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Embryonic stem cells (ESCs) preserve the unique ability to differentiate into any somatic cell lineage while maintaining their self-renewal potential, relying on a complex interplay of extracellular signals regulating the expression/activity of pluripotency transcription factors and their targets. Leukemia inhibitory factor (LIF)-activated STAT3 drives ESCs' stemness by a number of mechanisms, including the transcriptional induction of pluripotency factors such as Klf4 and the maintenance of a stem-like epigenetic landscape. However, it is unknown if STAT3 directly controls stem-cell specific non-coding RNAs, crucial to balance pluripotency and differentiation. Applying a bioinformatic pipeline, here we identify Lncenc1 in mouse ESCs as an STAT3-dependent long non-coding RNA that supports pluripotency. Lncenc1 acts in the cytoplasm as a positive feedback regulator of the LIF-STAT3 axis by competing for the binding of microRNA-128 to the 3'UTR of the Klf4 core pluripotency factor mRNA, enhancing its expression. Our results unveil a novel non-coding RNA-based mechanism for LIF-STAT3-mediated pluripotency., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Crohn's disease (CD) is characterized by discontinuous inflammation. Failure to identify skipping lesions of the terminal ileum (TI) or transmural changes can lead to incorrect management., Methods: Eligible adult patients with CD undergoing ileo-colonoscopy and computed tomography enterography or magnetic resonance enterography within 6 months. We determined the prevalence of endoscopic skipping (normal ileum on colonoscopy but proximal small bowel inflammation on cross-sectional imaging), skip lesions (discontinuous inflammation along the gastrointestinal tract identified on cross-sectional imaging), structuring, and penetrating complications., Results: Among 202 patients, 45 (22.3%) had endoscopic skipping proximal to TI intubation. Fifty patients (24.5%) had small bowel skip lesions, primarily in the ileum. Strictures were identified in 34 patients (16.8%) through both imaging and ileo-colonoscopy, in 21 patients (10.4%) solely through cross-sectional imaging, and in 3 patients (1.5%) solely through ileo-colonoscopy. Approximately 36.2% of stricturing cases would be missed without cross-sectional imaging. Penetrating complications, including abscesses (2.5%) and various fistula types (4.9%), were detected in 15 (7.4%) patients., Conclusions: Ileo-colonoscopy missed detection of active CD in approximately one-fifth of cases due to more proximal disease location. Stricturing disease might be missed in more than a third of cases if cross-sectional imaging is not performed., (© 2024 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Peroral endoscopic myotomy (POEM) is an established treatment for achalasia, yet there is still a lack of technical standardization. No clear definition of 'long', 'standard', or 'short' POEM exists to date. We conducted a systematic review with meta-analysis to analyze current POEM length standards. We included studies reporting technical details of POEM, in which no definite or comparative myotomy length was intentionally adopted (standard myotomy). The primary outcome was the pooled mean total myotomy length. Sub-group analyses were performed to explore heterogeneity across studies. From the initial 7172 records, 31 studies with 3023 patients were included. Pooled mean of total myotomy length was 10.39 cm (95% CI 10.06-10.71; I2 99.3%). Pooled mean of esophageal and gastric myotomy length, provided by 17 studies, was 7.11 cm (95% CI 6.51-7.71; I2 99.8%) and 2.81 cm (95% CI 2.41-3-22; I2 99.8%), respectively. On subgroup analysis for achalasia subtypes, pooled mean length in non-spastic achalasia (type I and II) was 10.17 cm (95% CI 9.91-10.43; I2 94.2%), while in type III it was 14.02 cm (95% CI 10.59-17.44; I2 98.9%). Pooled mean myotomy length for studies conducted between 2014-2020 was 10.53 cm (95% CI, 10.22-10.84; I2 99.1%) and 9.74 cm (95% CI, 7.95-11.54; I2 99.7%) in 2021-2022. Myotomy length during a 'standard' POEM is 10.4 cm, remaining over 10 cm in non-spastic achalasia. The high heterogeneity across studies confirms that the POEM technique needs further standardization. We found no significant time trend towards adopting short POEM, despite recent evidence supporting its use., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.)

Background: Deterioration of neurocognitive function in adult patients with a primary brain tumor is the most concerning side effect of radiotherapy. This study aimed to develop and evaluate normal-tissue complication probability (NTCP) models using clinical and dose-volume measures for 6-month, 1-year, and 2-year Neurocognitive Decline (ND) postradiotherapy., Methods: A total of 219 patients with a primary brain tumor treated with radical photon and/or proton radiotherapy (RT) between 2019 and 2022 were included. Controlled oral word association test, Hopkins verbal learning test-revised, and trail making test were used to objectively measure ND. A comprehensive set of potential clinical and dose-volume measures on several brain structures were considered for statistical modeling. Clinical, dose-volume and combined models were constructed and internally tested in terms of discrimination (area under the curve, AUC), calibration (mean absolute error, MAE), and net benefit., Results: Fifty percent, 44.5%, and 42.7% of the patients developed ND at 6-month, 1-year, and 2-year time points, respectively. The following predictors were included in the combined model for 6-month ND: age at radiotherapy > 56 years (OR = 5.71), overweight (OR = 0.49), obesity (OR = 0.35), chemotherapy (OR = 2.23), brain V20 Gy ≥ 20% (OR = 3.53), brainstem volume ≥ 26 cc (OR = 0.39), and hypothalamus volume ≥ 0.5 cc (OR = 0.4). Decision curve analysis showed that the combined models had the highest net benefits at 6-month (AUC = 0.79, MAE = 0.021), 1-year (AUC = 0.72, MAE = 0.027), and 2-year (AUC = 0.69, MAE = 0.038) time points., Conclusions: The proposed NTCP models use easy-to-obtain predictors to identify patients at high risk of ND after brain RT. These models can potentially provide a base for RT-related decisions and post-therapy neurocognitive rehabilitation interventions., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Objectives: Cardiovascular involvement in systemic lupus erythematosus (SLE) is frequent but little is known about possible distinctive traits of SLE-related myocarditis (myoSLE) in comparison to patients with SLE (onlySLE) or myocarditis alone (onlyMyo)., Methods: A retrospective analysis was performed comparing patients with myoSLE (n = 25) from three centres with consecutive patients with onlySLE (n = 279) and onlyMyo (n = 88). SLE patients were dichotomised by disease duration ≤1 vs >1 year into recent onlySLE/early myoSLE vs longstanding onlySLE/late myoSLE. Further stratification into disease duration of 1-5, 5-10 and >10 years was also performed. SLE disease activity index 2000 (SLEDAI-2K) was used to estimate disease activity. Myocarditis was diagnosed through biopsy or magnetic resonance., Results: Women were significantly more frequent among myoSLE than among onlyMyo (72% vs 43%; p= 0.013). Compared with onlyMyo, myoSLE patients had a higher frequency of conduction abnormalities (22% vs 5%; p= 0.046) and presented with numerically higher frequencies of left ventricular function compromise (48% vs 30%), along with higher pro-brain natriuretic peptide levels. Inflammation markers were higher in myoSLE compared with onlyMyo and to patients with onlySLE with >10 years of disease duration. SLEDAI-2K was significantly higher in late myoSLE than in longstanding onlySLE. Antiphospholipid syndrome was more frequent in myoSLE than in onlySLE. Multivariate analysis showed an association among myoSLE, anti-beta-2-glycoprotein I antibodies (aB2GPI, p= 0.014) and a higher number of involved British Isles Lupus Assessment Group domains in patient history (p= 0.003)., Conclusion: myoSLE has unique clinical traits compared with other forms of myocarditis and is associated with aB2GPI and a more severe SLE course., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

The current study aimed to investigate determinants of severity in a previously healthy patient who experienced two life-threatening infections, from West Nile Virus and SARS-CoV2. During COVID19 hospitalization he was diagnosed with a thymoma, retrospectively identified as already present at the time of WNV infection. Heterozygosity for p.Pro554Ser in the TLR3 gene, which increases susceptibility to severe COVID-19, and homozygosity for CCR5 c.554_585del, associated to severe WNV infection, were found. Neutralizing anti-IFN-α and anti-IFN-ω auto-antibodies were detected, likely induced by the underlying thymoma and increasing susceptibility to both severe COVID-19 pneumonia and West Nile encephalitis., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Robotic thymectomy has been suggested and considered technically feasible for thymic tumours. However, because of small-sample series and the lack of data on long-term results, controversies still exist on surgical and oncological results with this approach. We performed a large national multicentre study sought to evaluate the early and long-term outcomes after robot-assisted thoracoscopic thymectomy in thymic epithelial tumours., Methods: All patients with thymic epithelial tumours operated through a robotic thoracoscopic approach between 2002 and 2022 from 15 Italian centres were enrolled. Demographic characteristics, clinical, intraoperative, postoperative, pathological and follow-up data were retrospectively collected and reviewed., Results: There were 669 patients (307 men and 362 women), 312 (46.6%) of whom had associated myasthenia gravis. Complete thymectomy was performed in 657 (98%) cases and in 57 (8.5%) patients resection of other structures was necessary, with a R0 resection in all but 9 patients (98.6%). Twenty-three patients (3.4%) needed open conversion, but no perioperative mortality occurred. Fifty-one patients (7.7%) had postoperative complications. The median diameter of tumour resected was 4 cm (interquartile range 3-5.5 cm), and Masaoka stage was stage I in 39.8% of patients, stage II in 56.1%, stage III in 3.5% and stage IV in 0.6%. Thymoma was observed in 90.2% of patients while thymic carcinoma occurred in 2.8% of cases. At the end of the follow-up, only 2 patients died for tumour-related causes. Five- and ten-year recurrence rates were 7.4% and 8.3%, respectively., Conclusions: Through the largest collection of robotic thymectomy for thymic epithelial tumours we demonstrated that robot-enhanced thoracoscopic thymectomy is a technically sound and safe procedure with a low complication rate and optimal oncological outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: The association between cancer and IgG4-related disease (IgG4-RD) is evolving. The primary aim of this study was to investigate the prevalence of malignancies in IgG4-RD. The secondary aim was to describe the epidemiological and clinical characteristics of IgG4-RD patients with a history of cancer., Methods: Two hundred and ten patients with IgG4-RD were included in this retrospective study. IgG4-RD phenotypes, clinical and serological variables were analyzed. The prevalence of cancer in IgG4-RD was compared with that in the Italian population using the registry of the Global Cancer Observatory (GCO) of the World Health Organization. The Standardized Incidence Ratio (SIR) for cancer in IgG4-RD was obtained based on the 5-years Limited Duration Prevalence (2015-2020) of tumors in the Italian population., Results: Thirty-seven/210 patients (18%) developed cancer before or after the diagnosis of IgG4-RD. Solid and hematologic tumors were more frequently observed in pancreato-biliary IgG4-RD. The SIR for malignancy in IgG4-RD patients was 2.54 higher than the general Italian population (p= 0.007). The SIR was 2.78 higher for males (p= 0.005) and 1.15 higher for females (p> 0.05). Thirty-two malignancies were diagnosed before and 16 after IgG4-RD diagnosis. Interval "from IgG4-RD to cancer" was shorter than that "from cancer to IgG4-RD". Most tumors occurring after IgG4-RD developed within 36 months from diagnosis of IgG4-RD., Conclusions: The prevalence of cancer in patients with IgG4-RD is increased compared with the Italian population and mechanistically suggests a possible paraneoplastic association. Close surveillance is warranted for the first 36 months after IgG4-RD diagnosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Standardising health outcome measurements supports delivery of care, enables data-driven learning systems, and secondary data use for research. As part of the Health Outcomes Observatory initiative and building on existing knowledge, a core outcome set (COS) for inflammatory bowel diseases (IBD) was defined through an international modified Delphi method., Methods: Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group. Two consecutive consensus meetings were held to discuss results and formulate recommendations for measurement in clinical practice. Variables scoring 7 or higher by ≥80% of the participants, or based on consensus meeting agreement, were included in the final set., Results: In total, 136 stakeholders (45 IBD patients (advocates), 74 healthcare professionals/researchers, 13 industry representatives and 4 regulators), from 20 different countries participated. The final set includes 18 case-mix variables, 3 biomarkers (haemoglobin to detect anaemia, C-reactive protein and faecal calprotectin to detect inflammation) for completeness and 28 outcomes (including 16 patient-reported outcomes (PROs) and 1 patient-reported experience). The PRO-2 and IBD-Control questionnaires were recommended to collect disease-specific PROs at every contact with an IBD practitioner, and the Subjective Health Experience model questionnaire, PROMIS Global Health and Self-Efficacy short form to collect generic PROs annually., Conclusions: A COS for IBD, including a recommendation for use in clinical practice, was defined. Implementation of this set will start in Vienna, Berlin, Barcelona, Leuven and Rotterdam, empowering patients to better manage their care. Additional centres will follow worldwide., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

IgG4-related disease (IgG4-RD) is an increasingly recognized immune-mediated fibroinflammatory disorder that promptly responds to glucocorticoids but commonly relapses during steroid tapering or after discontinuation. In the last few years, B-cell depletion therapy with rituximab (RTX) proved to be effective in the induction of remission and maintenance treatment of IgG4-RD, providing a new powerful tool in the management of this emerging condition. In this review, we outline the pathogenetic rationale for using B-cell depleting agents in IgG4-RD, we summarize available clinical experience with RTX in this disease, and we describe future possible therapies targeting B-lymphocytes that are now in the pipeline., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage HER2-positive breast cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty acid uptake, a process mediated by the transmembrane transporter CD36, has recently emerged as a potential determinant of resistance to anti-HER2 treatments in preclinical HER2+ BC models., Methods: Here, we investigated the association between baseline intratumor CD36 gene expression and event-free survival in 180 patients enrolled in the phase III trial Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimization (NeoALTTO), which randomly assigned stage II-III HER2+ BC patients to receive neoadjuvant lapatinib, trastuzumab, or lapatinib-trastuzumab in combination with chemotherapy. To this aim, we selected NeoALTTO trial patients for whom pretreatment whole transcriptomic data were available. The main study results were validated in an independent cohort of patients enrolled in the neoadjuvant phase II trial NeoSphere., Results: In 180 NeoALTTO patients, high intratumor CD36 expression was independently associated with worse event-free survival in patients treated with trastuzumab-based therapy (hazard ratio [HR] = 1.72, 95% confidence interval [CI] = 1.20 to 2.46), but not with lapatinib-based (HR = 1.02, 95% CI = 0.68 to 1.53) or trastuzumab-lapatinib-based (HR = 1.08, 95% CI = 0.60 to 1.94) therapy. Among 331 NeoSphere patients evaluated, high CD36 expression was independently associated with worse patient disease-free survival in both the whole study cohort (HR = 1.197, 95% CI = 1.002 to 1.428) and patients receiving trastuzumab-based neoadjuvant therapy (HR = 1.282, 95% CI = 1.049 to 1.568)., Conclusions: High CD36 expression predicts worse clinical outcomes in early-stage HER2+ BC treated with trastuzumab-based neoadjuvant therapy., (© The Author(s) 2022. Published by Oxford University Press.)

Purpose: To assess whether dysglycemia diagnosed during severe acute respiratory syndrome coronavirus 2 pneumonia may become a potential public health problem after resolution of the infection. In an adult cohort with suspected coronavirus disease 2019 (COVID-19) pneumonia, we integrated glucose data upon hospital admission with fasting blood glucose (FBG) in the year prior to COVID-19 and during postdischarge follow-up., Methods: From February 25 to May 15, 2020, 660 adults with suspected COVID-19 pneumonia were admitted to the San Raffaele Hospital (Milan, Italy). Through structured interviews/ medical record reviews, we collected demographics, clinical features, and laboratory tests upon admission and additional data during hospitalization or after discharge and in the previous year. Upon admission, we classified participants according to American Diabetes Association criteria as having (1) preexisting diabetes, (2) newly diagnosed diabetes, (3) hyperglycemia not in the diabetes range, or (4) normoglycemia. FBG prior to admission and during follow-up were classified as normal or impaired fasting glucose and fasting glucose in the diabetes range., Results: In patients with confirmed COVID (n = 589), the proportion with preexisting or newly diagnosed diabetes, hyperglycemia not in the diabetes range and normoglycemia was 19.6%, 6.7%, 43.7%, and 30.0%, respectively. Patients with dysglycemia associated to COVID-19 had increased markers of inflammation and organs' injury and poorer clinical outcome compared to those with normoglycemia. After the infection resolved, the prevalence of dysglycemia reverted to preadmission frequency., Conclusions: COVID-19-associated dysglycemia is unlikely to become a lasting public health problem. Alarmist claims on the diabetes risk after COVID-19 pneumonia should be interpreted with caution., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Study Question: Is late follicular elevated progesterone (LFEP) in the fresh cycle hindering cumulative live birth rates (CLBRs) when a freeze only strategy is applied?, Summary Answer: LFEP in the fresh cycle does not affect the CLBR of the frozen transfers in a freeze only approach, nor the embryo freezing rate., What Is Known Already: Ovarian stimulation promotes the production of progesterone (P) which has been demonstrated to have a deleterious effect on IVF outcomes. While there is robust evidence that this elevation produces impaired endometrial receptivity, the impact on embryo quality remains a matter of debate. In particular, previous studies have shown that LFEP is associated with a hindered CLBR. However, most clinical insight on the effect of progesterone on embryo quality in terms of CLBRs have focused on embryo transfers performed after the fresh transfer, thus excluding the first embryo of the cohort. To be really informative on the possible detrimental effects of LFEP, evidence should be derived from freeze-all cycles where no fresh embryo transfer is performed in the presence of progesterone elevation, and the entire cohort of embryos is cryopreserved., Study Design, Size, Duration: This was a matched case-control, multicentre (three centres), retrospective analysis including all GnRH antagonist ICSI cycles in which a freeze all (FA) policy of embryos on day 3/5/6 of embryonic development was applied between 2012 and 2018. A total of 942 patients (471 cases with elevated P and 471 matched controls with normal P values) were included in the analysis. Each patient was included only once., Participants/materials, Setting, Methods: The sample was divided according to the following P levels on the day of ovulation triggering: <1.50 ng/ml and ≥1.50 ng/ml. The matching of the controls was performed according to age (±1 year) and number of oocytes retrieved (±10%). The main outcome was CLBR defined as a live-born delivery after 24 weeks of gestation., Main Results and the Role of Chance: The baseline characteristics of the two groups were similar. Estradiol levels on the day of trigger were significantly higher in the elevated P group. There was no significant difference in terms of fertilisation rate between the two groups. The elevated P group had significantly more cleavage stage frozen embryos compared to the normal P group while the total number of cryopreserved blastocyst stage embryos was the same. The CLBR did not differ between the two study groups (29.3% and 28.2% in the normal versus LFEP respectively, P = 0.773), also following confounder adjustment using multivariable GEE regression analysis (accounting for age at oocyte retrieval, total dose of FSH, progesterone levels on the day of ovulation trigger, day of freezing, at least one top-quality embryo transferred and number of previous IVF cycles, as the independent variables)., Limitations, Reasons for Caution: This is a multicentre observational study based on a retrospective data analysis. Better extrapolation of the results could be validated by performing a prospective analysis., Wider Implications of the Findings: This is the first study demonstrating that LFEP in the fresh cycle does not hinder CLBR of the subsequent frozen cycles in a FA approach. Thus, a FA strategy circumvents the issue of elevated P in the late follicular phase., Study Funding/competing Interest(s): No funding was received for this study. Throughout the study period and manuscript preparation, authors were supported by departmental funds from: Centre for Reproductive Medicine, Brussels, Belgium; Infertility Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Centro Scienze Natalità, San Raffaele Scientific Institute, Milan, Italy; and IVI-RMA, Lisbon, Portugal. E.S. has competing interests with Ferring, Merck-Serono, Theramex and Gedeon-Richter outside the submitted work. E.P. reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from MSD and grants from IBSA outside the submitted work. All the other authors have no conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Question: Are uterine fluid-derived extracellular vesicles (UF-EVs) a 'liquid biopsy' reservoir of biomarkers for real-time monitoring of endometrial status?, Summary Answer: The transcriptomic cargo of UF-EVs reflects the RNA profile of the endometrial tissue as well as changes between the non-receptive and the receptive phase, possibly supporting its use for a novel endometrial receptivity test., What Is Known Already: EVs have been previously isolated from uterine fluid, where they likely contribute to the embryo-endometrium crosstalk during implantation. Based on a meta-analysis of studies on endometrial tissue implantation-associated genes and the human exosomes database, 28 of the 57 transcripts considered as receptivity markers refer to proteins present in human exosomes. However, the specific transcriptomic content of receptive phase UF-EVs has yet to be defined., Study Design, Size, Duration: Two experimental series were set up. First, we simultaneously sequenced RNA species derived from paired UF-EVs and endometrial tissue samples collected from physiologically cycling women. Second, we analyzed RNA species of UF-EVs collected during the non-receptive (LH + 2) and receptive (LH + 7) phase of proven fertile women and from the receptive (LH + 7) phase of a population of women undergoing ART and transfer of euploid blastocysts., Participants/materials, Setting, Methods: For paired UF-endometrial tissue sampling, endometrial tissue biopsies were obtained with the use of a Pipelle immediately after UF collection performed by lavage of the endometrial cavity. Overall, n = 87 UF samples were collected and fresh-processed for EV isolation and total RNA extraction, while western blotting was used to confirm the expression of EV protein markers of the isolated vesicles. Physical characterization of UF-EVs was performed by Nanoparticle Tracking Analysis. To define the transcriptomic cargo of UF-EV samples, RNA-seq libraries were successfully prepared from n = 83 UF-EVs samples and analyzed by RNA-seq analysis. Differential gene expression (DGE) analysis was used to compare RNA-seq results between different groups of samples. Functional enrichment analysis was performed by gene set enrichment analysis with g:Profiler. Pre-ranked gene set enrichment analysis (GSEA) with WebGestalt was used to compare RNA-seq results with the gene-set evaluated in a commercially available endometrial receptivity array., Main Results and the Role of Chance: A highly significant correlation was found between transcriptional profiles of endometrial biopsies and pairwise UF-EV samples (Pearson's r = 0.70 P < 0.0001; Spearman's ρ = 0.65 P < 0.0001). In UF-EVs from fertile controls, 942 gene transcripts were more abundant and 1305 transcripts less abundant in the LH + 7 receptive versus the LH + 2 non-receptive phase. GSEA performed to evaluate concordance in transcriptional profile between the n = 238 genes included in the commercially available endometrial receptivity array and the LH + 7 versus LH + 2 UF-EV comparison demonstrated an extremely significant and consistent enrichment, with a normalized enrichment score (NES)=9.38 (P < 0.001) for transcripts up-regulated in LH + 7 in the commercial array and enriched in LH + 7 UF-EVs, and a NES = -5.40 (P < 0.001) for transcripts down-regulated in LH + 7 in the commercial array and depleted in LH + 7 UF-EVs. When analyzing LH + 7 UF-EVs of patients with successful versus failed implantation after transfer of one euploid blastocyst in the following cycle, we found 97 genes whose transcript levels were increased and 64 genes whose transcript levels were decreased in the group of women who achieved a pregnancy. GSEA performed to evaluate concordance in transcriptional profile between the commercially available endometrial receptivity array genes and the comparison of LH + 7 UF-EVs of women with successful versus failed implantation, demonstrated a significant enrichment with a NES = 2.14 (P = 0.001) for transcripts up-regulated in the commercial array in the receptive phase and enriched in UF-EVs of women who conceived, and a not significant NES = -1.18 (P = 0.3) for transcripts down-regulated in the commercial array and depleted in UF-EVs. In terms of physical features, UF-EVs showed a homogeneity among the different groups analyzed except for a slight but significant difference in EV size, being smaller in women with a successful implantation compared to patients who failed to conceive after euploid blastocyst transfer (mean diameter ± SD 205.5± 22.97 nm vs 221.5 ± 20.57 nm, respectively, P = 0.014)., Large Scale Data: Transcriptomic data were deposited in NCBI Gene Expression Omnibus (GEO) and can be retrieved using GEO series accession number: GSE158958., Limitations, Reasons for Caution: Separation of RNA species associated with EV membranes might have been incomplete, and membrane-bound RNA species-rather than the internal RNA content of EVs-might have contributed to our RNA-seq results. Also, we cannot definitely distinguish the relative contribution of exosomes, microvesicles and apoptotic bodies to our findings. When considering patients undergoing ART, we did not collect UFs in the same cycle of the euploid embryo transfer but in the one immediately preceding. We considered this approach as the most appropriate in relation to the novel, explorative nature of our study. Based on our results, a validation of UF-EV RNA-seq analyses in the same cycle in which embryo transfer is performed could be hypothesized., Wider Implications of the Findings: On the largest sample size of human EVs ever analyzed with RNA-seq, this study establishes a gene signature to use for less-invasive endometrial receptivity tests. This report is indeed the first to show that the transcriptome of UF-EVs correlates with the endometrial tissue transcriptome, that RNA signatures in UF-EVs change with endometrial status, and that UF-EVs could serve as a reservoir for potential less-invasive collection of receptivity markers. This article thus represents a step forward in the design of less-invasive approaches for real-time monitoring of endometrial status, necessary for advancing the field of reproductive medicine., Study Funding/competing Interest(s): The study was funded by a competitive grant from European Society of Human Reproduction and Embryology (ESHRE Research Grant 2016-1). The authors have no financial or non-financial competing interests to disclose., Trial Registration Number: NA., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Context: Demonstrating the ability to mount a neutralizing antibody response to SARS-CoV-2 in the presence of diabetes is crucial to understand COVID-19 pathogenesis, reinfection potential, and vaccine development., Objective: The aim of this study was to characterize the kinetics and durability of neutralizing antibody (Nab) response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of hyperglycemia., Methods: Using a lentiviral vector-based SARS-CoV-2 neutralization assay to measure Nabs, we characterized 150 patients randomly selected from a cohort of 509 patients with confirmed COVID-19 pneumonia. We analyzed Nab response according to the presence of diabetes or hyperglycemia, at the time of hospitalization and during the postdischarge follow-up: 1-, 3-, and 6-month outpatient visits., Results: Among 150 randomly selected patients 40 (26.6%) had diabetes. Diabetes (hazard ratio [HR] 8.9, P < .001), glucose levels (HR 1.25 × 1.1 mmol/L, P < .001), and glucose variability (HR 1.17 × 0.6 mmol/L, P < .001) were independently associated with an increased risk of mortality. The neutralizing activity of SARS-CoV-2 antibodies in patients with diabetes was superimposable, as for kinetics and extent, to that of patients without diabetes. It was similar across glucose levels and correlated with the humoral response against the SARS-CoV-2 spike protein. Positivity for Nabs at the time of hospital admission conferred protection on mortality, both in the presence (HR 0.28, P = .046) or absence of diabetes (HR 0.26, P = .030). The longevity of the Nab response was not affected by diabetes., Conclusion: Diabetes and hyperglycemia do not affect the kinetics and durability of the neutralizing antibody response to SARS-CoV-2. These findings provide the rational to include patients with diabetes in the early phase of the vaccination campaign against SARS-CoV-2., (© 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.)

Objectives: Risk factors for thromboembolism in SLE are poorly understood. We hypothesized a possible role for protein C, based on its dual activity in inflammation and haemostasis and on the evidence of an association between acquired activated protein C (APC) resistance (APCR) and high-avidity anti-protein C antibodies (anti-PC) with a severe thrombotic phenotype in venous thrombosis APS patients., Methods: In a cross-sectional study of 156 SLE patients, the presence and avidity of IgG anti-PC was established by in house-ELISA, and APCR to exogenous recombinant human APC (rhAPC) and Protac (which activates endogenous protein C) was assessed by thrombin generation-based assays. Associations with aPL profile, thrombotic history and disease activity (BILAG and SLEDAI-2K) were also established., Results: Anti-PC were detected in 54.5% of patients and APCR in 59%. Anti-PC positivity was associated with APCR to both rhAPC (P <0.0001) and Protac (P =0.0001). High-avidity anti-PC, detected in 26.3% of SLE patients, were associated with APCR in patients with thrombosis only (P <0.05), and with the development of thrombosis over time (range: 0-52 years; P =0.014). High-avidity anti-PC levels correlated with SLEDAI-2K (P =0.033) and total BILAG (P =0.019); SLEDAI-2K correlated inversely with APCR to Protac (P =0.004)., Conclusion: Anti-PC occur in patients with SLE, independently of aPL profile, and are associated with APCR. High-avidity anti-PC are associated with thrombosis and with active disease and might prove a novel marker to monitor the risk of thrombosis and disease progression in SLE., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores β-cell function in patients with long-standing type 1 diabetes., Methods: A phase 2, single-center, randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomly assigned (1:1:1) to 4 weeks of rapamycin (group 2), 4 weeks of rapamycin plus 12 weeks of vildagliptin (group 3), or double placebo (group 1). The primary outcome was the proportion of participants with a positive response to the Mixed-Meal Tolerance Test (C-peptide at 90 minutes > 0.2 nmol/L) at weeks 4 and 12. Secondary end points included insulin requirement, standard measures of glycemic control, and hormonal and immunological profile., Results: Fifty-five patients were randomly assigned to group 1 (n = 18), group 2 (n = 19), or group 3 (n = 18). No patient in any group showed a positive C-peptide response, and there was no significant difference at 4 and 12 weeks for the primary outcome. At 4 weeks, insulin requirement decreased from 0.54 to 0.48 U/kg/day in group 2 (P = .013), from 0.59 to 0.51 U/kg/day in group 3 (P < .001), whereas it did not change in group 1. At 12 weeks, glycated hemoglobin significantly decreased both in group 2 (from 7.3% [56 mmol/mol] to 7% [53 mmol/mol]; P = .045] and in group 3 (from 7.2% [55.5 mmol/mol] to 6.9% [52 mmol/mol]; P = .001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile., Conclusions: Rapamycin reduced insulin requirement, but did not restore β-cell function in patients with long-standing type 1 diabetes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The ongoing coronavirus disease 2019 pandemic has forced the clinical and scientific community to try drug repurposing of existing antiviral agents as a quick option against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). Under this scenario, interferon (IFN) β-1a, whose antiviral potential is already known, and which is a drug currently used in the clinical management of multiple sclerosis, may represent as a potential candidate. In this report, we demonstrate that IFN-β-1a was highly effective in inhibiting in vitro SARS-CoV-2 replication at clinically achievable concentration when administered after virus infection., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Erectile dysfunction (ED) is widely considered as an early manifestation of cardiovascular diseases (CVDs), sharing similar risk factors., Aim: Assess rates and predictors of developing CVD and/or hypertension (HTN) over a long-term follow-up period using user-friendly and clinically reliable tools in men presenting with ED but without CVD/HTN or known vascular risk factors at baseline., Methods: Data from 108 patients presenting between 2005 and 2011 with ED were analyzed. All patients were free from CVD and/or HTN (CVD/HTN) at baseline. Patients completed the International Index of Erectile Function (IIEF) at baseline and were followed up every 6 months with clinical assessment or phone interview. Kaplan-Meier analyses estimated the probability of developing CVD/HTN over time. Cox-regression models tested the association between patient baseline characteristics (for example, age, Charlson Comorbidity Index, baseline IIEF-EF, ED severity, alcohol intake, smoking), response to phosphodiesterase type-5 inhibitors (PDE5is), and the risk of developing CVD/HTN., Results: Of all, 43 (40%) patients showed IIEF-EF scores suggestive of severe ED; 37 (39%) and 59 (61%) were nonresponders and responders to PDE5i, respectively. Median (interquartile range) age was 51 (41, 61) years. Median (interquartile range) follow-up was 95 (86-106) months. Overall, the estimated risk of developing CVD/HTN was 15% (95% confidence interval [CI]: 9-27) at 10-year assessment. Men with baseline severe ED had a higher risk of developing CVD/HTN (34%; 95% CI: 17-59, P = .03) at 10 years than patients with mild to moderate ED (5% [95% CI: 2-14]). At the Cox regression analysis, severe ED (Hazard ratio [HR], 4.62; 95% CI: 1.43, 8.89; P = .01) and baseline IIEF-EF score (HR, 0.92; 95% CI: 0.86, 0.99; P = .02) were associated to the risk of CVD/HTN overtime. Conversely, age and nonresponders to PDE5is (HR, 0.92; 95% CI: 0.32, 2.68; P = .9) were not associated to a risk of CVD/HTN over time., Clinical Implications: The use of an easy and user-friendly tool, as the IIEF-EF domain score, would allow to reliably assess which men with ED at first presentation may deserve a different, more specific and detailed cardiologic investigation to prevent inauspicious CV events., Strengths & Limitations: A single-center-based, observational longitudinal study, raising the possibility of selection biases are the main limits., Conclusions: Patients with severe ED and lower baseline IIEF-EF but no vascular risk factors at first presentation have more than 30% risk of developing CVD/HTN in 10-year time. Those patients may benefit from medical preventive strategies to lowering the risk of CV events and HTN. Pozzi E, Capogrosso P, Boeri L, et al. Longitudinal Risk of Developing Cardiovascular Diseases in Patients With Erectile Dysfunction-Which Patients Deserve More Attention?. J Sex Med 2020;17:1489-1494., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Erectile function (EF) outcomes after radical pelvic surgery vary widely among different studies, partly as a consequence of heterogeneity with regard to the data assessment and reporting methodology., Aim: Review the methodology of data assessment and reporting of studies evaluating EF outcomes after radical prostatectomy (RP), radical cystectomy (RC), and rectal surgery (RS) and provide detailed recommendations to conduct future high-quality research., Methods: The MEDLINE database was searched for randomized clinical trials and open-label prospective or retrospective studies., Main Outcome Measure: The panel reviewed the modality of data assessment and reporting concerning 3 specific areas: preoperative patients assessment, surgical technique description, and postoperative patients management and follow-up., Results: Overall, 280, 36, and 73 studies investigating EF after RP, RC, and RS, respectively, were included. Baseline EF was largely reported (88%) in studies on RP, but only 67% of the studies on either RC or RS assessed EF before surgery. Baseline comorbidities that could impact postoperative EF were reported in 62%, 64%, and 85% of studies on RP, RC, and RS, respectively. The type of surgical approach was provided in all studies, and surgical details relevant to EF (eg, nerve- or organ-sparing surgery) were reported by 86%, 81%, and 62% of studies on RP, RC, and RS, respectively. Conversely, surgeon experience was rarely reported across all studies. Validated tools were commonly used to assess postoperative EF (64% of studies for RP, 78% for RC, and 71% for RS). Only 41%, 17%, and 29% of studies on RP, RC, and RS, respectively, reported a follow-up of at least 2 years. Use of erectile dysfunction treatment after surgery was assessed by only 39%, 17%, and 4.1% of studies on RP, RC, and RS, respectively. Factors potentially influencing EF recovery (eg, urinary or fecal continence, urinary diversion) were commonly reported, but sexual desire after surgery was reported by only 18%, 42%, and 37% of studies on RP, RC, and RS, respectively., Clinical Implications: The use of a shared methodology for the assessment and reporting of data on EF outcomes after pelvic surgery would allow better estimation of EF outcomes after pelvic surgery., Strengths & Limitations: The modality of data assessment and reporting among studies investigating EF outcome after pelvic surgery was systematically investigated to provide recommendations allowing a proper interpretation of data., Conclusion: Studies on EF outcomes after radical pelvic surgery should fulfill specific criteria concerning preoperative patient assessment, reporting of surgical details, and postoperative functional outcome evaluation and management. Capogrosso P, Pozzi EP, Celentano V, et al. Erectile Recovery After Radical Pelvic Surgery: Methodological Challenges and Recommendations for Data Reporting. J Sex Med 2020;17:7-16., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Hydraulic penile prostheses have shown an overall good mechanical reliability up to 10 years after surgery; however, few data have been published on very long-term follow-up., Aim: We looked at long-term (≥15 years) complications, including functional and quality of life (QoL) outcomes, after 3-piece inflatable penile prosthesis (IPP) implantation in patients with erectile dysfunction (ED)., Methods: Data regarding 149 patients submitting to IPP placement before 2001 were analyzed. All patients were implanted with AMS CX and Ultrex Plus 3-piece prostheses., Main Outcome Measure: Patients were reassessed to evaluate rates of complications and functional outcomes. The validated questionnaire Quality of Life and Sexuality with Penile Prosthesis (QoLSPP) was used to assess patient QoL. Kaplan-Meier analysis estimated the probability of prosthesis survival (defined as working device/not-explanted)., Results: Median follow-up of 51 patients was 206 months (interquartile range [IQR], 145-257). The etiology of ED was vasculogenic (n = 20; 39%), Peyronie's disease (n = 15; 29%), pelvic surgery (n = 4; 7.8%), organic other than vasculogenic (n = 3; 5.9%), or other (n = 9; 18%). Throughout the follow-up, 24 patients (49%) experienced complications: mechanical failure (n = 19; 79%), pain (n = 3; 12%), orgasmic dysfunctions (n = 1; 4.5%), or device infection (n = 1; 4.5%). The estimated IPP survival was 53% (95% CI, 36-67) at 20-year follow-up. Baseline characteristics (age, Charlson comorbidity index, body mass index, and erectile dysfunction etiology) were not significantly associated with the risk of IPP failure over time by Cox regression analysis. At 20-year follow-up, 41% (95% CI, 19-49) of the patients were still using the device. Among them, QoLSPP median domain scores were high: functional 22/25 (IQR, 20-23), relational 17/20 (IQR, 15-18), personal 14/15 (IQR, 12-15), and social 14/15 (IQR, 11-15)., Clinical Implications: The longevity of the device and long-term satisfaction rates should be comprehensively discussed during patient consultation for IPP surgery., Strengths & Limitations: To our knowledge, this is the first study reporting long-term QoL outcomes using a dedicated questionnaire for penile prostheses. The low response rate for the telephone interviews, the retrospective design of the study, and the relatively small number of patients are the main limitations., Conclusion: Long-term follow-up data after IPP placement showed that almost half of the devices still worked properly 20 years after the original penile implant, as 60% of patients were still using the device with high satisfaction and adequate QoL outcomes. Both patients and physicians should be aware of the expected life and outcomes of IPP implants. Chierigo F, Capogrosso P, Dehò, et al. Long-Term Follow-Up After Penile Prosthesis Implantation-Survival and Quality of Life Outcomes. J Sex Med 2019;16:1827-1833., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: The impact of erectile dysfunction (ED) on patients' sexual satisfaction and mood profile could differ across different ages., Aim: To investigate the relationship between erectile function (EF), sexual satisfaction, and mood status among patients seeking medical help for ED., Methods: Data from 765 patients presenting at a single center for ED were analyzed. Patients were categorized as young (≤50 years), middle-aged (>50 and ≤65 years), and old (>65 years) individuals and completed the International Index of Erectile Function (IIEF) and the Beck's Inventory for Depression (BDI)., Main Outcome Measures: The IIEF overall satisfaction and intercourse satisfaction domain scores and the BDI score were used to investigate sexual life satisfaction and depressive symptoms (defined as BDI > 11) across ages and according to ED severity. Linear and logistic regression analyses assessed the relationship between satisfaction scores and the risk of depressive symptoms with age and EF., Results: Median (interquartile range) age at first assessment for ED was 50 (38, 59) years. Compared with older men, young and middle-aged patients showed significantly higher IIEF-OS and IIEF- Intercourse Satisfaction scores for increasing IIEF-EF scores. Older men showed no difference in terms of satisfaction scores for mild ED and normal EF status. At linear regression analysis, both IIEF-EF and age were significantly associated with sexual satisfaction (all P < .0001). The interaction term between age and EF was also significant, suggesting that the older the patients, the higher the feeling of sexual satisfaction for the same EF status (P = .004). Overall, 25% of patients reported depressive symptoms. Logistic regression analysis showed a 40% risk of depressive symptoms for patients <45 years with severe ED compared to a risk <20% for a man >65 years of age with the same EF status., Clinical Implications: Treating older patients with mild ED may not lead to a further improvement in sexual satisfaction as compared with younger patients with the same ED severity. Younger ED patients suffer more from depressive symptoms compared with older men, regardless of ED severity, thus supporting the need for a comprehensive psychological counseling., Strength & Limitations: The single-center design and the lack of the assessment of the impact of ED treatment are the main limits., Conclusions: The clinical management of ED should be tailored according to different ages: younger patients deserve to be investigated and eventually treated for depressive symptoms. Older patients should be counseled for treatment when a sexual satisfaction improvement is expected. Capogrosso P, Ventimiglia E, Boeri L, et al. Should We Tailor the Clinical Management of Erectile Dysfunction According to Different Ages? J Sex Med 2019;16:999-1004., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Cerebral and cardiovascular ischaemic events are frequent complications of SLE and constitute primary causes of permanent damage. However, the pathogenic determinants of an increased thromboembolic risk in patients with SLE are only partially understood. Atherosclerosis constitutes fertile soil for the development of thrombosis and shows disproportionately high prevalence and progression rates in patients with SLE. aPLs are independent risk factors for acute thrombosis but can also prompt long-term vascular inflammation. Aberrant interactions among immune cells and dysfunctions in the deployment of the coagulation cascade have historically been less explored in SLE, but recent evidence suggests they can also play a critical role at the crossroads between inflammation and haemostasis. In this review we discuss how different prothrombotic mechanisms can be prompted by and synergize with SLE-specific pathogenic events and speculate about novel potential directions for research and drug development., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Context: Recent studies have suggested that influenza A virus (IAV) might be involved in the etiology of diabetes., Objective and Methods: To address this question, we tested the ability of H1N1 pandemic IAV to infect, replicate, and damage human β cells/pancreatic islets in vitro and induce pancreatic damage and/or glucose metabolism alterations in chemical and autoimmune models of β cell damage in vivo. Moreover, we looked for direct and/or indirect evidence of correlation between IAV infection and autoimmunity/diabetes in humans., Results: Human H1N1 A/California/2009-derived viruses infected human pancreatic islets in vitro, inducing a proinflammatory response associated with substantial increases of CXCL9 and CXCL10 release. In vivo, infected mice showed a clear susceptibility to the virus, with its localization also found in extrapulmonary organs, including the pancreas. Infection was able to induce mild modifications of glycemia in C57B6 mice after chemical damage of islets but did not modulate the autoimmune damage of islets in NOD mice. One of 69 nasopharyngeal swabs collected from patients at the onset of type 1 diabetes yielded positive results for IAV. Pancreas sections from 17 organ donors available from the Network for Pancreatic Organ Donors With Diabetes showed the persistence of CXCL10-positive cells in islet autoimmunity-positive subjects; however, extremely rare cells stained for viral RNA and not preferentially in autoimmune subjects., Conclusion: Influenza H1N1 pdm strains are able to infect and replicate in mammalian pancreatic cells both in vitro and in vivo but did not cause any functional impairment consistent with diabetes.

Neuroendocrinology of bone is a new area of research based on the evidence that pituitary hormones may directly modulate bone remodeling and metabolism. Skeletal fragility associated with high risk of fractures is a common complication of several pituitary diseases such as hypopituitarism, Cushing disease, acromegaly, and hyperprolactinemia. As in other forms of secondary osteoporosis, pituitary diseases generally affect bone quality more than bone quantity, and fractures may occur even in the presence of normal or low-normal bone mineral density as measured by dual-energy X-ray absorptiometry, making difficult the prediction of fractures in these clinical settings. Treatment of pituitary hormone excess and deficiency generally improves skeletal health, although some patients remain at high risk of fractures, and treatment with bone-active drugs may become mandatory. The aim of this review is to discuss the physiological, pathophysiological, and clinical insights of bone involvement in pituitary diseases.

Motivation: Sanger sequencing is still being employed for sequence variant detection by many laboratories, especially in a clinical setting. However, chromatogram interpretation often requires manual inspection and in some cases, considerable expertise., Results: We present GLASS, a web-based Sanger sequence trace viewer, editor, aligner and variant caller, built to assist with the assessment of variations in 'curated' or user-provided genes. Critically, it produces a standardized variant output as recommended by the Human Genome Variation Society., Availability and Implementation: GLASS is freely available at http://bat.infspire.org/genomepd/glass/ with source code at https://github.com/infspiredBAT/GLASS., Contact: nikos.darzentas@gmail.com or malcikova.jitka@fnbrno.cz., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

The US Food and Drug Administration recently announced the need to evaluate the association between PDE5is and melanoma. We performed a meta-analysis on the association between PDE5i and melanoma using random effects models and examined whether it met Hill's criteria for causality. A systematic search of Medline, EMBASE, and the Cochrane Library from 1998 to 2016 identified three case-control studies and two cohort studies, including a total of 866 049 men, of whom 41 874 were diagnosed with melanoma. We found a summary estimate indicating an increased risk of melanoma in PDE5i users (relative risk = 1.11, 95% confidence interval = 1.02 to 1.22). However, the association was only statistically significant among men with low PDE5i exposure (not high exposure) and with low-stage melanoma (not high stage), indicating a lack of dose response and biological gradient. PDE5i use was also associated with basal cell cancer, suggesting a lack of specificity and likely confounding by ultraviolet exposure. Thus, although this meta-analysis found a statistically significant association between PDE5i and melanoma, it did not satisfy Hill's criteria for causality., (© The Author 2017. Published by Oxford University Press.)

Objective: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity., Methods: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio., Results: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD., Conclusions: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Introduction: Sexual dysfunction is common in patients after radical prostatectomy (RP) for prostate cancer., Aim: To provide the International Consultation for Sexual Medicine (ICSM) 2015 recommendations concerning management strategies for post-RP erectile function impairment and to analyze post-RP sexual dysfunction other than erectile dysfunction., Methods: A literature search was performed using Google and PubMed database for English-language original and review articles published up to August 2016., Main Outcome Measures: Levels of evidence (LEs) and grades of recommendations (GRs) are provided based on a thorough analysis of the literature and committee consensus., Results: Nine recommendations are provided by the ICSM 2015 committee on sexual rehabilitation after RP. Recommendation 6 states that the recovery of postoperative erectile function can take several years (LE = 2, GR = C). Recommendation 7 states there are conflicting data as to whether penile rehabilitation with phosphodiesterase type 5 inhibitors improves recovery of spontaneous erections (LE = 1, GR = A). Recommendation 8 states that the data are inadequate to support any specific regimen as optimal for penile rehabilitation (LE = 3, GR = C). Recommendation 9 states that men undergoing RP (any technique) are at risk of sexual changes other than erectile dysfunction, including decreased libido, changes in orgasm, anejaculation, Peyronie-like disease, and changes in penile size (LE = 2, GR = B)., Conclusion: This article discusses Recommendations 6 to 9 of the ICSM 2015 committee on sexual rehabilitation after RP. Salonia A, Adaikan G, Buvat J, et al. Sexual Rehabilitation After Treatment For Prostate Cancer-Part 2: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med 2017;14:297-315., (Copyright © 2017. Published by Elsevier Inc.)

Introduction: Sexual dysfunction is common in patients after radical prostatectomy (RP) for prostate cancer., Aim: To provide the International Consultation for Sexual Medicine (ICSM) 2015 recommendations concerning prevention and management strategies for post-RP erectile function impairment in terms of preoperative patient characteristics and intraoperative factors that could influence erectile function recovery., Methods: A literature search was performed using Google and PubMed databases for English-language original and review articles published up to August 2016., Main Outcome Measures: Levels of evidence (LEs) and grades of recommendations (GRs) based on a thorough analysis of the literature and committee consensus., Results: Nine recommendations are provided by the ICSM 2015 committee on sexual rehabilitation after RP. Recommendation 1 states that clinicians should discuss the occurrence of postsurgical erectile dysfunction (temporary or permanent) with every candidate for RP (expert opinion, clinical principle). Recommendation 2 states that validated instruments for assessing erectile function recovery such as the International Index of Erectile Function and Expanded Prostate Cancer Index Composite questionnaires are available to monitor EF recovery after RP (LE = 1, GR = A). Recommendation 3 states there is insufficient evidence that a specific surgical technique (open vs laparoscopic vs robot-assisted radical prostatectomy) promotes better results in postoperative EF recovery (LE = 2, GR = C). Recommendation 4 states that recognized predictors of EF recovery include but are not limited to younger age, preoperative EF, and bilateral nerve-sparing surgery (LE = 2, GR = B). Recommendation 5 states that patients should be informed about key elements of the pathophysiology of postoperative erectile dysfunction, such as nerve injury and cavernous venous leak (expert opinion, clinical principle)., Conclusions: This article discusses Recommendations 1 to 5 of the ICSM 2015 committee on sexual rehabilitation after RP. Salonia A, Adaikan G, Buvat J, et al. Sexual Rehabilitation After Treatment for Prostate Cancer-Part 1: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). J Sex Med 2017;14:285-296., (Copyright © 2017 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Testosterone deficiency (TD), also known as hypogonadism, is a condition affecting a substantial proportion of men as they age. The diagnosis and management of TD can be challenging and clinicians should be aware of the current literature on this condition., Aim: To review the available literature concerning the diagnosis and management of TD and to provide clinically relevant recommendations from the Fourth International Consultation for Sexual Medicine (ICSM) meeting., Methods: A literature search was performed using the PubMed database for English-language original and review articles published or e-published up to January 2016., Main Outcome Measures: Levels of evidence (LoEs) and grades of recommendations are provided based on a thorough analysis of the literature and committee consensus., Results: Recommendations were given for 12 categories of TD: definition, clinical diagnosis, routine measurement, screening questionnaires, laboratory diagnosis, threshold levels for the biochemical diagnosis of TD, prostate cancer, cardiovascular disease, fertility, testosterone (T) formulations, alternatives to T therapy, and adverse events and monitoring. A total of 42 recommendations were made: of these, 16 were unchanged from the Third ICSM and 26 new recommendations were made during this Fourth ICSM. Most of these recommendations were supported by LoEs 2 and 3. Several key new recommendations include the following: (i) the clinical manifestations of TD occur as a result of decreased serum androgen concentrations or activity, regardless of whether there is an identified underlying etiology [LoE = 1, Grade = A]; (ii) symptomatic men with total T levels lower than 12 nmol/L or 350 ng/dL should be treated with T therapy [LoE = 1, Grade = C]; (iii) a trial of T therapy in symptomatic men with total T levels higher than 12 nmol/L or 350 ng/dL can be considered based on clinical presentation [LoE = 3, Grade = C]; (iv) there is no compelling evidence that T treatment increases the risk of developing prostate cancer or that its use is associated with prostate cancer progression [LoE = 1, Grade = C]; and (v) the weight of evidence indicates that T therapy is not associated with increased cardiovascular risk [LoE = 2, Grade = B]., Conclusion: TD is an important condition that can profoundly affect the sexual health of men. We provide guidance regarding its diagnosis and management. Men with TD who receive treatment often experience resolution or improvement in their sexual symptoms and non-sexual health benefits., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Objectives: To report the 96 week results on efficacy, safety and bone mineral density (BMD) in subjects with HIV-1 that were virologically suppressed and treated with atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy., Methods: MODAt is a prospective, multicentre, open-label, non-inferiority, randomized, 96 week trial (NCT01511809) comparing efficacy of atazanavir/ritonavir monotherapy versus atazanavir/ritonavir triple therapy. Treatment success was defined as no occurrence of confirmed viral rebound (two consecutive HIV-RNA >50 copies/mL) or discontinuation for any cause of the ongoing regimen., Results: The 96 week treatment success was 64% in the atazanavir/ritonavir monotherapy arm and 63% in the triple-therapy arm (difference 1.3%, 95% CI: -17.5 to 20.1). In the atazanavir/ritonavir monotherapy arm, no PI- or NRTI-associated resistance mutations were observed at virological failure and all patients re-suppressed after re-intensification. In the monotherapy arm, treatment failure was more frequent in patients coinfected with hepatitis C virus [64% versus 28% (difference 35.4%, 95% CI: 3.7-67.2)]. Drug-related adverse events leading to discontinuation were 3 (6%) in the atazanavir/ritonavir monotherapy arm and 11 (21.5%) in the triple-therapy arm (P = 0.041). The 96 week adjusted mean percentage change in total proximal femur (not at lumbar spine) BMD was +1.16% and -1.64% in the atazanavir/ritonavir monotherapy arm and the triple-therapy arm, respectively (P = 0.012)., Conclusions: The 96 week analyses suggested that long-term efficacy of atazanavir/ritonavir monotherapy was inferior as compared with atazanavir/ritonavir triple therapy, particularly when administered in subjects coinfected with hepatitis C virus. In the atazanavir/ritonavir monotherapy arm, reintroduction of nucleosides, as needed, was always effective with no new resistance mutation; monotherapy was also associated with a lower incidence of adverse events and improvement in femur BMD., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Several definitions of erectile function (EF) recovery after bilateral nerve-sparing radical prostatectomy (BNSRP) have been proposed based on the results of the International Index of EF (IIEF)., Aim: We aimed at evaluating overall satisfaction (OS) after BNSRP according to the ability to achieve the pretreatment EF., Methods: We evaluated data of 652 patients treated with BNSRP for clinically localized prostate cancer (PCa). Erectile dysfunction (ED) was classified according to the IIEF-EF domain score. Return to baseline EF was defined as patients who reached the same preoperative ED category during the 3-year follow-up. Cox regression analyses were fitted to predict return to baseline IIEF-EF and to predict OS defined according to the IIEF-OS in the overall population. Logistic regression analyses were performed to analyze OS in men who reached the back to baseline status., Main Outcome Measures: The outcome of the study was to evaluate back to baseline EF status and to correlate it with postoperative OS., Results: Preoperative satisfaction was reported by 218 (33.4%) patients. Postoperative satisfaction was achieved by 103 patients. Overall, 383 patients were able to achieve the preoperative IIEF-EF score. However, only 26.9% reported being satisfied. Age and preoperative IIEF-EF score were significantly associated with baseline IIEF-EF recovery (all P ≤ .02). Patients who were able to return to baseline IIEF-EF were more likely to be satisfied (P < .001). Time elapsed between surgery and achievement of baseline IIEF-EF was significantly associated with OS (P < .001). Among patients who were able to achieve the baseline IIEF-EF score, a preoperative IIEF-EF of 22-25 and 26-30 was significantly associated with postoperative satisfaction (all P < .001)., Conclusion: After BNSRP, reaching the baseline IIEF-EF score is not always sufficient to obtain patient satisfaction. Only patients with a preoperative IIEF-EF ≥22 who reached the baseline score after surgery considered themselves satisfied. This should be taken into account in preoperative patient counseling., (Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Motivation: An ever-increasing body of evidence supports the importance of B cell receptor immunoglobulin (BcR IG) sequence restriction, alias stereotypy, in chronic lymphocytic leukemia (CLL). This phenomenon accounts for ∼30% of studied cases, one in eight of which belong to major subsets, and extends beyond restricted sequence patterns to shared biologic and clinical characteristics and, generally, outcome. Thus, the robust assignment of new cases to major CLL subsets is a critical, and yet unmet, requirement., Results: We introduce a novel application, ARResT/AssignSubsets, which enables the robust assignment of BcR IG sequences from CLL patients to major stereotyped subsets. ARResT/AssignSubsets uniquely combines expert immunogenetic sequence annotation from IMGT/V-QUEST with curation to safeguard quality, statistical modeling of sequence features from more than 7500 CLL patients, and results from multiple perspectives to allow for both objective and subjective assessment. We validated our approach on the learning set, and evaluated its real-world applicability on a new representative dataset comprising 459 sequences from a single institution., Availability and Implementation: ARResT/AssignSubsets is freely available on the web at http://bat.infspire.org/arrest/assignsubsets/, Contact: nikos.darzentas@gmail.com., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4(+) plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed., (© 2015 British Society for Immunology.)

Background: ST22-IV is a successful hospital-associated MRSA clone. Due to its known ability to replace other MRSA clones in hospitals, it became a dominant clone in Europe and beyond. So far, there are no studies investigating the relationship between the epidemiological success of MRSA clones and their capacity to withstand commonly encountered stresses., Methods: We investigated the fitness of ST22-IV in comparison with the replaced clone ST228-I, evaluating its resistance to oxidative stress, autolytic activity, growth at high osmolarity and in acid and alkaline environments and survival under desiccation and heat shock. We also compared their phenotypic characteristics and examined the impact of antibiotic consumption on epidemiological success., Results: Here we demonstrate that the dominance of ST22-IV is linked neither to changes in antibiotic consumption nor to acquisition of additional resistances over time. Strong α-haemolysin activity, the production of β-haemolysin and the presence of an active agr could partly explain the virulence of ST22-IV previously observed in a murine model of pneumonia. Most importantly, we show that ST22-IV compared with ST228-I, besides retaining susceptibility to most antibiotics over time, has a superior capacity to survive under all stress conditions tested, which bacteria commonly face during their life cycle., Conclusions: Our results support our hypothesis that ST22-IV has a fitness advantage over ST228-I. This fitness advantage could have allowed ST22-IV to displace ST228-I without acquiring additional resistances and could help explain its epidemic success in hospital settings and its spread in Europe and beyond., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Acute kidney injury (AKI) is an important complication of cardiac surgery. Recently, elevated levels of endogenous ouabain (EO), an adrenal stress hormone with haemodynamic and renal effects, have been associated with worse renal outcome after cardiac surgery. Our aim was to develop and evaluate a new risk model of AKI using simple preoperative clinical parameters and to investigate the utility of EO., Methods: The primary outcome was AKI according to Acute Kidney Injury Network stage II or III. We selected the Northern New England Cardiovascular Disease Study Group (NNECDSG) as a reference model. We built a new internal predictive risk model considering common clinical variables (CLIN-RISK), compared this model with the NNECDSG model and determined whether the addition of preoperative plasma EO improved prediction of AKI., Results: All models were tested on >800 patients admitted for elective cardiac surgery in our hospital. Seventy-nine patients developed AKI (9.9%). Preoperative EO levels were strongly associated with the incidence of AKI and clinical complication (total ICU stay and in-hospital mortality). The NNECDSG model was confirmed as a good predictor of AKI (AUC 0.74, comparable to the NNECDSG reference population). Our CLIN-RISK model had improved predictive power for AKI (AUC 0.79, CI 95% 0.73-0.84). Furthermore, addition of preoperative EO levels to both clinical models improved AUC to 0.79 and to 0.83, respectively (ΔAUC +0.05 and +0.04, respectively, P < 0.01)., Conclusion: In a population where the predictive power of the NNECDSG model was confirmed, CLIN-RISK was more powerful. Both clinical models were further improved by the addition of preoperative plasma EO levels. These new models provide improved predictability of the relative risk for the development of AKI following cardiac surgery and suggest that EO is a marker for renal vascular injury., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Partial forms of Shone complex are rare. Surgical outcomes of the complete forms have generally been poor, whereas there is a lack of data on long-term follow-up of surgically treated adult partial complex. Between 2001 and 2011, nine patients (age: 38 ± 8 years; six males, 67%) were referred for valvular heart disease. Transthoracic and transoesophageal echocardiography was performed. Data were confirmed by intra-operative findings and reports. Patients were diagnosed as partial Shone complex and presented with mitral stenosis (MS) (45%) or mitral regurgitation (22%) or aortic regurgitation (22%). All but one patient (89%) reported previous surgery: coarctation of the aorta repair (87.5%) and aortic valvulotomy (12.5%). Redo intervention included: mitral valve replacement (25%), mitral repair (25%), aortic valve replacement (37.5%) and subvalvular aortic ridge resection (25%). One patient refused surgery. Patients surgically treated before the age of 5 (87.5%) showed favourable outcome (survival rate: 100%) and a 23.6 (± 4.6)-year follow-up free from events. The patient who underwent first intervention at the age of 50 and the patient with MS who refused surgery showed a 45 (± 7)-year follow-up free from major morbidity. Patients with partial Shone complex, properly diagnosed and treated, show favourable surgical outcome free from major clinical events.

The mitral-aortic intervalvular fibrosa (MAIF) is involved in the functional integrity of the two valves. We discuss the clinical decision-making in a population with MAIF pseudoaneurysms following valve replacement surgery. From 2003 to 2010, 16 patients (age 65 ± 17 years) were referred to our institute with worsening valvular disease. All the patients had undergone previous aortic or mitral valve replacement surgery. Transthoracic and transesophageal echocardiography was performed in these patients. According to the echocardiographic findings, we described two groups of patients with MAIF pseudoaneurysms: group 1 (seven patients) without previously known infective disease, and group 2 (nine patients) with a medical history of endocarditis. For asymptomatic patients without an infective background or valve regurgitation (group 1), clinical and echocardiographic follow-up was selected. Reintervention was planned for postinfection pseudoaneurysms (group 2), on account of the residual paravalvular leak and the high-risk of MAIF rupture. The case series emphasizes the need for more awareness about MAIF pseudoaneurysms, rare complications of aortic and mitral valve surgery, which occur far more frequently than expected. Although clinical decision-making is debatable, it may be helpful to differentiate patients into those with or without previous endocarditis, and according to heart failure symptoms.

Study Objectives: To assess the longitudinal course of cognitive functions in a cohort of patients with idiopathic REM sleep behavior disorder (iRBD)., Design: Prospective study with baseline and 2-year follow-up., Setting: Sleep disorders center., Participants: Twenty-four cognitively asymptomatic iRBD patients (18 M; mean age: 69.5 ± 7.3 y) and 12 sex-, age-, and education-matched healthy subjects., Interventions: Participants underwent to a video-PSG, a focused neuropsychological evaluation and a neurological examination. Following the first evaluation, subjects were reassessed after a mean interval of 25.8 months., Measurements and Results: Executive functions, attention and language were normal at baseline and at 2 year follow-up examination. At baseline, iRBD patients showed poorer performance than controls in delayed verbal memory (story recall test: P = 0.001) and in visuo-constructional abilities (Copy of the Rey-Osterrieth complex figure: P = 0.0005). At follow-up, they not only performed worse than controls in the same tests (story recall: P = 0.0001; Copy of the Rey-Osterrieth complex figure: P = 0.0004), but they also showed an impairment in visuo-spatial learning (Corsi supraspan test; P < 0.0001). ANOVAs showed a significant worsening in visuo-spatial learning over time in RBD compared to controls (P = 0.0001). Furthermore, 3 patients fulfilled the UK Brain Bank criteria for Parkinson disease, but this was unrelated to cognitive deterioration., Conclusions: Although no patients developed dementia, the decline observed in some tests involving the memory and visuo-constructional domains in idiopathic RBD suggests the presence of an underlying evolving degenerative process.

Iatrogenic injuries of the superior vena cava (SVC) following surgical or endovascular treatments are rare but challenging complications and require prompt diagnosis and appropriate treatment. The additional diagnostic value of venography, contrast-enhanced computed tomography, and magnetic resonance imaging has been widely assessed in the clinical setting of the SVC obstruction, whereas the role of conventional transoesophageal echocardiography (TEE) is still uncertain. A 43-year-old female patient was admitted to the echocardiography laboratory because of a superior vena cava syndrome (SVCS) following a balloon SVC venoplasty with stent implantation. A standard transoesophageal echocardiography examination clearly detected the SVC obstruction on previously implanted stents. We found that fundamental steps of early diagnosis of SVCS would benefit from standard TEE.

Study Objectives: To compare the time structure of leg movements (LM) during sleep of patients with rapid eye movement (REM) sleep behavior disorder (RBD) with that of patients with restless legs syndrome (RLS) or control subjects., Design: The polysomnographically recorded tibialis anterior activity during sleep was analyzed by means of a new approach able to consider duration, intermovement interval, sleep stage and time of night distribution, and periodicity., Patients and Participants: Twenty patients with idiopathic RBD, 37 with idiopathic RLS and 14 age-matched control subjects were consecutively recruited., Measurements and Results: Most patients with RBD (85%) presented periodic leg movements during sleep (PLMS). PLMS occurred more frequently during non-REM sleep in patients with RLS and during REM sleep in patients with RBD. PLMS were shorter in duration, less often bilateral, and with a higher intermovement interval in patients with RBD compared to those with RLS. The number of PLMS decreased across the night in patients with RBD and in those with RLS, but not in control subjects. In all subjects, LM periodicity clearly depended on sleep state, with higher values during non-REM than during REM sleep. Patients with RBD showed a lower LM periodicity, compared with patients with RLS, in each of the sleep states., Conclusions: Significant differences, together with some similarities in LM time structure, were observed between patients with RBD and those with RLS; for this reason, our approach seems to indicate that their phenotype might be dependent on 2 factors: disease and sleep stage.

Background: There is still considerable uncertainty as to the best algorithm for interpreting human immunodeficiency virus (HIV) genotyping results., Methods: A total of 318 subjects with HIV RNA levels of >1000 copies/mL were enrolled in 41 centers throughout Italy from 2001 through 2003, stratified on the basis of their drug history, randomized (1:1) to 2 arms to have their treatments modified on the basis of the results of HIV genotyping (as interpreted by virtual phenotype analysis or with use of a rule-based interpretation system), and followed up for 48 weeks. At least 1 nucleoside reverse-transcriptase inhibitor and 1 protease inhibitor had to be included in any new regimen; nonnucleoside reverse-transcriptase inhibitor-naive patients were also prescribed a nonnucleoside reverse-transcriptase inhibitor. Only drugs licensed in Italy were allowed. The primary end point was a decrease in HIV RNA level to <400 copies/mL by week 12 according to on-treatment analysis., Results: The mean (+/- standard deviation) values at baseline were as follows: HIV RNA level, 4.1+/-0.74 log(10) copies/mL; CD4(+) T lymphocyte count, 410+/-262 cells/microL; reverse-transcriptase mutations, 4.8+/-2.9; and protease mutations, 2.8+/-2.5. There were 133 patients (41.8%) who were nonnucleoside reverse-transcriptase inhibitor naive and protease inhibitor experienced, 63 patients (19.8%) who were nonnucleoside reverse-transcriptase inhibitor experienced and protease inhibitor naive, and 122 patients (38.4%) who were 3-class experienced. A total of 192 patients completed 12 weeks of the treatment regimen assigned at baseline; at 12 weeks, 66.3% of patients in the virtual phenotype arm and 71.3% of patients in the rule-based interpretation arm had HIV RNA levels of <400 copies/mL (P = .46). No statistically significant difference between arms was observed by intention-to-treat analysis., Conclusion: Both the virtual phenotype and rule-based interpretation methods of HIV genotyping can guide the selection of effective antiretroviral drugs for a salvage regimen.

Introduction: With the success of Phosphodiesterase (PDE) type 5 inhibitors (i.e., sildenafil, tadalafil, vardenafil) in the treatment of erectile dysfunction (ED), PDEs are considered attractive targets for drug intervention in the urogenital tract., Aim: To review the role of PDEs, which exist as a superfamily of enzymes comprising 11 distinct families, in the urogenital system, focusing on anatomical locations, functions and dysfunctions, potential disorders that could be treated, and any promising new selective PDE inhibitors under development., Methods: Included are (i) abstracts from 2001, 2002, and 2003; (ii) a MEDLINE search from 1996 through December 2003; and (iii) a pipeline search for therapeutics in development. Data from animal experiments are presented when there is a paucity of human data, but with the caveat that the distribution of PDE isozymes in a specific tissue can vary between species., Results: PDE mRNA and protein have been localized throughout the normal human urogenital tract. Double-blind, placebo-controlled studies suggest possible new clinical roles for sildenafil, including prophylaxis to preserve penile smooth muscle and erectile function after radical prostatectomy, and treatment of ejaculatory delay secondary to serotonergic reuptake inhibitor antidepressant therapy. Open-label studies suggest a potential clinical role for: vinpocetine (a PDE1 inhibitor) in the treatment of incontinence and low-compliance bladder; and sildenafil in the treatment of premature ejaculation, prostate-related lower urinary tract symptoms, and in women who have had unsuccessful in vitro fertilization. Several new orally administered PDE5 inhibitors are in early clinical development for the treatment of ED. Potential indications for PDE inhibitors that are suggested by preclinical data include Peyronie's disease, ureteral colic, male and female birth control, and prevention of preterm labor., Conclusions: Drug selectivity and differential PDE tissue distribution allow for potential targeted intervention for numerous disorders related to the urogenital tract.