Hemorrhoidal disease: Epidemiological study and analysis of predictive factors for surgical management.

INTRODUCTION: There are very few French studies on hemorrhoidal disease and its management. PATIENTS AND METHODS: Prospective single-center study from July to December 2021 including 472 patients. RESULTS: Bleeding, prolapse and pain were the main reasons for consultation. Treatment modalities were medical (44%),±instrumental (72%), and surgical (17%). After treatment, the bleeding score and prolapse score decreased significantly (P=0.002 and P≤0.0001, respectively), but improvement was more marked in the surgery group with a better rate of "very good satisfaction" (73% vs. 54%, P=0.003). Factors associated with likelihood of surgical treatment were: age>44years, hypertrophic perianal skin tags, high scores (Bristol>5, bleeding>5, prolapse>2), severe impact on quality of life, smoking and reading during bowel movements. We have developed an online application, which aims to assess the risk of requiring hemorrhoidal surgery. CONCLUSION: Less than 20% of patients who present with hemorrhoidal disease require surgical treatment, but it is associated with better effectiveness despite more complex postoperative consequences that sometimes motivate patient refusal. We have highlighted factors associated with surgical management, which can guide the practitioner in their therapeutic choices.

Deep Learning in High-Resolution Anoscopy: Assessing the Impact of Staining and Therapeutic Manipulation on Automated Detection of Anal Cancer Precursors.

INTRODUCTION: High-resolution anoscopy (HRA) is the gold standard for detecting anal squamous cell carcinoma (ASCC) precursors. Preliminary studies on the application of artificial intelligence (AI) models to this modality have revealed promising results. However, the impact of staining techniques and anal manipulation on the effectiveness of these algorithms has not been evaluated. We aimed to develop a deep learning system for automatic differentiation of high-grade squamous intraepithelial lesion vs low-grade squamous intraepithelial lesion in HRA images in different subsets of patients (nonstained, acetic acid, lugol, and after manipulation). METHODS: A convolutional neural network was developed to detect and differentiate high-grade and low-grade anal squamous intraepithelial lesions based on 27,770 images from 103 HRA examinations performed in 88 patients. Subanalyses were performed to evaluate the algorithm's performance in subsets of images without staining, acetic acid, lugol, and after manipulation of the anal canal. The sensitivity, specificity, accuracy, positive and negative predictive values, and area under the curve were calculated. RESULTS: The convolutional neural network achieved an overall accuracy of 98.3%. The algorithm had a sensitivity and specificity of 97.4% and 99.2%, respectively. The accuracy of the algorithm for differentiating high-grade squamous intraepithelial lesion vs low-grade squamous intraepithelial lesion varied between 91.5% (postmanipulation) and 100% (lugol) for the categories at subanalysis. The area under the curve ranged between 0.95 and 1.00. DISCUSSION: The introduction of AI to HRA may provide an accurate detection and differentiation of ASCC precursors. Our algorithm showed excellent performance at different staining settings. This is extremely important because real-time AI models during HRA examinations can help guide local treatment or detect relapsing disease.

Unraveling Emerging Anal Cancer Clinical Biomarkers from Current Immuno-Oncogenomics Advances.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk human papillomavirus (HPV) and is currently one of the fastest-growing causes of cancer incidence and mortality in developed countries. Although next-generation sequencing technologies (NGS) have revolutionized cancer and immuno-genomic research in various tumor types, a limited amount of clinical research has been developed to investigate the expression and the functional characterization of genomic data in ASCC. Herein, we comprehensively assess recent advancements in "omics" research, including a systematic analysis of genome-based studies, aiming to identify the most relevant ASCC cancer driver gene expressions and their associated signaling pathways. We also highlight the most significant biomarkers associated with anal cancer progression, gene expression of potential diagnostic biomarkers, expression of therapeutic drug targets, and emerging treatment opportunities. This review stresses the urgent need for developing target-specific therapies in ASCC. By illuminating the molecular characteristics and drug-target expression in ASCC, this study aims to provide insights for the development of precision medicine in anal cancer.

Allogenic stem cells for Crohn's anal fistulas: Treating early improves the deep remission rate.

AIM: The aim of this study was to evaluate the real-life clinical and radiological efficacy of darvadstrocel injection into complex perianal fistulas in Crohn's disease. Secondary endpoints were to assess symptomatic efficacy, adverse effects and factors associated with complete combined clinical-radiological response (deep remission). METHODS: After marketing the product in France, all first patients treated consecutively were included. A complete clinical response was defined by a complete closure of all external openings with no discharge on pressure. A complete radiological response (MRI), evaluated at least after six months of follow-up, was defined by a completely fibrotic sequela without abscess. A deep remission was defined as the association of a complete clinical response with a complete radiological response. RESULTS: A total of 43 patients were included (M/F: 22/21, median age 37 [26-45] years). The fistulas were already drained with seton(s) and were on biologic treatment. After a median follow-up of 383 (359-505) days, 28 (65%) patients showed a clinical response (22 complete and 6 partial) and 16 (37%) achieved a deep remission. The Perineal Disease Activity Index decreased significantly after treatment: 39 (91%) patients reported symptomatic improvement in terms of discharge, pain, and induration, and 28 (65%) no longer had any perineal symptoms. No severe adverse events were reported. A short history of Crohn's disease <3 years was significantly associated with deep remission (OD 4.5 [1.0-19.1], p = 0.04). CONCLUSION: Darvadstrocel injection resulted in a clinical response for two thirds of patients and deep remission for one third. A shorter duration of Crohn's disease was associated with deep remission.

[Anal fistulas: Sparing the sphincter]. / Fistules anales, épargner le sphincter.

ANAL FISTULAS: SPARING THE SPHINCTER. Fistulotomy is the most used treatment for anal fistula. It is very effective with a cure rate of over 95% but carries a risk of incontinence. This has led to the development of various sphincter sparing techniques. The injection of biological glue or paste and the insertion of a plug have disappointing results and are expensive. The rectal advancement flap is still practised because of its cure rate of around 75% but it may result in some incontinence. Intersphincteric ligation of the fistula track and laser treatment are widely practised in France with cure rates between 60 and 70%. Video-assisted anal fistula treatment as well as injections of adipose tissue, stromal vascular fraction, platelet-enriched plasma and/or mesenchymal stem cells are emerging techniques for which even better results are expected.

FISTULES ANALES, ÉPARGNER LE SPHINCTER. La fistulotomie est le traitement le plus souvent utilisé dans la fistule anale. Elle est très efficace, avec un taux de guérison supérieur à 95 %, mais expose à un risque d'incontinence. Cela a conduit au développement de diverses techniques d'épargne sphinctérienne. L'injection de colle ou de pâte biologique ainsi que la mise en place d'un plug ont des résultats finalement décevants et un coût élevé. Le lambeau rectal d'avancement est encore pratiqué en raison de son taux de guérison aux alentours de 75 %, mais il peut se solder par quelques troubles séquellaires de la continence. La ligature intersphinctérienne du trajet fistuleux et le laser sont largement pratiqués en France, avec des taux de guérison oscillant entre 60 et 70 %. Le traitement vidéo-assisté du trajet fistuleux ainsi que les injections périfistuleuses de tissu adipeux, de fraction vasculaire stromale, de plasma enrichi en plaquettes et/ou de cellules souches mésenchymateuses sont des techniques émergentes dont on espère de meilleurs résultats encore.

[Pilonidal disease: The revolution in minimally invasive surgery]. / Sinus pilonidal infecté : la révolution de la chirurgie mini-invasive.

PILONIDAL DISEASE: THE REVOLUTION IN MINIMALLY INVASIVE SURGERY. Pilonidal disease is a common suppurative condition and affects 0.7% of the population. Surgical excision is the standard treatment. In France, the most common procedure is lay-open excision with healing by secondary intention. This procedure has low recurrence rates, but involves daily nursing care, long healing time and long period of sick-leave. Excision and primary repair or flap-based procedures are good alternatives to reduce these negative aspects but they expose to higher recurrence rates than excision with healing by secondary intention. The goal of minimally invasive techniques is to eradicate the suppuration, obtain healing as quick as possible, and limit the morbidity as much as possible. Old minimally invasive approaches such as phenolization or pit-picking are associated with low morbidity but with higher recurrence rates. Currently, new minimally invasive techniques are being developed. Endoscopic and laser treatment of pilonidal disease have shown promising results, with failure rates of less than 10% at 1 year, few complications and low morbidity. Complications are rare and minor. However, these interesting results need to be confirmed by better quality studies with longer follow-up.

SINUS PILONIDAL INFECTÉ : LA RÉVOLUTION DE LA CHIRURGIE MINI-INVASIVE. Le sinus pilonidal infecté est une pathologie fréquente qui affecterait 0,7 % de la population. Son traitement est chirurgical. En France, la technique de référence est l'exérèse, avec une plaie laissée ouverte, puis une cicatrisation dirigée. Elle a l'avantage de réduire le risque de récidive, au prix cependant de soins infirmiers quotidiens, d'une durée de cicatrisation longue impliquant un arrêt d'activité prolongé. Les techniques chirurgicales de fermeture ou de plastie visant à réduire la durée des soins sont moins contraignantes pour les patients, mais elles exposent à davantage de récidives que la technique ouverte. L'objectif des techniques mini-invasives est de simplifier les suites opératoires tout en limitant le risque de récidive. Les techniques mini-invasives anciennes comme la phénolisation ou le « pit picking ¼ exposent à un taux de récidive élevé malgré des suites simples. Aujourd'hui, de nouvelles techniques se développent, faisant appel, entre autres, à l'endoscopie ou encore au laser également utilisés pour le traitement des fistules anales. Les premiers résultats sont prometteurs, avec un taux d'échec globalement inférieur à 10 % à un an. Les complications sont rares, le plus souvent mineures, et les suites postopératoires sont simples sans nécessité de soins infirmiers. Cependant, ces résultats intéressants nécessitent d'être confirmés par des études de meilleure qualité avec un suivi prolongé.

[Management of secondary lesions in ano-perineal Crohn's disease]. / Prise en charge des lésions secondaires de la maladie de Crohn anopérinéale.

MANAGEMENT OF SECONDARY LESIONS IN ANO-PERINEAL CROHN'S DISEASE. Anoperineal involvement in Crohn's disease is common and affects around 1/3 of patients during their disease. It constitutes a pejorative factor with an increased risk of permanent colostomy and proctectomy and is associated with a major deterioration in quality of life. Secondary anal lesions in Crohn's disease are fistulas and abscesses. They are difficult to treat and often recurrent. A multidisciplinary medico-surgical management in several stages is essential. The classic sequence is based on a first phase of drainage of fistulas and abscesses, a second phase of medical treatment based primarily on anti-TNF alpha and finally a third phase of surgical closure of the fistula tract(s). Conventional closure techniques such as biologic glue, plug, advancement flap and intersphincteric ligation of the fistula tract have limited effectiveness, are not always feasible, require technical skills and some have an impact on anal continence. In recent years, we have witnessed a real enthusiasm generated by the arrival of cell therapy. This has not spared proctology since adipose-derived allogeneic mesenchymal stem cells have had Marketing Authorisation and have been reimbursed in France since 2020 in the treatment of complex anal fistulas in Crohn's disease after failure of at least one biologic therapy. This new treatment offers an additional alternative in patients often in a situation of therapeutic impasse. Preliminary results in real life are satisfactory with a good safety profile. However, it will be necessary to confirm these results in the longer term and to work to determine the profile of the patients who could benefit the most from this expensive therapy.

PRISE EN CHARGE DES LÉSIONS SECONDAIRES DE LA MALADIE DE CROHN ANOPÉRINÉALE. L'atteinte anopérinéale de la maladie de Crohn est fréquente ; elle affecte environ un tiers des patients durant leur maladie. Elle constitue un facteur péjoratif responsable d'une majoration du risque de colostomie définitive et de proctectomie, et est associée à une altération majeure de la qualité de vie. Les lésions anales secondaires de la maladie de Crohn sont des fistules et des abcès. Elles sont difficiles à traiter et souvent récidivantes. Une prise en charge multidisciplinaire médico-chirurgicale en plusieurs étapes s'impose. La séquence classique se fonde sur une phase de drainage des fistules et des abcès, une phase de traitement médical fondé en priorité sur les anti-TNF alpha et enfin une phase de fermeture chirurgicale du (ou des) trajet(s) fistuleux. Les techniques de fermeture classiques comme la colle biologique, le plug, le lambeau d'avancement et la ligature intersphinctérienne du trajet fistuleux ont une efficacité limitée, ne sont pas toujours réalisables, nécessitent des compétences techniques et ont, pour certaines, un impact sur la continence anale. Ces dernières années, l'arrivée de la thérapie cellulaire suscite un véritable enthousiasme. Cet engouement n'a pas épargné la proctologie, puisque les cellules souches mésenchymateuses (CSM) allogéniques d'origine adipocytaires ont obtenu une autorisation de mise sur le marché (AMM), sont commercialisées et remboursées en France depuis 2020 dans le traitement des fistules anales complexes de la maladie de Crohn en échec d'au moins une biothérapie. Cette thérapie offre une alternative supplémentaire à des patients souvent en situation d'impasse thérapeutique. Les résultats préliminaires en vraie vie sont satisfaisants, avec un bon profil d'innocuité. Toutefois, il faudra confirmer ces résultats à plus long terme et travailler à identifier le profil des patients qui pourraient bénéficier au mieux de cette thérapie onéreuse.

Prognostic Factors of Long-Term Outcomes after Primary Chemo-Radiotherapy in Non-Metastatic Anal Squamous Cell Carcinoma: An International Bicentric Cohort.

Anal squamous cell carcinoma (ASCC) is a rare malignancy with a rising incidence associated with human papillomavirus (HPV) infection. The locally advanced disease is associated with a 30% rate of treatment failure after standard chemoradiotherapy (CRT). We aimed to elucidate the prognostic factors for ASCC after curative CRT. A retrospective multicenter study of 176 consecutive patients with ASCC having completed CRT treated between 2010 and 2017 at two centers was performed. Complete response (CR), disease-free survival (DFS), and overall survival (OS) were analyzed by Kaplan-Meier estimates with log-rank tests. The hierarchical clustering on principal components (HCPC) method was employed in an unsupervised and multivariate approach. The CR rate was 70% and was predictive of DFS (p < 0.0001) and OS (p < 0.0001), where non-CR cases were associated with shorter DFS (HR = 16.5, 95% CI 8.19-33.21) and OS (HR = 8.42, 95% CI 3.77-18.81) in a univariate analysis. The median follow-up was 38 months, with a 3-year DFS of 71%. The prognostic factors for DFS were cT1-T2 (p = 0.0002), N0 (p = 0.035), HIV-positive (p = 0.047), HIV-HPV coinfection (p = 0.018), and well-differentiated tumors (p = 0.037). The three-year OS was 81.6%. Female sex (p = 0.05), cT1-T2 (p = 0.02) and well-differentiated tumors (p = 0.003) were associated with better OS. The unsupervised analysis demonstrated a clear segregation of patients in three clusters, identifying that poor prognosis clusters associated with shorter DFS (HR = 1.74 95% CI = 1.25-2.42, p = 0.0008) were enriched with the locally advanced disease, anal canal location, HIV-HPV coinfection, and non-CR. In conclusion, our results reinforce the prognostic value of T stage, N stage, sex, differentiation status, tumor location, and HIV-HPV coinfection in ASCC after CRT.

[The rôle of MRI in exploration anorectal pathologies]. / Place de l'IRM pour explorer les pathologies anorectales.

PLACE DE L'IRM POUR EXPLORER LES PATHOLOGIES ANORECTALES. L'imagerie par résonance magnétique (IRM) est l'un des examens d'imagerie les plus utiles à l'exploration des pathologies ano rectales. Elle est complémentaire de l'examen clinique et de l'endo scopie. Elle permet de fournir des données indispensables à une prise en charge optimale du patient par le proctologue, le chirurgien ou l'oncologue en fonction de la nature de l'atteinte anale ou rectale. Il est nécessaire de respecter les différentes indications de cet examen, qui ont été bien définies pour chaque pathologie par les différentes sociétés savantes. Le protocole de l'IRM varie en fonction de la zone explorée et de la pathologie suspectée. C'est pourquoi il est indispensable de fournir au radiologue les informations nécessaires telles que la suspicion diagnostique, les données cliniques, ainsi que les résultats des examens complémentaires déjà réalisés. Les indications les plus fréquentes de l'IRM en proctologie sont les tumeurs anales et rectales. L'IRM permet le bilan initial de l'extension locorégionale de la tumeur ainsi que le suivi oncologique précoce et tardif grâce à l'étude comparative des examens de surveillance par rapport au bilan initial. L'IRM est indispensable pour l'exploration des suppurations anopérinéales complexes, en particulier liées à la maladie de Crohn. Elle permet la réalisation du bilan lésionnel initial ainsi que le contrôle post-drainage. En cas de suspicion de maladie de Verneuil ou de sinus pilonidal infecté, l'IRM participe à l'orientation vers le diagnostic étiologique. La déféco-IRM est une variante particulière de l'IRM pelvienne et périnéale. Elle fait partie du bilan des dysfonctions du plancher pelvien, car elle permet l'étude du comportement des différents organes pelviens au cours des efforts de poussée et de défécation. Les fissures anales et les thromboses hémorroïdaires sont les causes les plus fréquentes de douleurs anales. Leur diagnostic est purement clinique. En cas d'examen proctologique normal, l'IRM sert à chercher une autre cause à ces douleurs.

THE ROLE OF MRI IN EXPLORATION ANORECTAL PATHOLOGIES. Magnetic resonance imaging (MRI) is one of the most useful imaging modalities for the exploration of anorectal pathologies. It is complementary to the clinical examination and endoscopy. It provides essential elements for optimal care of the patient by the proctologist, the surgeon or the oncologist depending on the nature of the anal or rectal condition. It is necessary to respect the different indications of this exam which have been well defined for each pathology by the different scientific societies. The MRI protocol varies depending on the site to be investigated and the pathology suspected. Therefore, it is essential to provide the radiologist with the necessary information such as the diagnostic suspicion, clinical findings, and the results of previous paraclinical examinations. MRI ensures the initial assessment of the locoregional extension of the tumor as well as the early and late oncological follow-up thanks to the comparative study of the surveillance examinations with the initial exam. MRI is essential for the assessment of complex anoperineal suppurations, in particular those related to Crohn's disease. It is necessary for the initial lesional assessment and for the post-drainage control. In case of suspicion of Verneuil's (hidradenitis suppurativa) disease or infected pilonidal sinus, MRI helps to orientate towards the right etiological diagnosis. MR defecating proctography is a particular variant of pelvic and perineal MRI. It is performed as part of the assessment of pelvic floor dysfunctions because it allows the study of the dynamics of the different pelvic organs during straining and defecation. Anal fissures and hemorrhoidal thrombosis are the most frequent etiologies of anal pain. Their diagnosis is purely clinical. If the proctological examination is normal, MRI is used to search for other causes of anal pain.

Ano-rectovaginal fistula after obstetrical anal sphincter injury: Diverting stoma does not improve the surgical results.

AIM: Ano-rectovaginal fistulas (ARVF) are challenging for the surgeon. Most of the series mix aetiologies, leading to confusion with respect to the conclusion. The aim of this study was to assess the factors associated with the success of ARVF management following obstetrical anal sphincter injury (OASIS). METHODS: This retrospective multicentric study included all the patients undergoing surgery for ARVF identified by the hospital codes. Patients for whom the aetiology of ARVF was not OASIS were excluded. The major outcome measure was the success of the procedure. RESULTS: Sixty patients with treated ARVF due to OASIS were identified. The success of overall management was 91.7%. Female patients underwent a mean of 2.5 (±1.7) procedures. A diverting stoma was formed in 29 patients (48.3%) of which 26 were closed at the end of the management period (89.7%). Of the 148 surgical procedures, only 55 were successful (37.2%). The order of the procedures (OR = 1.38; 95% CI: 0.75-2.51) or the diverting stoma (OR = 1.46; 95% CI: 0.31-6.91) were not significantly associated with the success of the surgery. However, Martius flap (OR = 4.13; 95% CI: 1.1-15.54) and Musset procedures (OR = 5.79; 95% CI: 1.77-18.87) produced better results than the endorectal advancement flap (ERAF). The other procedures did not show a significant correlation with management success. CONCLUSION: A diverting stoma is not mandatory in the management of ARVF due to OASIS to improve the success of the surgical procedure. While the Martius flap procedure offers better results, the ERAF procedure may be preferred as a primary intervention in the absence of sphincter injury as it is less invasive. In cases of residual sphincter injury, the Musset procedure is most likely to be the best option.

Increased Long-term Risk of Anal Fistula After Proctologic Surgery: A Case-Control Study.

PURPOSE: Anal fistula is a common condition in proctology, usually requiring surgical treatment. Few risk factors have been clearly identified based on solid evidence. Our research objective was to determine whether history of anal surgery was a risk factor for subsequent anal fistula. METHODS: We conducted a case-control study from January 1, 2012 through December 31, 2013 in our tertiary center, comprising 280 cases that underwent surgery for anal fistula and 123 control patients seeking a consultation for upper gastrointestinal symptoms. Patients with inflammatory bowel disease were excluded. For both cases and controls, the following variables were recorded: sex, any prior anal surgery, diabetes mellitus, infection with human immunodeficiency virus, and smoking status. For each variable, confidence interval and odds ratio (OR) were calculated. RESULTS: In univariate analysis, male sex (73.2% vs. 31.7%, P < 0.0001), active smoking (38.1% vs. 22%, P = 0.0015), and prior anal surgery (16.0% vs. 4.1%, P = 0.0008) were associated with higher risk of anal fistula. In multivariate analysis, only male sex (OR, 5.5; 95% confidence interval [CI], 5.42 to 9.10; P < 0.0001) and previous anal surgery (OR, 4.48; 95% CI, 1.79 to 13.7; P = 0.0008) remained independently associated with anal fistula occurrence. CONCLUSION: The epidemiology of anal fistula is poorly assessed despite the high frequency at which it is diagnosed. Our findings suggest that history of any kind of anal surgery is a risk factor for further onset of anal fistula. Surgeons and patients must be informed of this issue.

Proposal for a New Score: Hemorrhoidal Bleeding Score.

PURPOSE: We conducted a prospective study to evaluate a new hemorrhoidal bleeding score (HBS). METHODS: All consecutive patients who had consulted between May 1, 2016 and June 30, 2017 for bleeding hemorrhoidal disease were prospectively assessed at a proctological department. The study was conducted in 2 stages. The first stage assessed the validity of the score on a prospective patient cohort. A second stage assessed the interobserver reproducibility of the score on another prospective cohort. RESULTS: One hundred consecutive patients were studied (57 males; mean age, 49.70 years). A positive association between HBS and surgery indication was found (P<0.001). A cut-off value of the score of 5 (≤5 vs. >5) separated patients from surgical to medical-instrumental treatment with a sensitivity and specificity of 75.00% and 81.25%, respectively. In the multivariate analysis, only HBS was significantly associated with the operative decision (odds ratio, 12.22). Prolapse was no longer significantly associated with the surgical indication. After a mean follow-up after treatment of 7 months, HBS improved statistically significantly (P<0.0001). For the reproducibility of the score, an additional 30 consecutive patients (13 males; mean age, 53.14 years) were enrolled with an excellent agreement between 2 proctologists (kappa=0.983). CONCLUSION: HBS is sensitive, specific, and reproducible. It can assess the severity of hemorrhoidal bleeding. It can discriminate between the most severe surgery-indicated patients and does so in a more efficient way than the Goligher prolapse score. It also allows quantifying the extent of change in hemorrhoidal bleeding after treatment.

Human papillomavirus vaccine uptake among men in France: a national time series analysis for 2015-2018.

While national authorities recommended and provided reimbursement for men who have sex with men under 27 in 2016 and 2017, respectively, we aimed to comprehensively analyze human papillomavirus (HPV) vaccine uptake in French men over a 4-year period surrounding these changes. Data regarding HPV vaccine sales to men in all French pharmacies from 2015 through 2018 were retrieved through query made to the national public insurance database. Data were classified according to the age of patients and the time of dispensation so as to display aggregate uptake according to age over time. Time-series analysis was conducted and an exponential smoothing extrapolation was selected to analyze the impact of the reimbursement. Overall, 12,814 HPV vaccines were dispensed in men over the study period. Age was available for the majority of cases (12,793; 99.8%), averaging 29. Dispensation data for each year were the following: 1,917 (2015), 1,921 (2016), 2,643 (2017), 6,312 (2018). Age analysis showed that vaccine uptake among men over 26 was substantial (n = 5974; 46.7%). The exponential increase in the number of vaccines sold started after the second quarter of 2017. In conclusion, we found that HPV vaccine uptake among French men is partly misaligned with recommendations and reimbursement in terms of age, and still moderate overall even though we found signs of marked increase in uptake over the most recent period, suggesting an effective impact of insurance coverage.