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Background Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch–scratch cycle. Objective We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti–IL-31 receptor inhibitor nemolizumab. Method RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti–IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. Results Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. Conclusion These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here, we show that IRAK2, a member of the signaling complex downstream of IL-1 and IL-36, correlates positively with disease severity in both atopic dermatitis and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and atopic dermatitis-like inflammation. Specifically, we demonstrate that IRAK2 ties together proinflammatory and differentiation-dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation-associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.

Background The aim of this study is to evaluate risk factors for infection as well as infection rates after open reduction and internal fixation for distal tibia fractures with a distal tibia locking plate and/or isolated screws. Methods This is a retrospective and descriptive study based on 55 patients treated in our Major Trauma Centre from January 2009 to December 2016. All patients were classified by age, sex, open or closed fracture, injury mechanism, comorbidities, fixation and time from injury to surgery. 22 extraarticular fractures AO/OTA 43-A and 33 intraarticular (14 cases 43-B and 19 43-C) were recorded. High energy trauma was related in 27 patients, while open fractures were observed in 10 patients. Splint until surgery was applied routinely while temporary external fixation (EF) was performed in 21 patients (7 extraarticular and 14 intraarticular). Patients were treated by 5 different consultant surgeons performing isolated screws (SC) in 20% of the surgeries, antero-medial locking distal tibia plate (AM) and anterolateral (AL) were used in 47% and 33% of the patients respectively. After assessing normality and homogeneity of the subgroups, statistical contrast tests were performed. Results Infection rate was 31.5%, mainly caused by S. aureus. We obtained a statistically significant correlation between greater age and infection rate. In the same way, a positive statistical trend between infection and AL plating was found. The use of EF followed by ORIF was not observed as a risk factor for infection compared with splint followed by internal fixation, however, the group of patients in which a splint was used, a positive relationship was found between the infection rate and shorter time until the definitive fixation. No statistically significant associations were found between extra/intraarticular fracture pattern, use of corticosteroids or open fractures and infection rate. Conclusion Greater age was a predisposing factor for infection. The use of external fixation before definitive ORIF seems to be a safe procedure regarding risk infection, and if an external fixation is not used, we recommend longer waiting time until definitive ORIF. Screw fixation or antero-medial plates, if allowed by fracture pattern, can be an option to avoid infection.

Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction. A couple, where the male was carrier of the c.550G>A (p.Gly184Arg) mutation of the SERPING 1 gene causing hereditary angioedema (HAE) attended our clinic for PGT-M. Employing a strategy of preserving embryos after blastocyst trophectoderm biopsy by vitrification cryopreservation, we managed to screen 10 embryos collected from a single IVF cycle. Three embryos were found unaffected after preimplantation genetic analysis for the paternal mutation. The transfer of one normal blastocyst post-thaw resulted in a healthy and uneventful pregnancy and in the live birth of a male neonate on the 38th week of pregnancy. This is the first report of a live birth in Greece after blastocyst trophectoderm biopsy and preimplantation genetic analysis for hereditary angioedema.

BACKGROUND To document the evolution of cranial asymmetries in infants with signs of nonsynostotic occipital plagiocephaly (NSOP) who were undergo to many functional manual therapy treatments (in addition to the standard positioning recommendations) as well as to determine the feasibility of this methodology to conduct an outcome research investigating the impact of this intervention for infants with NSOP. METHODS Pilot clinical standardization project using pre-post design in which 10 infants participated. Nine infants presented an initial Oblique Diameter Difference Index (ODDI) over 104%, three an initial Ear Deviation Index (EDI) over 4%, and three a Cranial Proportional Index (CPI) over 90%. INTERVENTIONS Infants received three functional manual therapy treatments for week during the first month of intervention and two ones for week during the second month. RESULTS Plagiocephalometric measurememts were administered at the first assessment pre-intervention (T0), after 30 days (+/-5) (T1) and at a third time after 60 days (+/5) of treatment (T2). RESULTS 9/10 participants showed a significant decrease in ODDI under 104% between T0 and T2 assessments. 5/10 infants showed an EDI under 4%, and 3/10 showed a value about 0%. 3/10 maintained their CPI over 90% with a considerable decrease. CONCLUSIONS These clinical findings support the hypothesis that functional manual therapy treatments contribute to the improvement of cranial asymmetries in infants younger than 6.5 months old presenting with NSOP.

Tape stripping is a minimally invasive, nonscarring method that can be utilized to assess gene expression in the skin but is infrequently used given technical constraints. By comparing different tape stripping technologies and full-thickness skin biopsy results of lesional and nonlesional psoriatic skin from the same patients, we demonstrate that tape stripping with optimized high-resolution transcriptomic profiling can be used to effectively assess and characterize inflammatory responses in the skin. Upon comparison with single-cell RNA-sequencing data from psoriatic full-thickness skin biopsies, we illustrate that tape-stripping efficiently captures the transcriptome of the upper layers of the epidermis with sufficient resolution to assess the molecular components of the feed-forward immune amplification pathway in psoriasis. Notably, nonlesional psoriatic skin sampled by tape stripping demonstrates activated, proinflammatory changes when compared to healthy control skin, suggesting a prepsoriatic state, which is not captured on full-thickness skin biopsy transcriptome profiling. This work illustrates an approach to assess inflammatory response in the epidermis by combining noninvasive sampling with high throughput RNA-sequencing, providing a foundation for biomarker discoveries and mechanism of action studies for inflammatory skin conditions.

Cutaneous lupus erythematosus (CLE) is a disfiguring and poorly understood condition frequently associated with systemic lupus. Studies to date suggest that non-lesional keratinocytes play a role in disease predisposition, but this has not been investigated in a comprehensive manner or in the context of other cell populations. To investigate CLE immunopathogenesis, normal-appearing skin, lesional skin, and circulating immune cells from lupus patients were analyzed via integrated single-cell RNA-sequencing and spatial-seq. We demonstrate that normal-appearing skin of lupus patients represents a type I interferon-rich, ‘prelesional’ environment that skews gene transcription in all major skin cell types and dramatically distorts cell-cell communication. Further, we show that lupus-enriched CD16+ dendritic cells undergo robust interferon education in the skin, thereby gaining pro-inflammatory phenotypes. Together, our data provide a comprehensive characterization of lesional and non-lesional skin in lupus and identify a role for skin education of CD16+ dendritic cells in CLE pathogenesis.

Objective: Pediatric burns are a major source of injury and in the absence of adequate care can lead to lifelong functional loss and disfigurement. While split thickness skin autografts are the current standard of care for deep partial and full-thickness burns, this approach is associated with considerable morbidity. For this reason, alternative skin substitutes such as allografts have gained interest. Approach: In the present study, we present a case series of 30 children with various types of burns treated with dehydrated human amnion chorion membrane (dHACM). Results: We show that treatment with dHACM is associated with an excellent rate of healing comparable to split thickness skin grafts with less rate of hypertrophic scar and contracture. Innovation: Treatment with dHACM is particularly attractive as it consists of many tissue regenerative factors, such as growth factors and immune modulators, thus it will reduce the risk of scaring. Conclusion: While dHACM is associated with an increased upfront cost, treating patients with small to moderate-sized burns with dHACM in their regional centers works to decrease downstream costs such as management of prolonged pain from donor-site morbidity, revisional surgeries from scar and contractures of split thickness grafts, and avoiding the cost of transfer to higher level centers of care. Our findings challenge the current standard of care, suggesting that dHACM provides an alternative to the current use of split thickness skin grafting and is a safe, feasible, and potentially superior substitute for the management of small to moderate total body surface area partial and full-thickness pediatric burns.

Background A 20‐year‐old grey Warmblood gelding that had history of dermal melanomatosis. Objective To report surgical treatment of a 6‐cm large malignant metastatic melanoma located in the cutaneous trunci muscle of the left lateral thorax of a horse. Methods A 20‐year‐old grey Warmblood gelding was referred for evaluation of a large, rapidly growing, thoracic mass. Clinical examination revealed an ovoid, firm, non‐painful, movable mass, approximately 6 cm in diameter, located in the cutaneous trunci muscle of the left lateral thorax. Multiple melanocytic nodules were also found at the perianal region and ventral tail. Rectal examination, ultrasonography and endoscopy of the respiratory tract revealed no melanomas internally. Haematological and biochemical values were within normal limits. Surgical excision of both the thoracic mass and perianal nodules was the treatment of choice. Histopathology of the distant thoracic mass confirmed the diagnosis of malignant metastatic melanoma secondary to the perineal lesions that were confirmed as dermal melanomatosis. Results The horse recovered uneventfully. Up until 3 years post surgery there was no tumour regrowth at the excision sites. Conclusion Surgical excision of the metastatic melanoma was performed and considered successful, with no gross evidence of tumour reoccurrence. Despite the fact that surgical excision is considered a treatment option regarding equine dermal melanomatosis, there is no previously published study proposing surgical removal of distant malignant metastatic melanocytic masses. This is the first report of a successful surgical excision of a large (6 cm) metastatic melanocytic tumour from the skeletal muscle of the lateral thorax of a horse., A 20‐year‐old grey Warmblood gelding was referred for evaluation of a large, rapidly growing, thoracic mass. Histopathology of the distant thoracic mass confirmed the diagnosis of malignant metastatic melanoma. Surgical excision of the metastatic melanoma was performed and considered successful, with no gross evidence of tumour reoccurrence.This report proposes surgical excision as a treatment option for distant malignant metastatic melanocytic masses in skeletal muscle.

Background A majority of multiple sclerosis patients experience visual impairment, often as the initial presenting symptom of the disease. While structural changes in the retinal nerve fiber layer and optic nerve have demonstrated correlations with brain atrophy in multiple sclerosis using magnetic resonance imaging, a non-invasive, cost-effective, and clinically efficacious modality to identify early damage and facilitate prompt therapeutic intervention to slow the progression of multiple sclerosis and its ocular manifestations, is still urgently needed. In this study, we sought to determine the role of macular sensitivity measured by microperimetry in the detection of subclinical multiple sclerosis-related retinal damage and visual dysfunction. Methods This cross-sectional observational case-control study involved population-based samples of multiple sclerosis patients and age-, race-, and gender-matched healthy control subjects. Among the key criteria for the multiple sclerosis patients were diagnosis by the McDonald criteria, visual acuity greater than 20/25, and no history of optic neuritis. Macular sensitivity and average macular thickness were measured in all subjects using microperimetry and spectral-domain optical coherence tomography, respectively. Pearson correlation coefficients were measured using bivariate correlations. Sample means, mean differences, and 95% confidence intervals were calculated using independent sample t-tests. Results Twenty-eight eyes from 14 MS patients and 18 eyes from 9 control subjects were included. Mean macular sensitivity of control subjects and multiple sclerosis patients in decibels was 18.2 ± 0.4 and 16.5 ± 0.4, respectively, corresponding to a mean difference of 1.7 (95% CI, 1.1–2.4; P P = 0.01) but not control subjects (r = 0.15, P = 0.55). Conclusions Macular sensitivity as measured by microperimetry was decreased in multiple sclerosis patients with normal visual acuity and no history of optic neuritis. Furthermore, macular sensitivity demonstrated a positive correlation with macular thickness as measured by optical coherence tomography. As such, microperimetry may represent a non-invasive and efficient method to identify signs of subclinical visual dysfunction that correspond with early macular architectural changes characteristic of multiple sclerosis.

Psoriasis is a chronic inflammatory skin condition that has a fairly wide range of clinical presentations. Plaque psoriasis, which is the most common manifestation of psoriasis, is located on one end of the spectrum, dominated by adaptive immune responses, whereas the rarer pustular psoriasis lies on the opposite end, dominated by innate and autoinflammatory immune responses. In recent years, genetic studies have identified six genetic variants that predispose to pustular psoriasis, and these have highlighted the role of IL-36 cytokines as central to pustular psoriasis pathogenesis. In this review, we discuss the presentation and clinical subtypes of pustular psoriasis, contribution of genetic predisposing variants, critical role of the IL-36 family of cytokines in disease pathophysiology, and treatment perspectives for pustular psoriasis. We further outline the application of appropriate mouse models for the study of pustular psoriasis and address the outstanding questions and issues related to our understanding of the mechanisms involved in pustular psoriasis.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

Cutaneous lupus is commonly present in patients with systemic lupus erythematosus (SLE) but can also exist as an isolated manifestation without further systemic involvement. T cells have been strongly suspected to contribute to the pathology of cutaneous lupus, yet our understanding of the T cell phenotypes and functions in the skin in lupus remains incomplete, and the extent to which lupus T cell infiltrates in skin resemble those in other tissue beds is unknown. Here, we present a detailed single-cell RNA sequencing profile of T and NK cell populations present within lesional and non-lesional skin biopsies of patients with cutaneous lupus. We identified multiple lymphocyte clusters, including both CD4 and CD8 T cells, NK cells, regulatory T cells, and a population of strongly interferon-responding cells that was present in patients with cutaneous lupus but absent in healthy donors. T cells across clusters from both lesional and non-lesional skin biopsies expressed elevated levels of interferon simulated genes (ISGs); however, compared to T cells from control skin, T cells from cutaneous lupus lesions did not show elevated expression profiles of activation, cytotoxicity, or exhaustion. Integrated analyses comparing skin T/NK cells to lupus nephritis kidney T/NK cells indicated that skin lymphocytes appeared less activated and lacked the expanded cytotoxic populations prominent in lupus nephritis. An integrated comparison of skin T cells from lupus and systemic sclerosis revealed similar activation profiles but an elevated ISG signature specific to cells from lupus skin biopsies. Overall, these data represent the first detailed transcriptomic analysis of the of T and NK cells in cutaneous lupus at the single cell level and have enabled a cross-tissue comparison that highlighted the stark differences in composition and activation of T/NK cells in distinct tissues in lupus.

Altered epidermal differentiation along with increased keratinocyte proliferation is a characteristic feature of psoriasis and pityriasis rubra pilaris (PRP). However, despite this large degree of overlapping clinical and histologic features, the molecular signatures these skin disorders share are unknown. Using global transcriptomic profiling, we demonstrate that plaque psoriasis and PRP skin lesions have high overlap, with all differentially expressed genes in PRP relative to normal skin having complete overlap with those in psoriasis. The major common pathway shared between psoriasis and PRP involves the phospholipases PLA2G2F, PLA2G4D, and PLA2G4E, which were found to be primarily expressed in the epidermis. Gene silencing each of the 3 PLA2s led to reduction in immune responses and epidermal thickness both in vitro and in vivo in a mouse model of psoriasis, establishing their proinflammatory roles. Lipidomic analyses demonstrated that PLA2s affect mobilization of a phospholipid-eicosanoid pool, which is altered in psoriatic lesions and functions to promote immune responses in keratinocytes. Taken together, our results highlight the important role of PLA2s as regulators of epidermal barrier homeostasis and inflammation, identify PLA2s as a shared pathogenic mechanism between PRP and psoriasis, and as potential therapeutic targets for both diseases.

Objective Long-term outcomes after endovascular aneurysm repair (EVAR) are threatened by aortic neck dilation (AND), graft migration, and subsequent endoleak development. The aim of this study was to determine the rate of AND and the occurrence of endoleaks after fenestrated EVAR of juxtarenal aneurysms with physician-modified endovascular grafts (PMEGs). Methods The study included 77 patients presenting with asymptomatic and ruptured juxtarenal abdominal aortic aneurysms treated with PMEGs who received radiologic follow-up. Analysis of computed tomography images took place on a three-dimensional workstation (TeraRecon, San Mateo, Calif). Aortic neck diameter was measured before and after EVAR at the lowest patent renal artery outer wall to outer wall. Significant AND was defined as >3-mm increase between baseline and follow-up, and sac regression >5 mm was considered significant. The patient's 1-month initial postoperative computed tomography measurement was considered baseline. The rate of AND was measured by comparing the baseline measurement with measurements at 6 months, 12 months, and annually thereafter up to 4 years. Results In this cohort of patients, 75% were men with a mean age of 74 ± 7.9 years. Median preoperative aneurysm size was 62 (57-73) mm, and median follow-up was 12 (3.5-30) months. Mean endograft oversizing was 17% ± 12.5%, and mean seal zone length was 41 ± 11 mm. At 1-year follow-up, the median aortic neck increase was 1.7 (0-3) mm. Maximum aneurysm size decreased dramatically during the first postoperative year, with significant sac regression in 65% of the patients. Aortic neck diameter at 1 year did correlate positively with the percentage of device oversizing. No other correlations were found. During the 4-year follow-up, there were no cases of type IA endoleaks. Conclusions AND does not influence outcome after endovascular repair of juxtarenal aneurysms using PMEGs. These midterm results support the applicability of PMEGs in juxtarenal aneurysm repair.

Phosphoinositide-specific phospholipases C (PLCs) are a class of enzymes involved in several cell activities, such as cell cycle regulation, proliferation, differentiation and cytoskeletal dynamics. Among these enzymes, PLCγ1 is one of the most expressed PLCs in the brain, contributing to a complex network in the developing nervous system. Several studies have shown that PLCγ1 signaling imbalance is linked to several brain disorders, including glioblastoma, the most aggressive brain tumor in adults. Indeed, it has been demonstrated a link between PLCγ1 inhibition and the arrest of glioma cell motility of fetal rat brain aggregates and the impairment of cell invasion abilities following its down-regulation. This study aims to determine the pathological influence of PLCγ1 in glioblastoma, through a translational study which combines in silico data, data from glioblastoma patients' samples and data on engineered cell lines. We found out that PLCγ1 gene expression correlates with the pathological grade of gliomas, and it is higher in fifty patients' glioblastoma tissue samples compared to twenty healthy controls. Moreover, it was demonstrated that PLCγ1 silencing in U87-MG leads to a reduction in cell migration and invasion abilities. The opposite trend was observed following PLCγ1 overexpression, suggesting an interesting possible involvement of PLCγ1 in gliomas' aggressiveness.

Background A major issue with the current management of psoriasis is our inability to predict treatment response. Objective Our aim was to evaluate the ability to use baseline molecular expression profiling to assess treatment outcome for patients with psoriasis. Methods We conducted a longitudinal study of 46 patients with chronic plaque psoriasis treated with anti-TNF agent etanercept, and molecular profiles were assessed in more than 200 RNA-seq samples. Results We demonstrated correlation between clinical response and molecular changes during the course of the treatment, particularly for genes responding to IL-17A/TNF in keratinocytes. Intriguingly, baseline gene expressions in nonlesional, but not lesional, skin were the best marker of treatment response at week 12. We identified USP18, a known regulator of IFN responses, as positively correlated with Psoriasis Area and Severity Index (PASI) improvement (P = 9.8 × 10−4) and demonstrate its role in regulating IFN/TNF responses in keratinocytes. Consistently, cytokine gene signatures enriched in baseline nonlesional skin expression profiles had strong correlations with PASI improvement. Using this information, we developed a statistical model for predicting PASI75 (ie, 75% of PASI improvement) at week 12, achieving area under the receiver-operating characteristic curve value of 0.75 and up to 80% accurate PASI75 prediction among the top predicted responders. Conclusions Our results illustrate feasibility of assessing drug response in psoriasis using nonlesional skin and implicate involvement of IFN regulators in anti-TNF responses.

Background. The hypermobile type of Ehlers–Danlos syndrome (hEDS) is likely the most common hereditary disorder of connective tissue mainly characterized by joint hypermobility. Patients with hEDS suffer joint pain, in particular low back pain, commonly resistant to drug therapy. The aim of this research was to evaluate a neurocognitive rehabilitation approach based not only on the motion and function recovery but also on the pain management. Methods. In this nonrandomized clinical trial, eighteen hEDS patients (4 males and 14 females) with mean age 21 years (range 13-55) were recruited and evaluated before and after three months of rehabilitation treatment. Results. The outcome scores showed significant statistical results after treatment in reducing pain symptoms (numerical rating scale, P = 0.003 ; McGill (total score), P = 0.03 ), fatigue (fatigue severity scale, P = 0.03 ), fear of movement (Tampa scale, P = 0.003 ), and pain-associated disability (Oswestry disability index, P = 0.03 ). Conclusion. The clinical results observed in our study seem to confirm the role of a specific neurocognitive rehabilitation program in the chronic pain management in the Ehlers–Danlos syndrome; the rehabilitation treatment should be tailored on patient problems and focused not only in the recovery of movement but also on pain perception.

Osteoarthritis (OA) impacts hundreds of millions of people worldwide, with those affected incurring significant physical and financial burdens. Injuries such as focal defects to the articular surface are a major contributing risk factor for the development of OA. Current cartilage repair strategies are moderately effective at reducing pain but often replace damaged tissue with biomechanically inferior fibrocartilage. Here we describe the development, transcriptomic ontogenetic characterization and quality assessment at the single cell level, as well as the scaled manufacturing of an allogeneic human pluripotent stem cell-derived articular chondrocyte formulation that exhibits long-term functional repair of porcine articular cartilage. These results define a new potential clinical paradigm for articular cartilage repair and mitigation of the associated risk of OA.

Sex bias in immune function has been well-described, and women have been shown to counter immunologically stimulating phenomena such as infection, malignancy, and trauma with more protective responses than men. Heightened immunity in women may also result in a predisposition for loss of self-tolerance and development of autoimmunity, reflected by the overwhelming female sex bias of patients with autoimmune diseases. In this review, we discuss the postulated evolutionary etiologies for sexual dimorphism in immunity. We also review the molecular mechanisms underlying divergent immune responses in men and women, including sex hormone effects, X chromosome dosage, and autosomal sex-biased genes. With increasing evidence that autoimmune disease susceptibility is influenced by numerous hormonal and genetic factors, a comprehensive understanding of these topics may facilitate the development of much-needed targeted therapeutics.

Introduction: Langerhans Cell Histiocytosis is a rare disease that in adults uses to affect the lung (PLCH). Disease mechanisms are not fully understood as inflammatory pathways leading to tissue damage has not been fully described. Objectives: To investigate the cytokine bronchoalveolar lavage (BAL) profile in PLCH subjects compare to other interstitial lung disease (ILD). Methods: BAL samples and clinical data were collected from new cases of adult patients with pulmonary PLCH and other ILD referred to an ILD Clinic. Cytokine profile in BAL of these patients were analysed using the Cytokine Human Membrane Antibody Array. Results: Nine patients with PLCH, fourteen with FPI, and twelve smokers with fibrosing ILD (f-ILD) were included. Regarding the 80 cytokine evaluated, when comparing PLCH to others groups there were differences in 73 cytokines. There were no differences between IPF and other f-ILD. There were statistical significant changes in IL-10, CCL-18 and IGFBP-4 (see figure). Conclusions: BAL cytokines in PLCH shows different profile compared to other ILDs. Physiopathological significance of this finding needs further research.

Skin lesions in dermatomyositis (DM) are common, are frequently refractory, and have prognostic significance. Histologically, DM lesions appear similar to cutaneous lupus erythematosus (CLE) lesions and frequently cannot be differentiated. We thus compared the transcriptional profile of DM biopsies with CLE lesions to identify unique features. Type I IFN signaling, including IFN-κ upregulation, was a common pathway in both DM and CLE; however, CLE also exhibited other inflammatory pathways. Notably, DM lesions could be distinguished from CLE by a 5-gene biomarker panel that included IL18 upregulation. Using single-cell RNA-sequencing, we further identified keratinocytes as the main source of increased IL-18 in DM skin. This study identifies a potentially novel molecular signature, with significant clinical implications for differentiating DM from CLE lesions, and highlights the potential role for IL-18 in the pathophysiology of DM skin disease., IL-18 distinguishes dermatomyositis skin inflammation from cutaneous lupus erythematosus lesions.

Patients with COVID-19 pneumonia can develop hypoxemic acute respiratory failure (hARF) with the need for positive end-expiratory pressure (PEEP). The administration of a continuous positive airway pressure (CPAP) through a helmet improves oxygenation and avoids intubation [1, 2]. A European consensus document suggests that helmet CPAP should be the first therapeutic choice for hARF caused by COVID-19 pneumonia, mainly for minimising aerosol generation [3–5]. However, recommendations are based on experts' opinion and consider only evidence obtained in critically ill COVID-19 patients [3]. The Surviving Sepsis Campaign does not recommend the administration of CPAP for the initial management of severe COVID-19 [6]., Helmet CPAP treatment fails in up to 44% of patients with moderate-to-severe hypoxemic acute respiratory failure due to COVID-19 pneumonia

Myeloid-specific Asxl2 deletion renders mice resistant to high-fat diet–induced obesity and related complications by regulating brown adipose tissue.

Secretion of IFN-γ in sepsis contributes to post-sepsis immunosuppression and secondary candidemia.

Author(s): Ghalayani Esfahani, A; Lazazzera, B; Draghi, L; Fare, S; Chiesa, R; De Nardo, L; Billi, F | Abstract: AimsThe aim of this study was to develop a new class of gallium (Ga)-doped chitosan (CS) coatings fabricated by electrophoretic deposition (EPD) in staphylococcal infection therapy.Methods and resultsBiofilm formation on EPD CS/Ga coatings by Staphylococcus epidermidis and Staphylococcus aureus, which are the main strains involved in postarthroplasty infections, was assessed. The codeposition of an antibacterial agent was effective; Ga loaded into CS matrix reduces biofilm viability by up to 86% and 80% for S. epidermidis and S. aureus strains respectively. Lastly, the influence of pulsed electromagnetic field (PEMF) on the bactericidal activity of CS/Ga coatings was investigated in vitro. To this end, the coatings were incubated with S. epidermidis and S. aureus and exposed to the PEMF using two different frequencies and times. Biofilm viability for S. epidermidis was decreased by 35-40% in the presence of low-frequency (LF) and high-frequency (HF) PEMF respectively. Biofilm viability by S. aureus was not further reduced in the presence of LF PEMF, but decreased by 38% at HF PEMF.ConclusionsThis study has established that a combination of PEMFs with the antibacterial agent improves bactericidal activity of Ga against S. epidermidis strain 14990 and S. aureus strain 12600.Significance and impact of the studyThis new integrated approach could reduce the incidence of infection in orthopaedic implant applications. It also clearly demonstrates that the combination of Ga treatment with PEMF could aid biofilm-associated infection therapy due to improved Ga efficiency.

Objective Fenestrated endovascular aneurysm repair (FEVAR) has been used successfully to treat patients with juxtarenal abdominal aortic aneurysms (JAAAs). Barriers to wide adoption of FEVAR include complexity in planning of fenestration locations on endografts. The purpose of this study was to validate the use of automated planning software to design fenestrated endografts and to treat patients with complex abdominal aortic aneurysms. Methods Patients with JAAA who were not candidates for open repair were enrolled into the automated planning arm of an ongoing investigational device exemption clinical trial and treated with FEVAR. Patient-specific fenestration size and location were determined by automated planning software using patient imaging data and algorithms that account for the interaction between the endograft delivery system and angulated aortic anatomy. Standard, off-the-shelf abdominal aortic aneurysm endografts from multiple manufacturers were modified on the back table by the physician according to the automated graft plan in the form of a patient-specific three-dimensional printed cylindrical template. Endografts typically included fenestrations for the superior mesenteric artery and both renal arteries. Procedural, perioperative, and long-term clinical and imaging data were collected per protocol. Results Thirty nonoperative JAAA candidate patients (American Society of Anesthesiologists class ≥3) were consented and treated with fenestrated endografts planned by automated software. The mean age was 74 ± 7 (61-86) years. The mean aneurysm diameter was 61.3 mm (range, 49-96 mm), and the mean infrarenal neck length was 6.1 mm (range, 2-15 mm). At the index procedure, 100% (30/30) of the patient-specific, surgeon-modified grafts were implanted with preservation of 97% (84/87) of branch vessels and a mean final proximal seal zone length of 41.9 mm (range, 27.3-60.6 mm). Three renal arteries were not cannulated during the index procedure because of complications not related to graft planning. The 30-day mortality rate in these high-risk JAAA patients was 6.7% (2/30), and both deaths were unrelated to the aneurysm. The 30-day major adverse event rate was 16.7% (5/30). There were no type IA or type III endoleaks, ruptures, or conversions to open surgery through 30 days. Conclusions This automated FEVAR planning software accurately and efficiently identifies fenestration locations for vital branch arteries, thus simplifying the planning process and facilitating the FEVAR procedure. Validated automated FEVAR planning could help bring this beneficial therapy to most patients harboring JAAAs.

Objective Sepsis mortality is reported to be high worldwide, however recently the attributable fraction of mortality due to sepsis (AFsepsis) has been questioned. If improvements in treatment options are to be evaluated, it is important to know what proportion of deaths are potentially preventable or modifiable after a sepsis episode. The aim of the study was to establish the fraction of deaths directly related to the sepsis episode on the general wards and emergency departments. Results 839 patients were recruited over the two 24-h periods in 2016 and 2017. 521 patients fulfilled SEPSIS-3 criteria. 166 patients (32.4%) with sepsis and 56 patients (17.6%) without sepsis died within 90 days. Out of the 166 sepsis deaths 12 (7.2%) could have been directly related to sepsis, 28 (16.9%) possibly related and 96 (57.8%) were not related to sepsis. Overall AFsepsis was 24.1%. Upon analysis of the 40 deaths likely to be attributable to sepsis, we found that 31 patients (77.5%) had the Clinical Frailty Score ≥ 6, 28 (70%) had existing DNA-CPR order and 17 had limitations of care orders (42.5%). Electronic supplementary material The online version of this article (10.1186/s13104-018-3819-2) contains supplementary material, which is available to authorized users.

The aim of this consensus conference was to provide clinical guidelines, based on the available evidence and on the author's daily practice and experience, for general dentistry and dental practitioners to allow them to delivery long-term successful restorations. Three groups of expert clinicians and dental technicians were invited to evaluate all of the scientific literature from 1967 up to March 2017 to identify relevant studies on assigned topics and to prepare in advance narrative/systematic review, written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, to fulfill the consensus statement criteria. The three topics assigned to the three groups were abutment/framework materials and customization (metal vs. metal-free restorations), abutment/framework protocols and designs, and abutment/framework retentions (cemented- vs. screw-retained implant-supported prostheses). All the expert clinicians presented their results, and the lectures were followed by discussions. No significant differences in clinical parameters (marginal bone loss, bleeding on probing, and pocket probing depth) between screw- or cemented-retained were found for single and multiple implant-supported restorations. There is moderate evidence that nonoriginal abutments provide worse mechanical behavior than originals and high evidence that different implant neck designs do not offer any clinical or radiographic advantage. All the participants agreed that it is desirable to connect and remove abutments as few times as possible. There is medium evidence that an adequate platform switching tends to enhance tissue volume and stability in the medium- and long-term follow-up. No statistically significant differences exist between metal and zirconia as a framework material. The authors discussed and all agreed that retrievability and patient's expectation (function and esthetics) should guide the choice of the most adequate technique, component, and material.

Objective: Data about Hepatitis E virus (HEV) prevalence are variable in Europe and also limited inItaly.WeaimedtodescribetheseroprevalenceofimmunoglobulinG(IgG)antibodiesagainst HEV infection among blood donors (BDs) in the Greater Romagna area, North-Eastern Italy. Materials and Methods: All serum samples were at first screened for anti-HEV IgG antibodies by a commercial enzyme-linked immunosorbent assay (ELISA) (DIA.PRO Diagnostic Bioprobes, Sesto San Giovanni (MI), Italy), used in our diagnostic routine and so considered as the reference test. Then, all serum samples were re-tested for anti-HEV IgG antibodies by the other two commercial ELISA (Wantai, Biologic Pharmacy Enterprise, Beijing, China; Euroimmun, Lübeck, Germany). The seroprevalence rate was calculated based on the immunoblotting (IB) assay confirmation. Results: A total of 500 BDs samples were tested by three commercial ELISA tests; positive and borderline results were confirmed by an IB assay. The overall anti-HEV IgG prevalence was 3.8% (CI: 2.303 – 5.871), 1.6% (CI: 0.693 – 3.128) and 2.8% (CI: 1.539 – 4.653) when samples were tested with DIA.PRO, Euroimmun and Wantai methods, respectively. The seroprevalence of IgG antibodies against HEV infection was found to be similar or lower than the previous reports in Italy. The results obtained by the different ELISA tests were similar. Conclusion: The data obtained in this study underline the need for achieving a harmonised testing algorithm that is necessary in order to be able to compare data from different studies. We suggest that the identification of potential HEV human infection should be added to the standard laboratory work-up for viral hepatitis.

Phosphoinositides (PI) form just a minor portion of the total phospholipid content in cells but are significantly involved in cancer development and progression. In several cancer types, phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] play significant roles in regulating survival, proliferation, invasion, and growth of cancer cells. Phosphoinositide-specific phospholipase C (PLC) catalyze the generation of the essential second messengers diacylglycerol (DAG) and inositol 1,4,5 trisphosphate (InsP3) by hydrolyzing PtdIns(4,5)P2. DAG and InsP3 regulate Protein Kinase C (PKC) activation and the release of calcium ions (Ca2+) into the cytosol, respectively. This event leads to the control of several important biological processes implicated in cancer. PLCs have been extensively studied in cancer but their regulatory roles in the oncogenic process are not fully understood. This review aims to provide up-to-date knowledge on the involvement of PLCs in cancer. We focus specifically on PLCβ, PLCγ, PLCδ, and PLCε isoforms due to the numerous evidence of their involvement in various cancer types.

STUDY OBJECTIVE: To clarify the relationship of hypogastric nerves (HNs) with several pelvic anatomic landmarks and to assess any anatomic differences between the 2 sides of the pelvis, both in cadaveric and in vivo dissections. DESIGN: Prospective observational study. SETTING: An anatomic theater for cadaveric dissections and a university hospital for in vivo laparoscopy. PATIENTS: Five nulliparous female cadavers underwent laparotomic dissection; 10 nulliparous patients underwent laparoscopic surgery for rectosigmoid endometriosis without posterolateral parametrial infiltration. INTERVENTIONS: Measurements of the closest distance between HNs and ureters, the midsagittal plane, the midcervical plane, and uterosacral ligaments on both hemipelvises. A comparison of anatomic data of the 2 hemipelvises was conducted. MEASUREMENTS AND MAIN RESULTS: The right and left HNs were identified in all specimens, both on cadavers and in vivo dissections. A wide anatomic variability was reported. Regarding the differences between the 2 hemipelvises, we found that the right HN was significantly (p .05). CONCLUSIONS: Despite a wide anatomic variability of position and appearance, the HNs are reproducibly identifiable using an "interfascial" technique and considering the ureters and uterosacral ligaments as anatomic landmarks.

Recently, an alternative endoscopic endonasal approach to Meckel’s cave (MC) tumors has been proposed. To date, few studies have evaluated the results of this route. The aim of our study was to evaluate long-term surgical and clinical outcome associated with this technique in a cohort of patients with intrinsic MC tumors. All patients with MC tumors treated at out institution by endoscopic endonasal approach (EEA) between 2002 and 2016 were included. Patients underwent brain MRI, CT angiography, and neurological evaluation before surgery. Complications were considered based on the surgical records. All examinations were repeated after 3 and 12 months, then annually. The median follow-up was of 44.1 months (range 16–210). The series included 8 patients (4 F): 5 neuromas, 1 meningioma, 1 chondrosarcoma, and 1 epidermoid cyst. The median age at treatment was 54.5 years (range 21–70). Three tumors presented with a posterior fossa extension. Radical removal of the MC portion of the tumor was achieved in 7 out of 8 cases. Two patients developed a permanent and transitory deficit of the sixth cranial nerve, respectively. No tumor recurrence was observed at follow-up. In this preliminary series, the EEA appeared an effective and safe approach to MC tumors. The technique could be advantageous to treat tumors located in the antero-medial aspects of MC displacing the trigeminal structures posteriorly and laterally. A favorable index of an adequate working space for this approach is represented by the ICA medialization, while tumor extension to the posterior fossa represents the main limitation to radical removal of this route.

Background Globally, overweight and obesity are becoming a mounting concern, impacting negatively on the health of populations especially in low-income settings. However, there is paucity of epidemiological information available in Ghana to support intervention activities. We conducted a study among public servants to estimate overweight/obesity, hypertension and diabetes prevalence and associated risk factors. Methods A descriptive cross sectional survey involving 271 purposively sampled public servants aged 20 to 59 years was conducted. We used a structured questionnaire to collect data on eating patterns, risk factors for overweight and obesity, as well as data on socio-demographics and physical activity. Anthropometric measurements were carried out and body mass index (BMI) calculated. Information on blood pressure and diabetes was also gathered. We used descriptive statistical and logistic regression analyses to, respectively, estimate overweight/obesity prevalence, and examine associations between behavioral factors and overweight/obesity and hypertension/diabetes. Results The overall hypertension/diabetes, overweight and obesity prevalence were 20, 29.9 and 4.8% respectively. The study found that marital status (p

Airborne pollen reflects local vegetative composition and is a proxy for flowering phase. Long-term pollen data might reflect changes in biodiversity and phenology, attributable also to the effect of climate change. The present study, based on pollen data collected within the Italian aerobiological network POLLnet, aimed to verify whether there is any evidence of temporal changes in pollen season timing and its relation with meteorological variables. To this purpose, nine stations located in North and Central Italy were selected, and twelve pollen taxa, both arboreal and herbaceous, were considered. For each taxon and station, 11–17-year datasets of airborne pollen concentration within the period 2000–2016 were analysed. Four different pollen season descriptors were elaborated (start, end and peak date, season length) and analysed their temporal trend, also in relation to temperature and precipitation. Overall, the results showed a negative temporal trend in pollen season starting date, which indicates a tendency towards an earlier flowering for Corylus, Quercus, Gramineae and Urticaceae in all stations (even if statistically significant in six out of 36 cases). The effect of meteorological parameters was evidenced by negative correlations between pollen season starting date and temperature. With the exception of Olea, Ambrosia and Artemisia, all the remaining pollen taxa showed significant (negative) correlations between pollen season start date and average temperature of the previous months in at least half of the stations. As for precipitation, no relevant correlations were detected with pollen season parameters. The results are also interpreted considering the different biogeographic areas in which the nine stations are located. Long-term pollen dataset is useful in phenological studies and for the detection of climate change effects.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS., B-cells and plasma cells are critical pathogenic cell populations in chronic Hidradenitis Suppurativa and are potential therapeutic targets.

Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease hypothesized to promote inflammation via cleavage of protease-activated receptor 1 (PAR1) and PAR2. KLK6 levels are elevated in multiple inflammatory and autoimmune conditions, but no definitive role in pathogenesis has been established. Here, we show that skin-targeted overexpression of KLK6 causes generalized, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease. The psoriatic skin and joint phenotypes are reversed by normalization of skin KLK6 levels and attenuated following genetic elimination of PAR1 but not PAR2. Conservation of this regulatory pathway was confirmed in human psoriasis using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from patients with psoriasis. Beyond defining a critical role for KLK6/PAR1 signaling in promoting psoriasis, our results demonstrate that KLK6/PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.

Background Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. Objectives We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. Methods We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings. Results Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, TH1, TH2, and TH17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of TH1, TH2, and TH17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator. Conclusions Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened TH2, TH1, TH17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

Interleukin-17 receptor D (IL-17RD) heterodimerizes with IL-17RA to form a receptor selective for the cytokine IL-17A. (See the related Research Article by Su et al. )

Autoimmune disease is 4 times more common in women than men. This bias is largely unexplained. Female skin is "autoimmunity prone," showing upregulation of many proinflammatory genes, even in healthy women. We previously identified VGLL3 as a putative transcription cofactor enriched in female skin. Here, we demonstrate that skin-directed overexpression of murine VGLL3 causes a severe lupus-like rash and systemic autoimmune disease that involves B cell expansion, autoantibody production, immune complex deposition, and end-organ damage. Excess epidermal VGLL3 drives a proinflammatory gene expression program that overlaps with both female skin and cutaneous lupus. This includes increased B cell-activating factor (BAFF), the only current biologic target in systemic lupus erythematosus (SLE); IFN-κ, a key inflammatory mediator in cutaneous lupus; and CXCL13, a biomarker of early-onset SLE and renal involvement. Our results demonstrate that skin-targeted overexpression of the female-biased factor VGLL3 is sufficient to drive cutaneous and systemic autoimmune disease that is strikingly similar to SLE. This work strongly implicates VGLL3 as a pivotal orchestrator of sex-biased autoimmunity.

Pathological hypoxia-induced organ dysfunction contributes to the high mortality of sepsis. Because of the microcirculation dysfunction following severe sepsis, it is difficult for erythrocytes to transport oxygen to hypoxic tissues. Haemoglobin-based oxygen carriers (HBOCs) are capable of delivering oxygen to hypoxic tissues. The aim of this study is to observe the potential benefits of a novel bovine-derived, non-polymerized, cell-free HBOC solution, YQ23, on sepsis in rats. Cecum ligation and puncture was performed to induce sepsis in Sprague-Dawley rats. Effects of Lactate Ringer's solution (LR), YQ23, and whole blood on oxygen delivery and consumption, mitochondrial function, organ protection and animal survival were observed. LR failed to restore oxygen delivery and the therapeutic effects were limited, whereas low dosage of YQ23 and whole blood significantly increased the tissue oxygen delivery and consumption, improved the mitochondrial function of heart, liver, kidney and intestine, prevented the vital organs injuries and improved the animal survival. The effects of 0.15 g·kg-1 YQ23 resembled that of the whole blood. In addition, YQ23 did not induce renal toxicity, severe oxidative effect and acute vasoconstriction. Thus, YQ23 is a safe and effective resuscitation fluid for sepsis.