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Background/Aim: Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. Patients and Methods: We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy – General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. Results: Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. Conclusion: An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.

High prevalences of HIV and other sexually transmitted infections (STIs) have been reported in the current global monkeypox outbreak, which has affected primarily gay, bisexual, and other men who have sex with men (MSM) (1-5). In previous monkeypox outbreaks in Nigeria, concurrent HIV infection was associated with poor monkeypox clinical outcomes (6,7). Monkeypox, HIV, and STI surveillance data from eight U.S. jurisdictions* were matched and analyzed to examine HIV and STI diagnoses among persons with monkeypox and assess differences in monkeypox clinical features according to HIV infection status. Among 1,969 persons with monkeypox during May 17-July 22, 2022, HIV prevalence was 38%, and 41% had received a diagnosis of one or more other reportable STIs in the preceding year. Among persons with monkeypox and diagnosed HIV infection, 94% had received HIV care in the preceding year, and 82% had an HIV viral load of200 copies/mL, indicating HIV viral suppression. Compared with persons without HIV infection, a higher proportion of persons with HIV infection were hospitalized (8% versus 3%). Persons with HIV infection or STIs are disproportionately represented among persons with monkeypox. It is important that public health officials leverage systems for delivering HIV and STI care and prevention to reduce monkeypox incidence in this population. Consideration should be given to prioritizing persons with HIV infection and STIs for vaccination against monkeypox. HIV and STI screening and other recommended preventive care should be routinely offered to persons evaluated for monkeypox, with linkage to HIV care or HIV preexposure prophylaxis (PrEP) as appropriate.

The e-Archeo project, commissioned from ALES S.p.A.by the Ministry of Culture (MIC), aims to valorise the multimedia experience of eight Italian archaeological sites. This paper discusses the University of Verona’s contribution to this project, which focuses on the virtual reconstruction of two Roman villas located in Sirmione and Desenzano (Lombardy). This paper outlines the 3D survey methodologies and scientific back-end approach using Extended Matrix. The architectural and decorative reconstruction process for each site is elucidated, providing a comprehensive understanding of the process followed. Furthermore, the University developed a narrative to accompany virtual visits. One of the main project outputs was e-Archeo 3d, a virtual reality web app that allows remote and on-site use.

Klinefelter syndrome (KS) frequently causes skeletal fragility characterized by profound alterations in bone microstructure with increased risk of fractures. Increased body fat mass associated with decreased body lean mass are frequent features of KS with possible detrimental effects on skeletal health. In this cross-sectional study, we evaluated the associations between body composition parameters, vertebral fractures (VFs) and trabecular bone score (TBS) in adult subjects with KS.Seventy-one adult males (median age 41 years, range 18-64) with 47, XXY KS were consecutively enrolled by two Endocrinology and Andrology Units (IRCCS Humanitas Research Hospital in Milan and ASST Spedali Civili in Brescia). Dual-energy X-ray absorptiometry (DXA) was performed to assess bone mineral density (BMD) at lumbar spine, femoral neck and total hip, TBS and body composition. Prevalence of VFs was assessed by quantitative morphometry on lateral spine X-rays.VFs were detected in 14 patients (19.7%), without significant association with low BMD (p = 0.912). In univariate logistic regression analysis, VFs were significantly associated with truncal/leg fat ratio (OR 2.32 per tertile; 95% CI 1.05-5.15; p = 0.038), whereas impaired TBS (detected in 23.4% of subjects) was associated with older age at study entry (p = 0.001) and at diagnosis of disease (p = 0.015), body mass index (BMI; p = 0.001), waist circumference (p = 0.007), fat mass index (FMI; p 0.001), FMI/lean mass index (LMI) ratio (p = 0.001). Prevalence of VFs was not significantly different between subjects with impaired TBS as compared to those with normal TBS (26.7 vs. 18.4%; p = 0.485). Skeletal end-points were not significantly associated with duration of testosterone replacement therapy and serum testosterone and 25hydroxyvitamin D values.Body composition might influence bone quality and risk of VFs in subjects with KS.

Purpose: The aim of this study was to investigate the relationship between youth road cycling success and becoming a professional cyclist. Specifically, the authors sought to analyze (1) the differences in the success scores in youth categories between future professional (PRO) and future nonprofessional (NON-PRO) cyclists, (2) whether relative age effect influences youth road cycling career pathways, and (3) whether youth competition success could predict a future career as a professional cyclist. Methods: The number of points gathered in the annual national ranking of 1345 Italian cyclists in the U17, U19, and U23 categories were retrospectively analyzed. Participants were divided into 2 groups: PRO (n = 43) and future NON-PRO (n = 1302), depending on whether they reached the professional level. Results: PRO outperformed NON-PRO in all the youth categories considered (ie, U17, U19, and U23). Older cyclists within the same annual age group were not overrepresented in PRO and do not have an advantage over younger cyclists within all the competition years. The number of points gathered in youth competitions provides an indication of probability of becoming professional cyclists from U17 onward with the predictive value increasing with age category. Conclusions: Handling the transition to a new age group well (especially the U19–U23 transition), and therefore having success competing against older and more experienced cyclists, is an important factor for talent identification in youth cycling.

To investigate whether routine assessment of free testosterone improves the diagnostic accuracy of functional hypogonadism.Total and free testosterone (calculated on SHBG levels) were determined in 188 patients with sexual symptoms and 184 with infertility.Hypogonadism (calculated free testosterone63 pg/ml) was found in 47/188 (25.0%) patients with sexual symptoms and in 21/184 (11.4%) with infertility. Total testosterone determination misdiagnosed hypogonadism in 8.4% (12/143) of men with sexual symptoms and in 2% (3/152) with infertility. In subjects with borderline total testosterone, only 24.7% (19/77) had hypogonadism confirmed by free testosterone levels. Free testosterone levels significantly correlated with age, haematocrit, gonadotropins, gynecomastia, BMI, and number of co-morbidities, whereas total testosterone associated only with the latter two. Furthermore, age, haematocrit, BMI, and the presence of erectile dysfunction and of low libido were significantly different between men with normal and low free testosterone, whereas only BMI and low libido were significantly different between patients with normal and low total testosterone.Routine assessment of free testosterone allows a more accurate diagnosis of functional hypogonadism, especially in men with sexual symptoms. Free testosterone levels associate with clinical and biochemical parameters of androgen deficiency better than total testosterone levels.

ObjectiveHypogonadism is common in male patients with adrenocortical carcinoma (ACC) who are under treatment with mitotane, but the phenomenon is underestimated, and its prevalence has been poorly studied. This single-center retrospective longitudinal study was undertaken to assess the frequency of testosterone deficiency before and after mitotane therapy, the possible mechanism involved, and the relationship between hypogonadism with serum mitotane levels and prognosis.Research design and methodsConsecutive male ACC patients followed at the Medical Oncology of Spedali Civili Hospital in Brescia underwent hormonal assessment to detect testosterone deficiency at baseline and during mitotane therapy.ResultsA total of 24 patients entered the study. Of these patients, 10 (41.7%) already had testosterone deficiency at baseline. During follow-up, total testosterone (TT) showed a biphasic evolution over time with an increase in the first 6 months followed by a subsequent progressive decrease until 36 months. Sex hormone binding globulin (SHBG) progressively increased, and calculated free testosterone (cFT) progressively decreased. Based on cFT evaluation, the proportion of hypogonadic patients progressively increased with a cumulative prevalence of 87.5% over the study course. A negative correlation was observed between serum mitotane levels >14 mg/L and TT and cFT.ConclusionTestosterone deficiency is common in men with ACC prior to mitotane treatment. In addition, this therapy exposes these patients to further elevated risk of hypogonadism that should be promptly detected and counteracted, since it might have a negative impact on quality of life.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

PurposeTo describe the current knowledge on thyroid hormonal profile in patients on liquid L-T4 therapy and drugs known to interfere with L-T4 absorption.MethodsA PubMed/MEDLINE, Web of Science, and Scopus research was performed. Case reports, case series, original studies and reviews written in English and published online up to 31 August 2022 were selected and reviewed. The final reference list was defined based on the relevance of each paper to the scope of this review.ResultsThe available data showed that novel levothyroxine formulations circumvent gastric pH impairment due to multiple interfering drugs such as proton pump inhibitors, calcium or iron supplements, sevelamer, aluminum/magnesium hydroxide and sodium alginate.ConclusionNew formulations can be taken simultaneously with drugs interfering with L-T4 absorption, in particular liquid formulations. Softgel capsules need more studies to support these data.

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Often in a virtual reconstruction process, the efforts are mainly addressed to obtain an excellent and photorealistic outcome, not taking care of the risk of dramatically losing all the intermediate data processed and the knowledge of the process itself, which we want to make consistent with the Findable, Accessible, Interoperable, and Re-usable (FAIR) principles1. Thus, we need to consider and overcome some general issues inherent in the processes of the virtual reconstruction of a cultural object. For example, raw data collected during the survey campaign are often stored on various media without creating a proper data structure to preserve their logic and semantic meaning over time. Furthermore, the entire reasoning process is often described in a single scientific publication, which, although of value, describes the decisions taken in a narrative and non-specific way. Recently, these ambitious challenges have been addressed within the Social Sciences & Humanities Open Cloud (SSHOC) project2 as a dedicated case study of the Roman Catania theatre, for which we made a new virtual reconstruction. Part of the data collected comes from earlier projects which provided a hypothetical reconstruction of the Roman theatre.

Introduction In humans, heterozygous mutations of hepatocyte nuclear factor 1beta (HNF1B) are responsible for a dominant inherited disease with both renal and extrarenal phenotypes. HNF1B nephropathy is the umbrella term that includes the various kidney phenotypes of the disease, ranging from congenital anomalies of the kidney and urinary tract (CAKUT), to tubular transport abnormalities, to chronic tubulointerstitial and cystic renal disease. Methods We describe 7 families containing 13 patients with ascertained HNF1B nephropathy. All patients underwent genetic testing and clinical, laboratory, and instrumental assessment, including renal imaging and evaluation of extrarenal HNF1B manifestations. Results Significant inter- and intrafamilial variability of HNF1B nephropathy has been observed. In our cohort, HNF1B pathogenic variants presented with renal cysts and diabetes syndrome (RCAD); renal cystic phenotype mimicking autosomal dominant polycystic kidney disease (ADPKD); autosomal dominant tubulointerstitial kidney disease (ADTKD) with or without hyperuricemia and gout; CAKUT; and nephrogenic diabetes insipidus (NDI). Of note, for the first time, we describe the occurrence of medullary sponge kidney (MSK) in a family harboring the HNF1B whole-gene deletion at chromosome 17q12. Genotype characterization led to the identification of an additional 6 novel HNF1B pathogenic variants, 3 frameshift, 2 missense, and 1 nonsense. Conclusion HNF1B nephropathy may present with a highly variable renal phenotype in adult patients. We expand the HNF1B renal clinical picture to include MSK as a potential new finding. Finally, we expand the allelic repertoire of the disease by adding novel HNF1B pathogenic variants., Graphical abstract

Male hypogonadism is defined as low circulating testosterone level associated with signs and symptoms of testosterone deficiency. Although the bidirectional link between hypogonadism and cardiovascular disease has been clarified, the association between testosterone and chronic heart failure (HF) is more controversial. Herein, we critically review published studies relating to testosterone, hypogonadism, and HF and provide practical clinical information on proper diagnosis and treatment of male hypogonadism in patients with HF. In general, published studies are extremely heterogeneous, frequently have not adhered to hypogonadism guidelines, and suffer from many intrinsic methodological inaccuracies; therefore, data provide only low-quality evidence. Nevertheless, by selecting the few methodologically robust studies, we show the prevalence of testosterone deficiency (30%–50%) and symptomatic hypogonadism (15%) in men with HF is significant. Low testosterone correlates with HF severity, New York Heart Association class, exercise functional capacity, and a worse clinical prognosis and mortality. Interventional studies on testosterone treatment in men with HF are inconclusive but do suggest beneficial effects on exercise capacity, New York Heart Association class, metabolic health, and cardiac prognosis. We suggest that clinicians should measure testosterone levels in men with HF who have symptoms of a testosterone deficiency and conditions that predispose to hypogonadism, such as obesity and diabetes. These patients—if diagnosed as hypogonadal—may benefit from the short- and long-term effects of testosterone replacement therapy, which include improvements in both cardiac prognosis and systemic outcomes. Further collaborative studies involving both cardiologists and endocrinologists are warranted.

SARS-CoV-2 infection, responsible for the coronavirus disease 2019 (COVID-19), can impair any organ system including endocrine glands. However, hypothalamic–pituitary dysfunctions following SARS-CoV-2 infection remain largely unexplored. We described a case of hypothalamic amenorrhea following SARS-CoV-2 infection in a 36-year-old healthy woman. The diagnostic workup excluded all the causes of secondary amenorrhea, in agreement to the current guidelines, whereas the gonadotropin increase in response to GnRH analogue tests was suggestive for hypothalamic impairment. Therefore, since our patient did not present any organic cause of hypothalamic–pituitary disorder, we hypothesized that her hypothalamic deficiency may have been a consequence of SARS-CoV-2 infection. This assumption, besides on the temporal consecutio, is strengthened by the fact that SARS-CoV-2 infection can impair the hypothalamic circuits, altering the endocrine axes, given that angiotensin-converting enzyme 2 receptors have also been observed in the hypothalamus. We reviewed the literature regarding hypothalamic–pituitary dysfunction in patients with SARS-CoV-2 infection. No study has previously described female hypogonadotropic hypogonadism with secondary amenorrhea following COVID-19. We suggest clinicians focusing greater attention on this possible endocrine disorder.

Biological markers (biomarkers) play a key role in drug development, regulatory approval and clinical care of patients and are linked to clinical and surrogate outcomes. : Both acromegaly and Growth Hormone Deficiency (GHD) are pathological conditions related to important comorbidities that, in addition to having stringent diagnostic criteria, require valid markers for the definition of treatment, treatment monitoring and follow-up. GH and insulin-like growth factor-I (IGF-I) are the main biomarkers of GH action in children and adults while, in acromegaly, both GH and IGF-I are established biomarkers of disease activity. : However, although GH and IGF-I are widely validated biomarkers of GHD and acromegaly, their role is not completely exhaustive or suitable for clinical classification and follow-up. Therefore, new biological markers for acromegaly and GH replacement therapy are strongly needed. : The aim of this paper is to review and summarize the current state in the field pointing out new potential biomarkers for acromegaly and GH use/abuse.

The outcome of kidney transplant patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. Here we describe the clinical characteristics, disease outcome, and risk factors for acute respiratory distress syndrome (ARDS) and death of a cohort of 53 kidney transplant patients with coronavirus disease 2019 (COVID-19). Eight of 53 have been handled as outpatients because of mild disease, on average with immunosuppression reduction and the addition of hydroxychloroquine and azithromycin; no patients required admission, developed ARDS, or died. Because of severe symptoms, 45/53 required admission: this cohort has been managed with immunosuppression withdrawal, methylprednisolone 16 mg/d, hydroxychloroquine, and antiviral drugs. Dexamethasone and tocilizumab were considered in case of ARDS. About 33% of the patients developed acute kidney injury, 60% ARDS, and 33% died. In this group, thrombocytopenia was associated to ARDS whereas lymphopenia at the baseline, higher D-dimer, and lack of C-reactive protein reduction were associated with risk of death. In the overall population, dyspnea was associated with the risk of ARDS and age older than 60 years and dyspnea were associated with the risk of death with only a trend toward an increased risk of death for patients on tacrolimus. In conclusion, SARS-CoV-2 infection may have a variable outcome in renal transplant patients, with higher risk of ARDS and death in the ones requiring admission.

Male osteoporosis has been neglected for too long time and there is need for a change. This condition is clearly under-estimated, under-diagnosed and under-treated. The diagnosis is often made late in the natural history of the pathology or even after a fracture event. Guidelines on screening politics do not agree whether and when men should be considered, and clinical trials are far less performed in men with respect to women. Actually, most of our knowledge on male osteoporosis, especially regarding treatment, is extrapolate from the female counterpart. Male osteoporosis is frequently secondary to other conditions and often associated with comorbidities. Therefore, identification of specific causes of male osteoporosis is essential to drive a correct and personalized treatment. Moreover, men have more osteoporosis-related complications and higher mortality rate associated with fractures. Furthermore, not only fewer men receive a correct and timely diagnosis, but also fewer men receive adequate treatment, and adherence to therapy is far less in men than in women. Of note, very few studies assessed the effect of antiosteoporotic treatments in men and most of them considered only bone density as primary endpoint. This review focuses on the areas that are still nebulous in male osteoporosis field, from identification of subjects who need to be evaluated for osteoporosis and screening programs dealing with primary prevention to diagnostic procedures for good estimates of bone quantity and quality and precise calculation of fracture risk and personalized treatment that take into account the pathophysiology of osteoporosis.

The SARS-CoV-2 epidemic is pressuring health care systems worldwide. Disease outcomes in certain subgroups of patients are still scarce, and data are needed. Therefore, we describe here the experience of four dialysis centers of the Brescia Renal COVID task force. During March 2020, within an overall population of 643 hemodialysis patients, SARS-CoV-2 RNA positivity was detected in 94 (15%). At disease diagnosis, 37 of the 94 (39%) patients (group 1) were managed on an outpatient basis whereas the remaining 57 (61%) (group 2) required hospitalization. Choices regarding management strategy were made based on disease severity. In group 1, 41% received antivirals and 76% hydroxychloroquine. Eight percent died and 5% developed acute respiratory distress syndrome (ARDS). In group 2, 79% received antivirals and 77% hydroxychloroquine. Forty two percent died and 79% developed ARDS. Overall mortality rate for the entire cohort was 29%. History of ischemic cardiac disease, fever, older age (over age 70) and dyspnea at presentation were associated with the risk of developing ARDS whereas fever, cough and a C-reactive protein higher than 50 mg/l at disease presentation were associated with the risk of death. Thus, in our population of hemodialysis patients with SARS-CoV-2 infection, we documented a wide range of disease severity. The risk of ARDS and death is significant for patients requiring hospital admission at disease diagnosis., Graphical abstract

The outcome of SARS-CoV2 infection in patients who have received a kidney allograft and are being treated with immunosuppression is unclear. We describe 20 kidney transplant recipients (median age 59 years [inter quartile range 51-64 years], median age of transplant 13 years [9-20 years], baseline eGFR 36.5 [23-47.5]) with SARS-CoV2 induced pneumonia. At admission, all had immunosuppression withdrawn and were started on methylprednisolone 16 mg/day, all but one was commenced on antiviral therapy and hydroxychloroquine with doses adjusted for kidney function. At baseline, all patients presented fever but only one complained of difficulty in breathing. Half of patients showed chest radiographic evidence of bilateral infiltrates while the other half showed unilateral changes or no infiltrates. During a median follow-up of seven days, 87% experienced a radiological progression and among those 73% required escalation of oxygen therapy. Six patients developed acute kidney injury with one requiring hemodialysis. Six of 12 patients were treated with tocilizumab, a humanized monoclonal antibody to the IL-6 receptor. Overall, five kidney transplant recipients died after a median period of 15 days [15-19] from symptom onset. These preliminary findings describe a rapid clinical deterioration associated with chest radiographic deterioration and escalating oxygen requirement in renal transplant recipients with SARS-Cov2 pneumonia. Thus, in this limited cohort of long-term kidney transplant patients, SARS-CoV-2 induced pneumonia is characterized by high risk of progression and significant mortality.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

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Purpose To evaluate in men with type 2 diabetes the association of cardiometabolic indices [Visceral Adiposity Index (VAI), Triglyceride Glucose Index (TyG), and lipid accumulation product (LAP)] with total testosterone (TT) levels, and their predictive cut-off values in identifying hypogonadism. Methods 265 consecutive men aged 40–70 years with type 2 diabetes performed an andrological evaluation; metabolic parameters and TT were determined. Receiver operating characteristic (ROC) curves were used to identify cut-off values of cardiometabolic indices in predicting low testosterone (TT Results VAI, TyG, and LAP were negatively associated with TT levels. The prevalence of hypogonadism in men in the fourth quartiles of VAI, TyG, and LAP was ~ 70.0–75.0% compared to ~ 10.0–17.0% in men in the first quartiles (p Conclusion This is the first study evaluating the association of VAI, TyG, and LAP with hypogonadism in men with type 2 diabetes. Alterations in these indices should direct the patients to andrological evaluation.

Data exploration and inspection within semantically enriched multi-dimensional contexts, may benefit of immersive VR presentation when proper 3D user interfaces are adopted. WebXR represents a great opportunity to investigate, experiment, develop and assess advanced multi-dimensional interactive tools for Cultural Heritage, making them accessible through a common web browser. We present and describe the potential of WebXR and a set of building blocks for crafting such immersive data inspection tools, exploiting recent web standards and spatial user interfaces. We describe the current state of the EMviq tool - developed within SSHOC European project - and how it is taking advantage of these components for online immersive sessions. The EMviq tool allows to visually inspect and query an Extended Matrix dataset, allowing to query and explore all the information within the knowledge graph relating to the interpretative datasets - in this paper applied to the case studies of the Roman theatre of Catania and Montebelluna smithy. The main functionalities discussed are spatio-temporal exploration, search and selection of stratigraphic units, and the presentation of metadata and paradata related to the data provenance (both objective and interpretative).

Some evidence suggests that diabetes mellitus type 1 (DM1) could affect male fertility, gonadal axis, semen parameters, and spermatogenesis because of effects of hyperglycemia and insulin deficiency. Anyhow, the exact impact of DM1 on male fertility is unclear.To review the studies evaluating paternity rate, male gonadal axis, and semen parameters in men with DM1.A review of relevant literature from January 1980 to December 2020 was performed. Only studies published in English reporting data on fatherhood (rate of children by natural fertility), hormonal and seminal parameters were included. Out of 14 retrieved articles, the eight studies evaluating semen parameters were meta-analyzed.The rate of children (four studies) was lower than controls among men affected by DM1, especially in men with a longer duration of disease. The data of gonadal hormonal profile in DM1 men (six studies) are very heterogeneous and a neutral effect of DM1 or a condition of subclinical hypogonadism could not be concluded. Meta-analysis showed that men with DM1 (n = 380), compared with controls (n = 434), have significantly lower normal sperm morphology [-0.36% (-0.66; -0.06), p 0.05, six studies] and sperm progressive motility [33.62% (-39.13; -28.11), p 0.001, two studies] and a trend toward a lower seminal volume [-0.51 (-1.03; 0.02), p = 0.06, eight studies], without difference in total sperm count and concentration. Data on scrotal ultrasound and sperm DNA fragmentation are too few. No study evaluated other factors of male infertility, such as transrectal ultrasound, semen infections, sperm auto-antibodies, and retrograde ejaculation.DM1 might impair male fertility and testis functions (endocrine, spermatogenesis), but definition of its actual impact needs further studies.Men with DM1 should be evaluated with a complete hormonal, seminal, and ultrasound workup to better define their fertility potential and need for follow up of testis functions.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. We performed a genome-wide association study involving 10,146 kidney biopsy-diagnosed IgAN cases and 28,751 matched controls across 17 international cohorts. We defined 30 independent genome-wide significant risk loci jointly explaining 11% of disease risk. A total of 16 loci were novel, including TNFSF4, REL, CD28, CXCL8/PF4V1, LY86, LYN, ANXA3, TNFSF8/15, REEP3, ZMIZ1, RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The SNP-based heritability of IgAN was estimated at 23%. We observed a positive genetic correlation between IgAN and total serum IgA levels, allergy, tonsillectomy, and several infections, and a negative correlation with inflammatory bowel disease. All significant non-HLA loci shared with serum IgA levels had a concordant effect on the risk of IgAN. Moreover, IgAN loci were globally enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. The explained heritability was enriched in the regulatory elements of cells from the immune and hematopoietic systems and intestinal mucosa, providing support for the pathogenic role of extra-renal tissues. The polygenic risk of IgAN was associated with early disease onset, increased lifetime risk of kidney failure, as well as hematuria and several other traits in a phenome-wide association study of 590,515 individuals. In the comprehensive functional annotation analysis of candidate causal genes across genome-wide significant loci, we observed the convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Primary Membranous Nephropathy (PMN) is the most frequent cause of nephrotic syndrome in adults. If untreated, PMN can lead to end-stage renal disease; moreover, affected patients are at increased risk of complications typical of nephrotic syndrome such as fluid overload, deep vein thrombosis and infection. The association of PMN with HLA-DQA1 and the identification in around 70% of cases of circulating autoantibodies, mainly directed towards the phospholipase A2 receptor, supports the autoimmune nature of the disease. In patients not achieving spontaneous remission or in the ones with deteriorating kidney function and severe nephrotic syndrome, immunosuppression is required to increase the chances of achieving remission. The aim of this review is to discuss the evidence base for the different immunosuppressive regimens used for PMN in studies published so far; the manuscript also includes a section where the authors propose, based upon current evidence, their recommendations regarding immunosuppression in the disease, while highlighting the still significant knowledge gaps and uncertainties.

Background and Aims Idiopathic Focal Segmental Glomerulosclerosis (FSGS) is a rare glomerulonephritis often complicated by a chronic relapsing course frequently characterized by dependency or resistance to immunosuppressive treatment. Moreover, about half of the patients with active disease would develop end-stage renal disease within 10 years from the diagnosis, highlighting the need of novel therapeutic approaches. Rituximab (RTX), a chimeric monoclonal antibody against CD20, showed promising results in pediatric steroid-dependent/frequently relapsing FSGS and in post-transplantation recurrence. However, evidence about its role in the FSGS of the adult is still lacking with small case series suggesting conflicting results. In this study we assess the efficacy of RTX in the largest cohort of adults with FSGS currently available in literature. Methods Adults with biopsy proven idiopathic FSGS treated with RTX were retrospectively identified among several Italian nephrology units. Response to RTX was evaluated at 3, 6, 12 months and, when available, during the long-term follow-up. A positive response (POR) was defined as: (1) proteinuria 50% compared to baseline, (2) stable renal function (3) decreased or stable dose of glucocorticoids and other immunosuppressants. Severe Adverse Events (SAEs) have been recorded. Results 31 patients have been identified: 18 steroid-dependent, 11 steroid-resistant, and 2 patients with major contraindication to steroid therapy. RTX has been administered at a median of 87 months (IQR 54–96) from the diagnoses using heterogeneous schedules of administration. Overall, the POR rate at 6 months was 52% (steroid-dependent=69%; steroid-resistant=22%). At univariate analyses, POR to RTX at 6 months was associated to the steroid-dependent status (p=0.0347) and a proteinuria at RTX Conclusion RTX may be an option in the FSGS of the adult, especially in the steroid-dependent patients and the ones with less severe nephrotic syndrome. In the responders, a RTX based maintenance therapy may be required.

Background Dialysis and kidney transplant patients with moderate-severe COVID-19 have a high mortality rate, around 30%, that is similar in the two populations, despite differences in their baseline characteristics. In these groups, the immunology of the disease has been poorly explored. Methods Thirty-two patients on dialysis or with kidney transplant and SARS-CoV-2 infection requiring hospitalization (COV group) were included in our study. Lymphocyte subsets, dendritic cell (DC) counts and monocyte activation were studied. SARS-CoV-2 anti-spike/anti-nucleocapsid were monitored, and baseline cytokines and chemokines were measured in 10 patients. Results The COV group, compared to healthy subjects and uninfected dialysis/kidney transplant controls, showed lower numbers of CD4 + and CD8 + T cells, Natural-Killer (NK), B cells, plasmacytoid and myeloid DCs, while the proportion of terminally differentiated B-cells was increased. IL6, IL10, IFN-α and chemokines involved in monocyte and neutrophil recruitment were higher in the COV group, compared to uninfected dialysis/kidney transplant controls. Patients with severe disease had lower CD4 + , CD8 + and B-cell counts and lower monocyte HLA-DR expression. Of note, when comparing dialysis and kidney transplant patients with COVID-19, the latter group presented lower NK and pDC counts and monocyte HLA-DR expression. Up to 60 days after symptom onset, kidney transplant recipients showed lower levels of anti-spike antibodies compared to dialysis patients. Conclusions During SARS-CoV-2 infection, dialysis and kidney transplant patients manifest immunophenotype abnormalities; these are similar in the two groups, however kidney transplant recipients show more profound alterations of the innate immune system and lower anti-spike antibody response. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s40620-021-01214-8.

Purpose The prevalence of low testosterone and symptoms of hypogonadism in HIV-infected men is still debated. We aimed to estimate the prevalence and type of hypogonadism in HIV-infected males complaining about sexual symptoms, and to evaluate the role of calculated free testosterone (cFT) vs total testosterone (TT) for diagnosis. Furthermore, we evaluated relationship between sex hormone-binding globulin (SHBG), gonadal status and clinical and virologic parameters. Methods We retrospectively evaluated 169 HIV-infected men with sexual symptoms, with TT available. Among them, we selected 94 patients with TT, SHBG, cFT, and luteinizing hormone (LH) available, and classified hypogonadism into overt (low TT and/or low cFT) and compensated (high LH, normal TT and cFT). Comparison was performed by non-parametric Kruskal–Wallis test and Spearman’s correlation was calculated to verify the possible associations. Results Overt and compensated hypogonadism were found in 20.2% and 13.8% of patients, respectively. With reliance on TT alone, only 10.6% of patients would have met diagnosis. SHBG values were elevated in one third of patients, and higher in men with compensated hypogonadism. Significant positive correlation was found between SHBG and HIV infection duration, TT and LH. Conclusion Only a complete hormonal profile can properly diagnose and classify hypogonadism in HIV-infected men complaining about sexual symptoms. TT alone reliance may lead to half of diagnoses missing, while lack of gonadotropin prevents the identification of compensated hypogonadism. This largely comes from high SHBG, which seems to play a central role in the pathogenesis of hypogonadism in this population.

Causative mutations in the GANAB gene have been described in only 14 families, 9 diagnosed with late-onset Autosomal Dominant Polycystic Kidney Disease (ADPKD) and 5 with Autosomal Dominant Polycystic Liver Disease (ADPLD). Diagnosis of ADPKD was made in a 45-year old man during screening for hernia repair. CT scan showed enlarged cystic kidneys, nephrolithiasis and normal-sized liver with multiple cysts. Hematuria, hypertension and aortic root dilatation were also documented. Renal function was normal. Molecular analysis of PKD genes disclosed a heterozygous p.R839W GANAB variant inherited from the mother. Both his elderly parents presented normal-sized bilateral cystic kidneys but normal renal function. The GANAB-ADPKD mother had no liver cysts. The father was screened for PKD-related genes and no variant was found. We describe a new family with late-onset ADPKD due to the p.R839W GANAB variant, previously reported in a severe ADPLD patient, requiring liver transplantation. Since ADPKD-GANAB is an ultrarare, recently described disease, reporting further patients may help unraveling gene-related phenotype. In our patients the p.R839W GANAB variant was not related to severe ADPLD, as previously reported, but with mild ADPKD and a plethora of renal and extrarenal manifestations, usually described in PKD1/PKD2 patients. The evidence that the GANAB variant may cause both ADPKD and ADPLD of variable severity supports that renal and hepatic cystogenesis are the result of a common defective polycystin-1 pathway.

Contains fulltext : 245229.pdf (Publisher’s version ) (Open Access) Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of "the new standard."

Purpose Hypogonadism and osteoporosis are frequently reported in HIV-infected men and, besides multifactorial pathogenesis, they might be directly linked because of testicular involvement in bone health. We evaluated the prevalence of osteoporosis and vertebral fractures (VFs) in HIV-infected men, and assessed their relationship with gonadal function. Methods We enrolled 168 HIV-infected men (median age 53). Osteoporosis and osteopenia were defined with T-score ≤ – 2.5SD and T-score between – 1 and – 2.5SD, respectively. VFs were assessed by quantitative morphometric analysis. Total testosterone (TT), calculated free testosterone (cFT), Sex Hormone Binding Globulin (SHBG), Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) were obtained; overt hypogonadism was defined on symptoms and low TT or cFT, and classified into primary and secondary according to gonadotropins; compensated hypogonadism was defined as normal TT and cFT with high LH levels. Results Overall, osteoporosis and osteopenia were found in 87.5% of patients, and VFs were detected in 25% of them; hypogonadism was identified in 26.2% of cases. Osteoporotic patients had higher SHBG vs those with normal bone mineral density (BMD). Fractured patients were more frequently hypogonadal and with higher SHBG. SHBG showed negative correlation with both spine and femoral BMD, and positive correlation with VFs. In multivariate models, FSH showed negative impact only on femoral BMD, whereas older age and higher SHBG predicted VFs. Conclusion We found a high burden of bone disease and hypogonadism in HIV-infected men, and we showed that the impact of gonadal function on bone health is more evident on VFs than on BMD.

Background A cyclic corticosteroid-cyclophosphamide regimen is the first-line therapy for membranous nephropathy. Compared with this regimen, rituximab therapy might have a more favorable safety profile, but a head-to-head comparison is lacking. Methods We randomly assigned 74 adults with membranous nephropathy and proteinuria >3.5 g/d to rituximab (1 g) on days 1 and 15, or a 6-month cyclic regimen with corticosteroids alternated with cyclophosphamide every other month. The primary outcome was complete remission of proteinuria at 12 months. Other outcomes included determination of complete or partial remission at 24 months and occurrence of adverse events. Results At 12 months, six of 37 patients (16%) randomized to rituximab and 12 of 37 patients (32%) randomized to the cyclic regimen experienced complete remission (odds ratio [OR], 0.4; 95% CI, 0.13 to 1.23); 23 of 37 (62%) receiving rituximab and 27 of 37 (73%) receiving the cyclic regimen had complete or partial remission (OR, 0.61; 95% CI, 0.23 to 1.63). At 24 months, the probabilities of complete and of complete or partial remission with rituximab were 0.42 (95% CI, 0.26 to 0.62) and 0.83 (95% CI, 0.65 to 0.95), respectively, and 0.43 (95% CI, 0.28 to 0.61) and 0.82 (95% CI, 0.68 to 0.93), respectively, with the cyclic regimen. Serious adverse events occurred in 19% of patients receiving rituximab and in 14% receiving the cyclic regimen. Conclusions This pilot trial found no signal of more benefit or less harm associated with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in the treatment of membranous nephropathy. A head-to-head, pragmatic comparison of the cyclic regimen versus rituximab may require a global noninferiority trial. Clinical trial registry name and registration number Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO), NCT03018535.

Context Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis. Objective To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis. Design, Setting, and Patients Retrospective study from a prospectively collected database of 129 male subjects >18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy. Main outcome measures We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility. Results Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients ( Conclusion In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.

Cryotherapy has been shown to reduce pro-inflammatory response, relieve pain and enhance muscles’ post-exercise recovery. Cryostimulation could be also proposed as an alternative strategy to trigger cold-induced thermogenesis in overweight/obese subjects. In this study, 16 obese (BMI: 32±4 kg/m2) women (43.4±4.8 years) underwent Partial-Body Cryotherapy (PBC) (-130°C x 150sec) for 5 days (1/day, h 07:00 AM). Resting energy metabolism (REE) was assessed by indirect calorimetry pre- and post-PBC on day 1 and day 5. Subjects were energy-controlled (physical activity and dietary intake). Before 5th-day PBC, REE was increased by 5.5% versus pre-1st-day PBC values (1755±265 vs. 1664±241 kcal/day; p=0.0005). With a similar design, in a larger sample of 80 subjects (F=61; M=19; 34.4±11.1 years; BMI: 24.4±4.8 kg/m2), REE augmented by 1.89% (p=0.02) after PBC of day 1. In a multivariate analysis, multiple regression output a positive relationship between cryostimulated REE and body weight (Spearman r=0.68; p Disclosure R. Codella: None. M. De Nardi: None. S. Delbarba: None. C. Facheris: None. L. Luzi: None.

Background and Aims Discordant affected relative-pairs are seen in ∼10% of families with Autosomal Dominant Polycystic Kidney Disease (ADPKD); Method Among our single-center ADPKD cohort (186 index patients), we selected pedigrees (P) in which marked familial phenotypic variability or severe and early onset disease was investigated by NGS and MLPA analysis of PKD1 and PKD2 genes and NGS analysis of other cystogenes. Segregation analysis by Sanger sequencing of PKD variants was performed in available affected and unaffected family members. Results In P1 and P2, the index cases (IC), presented with very early onset (VEO) disease characterized by prenatal/neonatal enlarged and hyperechogenic kidneys mimicking autosomal recessive polycystic kidney disease (ARPKD). In P1, with neonatal onset, the ADPKD affected father transmitted a PKD1 PT variant p.Gln4231*, whereas the mother, without renal cystic phenotype, transmitted a PKD1 hypomorphic variant p.Asp1332Asn. In P2, the ADPKD-PKD2 mother’s pregnancy was complicated by Potter sequence. Parent’s PKHD1 gene analysis was negative. Two missense NT variants in PKD1/PKD2 genes were detected in the healthy father, respectively p.Gly1944Arg and p.Thr203Ile. Therefore, a complex PKD inheritance was supposed in the fetus. Fetus DNA was not available. In P3 early onset (EO) ADPKD in two monozygous twins was underpinned by a PKD1 NT variant (p.Arg1951Gln) inherited by the ADPKD mild affected father and worsened by a de novo PKD1 truncating variant p.Arg2402*. In P4 and P5 a digenic ADPKD (PKD1 +PKD2 and PKD1 +PKHD1) was diagnosed in severe ADPKD IC. In P4 the two most severely affected siblings carried a PKD2 T variant (p.Ala365fs) and a PKD1 NT variant p-Cys259Tyr. In P5 the IC presented with EO ADPKD, a de novo splicing variant c.2097 + 5_+6insT in PKD1 gene was discovered but the phenotype was probably worsened by the presence of biallelic variant in a second cystogene PKHD1: one paternally inherited: p.Gly1712Arg and one maternally inherited: p.Asp3088Asn . Elderly parents in P6 had mild ADPKD with bilateral few kidney cysts and preserved eGFR, whereas IC showed moderate/severe CKD due to ADPKD biallelic variants. The IC carried a homozygous PKD1 NT variant (p.Arg4154Cys): each mutant allele inherited from the mild ADPKD affected parents. Conclusion Our study illustrates the genetic complexity in an otherwise “simple” Mendelian disorder, providing insights into the genetic basis of severity of ADPKD cases and into ADPKD intrafamilial disease variability. In our pedigree all cases with more severe clinical picture in the family presented at least two PKD variants. In P5 we found for the first time an EO ADPKD due to both PKD1 and PKHD1 variants. PKD1 and PKD2 sequence analysis together with cystic kidney disease gene panel analysis is recommended in those patients with discordant phenotype compared to family members. Molecular study of PKD patients is expected to be a good prognostic tool together with clinical and renal imaging data to better manage disease therapy, follow-up and reproductive issues.

Background and Aims Causative GANAB mutations have been described in only 123 families, 98 diagnosed with late-onset mild ADPKD and 35 with ADPLD. We describe a new family with mild, late-onset ADPKD due to p. R839W GANAB mutation, previously reported in an ADPLD patient requiring liver transplantation. Method Mutation analysis of PKD1, PKD2, GANAB genes was performed by targeted NGS analysis. To analyze GANAB gene we developed a custom panel of 11 kidney cystogenes (GANAB, PKDH1, TSC1, TSC2, UMOD, HNF1B, REN, OFD1, PARN, DNAJB11, SEC61A1) designed using Ion Ampliseq Designer. Sanger sequencing was performed in order to validate all the variants classified as pathogenic, likely pathogenic and VUS. Raw sequence data analysis, including base calling, demultiplexing, alignment to the hg19 human reference genome, was performed using the Torrent Suite Software version 5.5; the average depth of total coverage was set at 500X and for variant calls at minimum of 30X. Deletion and duplication analysis of PKD1 and PKD2 was performed using MLPA P351-C1 and P352-D1 probemixes, MRC-Holland. Results Diagnosis of ADPKD was made in a 45-year old man during pre-surgical screening for umbilical and inguinal hernia repair. The patient's clinical course was characterized by several complications pertaining to the ADPKD spectrum: nephrolithiasis (20 yo); umbilical/bilateral inguinal hernia repair, hypertension and mild aortic root dilation (45 yo) and AKI due to ureteral obstruction (50 yo). Abdomen CT scan showed bilateral renal cysts (TKV 565 cc), nephrolithiasis, normal-sized liver with multiple cysts, and sigmoid colon diverticulosis. Renal function was normal (SCr 0.69 mg/dL, CKD-EPI 115 ml/min). In the index case, NGS and MLPA analysis of PKD1 and PKD2 genes did not detect variants. We then use the abovementioned multigene NGS panel and identified a missense heterozygous c.2515C>T (p.R839W) variant in the GANAB gene. Screening was then extended to family members. No family members displayed renal function impairment. Both the 80 yo mother and the 84 yo father were found to have multiple bilateral kidney cysts (HtTKV of 239 ml and 435 ml, respectively), no liver cysts were found in either of them. Parents segregation analysis identified the GANAB variant p.R839W in the mother and in the maternal aunt. The father tested negative for all the abovementioned cystogenes. Conclusion we confirm that the renal phenotype caused by mutations in GANAB is very different from those due to mutations in PKD1 and PKD2, giving rise to a mild form of renal cystic disease, usually not progressing to ESRD. Despite the mild renal cystic burden, the index case showed a plethora of renal and extrarenal manifestations of ADPKD. The finding that patients with GANAB mutation can present with renal and liver cystic phenotype is intriguing, indicating a commonality between pathogenic background of two different inherited disorders, ADPKD and ADPLD. The missense GANAB mutation identified in our ADPKD family was first described in a pedigree reported by Porath et al. and diagnosed as ADPLD. This suggests that, beyond the effect of the shared mutation on GII subunit α, other modifier loci and environmental factors may influence the course of liver disease development and progression. Our study illustrates the important diagnostic role of a broader genetic testing, able to screen not only for PKD1 and PKD2 variants, but also for pathogenic variants in other cystogenes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease (COVID-19), is a major pandemic challenging health care systems around the world. The optimal management of patients infected with COVID-19 is still unclear, although the consensus is moving toward the need of a biphasic approach. During the first phase of the disease (from onset of the symptoms up to 7–10 days) viral-induced effects are prominent, with the opportunity to institute antiviral therapy. In the second inflammatory phase of the disease, immunosuppressive strategies (for example with glucocorticoids or anticytokine drugs) may be considered. This latter stage is characterized by the development of progressive lung involvement with increasing oxygen requirements and occasionally signs of the hemophagocytic syndrome. The management of the disease in patients with kidney disease is even more challenging, especially in those who are immunosuppressed or with severe comorbidities. Here we present the therapeutic approach used in Brescia (Italy) for managing patients infected with COVID-19 who underwent kidney transplantation and are receiving hemodialysis. Furthermore, we provide some clinical and physiopathological background, as well as preliminary outcome data of our cohort, to better clarify the pathogenesis of the disease and clinical management. Key Words: COVID-19, dialysis, kidneys, management, patients, SARS-CoV-2, transplant