Patients' unmet needs and treatment preferences concerning digital ulcers in systemic sclerosis.

INTRODUCTION: Digital ulcers (DUs) significantly impact on quality of life and function in patients with systemic sclerosis (SSc). The aim of our survey was to explore patients' perspectives and their unmet needs concerning SSc-DUs. MATERIALS: SSc patients were invited through international patient associations and social media to participate in an online survey. RESULTS: 358 responses were obtained from 34 countries: US (65.6%), UK (11.5%) and Canada (4.5%). Recurrent DUs are common: >10 DUs (46.1%), 5-10 DUs (21.5%), 1-5 DUs (28.5%), 1 DU (3.9%). Fingertip DUs were most frequent (84.9%), followed by those overlying the interphalangeal joints (50.8%). The impact of DUs in patients is broad, from broad-ranging emotional impacts to impact on activities of daily living, and personal relationships. Half (51.7%) of respondents reported that they received wound/ulcer care, most often provided by non-specialist wound care clinics (63.8%). There was significant variation in local (wound) DU care, in particular the use of debridement and pain management. DU-related education was only provided to one-third of patients. One-quarter (24.6%) were 'very satisfied' or 'satisfied' that the provided DU treatment(s) relieved their DU symptoms. Pain, limited hand function, and ulcer duration/chronicity were the main reasons for patients to consider changing DU treatment. CONCLUSIONS: Our data show that there is a large variation in DU treatment between countries. Patient access to specialist wound-care services is limited and only a small proportion of patients had their DU needs met. Moreover, patient education is often neglected. Evidence-based treatment pathways are urgently needed for DU management.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), demographical, clinical, therapeutic and prognostic aspects: a retrospective monocentric analysis.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), also known as PCS-TCLPD, represent a rare group of hematologic diseases primarily affecting the skin. In this retrospective single-centre case series study, we aimed to investigate the demographic, clinical, therapeutic, and prognostic aspects of SMPLPD. We collected data from cases diagnosed between 2010 and the present, employing histopathological and immunohistochemical methods following WHO criteria. We included 22 patients with a median age of 61.50 years and median time between clinical onset and diagnosis of 3.00 months. Surgical excision with conservative margins was the primary choice, showing clinical remission in 17 cases, while non-surgical treatments, including radiotherapy, high-potency steroid treatment and ablative laser, achieved clinical remission in four cases. Clinical presentations varied, but the most common one was a single violaceous nodule/papule on upper body parts. In conclusion, our single-centre case series provides valuable insights into SMPLPD, highlighting the effectiveness of surgical treatments and the potential of non-surgical ones. Even if controversial, the benign nature of SMPLPD emphasizes the importance of achieving tumour clearance with acceptable aesthetic outcomes.

Spindly is a nucleocytosolic O-fucosyltransferase in Dictyostelium and related proteins are widespread in protists and bacteria.

O-GlcNAcylation is a prominent modification of nuclear and cytoplasmic proteins in animals and plants and is mediated by a single O-GlcNAc transferase (OGT). Spindly (Spy), a paralog of OGT first discovered in higher plants, has an ortholog in the apicomplexan parasite Toxoplasma gondii, and both enzymes are now recognized as O-fucosyltransferases (OFTs). Here we investigate the evolution of spy-like genes and experimentally confirm OFT activity in the social amoeba Dictyostelium-a protist that is more related to fungi and metazoa. Immunofluorescence probing with the fucose-specific Aleuria aurantia lectin (AAL) and biochemical cell fractionation combined with western blotting suggested the occurrence of nucleocytoplasmic fucosylation. The absence of reactivity in mutants deleted in spy or gmd (unable to synthesize GDP-Fuc) suggested monofucosylation mediated by Spy. Genetic ablation of the modE locus, previously predicted to encode a GDP-fucose transporter, confirmed its necessity for fucosylation in the secretory pathway but not for the nucleocytoplasmic proteins. Affinity capture of these proteins combined with mass spectrometry confirmed monofucosylation of Ser and Thr residues of several known nucleocytoplasmic proteins. As in Toxoplasma, the Spy OFT was required for optimal proliferation of Dictyostelium under laboratory conditions. These findings support a new phylogenetic analysis of OGT and OFT evolution that indicates their occurrence in the last eukaryotic common ancestor but mostly complementary presence in its eukaryotic descendants with the notable exception that both occur in red algae and plants. Their generally exclusive expression, high degree of conservation, and shared monoglycosylation targets suggest overlapping roles in physiological regulation.

Metabolic bariatric surgery as a therapeutic option for patients with type 2 diabetes: A meta-analysis and network meta-analysis of randomized controlled trials.

AIM: To compare different types of metabolic surgery with non-surgical therapy for the treatment of type 2 diabetes (T2D). METHODS: The present network meta-analysis (NMA) includes randomized clinical trials (duration ≥ 52 weeks) comparing different surgery techniques with non-surgical therapy in diabetes patients. The primary endpoints were endpoint HbA1c, body mass index (BMI) and diabetes remission. The secondary endpoints included fasting plasma glucose, lipid profile, blood pressure, arterial hypertension and dyslipidaemia remission, quality of life and surgical adverse events. Indirect comparisons of different types of surgery were performed by NMA. Mean and 95% confidence intervals for continuous variables, and the Mantel-Haenzel odds ratio for categorial variables, were calculated. RESULTS: The types of surgical procedure included laparoscopic adjustable gastric banding, Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), bilio-pancreatic diversion (BPD), greater curvature plication (GCP), one-anastomosis gastric bypass (OAGB) and Duodeno-Jejunal bypass. Thirty-six trials were included. Metabolic bariatric surgery (MBS) was associated with a significantly higher reduction of HbA1c, diabetes remission and BMI compared with medical therapy. In the NMA, a significant reduction of HbA1c was observed with OAGB and SG. Complete diabetes remission significantly increased with all surgical procedures in comparison with non-surgical therapy, except for GCP. In addition, only BPD, RYGB and OAGB were associated with a significant reduction of BMI. CONCLUSIONS: MBS is an effective option for the treatment of T2D in patients with obesity. Further long-term trials of appropriate quality are needed for assessing the risk-benefit ratio in some patient cohorts, such as those with a BMI of less than 35 kg/m2 and aged older than 65 years.

The nucleocytosolic O-fucosyltransferase SPINDLY affects protein expression and virulence in Toxoplasma gondii.

Once considered unusual, nucleocytoplasmic glycosylation is now recognized as a conserved feature of eukaryotes. While in animals, O-GlcNAc transferase (OGT) modifies thousands of intracellular proteins, the human pathogen Toxoplasma gondii transfers a different sugar, fucose, to proteins involved in transcription, mRNA processing, and signaling. Knockout experiments showed that TgSPY, an ortholog of plant SPINDLY and paralog of host OGT, is required for nuclear O-fucosylation. Here we verify that TgSPY is the nucleocytoplasmic O-fucosyltransferase (OFT) by 1) complementation with TgSPY-MYC3, 2) its functional dependence on amino acids critical for OGT activity, and 3) its ability to O-fucosylate itself and a model substrate and to specifically hydrolyze GDP-Fuc. While many of the endogenous proteins modified by O-Fuc are important for tachyzoite fitness, O-fucosylation by TgSPY is not essential. Growth of Δspy tachyzoites in fibroblasts is modestly affected, despite marked reductions in the levels of ectopically expressed proteins normally modified with O-fucose. Intact TgSPY-MYC3 localizes to the nucleus and cytoplasm, whereas catalytic mutants often displayed reduced abundance. Δspy tachyzoites of a luciferase-expressing type II strain exhibited infection kinetics in mice similar to wild-type but increased persistence in the chronic brain phase, potentially due to an imbalance of regulatory protein levels. The modest changes in parasite fitness in vitro and in mice, despite profound effects on reporter protein accumulation, and the characteristic punctate localization of O-fucosylated proteins suggest that TgSPY controls the levels of proteins to be held in reserve for response to novel stresses.

Lung ultrasound B-lines in systemic sclerosis: cut-off values and methodological indications for interstitial lung disease screening.

OBJECTIVES: Lung ultrasound (LUS), through assessment of B-lines and pleural line alterations, is able to evaluate interstitial lung disease (ILD), a frequent complication of SSc. Different scanning schemes and counting methods have been proposed but no clear cut-off values have been indicated for screening. We aimed to evaluate the accuracy of different LUS methodological approaches to detect ILD compared with high-resolution CT (HRCT) as the gold standard. METHODS: Sixty-nine SSc patients underwent LUS and chest HRCT on the same day. Both exams were scored by expert readers. The accuracy of different scanning schemes and counting methods was assessed and clinical and functional data were compared with imaging findings. RESULTS: B-lines were more numerous in patients with the diffuse skin subset and Scl70 autoantibody positivity. The number of B-lines correlated with the Scleroderma Lung Study (SLS) I HRCT score (R = 0.754, P < 0.0001). A total of >10 B-lines on the whole chest or >1 B-line on the postero-basal chest showed 97% sensitivity for detecting even very early ILD signs (corresponding to an SLS I score of 1). Sensitivity increased to 100% when pleural line alterations were included in the analysis. CONCLUSIONS: LUS has a very high sensitivity in detecting SSc-related ILD. A cut-off value of >10 B-lines on the whole chest or >1 B-line on the postero-basal chest can be used for the screening of SSc-ILD. Assessing only the postero-basal chest seems to be mostly effective, combining high sensitivity with a less time-consuming approach.

Caring for nursing home residents with COVID-19: a "hospital-at-nursing home" intermediate care intervention.

BACKGROUND: Nursing home (NH) residents have been dramatically affected by COVID-19, with extremely high rates of hospitalization and mortality. AIMS: To describe the features and impact of an assistance model involving an intermediate care mobile medical specialist team (GIROT, Gruppo Intervento Rapido Ospedale Territorio) aimed at delivering "hospital-at-nursing home" care to NH residents with COVID-19 in Florence, Italy. METHODS: The GIROT activity was set-up during the first wave of the pandemic (W1, March-April 2020) and became a structured healthcare model during the second (W2, October 2020-January 2021). The activity involved (1) infection transmission control among NHs residents and staff, (2) comprehensive geriatric assessment including prognostication and geriatric syndromes management, (3) on-site diagnostic assessment and protocol-based treatment of COVID-19, (4) supply of nursing personnel to understaffed NHs. To estimate the impact of the GIROT intervention, we reported hospitalization and infection lethality rates recorded in SARS-CoV-2-positive NH residents during W1 and W2. RESULTS: The GIROT activity involved 21 NHs (1159 residents) and 43 NHs (2448 residents) during W1 and W2, respectively. The percentage of infected residents was higher in W2 than in W1 (64.5% vs. 38.8%), while both hospitalization and lethality rates significantly decreased in W2 compared to W1 (10.1% vs 58.2% and 23.4% vs 31.1%, respectively). DISCUSSION: Potentiating on-site care in the NHs paralleled a decrease of hospital admissions with no increase of lethality. CONCLUSIONS: An innovative "hospital-at-nursing home" patient-centred care model based on comprehensive geriatric assessment may provide a valuable contribution in fighting COVID-19 in NH residents.

CRISPR/Cas9 and glycomics tools for Toxoplasma glycobiology.

Infection with the protozoan parasite Toxoplasma gondii is a major health risk owing to birth defects, its chronic nature, ability to reactivate to cause blindness and encephalitis, and high prevalence in human populations. Unlike most eukaryotes, Toxoplasma propagates in intracellular parasitophorous vacuoles, but like nearly all other eukaryotes, Toxoplasma glycosylates many cellular proteins and lipids and assembles polysaccharides. Toxoplasma glycans resemble those of other eukaryotes, but species-specific variations have prohibited deeper investigations into their roles in parasite biology and virulence. The Toxoplasma genome encodes a suite of likely glycogenes expected to assemble N-glycans, O-glycans, a C-glycan, GPI-anchors, and polysaccharides, along with their precursors and membrane transporters. To investigate the roles of specific glycans in Toxoplasma, here we coupled genetic and glycomics approaches to map the connections between 67 glycogenes, their enzyme products, the glycans to which they contribute, and cellular functions. We applied a double-CRISPR/Cas9 strategy, in which two guide RNAs promote replacement of a candidate gene with a resistance gene; adapted MS-based glycomics workflows to test for effects on glycan formation; and infected fibroblast monolayers to assess cellular effects. By editing 17 glycogenes, we discovered novel Glc0-2-Man6-GlcNAc2-type N-glycans, a novel HexNAc-GalNAc-mucin-type O-glycan, and Tn-antigen; identified the glycosyltransferases for assembling novel nuclear O-Fuc-type and cell surface Glc-Fuc-type O-glycans; and showed that they are important for in vitro growth. The guide sequences, editing constructs, and mutant strains are freely available to researchers to investigate the roles of glycans in their favorite biological processes.

O-Fucosylation of thrombospondin-like repeats is required for processing of microneme protein 2 and for efficient host cell invasion by Toxoplasma gondii tachyzoites.

Toxoplasma gondii is an intracellular parasite that causes disseminated infections that can produce neurological damage in fetuses and immunocompromised individuals. Microneme protein 2 (MIC2), a member of the thrombospondin-related anonymous protein (TRAP) family, is a secreted protein important for T. gondii motility, host cell attachment, invasion, and egress. MIC2 contains six thrombospondin type I repeats (TSRs) that are modified by C-mannose and O-fucose in Plasmodium spp. and mammals. Here, using MS analysis, we found that the four TSRs in T. gondii MIC2 with protein O-fucosyltransferase 2 (POFUT2) acceptor sites are modified by a dHexHex disaccharide, whereas Trp residues within three TSRs are also modified with C-mannose. Disruption of genes encoding either POFUT2 or the putative GDP-fucose transporter (NST2) resulted in loss of MIC2 O-fucosylation, as detected by an antibody against the GlcFuc disaccharide, and in markedly reduced cellular levels of MIC2. Furthermore, in 10-15% of the Δpofut2 or Δnst2 vacuoles, MIC2 accumulated earlier in the secretory pathway rather than localizing to micronemes. Dissemination of tachyzoites in human foreskin fibroblasts was reduced for these knockouts, which both exhibited defects in attachment to and invasion of host cells comparable with the Δmic2 phenotype. These results, indicating that O-fucosylation of TSRs is required for efficient processing of MIC2 and for normal parasite invasion, are consistent with the recent demonstration that Plasmodium falciparum Δpofut2 strain has decreased virulence and also support a conserved role for this glycosylation pathway in quality control of TSR-containing proteins in eukaryotes.

Protein O- and C-Glycosylation pathways in Toxoplasma gondii and Plasmodium falciparum.

Apicomplexan parasites are amongst the most prevalent and morbidity-causing pathogens worldwide. They are responsible for severe diseases in humans and livestock and are thus of great public health and economic importance. Until the sequencing of apicomplexan genomes at the beginning of this century, the occurrence of N- and O-glycoproteins in these parasites was much debated. The synthesis of rudimentary and divergent N-glycans due to lineage-specific gene loss is now well established and has been recently reviewed. Here, we will focus on recent studies that clarified classical O-glycosylation pathways and described new nucleocytosolic glycosylations in Toxoplasma gondii, the causative agents of toxoplasmosis. We will also review the glycosylation of proteins containing thrombospondin type 1 repeats by O-fucosylation and C-mannosylation, newly discovered in Toxoplasma and the malaria parasite Plasmodium falciparum. The functional significance of these post-translational modifications has only started to emerge, but the evidence points towards roles for these protein glycosylation pathways in tissue cyst wall rigidity and persistence in the host, oxygen sensing, and stability of proteins involved in host invasion.

O-fucosylated glycoproteins form assemblies in close proximity to the nuclear pore complexes of Toxoplasma gondii.

Toxoplasma gondii is an intracellular parasite that causes disseminated infections in fetuses and immunocompromised individuals. Although gene regulation is important for parasite differentiation and pathogenesis, little is known about protein organization in the nucleus. Here we show that the fucose-binding Aleuria aurantia lectin (AAL) binds to numerous punctate structures in the nuclei of tachyzoites, bradyzoites, and sporozoites but not oocysts. AAL also binds to Hammondia and Neospora nuclei but not to more distantly related apicomplexans. Analyses of the AAL-enriched fraction indicate that AAL binds O-linked fucose added to Ser/Thr residues present in or adjacent to Ser-rich domains (SRDs). Sixty-nine Ser-rich proteins were reproducibly enriched with AAL, including nucleoporins, mRNA-processing enzymes, and cell-signaling proteins. Two endogenous SRDs-containing proteins and an SRD-YFP fusion localize with AAL to the nuclear membrane. Superresolution microscopy showed that the majority of the AAL signal localizes in proximity to nuclear pore complexes. Host cells modify secreted proteins with O-fucose; here we describe the O-fucosylation pathway in the nucleocytosol of a eukaryote. Furthermore, these results suggest O-fucosylation is a mechanism by which proteins involved in gene expression accumulate near the NPC.

Genetic metabolic complementation establishes a requirement for GDP-fucose in Leishmania.

To survive in its sand fly vector, the trypanosomatid protozoan parasite Leishmania first attaches to the midgut to avoid excretion, but eventually it must detach for transmission by the next bite. In Leishmania major strain Friedlin, this is controlled by modifications of the stage-specific adhesin lipophosphoglycan (LPG). During differentiation to infective metacyclics, d-arabinopyranose (d-Arap) caps the LPG side-chain galactose residues, blocking interaction with the midgut lectin PpGalec, thereby leading to parasite detachment and transmission. Previously, we characterized two closely related L. major genes (FKP40 and AFKP80) encoding bifunctional proteins with kinase/pyrophosphorylase activities required for salvage and conversion of l-fucose and/or d-Arap into the nucleotide-sugar substrates required by glycosyltransferases. Whereas only AFKP80 yielded GDP-d-Arap from exogenous d-Arap, both proteins were able to salvage l-fucose to GDP-fucose. We now show that Δafkp80- null mutants ablated d-Arap modifications of LPG as predicted, whereas Δfkp40- null mutants resembled wild type (WT). Fucoconjugates had not been reported previously in L. major, but unexpectedly, we were unable to generate fkp40-/afkp80- double mutants, unless one of the A/FKPs was expressed ectopically. To test whether GDP-fucose itself was essential for Leishmania viability, we employed "genetic metabolite complementation." First, the trypanosome de novo pathway enzymes GDP-mannose dehydratase (GMD) and GDP-fucose synthetase (GMER) were expressed ectopically; from these cells, the Δfkp40-/Δafkp80- double mutant was now readily obtained. As expected, the Δfkp40-/Δafkp80-/+TbGMD-GMER line lacked the capacity to generate GDP-Arap, while synthesizing abundant GDP-fucose. These results establish a requirement for GDP-fucose for L. major viability and predict the existence of an essential fucoconjugate(s).

Apicomplexan C-Mannosyltransferases Modify Thrombospondin Type I-containing Adhesins of the TRAP Family.

In many metazoan species, an unusual type of protein glycosylation, called C-mannosylation, occurs on adhesive thrombospondin type 1 repeats (TSRs) and type I cytokine receptors. This modification has been shown to be catalyzed by the Caenorhabditis elegans DPY-19 protein and orthologues of the encoding gene were found in the genome of apicomplexan parasites. Lately, the micronemal adhesin thrombospondin-related anonymous protein (TRAP) was shown to be C-hexosylated in Plasmodium falciparum sporozoites. Here, we demonstrate that also the micronemal protein MIC2 secreted by Toxoplasma gondii tachyzoites is C-hexosylated. When expressed in a mammalian cell line deficient in C-mannosylation, P. falciparum and T. gondii Dpy19 homologs were able to modify TSR domains of the micronemal adhesins TRAP/MIC2 family involved in parasite motility and invasion. In vitro, the apicomplexan enzymes can transfer mannose to a WXXWXXC peptide but, in contrast to C. elegans or mammalian C-mannosyltransferases, are inactive on a short WXXW peptide. Since TSR domains are commonly found in apicomplexan surface proteins, C-mannosylation may be a common modification in this phylum.

Ethanol and isopropanol in concentrations present in hand sanitizers sharply reduce excystation of Giardia and Entamoeba and eliminate oral infectivity of Giardia cysts in gerbils.

Enteric protozoan parasites, which are spread by the fecal-oral route, are important causes of diarrhea (Giardia duodenalis) and amebic dysentery (Entamoeba histolytica). Cyst walls of Giardia and Entamoeba have a single layer composed of fibrils of ß-1,3-linked GalNAc and ß-1,4-linked GlcNAc (chitin), respectively. The goal here was to determine whether hand sanitizers that contain ethanol or isopropanol as the active microbicide might reduce transmission of these parasites. We found that treatment with these alcohols with or without drying in a rotary evaporator (to model rapid evaporation of sanitizers on hands) kills 85 to 100% of cysts of G. duodenalis and 90 to 100% of cysts of Entamoeba invadens (a nonpathogenic model for E. histolytica), as shown by nuclear labeling with propidium iodide and failure to excyst in vitro. Alcohols with or without drying collapsed the cyst walls of Giardia but did not collapse the cyst walls of Entamoeba. To validate the in vitro results, we showed that treatment with alcohols eliminated oral infection of gerbils by 1,000 G. duodenalis cysts, while a commercial hand sanitizer (Purell) killed E. invadens cysts that were directly applied to the hands. These results suggest that expanded use of alcohol-based hand sanitizers might reduce the transmission of Giardia and Entamoeba.

Biosynthesis of GDP-fucose and other sugar nucleotides in the blood stages of Plasmodium falciparum.

Carbohydrate structures play important roles in many biological processes, including cell adhesion, cell-cell communication, and host-pathogen interactions. Sugar nucleotides are activated forms of sugars used by the cell as donors for most glycosylation reactions. Using a liquid chromatography-tandem mass spectrometry-based method, we identified and quantified the pools of UDP-glucose, UDP-galactose, UDP-N-acetylglucosamine, GDP-mannose, and GDP-fucose in Plasmodium falciparum intraerythrocytic life stages. We assembled these data with the in silico functional reconstruction of the parasite metabolic pathways obtained from the P. falciparum annotated genome, exposing new active biosynthetic routes crucial for further glycosylation reactions. Fucose is a sugar present in glycoconjugates often associated with recognition and adhesion events. Thus, the GDP-fucose precursor is essential in a wide variety of organisms. P. falciparum presents homologues of GDP-mannose 4,6-dehydratase and GDP-L-fucose synthase enzymes that are active in vitro, indicating that most GDP-fucose is formed by a de novo pathway that involves the bioconversion of GDP-mannose. Homologues for enzymes involved in a fucose salvage pathway are apparently absent in the P. falciparum genome. This is in agreement with in vivo metabolic labeling experiments showing that fucose is not significantly incorporated by the parasite. Fluorescence microscopy of epitope-tagged versions of P. falciparum GDP-mannose 4,6-dehydratase and GDP-L-fucose synthase expressed in transgenic 3D7 parasites shows that these enzymes localize in the cytoplasm of P. falciparum during the intraerythrocytic developmental cycle. Although the function of fucose in the parasite is not known, the presence of GDP-fucose suggests that the metabolite may be used for further fucosylation reactions.

The resistive and pulsatility indices of the dorsal metatarsal artery for the screening of peripheral lower artery disease in patients with and without diabetes.

BACKGROUND: In lower extremity peripheral artery disease (PAD), the ankle-brachial index (ABI) is an easily reproducible diagnostic tool for PAD, but it loses reliability when > 1.4 due to calcification of the vessel wall. Patients with diabetes are at higher risk for wall calcification. In order to overcome the limitation and reliability of ABI, particularly in patients with diabetes, we decided to assess resistive (RI) and pulsatility index (PI) by ultrasound doppler of the dorsal metatarsal artery (DMA). RESULTS: We therefore analyzed 51 legs (32 patients), evaluating the correlation between PI, RI, and ABI. Patients with diabetes were 21 (65.6 %), accounting for 33 legs (64.7 %). Out of 51 legs assessed, 37 (72.5 %) cases had compressible arteries, whereas in 14 legs (27.5 %) ABI was not calculable due to wall calcification. PAD was significantly associated with lower both RI and PI of the DMA (both p < 0.000). RI, but not PI, showed a significant correlation (r = 0.535) with ABI, when ABI was less than 1.4, but not when ABI > 1.4. When analyzed separately, patients with diabetes showed a similar figure in comparison with those without diabetes (r = 0.600), RI, but not PI, showed a significant correlation with ABI. CONCLUSION: Dorsal metatarsal artery resistive index (MARI) showed a significant inverse correlation with PAD, similarly to ABI, irrespective of the presence of diabetes. MARI seems to be an effective screening tool for PAD even in patients with wall calcification. Further studies are needed for confirming the results of the present pilot study.

Hemophagocytic syndrome related by EBV infection: case report.

A 34-year-old woman of Asian origin with diffuse lymphadenopathy and hepatosplenomegaly in hemophagocytic syndrome induced by Epstein Barr Virus (EBV) infection. The rapidity of progression of clinical manifestations lead to early orotracheal intubation and death due to multiple organ failure (MOF).

Nailfold Capillaroscopy Analysis Can Add a New Perspective to Biomarker Research in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), all of which are characterised by inflammation of small-medium-sized vessels. Progressive understanding of these diseases has allowed researchers and clinicians to start discussing nailfold video capillaroscopy (NVC) as a future tool for many applications in daily practice. Today, NVC plays a well-established and validated role in differentiating primary from secondary Raynaud's phenomenon correlated with scleroderma. Nevertheless, there has not been sufficient attention paid to its real potential in the ANCA-associated vasculitis. In fact, the role of NVC in vasculitis has never been defined and studied in a multicentre and multinational study. In this review, we carried out a literature analysis to identify and synthesise the possible role of capillaroscopy for patients with ANCA-associated vasculitis. METHODS: Critical research was performed in the electronic archive (PUBMED, UpToDate, Google Scholar, ResearchGate), supplemented with manual research. We searched in these databases for articles published until November 2023. The following search words were searched in the databases in all possible combinations: capillaroscopy, video capillaroscopy, nailfold-video capillaroscopy, ANCA-associated vasculitis, vasculitis, granulomatosis with polyangiitis, EGPA, and microscopic polyangiitis. RESULTS: The search identified 102 unique search results. After the evaluation, eight articles were selected for further study. The literature reported that capillaroscopy investigations documented non-specific abnormalities in 70-80% of AAV patients. Several patients showed neoangiogenesis, capillary loss, microhaemorrhages, and bushy and enlarged capillaries as the most frequent findings. Furthermore, the difference between active phase and non-active phase in AAV patients was clearly discernible. The non-active phase showed similar rates of capillaroscopy alterations compared to the healthy subjects, but the active phase had higher rates in almost all common abnormalities instead. CONCLUSIONS: Microvascular nailfold changes, observed in patients affected by vasculitis, may correlate with the outcome of these patients. However, these non-specific abnormalities may help in the diagnosis of vasculitis. As such, new analysis analyses are necessary to confirm our results.

Offloading systems for the treatment of neuropathic foot ulcers in patients with diabetes mellitus: a meta-analysis of randomized controlled trials for the development of the Italian guidelines for the treatment of diabetic foot syndrome.

AIM: To compare the effectiveness of commonly used offloading devices for the treatment of neuropathic foot ulcers in patients with diabetes mellitus. This meta-analysis (MA) has been performed for giving an answer to clinical questions on this topic of the Italian guideline on diabetic foot syndrome. METHODS: The present MA includes randomized controlled studies (duration > 12 weeks) comparing, in patients with diabetes mellitus and non-infected neuropathic foot ulcer: any offloading device vs either no offloading device or conventional footwear; removable versus non-removable offloading devices; surgical procedure vs other offloading approaches. The primary endpoint was ulcer healing. RESULTS: A total of 184 studies were identified, and 18 were considered eligible for the analysis. We found that: any plantar off-loading, when compared to the absence of plantar offloading device, is associated with a higher ulcer healing (MH-OR: 3.13 [1.08, 9.11], p = 0.04, I2 = 0%); total contact cast or nonremovable knee-high walker, compared to other offloading devices, had a higher ulcer healing rate (MH-OR: 2.64 [1.43, 4.89], p = 0.002, I2 = 51%); surgical offloading for active ulcers in combination with post-surgery offloading achieves higher ulcer healing rate when compared to offloading devices alone (MH-OR: 6.77 [1.64, 27.93], p = 0.008, I2 = 0%). CONCLUSIONS: Any plantar offloading, compared to the absence of plantar offloading device, is associated with a higher ulcer healing rate. Total contact cast or nonremovable knee-high walker, compared to other offloading devices, is preferable. Surgical offloading for active ulcers, in combination with post-surgery offloading devices, achieves a higher ulcer healing rate when compared to other offloading devices alone. Further studies with a larger cohort of patients with diabetic neuropathic foot ulcers and extended follow-up periods are necessary.