressing cardiovascular risk factors in poor areas to mitigate the burden of CVD., (Copyright © 2024 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Ultrasonography (US) represents the gold standard imaging method for the assessment of testicular lesions (TL). The gray-scale (GSUS) and color-Doppler (CDUS) ultrasound examination allow sonographers to investigate the size, margins, echotexture, and vascular features of TLs with the aim to differentiate benign from malignant lesions. Recently, the use of contrast-enhanced US (CEUS) and sonoelastography (SE) has led to further improvements in the differential diagnosis of TL. Although GSUS and CDUS are often sufficient to suggest the benign or malignant nature of the TL, CEUS can be decisive in the differential diagnosis of unclear findings, while SE can help to strengthen the diagnosis. The contemporary combination of GSUS, CDUS, CEUS, and SE has led to a new diagnostic paradigm named multiparametric US (mp-US), which is able to provide a more detailed characterization of TLs than single techniques alone. This narrative and pictorial review aimed to describe the mp-US appearance of several TLs., Methods: An extensive Medline search was performed to identify studies in the English language focusing on the mp-US evaluation of TLs., Results: A practical mp-US "identity card" and iconographic characterization of several benign and malignant TLs is provided herein., Conclusions: The mp-US characterization of TL reported herein can be useful in daily clinical practice.

Objective: Klinefelter syndrome is the most common chromosomal disorder in males and the most common cause of hypergonadotropic hypogonadism. We describe the natural history of testicular dysfunction in patients with Klinefelter syndrome through the integration of clinical, hormonal, and quantitative ultrasound data in a life-course perspective., Design: Prospective semilongitudinal study., Methods: We included 155 subjects with 47,XXY karyotype (age range: 7 months-55 years) naïve to testosterone replacement therapy. Subjects were divided according to pubertal stage and age group (transition age and adults). Serial clinical, hormonal, and testicular ultrasound (US) assessments were performed., Results: Testicular development progresses until Tanner stage 4, with subsequent regression, whereas Sertoli and germ cell impairment is not hormonally detected before Tanner stages 3-4, as reflected by normal inhibin B values until stage 4 and the fall in the inhibin B/follicle-stimulating hormone ratio thereafter. The testosterone/luteinizing hormone ratio peaks during Tanner stages 2-3 and declines from Tanner stage 4 onward, preceding the development of overt hypogonadism. US echotexture progressively worsens until transition age, reflecting ongoing gonadal compromise, whereas quantitative US echotexture measures and the presence of both hypoechoic lesions and microlithiasis independently and significantly predict a lower circulating testosterone level., Conclusions: The findings from this large prospective study contribute to our understanding of the natural history of testicular dysfunction in Klinefelter syndrome, underlining the importance of quantitative testicular US in infancy and childhood, as well as during pubertal development and transition age, for the optimal care of Klinefelter syndrome patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Neuroendocrine tumors (NETs) early diagnosis is a clinical challenge that require a deep understanding of molecular and genetic features of this heterogeneous group of neoplasms. However, few biomarkers exist to aid diagnosis and to predict prognosis and treatment response. In the oncological field, tumor-educated platelets (TEPs) have been implicated as central players in the systemic and local responses to tumor growth, thereby altering tumor specific RNA profile. Although TEPs have been found to be enriched in RNAs, few studies have investigated the potential of a type of RNA, circular RNAs (circRNA), as platelet-derived biomarkers for cancer. In this proof-of-concept study, we aim to demonstrate whether the circRNAs signature of tumor educated platelets can be used as a liquid biopsy biomarker for the detection of gastroenteropancreatic (GEP)-NETs and the prediction of the early response to treatment., Methods: We performed a 24-months, prospective proof-of-concept study in men and women with histologically proven well-differentiated G1-G2 GEP-NET, aged 18-80 years, naïve to treatment. We performed a RNAseq analysis of circRNAs obtained from TEPs samples of 10 GEP-NETs patients at baseline and after 3 months from therapy (somatostatin analogs or surgery) and from 5 patients affected by non-malignant endocrinological diseases enrolled as a control group., Results: Statistical analysis based on p < 0.05 resulted in the identification of 252 circRNAs differentially expressed between GEP-NET and controls of which 109 were up-regulated and 143 were down-regulated in NET patients. Further analysis based on an FDR value ≤ 0.05 resulted in the selection of 5 circRNAs all highly significant downregulated. The same analysis on GEP-NETs at baseline and after therapy in 5 patients revealed an average of 4983 remarkably differentially expressed circRNAs between follow-up and baseline samples of which 2648 up-regulated and 2334 down-regulated, respectively. Applying p ≤ 0.05 and FDR ≤ 0.05 filters, only 3/5 comparisons gave statistically significant results., Conclusions: Our findings identified for the first time a circRNAs signature from TEPs as potential diagnostic and predictive biomarkers for GEP-NETs., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of tumors. Natural killer (NK) cells can play an important role in cancer immune surveillance. The aim of this prospective observational study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with advanced non-small-cell lung cancer (NSCLC) receiving ICIs in order to identify predictive factors for better survival outcomes., Methods: Forty-seven stage IV NSCLC patients were enrolled. Patients underwent baseline (T 0 ) and longitudinal (T 1 ) evaluations after ICIs. Peripheral immune blood cell counts were analyzed using flow cytometry., Results: Basal levels of CD3 - CD56 + NK cells were higher in patients with controlled disease (DC) compared to progression disease (PD) patients (127 cells/µL vs. 27.8 cells/µL, p < 0.001). Lower NK cell values were independent prognostic factors for shorter overall survival (OS) (HR 0.992; 95% CI 0.987-0.997, p < 0.001) and progression-free survival (PFS) (HR 0.988; 95% CI 0.981-0.994, p < 0.001). During the longitudinal evaluation, CD3 - CD56 + NK cells (138.1 cells/µL vs. 127 cells/µL, p = 0.025) and CD56 bright NK cells (27.4 cells/µL vs. 18.1 cells/µL, p = 0.034) significantly increased in the DC group. Finally, lower values of CD3 - CD56 + NK cells (28.3 cells/µL vs. 114.6 cells/µL, p = 0.004) and CD56 dim NK cells (13.2 cells/µL vs. 89.4 cells/µL, p < 0.001) were found in sarcopenic patients compared to patients without sarcopenia., Conclusions: Peripheral NK cells could represent a non-invasive and useful tool to predict ICI therapy response in NSCLC patients, and the association of low NK cell levels with sarcopenia deserves even more attention in clinical evaluation.

Recombinant follicle-stimulating hormone (FSH) is commonly used for the treatment of female infertility and is increasingly being used in males as well, as recommended by notable guidelines. FSH is composed of an α subunit, shared with other hormones, and a β subunit, which confers specificity of biological action by interacting with its surface receptor (FSHR), predominantly located in granulosa and Sertoli cells. However, FSHRs also exist in extra-gonadal tissues, indicating potential effects beyond male fertility. Emerging evidence suggests that FSH may have extra-gonadal effects, including on bone metabolism, where it appears to stimulate bone resorption by binding to specific receptors on osteoclasts. Additionally, higher FSH levels have been associated with worse metabolic and cardiovascular outcomes, suggesting a possible impact on the cardiovascular system. FSH has also been implicated in immune response modulation, as FSHRs are expressed on immune cells and may influence inflammatory response. Furthermore, there is growing interest in the role of FSH in prostate cancer progression. This paper aims to provide a comprehensive analysis of the literature on the extra-gonadal effects of FSH in men, with a focus on the often-conflicting results reported in this field. Despite the contradictory findings, the potential for future development in this area is substantial, and further research is needed to elucidate the mechanisms underlying these effects and their clinical implications.

Cyclic adenosine monophosphate/Protein kinase A (cAMP/PKA) signaling pathway is the master regulator of endocrine tissue function. The level, compartmentalization and amplitude of cAMP response are finely regulated by phosphodiesterases (PDEs). PDE8 is responsible of cAMP hydrolysis and its expression has been characterized in all steroidogenic cell types in rodents including adrenal and Leydig cells in rodents however scarce data are currently available in humans. Here we demonstrate that human Leydig cells express both PDE8A and PDE8B isoforms. Interestingly, we found that the expression of PDE8B but not of PDE8A is increased in transformed Leydig cells (Leydig cell tumors-LCTs) compared to non-tumoral cells. Immunofluorescence analyses further reveals that PDE8A is also highly expressed in specific spermatogenic stages. While the protein is not detected in spermatogonia it accumulates nearby the forming acrosome, in the trans-Golgi apparatus of spermatocytes and spermatids and it follows the fate of this organelle in the later stages translocating to the caudal part of the cell. Taken together our findings suggest that 1) a specific pool(s) of cAMP is/are regulated by PDE8A during spermiogenesis pointing out a possible new role of this PDE8 isoform in key events governing the differentiation and maturation of human sperm and 2) PDE8B can be involved in Leydig cell transformation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Campolo, Capponi, Tarsitano, Tenuta, Pozza, Gianfrilli, Magliocca, Venneri, Vicini, Lenzi, Isidori and Barbagallo.)

Nitrous oxide (N 2 O) is an important greenhouse gas (GHG) that also contributes to depletion of ozone in the stratosphere. Agricultural soils account for about 60% of anthropogenic N 2 O emissions. Most national GHG reporting to the United Nations Framework Convention on Climate Change assumes nitrogen (N) additions drive emissions during the growing season, but soil freezing and thawing during spring is also an important driver in cold climates. We show that both atmospheric inversions and newly implemented bottom-up modeling approaches exhibit large N 2 O pulses in the northcentral region of the United States during early spring and this increases annual N 2 O emissions from croplands and grasslands reported in the national GHG inventory by 6 to 16%. Considering this, emission accounting in cold climate regions is very likely underestimated in most national reporting frameworks. Current commitments related to the Paris Agreement and COP26 emphasize reductions of carbon compounds. Assuming these targets are met, the importance of accurately accounting and mitigating N 2 O increases once CO 2 and CH 4 are phased out. Hence, the N 2 O emission underestimate introduces additional risks into meeting long-term climate goals.

Transplantation of B cells engineered ex vivo to secrete broadly neutralizing antibodies (bNAbs) has shown efficacy in disease models. However, clinical translation of this approach would require specialized medical centers, technically demanding protocols and major histocompatibility complex compatibility of donor cells and recipients. Here we report in vivo B cell engineering using two adeno-associated viral vectors, with one coding for Staphylococcus aureus Cas9 (saCas9) and the other for 3BNC117, an anti-HIV bNAb. After intravenously injecting the vectors into mice, we observe successful editing of B cells leading to memory retention and bNAb secretion at neutralizing titers of up to 6.8 µg ml -1 . We observed minimal clustered regularly interspaced palindromic repeats (CRISPR)-Cas9 off-target cleavage as detected by unbiased CHANGE-sequencing analysis, whereas on-target cleavage in undesired tissues is reduced by expressing saCas9 from a B cell-specific promoter. In vivo B cell engineering to express therapeutic antibodies is a safe, potent and scalable method, which may be applicable not only to infectious diseases but also in the treatment of noncommunicable conditions, such as cancer and autoimmune disease., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Diabetes mellitus (DM), a chronic metabolic disease characterised by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM have been increasing over the years. The complications of DM represent a serious health problem. The long-term complications include macroangiopathy, microangiopathy and neuropathy as well as sexual dysfunction (SD) in both men and women. Erectile dysfunction (ED) has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5-fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity and increased caloric consumption. Although lifestyle changes may help improve sexual function, specific treatments are often needed. This study aims to review the definition and prevalence of ED in DM, the impact of DM complications and DM treatment on ED and, finally, the current and emerging therapies for ED in patients with DM., (© 2021 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Context: Experimental studies on Klinefelter syndrome (KS) reported increased intratesticular testosterone (T) levels coexisting with reduced circulating levels. Abnormalities in testicular microcirculation have been claimed; however, no studies investigated in vivo testicular blood flow dynamics in humans with KS., Objective: To analyze the testicular microcirculation in KS by contrast-enhanced ultrasonography (CEUS) and correlate vascular parameters with endocrine function., Design and Setting: Prospective study. University setting., Patients: Sixty-eight testicular scans, 34 testes from 19 T-naïve subjects with KS and 34 testes from age-matched eugonadal men (control) who underwent CEUS for incidental nonpalpable testicular lesions., Main Outcomes: CEUS kinetic parameters., Results: CEUS revealed slower testicular perfusion kinetics in subjects with KS than in age-matched controls. Specifically, the wash-in time (P = 0.018), mean transit time (P = 0.035), time to peak (P < 0.001), and wash-out time (P = 0.004) were all prolonged. Faster testicular blood flow was associated with higher total T levels. Principal component analysis and multiple linear regression analyses confirmed the findings and supported a role for reduced venous blood flow as independent predictor of total T levels., Conclusions: Testicular venous blood flow is altered in KS and independently predicts T peripheral release., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Sarcopenia is a condition characterized by loss of skeletal muscle mass associated with worse clinical outcomes in cancer patients. Data on sarcopenia in patients undergoing immune checkpoint inhibitors (ICI) therapy are still limited. The aim of this prospective observational study was to investigate the relationship between sarcopenia, ICI treatment response and immunological profile, in patients with advanced non-small cell lung cancer (NSCLC)., Methods: Forty-seven stage IV NSCLC patient candidates for starting ICI, were enrolled from the Policlinico Umberto I outpatient Oncology. Patients underwent baseline blood test, inflammatory markers, cytokine assessment and body composition with dual-energy X-ray absorptiometry (DXA). Sarcopenia was defined with appendicular skeletal muscle mass over height 2 (ASM/heigh 2 )., Results: Overall, 19/47 patients (40.4%) results were sarcopenic. Sarcopenic patients showed significantly shorter PFS than non-sarcopenic ones (20.3 weeks, 95% CI 7.5-33.1 vs. 61 weeks, 95% CI 22.5-99.4, p = 0.047). Specifically, they had an 8.1 times higher risk of progression disease (PD) than non-sarcopenic patients (OR 8.1, 95%, p = 0.011)., Conclusions: Sarcopenic patients showed worse PFS and had a higher risk of PD compared to non-sarcopenic ones. Therefore, sarcopenia may reflect the increased metabolic activity of more aggressive tumors, which involves systemic inflammation and muscle wasting and could be considered a negative predictive factor for ICI response.

It remains unclear how the source and rate of nitrogen (N) fertilizers affect N 2 O concentration and effluxes along the soil profile under the drip-fertigated agricultural system. A plot-based field study was performed in 2017 and 2018 in a cotton field in arid northwestern China, with an objective to elucidate the impact of the applications of conventional urea (Urea), polymer-coated urea (ESN) and stabilized urea (SuperU) at rates of 120 and 240 kg N ha -1 on concentration and efflux of N 2 O in the soil profile and its relationship with N 2 O surface emissions. The in-situ N 2 O concentrations at soil depths of 5, 15, 30 and 60 cm were measured and used to estimate soil profile N 2 O effluxes. Estimates of surface N 2 O flux using the concentration gradient-based (GM) were compared with those measured using the chamber-based (CM) method. In both years, soil N 2 O concentrations at all depths increased in response to basal N application at planting or in-season fertigation events. However, N rate or source did not affect soil N 2 O concentrations or effluxes at each depth. Surface emissions of N 2 O were mostly associated with that presented in the top layer of 0-15 cm. Surface N 2 O efflux determined by GM was poorly or not associated with those of chamber measurements, which was attributed to the low N 2 O production restricted by soil moisture condition under the drip-fertigated condition. These results highlight the challenge of applying the enhanced efficiency N fertilizer products in the drip-fertigated agricultural system., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Contrast-enhanced ultrasound (CEUS) is a sonographic technique that increases the diagnostic accuracy of ultrasound and color Doppler ultrasound (CDUS) when studying testicular abnormalities. However, its role in clinical practice is still debatable because there are no accepted standards regarding how and when this technique should be used for patients with testicular disease., Objectives: To perform a nonsystematic review of the current literature to highlight the strength and flaws of performing CEUS and to provide a critical overview of current research evidence on this topic., Materials and Methods: A thorough search of published peer-reviewed studies in PubMed was performed using proper keywords., Results: Strong enhancement of neoplastic lesions (both benign and malignant) during CEUS aids in differential diagnosis with non-neoplastic lesions, which usually appears either nonenhanced or enhanced in a manner similar to that of the surrounding parenchyma. CEUS enhancement has a high predictive value in the identification of neoplastic lesions, whereas a similar or complete absence of enhancement may be interpreted as strong evidence of benignity, although there are exceptions. Literature on quantitative analysis is still scarce, though promising, particularly in distinguishing benign from malignant neoplasms. Furthermore, CEUS may be useful in many emergency situations, such as acute scrotum, blunt scrotal trauma, and focal infarction of the testis. Finally, CEUS can help increase the probability of sperm recovery in azoospermic males., Discussion and Conclusion: CEUS is a safe, easy-to-perform, and cost-effective diagnostic tool that can provide a more accurate diagnosis in testicular lesions and acute scrotal disease. However, further studies with larger cohorts are required to refine the differential diagnosis between benign and malignant neoplasms. Finally, these preliminary results can instigate the development of innovative research on pre-testicular sperm extraction to increase the chances of sperm recovery., (© 2021 American Society of Andrology and European Academy of Andrology.)

Drip irrigation is a useful practice to enhance water and fertilizer nitrogen (N) use efficiency. However, the use of drip irrigation to mitigate nitrous oxide (N 2 O) emissions in agricultural systems globally is uncertain. Here, we performed a global meta-analysis of 485 field measurements of N 2 O emissions from 74 peer-reviewed publications prior to March 2021, to quantify the fertilizer-induced N 2 O emission factor (EF) of drip irrigation and examine the influencing factors of climate, crop, soil properties, and source and rate of fertilizer N application. The results showed that drip irrigation reduced (p < 0.05) N 2 O emissions by 32% and 46% compared to furrow and sprinkler irrigation systems, respectively. The overall average EF with drip irrigation was 0.35%, being two-thirds lower than the IPCC Tier I default value of 1% (kg N 2 O-N/kg added fertilizer N). The EF was not significantly affected by climate, crop, soil texture, soil organic carbon content, and pH. The EF was also not significantly (p > 0.05) affected by synthetic N fertilizer source despite a lower numerical value with enhanced efficiency than conventional fertilizers. The EF increased significantly (p < 0.001) with N addition rate in a binomial distribution. Using the IPCC default EF overestimated N 2 O emissions inventories for drip-irrigated cropping systems by 7614 and 13,091 Mg per year for China and the globe, respectively. These results indicate that drip irrigation should be recommended as an essential N 2 O mitigation strategy for irrigated crop production., (© 2021 John Wiley & Sons Ltd.)

Background: The hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-somatotropic (HPS) axes are strongly interconnected. Interactions between these axes are complex and poorly understood. These interactions are characterized by redundancies in reciprocal influences at each level of regulation and the combination of endocrine and paracrine effects that change during development., Objectives: To comprehensively review the crosstalk between the HPG and HPS axes and related pathological and clinical aspects during various life stages of male subjects., Materials and Methods: A thorough search of publications available in PubMed was performed using proper keywords., Results: Molecular studies confirmed the expressions of growth hormone (GH) and insulin-like growth factor-I (IGF-I) receptors on the HPG axis and reproductive organs, indicating a possible interaction between HPS and HPG axes at various levels. Insulin growth factors participate in sexual differentiation during fetal development, indicating that normal HPS axis activity is required for proper testicular development. IGF-I contributes to correct testicular position during minipuberty, determines linear growth during childhood, and promotes puberty onset and pace through gonadotropin-releasing hormone activation. IGF-I levels are high during transition age, even when linear growth is almost complete, suggesting its role in reproductive tract maturation. Patients with GH deficiency (GHD) and insensitivity (GHI) exhibit delayed puberty and impaired genital development; replacement therapy in such patients induces proper pubertal development. In adults, few studies have suggested that lower IGF-I levels are associated with impaired sperm parameters., Discussion and Conclusion: The role of GH-IGF-I in testicular development remains largely unexplored. However, it is important to evaluate gonadic development in children with GHD. Additionally, HPS axis function should be evaluated in children with urogenital malformation or gonadal development alterations. Correct diagnosis and prompt therapeutic intervention are needed for healthy puberty, attainment of complete gonadal development during transition age, and fertility potential in adulthood., (© 2020 American Society of Andrology and European Academy of Andrology.)

Drip irrigation is an effective water-saving strategy for crop production in arid regions. However, limited information is available on how fertilizer nitrogen (N) management affects soil nitrous oxide (N 2 O) emission under drip irrigation. A two-year (2017-2018) field experiment was conducted in arid northwestern China to test management options of fertilizer N to reduce N 2 O emission and improve NUE of cotton (Gossypium hirsutum L.) under drip irrigation. Treatment included a factorial design of rate (120, 240 kg N ha -1 ) and source of N fertilizer (Urea, polymer-coated urea-ESN, stabilized urea with nitrification and urease inhibitors-SuperU), and an unfertilized Control. Urea was split-applied with irrigation water (fertigation) whereas ESN and SuperU were all side-banded at pre-plant. Crop yield and N uptake, soil mineral N concentrations, soil temperature and moisture, and N 2 O fluxes were determined. Across the two growing seasons, a single pre-plant application with ESN or SuperU significantly increased growing season cumulative N 2 O emissions (ƩN 2 O) by 29-47% and applied N-scaled emission factor (EF) by 57-83% compared to urea fertigation, irrespectively of application rate. In contrast, cotton yield, agronomic NUE, apparent N recovery (ANR), and yield-based N 2 O emission intensity (EI) were not affected by N source. Reducing N rate from 240 to 120 kg N ha -1 significantly decreased ƩN 2 O by 35% in 2017 and 36% in 2018 while simultaneously reduced cotton yield in both years. The increased N 2 O emissions with ESN and SuperU were attributed to greater availability of inorganic N resulted from one-time application at pre-plant and higher soil temperature. We concluded that fertigation with urea at the recommended rate is the best option to ensure agronomic productively and agronomic NUE with minimal risk of N 2 O emissions. In contrast, the benefit of enhanced efficiency N fertilizer is limited and recommendation on using of these products is challenging for arid croplands under drip irrigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

HIV broadly neutralizing antibodies (bnAbs) can suppress viremia and protect against HIV infection. However, their elicitation is made difficult by low frequencies of appropriate precursor B cell receptors and the complex maturation pathways required to generate bnAbs from these precursors. Antibody genes can be engineered into B cells for expression as both a functional antigen receptor on cell surfaces and as secreted antibody. Here, we show that HIV bnAb-engineered primary mouse B cells can be adoptively transferred and vaccinated in immunocompetent mice resulting in the expansion of durable bnAb memory and long-lived plasma cells. Somatic hypermutation after immunization indicates that engineered cells have the capacity to respond to an evolving pathogen. These results encourage further exploration of engineered B cell vaccines as a strategy for durable elicitation of HIV bnAbs to protect against infection and as a contributor to a functional HIV cure.

Background: Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH)., Objective: To review the mechanism by which TRT could damage the cardiovascular system., Materials and Methods: Comprehensive literature search of recent clinical and experimental studies., Results: The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via β1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in TNF-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed., Discussion: The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors., Conclusions: Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed., (© 2020 American Society of Andrology and European Academy of Andrology.)

Background: Testicular ultrasound (US) is routinely employed in the evaluation of reproductive and sexual function. However, its use for characteristics other than testicular volume is hampered by a lack of information on the prognostic value of its findings, which to date have only been incorporated in a score proposed by Lenz et al in 1993., Objectives: We sought to explore whether testicular US examination can predict the quality of spermatogenesis and provide information on testicular endocrine function., Materials and Methods: We retrospectively reviewed 6210 testicular US examinations, finally selecting examinations from 2230 unique men. The following variables were considered: bitesticular volume and testicular asymmetry, parenchymal echotexture, echogenicity and presence of microlithiasis, solid lesions and varicocoele. Concurrent fasting hormonal data were available for 1160 men, while 979 had a semen sample available from the same day as the US examination., Results: We derived a new US score, termed TU score, that can predict both impaired spermatogenesis (AUC 0.73, sensitivity 72%, specificity 61%, P < .001) and hypogonadism (AUC 0.71, sensitivity 71%, specificity 53%, P < .001) more accurately than the Lenz's score. In a multivariate analysis, a reduced sperm composite index (defined as total spermatozoa × total motility × normal forms) was independently predicted by bitesticular volume and by inhomogeneous echotexture, while hypogonadism was independently predicted also by reduced echogenicity and presence of microlithiasis., Discussion and Conclusions: We describe the testicular US characteristics that are independently associated with impaired spermatogenesis and hypogonadism and propose the TU score as a simple screening method for use in subjects referred for testicular US., (© 2020 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Background: Benign prostatic hyperplasia (BPH) etiology remains poorly understood, but chronic low-grade inflammation plays a role. Pulsed electromagnetic field therapy (PEMF) (1-50 Hz) is effective in reducing tissue inflammation., Objectives: We designed a pilot study to evaluate the effects of PEMF on prostate volume (PV) in BPH., Materials and Methods: This is a prospective interventional trial on 27 naive patients with BPH and lower urinary tract symptoms (LUTS). At baseline (V 0 ), all patients had blood tests, transrectal ultrasound, and questionnaires (IPSS, IIEF-15) and received a perineal PEMF device (Magcell ® Microcirc, Physiomed Elektromedizin). PEMF was delivered on perineal area 5 minutes twice daily for 28 days, then (V 1 ) all baseline evaluations were repeated. Afterward, nine patients continued therapy for 3 more months (PT group) and 15 discontinued (FU group). A 4-month evaluation (V 2 ) was performed in both groups., Results: A reduction was observed both at V 1 and at V 2 in PV: PV V0 44.5 mL (38.0;61.6) vs PV V1 42.1 mL (33.7;61.5, P = .039) vs PV V2 41.7mL (32.7;62.8, P = .045). IPSS was reduced both at V 1 and at V 2 : IPSS V0 11 (5.7;23.2) vs IPSS V1 10 (6;16, P = .045) vs IPSS V2 9 (6;14, P = .015). Baseline IPSS was related to IPSS reduction both at V 1 (r s  = 0.313;P = .003) and at V 2 (r s  = 0.664;P < .001). PV reduction in patients without metabolic syndrome (ΔPV V1nMetS -4.7 mL, 95%CI -7.3;-2.0) was greater than in affected patients (ΔPV V1MetS 1.7 mL, 95%CI -2.69;6.1)(P = .017, Relative Risk MetS  = 6). No changes were found in gonadal hormones or sexual function., Discussion: PEMF was able to reduce PV after 28 days of therapy. Symptoms improved in a short time, with high compliance and no effects on hormonal and sexual function or any side effects. Patients with moderate-severe LUTS and without MetS seem to benefit more from this treatment., Conclusion: PEMF reduces PV and improves LUTS in a relative short time, in BPH patients. These benefits seem greater in those patients with moderate-severe LUTS but without MetS., (© 2020 The Authors. Andrology published by Wiley Periodicals, Inc. on behalf of American Society of Andrology and European Academy of Andrology.)

It is uncertain whether process-based models are currently capable of simulating the complex soil, plant, climate, manure management interactions that influence soil nitrous oxide (N 2 O) emissions from perennial cropping systems. The objectives of this study were (1) to calibrate and evaluate the DeNitrification DeComposition (DNDC) model using multi-year datasets of measured nitrous oxide (N 2 O) fluxes, soil moisture, soil inorganic nitrogen, biomass and soil temperature from managed grasslands applied with manure slurry in contrasting climates of Canada, and (2) to simulate the impact of different manure management practices on N 2 O emissions including slurry application i) rates (for both single vs. split); and ii) timing (e.g., early vs. late spring). DNDC showed "fair" to "excellent" performance in simulating biomass (4.7% ≤ normalized root mean square error (NRMSE) ≤ 29.8%; -9.5% ≤ normalized average relative error (NARE) ≤ 16.1%) and "good" performance in simulating soil temperature (13.2% ≤ NRMSE ≤ 18.1%; -0.7% ≤ NARE ≤ 10.8%) across all treatments and sites. However, the model only showed "acceptable" performances in estimating soil water and inorganic N contents which was partially attributed to the limitation of a cascade water sub-model and inaccuracies in simulating root development/uptake. Although, the DNDC model only demonstrated "fair" performance in simulating daily N 2 O fluxes, it generally captured the impact of the timing and rate of slurry application and soil texture (loam vs. sandy loam) on total N 2 O emissions. The DNDC model simulated N 2 O emissions from spring better than split manure application (fall and spring) at the Manitoba site partially due to the overestimation of available substrates for microbial denitrification from fall application during the wet spring periods. Although DNDC performed adequately for simulating most of the manure management impacts considered in this study we recommend improvements in the simulation of soil freeze-thaw cycles, manure decomposition dynamics, soil water storage, rainfall canopy interception, and microbial denitrification and nitrification activities in grasslands., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: Programmed death 1 (PD-1) inhibitors are frequently associated with thyroid-related adverse events (TAEs), but many aspects remain unclear. This study aims to evaluate the incidence and characteristics of such events and to find any predictive factor for its development., Methods: We retrospectively analysed data from patients with advanced solid tumours (non-small-cell lung carcinoma, renal cell carcinoma, metastatic melanoma) treated with PD-1 inhibitors (nivolumab, pembrolizumab) in Oncology Unit B, Policlinico Umberto I of Rome, from June 2015 to December 2018. All patients underwent baseline thyroid function evaluations repeated monthly., Results: The cohort consisted of 126 patients (66.7% male, mean age 66.4 ± 9.7 years). One hundred and seven received nivolumab and 19 pembrolizumab. Twenty-three per cent of patients experienced TAEs (mainly CTCAE grade 1), with hypothyroidism in 15.1% (subclinical: 11.9%, overt: 3.2%) and hyperthyroidism in 8.0% (subclinical: 4.8%, overt: 3.2%). Median time to TAE onset was 8.7 ± 6.8 weeks (10.4 ± 7.6 weeks for hypothyroidism, 5.4 ± 3.0 weeks for hyperthyroidism). Most TAEs (89.7%) appeared within the first 3 months, none after 8 months. Most hypothyroid patients (63.2%) had previously been treated with a tyrosine kinase inhibitor (TKI). Logistic regression analysis showed that pretreatment with a TKI was a major predisposing factor for the development of hypothyroidism (OR 9.2, 95% CI: 1.4-59.9, P = .020)., Conclusions: TAEs are common during anti-PD-1 therapy and usually occur within the first 3 months of treatment. This is the first study evaluating the impact of previous oncologic therapies on TAEs, identifying TKI as a major risk factor for the development of hypothyroidism in patients treated with anti-PD-1., (© 2019 John Wiley & Sons Ltd.)

Purpose: Hypothyroidism is a common side effect of Sunitinib (SUN) treatment in metastatic renal cell carcinoma (mRCC) patients. We aimed to evaluate thyroid profile during the alternative 2/1 SUN treatment schedule and to assess the predictive value of hypothyroidism in terms of survival., Methods: We performed a prospective observational study enrolling 42 consecutive mRCC patients starting first-line alternative SUN dosing 2/1 schedule. Thyroid function was assessed at baseline and during the first three SUN cycles (1 cycle = 6 weeks = 2 ON/1 OFF + 2 ON/1 OFF), and then after 6 and 12 months. Thyroid ultrasound was performed at baseline and after 3, 6, and 12 months., Results: Subclinical hypothyroidism developed in 24% of patients during the first cycle; in other 24% in the second cycle and in 14% in the third cycle. The highest TSH values were reached during the second cycle, ON phase (6.58 ± 5.74 μI U/l). We observed a reduction in thyroid size, in echogenicity and in parenchymal perfusion in all patients. Progression-free survival (PFS) tended to be longer in patients with TSH ≥ 5 μI U/ml during the second cycle (p = 0.069). TSH level was an independent risk factor for PFS in men (p = 0.009) but not in women (p = 0.285)., Conclusions: This is the first study investigating functional and morphological effects on thyroid during the alternative 2/1 SUN schedule in mRCC patients. We detected an early onset of subclinical hypothyroidism, observing the association between TSH ≥ 5 μI U/ml and: (i) longer PFS in men; (ii) progressive decrease of thyroid size in absence of significant changes in autoimmune thyroid profile.

Interest in the use of enhanced-efficiency nitrogen (N) fertilizers (EENFs) has increased in recent years due to their potential to increase crop yield and reduce environmental N loss. Drip-fertigation is widely used for crop production in arid regions to improve water and nutrient use efficiency whereas the effectiveness of EENFs with drip irrigation remains unclear. A field experiment was conducted in 2015 and 2016 to examine the effects of EENFs on yield, N use and quality of cotton (Gossypium hirsutum) grown under drip-fertigation in arid NW China. Treatments included an unfertilized control and application of 240 kg N ha -1 by polymer-coated urea (ESN), urea alone, or urea plus urease (NBPT) and nitrification (DCD) inhibitors. ESN was all banded in the plant row at planting, whereas urea was applied with 20% N banded at planting and 80% N by six fertigation events over the growing season. Results showed there was generally no treatment effect on seed and lint yield, N concentration or allocations, N recovery efficiency and fiber quality index of cotton. A lack of treatment effect could be due to N supplied with drip-fertigation better synthesized with crop N needs and the relatively high soil native NO 3 - availability, which hindered the effect of polymer-coated urea and double inhibitors. These results highlight the challenge of the employment of EENFs products for drip-fertigation system in arid area. Further research is required to define the field conditions under which the agronomic efficiency of EENFs products may be achieved in accordance with weather conditions.

Spring-thaw represents a significant source for nitrous oxide (N 2 O) emissions from fertilized croplands in temperate regions. In this study, we present surface N 2 O fluxes, soil-profile N 2 O concentrations at 5, 15, 30 and 60 cm depths along with the abundance of nitrifiers and denitrifiers over the winter and spring-thaw periods in an arid, drip- fertigated cotton field, which had received spring application of 240 kg N ha -1 as urea alone (Urea), polymer-coated urea (ESN), and urea plus urease and nitrification inhibitors. Nitrous oxide emissions from December to April were generally unaffected by fertilizer treatments with a cumulative average of 186 g N ha -1 , accounting for 39% of the annual N 2 O emissions. Emission peaks occurred at spring-thaw and coincided with increasing soil-profile N 2 O concentrations at all depths, suggesting the burst in N 2 O fluxes was due to new N 2 O production, rather than a physical release of N 2 O trapped in the soil profiles over winter. The abundance of nitrifier and denitrifier genes changed over the winter and spring-thaw periods but was not affected by fertilizer treatments from the previous spring, suggesting the abundance of N 2 O-producing microorganism was more controlled by environmental conditions than N sources applied in the previous spring. The daily N 2 O flux rate from December to April was positively correlated with soil temperature, water-filled pore space, and denitrifying enzyme activity, but not with the gene copy number of AOA, AOB, narG, nirS, nirK and nosZ, indicating that variation in the abundance of these genes was not contributing to the N 2 O emissions. These results suggest that N 2 O emissions in spring-thaw are substantial for drip-fertigated croplands in the arid regions and should be considered in the annual budgets. The environmental factors such as soil temperature and moisture are likely more important than the copy-numbers of N 2 O-producing functional genes in driving the variability in spring-thaw emissions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Application of inorganic nitrogen (N) fertilizer and manure can increase nitrous oxide (N 2 O) emissions. We tested the hypothesis that increased N 2 O flux from soils amended with manure reflects a change in bacterial community structure and, specifically, an increase in the number of denitrifiers. To test this hypothesis, a field experiment was conducted in a drip-irrigated cotton field in an arid region of northwestern China. Treatments included plots that were not amended (Control), and plots amended with urea (Urea), animal manure (Manure) and a 50/50 mix of urea and manure (U+M). Manure was broadcast-incorporated into the soil before seeding while urea was split-applied with drip irrigation (fertigation) over the growing season. The addition treatments did not, as assessed by nextgen sequencing of PCR-amplicons generated from rRNA genes in soil, affect the alpha diversity of bacterial communities but did change the beta diversity. Compared to the Control, the addition of manure (U+M and Manure) significantly increased the abundance of genes associated with nitrate reduction ( narG ) and denitrfication ( nirK and nosZ ). Manure addition (U+M and Manure) did not affect the nitrifying enzyme activity (NEA) of soil but resulted in 39-59 times greater denitrifying enzyme activity (DEA). In contrast, urea application had no impact on the abundances of nitrifier and denitrifier genes, DEA and NEA; likely due to a limitation of C availability. DEA was highly correlated ( r = 0.70-0.84, P < 0.01) with the abundance of genes narG , nirK and nosZ . An increase in the abundance of these functional genes was further correlated with soil NO 3 - , dissolved organic carbon, total C, and total N concentrations, and soil C:N ratio. These results demonstrated a positive relationship between the abundances of denitrifying functional genes ( narG , nirK and nosZ ) and denitrification potential, suggesting that manure application increased N 2 O emission by increasing denitrification and the population of bacteria that mediated that process., Competing Interests: The authors declare that they have no competing interests., (© 2019 Yin et al.)

Study Question: When should 'not so rare' Leydig cell tumors (LCTs) of the testis be suspected, diagnosed, and treated?, Summary Answer: LCTs are more frequent than generally believed, are associated with male infertility, cryptorchidism and gynecomastia, and should be treated conservatively (in compliant patients) with active surveillance, which appears to be a safe alternative to surgical enucleation., What Is Known Already: Increasing referrals for testicular imaging have led to an increase in findings of LCTs. The features and natural history of these tumors remain largely unknown, as the available studies are small and heterogeneous. LCTs were previously treated aggressively and follow-up data are lacking., Study Design, Size, Duration: A case-cohort study of consecutive patients diagnosed with LCTs over a 10-year period was prospectively enrolled from 2009 to 2018 and compared to matched cohorts of patients with seminomas or no testicular lesions screened in the same timeframe., Participants/materials, Setting, Methods: Of the 9949 inpatients and outpatients referred for scrotal ultrasound, a total of 83 men with LCTs were included. Enrolled subjects underwent medical history and clinical examination and were asked to undergo routine blood tests, hormone investigations (FSH, LH, total testosterone, estradiol, inhibin B, sex hormone-binding globulin (SHBG), prolactin), and semen analysis. Patients who consented also underwent contrast-enhanced ultrasound, elastography, gadolinium-enhanced scrotal magnetic resonance imaging, and hCG stimulation test (5000 IU i.m.) with serum total testosterone and estradiol measured at 0, 24, 48, and 72 hours., Main Results and the Role of Chance: In total, 83 patients diagnosed with LCTs were compared against 90 patients diagnosed with seminoma and 2683 patients without testicular lesions (NoL). LCTs were diagnosed by enucleation (48.2%), orchiectomy (13.3%), or clinical surveillance (38.5%). Testicular volume, sperm concentration, and morphology were lower (P = 0.001, P = 0.001, and P < 0.001, respectively) in patients with LCTs than in the NoL group. FSH, LH, and SHBG were higher and the testosterone/LH ratio was lower in LCTs than in the NoL group (P < 0.001). The LCT group showed higher SHBG (P = 0.018), lower sperm concentration (P = 0.029), and lower motility (P = 0.049) than the seminoma group. Risk factors for LCTs were cryptorchidism (χ2 = 28.27, P < 0.001), gynecomastia (χ2 = 54.22, P < 0.001), and low testicular volume (χ2 = 11.13, P = 0.001). Five cases were recurrences or bilateral lesions; none developed metastases during follow-up (median, 66 months)., Limitations, Reasons for Caution: This study has some limitations. First, hCG and second-line diagnostic investigations were not available for all tumor patients. Second, ours is a referral center for infertility, thus a selection bias may have altered the baseline features of the LCT population. However, given that the comparison cohorts were also from the same center and had been managed with a similar protocol, we do not expect a significant effect., Wider Implications of the Findings: LCTs are strongly associated with male infertility, cryptorchidism, and gynecomastia, supporting the hypothesis that testicular dysgenesis syndrome plays a role in their development. Patients with LCTs are at a greater risk of endocrine and spermatogenesis abnormalities even when the tumor is resected, and thus require long-term follow-up and prompt efforts to preserve fertility after diagnosis.LCTs have a good oncological prognosis when recognized early, as tissue-sparing enucleation is curative and should replace orchiectomy. Conservative surgery and, in compliant patients, active surveillance through clinical and radiological follow-up are safe options, but require monitoring of testicular failure and recurrence., Study Funding/competing Interest(s): The project was funded by the Ministry of University and Research Grant MIUR 2015ZTT5KB. There are no conflicts of interest., Trial Registration Number: ALCeP trial (ClinicalTrials.gov Identifier: NCT01206270)., (© The Author(s) 2019. Published by Oxford University Press.)

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.

Ditylenchus weischeri that parasitizes the weed Cirsium arvense (L.) Scop., 1772, (creeping thistle) was described in 2011 from Russia based on their morphology, ITS-RFLP analysis, and Hsp 90 gene sequence of a few individuals and one field collection of the plant. More recently, we found C. arvense parasitized by D. weischeri in the Prairie Provinces of Canada. Plant host preference for D. weischeri was also distinct from D. dipsaci (Kühn) Filipjev, 1936. In the current study, a comprehensive molecular analysis of many D. weischeri specimens from Canada is presented. Individuals from 41 C. arvense or yellow pea grain samples with seeds of C. arvense from the Prairie Provinces were sequenced for the internal transcribed spacer (ITS rDNA), large subunit (LSU) D2D3 28S rDNA, partial segment of small subunit (SSU) 18S rDNA, and the heat shock protein Hsp 90 gene. The analysis also included D. weischeri individuals from C. arvense from Russia and garlic with D. dipsaci from the Provinces of Ontario and Quebec in Canada. Available sequence data of Ditylenchus species retrieved from GenBank were used to phylogenetically position this species within the genus Ditylenchus . In all studied genes, several single-nucleotide polymorphisms between the Canadian D. weischeri and both Russian haplotype and individuals of D. weischeri from C. arvense from Russia were found. The sequences of ITS rDNA, LSU D2D3 28S rDNA, and Hsp 90 were used to construct separate dendrograms. For each of the three genes examined, D. weischeri was grouped separately from the other Ditylenchus . Ditylenchus samples from C. arvense was positioned to a single clade such as D. weischeri and distinct from D. dipsaci . With past reports of plant host preference and morphology, the results of this study provide further evidence for the fact that D. weischeri is distinct to be separated from D. dipsaci . Furthermore, minor differences in molecular divergence and morphology to the Russian haplotype and limited symptoms of disease on C. arvense in Prairie Canada suggest the Canadian and Russian populations of D. weischeri may be diverging., (© The Society of Nematologists.)

Fabry disease (FD) [OMIM 301500] is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme alpha-galactosidase A, resulting in progressive multisystem accumulation of globotriaosylceramide (Gb3). Although the introduction of Enzyme Replacement Therapy (ERT) resulted in a variety of clinical benefits, life-long intravenous (IV) treatment with ERT with an every other week schedule, may interfere with daily life activities and impact on QoL. We report here a multicentric, observational, longitudinal data analysis on a large cohort of 85 Italian FD patients (45 males, 40 females) from 11 out of 20 Italian regions, who received a cumulative number of 4269 home infusions of agalsidase alfa. For the whole cohort, the average duration of home therapy was 1 year and 11 months (range 3 months-4 years and 6 months), and during this period, compliance to treatment (number of infusions performed vs scheduled) reached 100%. The EQ-5 VAS scale was administered to patients to evaluate the self-reported QoL, 58% of patients showing an increase of EQ-5 VAS score at follow up compared to baseline (home treatment start) or remaining stable. A mild increase of average disease severity, measured through Mainz Severity Score Index (MSSI), was found during hospital treatment (p < 0,007), while it remained stable between the first home therapy infusion and last follow up. Interestingly, 4 out of 7 (57%) patients, showing an improvement in FD-related clinical status after starting home therapy, had previously a sub-optimal compliance to treatment during the period of hospital treatment management. Only 4 adverse non serious reactions (0,093%) were reported totally in 2 patients during home treatment. We conclude that home infusions in eligible patients with FD are safe, contribute to improve treatment compliance and therapeutic clinical outcomes, and may have a positive impact on self-perceived QoL.

The ability of the recently described stem nematode of creeping thistle (Cirsium arvense L.), Ditylenchus weischeri, to develop on and parasitize yellow pea (Pisum sativum L.) is uncertain. The current study examined nematode life-stage progression and generation time on yellow pea as affected by temperature with the related pest, D. dipsaci, used as a positive control. Relationships for body length of the two nematode species and life stage were unaffected by rearing on plant hosts compared with carrot disks. Then plant-reared J4 individuals of both nematode species were used to determine the effect of temperature (17, 22, and 27°C) on life-stage progression and minimum generation time with yellow pea. At 17 and 22°C, D. weischeri J4 individuals progressed to only the adult stage whereas, at 27°C, the minimum generation time from J4 to J4 was 30 days or 720 growing degree-days. The minimum generation time for D. dipsaci was 24, 18, and 22 days or 336, 342, and 528 growing degree-days at 17, 22, and 27°C, respectively. The results indicate that development of D. weischeri is temperature dependent and reproduction is unlikely on yellow pea in the Canadian Prairies, where mean daily air temperatures of 27°C are rare and not sustained.

Anaerobic conditions induced by prolonged flooding often lead to an enhanced release of phosphorus (P) to floodwater; however, this effect is not consistent across soils. This study aimed to develop an index to predict P release potential from alkaline soils under simulated flooded conditions. Twelve unamended or manure-amended surface soils from Manitoba were analyzed for basic soil properties, Olsen P (Ols-P), Mehlich-3 extractable total P (M3P), Mehlich-3 extractable molybdate-reactive P (M3P), water extractable P (WEP), soil P fractions, single-point P sorption capacity (P), and Mehlich-3 extractable Ca (M3Ca), and Mg (M3Mg). Degree of P saturation (DPS) was calculated using Ols-P, M3P or M3P as the intensity factor, and an estimated adsorption maximum based on either P or M3Ca + M3Mg as the capacity factor. To develop the model, we used the previously reported floodwater dissolved reactive P (DRP) concentration changes during 8 wk of flooding for the same unamended and manured soils. Relative changes in floodwater DRP concentration (DRP), calculated as the ratio of maximum to initial DRP concentration, ranged from 2 to 15 across ten of the soils, but were ≤1.5 in the two soils with the greatest clay content. Partial least squares analysis indicated that DPS3 calculated using M3P as the intensity factor and (2 × P) + M3P as the capacity factor with clay percentage can effectively predict DRP ( = 0.74). Results suggest that P release from a soil to floodwater may be predicted using simple and easily measurable soil properties measured before flooding, but validation with more soils is needed., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Fall application of anhydrous ammonia in Manitoba is common but its impact on nitrous oxide (NO) emissions is not well known. A 2-yr study compared application before freeze-up in late fall to spring pre-plant application of anhydrous ammonia on nitrous oxide (NO) emissions from a clay soil in the Red River Valley, Manitoba. Spring wheat ( L.) and corn ( L.) were grown on two 4-ha fields in 2011 and 2012, respectively. Field-scale flux of NO was measured using a flux-gradient micrometeorological approach. Late fall treatment did not induce NO emissions soon after application or in winter likely because soil was frozen. Application time did alter the temporal pattern of emissions with late fall and spring pre-plant applications significantly increasing median daily NO flux at spring thaw and early crop growing season, respectively. The majority of emissions occurred in early growing season resulting in cumulative emissions for the crop year being numerically 33% less for late fall than spring pre-plant application. Poor yield in the first year with late fall treatment occurred because of weed and volunteer growth with delayed planting. Results show late fall application of anhydrous ammonia before freeze-up increased NO emissions at thaw and decreased emissions for the early growing season compared to spring pre-plant application. However, improved nitrogen availability of late fall application to crops the following year is required when planting is delayed because of excessive moisture in spring., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

The stem nematode Ditylenchus weischeri was recently reported on creeping thistle (Cirsium arvense) in Canada. Two greenhouse studies examined host suitability of crops commonly grown in the Canadian Prairies for D. weischeri and the closely related parasite of many crops, D. dipsaci. In the first study, common pulse crops (yellow pea, chickpea, common bean, and lentil), spring wheat, canola, creeping thistle, and garlic were evaluated. Plant biomass and reproductive factor (R f = nematode recovered/inoculated) 8 weeks postinoculation were used to determine host suitability. Creeping thistle biomass was reduced by D. weischeri whereas D. dipsaci reduced biomass of four of five pea and two of three bean varieties. Two pea varieties were weak hosts for D. weischeri, with R f slightly >1. D. weischeri aggressively reproduced on creeping thistle (R f = 5.4). D. dipsaci reproduced aggressively on garlic (R f = 6.4; a known host), moderately on pea varieties (R f > 2), and weakly on chickpea and bean (R f > 1). In the second study, using creeping thistle and yellow pea, D. weischeri was recovered from aboveground parts of the plants and seed of the former and D. dipsaci from the later. The results show that D. weischeri parasitizes creeping thistle but not other crops and that D. weischeri host preference is different from that of D. dipsaci.

Anaerobic soil conditions resulting from flooding often enhance release of phosphorus (P) to overlying water. Enhanced P release is well documented for flooded acidic soils; however, there is little information for flooded alkaline soils. We examined the effect of flooding and anaerobic conditions on P mobilization using 12 alkaline soils from Manitoba that were either unamended or amended with solid cattle manure. Pore water and floodwater were analyzed over 8 wk of simulated flooding for dissolved reactive P (DRP), Ca, Mg, Fe, and Mn. As expected, manured soils had significantly greater pore and floodwater DRP concentrations than unamended. Flooding increased pore water DRP concentrations significantly in all soils and treatments except one manured clay in which concentrations increased initially and then decreased. Floodwater DRP concentrations increased significantly by two- to 15-fold in 10 soils regardless of amendment treatment but remained relatively stable in the two soils with greatest clay content. Phosphorus release at the onset of flooding was associated with the release of Ca, Mg, and Mn, suggesting that P release may be controlled by the dissolution of Mg and Ca phosphates and reductive dissolution of Mn phosphates. Thereafter, P release was associated with release of Fe, suggesting the reductive dissolution of Fe phosphates. Differences in pore water and floodwater DRP concentrations among soils and amendment treatments and the high variability in P mobilization from pore water to floodwater among soils indicate the need to further investigate chemical reactions responsible for P release and mobility under anaerobic conditions., (Copyright © by the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, Inc.)

Obesity is associated with blunted growth hormone (GH) secretion. In some individuals, hypothalamic-pituitary (HP) structural lesions may contribute to GH deficiency (GHD). We explored pituitary morphology in obese patients with suspected GHD and its association with cardiovascular risk factors, body composition, and cardiac morphology. One hundred and eighty-four adults obese patients with symptoms and signs of GHD (147 females and 37 males; mean age 46.31 ± 12.11 years), out of 906 consecutive white obese outpatients, were evaluated. The main measures were anthropometric data, blood pressure, lipid profile, glycemic parameters, pituitary hormones, and insulin-like growth factor-1 values, echocardiography, magnetic resonance imaging (MRI) of the HP region, body composition, and growth hormone-releasing hormone plus arginine test. Seventy patients had GHD (GH peak values <4.2 μg/mL). GHD patients showed significantly higher body mass index and fat mass, lower lumbar bone mineral density, increased left ventricular mass index, and epicardial fat thickness. The MRI of the HP region showed empty sella (ES) in 69 and normal pituitary in one of the 70 GHD patients; the 114 patients with normal GH response had ES (n = 62, 54 %), normal pituitary (n = 37, 32 %), microadenomas (n = 10, 8 %), and other pituitary abnormalities (n = 5, 4 %). ES was a significant independent predictor of GH secretory capacity as determined by multiple regression analysis. The close relationship between ES and GH secretory capacity points out to the possibility of the organic nature of GHD in a portion of obese individuals and opens a new scenario with regard to the potential of GH treatment on metabolic consequences of obesity.

The stem nematode, a parasite of the herbaceous perennial weed, Cirsium arvense (L.) Scop. and identified as Ditylenchus dipsaci (Kühn) Filipjev, was reported in the Canadian prairies in 1979. Recently, D. weischeri Chizhov parasitizing Cirsium arvense was described in Russia, and it has been shown that this species is not an agricultural pest. In this study, we examined Ditylenchus species found in field pea (Pisum sativum L.) grain harvest samples in 2009 and 2010 and from C. arvense shoots in pea fields in the Saskatchewan, Alberta, and Manitoba provinces. Samples from 538 fields (mainly yellow pea) were provided by 151 growers throughout the main pea-growing area of the Canadian prairies. Of the samples collected, 2% were positive for Ditylenchus. The population density of the nematode ranged between 4 and 1,500 nematodes kg(-1) pea harvest sample and related to presence of C. arvense seeds. Positive samples occurred in 2009 but not in 2010 and were from throughout the pea-growing area of the Canadian prairies and not related to cropping history. C. arvense collected from yellow pea fields in Saskatchewan and Manitoba, but not Alberta, were infested with Ditylenchus. Morphological and molecular (ITS-PCR-RFLP) traits indicated that this species belongs to D. weischeri. The results indicated the stem nematode found in yellow pea grain is D. weischeri which resided with C. arvense seeds and debris to pea samples. Unlike D. dipsaci, D. weischeri is not a nematode pest of economic importance; therefore, its presence in the pea harvest samples was not a concern.

Soil nematode community response to treatments of three, four-year crop rotations (spring wheat-pea-spring wheat-flax, spring wheat-green manure-spring wheat-flax, and spring wheat-alfalfa-alfalfa-flax) under conventional and organic management, and native tall grass restoration (restored prairie) were assessed in June 2003, and July and August 2004. The research site was the Glenlea Long-term Rotation and Crop Management Study, in the Red River Valley, Manitoba, established in 1992. The nematode community varied more with sample occasion than management and rotation. The restored prairie favored high colonizer-persister (c-p) value omnivores and carnivores, and fungivores but less bacterivores. The restored prairie soil food web was highly structured, mature and low-to-moderately enriched as indicated by structure (SI), maturity (MI) and enrichment (EI) index values, respectively. Higher abundance of fungivores and channel index (CI) values suggested fungal-dominated decomposition. Nematode diversity was low even after more than a decade of restoration. A longer time may be required to attain higher diversity for this restored fragmented prairie site distant from native prairies. No consistent differences were found between organic and conventional management for nematode trophic abundance, with the exception of enrichment opportunists of the c-p 1 group which were favored by conventional management. Although EI was lower and SI was higher for organic than conventional their absolute values suggested decomposition channels to be primarily bacterial, and fewer trophic links with both management scenarios. A high abundance of fungivores in the rotation including the green manure indicates greater fungal decomposition.

The purpose of this review is to highlight key developments in nematode ecology from its beginnings to where it stands today as a discipline within nematology. Emerging areas of research appear to be driven by crop production constraints, environmental health concerns, and advances in technology. In contrast to past ecological studies which mainly focused on management of plant-parasitic nematodes, current studies reflect differential sensitivity of nematode faunae. These differences, identified in both aquatic and terrestrial environments include response to stressors, environmental conditions, and management practices. Methodological advances will continue to influence the role nematodes have in addressing the nature of interactions between organisms, and of organisms with their environments. In particular, the C. elegans genetic model, nematode faunal analysis and nematode metagenetic analysis can be used by ecologists generally and not restricted to nematologists.

Context: Studies have found that patients with acute coronary syndromes (ACS) often do not receive evidence-based therapies in community practice. This is particularly true in low- and middle-income countries., Objective: To evaluate whether a multifaceted quality improvement (QI) intervention can improve the use of evidence-based therapies and reduce the incidence of major cardiovascular events among patients with ACS in a middle-income country., Design, Setting, and Participants: The BRIDGE-ACS (Brazilian Intervention to Increase Evidence Usage in Acute Coronary Syndromes) trial, a cluster-randomized (concealed allocation) trial conducted among 34 clusters (public hospitals) in Brazil and enrolling a total of 1150 patients with ACS from March 15, 2011, through November 2, 2011, with follow-up through January 27, 2012., Intervention: Multifaceted QI intervention including educational materials for clinicians, reminders, algorithms, and case manager training, vs routine practice (control)., Main Outcome Measures: Primary end point was the percentage of eligible patients who received all evidence-based therapies (aspirin, clopidogrel, anticoagulants, and statins) during the first 24 hours in patients without contraindications., Results: Mean age of the patients enrolled was 62 (SD, 13) years; 68.6% were men, and 40% presented with ST-segment elevation myocardial infarction, 35.6% with non-ST-segment elevation myocardial infarction, and 23.6% with unstable angina. The randomized clusters included 79.5% teaching hospitals, all from major urban areas and 41.2% with 24-hour percutaneous coronary intervention capabilities. Among eligible patients (923/1150 [80.3%]), 67.9% in the intervention vs 49.5% in the control group received all eligible acute therapies (population average odds ratio [OR(PA)], 2.64 [95% CI, 1.28-5.45]). Similarly, among eligible patients (801/1150 [69.7%]), those in the intervention group were more likely to receive all eligible acute and discharge medications (50.9% vs 31.9%; OR(PA),, 2.49 [95% CI, 1.08-5.74]). Overall composite adherence scores were higher in the intervention clusters (89% vs 81.4%; mean difference, 8.6% [95% CI, 2.2%-15.0%]). In-hospital cardiovascular event rates were 5.5% in the intervention group vs 7.0% in the control group (OR(PA), 0.72 [95% CI, 0.36-1.43]); 30-day all-cause mortality was 7.0% vs 8.4% (ORPA, 0.79 [95% CI, 0.46-1.34])., Conclusion: Among patients with ACS treated in Brazil, a multifaceted educational intervention resulted in significant improvement in the use of evidence-based therapies., Trial Registration: clinicaltrials.gov Identifier: NCT00958958.

Translating evidence into clinical practice in the management of acute coronary syndromes (ACS) is challenging. Few ACS quality improvement interventions have been rigorously evaluated to determine their impact on patient care and clinical outcomes. We designed a pragmatic, 2-arm, cluster-randomized trial involving 34 clusters (Brazilian public hospitals). Clusters were randomized to receive a multifaceted quality improvement intervention (experimental group) or routine practice (control group). The 6-month educational intervention included reminders, care algorithms, a case manager, and distribution of educational materials to health care providers. The primary end point was a composite of evidence-based post-ACS therapies within 24 hours of admission, with the secondary measure of major cardiovascular clinical events (death, nonfatal myocardial infarction, nonfatal cardiac arrest, and nonfatal stroke). Prescription of evidence-based therapies at hospital discharge were also evaluated as part of the secondary outcomes. All analyses were performed by the intention-to-treat principle and took the cluster design into account using individual-level regression modeling (generalized estimating equations). If proven effective, this multifaceted intervention would have wide use as a means of promoting optimal use of evidence-based interventions for the management of ACS., (Copyright © 2012 Mosby, Inc. All rights reserved.)

The effects of sheep urine and dung patches on methane (CH4) and carbon dioxide (CO2) fluxes were investigated during the summer-autumn in 2010, to evaluate their contribution to climate change in a desert grassland in Inner Mongolia, China. Results indicate that the cumulative CH4 emissions for dung patches, urine patches and control plots were - -0.076, -0.084, and -0.114 g/m(2) and these were net CH4 sinks during the measured period. The level of CH4 intake from urine and dung plots decreased 25.7%, and 33.3%, respectively, compared with a control plot. CO2 fluxes differed (p<0.01) in urine plots, with an average of 569.20 mg/m(2)/h compared with control plots (357.62 mg/m(2)/h) across all sampling days. Dung patches have cumulative CO2 emissions that were 15.9% higher compared with the control during the 55-d period. Overall, sheep excrement weakened CH4 intake and increased CO2 emissions.

Background: Obstructive sleep apnea (OSA) and metabolic syndrome, both closely related to obesity, often coexist in affected individuals; however, body mass index is not an accurate indicator of body fat and thus is not a good predictor of OSA and other comorbidities. The aim of this study was to investigate whether the occurrence of OSA could be associated with an altered body fat distribution and a more evident cardio metabolic risk independently from obesity and metabolic syndrome., Methods and Results: 171 consecutive patients (58 men and 113 women) were included in the study and underwent overnight polysomnography. Anthropometric data, blood pressure, lipid profile, glycaemic parameters were recorded. Body composition by DXA, two-dimensional echocardiography and carotid intima/media thickness measurement were performed. 67 patients (39.2%) had no OSA and 104 (60.8%) had OSA. The percentage of patients with metabolic syndrome was significantly higher among OSA patients (65.4%) that were older, heavier and showed a bigger and fatter heart compared to the control group. Upper body fat deposition index , the ratio between upper body fat (head, arms and trunk fat in kilograms) and lower body fat (legs fat in kilograms), was significantly increased in the OSA patients and significantly related to epicardial fat thickness. In patients with metabolic syndrome, multivariate regression analyses showed that upper body fat deposition index and epicardial fat showed the best association with OSA., Conclusion: The occurrence of OSA in obese people is more closely related to cardiac adiposity and to abnormal fat distribution rather than to the absolute amount of adipose tissue. In patients with metabolic syndrome the severity of OSA is associated with increase in left ventricular mass and carotid intima/media thickness.