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Background Early start of highly active antiretroviral therapy (HAART) in perinatally HIV-1 infected children is the optimal strategy to prevent immunological and clinical deterioration. To date, according to EMA, only 35% of antiretroviral drugs are licenced in children Methods An observational retrospective study investigating the rate and the outcomes of off-label prescription of HAART was conducted on 225 perinatally HIV-1 infected children enrolled in the Italian Register for HIV Infection in Children and followed-up from 2001 to 2018. Results 22.2% (50/225) of included children were receiving an off-label HAART regimen at last check. Only 26% (13/50) of off-label children had an undetectable viral load (VL) before the commencing of the regimen and the 52.0% (26/50) had a CD4 + T lymphocyte percentage > 25%. At last check, during the off label regimen, the 80% (40/50) of patients had an undetectable VL, and 90% (45/50) of them displayed CD4 + T lymphocyte percentage > 25%. The most widely used off-label drugs were: dolutegravir/abacavir/lamivudine (16%; 8/50), emtricitbine/tenofovir disoproxil (22%; 11/50), lopinavir/ritonavir (20%; 10/50) and elvitegravir/cobicistat/emtricitabine/ tenofovir alafenamide (10%; 10/50). At logistic regression analysis, detectable VL before starting the current HAART regimen was a risk factor for receiving an off-label therapy (OR: 2.41; 95% CI 1.13–5.19; p = 0.024). Moreover, children Conclusion The prescription of an off-label HAART regimen in perinatally HIV-1 infected children was common, in particular in children with detectable VL despite previous HAART and in younger children, especially those receiving their first regimen. Our data suggest similar proportions of virological and immunological successes at last check among children receiving off-label or on-label HAART. Larger studies are needed to better clarify efficacy and safety of off-label HAART regimens in children, in order to allow the enlargement of on-label prescription in children.

Background A chief complaint of men with stuttering priapism (SP) and sleep-related painful erections (SRPE) is bothersome nocturnal erections that wake them up and result in poor sleep and daytime tiredness. SP and SRPE are rare entities that have similarities in their clinical features, but that require different treatment approaches. Aim The aim of this study was to describe the clinical features, investigations, and effective management options for men with SP and SRPE. Methods Retrospective cohort study of 133 men with bothersome nocturnal painful erections that attended a tertiary andrology unit between 2004 and 2018. These men were divided into 3 groups. Group 1 (n = 62) contains men with sickle cell SP; group 2 (n = 40) has men with non-sickle cell SP and group 3 (n = 31) contains men with SRPE. Outcome To determine the effectiveness of medical and surgical treatments for men with SP and SRPE. Results Hydroxyurea and automated exchange transfusion were the most effective treatment options in the sickle cell SP group. Hormonal manipulation and α-agonist therapies were effective in both SP cohorts (groups 1 and 2). Baclofen was the most effective therapy in men with SRPE. For men who failed medical management, implantation of a penile prosthesis resulted in complete resolution of the symptoms in men with SP (groups 1 and 2). Surgical management (penile prosthesis implantation and embolization) did not improve the patients’ symptoms in the SRPE group. Clinical Implications This study differentiates between sickle cell SP, non-sickle cell SP, and SRPE and describes effective treatment options for each group. Strengths & Limitations This is the largest cohort study for both SP and SRPE, respectively. Limitations include its retrospective nature and single-center experience. Conclusion Managing men in these 3 groups differently and in accordance with the proposed treatment pathway provides a more structured approach to the management of these rare conditions. Johnson M, McNeillis S, Chiriaco G, et al. Rare Disorders of Painful Erection: A Cohort Study of the Investigation and Management of Stuttering Priapism and Sleep-Related Painful Erection. J Sex Med 2021;18:376–384.

The spaceborne active sounders have been contributing invaluable vertically resolved information of atmospheric optical properties since the launch of CALIPSO (Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation) in 2006. To ensure the continuity of climate studies and monitoring the global changes, one has to understand the differences between lidars operating at different wavelengths, flying at different orbits, and utilizing different observation geometries, receiving paths, and detectors. In this article, we show the results of an intercomparison study of ALADIN (Atmospheric Laser Doppler INstrument) and CALIOP (Cloud-Aerosol Lidar with Orthogonal Polarization) lidars using their scattering ratio (SR) products for the period of 28/06/2019−31/12/2019. We suggest an optimal set of collocation criteria (Δdist&thinsp

In the present study we aimed to investigate the surgical outcomes of patients with persistent penile curvature (PC) after Collagenase Clostridium histolyticum (CCH) intraplaque injections. Data from 90 patients with persistent PC after CCH in a multicentre study from 6 andrological centres were retrospectively reviewed. Three standardized surgical techniques were performed. Group 1: plaque incision grafting (PIG) with penile prosthesis implant (PPI); Group 2: PIG without PPI; Group 3: Nesbit technique. Hospital stay, operative time, postoperative complications and PC persistency/recurrence (> 20°) were evaluated. Overall satisfaction and functional outcomes were assessed through International Index of Erectile Function-Erectile Function (IIEF-EF), Peyronie’s Disease Questionnaire (PDQ), Female Sexual Function Index (FSFI) administered pre and 3 months postoperatively. Of all, 25 (27.8%) patients received grafting procedure + PPI (Group 1), 18 (20.0%) patients belonged to Group 2, and 47 (52.2%) to Group 3. Bovine pericardium graft and collagen fleece have been used in in 22 (51.2%) and 21 (48.8%) patients, respectively. Median penile length after surgery was 13.0 cm (IQR 12.0–15.0). After surgery, Group 1 showed higher increase in penile length after surgery and better improvements in terms of PDQ-PS. In contrast, both IIEF-EF and FSFI scores did not differ among groups. Overall, 86 (95.6%) did not report any complication. 4 (4.4%) patients had PC recurrence; of those, 2 (8.0%), 1 (5.6%) and 1 (2.1%) cases were observed in Group 1, Group 2 and Group 3, respectively. In case of persistent PC after CCH, surgical correction by grafting with or without concomitant PPI or Nesbit technique emerged as a technically feasible, effective and safe procedure, with no significant postoperative complications. post-print 1243 KB

Activated PI3K-kinase Delta Syndrome (APDS) is an autosomal-dominant primary immunodeficiency (PID) caused by the constitutive activation of the PI3Kδ kinase. The consequent hyperactivation of the PI3K-Akt-mTOR pathway leads to an impaired T- and B-cells differentiation and function, causing progressive lymphopenia, hypogammaglobulinemia and hyper IgM. Patients with APDS show recurrent sinopulmonary and chronic herpes virus infections, immune dysregulation manifestations, including cytopenia, arthritis, inflammatory enteropathy, and a predisposition to persistent non-neoplastic splenomegaly/lymphoproliferation and lymphoma. The recurrence of the lymphoproliferative disorder and the difficulties in the proper definition of malignancy on histological examination represents the main challenge in the clinical management of APDS patients, since a prompt and correct diagnosis is needed to avoid major complications. Targeted therapies with PI3Kδ-Akt-mTOR pathway pharmacologic inhibitors (i.e., Rapamycin, Theophylline, PI3K inhibitors) represent a good therapeutic strategy. They can also be used as bridge therapies when HSCT is required in order to control refractory symptoms. Indeed, treated patients showed a good tolerance, improved immunologic phenotype and reduced incidence/severity of immune dysregulation manifestations. Here, we describe our experience in the management of four patients, one male affected with APDS1 (P1) and the other three, a male and two females, with APDS2 (P2, P3, P4) presenting with chronic EBV replication, recurrent episodes of immune dysregulation manifestations and lymphomas. These cases highlighted the importance of a tailored and close follow-up, including serial endoscopic and lymph nodes biopsies control to detect a prompt and correct diagnosis and offer the best therapeutic strategy.

Gut involvement is frequent in immunologic disorders, especially with inflammatory manifestations but also with cancer. In the last years, advances in functional and genetic testing have improved the diagnostic and therapeutic approach to immune dysregulation syndromes. CTLA-4 deficiency is a rare disease with variable phenotype, ranging from absence of symptoms to severe multisystem manifestations and complications. We describe a rare case of CTLA-4 deficiency in a boy with gastric cancer, very early onset inflammatory bowel disease and polyautoimmunity, the second-ever reported in the literature with the same characteristics. A 17-year-old boy was referred to Bambino Gesu Children's Hospital of Rome, a tertiary care center, for a gastric mass and a long-term history of very early onset inflammatory bowel disease, diabetes mellitus type 1, polyarthritis and psoriasis. Histology of gastric biopsies revealed the presence of neoplastic signet ring cells. Imaging staging showed localized cancer; therefore, the patient underwent subtotal gastrectomy with termino-lateral gastro-jejunal anastomosis. Immunological work up and genetic testing by next-generation sequencing panels for primary immunodeficiencies led to the diagnosis of CTLA-4 deficiency. Good disease control was obtained with the administration of Abatacept. The patient experienced an asymptomatic SARS-CoV-2 infection without any concern. Eighteen months after treatment initiation, the patient is alive and well. Immunologic and genetic testing, such as next-generation sequencing, should always be part of the diagnostic approach to patients with complex immune dysregulation syndrome, severe clinical course, poor response to treatments or cancer. The early recognition of the monogenic disease is the key for disease management and targeted therapy.

Background: Primary Immunodeficiencies (PIDs) are a heterogeneous group of genetic immune disorders. While some PIDs can manifest with more than one phenotype, signs, and symptoms of various PIDs overlap considerably. Recently, novel defects in immune-related genes and additional variants in previously reported genes responsible for PIDs have been successfully identified by Next Generation Sequencing (NGS), allowing the recognition of a broad spectrum of disorders. Objective: To evaluate the strength and weakness of targeted NGS sequencing using custom-made Ion Torrent and Haloplex (Agilent) panels for diagnostics and research purposes. Methods: Five different panels including known and candidate genes were used to screen 105 patients with distinct PID features divided in three main PID categories: T cell defects, Humoral defects and Other PIDs. The Ion Torrent sequencing platform was used in 73 patients. Among these, 18 selected patients without a molecular diagnosis and 32 additional patients were analyzed by Haloplex enrichment technology. Results: The complementary use of the two custom-made targeted sequencing approaches allowed the identification of causative variants in 28.6% (n = 30) of patients. Twenty-two out of 73 (34.6%) patients were diagnosed by Ion Torrent. In this group 20 were included in the SCID/CID category. Eight out of 50 (16%) patients were diagnosed by Haloplex workflow. Ion Torrent method was highly successful for those cases with well-defined phenotypes for immunological and clinical presentation. The Haloplex approach was able to diagnose 4 SCID/CID patients and 4 additional patients with complex and extended phenotypes, embracing all three PID categories in which this approach was more efficient. Both technologies showed good gene coverage. Conclusions: NGS technology represents a powerful approach in the complex field of rare disorders but its different application should be weighted. A relatively small NGS target panel can be successfully applied for a robust diagnostic suspicion, while when the spectrum of clinical phenotypes overlaps more than one PID an in-depth NGS analysis is required, including also whole exome/genome sequencing to identify the causative gene.

Introduction: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is a rare primary immune regulatory disorder caused by heterozygous gain of function mutation in the PIK3R1 gene encoding PI3Kδ regulatory p85α subunit and resulting in PI3Kδ hyperactivation. Clinical features range from recurrent infections to manifestations of immune dysregulation like autoimmunity, inflammation, systemic lymphoproliferation, and increased risk of cancer. We describe a new dominant PIK3R1 mutation causing APDS2 presenting with lymphoma and systemic refractory autoimmunity.Case Presentation: A 30-year-old woman was referred to the Immunology Unit of our hospital for uncontrolled systemic lupus erythematosus, including chilblains lesions, systemic lymphoproliferation and IgA deficiency. At 19 years of age, she was diagnosed with Hodgkin's lymphoma. Subsequently, she presented systemic lupus erythematosus onset, with episodes of severe exacerbation, including autoimmune hemolytic anemia and pleuro-pericarditis. Initial clinical response to conventional treatments was reported. Immunological investigations performed during our first observation showed severe lymphopenia, IgA deficiency, elevated IgM with reduced IgG2 levels, and low vaccination antibody titers. Quantitative real-time polymerase chain reaction (PCR) assay for Cytomegalovirus and Epstein-Barr virus showed low viral loads for both viruses in serum. An increase of serum inflammatory markers highlighted persistent systemic hyperinflammation. The next-generation sequencing (NGS)-based gene panel tests for primary immunodeficiency showed a heterozygous A>G substitution in the splice acceptor site at c.1300-2 position of PIK3R1, leading to exon-skipping.Conclusion: This case emphasizes the importance of suspecting primary immune regulatory disorders in young adults, predominantly showing a severe, aggressive, and refractory to treatment immune dysregulation phenotype, even in the absence of major infectious diseases at the onset. Different treatments can be promptly started, and a delayed diagnosis can highly impact the outcome. Targeted therapy against PI3Kδ pathway defect effectively improves drug-resistant autoimmunity, lymphoproliferation, and risk of progression to malignancy; eligible patients could benefit from its use even as a bridge therapy to transplantation, currently the only definitive curative treatment. Therefore, identifying genetic mutation and prompt targeted treatment are essential to control disease manifestations, prevent long-term sequelae, and enable curative HSCT in APDS2 patients.

Study question What is the role of endocrine stimulation therapy prior to mTESE in men with hypogonadism and non obstructive azoospermia (NOA)? Summary answer In hypogonadal men there is a positive correlation between change of serum Testosterone (ΔT) before and after stimulation, and a successful mTESE. What is known already NOA is the most common cause of azoospermia and it is often associated with hypogonadism and testicular failure. It is common practice for endocrine stimulation therapies such as gonadotropines or selective estrogens receptor modulators to be used prior mTESE; however there is currently paucity of data regarding their efficacy. Study design, size, duration Retrospective analysis on infertile men with hypogonadism (defined as T Participants/materials, setting, methods Retrospective study on infertile men who underwent mTESE with or without prior endocrine stimulation therapy. Hypogonadism was defined as serum testosterone (T) level Main results and the role of chance One-hundred-sixty-eight men underwent mTESE out of which 59 men received endocrine stimulation therapy for NOA between 2015–2020. Among them, we selected men with hypogonadism defined as serum T Testosterone levels significantly increased after endocrine stimulation (6.3±3.3nm/L vs 11.7±7.4nm/L) with mean change in serum testosterone (ΔT) of 5.7 nm/L (–5.5–23.3, N35). In the stimulated group, pre-operative serum T levels were significantly higher (11.7±7.4 vs 7.8±3.0 p:0.007) as compared to unstimulated men but the success rate of mTESE did not differ significantly (16/40–40%) vs 13/31–42%). Men with Klinefelter syndrome demonstrated significant differences with regards to age, lower T levels, higher FSH and LH levels, lower Johnsen score and success rates compared to other causes of NOA. Comparing men who had successful mTESE vs unsuccessful mTESE - higher T and lower FSH and LH seemed to correlate with successful sperm retrieval. Among men who received endocrine stimulation therapy the ΔT before and after stimulation seemed to correlate with successful sperm retrieval (AUC:0.701, SE:0.089, p:0.043). In the stimulated group a ΔT>3.5nm/L showed a significant association with successful mTESE(p:0.041). Limitations, reasons for caution Retrospective study limitations. Wider implications of the findings: Our study shows a significant improvement of serum T following endocrine stimulation therapy. Overall, in hypogonadal men, the hormonal stimulation seems not to be related to a higher success rate of mTESE but our data do suggest a positive correlation between ΔT before and after stimulation, and a successful mTESE. Trial registration number Not applicable

Ischaemic priapism (IP) is characterised by a persistent, painful penile erection lasting for >4 h. Many causes of IP have been identified including haematological dyscrasias (particularly, sickle cell disease), drugs and rarely malignancy. There are also a large proportion of men, in which no aetiology is identified. Identification of men at risk for malignancy provides a diagnostic challenge to the clinicians looking after these patients. All cases of IP between 2007 and 2017 at a single tertiary andrology unit were identified. The case notes and electronic records of these patients were reviewed to identify cases of malignant priapism. Men with idiopathic IP were used as a control group for comparative statistics. In total, 412 men with IP were identified, 202 of which had idiopathic IP. Within this group, the prevalence of malignant priapism was 3.5% (n = 11). MP secondary to local invasion or penile metastases occurred in seven of the 11 men (bladder × 3, prostate, lung, urethral and chondrosarcoma of the pelvis). MP secondary to haematological malignancy occurred in the remaining four (chronic myeloid leukaemia × 2, chronic lymphocytic leukaemia, and myelodysplasia). IP was the initial presentation of malignancy in seven of the patients (64%). An abnormally low haemoglobin value (reference range 130-180 g/dl) was found in 82% (n = 9) of the men with MP. The mean haemoglobin value in men with MP was 109.64 ± 20.30 g/dl compared to the control of 131.87 ± g/dl. This difference was considered highly significant p = 0.0046. Men with MP also appear to have a very poor prognosis with an 18-month mortality of 64% (n = 7). Malignancy is a rare and important cause of IP. A low haemoglobin is a predictor of malignancy and warrants further investigation in IP.

Purpose We described clinical, immunological, and molecular characterization within a cohort of 22 RAG patients focused on the possible correlation between clinical and genetic data. Methods Immunological and genetic features were investigated by multiparametric flow cytometry and by Sanger or next generation sequencing (NGS) as appropriate. Results Patients represented a broad spectrum of RAG deficiencies: SCID, OS, LS/AS, and CID. Three novel mutations in RAG1 gene and one in RAG2 were reported. The primary symptom at presentation was infections (81.8%). Infections and autoimmunity occurred together in the majority of cases (63.6%). Fifteen out of 22 (68.2%) patients presented autoimmune or inflammatory manifestations. Five patients experienced severe autoimmune cytopenia refractory to different lines of therapy. Total lymphocytes count was reduced or almost lacking in SCID group and higher in OS patients. B lymphocytes were variably detected in LS/AS and CID groups. Eighteen patients underwent HSCT permitting definitive control of autoimmune/hyperinflammatory manifestations in twelve of them (80%). Conclusion We reinforce the notion that different clinical phenotype can be found in patients with identical mutations even within the same family. Infections may influence genotype–phenotype correlation and function as trigger for immune dysregulation or autoimmune manifestations. Severe and early autoimmune refractory cytopenia is frequent and could be the first symptom of onset. Prompt recognition of RAG deficiency in patients with early onset of autoimmune/hyperinflammatory manifestations could contribute to the choice of a timely and specific treatment preventing the onset of other complications.

Men with Stuttering Priapism (SP) and sleep-related painful erections (SRPE) experience bothersome nocturnal painful erections resulting in poor sleep. The aim of this study is to observe common features and differences between men with SP and SRPE based on polysomnography, nocturnal penile tumescence (NPT), and penile doppler ultrasound (PDU). This is a prospective cohort study of 20 participants divided into two groups (Group 1 = SP [n = 12]; Group 2 = SRPE [n = 8]) with bothersome painful nocturnal erections. All participants were referred to the sleep disorder clinic to be assessed and consented for overnight polysomnography with simultaneous NPT recording and to complete validated sleep, sexual dysfunction and health-related quality of life questionnaires. Unstimulated PDU was also performed. Abnormal Polysomnographic findings (reduced sleep efficiency, total sleep time, and awake after sleep onset) were identified in both groups suggesting poor sleep. Men with SP had significantly longer erections (60.0 vs 18.5; p = 0.002) and took longer to detumesce once awake (25.7 vs 5.4 min; p = 0.001) than men with SRPE. They also had significantly higher peak systolic and end diastolic velocities on unstimulated PDU with an abnormal low resistance waveform identified. No sleep pathology was identified in men with SP. This implies a local (penile) etiology in men with SP. Men with SRPE had a normal resting PDU and abnormal sleep architecture with REM awakenings and significantly more Periodic limb movements (p = 0.04) than men with SP suggesting a central (sleep-related) cause in men with SRPE. Sexual dysfunction and poor HR-QoL was identified on validated questionnaires in both groups. SP and SRPE are rare entities that share similar symptoms (painful nocturnal erections and poor sleep) but dissimilar features of nocturnal erection onset, duration and resolution with different polysomnographic features which may allude to a different pathophysiology.

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive neurodegenerative disease. Richardson's syndrome (PSP-RS) and predominant parkinsonism (PSP-P) are characterized by wide range of cognitive and behavioural disturbances, but these variants show similar cognitive pattern of alterations, leading difficult differential diagnosis. For this reason, we explored with an Artificial Intelligence approach, whether cognitive impairment could differentiate the phenotypes. Forty Parkinson's disease (PD) patients, 25 PSP-P, 40 PSP-RS, and 34 controls were enrolled following the consensus criteria diagnosis. Participants were evaluated with neuropsychological battery for cognitive domains. Random Forest models were used for exploring the discriminant power of the cognitive tests in distinguishing among the four groups. The classifiers for distinguishing diseases from controls reached high accuracies (86% for PD, 95% for PSP-P, 99% for PSP-RS). Regarding the differential diagnosis, PD was discriminated from PSP-P with 91% (important variables: HAMA, MMSE, JLO, RAVLT_I, BDI-II) and from PSP-RS with 92% (important variables: COWAT, JLO, FAB). PSP-P was distinguished from PSP-RS with 84% (important variables: JLO, WCFST, RAVLT_I, Digit span_F). This study revealed that PSP-P, PSP-RS and PD had peculiar cognitive deficits compared with healthy subjects, from which they were discriminated with optimal accuracies. Moreover, high accuracies were reached also in differential diagnosis. Most importantly, Machine Learning resulted to be useful to the clinical neuropsychologist in choosing the most appropriate neuropsychological tests for the cognitive evaluation of PSP patients.

Chronic granulomatous disease (CGD) is a rare inborn error of immunity (IEI), characterized by a deficient phagocyte killing due to the inability of NADPH oxidase to produce reactive oxygen species in the phagosome. Patients with CGD suffer from severe and recurrent infections and chronic inflammatory disorders. Onset of CGD has been rarely reported in neonates and only as single case reports or small case series. We report here the cases of three newborns from two different kindreds, presenting with novel infectious and inflammatory phenotypes associated with CGD. A girl with CYBA deficiency presented with necrotizing pneumonia, requiring a prolonged antibiotic treatment and resulting in fibrotic pulmonary changes. From the second kindred, the first of two brothers developed a fatal Burkholderia multivorans sepsis and died at 24 days of life. His younger brother had a diagnosis of CYBB deficiency and presented with Macrophage Activation Syndrome/Hemophagocytic Lympho-Histiocytosis (MAS/HLH) without any infection, that could be controlled with steroids. We further report the findings of a review of the literature and show that the spectrum of microorganisms causing infections in neonates with CGD is similar to that of older patients, but the clinical manifestations are more diverse, especially those related to the inflammatory syndromes. Our findings extend the spectrum of the clinical presentation of CGD to include unusual neonatal phenotypes. The recognition of the very early, potentially life-threatening manifestations of CGD is crucial for a prompt diagnosis, improvement of survival and reduction of the risk of long-term sequelae.

Background: Glucose alterations are associated with impaired cognition. The 1-h-post-load plasma glucose ≥155 mg/dl in non-diabetic subjects confers an increased risk of cardiovascular events and diabetes. This pilot study aimed to investigate whether the 1-h-post-load plasma glucose ≥155 mg/dl negatively affects the subcortical regions of the brain and the cognitive functions.Methods: We enrolled 32 non-diabetic subjects. Patients were divided into two groups based on 1-h- post-load plasma glucose value > or < 155 mg/dl: normal glucose tolerance (NGT) 1-h-high and NGT 1-h-low subjects. All subjects underwent 3 Tesla MRI and standard neuropsychological tests.Results: NGT 1-h-high subjects showed significantly lower values of both right (4.9 ± 0.9 vs. 5.1 ± 0.9 ml) and left (4.8 ± 1.1 vs. 5.1 ± 1.1 ml) hippocampal hemisphere volume, while right hemisphere hippocampal diffusivity was lower in the NGT 1-h-high group (10.0 ± 0.6 vs. 10.6 ± 0.5 10−4 mm2s−1). NGT 1-h-high subjects also showed a poorer memory performance. In particular, for both Rey Auditory Verbal Learning Task (RAVLT)—immediate-recall and Free and Cued Selective Reminding Test (FCSRT)—delayed total recall, we found lower cognitive test scores in the NGT-1 h-high group (26.5 ± 6.3 and 10.4 ± 0.3, respectively).Conclusions: One-hour-post-load hyperglycemia is associated with morpho-functional subcortical brain alterations and poor memory performance tests.

We described for the first time a female patient with the simultaneous presence of two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial infections, elevated IgE, and persistent EBV viremia. In addition to defective TLR/IL1R-signaling, we described novel functional alterations into the myeloid compartment. In particular, we demonstrated a defective production of reactive oxygen species exclusively in monocytes upon E. coli stimulation, the inability of immature mono-derived DCs (iDCs) to differentiate into mature DCs (mDCs) and the incapacity of mono-derived macrophages (MDMs) to resolve BCG infection in vitro. Our data do not provide any evidence for digenic inheritance in our patient, but rather for the association of two monogenic disorders. This case illustrates the importance of using next generation sequencing (NGS) to determine the most accurate and early diagnosis in atypical clinical and immunological phenotypes, and with particular concern in consanguineous families. Indeed, besides the increased susceptibility to recurrent invasive pyogenic bacterial infections due to MYD88 deficiency, the identification of CARD9 mutations underline the risk of developing invasive fungal infections emphasizing the careful monitoring for the occurrence of fungal infection and the opportunity of long-term antifungal prophylaxis. Highlights - Patient with atypical primary immunodeficiency - Clinical manifestations: pyogenic bacterial infections, high IgE level, and persistent EBV viremia - Next-generation sequencing reveals two homozygous mutations in MYD88 and CARD9 genes leading to complete absence of proteins - Monocytes/macrophages function and DC differentiation were severely compromised - NGS has a key role to determine the correct diagnosis in atypical primary immunodeficiency leading to reconsider the individualized treatment.

BACKGROUND: Interferon-induced expression of programmed cell death ligands (PD-L1/PD-L2) may sustain tumour immuneevasion. Patients featuring MET amplification, a genetic lesion driving transformation, may benefit from anti-MET treatment. We explored if MET-targeted therapy interferes with Interferon-gamma modulation of PD-L1/PD-L2 in MET-amplified tumours.METHODS: PD-L1/PD-L2 expression and signalling pathways downstream of MET or Interferon-gamma were analysed in MET-amplified tumour cell lines and in patient-derived tumour organoids, in basal condition, upon Interferon-gamma stimulation, and after anti-MET therapy.RESULTS: PD-L1 and PD-L2 were upregulated in MET-amplified tumour cells upon Interferon-gamma treatment. This induction was impaired by JNJ-605, a selective inhibitor of MET kinase activity, and MvDN30, an antibody inducing MET proteolytic cleavage. We found that activation of JAKs/STAT1, signal transducers downstream of the Interferon-gamma receptor, was neutralised by MET inhibitors. Moreover, JAK2 and MET associated in the same signalling complex depending on MET phosphorylation. Results were confirmed in MET-amplified organoids derived from human colorectal tumours, where JNJ-605 treatment revoked Interferon-gamma induced PD-L1 expression.CONCLUSIONS: These data show that in MET-amplified cancers, treatment with MET inhibitors counteracts the induction of PD-1 ligands by Interferon-gamma. Thus, therapeutic use of anti-MET drugs may provide additional clinical benefit over and above the intended inhibition of the target oncogene.

Lam et al. characterize a novel hematological/autoinflammatory disorder due to a de novo recurrent missense mutation of CDC42. The authors use in silico, in vitro, and in vivo analyses to correlate the molecular mechanisms altering CDC42 function to the observed phenotype., Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival., Graphical Abstract

INTRODUCTION AND OBJECTIVE:The goal of genital female-to-male (FTM) gender affirming surgery is to create an aesthetically acceptable phallus to allow voiding while standing and penetrative sexual ...

Perinatally HIV-infected children (PHIV), despite successful antiretroviral therapy, present suboptimal responses to vaccinations compared to healthy-controls (HC). Here we investigated phenotypic and transcriptional signatures of H1N1-specific B-cells (H1N1-Sp) in PHIV, differentially responding to trivalent-influenza-vaccine (TIV), and HC. Patients were categorized in responders (R) and non-responders (NR) according to hemagglutination-inhibition-assay at baseline and 21 days after TIV. No differences in H1N1-Sp frequencies were found between groups. H1N1-Sp transcriptional analysis revealed a distinct signature between PHIV and HC. NR presented higher PIK3C2B and NOD2 expression compared to R, confirmed by downregulation of PIK3C2B in resting-memory of R after H1N1 in-vitro stimulation. In conclusion this study confirms that qualitative rather than quantitative analyses are needed to characterize immune responses in PHIV. These results further suggest that higher PIK3C2B in H1N1-Sp of NR is associated with lower H1N1 immunogenicity and may be targeted by future modulating strategies to improve TIV responses in PHIV.

Collagenase clostridium histiolyticum (CCH), administered as an intra-lesional injection, is the first licensed, non-surgical treatment for Peyronie’s Disease. Its safety and efficacy have been widely demonstrated in the literature, which includes several large, randomised controlled trials. Each treatment cycle described in these trials involved two injections of CCH at six-weekly intervals, combined with physician modeling. A modified protocol has been developed in London, wherein only a single injection is given in each cycle, and physician modeling is replaced by manual stretching and the use of a vacuum pump by the patient at home. Further refinements are currently underway. While the response to treatment with CCH is difficult to predict, several factors have been identified that influence the likelihood of success. Thorough clinical assessment and careful patient counseling are also imperative to optimize this.

Machine Learning application on clinical data in order to support diagnosis and prognostic evaluation arouses growing interest in scientific community. However, choice of right algorithm to use was fundamental to perform reliable and robust classification. Our study aimed to explore if different kinds of Machine Learning technique could be effective to support early diagnosis of Multiple Sclerosis and which of them presented best performance in distinguishing Multiple Sclerosis patients from control subjects. We selected following algorithms: Random Forest, Support Vector Machine, Naïve-Bayes, K-nearest-neighbor and Artificial Neural Network. We applied the Independent Component Analysis to resting-state functional-MRI sequence to identify brain networks. We found 15 networks, from which we extracted the mean signals used into classification. We performed feature selection tasks in all algorithms to obtain the most important variables. We showed that best discriminant network between controls and early Multiple Sclerosis, was the sensori-motor I, according to early manifestation of motor/sensorial deficits in Multiple Sclerosis. Moreover, in classification performance, Random Forest and Support Vector Machine showed same 5-fold cross-validation accuracies (85.7%) using only this network, resulting to be best approaches. We believe that these findings could represent encouraging step toward the translation to clinical diagnosis and prognosis.

Background Jagunal homolog 1 (JAGN1) gene was identified as a novel responsible for severe congenital neutropenia. The protein encoded by this gene is required for neutrophil differentiation, survival and function in microbial activity. JAGN1-deficient human neutrophils are characterized by alterations in trafficking within the endoplasmic reticulum and golgi compartments because of ultrastructural defects in endoplasmic reticulum and susceptibility to apoptosis. Observations We report a patient exhibiting an intermittent neutropenia, for which a next-generation sequencing revealed a homozygous mutation in the JAGN1 gene. Conclusions The patient extends the clinical variability associated to JAGN1 mutations, and this case highlights the importance of genetic investigations in patients with suspected neutropenia.

Multiparametric flow cytometry (MFC) represents a rapid, highly reproducible, and sensitive diagnostic technology for primary immunodeficiencies (PIDs), which are characterized by a wide range of T cell perturbations and a broad clinical and genetic heterogeneity. MFC data from CD4+ and CD8+ T cell subsets were examined in 100 patients referred for Primary Immunodeficiencies to our center. Naïve, central memory, effector memory, and terminal effector memory cell differentiation stages were defined by the combined expression CD45RA/CD27 for CD4 and CD45RA/CCR7 for CD8. Principal component analysis (PCA), a non-hypothesis driven statistical analysis, was applied to analyze MFC data in order to distinguish the diverse PIDs. Among severe lymphopenic patients, those affected by severe combined and combined immunodeficiency (SCID and CID) segregated in a specific area, reflecting a homogenous, and a more severe T cell impairment, compared to other lymphopenic PID, such as thymectomized and partial DiGeorge syndrome patients. PID patients with predominantly antibody defects were distributed in a heterogeneous pattern, but unexpectedly PCA was able to cluster some patients' resembling CID, hence warning for additional and more extensive diagnostic tests and a diverse clinical management. In conclusion, PCA applied to T cell MFC data might help the physician to estimate the severity of specific PID and to diversify the clinical and diagnostic approach of the patients.

Patients with severe combined immunodeficiency (SCID) exhibit T lymphopenia and profound impairments in cellular and humoral immunity. IL-7 receptor α (IL-7Rα) deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive and high risk of mortality unless treated. Here, we reported an atypical and delayed onset of IL7Rα-SCID in a 15-month-old girl presenting with thrombocytopenia. Immunological investigations showed a normal lymphocyte count with isolated CD4-penia, absence of naïve T cells, marked hypergammaglobulinemia, and maternal T cell engraftment. Targeted next generation sequencing (NGS) revealed two novel compound heterozygous mutations in the IL-7Rα gene: c.160T>C (p.S54P) and c.245G>T (p.C82F). The atypical onset and the unusual immunological phenotype expressed by our patient highlights the diagnostic challenge in the field of primary immunodeficiencies (PID) and in particular in SCID patients where prompt diagnosis and therapy greatly affects survival.

Priapism is a urological emergency that is defined as a prolonged penile erection lasting more than 4 h, remaining despite orgasm and in the absence of sexual stimulation. Without prompt and complete detumescence, time-dependent changes occur to the smooth muscle of the corpus cavernosa that can result in permanent erectile dysfunction and penile deformity (curvature, shortening and loss of girth). The diagnosis is confirmed with a hypoxic and acidotic blood sample from the corpus cavernosa. The trapped blood inside the corpus cavernosa is aspirated and can be irrigated with 0.9% normal saline. Intracavernosal injection of a sympathomimetic agent is used to cause smooth muscle contraction if the previous measures fail. Failure or recurrence of priapism following these conservative measures is an indication for surgical management. Shunt procedures that create a connection with the corpus cavernosa and a neighbouring structure are often used first line. Multiple shunt procedures have been described and these are summarised in this article. Distal shunt procedures are the most commonly used as they are easier to perform and seem to have at least comparable detumescence and potency rates. Refractory or prolonged (>48 h) ischaemic priapism maybe an indication of immediate placement of a penile prosthesis.

Objective: REM sleep behavior disorder (RBD) is an important risk factor for the dementia development and for the deterioration of autonomic functions in patients with Parkinson's Disease. RBD has also been reported in patients with Essential Tremor (ET). However, its clinical significance in ET remains still unknown. We aimed to investigate clinical, neuropsychological and cardiac autonomic scintigraphic differences between ET patients with and without RBD. Methods: To assess RBD symptoms, RBD Single-Question has been administered in a cohort of 55 patients with a clinical diagnosis of ET. Patients with clinical RBD underwent polysomnography (PSG) confirmation. All patients completed a battery of neuropsychological assessment of memory, executive function, attention, language, and visuospatial function. Cardiac MIBG scintigraphy was performed in order to measure the cardiac autonomic innervation. Results: Ten ET patients (18%) had a PSG-confirmed RBD (ETRBD+). Compared to ET patients without RBD (ETRBD-), significantly reduced scores on memory domain tests such as Rey auditory verbal learning test immediate recall (p = 0.015) and Rey auditory verbal learning test delayed recall (p = 0.004) and phonemic fluency test (p = 0.028) were present in ETRBD+. By contrast, no other significant clinical difference has emerged from the comparison between two ET groups. Similarly, ETRBD+ patients have cardiac MIBG tracer uptake in the normal value range as occurred in those with ETRBD-. Conclusions: This study improves the knowledge on clinical significance of RBD symptoms in ET patients. Our preliminary findings demonstrate that presence of RBD in ET is associated with neurocognitive impairment, but not with cardiac autonomic dysfunction. Further longitudinal studies are needed to investigate whether ET patients with RBD will develop a frank dementia over the time.

Introduction There is growing evidence that a proportion of patients with Essential Tremor (ET) may develop a memory impairment over time. However, no studies have evaluated whether hippocampal damage really occur in ET. This study investigated the macro and micro-structural integrity of the hippocampus in ET subjects using a multimodal MRI approach. Methods Neuropsychological and MRI data were acquired from 110 participants (60 patients with ET and 50 age-, sex-, and education-matched healthy controls [HC]). Whole-brain T1-weighted and Diffusion Tensor Imaging (DTI) were performed to assess macro-and microstructural alterations. MRI parameters (volume; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi were obtained. In order to evaluate the relationship between MRI alterations and neurocognitive impairment, hippocampal parameters were also correlated with cognitive test scores. Results Compared to controls, ET patients showed a subclinical memory impairment with significantly lower memory scores, but within the normal ranges. Despite the subclinical damage, however, ET patients showed a significant increase in MD values in the bilateral hippocampi in comparison with HC. A significant correlation was also found between MD and memory scores in ET. Conclusion This study improves the knowledge on memory impairment in ET, as our results demonstrate for the first time the hippocampal microstructural damage related to subclinical memory impairment in ET patients. Further studies are needed before these findings can be considered predictive of a distinct ET subtype or suggestive of a co-occurent dementia.

INTRODUCTION AND OBJECTIVES:Total penile reconstruction (TPC) is challenging, with surgical goals including an acceptable cosmetic and functional phallus, with restoration of sufficient penile leng...

INTRODUCTION AND OBJECTIVES:There is still a lack of consensus in the literature about the timing of penile (PP) prosthesis surgery following refractory ischaemic priapism (IP). The aim of this stu...

In the context of an atmospheric network of multi-instrumented sites equipped with sky camera for cloud monitoring, we present an algorithm named ELIFAN which aims at estimating the cloud cover amount from full sky visible daytime images with a common principle and procedure. ELIFAN was initially developped for a self-made full sky image system presented in this article, and adapted to a set of other systems in the network. It is based on red over blue ratio thresholding for the distinction of cloudy and clear sky pixels of the image, and on the use of a blue sky library. Both an absolute (without use of reference image) and a differential (based on a blue sky reference image) red/blue ratio thresholding are used. An evaluation of the algorithm based on a one-year long series of images shows that the proposed algorithm is very convincing for most of the images, with more than 95 % of relevance in the process, outside the sunrise and sunset transitions. During those latter periods though, ELIFAN has large difficulties to appropriately process the image, due to a drastic difference of color composition and a potential confusion between clear and cloudy sky at that time. The two thresholding methodologies, the absolute and the differential red/blue ratio thresholding processes, agree very well with departure usually below 8 %, except in sunrise/sunset periods and in some specific conditions. The use of the clear sky library gives generally better results than the absolute process. Especially, it better detects the thin cirrus clouds. But the absolute thresholding process turns out to be sometimes better, for example in fully cloudy skies. The combination of pyranometer, ceilometer and sky camera illustrates the performance of ELIFAN, and reveals the comple-mentarity of the three instruments. We especially show that a similar cloud cover amount is deduced from both the sky imager and the ceilometer when the clouds are low (below 3 km). But they can lead to significantly different cloud cover estimates when the clouds are high. In this case, we find that the sky imager catches more appropriately the cloud cover estimate, due to its 2D integrated point of view and to the loss of sensitivity of the ceilometer above 7 km.

International audience; In this paper we characterize the seasonal and inter-annual variabilities of cloud fraction profiles in both observations and simulation since they are critical to better assess the impact of clouds on climate variability. The spaceborne lidar onboard CALIPSO, providing cloud vertical profiles since 2006, is used together with a 23-year WRF simulation at 20 km resolution. A lidar simulator helps to compare consistently model with observations. The bias in observations due to the satellite under-sampling is first estimated. Then we examine the vertical variability of both occurrence and properties of clouds. It results that observations indicate a similar occurrence of low and high clouds over continent, and more high than low clouds over the sea except in summer. The simulation shows an overestimate (underestimate) of high (low) clouds comparing to observations, especially in summer. However the seasonal variability of cloud vertical profiles is well captured by WRF. Concerning inter-annual variability, observations show that in winter, those of high clouds is twice the low clouds one, an order of magnitude that is is well simulated. In summer, the observed inter-annual variability is vertically more homogeneous while the model still simulates more variability for high clouds than for low clouds. The good behavior of the simulation in winter allows us to use the 23 years of simulation and 8 years of observations to estimate the time period required to characterize the natural variability of the cloud fraction profile in winter, i.e. the time period required to detect significant anomalies and trends.

Background: Despite the introduction of direct-acting antiviral agents for chronic hepatitis C virus (HCV) infection, peginterferon alfa/ribavirin remains relevant in many resource-constrained settings. The non-randomized GUARD-C cohort investigated baseline predictors of safety-related dose reductions or discontinuations (sr-RD) and their impact on sustained virologic response (SVR) in patients receiving peginterferon alfa/ribavirin in routine practice. Methods: A total of 3181 HCV-mono-infected treatment-naive patients were assigned to 24 or 48 weeks of peginterferon alfa/ribavirin by their physician. Patients were categorized by time-to-first sr-RD (Week 4/12). Detailed analyses of the impact of sr-RD on SVR24 (HCV RNA

Background and purpose: Corpus callosum (CC) is frequently involved in relapsing-remitting multiple sclerosis (RRMS). Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) allow to study CC macrostructural and microstructural tissue integrity. Here, we applied a data-driven approach to MRI and DTI data of normal-appearing CC in RRMS subjects, and subsequently evaluated if differences in tissue integrity corresponded to different levels of physical disability and cognitive impairment. Methods: 74 RRMS patients and 20 healthy controls (HC) underwent 3 T MRI and DTI. Thickness and fractional anisotropy (FA) along midsagittal CC were extracted, and values from RRMS patients were fed to a hierarchical clustering algorithm. We then used ANOVA to test for differences in clinical and cognitive variables across the imaging-based clusters and HC. Results: We found three distinct MRI-based subgroups of RRMS patients with increasing severity of CC damage. The first subgroup showed callosal integrity similar to HC (Cluster 1); Cluster 2 had milder callosal damage; a third subgroup showed the most severe callosal damage (Cluster 3). Cluster 3 included patients with longer disease duration and worst scores in Expanded Disability Status Scale. Cognitive domains of verbal memory, executive functions and processing speed were impaired in Cluster 3 and Cluster 2 compared to Cluster 1 and HC. Conclusions: Within the same homogeneous cohort of patients, we could identify three neuroimaging RRMS clusters characterized by different involvement of normal-appearing CC. Interestingly, these corresponded to three distinct levels of clinical and cognitive disability.

International audience; Synthetic multi‐decadal space‐borne lidar records are used to examine when a cloud response to anthropogenic forcing would be detectable from space‐borne lidar observations. The synthetic records are generated using long‐term cloud changes predicted by two CMIP5 (Coupled Model Intercomparison Program 5) models seen through the COSP/lidar (CFMIP –Cloud Feedback Model Intercomparison Project, Observation Simulators Package), and cloud inter‐annual variability observed by the CALIPSO (Cloud Aerosol Lidar and Infrared Pathfinder Satellite Observations) spaceborne lidar during the past decade.CALIPSO observations do not show any significant trend yet. Our analysis of the synthetic time series suggests, the Tropical cloud longwave feedback and the Southern ocean cloud shortwave feedback might be constrained with 70% confidence with, respectively, a 20‐year and 29‐year uninterrupted lidar‐in‐space record. A 27‐year record might be needed to separate the two different models predictions in the tropical subsidence clouds.Assuming that combining the CALIPSO and Earth‐CARE (Earth Clouds, Aerosols and Radiation Explorer) missions will lead to a space‐borne lidar record of at least 16 years, we examine the impact of gaps and calibration offsets between successive missions. A 2‐year gap between EarthCARE and the following space‐borne lidar would have no significant impact on the capability to constrain the cloud feedback if all the space lidars were perfectly inter‐calibrated. Any intercalibration shift between successive lidar missions would delay the capability to constrain the cloud feedback mechanisms, larger shifts leading to longer delays.

Aim of the Study: In male infertility, the current challenge is to properly reconcile new and old techniques taking into account costbenefit and scientific evidence for both. The aim of our work was to evaluate if microsurgical reconstruction of the seminal pathway in patients with proximal obstruction can still be considered an effective treatment for infertile men suffering from obstructive azoospermia in the light of new medically assisted procreation techniques. Materials and Methods: From 1995 to 2016, at the Urological Clinic of the University of Trieste and the University College London Hospital (UCLH), 242 patients with obstructive azoospermia underwent microsurgical treatment of recanalization of the seminal pathways. Among these patients, 161 patients underwent Vasoepididimostomy (EDV), 72 at vasovasostomy (VV) and 9 at VV + EDV. The average age was 41 (±7.9). Patients were subdivided according to the type of microsurgical reconstruction performed. Patients previously undergoing unsuccessful attempts at microsurgical reconstruction, patients with infertile or poorly motivated female partners to have a child and patients undergoing recanalization after retention pain vasectomy were excluded from the study. The primary objective of the study was to evaluate the rate of patency of the seminal pathways and the pregnancy rate. Results: In patients undergoing EDV and VV, the success rate in terms of patency of the anastomosis was 75% and 42%, respectively, while the pregnancy rate of 55% and 13%. The patency of the cumulative anastomosis was 48% (109/185) and the general pregnancy rate of 19% (30/161). In the 92 patients who underwent “vasectomy reversal” the mean time interval between vasectomy and microsurgical reconstruction (IT) was 12.2 years (SD: 12.2 ± 6.41; 1–27). In this category of patients the results were inversely proportional to the average time spent by vasectomy. Discussion: According to the literature, our results confirm that microsurgical reconstruction of the seminal pathways remains a valid therapeutic option with an excellent cost/benefit ratio in patients with obstructive azoospermia. The best results are in previously vasectomized patients and are inversely proportional to the time elapsed.

Introduction Differentiating clinically progressive supranuclear palsy-parkinsonism (PSP-P) from Parkinson's disease (PD) may be challenging, especially in the absence of vertical supranuclear gaze palsy (VSGP). The Magnetic Resonance Parkinsonism Index (MRPI) has been reported to accurately distinguish between PSP and PD, yet few data exist on the usefulness of this biomarker for the differentiation of PSP-P from PD. Methods Thirty-four patients with PSP-P, 46 with PSP-Richardson's syndrome (PSP-RS), 53 with PD, and 53 controls were enrolled. New consensus criteria for the clinical diagnosis of PSP were used as the reference standard. The MRPI, and a new index termed MRPI 2.0 including the measurement of the third ventricle width (MRPI multiplied by third ventricle width/frontal horns width ratio), were calculated on T1-weighted MR images. Results The MRPI differentiated patients with PSP-P from those with PD with sensitivity and specificity of 73.5% and 98.1%, respectively, while the MRPI 2.0 showed higher sensitivity (100%) and similar specificity (94.3%) in differentiating between these two groups. Both biomarkers showed excellent performance in differentiating PSP-P patients with VSGP from those with PD, but the MRPI 2.0 was much more accurate (95.8%) than MRPI in differentiating PSP-P patients with slowness of vertical saccades from PD patients. Conclusion The MRPI 2.0 accurately differentiated PSP-P patients from those with PD. This new index was more powerful than MRPI in differentiating PSP patients in the early stage of the disease with slowness of vertical saccades from patients with PD, thus helping clinicians to consolidate the diagnosis based on clinical features, in vivo.

Monogenic defects in genes related to primary immunodeficiencies can be responsible for inflammatory bowel disease (IBD). Mutations in the X-linked inhibitor of apoptosis (XIAP) gene have been described in several patients suffering from IBD and, in particular, with very early-onset inflammatory bowel disease (VEOIBD) features. We report a VEOIBD child with a novel XIAP gene mutation characterized by a complicated disease course, which is unresponsive to several medical treatment options. A next-generation sequencing was performed and revealed a de novo hemizygous mutation in XIAP gene: c.565T>C p.L189P. After mutation discovery, we investigated the XIAP protein expression and nucleotide-binding oligomerization domain protein 2 (NOD2) signaling by western blotting. Flow-cytometry was used to analyze intracellular protein expression in different cell subsets and T cell apoptosis. We observed reduced protein expression in lymphocytes, granulocytes, monocytes, an Epstein–Barr virus-immortalized B cell line as well as increased apoptosis, and impairment in NOD2 signaling. The child was successfully treated with HLA-haploidentical hemapoietic stem cells transplant, acquired from his mother, after ex vivo elimination of α/β T cells and CD19 B cells. One year after the transplant, we repeated the analysis to appreciate the changes in his impairments. The recovery of XIAP protein expression, function, and normalization of apoptosis were observed. Our report emphasizes the important role of genetic analysis in the diagnosis of VEOIBD, illustrates the complete immunological and gastrointestinal recovery after transplant, and shows one of the few successful transplant cases of XIAP patients.

Alzheimer’s disease (AD) and Parkinson’s disease with dementia (PDD) are characterized by a different mnesic failure, particularly in memory cued recall. Although hippocampal involvement has been shown in both these diseases, it remains unknown whether a selective damage of specific subfields within the hippocampus may be responsible for the peculiar mnesic profile observed in AD and PDD. To explore this topic, we combined a multimodal 3 T-MRI hippocampal evaluation (whole-brain T1-weighted and diffusion tensor imaging) with a hippocampal-targeted neuropsychological assessment (Free and Cued Selective Reminding Test [FCSRT]) in 22 AD subjects, 18 PDD and 17 healthy controls. Macro- and microstructural features (volume; shape; mean diffusivity [MD]; fractional anisotropy [FA]) of bilateral hippocampi (whole and subfields) were obtained. Correlations between MRI-derived parameters and neuropsychological evaluations were performed. In the comparison between AD and PDD, the multimodal analysis allowed us to identify that subiculum, CA1 and CA4-DG were differently involved in these diseases and correlated with immediate and delayed total recall items of FCSRT. Moreover, compared to controls, AD showed a reduction in almost all subfields, with a MD increase in the same regions, whereas PDD displayed a volume loss, less severe than AD, more evident in the CA2-3 and presubiculum subfields. Our study provides new evidence that hippocampal subregions had different vulnerability to damage related to AD and PDD. The combination of the in vivo analysis of hippocampal subfields with the FCSRT paradigm provided important insights into whether changes within specific hippocampal subfields are related to the different mnesic profile in AD and PDD patients.