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Summary: Despite the widespread adoption of nasal endoscopy (NE) in the evaluation of sinonasal disease, its diagnostic potential may still be underutilized. Developments in endoscopic technology have led to significant improvements in video quality and maneuverability. However, there is concern that NE continues to be used primarily for the identification of gross pathology, with relative neglect of more subtle findings such as surface features of inflammation and mucus. With fewer technical limitations to perceive these abnormalities, there is potential to greatly improve the diagnostic value of NE. The reader is herein asked to consider several important visual nuances encountered during NE, with the hope that this engenders an appreciation of the versatility of NE as a diagnostic tool. [ABSTRACT FROM AUTHOR]

Interleukin-22 (IL-22) is an important cytokine in the intestinal environment. IL-22 is mainly produced by immune cells and targeted at nonimmune cells such as epithelial and stromal cells in a broad array of tissues such as - but not restricted to- the liver and adipose tissue. IL-22 therefore connects immune functions with metabolic functions of the host, and since it is induced by the microbiota, connects host functioning to the outside environment. IL-22 induces epithelial cell proliferation aiding in rapid epithelium regeneration and wound healing. Additionally, IL-22 activates antiapoptotic genes and DNA damage response pathways, enhancing epithelial cell survival. Recently, it has also been shown that IL-22 induces Paneth cell differentiation in humans. However, IL-22 can also contribute to intestinal epithelium damage and reduces microbial diversity in the intestine directly or indirectly by inducing excessive antimicrobial peptide production by epithelial cells. Moreover, IL-22 enhances angiogenesis and may therefore support tumorigenesis in the intestine. In conclusion, it appears that whether IL-22 has a beneficial or harmful effect in the mammalian intestine largely depends on its regulation. This review aims to provide a comprehensive overview of the current literature and emphasizes that IL-22 signaling outcome depends on the timing and duration of IL-22 production, the presence of it regulators such as IL-22BP, and the specific location of the cytokine production in the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Background: Until recently, most data regarding the effects of non‐barrier contraceptives on the mucosal microbiome have derived from observational studies, which are potentially biased due to behavioral confounders that may mask their true biological effects. Method of Study: This narrative review summarises recent evidence of the effect of contraceptives on the cervicovaginal microbiome, emphasising data obtained through randomized trials. Results: Good quality data describe that initiation of long‐acting progestin‐only contraceptives, including levonorgestrel (LNG)‐implant and the injectables depot‐medroxyprogesterone acetate (DMPA‐IM) and norethisterone enanthate (NET‐EN) do not alter the mucosal microbial environment. Likewise, no strong evidence exists that the use of oral contraceptive pills (OCPs) is associated with alterations of the vaginal microbiome or increased risk of bacterial sexually transmitted infections (STIs). Limited data on the effect of intravaginal rings (IVRs) on the mucosal environment exist and show conflicting effects on the vaginal microbiota. Copper intrauterine device (Cu‐IUD) initiation has been associated with bacterial vaginosis (BV) acquisition, including in a randomized trial. LNG‐IUDs may have similar affects but need to be evaluated further. Conclusion: Different synthetic hormones have divergent effects on the microbiome and therefore novel hormonal methods need to be rigorously evaluated. Furthermore, the addition of antiretrovirals into multipurpose technologies may alter the effects of the hormonal component. There is thus a critical need to improve our understanding of the biological effects of contraceptive hormones and delivery methods with different pharmacokinetic and chemical properties on the mucosal microbiome in rigorous trials, to inform the development of novel contraceptives and improve individual family planning guidance. [ABSTRACT FROM AUTHOR]

This article discusses a case of infantile bullous pemphigoid (IBP), a rare autoimmune bullous disease that typically affects individuals over 60 years old. The case involves a 6-month-old male who presented with erythema and blisters on the skin. The diagnosis was confirmed through histopathologic examination and direct immunofluorescence. The patient was treated with methyprednisolone and topical mupirocin ointment, and showed no recurrence or scarring after 12 years of follow-up. The article also explores the etiology, treatment options, and prognosis of IBP, as well as genetic and cultural factors that may contribute to its development. [Extracted from the article]

Summary: Immune checkpoint inhibitor (ICI) therapy has revolutionized the field of oncology over the past decade, leading to durable remissions in some patients but also producing a wide spectrum of treatment‐limiting inflammatory toxicities that are referred to as immune‐related adverse events (irAEs). Although irAEs can involve any organ system in the body, they most commonly affect the barrier tissues, including the gastrointestinal tract with colitis and enterocolitis affecting a significant fraction of patients on ICIs. We are beginning to understand the mechanisms that drive ICI colitis, with early experiments indicating a role for CD8+ resident memory T cells (TRMs) in the gut, which become activated and differentiate into cytotoxic cells in response to ICI therapy. The risk factors that define who will develop ICI colitis are not understood and substantial efforts are underway to identify potential biomarkers for risk of this and other toxicities. Optimal management of ICI colitis is also an area of active investigation. Current standard treatments are based largely on small, retrospective analyses, and while drugs like systemic glucocorticoids or the TNFα inhibitor infliximab do appear to be highly active in ICI colitis, the impact of these therapies on antitumor responses is poorly understood. As discussed in this review, future work will have to define the immune mechanisms driving ICI colitis in more detail and in comparison to antitumor responses in order to identify candidate pathways that can be targeted to improve ICI colitis without interfering in antitumor immunity. Studying these interventions will require randomized, controlled trials with both tumor and colitis endpoints, a goal that will necessitate collaboration across institutions and funding agencies. We are at a point where such collaborative trials are feasible, and have the potential to greatly improve the care of patients with ICI colitis as well as other irAEs. [ABSTRACT FROM AUTHOR]

Background: Intensity modulated radiotherapy (IMRT) for head and neck cancer has led to a reduction in radiotherapy doses to normal tissues, like the salivary glands, while maintaining high rates of local control. Oral mucosal and skin toxicity is still a major source of treatment—related morbidity, occurring in most patients. Purpose: We conducted a dosimetric feasibility study with the goal of creating a methodology that could theoretically reduce the dose of radiation to skin and oral mucosa, while maintaining comparable avoidance of other organs at risk, and planning target volume (PTV) coverage. Methods: The clinical plans of patients treated previously were replanned using coplanar VMAT arcs on a TrueBeam STx using the photon optimizer (PO) version 15.6 and the Acuros XB dose calculation algorithm. Comparisons were made between three methodologies: "Conventional," "Skin Sparing" and a skin/mucosa avoiding ("SMART") technique, with dose metrics being compared using analysis of variance, with a Bonferroni correction to account for multiple pairwise comparisons. The maximum grade of mucositis and radiation dermatitis during treatment was correlated to different dose‐volume metrics to predict what could be clinically meaningful. Results: Sixteen patients met the study criteria and were replanned using the skin sparing and SMART techniques. Maximum doses to the skin sparing structure were reduced from 64.2 Gy to 56.6 and 55.9 Gy, in the skin sparing and SMART plans (p < 0.0001), and mean doses reduced from 26.7 Gy to 20.0 and 20.2 Gy, respectively (p < 0.0001). Maximum doses to the oral cavity structure were not reduced by either technique, however mean dose to the oral cavity structure was reduced from 39.03 Gy to 33.5 Gy by the SMART technique (p < 0.0001). There was a slight reduction in PTV_High coverage by the V95% in the SMART plans (99.52% vs. 98.79%, p = 0.0073), and a similar slight reduction in PTV_Low coverage by the V95% by both the skin sparing and SMART plans (99.74% vs. 97.89% vs. 97.42%, p < 0.0001). Maximum doses to organs at risk were not statistically different between techniques. Dose to oral cavity and maximum grade experienced during radiotherapy correlated. The Spearman correlation coefficient for dose to 20%, 50%, and 80% of the volume of oral cavity was 0.5 (p = 0.048), 0.64 (p = 0.007), and 0.62 (p = 0.010), respectively. Skin toxicity grade was only found to be correlated with the D20% of the skin sparing structure (Spearman correlation coefficient of 0.58, p = 0.0177). Conclusion: The SMART technique appears to be able to reduce maximum and mean skin dose, as well as mean oral cavity doses, while only slightly reducing PTV coverage, with acceptable OAR doses. We feel the improvements warrant investigation in a clinical trial. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to evaluate peri‐implant tissue levels over a 3‐year period for implants connected to either convex or concave final abutments at the time of implant placement. Materials and Methods: In this randomized, double‐masked, controlled clinical study, 28 patients with one missing maxillary premolar were assigned to receive one single implant with a permanent abutment of either convex (CONVEX Group) or concave (CONCAVE Group) emergence shape at the time of implant placement. Clinical and radiographic data were collected at the time of implant placement (IP), final prosthesis delivery (PR), 12 months (FU‐1), and 36 months (FU‐3) following implant placement. Results: At the FU‐3 13 patients were available from the CONCAVE Group (n = 13) and eleven from the CONVEX Group (n = 11). The mean change in buccal peri‐implant mucosa position (MP) from IP to FU‐3 was −0.54 ± 0.93 mm for the CONVEX Group and − 0.53 ± 0.87 mm for CONCAVE Group (p =.98). The amount of bone remodeling above the implant platform from IP to FU‐3 was −0.69 ± 0.48 mm for the CONVEX Group and −0.16 ± 0.22 mm for the CONCAVE Group (p =.005). Conclusion: The study failed to support the hypothesis that abutment macro‐design has an effect on buccal peri‐implant mucosa margin position over time. [ABSTRACT FROM AUTHOR]

Objectives: To report a summary of published patient‐reported esthetic outcome measures (PROMs) of implant‐supported single crowns (SCs) compared with those of tooth‐supported SCs. Materials and Methods: Cochrane, Medline (PubMed), and EMBASE database search was performed by three reviewers on reports with patient‐reported esthetic outcomes of tooth‐ and implant‐supported SCs. Clinical studies with at least 12 months of mean follow‐up period and a minimum of 10 patients, and English, French, or German reports were included. To compare the subgroups, for aggregate‐level data, random‐effects meta‐regression was used. Results: Two thousand fifteen titles were identified (initial search) and screened independently concluding 53 full‐text articles to include in data extraction. Twenty‐two studies with 29 study cohorts were included. Patients were satisfied with the esthetics of implant‐ and tooth‐ supported crowns Mean visual analogue scale (VAS) value from the PROMs data of 1270 implant‐supported SCs evaluated by 1051 patients was 89.6% (80.0%–94.1%). The mean VAS value of patients (n = 201), who evaluated the esthetic outcome of 486 tooth‐supported SCs was 94.4% (92.3%–96.0%). VAS scores of patients regarding their perception of esthetics did not show any difference among different crown materials or type of implant used. The patients' perception of esthetics focusing on SC had a tendency to be higher when the crowns were supported by teeth, however, no statistical difference was found when compared with implant‐supported crowns (p = 0.067). Conclusions: Patient perception of esthetics in SCs was not affected by the type of support, crown material, implant, and presence of provisional crown for both implant‐ and tooth‐supported SCs. Clinical Significance: Despite that patient's expectations are increasing overall Patients are satisfied with with esthetic outcome of implant‐ and tooth‐supported crowns. [ABSTRACT FROM AUTHOR]

The morphology of the small intestinal mucosa is reflected by the degree of stimuli. Previous studies have come to different conclusion about whether the mucosa is equally symmetrical. The aim of the study is to investigate whether there are structural differences in the mesenteric versus antimesenteric mucosa in mice, rats, and humans. Jejunal biopsies from mice and rats were saved. Samples from human small intestine were obtained from patients undergoing Roux‐en‐Y gastric bypass surgery. Fixed samples were used to morphologically evaluate villus height and enlargement factor due to villi. The number of goblet cells, mast cells, enteroendocrine cells, and Paneth cells were histologically analyzed in the villus structure. Cell turnover was analyzed by Ki‐67 staining. There was a significant increased villi height and villus enlargement factor antimesenterically in mice, rats, and human small intestines. The distribution of goblet cells, mast cells, and Paneth cells were equal while the number of enteroendocrine cells was increased antimesenteric in the human samples. The crypt mitotic activity was almost 20% higher in the antimesenteric part of jejunum. In summary we found longer villi, greater surface enlargement, and increased number of enteroendocrine cells as well as increased cell turnover antimesenterically. These differences may be of importance in understanding normal gastrointestinal physiology in health and disease. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic chronic rhinosinusitis is an often treatment‐resistant inflammatory disease mediated by type‐2 cytokines, including interleukin (IL)‐5. Mepolizumab, a monoclonal antibody drug targeting IL‐5, has demonstrated efficacy and safety in inflammatory airway disease, but there is negligible evidence on direct tissue response. The study's aim was to determine the local effect of mepolizumab on inflammatory biomarkers in sinonasal tissue of eosinophilic chronic rhinosinusitis patients. Methods: Adult patients with eosinophilic chronic rhinosinusitis received 100mg mepolizumab subcutaneously at four‐weekly intervals for 24 weeks in this prospective phase 2 clinical trial. Tissue eosinophil counts, eosinophil degranulation (assessed as submucosal eosinophil peroxidase deposition by immunohistochemistry) and cytokine levels (measured in homogenates by immunoassay) were evaluated in ethmoid sinus tissue biopsies collected at baseline and at weeks 4, 8, 16 and 24. Results: Twenty patients (47.7 ± 11.7 years, 50% female) were included. Sinonasal tissue eosinophil counts decreased after 24 weeks of treatment with mepolizumab (101.64 ± 93.80 vs 41.74 ± 53.76 cells per 0.1 mm2; p =.035), eosinophil degranulation remained unchanged (5.79 ± 2.08 vs 6.07 ± 1.20, p =.662), and type‐2 cytokine levels increased in sinonasal tissue for IL‐5 (10.84 ± 18.65 vs 63.98 ± 50.66, p =.001), IL‐4 (4.48 ± 3.77 vs 9.38 ± 7.56, p =.004), IL‐13 (4.02 ± 2.57 vs 6.46 ± 3.99, p =.024) and GM‐CSF (1.51 ± 1.74 vs 4.50 ± 2.97, p =.001). Conclusion: Mepolizumab reduced eosinophils in sinonasal tissue, demonstrating that antagonism of IL‐5 suppresses eosinophil trafficking. With reduced tissue eosinophils, a local type‐2 inflammatory feedback loop may occur. The study exposes mechanistic factors which may explain incomplete treatment response. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effect of cold atmospheric plasma (CAP) treatment combined with adhesive filling therapy on rat dental pulps. Cavities were prepared in the first maxillary molars of 20 Sprague Dawley rats. The first molar and the unprepared second molar of one randomly selected maxillary quadrant were treated with CAP. The prepared cavities were filled with composite. After 24 h and 28 days, 10 rats each were killed. Teeth were demineralized and embedded in paraffin and histological sections were stained with hematoxylin–eosin and chloracetatesterase. None of the pulps displayed necrosis. Plasma treatment caused no additional alteration to the dental pulp in combination with adhesive filling therapy. These findings indicate that plasma treatment is compatible with the regenerative potential of the pulp. [ABSTRACT FROM AUTHOR]

Background: Offset analgesia (OA) is commonly used to quantify endogenous pain inhibition. However, the potential role of afferent inputs and the subsequent peripheral factors from different body areas on the underlying mechanisms are still unclear. Objectives: The aim of this cross‐sectional study was to compare the magnitude of OA in four different body areas representing (a) glabrous and non‐glabrous skin, (b) trigeminal and extra‐trigeminal areas, and (c) intra‐ and extra‐oral tissue. Methods: OA was assessed at the oral mucosa of the lower lip, the skin of the cheek, the forearm and the palm of the hand in 32 healthy and pain‐free participants. OA testing included two trials: (1) a constant trial (30 s of constant heat stimulation at an individualised temperature of Pain50 [pain intensity of 50 out of 100]) and (2) an offset trial (10 s of individualised Pain50, followed by 5 s at Pain50 + 1°C and 15 s at Pain50). Participants continuously rated their pain during each trial with a computerised visual analogue scale. Results: A significant OA response was recorded at the oral mucosa (p <.001, d = 1.24), the cheek (p <.001, d = 0.84) and the forearm (p <.001, d = 1.04), but not at the palm (p =.19, d = 0.24). Significant differences were shown for OA recorded at the cheek versus the mucosa (p =.02), and between palm and mucosa (p =.007), but not between the remaining areas (p >.05). Conclusion: This study suggests that intra‐oral endogenous pain inhibition assessed with OA is enhanced and supports the role of peripheral mechanisms contributing to the OA response. [ABSTRACT FROM AUTHOR]

The prevalence and severity of mucocutaneous manifestations in Covid‐19 infection are generally higher than those reported in Covid vaccines. Therefore, comparing the mucocutaneous reactions of the Covid‐19 infection and vaccination is necessary to enhance our knowledge about such reactions and guide us to evaluate the risk of infection or vaccination. A thorough literature search was conducted on PubMed, Google Scholar, and EBSCO (LISTA), and 2069 articles were downloaded. After screening, 11 studies remained for the final review. The literature review revealed that the prevalence and severity of postvaccine mucocutaneous adverse reactions have been less common compared to Covid‐19 infection. Postvaccine adverse reactions primarily occurred after the first dose administration and such reactions were manageable with antihistamines and corticosteroids administration. This comparative analysis highlights the frequency and potential severity of mucocutaneous reactions due to Covid‐19 infection and Covid‐19 vaccination. It also affirmed that potentially critical (serious) mucocutaneous reactions are more likely to occur in Covid‐19 infection compared to Covid vaccination. Moreover, postvaccine reactions predominantly happened after the first dose and were reported to be non‐life‐threatening, self‐manageable and with a lower incidence of potentially critical events. It was also concluded that the incidence of mucocutaneous reactions decreased in the following doses. Hence, given the low rate of such reactions following Covid‐19 vaccination, vaccines have a lower risk of mucocutaneous reactions occurrence than Covid‐19 infection. Further, due to the limited number of studies, we recommend that large‐scale trials evaluate such reactions comparing various types of Covid‐19 vaccines in healthy individuals and those with autoimmune skin disorders. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: Tumor‐infiltrating lymphocytes (TILs) predict better outcome in several types of cancers. However, the prognostic value of TILs in sinonasal mucosal melanoma (SNMM) is uncertain. Here, we investigated whether TILs can be used as a prognostic indicator for survival in SNMM. Study Design: Retrospective cohort study. Methods: Patient history and histologic specimens from 27 patients with primary SNMM were retrospectively analyzed. TIL grade was determined and associations between TILs and AJCC tumor stage, overall survival, and recurrence‐free survival were analyzed. Results: Patients with TILs in the primary tumor classified as brisk or non‐brisk survived significantly longer than patients with SNMMs lacking lymphocyte infiltrates. Brisk TILs were associated with the lower T3 stage and increased recurrence‐free and 5‐year survival. Conclusion: Our results indicate that TIL density is a strong prognostic factor for better survival in SNMM. Prospective studies with larger case numbers are warranted to determine whether TILs should be included in future AJCC staging guidelines. Level of Evidence: 3 Laryngoscope, 132:1334–1339, 2022 [ABSTRACT FROM AUTHOR]

Background: The prosthetic emergence profile design might be an important factor in postsurgical mucosal recession etiology. Therefore, a restorative buccal emergence profile designed correctly might reduce gingival margin recession. Purpose: To compare the marginal gingival level and the width/height (W/H) ratio between two profile configurations of single implant‐supported restorations at molar sites. Materials and Methods: Twenty‐one patients requiring a single mandibular molar tooth replacement with supracrestal mucosal thickness ≥2 mm were recruited and randomly assigned to a prosthesis buccal emergence profile design based on the buccal mucosal W/H ratio (Test Group) or maintained the original emergence profile of the healing abutment (Control Group). Assessments were made before delivery of the definitive restoration (T0), at prosthesis placement (T1), one (T2), and 12 (T3) months after loading. The gingival margin level change (△GM), initial emergence angle, buccal mucosal W/H ratio, marginal bone loss (MBL), implant failure, and complications were assessed. Results: The gingival recession in the test group (0.13 ± 0.32 mm) was significantly lower than in the control group (0.63 ± 0.38 mm) at T3 (p = 0.006). The initial emergence angle in the test group (31.4 ± 7.22 degrees) was significantly lower than the control group (40.0 ± 7.60 degrees) (p = 0.025). The W/H ratio in the test group at T2 was significantly higher than at T0 but remained stable thereafter. The W/H ratio presented a continued rising trend in the control group. Conclusions: When the initial supracrestal soft tissue thickness was ≥2 mm, a restorative emergence profile based on the W/H ratio significantly reduced gingival margin recession. An emergence angle of 32.4 degrees showed better behavior in maintaining the gingival margin than 40 degrees. Clinical Trial Registration Number: ChiCTR190002210. [ABSTRACT FROM AUTHOR]

Introduction: A thick peri‐implant mucosa is of importance to prevent recession, color alterations, bone remodeling and promote "creeping attachment." A volume stable porcine cross‐linked collagen matrix has been recently introduced for soft tissue regeneration and volume maintenance. The aim of this study was to investigate peri‐implant soft tissue healing and stability on 40 consecutive patients treated with buccal pedicle flap combined with the use of the collagen matrix. Case Series: The buccal pedicle flap combined with a volume stable collagen matrix was executed at second stage surgery. The average initial mucosa thickness was 1.32 mm whereas the average band of keratinized mucosa was 1.65 mm and the height 1.3 mm. Four months after surgical procedure and before delivering the final restoration, the peri‐implant soft tissue measurements were significantly increased: the average band of keratinized mucosa was 5.10 mm, the mucosa thickness was 3.27 mm, and the mucosa height was 3.32 mm. After 2 years of follow‐up, the superimposition of 3D models described an overall volumetric stability of the augmented mucosa with no signs of soft tissue collapse. Conclusion: The proposed modified buccal pedicle flap was demonstrated to perform well in terms of decreased morbidity, maintenance of blood supply, stabilization of the pedicle, superior haemostasis, and speed of treatment. No significant variations of the keratinized tissue were registered when the buccal pedicle flap was executed in conjunction with the collagen matrix that however provided color match with the surrounding tissue as well as an increased mucosa thickness. [ABSTRACT FROM AUTHOR]

Smooth muscle cells (SMCs) of the guinea pig seminal vesicle (SV) develop spontaneous phasic contractions, Ca2+ flashes and electrical slow waves in a mucosa‐dependent manner, and thus it was envisaged that pacemaker cells reside in the mucosa. Here, we aimed to identify the pacemaker cells in SV mucosa using intracellular microelectrode and fluorescence Ca2+ imaging techniques. Morphological characteristics of the mucosal pacemaker cells were also investigated using focused ion beam/scanning electron microscopy tomography and fluorescence immunohistochemistry. Two populations of mucosal cells developed spontaneous Ca2+ transients and electrical activity, namely basal epithelial cells (BECs) and subepithelial interstitial cells (SICs). Pancytokeratin‐immunoreactive BECs were located on the apical side of the basement membrane (BM) and generated asynchronous, irregular spontaneous Ca2+ transients and spontaneous transient depolarisations (STDs). The spontaneous Ca2+ transients and STDs were not diminished by 10 μM nifedipine but abolished by 10 μM cyclopiazonic acid (CPA). Platelet‐derived growth factor receptor α (PDGFRα)‐immunoreactive SICs were distributed just beneath the basal side of the BM and developed synchronous Ca2+ oscillations and electrical slow waves, which were suppressed by 3 μM nifedipine and abolished by 10 μM CPA. In SV mucosal preparations in which some smooth muscle bundles remained attached, SICs and residual SMCs developed temporally correlated spontaneous Ca2+ transients. Neurobiotin injected into SICs spread not only to neighbouring SICs but also to neighbouring SMCs or vice versa. These results suggest that PDGFRα+ SICs electrotonically drive the spontaneous contractions of SV smooth muscle. Key points: In many visceral smooth muscle organs, spontaneous contractions are electrically driven by non‐muscular pacemaker cells. In guinea pig seminal vesicles (SVs), as yet unidentified mucosal cells appear to drive neighbouring smooth muscle cells (SMCs).Two populations of spontaneously active cells are distributed in the SV mucosa. Basal epithelial cells (BECs) generate asynchronous, irregular spontaneous Ca2+ transients and spontaneous transient depolarisations (STDs). In contrast, subepithelial interstitial cells (SICs) develop synchronous Ca2+ oscillations and electrical slow waves.Pancytokeratin‐immunoreactive (IR) BECs are located on the apical side of the basement membrane (BM), while platelet‐derived growth factor receptor α (PDGFRα)‐IR SICs are located on the basal side of the BM.Spontaneous Ca2+ transients in SICs are synchronised with those in SV SMCs. Dye‐coupling between SICs and SMCs suggests that SICs act as pacemaker cells to drive the spontaneous contractions of SV smooth muscle. [ABSTRACT FROM AUTHOR]

Herein, I discuss the enduring mystery of the receptor layout in the vertebrate olfactory system. Since the awarding of the 2004 Nobel Prize to Axel and Buck for their discovery of the gene family that encodes olfactory receptors, our field has enjoyed a golden era. Despite this Renaissance, an answer to one of the most fundamental questions for any sensory system—what is the anatomical logic of its receptor array?—eludes us, still, for olfaction! Indeed, the only widely debated hypothesis, finding its origins in the musing of another Nobel laureate Sir Edgar Adrian, has it that the vertebrate nose organizes its receptors according to the "sorptive" properties of their ligands. This idea, known as the "sorption" or "chromatography" hypothesis, enjoys considerable support despite being controversial. Here, I review the history of the hypothesis—its rises and falls—and discuss the latest data and future prospects for this perennial idea whose history I liken to the mythical Phoenix. [ABSTRACT FROM AUTHOR]

Background: The combination of the antihistamine azelastine (AZE) with the corticosteroid fluticasone propionate (FP) in a single spray, has been reported to be significantly more effective at reducing allergic rhinitis (AR) symptoms than treatment with either corticosteroid or antihistamine monotherapy. However, the biological basis for enhanced symptom relief is not known. This study aimed to compare gene expression profiles (760 immune genes, performed with the NanoString nCounter) from peripheral blood and nasal brushing/lavage lysate samples in response to nasal spray treatment. Methods: Moderate/severe persistent dust mite AR sufferers received either AZE (125 μg/spray) nasal spray (n = 16), FP (50 μg/spray) nasal spray (n = 14) or combination spray AZE/FP (125 μg AZE and 50 μg FP/spray) (n = 14) for 7 days, twice daily. Self‐reported symptom questionnaires were completed daily for the study duration. Gene expression analysis (760 immune genes) was performed with the NanoString nCounter on purified RNA from peripheral blood and nasal brushing/lavage lysate samples. Results: In nasal samples, 206 genes were significantly differentially expressed following FP treatment; 182 genes downregulated (−2.57 to −0.45 Log2 fold change [FC]), 24 genes upregulated (0.49–1.40 Log2 FC). In response to AZE/FP, only 16 genes were significantly differentially expressed; 10 genes downregulated (−1.53 to −0.58 Log2 FC), six genes upregulated (1.07–1.62 Log2 FC). Following AZE treatment only five genes were significantly differentially expressed; one gene downregulated (−1.68 Log2 FC), four genes upregulated (0.59–1.19 Log2 FC). Immune gene changes in peripheral blood samples following treatment were minimal. AR symptoms improved under all treatments, but improvements were less pronounced following AZE treatment. Conclusion: AZE/FP, FP, and AZE had diverse effects on immune gene expression profiles in nasal mucosa samples. The moderate number of genes modulated by AZE/FP indicates alternative pathways in reducing AR symptoms whilst avoiding extensive local immune suppression. Key Highlights: Antihistamine, steroid and combination nasal sprays elicit distinct gene expression profiles in nasal mucosa samples.Modest mucosal gene expression changes were noted for combination therapy compared with a steroid‐only formulation. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is the most common pattern of primary glomerular disease reported worldwide. Up to 40% of those with IgAN progress to end‐stage kidney disease within 20 years of diagnosis, with no currently available disease‐specific treatment. This is likely to change rapidly, with evolving insights into the mechanisms driving this disease. IgAN is an immune‐complex–mediated disease, and its pathophysiology has been framed by the 'four‐hit hypothesis', which necessitates four events to occur for clinically significant disease to develop. However, this hypothesis does not explain the wide variability observed in its presentation or clinical progression. Recently, there has been great interest in exploring the role of the mucosal immune system in IgAN, especially given the well‐established link between mucosal infections and disease flares. Knowledge of antigen–mucosal interactions is now being successfully leveraged for therapeutic purposes; the gut‐directed drug Nefecon (targeted release formulation‐budesonide) is on track to become the first medication to be approved specifically for the treatment of IgAN. In this review, we examine established immunological paradigms in IgAN, explore how antigen–mucosal immune responses drive disease, and discuss how this knowledge is being used to develop new treatments. [ABSTRACT FROM AUTHOR]

Objectives: This randomized comparative study evaluated the clinical esthetic outcome of the peri‐implant mucosa following extraction and immediate implant placement in conjunction with anorganic bovine bone mineral (ABBM) and the use of a porcine acellular dermal matrix (pADM) versus an autogenous connective tissue graft (CTG) in the anterior maxilla. Materials and methods: Twenty patients (11 men, 9 women) with a mean age of 48,9 years (range 21–72) were included in the study and randomly assigned to either the test (pADM) or control group (CTG). They underwent extraction and immediate implant placement together with ABBM for socket grafting and either pADM or CTG for soft tissue augmentation. Twelve months after implant placement color measurements of the peri‐implant mucosa and a reference tooth were performed using a spectophotometer and the color difference (ΔE) was calculated. The overall esthetic appearance of the peri‐implant soft tissue was evaluated using the Pink Esthetic Score (PES). Statistical analysis was performed using Student's T‐Test, the alpha was set to 0.05. Results: All implants received osseointegration and were restored. The mean color difference of the peri‐implant mucosa 1 year after surgery amounted ΔE 4.06 ± 1.6 for the test group (pADM) and ΔE 3.58 ± 1.36 mm for the control group (CTG), showing no statistically significant difference (p = 0.47). The mean PES of the pADM group was 11.4 ± 1.4 and for the CTG group 10.7 ± 1.5, showing no statistically significant difference (p = 0.29). Conclusion: Twelve months after surgery, a porcine acellular dermal matrix for soft tissue augmentation in conjunction with immediate implant placement showed no difference in the overall esthetic appearance regarding color match and Pink Esthetic Score in comparison to autogenous soft tissue graft. Clinical Significance: Connective tissue grafts have become a standard in order to enhance the soft tissue quality and esthetic appearance in immediate implant placement. The use of new biomaterials like porcine acellular dermal matrices may avoid the need to harvest autogenous grafts resulting in simplified treatment and less postoperative morbidity. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) is a complex disease involving both mucosal and systemic immune compartments. Greater understanding of the immune networks underpinning AR pathophysiology may assist with further refining disease‐specific biomarkers. Objective: To compare immune gene expression profiles in nasal mucosa and peripheral blood samples between adults with AR and controls without AR. Methods: This cross‐sectional study included 45 adults with moderate‐severe and persistent AR (37.6 ± 12.8 years; mean ± SD) and 24 adults without AR (36.6 ± 10.2). Gene expression analysis was performed using the NanoString nCounter PanCancer Immune profiling panel (n = 730 immune genes) in combination with the panel plus probe set (n = 30 allergy‐related genes) with purified RNA from peripheral blood and cell lysates prepared from combined nasal lavage and nasal brushing. Results: One hundred and thirteen genes were significantly differentially expressed in peripheral blood samples between groups (p <.05). In contrast, 14 genes were differentially expressed in nasal lysate samples between groups (p <.05). Upregulation of allergy‐related genes in nasal mucosa samples in the AR group was observed. Namely, chemokines CCL17 and CCL26 are involved in the chemotaxis of key effector cells and TPSAB1 encodes tryptase, an inflammatory mediator released from activated mast cells and basophils. Six differentially expressed genes (DEGs) were in common between the nasal mucosa and blood samples. In addition, counts of specific DEGs in nasal mucosa samples were positively correlated with eosinophil and dust mite‐specific immunoglobulin E (IgE) counts in blood. Conclusions and Clinical Relevance: Distinct gene expression profiles in blood and nasal mucosa samples were observed between AR sufferers and controls. The results of this study also provide evidence for a close interaction between the local site and systemic immunity. The genes identified in this study contribute to the current knowledge of AR pathophysiology and may serve as biomarkers to evaluate the effectiveness of treatment regimens, or as targets for drug discovery. [ABSTRACT FROM AUTHOR]

This mini‐review describes observations of the 1990ies with culturing of gluten‐specific and astrovirus‐specific CD4+ T cells from duodenal biopsies from subjects who presumably had a long time between the exposure to gluten or astrovirus antigens and the sampling of the biopsy. In these studies, it was also observed that antigen‐specific CD4+ T cells migrated out of the gut biopsies during overnight culture. The findings are suggestive of memory T cells in tissue which are resident, but which also can be mobilised on antigen stimulation. Of note, these findings were made years before the term tissue‐resident memory T cells was invoked. Since that time, many observations have accumulated on these gut T cells, particularly the gluten‐specific T cells, and we have insight into the turnover of CD4+ T cells in the gut lamina propria. These data make it evident that human antigen‐specific CD4+ T cells that can be cultured from gut biopsies indeed are bone fide tissue‐resident memory T cells. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence on the impact of thin gingival phenotype (TnP) and inadequate keratinized mucosa width (KMW <2 mm) around dental implants on peri-implant health. This study investigated the role of TnP and inadequate KMW (<2 mm) as risk indicators for peri-implantitis and mucositis and on dental patient-reported outcomes.Methods: Sixty-three patients with 193 implants (mean follow-up of 6.9 ± 3.7 years) were given a clinical and radiographic examination and a questionnaire to assess patient awareness of food impaction and pain/discomfort. Chi-squared tests and regression analysis for clustered data were used to compare outcomes.Results: Implants with TnP had a statistically higher prevalence of peri-implantitis (27.1% versus 11.3%; PR, 3.32; 95% confidence interval (CI), 1.64-6.72; P = 0.001) peri-implant mucositis (42.7% versus 33%; PR, 1.8; 95% CI, 1.12-2.9; P = 0.016) and pain/discomfort during oral hygiene (25% versus 5%; PR, 3.7; 95% CI, 1.06-12.96; P = 0.044) than thick phenotype. Implants with inadequate KMW had a statistically higher prevalence of peri-implantitis (24.1% versus 17%; PR, 1.87; 95% CI, 1.07-3.25; P = 0.027) and peri-implant mucositis (46.6% versus 34.1%; PR, 1.53; 95% CI, 1-2.33; P = 0.05) and pain/discomfort during oral hygiene (28% versus 10%; PR, 2.37; 95% CI, 1.1-5.1; P = 0.027) than the adequate KMW. TnP was strongly associated with inadequate KMW (PR = 3.18; 95% CI, 1.69-6.04; P <0.001).Conclusion: TnP and inadequate KMW (<2 mm) may be significant risk indicators for peri-implant disease and pain/discomfort during brushing. [ABSTRACT FROM AUTHOR]

Angiotensin‐converting enzyme 2 (ACE2) and transmembrane proteases (TMPRSS) are multifunctional proteins required for SARS‐CoV‐2 infection or for amino acid (AA) transport, and are abundantly expressed in mammalian small intestine, but the identity of the intestinal cell type(s) and sites of expression are unclear. Here we determined expression of SARS‐CoV‐2 entry factors in different cell types and then compared it to that of representative AA, electrolyte, and mineral transporters. We tested the hypothesis that SARS‐CoV‐2, AA, electrolyte, and mineral transporters are expressed heterogeneously in different intestinal cell types by making mouse enteroids enriched in enterocytes (ENT), goblet (GOB), Paneth (PAN), or stem (ISC) cells. Interestingly, the expression of ACE2 was apical and modestly greater in ENT, the same pattern observed for its associated AA transporters B0AT1 and SIT1. TMPRSS2 and TMPRSS4 were more highly expressed in crypt‐residing ISC. Expression of electrolyte transporters was dramatically heterogeneous. DRA, NBCe1, and NHE3 were greatest in ENT, while those of CFTR and NKCC1 that play important roles in secretory diarrhea, were mainly expressed in ISC and PAN that also displayed immunohistochemically abundant basolateral NKCC1. Intestinal iron transporters were generally expressed higher in ENT and GOB, while calcium transporters were expressed mainly in PAN. Heterogeneous expression of its entry factors suggests that the ability of SARS‐CoV‐2 to infect the intestine may vary with cell type. Parallel cell‐type expression patterns of ACE2 with B0AT1 and SIT1 provides further evidence of ACE2's multifunctional properties and importance in AA absorption. [ABSTRACT FROM AUTHOR]

The gut wall houses mast cells that are anatomically situated near enteric neuronal fibers. Roles of specific neuropeptides in modulating function of immune components like mast cells in response to challenge with bacterial components are relatively unknown. Investigating such interactions requires models that include diverse cellular elements in native anatomic arrangements. Using an organotypic slice model that maintains gut wall cellular diversity ex vivo, the present study compared responses between tissues derived from male and female mice to examine neural‐immune signaling in the gut wall after selected treatments. Ileum slices were treated with pharmacological reagents that block neuronal function (e.g., tetrodotoxin) or vasoactive intestinal peptide (VIP) receptors prior to challenge with lipopolysaccharide (LPS) to assess their influence on anatomic plasticity of VIP fibers and activation of mast cells. Sex differences were observed in the number of mucosal mast cells (c‐kit/ACK2 immunoreactive) at baseline, regardless of treatment, with female ileum tissue having 46% more ACK2‐IR mast cells than males. After challenge with LPS, male mast cell counts rose to female levels. Furthermore, sex differences were observed in the percentage of ACK2‐IR cells within 1 µm of a VIP+ neuronal fiber, and mast cell size, a metric previously tied to activation, with females having larger cells at baseline. Male mast cell sizes reached female levels after LPS challenge. This study suggests sex differences in neural‐immune plasticity and in mast cell activation both basally and in response to challenge with LPS. These sex differences could potentially impact functional neuroimmune response to pathogens. [ABSTRACT FROM AUTHOR]

Most antibodies produced in the body are of the IgA class. The dominant cell population producing them are plasma cells within the lamina propria of the gastrointestinal tract, but many IgA‐producing cells are also found in the airways, within mammary tissues, the urogenital tract and inside the bone marrow. Most IgA antibodies are transported into the lumen by epithelial cells as part of the mucosal secretions, but they are also present in serum and other body fluids. A large part of the commensal microbiota in the gut is covered with IgA antibodies, and it has been demonstrated that this plays a role in maintaining a healthy balance between the host and the bacteria. However, IgA antibodies also play important roles in neutralizing pathogens in the gastrointestinal tract and the upper airways. The distinction between the two roles of IgA ‐ protective and balance‐maintaining ‐ not only has implications on function but also on how the production is regulated. Here, we discuss these issues with a special focus on gut and airways. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: The endoscopic endonasal approach (EEA) is increasingly utilized for management of petrous apex cholesterol granuloma (PACG). Surgical goals include drainage and marsupialization of the cyst. Various techniques have been described to try to reduce the rates of recurrence. We studied the effect of mucosal grafting on recurrence. Study Design: Retrospective Cohort study. Methods: Patients who underwent EEA for PACG at two tertiary care centers between 1999 and 2018 were identified and divided into two cohorts: Mucosal versus no mucosal reconstruction. Surgical approach, reconstructive method, and recurrence were recorded. Primary endpoint was symptomatic or radiographic recurrence. Results: Thirty‐four patients were identified undergoing 37 surgeries. Four patients developed recurrences of which three elected to undergo revision. Some form of mucosa was used to line the drainage tract in 20 cases. A free mucosal graft was used in 8, and a small customized nasal septal flap (miniflap) in 12. All four recurrences occurred in cases where no mucosa was used, demonstrating decreased recurrences with mucosal reconstruction (P <.05). There was no difference found between free mucosal grafts and miniflaps. Conclusions: Utilization of mucosa to partially line a circumferentially de‐epithelialized drainage pathway after EEA for PACG reduce recurrence rates. Level of Evidence: 3 Laryngoscope, 131:E2513–E2517, 2021 [ABSTRACT FROM AUTHOR]

Objectives: To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft‐versus‐host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation. Subjects and Methods: The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day −3 to day 24 post‐transplant. Results: Eighty‐seven patients developed oral mucositis in the first 24 days post‐transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post‐transplant, no significant difference compared with the Tac/Sir group was found. Conclusions: The introduction of tacrolimus/sirolimus as a graft‐versus‐host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: The effects of different electrocautery power settings on mucosal contraction and margin status in the oral cavity have not been well established. The aim of this study was to examine how different levels of electrocautery energy outputs affect oral mucosal tissue margins. Study Design: Animal model. Methods: A model of 23 adult rats was used (two specimens per rat). After anesthetizing the animals, a 6‐mm biopsy punch marked the resection margin on the buccal mucosa (one per cheek). The specimens were excised by means of three energy levels, a cold knife, and monopolar diathermy that was set on either 20 W or 30 W cut modes. The specimens were evaluated for extent of contraction. Results: A total of 45 samples were obtained and measured, including 15 specimens in the cold‐knife group, 15 specimens in the 20 W group, and 15 specimens in the 30 W group. The median diameters of the specimens after resection were 4.5 mm for the cold‐knife group (interquartile range [IQR] = 4.0–5.0), 3.5 mm for the 20 W group (IQR = 3.5–4.0), and 2.8 mm for the 30 W group (IQR = 2.5–3.0). Specimen contraction was 25.0%, 41.7%, and 53.3%, respectively. The difference in shrinkage between each pair was statistically significant: cold knife versus 20 W, P =.001; cold knife versus 30 W, P <.0001; and 20 W versus 30 W, P <.001. Conclusions: Diathermy power settings result in a significant difference of mucosal tissue contraction, with higher outputs resulting in a narrower mucosal margin. It is imperative that the surgical team take into consideration the diathermy settings during initial resection planning. Laryngoscope, 131:E1514–E1518, 2021 [ABSTRACT FROM AUTHOR]

Introduction: The pathophysiology and temporal dynamics of affected tissues in chronic rhinosinusitis (CRS) remain poorly understood. Here, we present a multiomics‐based time‐series assessment of nasal polyp biopsies from three patients with CRS, assessing natural variability over time and local response to systemic corticosteroid therapy. Methods: Polyp tissue biopsies were collected at three time points over two consecutive weeks. Patients were prescribed prednisone (30 mg daily) for 1 week between Collections 2 and 3. Polyp transcriptome, proteome, and microbiota were assessed via RNAseq, SWATH mass spectrometry, and 16S ribosomal RNA and ITS2 amplicon sequencing. Baseline interpatient variability, natural intrapatient variability over time, and local response to systemic corticosteroids, were investigated. Results: Overall, the highly abundant transcripts and proteins were associated with pathways involved in inflammation, FAS, cadherin, integrin, Wnt, apoptosis, and cytoskeletal signaling, as well as coagulation and B‐ and T‐cell activation. Transcripts and proteins that naturally varied over time included those involved with inflammation‐ and epithelial–mesenchymal transition‐related pathways, and a number of common candidate target biomarkers of CRS. Ten transcripts responded significantly to corticosteroid therapy, including downregulation of TNF, CCL20, and GSDMA, and upregulation of OVGP1, and PCDHGB1. Members of the bacterial genus Streptococcus positively correlated with immunoglobulin proteins IGKC and IGHG1. Conclusions: Understanding natural dynamics of CRS‐associated tissues is essential to provide baseline context for all studies on putative biomarkers, mechanisms, and subtypes of CRS. These data further our understanding of the natural dynamics within nasal polypoid tissue, as well as local changes in response to systemic corticosteroid therapy. [ABSTRACT FROM AUTHOR]

The cathelin‐related antimicrobial peptide CRAMP protects the mouse colon from inflammation, inflammation‐associated carcinogenesis, and disrupted microbiome balance, as shown in systemic Cnlp−/− mice (also known as Camp−/− mice). However, the mechanistic basis for the role and the cellular source of CRAMP in colon pathophysiology are ill defined. This study, using either epithelial or myeloid conditional Cnlp−/−mice, demonstrated that epithelial cell‐derived CRAMP played a major role in supporting normal development of colon crypts, mucus production, and repair of injured mucosa. On the other hand, myeloid cell‐derived CRAMP potently supported colon epithelial resistance to bacterial invasion during acute inflammation with exacerbated mucosal damage and higher rate of mouse mortality. Therefore, a well concerted cooperation of epithelial‐ and myeloid‐derived CRAMP is essential for colon mucosal homeostasis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Objectives: Recent studies have suggested the necessity of therapeutic intervention for patients with ulcerative colitis at high risk of clinical relapse with a Mayo endoscopic score (MES) of 1. The aim of this retrospective cohort study was to demonstrate the impact of intramucosal capillary network changes and crypt architecture abnormalities to stratify the risk of relapse in patients with an MES of 1. Methods: All included patients had an MES of ≤1 and confirmed sustained clinical remission between October 2016 and April 2019. We classified patients with an MES of 1 as "intramucosal capillary/crypt (ICC)‐active" or "ICC‐inactive" using endocytoscopic evaluation. We followed patients until October 2019 or until relapse; the main outcome measure was the difference in clinical relapse‐free rates between ICC‐active and ICC‐inactive patients with an MES of 1. Results: We included 224 patients and analyzed data for 218 (82 ICC‐active and 54 ICC‐active with an MES of 1 and 82 with an MES of 0). During follow‐up, among the patients with an MES of 1, 30.5% (95% confidence interval 20.8–41.6; 25/82) of the patients relapsed in the ICC‐active group and 5.6% (95% confidence interval 1.2–15.4; 3/54) of the patients relapsed in the ICC‐inactive group. The ICC‐inactive group had a significantly higher clinical relapse‐free rate compared with the ICC‐active group (P < 0.01). Conclusions: In vivo intramucosal capillary network and crypt architecture patterns stratified the risk of clinical relapse in patients with an MES of 1 (UMIN 000032580; UMIN 000036359). [ABSTRACT FROM AUTHOR]

Background: Monoclonal antibody therapies have a growing role in treating refractory airway disease. Objective: The review aimed to summarize the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions. Design: We conducted a systematic review including risk of bias assessment. Data sources: MEDLINE, EMBASE and PubMed from 1 January 2000 to 16 November 2019 were searched. Eligibility criteria: Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single‐arm trials, were eligible. Results: There were 4195 articles screened, and full‐text analysis produced n = 11 studies with extractable data. Nine were RCTs, and two were single‐arm trials. These studies focused on asthma (n = 9 articles), chronic rhinosinusitis (n = 1) and allergic rhinitis (n = 1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n = 6) or unclear (n = 3) in the RCTs and moderate in the single‐arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL‐13, but not IL‐4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa. Conclusions: Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine. [ABSTRACT FROM AUTHOR]

We report the first series of melanomas (MMs) where the surgical margins were evaluated both by ex vivo confocal microscopy (EVCM) and in vivo reflectance confocal microscopy (RCM). We evaluated the surgical margins of 42 cutaneous MMs of lentigo maligna/lentigo maligna melanoma type and 2 mucosal MMs with EVCM. Cutaneous MMs also underwent RCM mapping. Imaging results were compared with histopathology. The rate of correct identification of the tumor margins (invaded or not invaded) was 97.6% for RCM (evaluations of cutaneous MMs) and 95.5% for EVCM (evaluations of both cutaneous and mucosal MMs). Our study showed that the MM extension is visible under EVCM and that the combination of in vivo RCM and EVCM can be a new strategy for the evaluation of surgical margins of MMs. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is a spectrum of complex inflammatory conditions of the sinonasal mucosa. Identification of biomarkers that enable classification and improved delineation among CRS endotypes is of increasing interest. However, the extent to which less invasive sampling methods identify genuine tissue inflammatory patterns is not well understood. The aim of this study was to investigate mucosal swab and cytobrush sampling as less invasive proxies for tissue transcription levels of putative biomarkers of CRS. Methods: Expression levels of 21 biomarkers of interest were assessed via custom TaqMan array cards from mucosal biopsy, cytobrush, and swab samples, in 32 patients with CRS. Reported expression levels were compared between each of the 3 sample types within each patient. Results: Reported transcription levels from swab samples for IL33, MUC5AC, IL1RN, CXCL8 (IL‐8), TNF, IFNG, IL5, OSM, IL1A, and IL17C, and cytobrush levels for IL33, MUC5AC, IL5RA, IL1RN, CXCL8 (IL‐8), and IL5 were significantly different to tissue levels from matched biopsy samples. Conclusion: Reported expression via swab and cytobrush sampling differed from patterns observed in matched tissue for 10 of 21 and 6 of 21 markers, respectively. Non–biopsy‐based studies for these particular markers may therefore not adequately represent tissue inflammatory processes and should be interpreted with caution. Cytobrush samples largely tracked tissue patterns for the remaining target biomarkers. In these cases, cytobrush sampling appears to adequately reflect tissue patterns for several putative biomarkers of CRS, supporting their use in clinical and research settings as a less‐invasive proxy for the assessment of mucosal tissue inflammatory transcription patterns. [ABSTRACT FROM AUTHOR]

Summary: Mucosal surfaces are key interfaces between the host and its environment, but also constitute ports of entry for numerous pathogens. The gut and lung mucosae act as points of nutrient and gas exchange, respectively, but the physiological purpose of the female reproductive tract (FRT) is to allow implantation and development of the fetus. Our understanding of immune responses in the FRT has traditionally lagged behind our grasp of the situation at other mucosal sites, but recently reproductive immunologists have begun to make rapid progress in this challenging area. Here, we review current knowledge of immune responses in the human FRT and their heterogeneity within and between compartments. In the commensal‐rich vagina, the immune system must allow the growth of beneficial microbes, whereas the key challenge in the uterus is allowing the growth of the semi‐allogeneic fetus. In both compartments, these objectives must be balanced with the need to eliminate pathogens. Our developing understanding of immune responses in the FRT will help us develop interventions to prevent the spread of sexually transmitted diseases and to improve outcomes of pregnancy for mothers and babies. [ABSTRACT FROM AUTHOR]

Superficial photothermal laser ablation (SPLA) may be useful as a therapeutic approach producing a depth of injury that is sufficient to eliminate mucosal lesion but not deep enough to induce thermal effects in deeper tissue layers. The purpose of this preliminary study is twofold: (a) to describe design steps of a fiber probe capable of delivering a tightly focused laser beam, including Monte‐Carlo‐based simulations, and (b) to complete the initial testing of the probe in a sheep esophagus model, ex vivo. The cone‐shaped (tapered) fiber tip was obtained by chemical etching of the optical fiber. A 1505 nm diode laser providing power up to 500 mW was operated in continuous wave. The successful SPLA of the sheep mucosa layer was demonstrated for various speed‐power combinations, including 300 mW laser power at a surface scanning rate of 0.5 mm/s and 450 mW laser power at a surface scanning rate of 2.0 mm/s. Upon further development, this probe may be useful for endoscopic photothermal laser ablation of the mucosa layer using relatively low laser power. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the expression of B1 and B2 receptors in patients with nasal polyps (NPs) compared to controls.Study Design: Retrospective case series.Settings: Single academic center.Subjects and Methods: Nasal biopsies of patients with NPs were compared to inferior turbinates of control patients. Comparisons included basic demographics and comorbidities, intensity of inflammation, and immunohistochemical staining of B1 and B2 receptors measured by immunohistochemistry staining scores (ISSs).Results: A total of 41 patients were enrolled, with 21 patients (51.2%) in the NP group and 20 patients as controls. No differences were found in the prevalence of allergic comorbidities and smoking between the groups. The NP group demonstrated significantly higher prevalence of moderate and severe mononuclear infiltrates compared to the control group (57.1% vs 5.3%, P < .001). The NP group had significantly lower B1 expression in smooth muscle compared to the control group (mean ISS 0.22 vs 1.56, P < .001, respectively) and significantly more B2 expression in epithelial cells (mean ISS 1.81 vs 0, P < .001, respectively).Conclusion: Patients with NPs exhibit different expression patterns of B1 and B2 compared to control patients. This implies that bradykinin receptor regulation participates in the pathogenesis of NPs. [ABSTRACT FROM AUTHOR]

Innervation of the intestinal mucosa has gained more attention with demonstrations of tuft and enteroendocrine cell innervation. However, the role(s) these fibers play in maintaining the epithelial and mucus barriers are still poorly understood. This study therefore examines the proximity of mouse ileal goblet cells to neuronal fibers, and the regulation of goblet cell production by vasoactive intestinal peptide (VIP). An organotypic intestinal slice model that maintains the cellular diversity of the intestinal wall ex vivo was used. An ex vivo copper‐free click‐reaction to label glycosaminoglycans was used to identify goblet cells. Pharmacological treatment of slices was used to assess the influence of VIP receptor antagonism on goblet cell production and neuronal fiber proximity. Goblet cells were counted and shown to have at least one peripherin immunoreactive fiber within 3 µm of the cell, 51% of the time. Treatment with a VIP receptor type I and II antagonist (VPACa) resulted in an increase in the percentage of goblet cells with peripherin fibers. Pharmacological treatments altered goblet cell counts in intestinal crypts and villi, with tetrodotoxin and VPACa substantially decreasing goblet cell counts. When cultured with 5‐Ethynyl‐2'‐deoxyuridine (EdU) as an indicator of cell proliferation, colocalization of labeled goblet cells and EdU in ileal crypts was decreased by 77% when treated with VPACa. This study demonstrates a close relationship of intestinal goblet cells to neuronal fibers. By using organotypic slices from mouse ileum, vasoactive intestinal peptide receptor regulation of gut wall goblet cell production was revealed. [ABSTRACT FROM AUTHOR]

To describe and illustrate the structure of the propria, the bladder of adult rats was fixed in controlled conditions of distension and examined by light and electron microscopy. The lamina propria, ~50 µm thick in the distended bladder, consists of a superficial part (the cellular component), adjacent to the urothelium, rich in nerves, capillaries, fibroblasts and thin bundles of collagen, and a deep, thicker part (the fibrous component), adjacent to the detrusor, rich in large collagen fibres and with few fibroblasts. In the cellular part there is an extensive plexus of afferent nerve fibers and a dense capillary network (with numerous pericytes), lying close to the urothelium, that is unique to the bladder. The main resident cells are fibroblasts, adhering to each other at the end of laminar extensions without forming specialized junctions. The deep part of the lamina propria is made of thick collagen fibers, interwoven and crisscrossing each other, with a few fibroblasts in the interstitial spaces between them. In summary, the superficial part of the lamina propria has most of the bladder afferent nerves, contains many fibroblasts and has a network of suburothelial capillaries. The deep part as a whole forms an ovoid balloon of woven fibrous material that is acted upon by the detrusor musculature attached to its outer surface. The lamina propria is a strong fibrous barrier between urothelium and musculature. The abundance of collagen points to the main role for its fibroblasts, that is, the production of collagen fibrils, assisting the mechanical role of the lamina propria. [ABSTRACT FROM AUTHOR]

Background: Preservation of contralateral mucosa with microscopic tumor invasion in unilateral septal involvement increases the recurrence risk. The purpose of this study was to analyze the risk of invasion of contralateral mucosa in unilateral septal involvement of cancer and to risk stratify patients. Methods: Retrospective chart review of patients with histologically proven malignancy with unilateral septal involvement and absence of gross septal tumor involvement on the contralateral side were included. Results: Among 40 patients, majority (55%) belonged to sixth and seventh decade. The most common type was squamous cell carcinoma (63%). Approximately one‐fourth (23%) showed microscopic contralateral invasion. Females (OR 12; 95% CI 2.01‐71.35) and patients with septal bone invasion (OR 28.5; CI 3.35‐242.0) had a higher risk of developing contralateral mucosal invasion. Conclusion: Complete resection of contralateral mucosa is preferred in areas along the bony septum. When complete resection is not performed, intraoperative frozen section is strongly recommended. [ABSTRACT FROM AUTHOR]

Objectives: The aim was to evaluate the peri‐implant tissue levels over a 1‐year period for implants connected to either convex or concave final abutments at the time of implant placement. Materials and Methods: In this randomized, double masked, controlled clinical study, twenty‐eight patients with one missing maxillary premolar were allocated to receive one single implant with abutment of either convex (CX Group) or concave (CV Group) emergence shape. A block randomization sequence was used to allocate treatments. Opaque sealed randomization envelopes were used for allocation concealment. All implants received final abutments and interim crowns at implant placement and permanent crowns following 3 months. Clinical and radiographic data were collected at the time of implant placement (IP), final prosthesis delivery (PR), and 12 months following implant placement (FU‐1). Results: One patient from the CX Group (n = 13) dropped out from the study and for one patient from CV Group (n = 13), the implant failed to integrate. The mean change in peri‐implant buccal mucosa position (MP) from IP to FU‐1 was −0.76 ± 0.72 mm for CX Group and −0.69 ± 0.89 mm for CV Group (p = 0.8). The amount of bone remodeling above the implant platform from IP to FU‐1 was −0.66 ± 0.46 mm for the CX Group and −0.24 ± 0.25 mm for the CV Group (p = 0.007). Buccal bone thickness was significantly correlated with the amount of buccal MP change from IP to FU‐1 (r = 0.4, p = 0.038). Conclusion: The study failed to support the hypothesis that abutment macro‐design has an effect on peri‐implant mucosa margin position changes over time. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this investigation was to evaluate whether the use of a provisional implant‐supported crown improves the final esthetic outcome of implant crowns that are placed within esthetic sites. Materials and Methods: Twenty endosseous implants were inserted in sites 13 to 23 (FDI) in 20 patients. Following the reopening procedure, a randomization process assigned them to either cohort group 1: a provisional phase with soft tissue conditioning using the "dynamic compression technique" or cohort group 2: without a provisional phase. Screw‐retained all ceramic crowns were inserted. Clinical follow‐up appointments were completed at 36 months evaluating clinical, radiographic outcomes, and implant success and survival. Results: After 3 years, all implants survived; one implant‐supported crown was excluded from the study due to adjacent tooth failure replaced with a further implant supported crown. Modified pink esthetic score (ModPES) scores were significantly different between groups 1 and 2 (P = .018); white esthetic scores (WES) were not statistically different between both groups (P = .194). Mean values of combined modPES and WES were 15.6 for group 1, with a SD of 3.20. Group 2 had a mean combined modPES and WES of 12.2, with a SD of 3.86. Mean bone loss after 3 year was −0.05 and −0.04 mm for groups 1 and 2 respectively, without being statistically significant. Conclusion: Fixed implant‐supported provisionals improve the final esthetic outcome of the peri‐implant mucosa. [ABSTRACT FROM AUTHOR]

It is now well appreciated that the human microbiome plays a significant role in a number of processes in the body, significantly affecting its metabolic, inflammatory, and immune homeostasis. Recent research has revealed that almost every mucosal surface in the human body is associated with a resident commensal microbiome of its own. While the gut microbiome and its role in regulation of host metabolism along with its alteration in a disease state has been well studied, there is a lacuna in understanding the resident microbiota of other mucosal surfaces. Among these, the scientific information on the role of lung microbiota in pulmonary diseases is currently severely limited. Historically, lungs have been considered to be sterile and lung diseases have only been studied in the context of bacterial pathogenesis. Recently however, studies have revealed a resilient microbiome in the upper and lower respiratory tracts and there is increased evidence on its central role in respiratory diseases. Knowledge of lung microbiome and its metabolic fallout (local and systemic) is still in its nascent stages and attracting immense interest in recent times. In this review, we will provide a perspective on lung‐associated metabolic disorders defined for lung diseases (e.g., chronic obstructive pulmonary disease, asthma, and respiratory depression due to infection) and correlate it with lung microbial perturbation. Such perturbations may be due to altered biochemical or metabolic stress as well. Finally, we will draw evidence from microbiome and classical microbiology literature to demonstrate how specific lung morbidities associate with specific metabolic characteristics of the disease, and with the role of microbiome in this context. © 2018 IUBMB Life, 71(1):152–165, 2019 [ABSTRACT FROM AUTHOR]

Abstract: Innate lymphoid cells (ILCs) resemble adaptive T lymphocytes based on transcription factor expression, cytokine production, and their presumptive roles in immunity, but are activated for effector function through cytokine signaling and not antigen‐specific receptors. The prevailing view is that ILCs adapt to specific microenvironments during development and operate as tissue‐resident cells in co‐operation with antigen‐specific T cells to provide host protection and contribute to tissue maintenance. In particular, conventional models equate the activity of different ILC subsets with CD4+ effector T‐cell types based on corresponding transcription factor expression and a potential for comparable cytokine production. Based on recent data from our laboratory, we suggest that these views on tissue residence and parallel functioning to CD4+ T cells are too restrictive. Our findings show that ILC2s can be mobilized from the gut under inflammatory conditions and contribute to distal immunity in the lungs during infection, whereas gut‐resident ILC3s operate in a quite distinct manner from Th17 CD4+ effector cells in responding to commensal microbes, with important implications for control of metabolic homeostasis. In this review, we discuss the recent advances leading to these revised views of ILC inter‐organ trafficking and the distinct and complementary function of ILCs with respect to adaptive T cells in establishing and maintaining a physiologic host environment. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this systematic review and meta‐analysis was to summarize the existing evidence on patient‐reported aesthetic outcome measures (PROMs) of implant‐supported, relative to tooth‐supported fixed dental prostheses. Material and Methods: In April 2017, two reviewers independently searched the Medline (PubMed), EMBASE, and Cochrane electronic databases, focusing on studies including patient‐reported aesthetic outcomes of implant‐ and tooth‐supported fixed dental prostheses (FDPs). Human studies with a mean follow‐up period of at least 1 year, a minimum of ten patients, and English, German, or French publication were included. For the comparison of subgroups, random‐effects meta‐regression for aggregate‐level data was used. Results: The systematic search for implant‐supported prostheses focusing on patient‐reported outcomes identified 2,675 titles, which were screened by two independent authors. Fifty full‐text articles were analyzed, and finally, 16 publications (including 19 relevant study cohorts) were included. For tooth‐supported prostheses, no studies could be included. A total of 816 implant‐supported reconstructions were analyzed by patients. Overall aesthetic evaluation by the patients' visual analogue scale (VAS) rating was high in implant‐supported FDPs (median: 90.3; min–max: 80.0–94.0) and the surrounding mucosa (median: 84.7; min–max: 73.0–92.0). Individual restorative materials, implant neck design (i.e., tissue or bone level type implants), and the use of a fixed provisional had no effect on patients' ratings of the definitive implant‐supported FDPs. Conclusions: Aesthetics is an important patient‐reported measure, which lacks in standardized methods; however, patients' satisfaction was high for implant‐ supported FDPs and the surrounding mucosa. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mucous membranes may be affected by various diseases and the diagnostic accessibility is limited. Multiphoton laser tomography (MPT) is a useful tool for in vivo evaluation of superficial skin structures and might also be useful for the imaging of mucosa. Objectives: In order to investigate the suitability of MPT for the evaluation of mucous membranes, tissue samples of different donors and anatomical localizations have been imaged. Methods: Human mucosa samples from the urinary bladder, palatine tonsil and ocular conjunctiva were investigated by MPT and subsequently compared with conventional histology. Results: Horizontal images of the epithelium and the underlying connective tissue were obtained using the autofluorescence and second harmonics generation signals by MPT. The stratification of multilayered epithelium was consistently reproduced. Also inflammatory changes like lymphocytic infiltrates and widened intercellular spaces were imaged in some cases. Conclusion: Mucous tissue samples were obtained and MPT imaging was successfully performed. In the direct comparison with histology of the same tissue samples, the characteristic morphology of the epithelia was found. Further studies are necessary in order to compare images of healthy and diseased mucosal epithelium and the use of MPT for its evaluation in vivo. [ABSTRACT FROM AUTHOR]