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Membranous glomerulonephritis (MGN) is a common cause of nephrotic syndrome in adults, mediated by glomerular antibody deposition to an increasing number of newly recognised antigens. Previous case reports have suggested an association between patients with anti-contactin-1 (CNTN1)-mediated neuropathies and MGN. In an observational study we investigated the pathobiology and extent of this potential cause of MGN by examining the association of antibodies against CNTN1 with the clinical features of a cohort of 468 patients with suspected immune-mediated neuropathies, 295 with idiopathic MGN, and 256 controls. Neuronal and glomerular binding of patient IgG, serum CNTN1 antibody and protein levels, as well as immune-complex deposition were determined. We identified 15 patients with immune-mediated neuropathy and concurrent nephrotic syndrome (biopsy proven MGN in 12/12), and 4 patients with isolated MGN from an idiopathic MGN cohort, all seropositive for IgG4 CNTN1 antibodies. CNTN1-containing immune complexes were found in the renal glomeruli of patients with CNTN1 antibodies, but not in control kidneys. CNTN1 peptides were identified in glomeruli by mass spectroscopy. CNTN1 seropositive patients were largely resistant to first-line neuropathy treatments but achieved a good outcome with escalation therapies. Neurological and renal function improved in parallel with suppressed antibody titres. The reason for isolated MGN without clinical neuropathy is unclear. We show that CNTN1, found in peripheral nerves and kidney glomeruli, is a common target for autoantibody-mediated pathology and may account for between 1 and 2% of idiopathic MGN cases. Greater awareness of this cross-system syndrome should facilitate earlier diagnosis and more timely use of effective treatment.

Background: Monkeypox virus (mpxv) started to spread to Europe and North America at the beginning of the current outbreak in May 2022, and the World Health Organization (WHO) declared Human Monkeypox (mpox) as a public health emergency of international concern (PHEIC) in July 2022. The aim of this observational analysis is to describe demographical data, symptoms presentation and clinical course till outcome of individuals diagnosed with mpox, between May and October 2022, at our open-access Sexual Health Clinic in IRCCS San Raffaele Hospital in Milan, Italy. Methods: Among people who accessed our Sexual Health Clinic, we considered, as suspected diagnosis of mpox, individuals with consistent symptoms and epidemiological criteria. Following the physical examination, oropharyngeal, anal, genital and cutaneous swabs, plus plasma, urine and seminal fluid were collected as biological materials to detect mpxv DNA. We also performed a screening for sexually transmitted infections (STIs). Results: Overall, 140 individuals with mpox were included in this study. Median age was 37 (interquartile, IQR 33, 43) years old. Males were 137 (98%) and men who have sex with men (MSM) were 134 (96%). As risk factors, we detected travels abroad in 35 (25%) individuals and close contact with mpox cases in 49 (35%). There were 66 (47%) people living with HIV (PLWH). Most frequent symptoms were fever (59%), lymphadenopathy (57%), cutaneous (77%), genital (42%), anal (34%) and oral (26%) lesions, proctitis (39%), sore throat (22%) and generalized rash (5%). At mpox diagnosis, we also observed N. gonorrhoeae in 18 (13%) cases, syphilis in 14 (10%) and C. trachomatis in 12 (9%). Two (1%) people received a concomitant diagnosis of HIV infection. We attended to 21 (15%) complications, with nine (6%) cases of hospitalization including six (IQR 3,7) median hospital days. Forty-five (32%) patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs), 37 (26%) with antibiotics and eight (6%) with antiviral drugs. Conclusions: Similarly to other international cohorts, sexual transmission was most frequently present, and concomitant STIs were common. Symptoms were heterogenous, self-resolving and responsive to therapy. Hospitalization was necessary in few patients. There is uncertainty about the future development of mpox and further studies (e.g., potential disease reservoirs, other possible means of transmission, predictors of severe disease) are still needed.

Immunoglobulin light chain (LC) amyloidosis (AL) is one of the most common types of systemic amyloidosis but there is no reliable in vivo model for better understanding this disease. Here, we develop a transgenic mouse model producing a human AL LC. We show that the soluble full length LC is not toxic but a single injection of pre-formed amyloid fibrils or an unstable fragment of the LC leads to systemic amyloid deposits associated with early cardiac dysfunction. AL fibrils in mice are highly similar to that of human, arguing for a conserved mechanism of amyloid fibrils formation. Overall, this transgenic mice closely reproduces human cardiac AL amyloidosis and shows that a partial degradation of the LC is likely to initiate the formation of amyloid fibrils in vivo, which in turn leads to cardiac dysfunction. This is a valuable model for research on AL amyloidosis and preclinical evaluation of new therapies. The pathophysiology of Amyloid light-chain (AL) amyloidosis remains poorly understood due to the lack of reliable in vivo models. Here, the authors describe a transgenic mouse model that reproduces cardiac AL amyloidosis and provides new information on the formation of AL amyloid fibrils.

Cardiac ATTR amyloidosis, a serious but much under-diagnosed form of cardiomyopathy, is caused by deposition of amyloid fibrils derived from the plasma protein transthyretin (TTR), but its pathogenesis is poorly understood and informative in vivo models have proved elusive. Here we report the generation of a mouse model of cardiac ATTR amyloidosis with transgenic expression of human TTR S52P . The model is characterised by substantial ATTR amyloid deposits in the heart and tongue. The amyloid fibrils contain both full-length human TTR protomers and the residue 49-127 cleavage fragment which are present in ATTR amyloidosis patients. Urokinase-type plasminogen activator (uPA) and plasmin are abundant within the cardiac and lingual amyloid deposits, which contain marked serine protease activity; knockout of α 2 -antiplasmin, the physiological inhibitor of plasmin, enhances amyloid formation. Together, these findings indicate that cardiac ATTR amyloid deposition involves local uPA-mediated generation of plasmin and cleavage of TTR, consistent with the previously described mechano-enzymatic hypothesis for cardiac ATTR amyloid formation. This experimental model of ATTR cardiomyopathy has potential to allow further investigations of the factors that influence human ATTR amyloid deposition and the development of new treatments. ATTR amyloidosis causes heart failure through the accumulation of misfolded transthyretin in cardiac muscle. Here the authors report a mouse model of ATTR amyloidosis and demonstrate the involvement of protease activity in ATTR amyloid deposition.

ObjectivesPre-exposure prophylaxis (PrEP) is effective for HIV prevention and is mostly used by men who have sex with men (MSM). The aim of this study was to describe the characteristics of a cohort of PrEP users at first PrEP counselling visits (baseline, BL).DesignCross-sectional study of a cohort of MSM receiving PrEP (Centro San Luigi, CSL-PrEP Cohort).SettingSecondary-level sexually transmitted infections (STI) centre in Milan, Italy, from May 2017 to May 2022.ParticipantsOverall, 624 MSM PrEP users were included; most users were Caucasian (97%), attended university (64%), with a median BL age of 34.5 years.ResultsOverall, 45% choose the daily-based PrEP regimen, 55% the event-based one. An increasing trend in PrEP counselling visits was observed (p=0.024). The majority had between 10 and 19 partners in the 3 months before BL and 41% were chemsex users. All had a HIV Incidence Risk Index for MSM (HIRI-MSM)>10, 54% between 20 and 29. Overall, 50% had ≥1 previous STI and 22% ≥1 BL STI. BL chlamydia (10%) was often more frequent than in the past (7%). The number of sexual partners was associated with BL chlamydia (p<0.001), gonorrhoea (p=0.002) and syphilis (p=<0.001), HIRI-MSM with chlamydia (p=0.001) and gonorrhoea (p=0.008), chemsex use with chlamydia (p=0.003) and gonorrhoea (p=0.030).ConclusionsWe observed an unbalanced access to PrEP in respect to all key populations which might benefit from PrEP, with a similar choice for event-based or daily-based regimens. High-risk behaviours and STIs were frequently observed. History of chlamydia was very frequently high in asymptomatic MSM at BL, compared with what observed before access to PrEP. High-risk behaviours and HIRI-MSM were associated with most of STIs.

Amyloidosis is a relatively rare human disease caused by the deposition of abnormal protein fibres in the extracellular space of various tissues, impairing their normal function. Proteomic analysis of patients’ biopsies, developed by Dogan and colleagues at the Mayo Clinic, has become crucial for clinical diagnosis and for identifying the amyloid type. Currently, the proteomic approach is routinely used at National Amyloidosis Centre (NAC, London, UK) and Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche (ITB-CNR, Milan, Italy). Both centres are members of the European Proteomics Amyloid Network (EPAN), which was established with the aim of sharing and discussing best practice in the application of amyloid proteomics. One of the EPAN’s activities was to evaluate the quality and the confidence of the results achieved using different software and algorithms for protein identification. In this paper, we report the comparison of proteomics results obtained by sharing NAC proteomics data with the ITB-CNR centre. Mass spectrometric raw data were analysed using different software platforms including Mascot, Scaffold, Proteome Discoverer, Sequest and bespoke algorithms developed for an accurate and immediate amyloid protein identification. Our study showed a high concordance of the obtained results, suggesting a good accuracy of the different bioinformatics tools used in the respective centres. In conclusion, inter-centre data exchange is a worthwhile approach for testing and validating the performance of software platforms and the accuracy of results, and is particularly important where the proteomics data contribute to a clinical diagnosis.

Current HIV treatment regimens provide sustained virologic suppression, at least partially restore the immune system and have limited side effects; however, they do not allow viral eradication and they are burdened by daily pill intake with a life-long commitment for the people living with HIV (PHIV). Injectable agents might represent a turning point in the care of PHIV, allowing less frequent administration of antiretroviral treatment (ART), more widespread use of pre-exposure prophylaxis (PrEP) and more stable drug levels in the blood, thus increasing the odds to get closer to end the HIV pandemic. The aim of this manuscript is to give a comprehensive review of injectable antiretrovirals that have been used in the past, which are available now, will be available in the future, and their role in the treatment of HIV infection

The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β 2 -microglobulin (D76N β 2 -m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β 2 -m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β 2 -m expressing worms. We also demonstrated the specificity of the β 2 -m variant in determining the pathological phenotype by rescuing the wild type phenotype when β 2 -m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.

The tissue diagnosis of amyloidosis and confirmation of fibril protein type, which are crucial for clinical management, have traditionally relied on Congo red (CR) staining followed by immunohistochemistry (IHC) using fibril protein specific antibodies. However, amyloid IHC is qualitative, non‐standardised, requires operator expertise, and not infrequently fails to produce definitive results. More recently, laser dissection mass spectrometry (LDMS) has been developed as an alternative method to characterise amyloid in tissue sections. We sought to compare these techniques in a real world setting. During 2017, we performed LDMS on 640 formalin‐fixed biopsies containing amyloid (CR+ve) comprising all 320 cases that could not be typed by IHC (IHC−ve) and 320 randomly selected CR+ve samples that had been typed (IHC+ve). In addition, we studied 60 biopsies from patients in whom there was a strong suspicion of amyloidosis, but in whom histology was non‐diagnostic (CR–ve). Comprehensive clinical assessments were conducted in 532 (76%) of cases. Among the 640 CR+ve samples, 602 (94%) contained ≥2 of 3 amyloid signature proteins (ASPs) on LDMS (ASP+ve) supporting the presence of amyloid. A total of 49 of the 60 CR‐ve samples were ASP–ve; 7 of 11 that were ASP+ve were glomerular. The amyloid fibril protein was identified by LDMS in 255 of 320 (80%) of the IHC–ve samples and in a total of 545 of 640 (85%) cases overall. The LDMS and IHC techniques yielded discordant results in only 7 of 320 (2%) cases. CR histology and LDMS are corroborative for diagnosis of amyloid, but LDMS is superior to IHC for confirming amyloid type.

The rate of reported syphilis cases is increasing worldwide, particularly among men who have sex with men. In this scenario, malignant syphilis is a rare, severe form of secondary syphilis, typically observed in immunocompromised individuals and characterized by rupioid skin lesions, together with systemic symptoms that could lead to potentially life-threatening complications. We report the complex case of a 42-year-old man, previously diagnosed with HIV infection, presenting with a five-day history of fever and multiple lymphadenopathies. His immunovirological status was well controlled, and he was fully adherent to antiretroviral therapy. His clinical presentation was severe and ambiguous, with neurological involvement being progressively excluded. The diagnosis was confirmed by serological tests, while histopathological examination of an excised lymph node revealed disrupted architecture with multiple granulomas. Differential diagnosis, including lymphoma and other potential etiologies, was performed. After completion of antibiotic therapy, clinical symptoms completely resolved. No Jarisch–Herxheimer reaction occurred. We also provide an updated review of the current literature, with a focus on HIV coinfection, which is frequently associated with the development of malignant syphilis, and discuss the need for enhanced interventions to prevent sexually transmitted infections, as well as the importance of judicious use of doxycycline post-exposure prophylaxis.