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Background To summarize HPV vaccine efficacy/effectiveness (VE) against anal HPV infection and anal intraepithelial neoplasia (AIN). Methods We performed literature review and meta-analysis to estimate VE stratified by age and analytic population (per-protocol efficacy [PPE] or intention-to-treat [ITT] population in clinical trials, or real-world studies). Results We identified 6 clinical trials and 8 real-world studies. In participants vaccinated at ≤26 years (mainly HIV-negative individuals), significant VE against incident/prevalent HPV infection was reported in clinical trials, with a higher estimate in PPE (2 studies; 2390 participants; VE 84%, 95%CI 77-90%; I2=0%) than ITT (2 studies; 4885 participants; 55%, 39-67%; 46%) or in real-world studies (4 studies; 2375 participants; 77%, 40-91%; 81%). HPV vaccination at ≤26 years was associated with significant VE in preventing persistent HPV infection and AIN. No significant VE against HPV infection or AIN in persons vaccinated >26 years (mainly people living with HIV [PLWH]) was found. Conclusion There is strong evidence for high VE against anal HPV infection and AIN in HIV-negative individuals vaccinated aged ≤26 years. Lower impact in ITT than PPE populations, and lack of significant effect in PLWH >26 years, however, highlights greatest vaccine impact in populations more naïve to sexual exposure to anal HPV.

Background Ulcerative colitis [UC] and Crohn’s disease [CD] can be associated with severe comorbidities, namely opportunistic infections and malignancies. We present the first systematic review and meta-analysis evaluating the burden of anal human papillomavirus disease in patients with UC and CD. Methods PubMed, Web of Science, and Scopus were searched until November 2022. Meta-analyses were performed using random effects models. The protocol was recorded at PROSPERO register with the number CRD42022356728. Results Six studies, including 78 711 patients with UC with a total follow-up of 518 969 person-years, described the anal cancer incidence rate. For anal cancer incidence rate in CD, six studies were selected, including 56 845 patients with a total follow-up of 671 899 person-years. The incidence of anal cancer was 10.2 [95% CI 4.3 − 23.7] per 100 000 person-years in UC and 7.7 [3.5 − 17.1] per 100 000 person-years in CD. A subgroup analysis of anal cancer in perianal CD, including 7105 patients, was calculated with incidence of 19.6 [12.2 − 31.6] per 100 000 person-years [three studies included]. Few studies described prevalence of anal cytological abnormalities [four studies including 349 patients] or high-risk human papillomavirus [three studies including 210 patients], with high heterogeneity. Prevalence of cytological abnormalities or high-risk human papillomavirus was not associated with pharmacological immunosuppression in the studies included. Conclusion The incidence of anal cancer is higher in UC than in CD, with the exception of perianal CD. There are limited and heterogeneous data on anal high-risk human papillomavirus infection and squamous intraepithelial lesions prevalence in this population.

Objectives Anal squamous cell carcinoma (ASCC) has a higher incidence described in certain groups, namely, in women with vulvar high-grade squamous intraepithelial lesions (vHSILs) and/or human papillomavirus squamous cell carcinoma (VSCC). This review describes terminology, vHSIL, and VSCC in their association with ASCC and the published recommendations for early detection of this cancer in these women. Materials and methods A narrative review was conducted by the authors on vHSIL and VSCC as risk factors for ASCC. Results The ASCC and VSCC incidence are increasing. Women with vHSIL and/or VSCC can present with ASCC at diagnosis, being one of the highest-risk groups. Suspicious symptoms include rectal bleeding, pain, and a sensation of an anal mass. Digital anorectal examination can help detect early ASCC. Sensitivity of anal cytology in women with vHSIL and VSCC seems low, with the exception of immunosuppressed women with genital neoplasia (cervix, vagina, and vulva). There are still insufficient data on high-resolution anoscopy in women with vHSIL and/or VSCC as a screening method. Conclusions Clinicians need be aware that women with vHSIL and VSCC comprise one of the highest-risk groups for ASCC. Inquiring suggestive symptoms of ASCC and a digital anorectal examination can help in the early detection of this type of cancer.

Anal squamous cell carcinoma is the most common type of anal cancer and is largely associated with anal human papillomavirus infection. The incidence of anal squamous cell carcinoma is increasing, and although still uncommon in the general population, a high incidence has been noted in specific population groups (eg, patients with HIV, men who have sex with men [MSM], recipients of solid organ transplants, women with genital neoplasia, and patients with systemic lupus erythematosus or inflammatory bowel disease). The higher incidence among individuals who are HIV-positive makes anal squamous cell carcinoma one of the most common non-AIDS-defining cancers among HIV-positive individuals. Anal cancer screening in high-risk groups aims to detect high-grade squamous intraepithelial lesions, which are considered anal precancerous lesions, and for which identification can provide an opportunity for prevention. A blind anal cytology is normally the first screening method, and for patients with abnormal results, this approach can be followed by an examination of the anal canal and perianal area under magnification, along with staining-a technique known as high-resolution anoscopy. Digital anorectal examination can enable early anal cancer detection. Several societies are in favour of screening for HIV-positive MSM and recipients of transplants. There are no current recommendations for screening of anal precancerous lesions via endoscopy, but in high-risk groups, a careful observation of the squamocolumnar junction should be attempted. Several treatments can be used to treat high-grade squamous intraepithelial lesions, including argon plasma coagulation or radiofrequency ablation, which are largely limited by high recurrence rates. Gastroenterologists need to be aware of anal squamous cell carcinoma and anal precancerous lesions, given that patients at high risk are frequently encountered in the gastroenterology department. We summarise simple procedures that can help in early anal squamous cell carcinoma detection.

The number of solid organ transplant recipients (SOTR), and their life expectancy, is increasing, with higher risk for long-term complications from immunosuppression. We carried out a systematic review describing the burden of anal squamous cell carcinoma (SCC), and its surrogates, in SOTR. We conducted mixed effect model-based meta-analyses evaluating incidence of anal SCC (standardized incidence ratio [SIR] vs general population, and absolute incidence rate [IR]), prevalence of anal squamous abnormalities, and human papillomavirus (HPV) 16. Generalized I2 statistics were calculated, quantifying heterogeneity. Anal SCC incidence in SOTR was elevated vs the general population (pooled SIR = 6.8, 95% confidence interval [CI], 4.3-10.9; 6 studies including 241 106 SOTR; I2 = 82.3%), with an absolute IR of 12.3 (95% CI, 10.4-14.7) per 100 000 person-years (5 studies including 1 079 489 person-years; I2 = 0%). Prevalence of abnormal anal cytology was 12.9% (95% CI, 9.2%-17.7%; 6 studies including 328 SOTR; I2 = 17.4%). For histology, the pooled prevalence estimate of anal squamous intraepithelial lesions was 22.4% (95% CI, 17.3%-28.5%; 3 studies including 214 SOTR; I2 = 0%), with 4.7% (95% CI, 2.5%-8.5%; I2 = 0%) high-grade squamous intraepithelial lesions. Pooled anal HPV16 prevalence was 3.6% (95% CI, 1.6%-7.8%; 4 studies including 254 SOTR; I2 = 17.6%). There was substantial and consistent evidence of elevated anal SCC incidence in SOTR.

Certain population groups are known to have higher than average anal cancer risk, namely persons living with HIV (PLHIV), men who have sex with men (MSM), women diagnosed with human papillomavirus (HPV)‐related gynecological precancerous lesions or cancer, solid organ transplant recipients (SOTRs) and patients with autoimmune diseases. Our aim was to provide robust and comparable estimates of anal cancer burden across these groups. Summary incidence rates (IRs), as cases per 100 000 person‐years (py), were calculated by fixed‐effects meta‐analysis. IRs were 85 (95% confidence interval [CI] = 82‐89) for HIV‐positive MSM (n = 7 studies; 2 229 234 py), 32 (95% CI = 30‐35) for non‐MSM male PLHIV (n = 5; 1626 448 py) and 22 (95% CI = 19‐24) for female PLHIV (n = 6; 1 472 123 py), with strong variation by age (eg, from 16.8 10 years after transplant. Anal cancer IRs were 10 (95% CI = 5‐19), 6 (95% CI = 3‐11) and 3 (95% CI = 2‐4) for systemic lupus erythematosus, ulcerative colitis and Crohn's disease, respectively. In conclusion, a unifying anal cancer risk scale, based upon comprehensive meta‐analysis, can improve prioritization and standardization in anal cancer prevention/research initiatives, which are in their public health infancy., What's new? Anal cancer (AC) is quite rare in the general population. However, some groups are known to be at higher risk. In this meta‐analysis, the authors identified these groups (e.g., HIV‐positive status, other HPV‐related cancers, etc.), and were then able to develop an AC‐risk scale based on incidence estimates. Because there is currently no consensus regarding standardized screening for AC, this risk scale can help clinicians to prioritize and compare risk profiles for AC research and prevention initiatives. These can then be guided by similar principles of management for populations with similar absolute risk.

Introduction Complications of cirrhosis are one the major causes of hospital admission associated with high morbimortality rates and social and economic charges. The aims of this study were to evaluate hospital readmission and mortality rates and predictive factors for hospital readmission and mortality. Methods Patients with decompensated cirrhosis admitted to our institution between 2008–2014 were retrospectively analyzed. Results Included 427 admissions from 177 patients with cirrhosis with mean age of 59.0 ± 12.3 years. The major cause was alcoholic-related liver disease and the median duration of admission was 9.0 days (IQR 6.0–14.0). During the follow-up period,there were 250 readmissions from 95 patients, with a median of 58 (IQR27-134) days for readmission, representing 58.5% of the total number of admissions.The 180-day mortality rate was 35.0%. In the multivariate analysis, ascites, smoking and MELD Na were associated with 180-day mortality. Creatinine, albumin, esophageal variceal bleeding, previous variceal banding, lactulose, rifaximin and proton pump inhibitors use were independently associated with need of readmission. Based on regression analysis, two models were calculated to predict 180-day mortality (AUROC 0.74 (0.682−0.794)) and need for readmission(AUROC 0.821 (0.781−0.861)), p Conclusion The readmission rate and mortality of cirrhotic patients are still very high and it is a priority to determine preventable risk factors to improve patient outcome. Two models were created to predict 180-day mortality(AUROC 0.74) and need for readmission(AUROC 0.821), that could guide the management of the patients at the time of admission.

The incidence and mortality of anal squamous cell carcinoma (SCC) are expected to continue to increase in the next 20 years. High-risk groups for anal SCC, i.e., human immunodeficiency virus (HIV)-positive patients, men who have sex with men (MSM), women with previous genital neoplasia, and solid-organ transplant recipients, have been identified. HIV-positive MSM have the highest risk, and some societies have advocated for anal cancer screening to be done in this population. Screening for anal SCC follows the same principles as that for cervical cancer since there are similarities between the two types of cancers. Anal cytology has been recommended as an initial screening method for high-risk groups, e.g., HIV-positive MSM. Normally, the cytology is liquid based and collected blindly by a clinician using a Dacron swab and it is especially used for internal lesions detection. The sensitivity to predict anal high-grade squamous intraepithelial lesions is higher in immunosuppressed patients with a high burden of the disease. The report should include the classification, normally according to the Bethesda terminology and the sample adequacy, in a manner similar to that for cervical cytology. In cases involving unsatisfactory samples, it is important to repeat the procedure given the prevalence of anal squamous cytological abnormalities in follow-up cytology procedures. The absence of transformation zone cells in anal cytology seems to increase the risk of false-negative results.

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

The Ros3 protein is a component of the MT-Ros3 transporter complex, considered as the main route of miltefosine entry in Leishmania. L. braziliensis clinical isolates presenting differences in miltefosine susceptibility and uptake were previously shown to differentially express ros3. In this work, we showed that the ros3 gene copy number was increased in the isolate presenting the highest rates of miltefosine uptake and, thus, the highest susceptibility to this drug. The role of the ros3 gene dosage in miltefosine susceptibility was then investigated through a modulation of the gene copy number using two distinct approaches: through an overexpression of ros3 in a tolerant L. braziliensis clinical isolate and in L. major and by generating mono- and diallelic knockouts of this gene in L. major using clustered regularly interspaced short palindromic repeats (CRISPR) Cas9 (Cas = CRISPR-associated). Although the levels of ros3 mRNA were increased at least 40-fold in overexpressing clones, no significant reduction in the half-maximal effective concentration (EC50) for miltefosine was observed in these parasites. The partial or complete deletion of ros3 in L. major, in turn, resulted in a significant increase of 3 and 20 times, respectively, in the EC50 to miltefosine. We unequivocally showed that the ros3 copy number is one of the factors involved in the differential susceptibility and uptake of miltefosine. Wellcome Trust de Reino Unido. 104627/Z/14/Z Fundação de Amparo à Pesquisa do Estado de São Paulo. FAPESP 2015/09080-2, 2016/23405-4, 2016/21171-6 y 2018/25299-2 Fundação para a Ciência e a Tecnologia de Portugal UID/04413/2020 UK Research and Innovation. MR/P027989/ 1 Ministerio de Educación y Ciencia de España. BQU2003- 04413 Ministerio de Ciencia e Innovación de España. RYC-2017-22294

Background There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. Methods Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. Results 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21–2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, pp=0.006). Conclusions Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.

INTRODUCTION : The introduction and broad use of new immunosuppressive agents, including biologic agents and JAK inhibitors, have revolutionised treatment of inflammatory bowel disease [IBD] in recent decades. With such immunosuppression, the potential for opportunistic infection is a key safety concern. [...]

C-Mannosylation is a common modification of thrombospondin type 1 repeats present in metazoans and recently identified also in apicomplexan parasites. This glycosylation is mediated by enzymes of the DPY19 family that transfer α-mannoses to tryptophan residues in the sequence WX2WX2C, which is part of the structurally essential tryptophan ladder. Here, deletion of the dpy19 gene in the parasite Toxoplasma gondii abolished C-mannosyltransferase activity and reduced levels of the micronemal protein MIC2. The loss of C-mannosyltransferase activity was associated with weakened parasite adhesion to host cells and with reduced parasite motility, host cell invasion, and parasite egress. Interestingly, the C-mannosyltransferase–deficient Δdpy19 parasites were strongly attenuated in virulence and induced protective immunity in mice. This parasite attenuation could not simply be explained by the decreased MIC2 level and strongly suggests that absence of C-mannosyltransferase activity leads to an insufficient level of additional proteins. In summary, our results indicate that T. gondii C-mannosyltransferase DPY19 is not essential for parasite survival, but is important for adhesion, motility, and virulence.

Background Information is lacking regarding anal/perianal precancerous lesions in referral cohorts of pharmacologically immunocompromised patients. Objective The aim of this study is to evaluate the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of patients on immunomodulator/immunosuppressive medications, who were assessed and followed with high-resolution anoscopy. Design This is a retrospective study. Setting This study was conducted in a single anal neoplasia service from January 2012 to June 2017. Patients Patients on chronic immunomodulator/immunosuppressive medications were included. Cases of concomitant immunosuppression due to HIV infection were excluded, and immunosuppression due to chemotherapy was not considered for this analysis. Intervention High-resolution anoscopy was performed. Main outcome The primary outcome measured was the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of pharmacologically immunocompromised patients. Results Fifty-four patients were included, of whom 40 were women (74%), with a mean age of 48 ± 17 years. A total of 232 high-resolution anoscopy examinations were performed in this cohort. At the first evaluation, 28 patients (52%) were diagnosed with anal and/or perianal high-grade squamous intraepithelial lesions (including 2 cases of perianal squamous cell carcinoma); 11 cases (20%) were new diagnoses. Ten of 46 patients (22%) with follow-up developed a new lesion (high-grade/cancer) during a median follow-up period of 17 (interquartile range, 6-28) months. Overall, 37 patients (69%) in our cohort had anal/perianal high-grade squamous intraepithelial lesions ever diagnosed (including previous history, first visit, and follow-up); 5 patients had perianal squamous cell carcinoma. At our center, 6% of the new referrals were known to be pharmacologically immunocompromised patients. Limitations The retrospective nature of this study, the heterogeneity of the cohort, and the absence of human papillomavirus testing were limitations of this study. Conclusions The presence of anal and/or perianal high-grade squamous intraepithelial lesions or cancer detected by high-resolution anoscopy in this referral population was high, and the detection of new lesions suggests that long-term follow-up is needed. Patients on immunomodulator/immunosuppressive drugs represented only a small percentage of the new referrals to our center. See Video Abstract at http://links.lww.com/DCR/A748.

Background Information on the performance of anal cytology in women who are high risk for human papillomavirus-related lesions and the factors that might influence cytology are largely lacking. Methods Retrospective study including all new referrals of women with a previous history of anogenital neoplasia from January 2012 to July 2017, with concomitant anal cytology and high-resolution anoscopy with or without biopsies. Results Six hundred and thirty six anal cytology samples and 323 biopsies obtained from 278 women were included. Overall sensitivity and specificity of "any abnormality" on anal cytology to predict any abnormality in histology was 47% (95% confidence interval [CI], 41%-54%) and 84% (95% CI, 73%-91%), respectively. For detecting high-grade squamous intraepithelial lesions (HSIL)/cancer, sensitivity was 71% (95% CI, 61%-79%) and specificity was 73% (95% CI, 66%-79%). There was a poor concordance between cytological and histological grades (κ = 0.147). Cytology had a higher sensitivity to predict HSIL/cancer in immunosuppressed vs nonimmunosuppressed patients (92% vs 60%, P = .002). The sensitivity for HSIL detection was higher when 2 or more quadrants were affected compared with 1 (86% vs 57%, P = .006). A previous history of vulvar HSIL/cancer (odds ratio [OR], 1.71, 1.08-2.73; P = .023), immunosuppression (OR, 1.88, 1.17-3.03; P = .009), and concomitant genital HSIL/cancer (OR, 2.51, 1.47-4.29; P = .001) were risk factors for abnormal cytology. Conclusions Women characteristics can influence the performance of anal cytology. The sensitivity for detecting anal HSIL/cancer was higher in those immunosuppressed and with more extensive disease.

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

Background: Perianal Crohn’s disease is a disabling condition, with little known about anorectal function in healed/inactive perianal Crohn’s disease; Aim: To evaluate anorectal function in a cohort of patients with treated/healed perianal Crohn’s disease; Methods: Prospective cohort study, including high-resolution anorectal manometry, balloon expulsion test, and 3D-endoanal ultrasound in all patients; Results: Of the 16 patients studied (mean age ± SD, 42 ± 13 years), 12 (75%) were men. A laceration of the internal anal sphincter and/or anal scarring was seen in nine (56%) patients; there was no laceration of the external anal sphincter. Five (56%) of these nine patients had never experienced faecal incontinence. All had normal anal resting and squeeze pressures. Manometry suggested dyssynergia in 11 (69%) patients, with only one (6%) fulfilling the criteria for obstructed defecation. Hyposensitivity for at least one sensory parameter was seen in 11 (69%) patients and hypersensitivity in five (31%) patients; Conclusions: This study detected sphincter abnormalities in more than half of patients, many of whom were asymptomatic. Alterations in rectal sensation were frequently seen, more commonly with rectal hyposensitivity. Trial registration: ClinicalTrials.gov (NCT03819257).

Background: Anal squamous intraepithelial lesions (ASIL) are precancerous lesions of anal squamous cell carcinoma, with a higher prevalence in immunosuppressed patients. There are some studies in kidney transplant recipients, but there is no information regarding prevalence in liver transplantation. Our aim was to evaluate the prevalence of ASIL in this setting. Methods: Prospective case–control study involving liver transplant recipients without any other known risk factor for ASIL (n=59), which were compared with a healthy control group (n=57). All were submitted to anal cytology and high-resolution anoscopy was performed in those with abnormal results. Results: Ten (17%) of liver transplant recipients had abnormal cytological results, seven patients had atypical squamous cells of undetermined significance (ASC-US), one patient had atypical squamous cells that cannot exclude high-grade (ASC-H) and two patients had high-grade squamous intraepithelial lesions (HSIL). In the control group, one patient (2%) had an ASC-US result (P=0.005). Anal squamous intraepithelial lesions were confirmed in 7 out of 10 of liver transplant patients and 0 out of 1 in the controls (P=0.013) by high-resolution anoscopy with biopsies. Current smoking was the only risk factor for abnormal cytology (odds ratio=5.87, 95% confidence intervals=1.22–28.12, P=0.027). Conclusions: Liver transplant patients have a higher risk of ASIL. Screening should be considered, especially in smokers.

Objectives To evaluate anal sphincter abnormalities detected by endoanal ultrasound in obstructed defecation due to rectocele and rectal intussusception. Methods The retrospective analysis includes 45 patients with obstructed defecation syndrome due to rectocele and/or rectal intussusception with or without fecal incontinence, and submitted to endoanal ultrasound. Results Ninety-three percent (n = 42) were women (mean age of 63 ± 12 years), and 47% (n = 21) of the patients had fecal incontinence. In total, 29% (n = 13) had a previous anorectal surgery, and 93% (n = 39) of the women had a previous vaginal delivery. An isolated rectal intussusception was diagnosed in 20% (n = 9) of the patients, an isolated rectocele in 24% (n = 11), and rectal intussusception and rectocele in 56% (n = 25). Thirty-six percent of patients had anal sphincter lacerations (n = 16): 12% (n = 2) had only internal laceration, 69% (n = 11) had only external laceration, and 19% (n = 3) had both. Two patients had a thinner internal anal sphincter with 0.9 and 1.2 mm, respectively. In total, 25% of the patients without fecal incontinence had an occult anal sphincter laceration, and all were women with an external sphincter laceration in the anterior quadrant and a previous vaginal delivery. In patients with obstructed defecation and fecal incontinence, 48% had sphincter lacerations. Previous anorectal surgery was a predictor of anal sphincter laceration (odds ratio [OR] 4.8; 95% confidence interval [CI] = 1.214–18.971; P = .025), but fecal incontinence (OR 2.7; 95% CI = 0.774–9.613; P = .119) and previous vaginal delivery (OR 1.250; 95% CI = 0.104–15.011; P = .860) were not. Conclusions Endoanal ultrasound should be considered in obstructed defecation with or without fecal incontinence, especially if surgical correction is planned.

Glycosyltransferases that use polyisoprenol-linked donor substrates are categorized in the GT-C superfamily. In eukaryotes, they act in the endoplasmic reticulum (ER) lumen and are involved in N-glycosylation, glypiation, O-mannosylation, and C-mannosylation of proteins. We generated a membrane topology model of C-mannosyltransferases (DPY19 family) that concurred perfectly with the 13 transmembrane domains (TMDs) observed in oligosaccharyltransferases (STT3 family) structures. A multiple alignment of family members from diverse organisms highlighted the presence of only a few conserved amino acids between DPY19s and STT3s. Most of these residues were shown to be essential for DPY19 function and are positioned in luminal loops that showed high conservation within the DPY19 family. Multiple alignments of other eukaryotic GT-C families underlined the presence of similar conserved motifs in luminal loops, in all enzymes of the superfamily. Most GT-C enzymes are proposed to have an uneven number of TDMs with 11 (POMT, TMTC, ALG9, ALG12, PIGB, PIGV, and PIGZ) or 13 (DPY19, STT3, and ALG10) membrane-spanning helices. In contrast, PIGM, ALG3, ALG6, and ALG8 have 12 or 14 TMDs and display a C-terminal dilysine ER-retrieval motif oriented towards the cytoplasm. We propose that all members of the GT-C superfamily are evolutionary related enzymes with preserved membrane topology.

Anal squamous intraepithelial lesions (ASIL) or anal intraepithelial neoplasia (AIN) are precancerous lesions. microRNAs (miRNAs) have been implicated in cervical carcinogenesis, but have never been assessed in anal precancerous lesions. Our aim was to evaluate the expression of miR-16, miR-20a, miR-150 and miR-155 in several grades of ASIL obtained from high-risk patients, submitted to anal cancer screening from July 2016 to January 2017. Lesions were classified according to the Lower Anogenital Squamous Terminology (LAST) in low-grade (LSIL) and high-grade squamous intraepithelial lesions (HSIL), and the AIN classification in AIN1, AIN2 and AIN3. A hundred and five biopsies were obtained from 60 patients. Ten samples were negative (9.5%), 63 were LSIL (60%) and 32 were HSIL (30.5%) according to the LAST. Twenty seven (26%) were negative for dysplasia, 46 were classified as AIN1 (44%), 14 as AIN2 (13%) and 18 as AIN3 (17%) according to the AIN classification. There was no statistically significant difference in the fold expression of miR-16, miR-20a, miR-150 and miR-155, according to either classification. Although non- significant, there was an increasing trend in the miR-155 fold expression from negative samples to HSIL, with the highest fold expression increase in both LSIL and HSIL compared to the other miRNAs.

Background and Aims: Histological healing has emerged as a promising therapeutic goal in ulcerative colitis. This is especially important in the context of biological therapies. The objectives of the present study were to investigate the ability of infliximab to induce histological remission in ulcerative colitis [UC] patients and to explore the utility of faecal calprotectin and lactoferrin in predicting histological activity. Methods: Multi-centre, single-cohort, open-label, 52-week trial including moderately to severely biological-naive UC patients receiving intravenous infliximab [5mg/kg]. The primary outcome was the proportion of patients with histological remission [Geboes index ≤ 3.0] after 8 weeks of treatment, scored by two independent pathologists. Results: Twenty patients were included. The rate of histological remission increased from 5% at baseline to 15% and 35% at Week 8 and Week 52, respectively. At Week 8, 40% of patients were in clinical remission [Mayo ≤ 2] and 45% achieved mucosal healing [Mayo endoscopy subscore 0–1]. At Week 52, 25% of patients had clinical, endoscopic and histological remission. Faecal calprotectin and lactoferrin showed the highest correlation with histological activity at Week 8 (area under the curve [AUC] 94%, p = 0.017; and 96%, p = 0.013, respectively) and both markers revealed an excellent positive predictive value for this outcome at this time point [100%, p = 0.017; and 94%, p = 0.013, respectively]. Conclusions: Infliximab was able to induce histological remission. There was a good agreement between histology and faecal biomarkers. Faecal calprotectin and lactoferrin were good predictors of histological remission. Our data support inclusion of histology as a treatment target complementary to endoscopy in clinical trials when evaluating therapeutic response in UC.

Histological grading of squamous intraepithelial lesions or intraepithelial neoplasia is fundamental for clinical management and for assessment of the risk of progression. Biomarkers are important for assisting correct grading of these lesions, reducing inter and intraobserver variability and most promising, for prognosis. Although p16 is the most studied biomarker in this setting, there are several other biomarkers that have been studied, reflecting also the need to find a better single or association option that can be more suitable, especially for classification purposes. A PubMed and Embase search was conducted from their inception until April 2018, aiming to identify biomarkers evaluated in histological samples of anal squamous intraepithelial lesions, other than p16. Information on "Ki-67", "ProExTM C", "p53", "human papillomavirus L1 capsid protein", "stathmin-1", "minichromosome maintenance protein", "p21", "proliferating cell nuclear antigen", "histones", "human papillomavirus E4", "chromosomal abnormalities" and "methylation" was collected and reviewed. From these, the most studied biomarker was by far Ki-67. In many cases there were few studies performed for each biomarker, with no clear standardized interpretation of the immunostaining. An increased positive rate with more severe grades of lesions was shown in many cases. Prognostic data are limited and need to be further validated.

Human papillomavirus is associated with several anogenital and oropharyngeal lesions, including warts, premalignant lesions, and cancer. There are specific groups that were identified as high-risk groups for anal squamous cell carcinoma and anal human papillomavirus infection, namely HIV-positive patients, men who have sex with men, women with genital tract neoplasia, and solid organ transplant recipients. Condylomas have classically been considered to be a benign lesion, with an exception made for the Buschke-Loewenstein tumor, but several publications have shown that a high percentage of condylomas harbor high-grade lesions. Due to the similarities between anal and cervical carcinogenesis, anal cancer screening based on anal cytology and referral to high-resolution anoscopy, in case of abnormalities, have been advocated. Testing for anal human papillomavirus is not routinely done in anal cancer screening, because of the very high prevalence in high-risk populations. The large majority of anal cancers are squamous cell carcinomas (SCC), and around 90% are attributed to human papillomavirus. Human papillomavirus positivity in anal SCC seems to have a prognostic value, with better survival in those patients with positive tumors. Prophylactic vaccination has been shown to be important for prevention of anal human papillomavirus-related lesions.

Background and Aims: Despite the increasing use of noninvasive methods for the assessment of liver fibrosis and steatosis, the effect of fasting and food intake on these parameters is not yet clear. Our aims were to evaluate the effect of food intake on liver stiffness (LS) (measured by transient elastography) and controlled attenuation parameter (CAP) in patients with different degrees of liver disease and healthyvolunteers, and secondarily, to assess possible factors associated with variations of LS and CAP. Methods: We performed a prospective single-center study including patients with liver disease and healthy volunteers. LS and CAP were evaluated using FibroScan® (Echosens, Paris, France), before (fasting ≥8 h) and 30 min after intake of a standardized breakfast. We used common cutoffs for LS: > 7 kPa for significant fibrosis (F2 to F4) and > 11 to 14 kPa (mean 12.5 kPa) for cirrhosis. Results: Fifty-nine (72%) patients with liver disease and 22 (28%) healthy volunteers were included. LS significantly increased 30 min after food intake (pre-meal 6.1 kPa [IQR: 4.7-9.8] vs. after-meal 6.8 kPa [IQR: 5.5-10.6]; p < 0.001). This difference was only significant in patients with chronic liver disease (p = 0.02) and not in healthy volunteers (p = 0.106). CAP values did not increase significantly after food intake. Gender, body mass index, mass of body fat, lean body mass, and percent of body fat were not related with significant variations of LS and CAP values after meal intake. Conclusions: Significant variations of LS were observed after ingestion of a standard meal, which may have consequences for patient management. CAP values were not significantly affected by food intake. Therefore, we consider that before the isolated evaluation of CAP, it is not necessary to perform any fasting period. Introdução e Objetivos: Apesar do uso crescente de métodos não invasivos para a avaliação da fibrose hepática e da esteatose, ainda não está claro o efeito do jejum e da ingestão alimentar na determinação destes parâmetros. Os nossos objetivos foram avaliar o efeito da ingestão de alimentos sobre a rigidez hepática (LS) (medida por elastografia transitória) e o parâmetro de atenuação controlada (CAP) em doentes com diferentes graus de doença hepática e voluntários saudáveis e, secundariamente, avaliar possíveis fatores associados às variações de LS e CAP. Métodos: Realizámos um estudo prospetivo, num único centro, incluindo doentes com doença hepática crónica e voluntários saudáveis. A LS e o CAP foram determinados com a utilização de FibroScan®, antes (jejum ≥8 h) e 30 minutos após a ingestão de um pequeno-almoço padronizado. Foram usados pontos de corte comuns para a elastografia: > 7 kPa para fibrose significativa (F2 a F4) e > 11-14 kPa (média 12.5 kPa) para cirrose. Resultados: Cinquenta e nove (72%) doentes com doença hepática crónica e 22 (28%) voluntários saudáveis foram incluídos. A LS aumentou significativamente 30 minutos após a ingestão de alimentos (pré-refeição 6.1 kPa [IQR: 4.7-9.8] versus após a refeição 6.8 kPa [IQR: 5.5-10.6], p < 0.001). Essa diferença foi significativa em doentes com doença hepática crónica (p = 0.02) mas não nos voluntários saudáveis (p = 0.106). Os valores da CAP não variaram significativamente após a ingestão de alimentos. O género, o IMC, a massa de gordura corporal, a massa corporal magra e a percentagem de gordura corporal não se associaram a variações significativas dos valores de LS e CAP após a ingestão da refeição. Conclusões: Verificaram-se variações significativas da LS após a ingestão de uma refeição padrão, o que pode ter consequências na avaliação dos doentes. Os valores da CAP não foram significativamente afetados pela ingestão de alimentos. Por isso, consideramos que perante a avaliação isolada de CAP não é necessário a realização de qualquer período de jejum.

Myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms associated with aberrant myeloid differentiation and ineffective hematopoiesis leading to cytopenias. In more than 20% of affected patients the MDS transforms into secondary acute myeloid leukemia (s-AML). To date

p16 is the most widely studied biomarker in lower anogenital tract squamous intraepithelial lesions and, currently the only recommended biomarker for histological grade assessment. The aim of this systematic review and meta-analysis was to evaluate p16-positive rates according to anal squamous intraepithelial lesions/anal intraepithelial neoplasia (AIN) grade. Two investigators independently searched four electronic databases: PubMed, Web of Sciences, Scopus, and Embase from inception until August 2017. Studies that evaluated p16 immunostaining in histological samples of anal and/or perianal squamous intraepithelial lesions and defined a p16-positive result as diffuse block staining with nuclear or nuclear plus cytoplasmic staining were included. A meta-analysis was performed using a random effects model. Fifteen studies consisting of 790 samples were included. The proportion of p16 expression increased with the severity of histological grade. p16 positivity was 2% (95% CI: 0.2-5%) in normal histology, 12% (95% CI: 2-27%) in low-grade squamous intraepithelial lesions (LSILs)/AIN1 (excluding condylomas), 7% (95% CI: 2-13%) in all LSIL (AIN1/LSIL/condyloma), 76% (95% CI: 61-88%) in AIN2, and 90% (95% CI: 82-95%) in AIN3. For anal high-grade squamous intraepithelial lesions (HSILs), in studies using a two-tiered nomenclature, p16 positivity was 84% (95% CI: 66-96%) and for all HSIL (AIN2, AIN3, HSIL combined) it was 82% (95% CI: 72-91%). In summary, p16 positivity in anal squamous intraepithelial lesions appears to be in a similar range to the commonly described cervical squamous intraepithelial lesions, however, for anal low-grade lesions positivity seems to be lower.

Background In patients with suspected or known obstructive gastrointestinal pathology, the use of patency capsule (PC) aims to minimize the risk of subsequent retention of the endoscopic capsule. However, its clinical utility is not consensual. The aim was to evaluate the indications, results and safety profile of the PC. Methods Retrospective analysis of PCs (agile patency capsule) conducted between 2011 and 2015. Patency evaluation was performed after 30 hours, with radiological confirmation if PC was detected. Results We included 369 PCs, 54% female. The average age was 42±16 years. Main indications included suspected Crohn disease (CD) (45%), CD staging (32%), neoplastic diseases (9%), radic enteritis (3%), prior surgery (3%), NSAIDs enteropathy (2%) and anemia (2%). Before the exam 5% of patients were taking constipation-induced medications and 5% reported occlusive symptoms; 38% of patients had previous abdominal surgeries, most often ileal resection due to CD (24%); 42% of patients had previous imaging studies, revealing strictures in 20% and bowel dilation in 11%. Patency capsule was negative (patent gastrointestinal tract) in 73% of cases at 30h and 2% of PCs were fully recovered in the following days. Seven patients (2.5%) showed self-limiting occlusive symptoms during the procedure. All patients with negative PC subsequently performed capsule endoscopy with no cases of retention. History of occlusive symptoms (P=0.023) and strictures in imaging studies (P=0.029) were associated with the detection of the PC at 30 hours. Conclusions PC is a safe and effective exam. Occlusive symptoms and imaging strictures were significantly associated with the retention. The retention rate was 25%, a similar result to that described in other series but higher than expected for the various indications, suggesting the importance of new research studies.