Resolution of Acinar Dedifferentiation Regulates Tissue Remodeling in Pancreatic Injury and Cancer Initiation.

BACKGROUND & AIMS: Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human. METHODS: We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26-LSL-YFPLSL-YFP; Sox4fl/fl) with and without an activating mutation in Kras (KrasLSL-G12D/+). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing. RESULTS: We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression. CONCLUSIONS: Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma.

SEM Image Processing Assisted by Deep Learning to Quantify Mesoporous γ-Alumina Spatial Heterogeneity and Its Predicted Impact on Mass Transfer.

The pore network architecture of porous heterogeneous catalyst supports has a significant effect on the kinetics of mass transfer occurring within them. Therefore, characterizing and understanding structure-transport relationships is essential to guide new designs of heterogeneous catalysts with higher activity and selectivity and superior resistance to deactivation. This study combines classical characterization via N2 adsorption and desorption and mercury porosimetry with advanced scanning electron microscopy (SEM) imaging and processing approaches to quantify the spatial heterogeneity of γ-alumina (γ-Al2O3), a catalyst support of great industrial relevance. Based on this, a model is proposed for the spatial organization of γ-Al2O3, containing alumina inclusions of different porosities with respect to the alumina matrix. Using original, advanced SEM image analysis techniques, including deep learning semantic segmentation and porosity measurement under gray-level calibration, the inclusion volume fraction and interphase porosity difference were identified and quantified as the key parameters that served as input for effective tortuosity factor predictions using effective medium theory (EMT)-based models. For the studied aluminas, spatial porosity heterogeneity impact on the effective tortuosity factor was found to be negligible, yet it was proven to become significant for an inclusion content of at least 30% and an interphase porosity difference of over 20%. The proposed methodology based on machine-learning-supported image analysis, in conjunction with other analytical techniques, is a general platform that should have a broader impact on porous materials characterization.

SOXC are critical regulators of adult bone mass.

Pivotal in many ways for human health, the control of adult bone mass is governed by complex, incompletely understood crosstalk namely between mesenchymal stem cells, osteoblasts and osteoclasts. The SOX4, SOX11 and SOX12 (SOXC) transcription factors were previously shown to control many developmental processes, including skeletogenesis, and SOX4 was linked to osteoporosis, but how SOXC control adult bone mass remains unknown. Using SOXC loss- and gain-of-function mouse models, we show here that SOXC redundantly promote prepubertal cortical bone mass strengthening whereas only SOX4 mitigates adult trabecular bone mass accrual in early adulthood and subsequent maintenance. SOX4 favors bone resorption over formation by lowering osteoblastogenesis and increasing osteoclastogenesis. Single-cell transcriptomics reveals its prevalent expression in Lepr+ mesenchymal cells and ability to upregulate genes for prominent anti-osteoblastogenic and pro-osteoclastogenic factors, including interferon signaling-related chemokines, contributing to these adult stem cells' secretome. SOXC, with SOX4 predominantly, are thus key regulators of adult bone mass.

Skeletal growth is enhanced by a shared role for SOX8 and SOX9 in promoting reserve chondrocyte commitment to columnar proliferation.

SOX8 was linked in a genome-wide association study to human height heritability, but roles in chondrocytes for this close relative of the master chondrogenic transcription factor SOX9 remain unknown. We undertook here to fill this knowledge gap. High-throughput assays demonstrate expression of human SOX8 and mouse Sox8 in growth plate cartilage. In situ assays show that Sox8 is expressed at a similar level as Sox9 in reserve and early columnar chondrocytes and turned off when Sox9 expression peaks in late columnar and prehypertrophic chondrocytes. Sox8-/- mice and Sox8fl/flPrx1Cre and Sox9fl/+Prx1Cre mice (inactivation in limb skeletal cells) have a normal or near normal skeletal size. In contrast, juvenile and adult Sox8fl/flSox9fl/+Prx1Cre compound mutants exhibit a 15 to 20% shortening of long bones. Their growth plate reserve chondrocytes progress slowly toward the columnar stage, as witnessed by a delay in down-regulating Pthlh expression, in packing in columns and in elevating their proliferation rate. SOX8 or SOX9 overexpression in chondrocytes reveals not only that SOX8 can promote growth plate cell proliferation and differentiation, even upon inactivation of endogenous Sox9, but also that it is more efficient than SOX9, possibly due to greater protein stability. Altogether, these findings uncover a major role for SOX8 and SOX9 in promoting skeletal growth by stimulating commitment of growth plate reserve chondrocytes to actively proliferating columnar cells. Further, by showing that SOX8 is more chondrogenic than SOX9, they suggest that SOX8 could be preferred over SOX9 in therapies to promote cartilage formation or regeneration in developmental and degenerative cartilage diseases.

Phytophthora capsici genome assembly for two isolates using long-read Oxford Nanopore Technology sequencing.

The oomycete Phytophthora capsici is a common pathogen of the Solanaceae and Cucurbitaceae families. An improved assembly for the reference isolate LT1534 was constructed using Oxford Nanopore Technologies and Illumina data. Additionally, an unpolished assembly was produced for the European isolate Pc285 collected on chili pepper using Oxford Nanopore reads.

En bloc resection of pararectal ectopic thyroid tissue: a case report.

A pararectal mass' specific diagnosis can be challenging as a broad range of both benign and malignant tumors are possible. Many of these lesions are congenital and do not require treatment, if asymptomatic. Special attention is to be paid when imaging findings are not typical. In such cases, definitive diagnostic can require surgical excision. To this day, ectopic thyroid tissue was not part of known differential diagnosis. This is the first reported case of thyroid adenoma found in the perirectal area. Ectopic thyroid gland can progress over time and include malignant transformation, although rare. It needs to be considered when managing these cases, especially in unusual locations. This case report offers a systematic approach to the atypical pararectal tumor. It shares new specific clinical experience in managing a case  of pararectal ectopic thyroid adenoma, from both a surgical and a histopathological point of view.

Analysis of >3400 worldwide eggplant accessions reveals two independent domestication events and multiple migration-diversification routes.

Eggplant (Solanum melongena) is an important Solanaceous crop, widely cultivated and consumed in Asia, the Mediterranean basin, and Southeast Europe. Its domestication centers and migration and diversification routes are still a matter of debate. We report the largest georeferenced and genotyped collection to this date for eggplant and its wild relatives, consisting of 3499 accessions from seven worldwide genebanks, originating from 105 countries in five continents. The combination of genotypic and passport data points to the existence of at least two main centers of domestication, in Southeast Asia and the Indian subcontinent, with limited genetic exchange between them. The wild and weedy eggplant ancestor S. insanum shows admixture with domesticated S. melongena, similar to what was described for other fruit-bearing Solanaceous crops such as tomato and pepper and their wild ancestors. After domestication, migration and admixture of eggplant populations from different regions have been less conspicuous with respect to tomato and pepper, thus better preserving 'local' phenotypic characteristics. The data allowed the identification of misclassified and putatively duplicated accessions, facilitating genebank management. All the genetic, phenotypic, and passport data have been deposited in the Open Access G2P-SOL database, and constitute an invaluable resource for understanding the domestication, migration and diversification of this cosmopolitan vegetable.

Multi-environment association study highlights candidate genes for robust agronomic quantitative trait loci in a novel worldwide Capsicum core collection.

Investigating crop diversity through genome-wide association studies (GWAS) on core collections helps in deciphering the genetic determinants of complex quantitative traits. Using the G2P-SOL project world collection of 10 038 wild and cultivated Capsicum accessions from 10 major genebanks, we assembled a core collection of 423 accessions representing the known genetic diversity. Since complex traits are often highly dependent upon environmental variables and genotype-by-environment (G × E) interactions, multi-environment GWAS with a 10 195-marker genotypic matrix were conducted on a highly diverse subset of 350 Capsicum annuum accessions, extensively phenotyped in up to six independent trials from five climatically differing countries. Environment-specific and multi-environment quantitative trait loci (QTLs) were detected for 23 diverse agronomic traits. We identified 97 candidate genes potentially implicated in 53 of the most robust and high-confidence QTLs for fruit flavor, color, size, and shape traits, and for plant productivity, vigor, and earliness traits. Investigating the genetic architecture of agronomic traits in this way will assist the development of genetic markers and pave the way for marker-assisted selection. The G2P-SOL pepper core collection will be available upon request as a unique and universal resource for further exploitation in future gene discovery and marker-assisted breeding efforts by the pepper community.

Strive or thrive: Trends in Phytophthora capsici gene expression in partially resistant pepper.

Partial resistance in plants generally exerts a low selective pressure on pathogens, and thus ensuring their durability in agrosystems. However, little is known about the effect of partial resistance on the molecular mechanisms of pathogenicity, a knowledge that could advance plant breeding for sustainable plant health. Here we investigate the gene expression of Phytophthora capsici during infection of pepper (Capsicum annuum L.), where only partial genetic resistance is reported, using Illumina RNA-seq. Comparison of transcriptomes of P. capsici infecting susceptible and partially resistant peppers identified a small number of genes that redirected its own resources into lipid biosynthesis to subsist on partially resistant plants. The adapted and non-adapted isolates of P. capsici differed in expression of genes involved in nucleic acid synthesis and transporters. Transient ectopic expression of the RxLR effector genes CUST_2407 and CUST_16519 in pepper lines differing in resistance levels revealed specific host-isolate interactions that either triggered local necrotic lesions (hypersensitive response or HR) or elicited leave abscission (extreme resistance or ER), preventing the spread of the pathogen to healthy tissue. Although these effectors did not unequivocally explain the quantitative host resistance, our findings highlight the importance of plant genes limiting nutrient resources to select pepper cultivars with sustainable resistance to P. capsici.

Pepper variome reveals the history and key loci associated with fruit domestication and diversification.

Pepper (Capsicum spp.) is an important vegetable crop that provides a unique pungent sensation when eaten. Through construction of a pepper variome map, we examined the main groups that emerged during domestication and breeding of C. annuum, their relationships and temporal succession, and the molecular events underlying the main transitions. The results showed that the initial differentiation in fruit shape and pungency, increase in fruit weight, and transition from erect to pendent fruits, as well as the recent appearance of large, blocky, sweet fruits (bell peppers), were accompanied by strong selection/fixation of key alleles and introgressions in two large genomic regions. Furthermore, we identified Up, which encodes a BIG GRAIN protein involved in auxin transport, as a key domestication gene that controls erect vs pendent fruit orientation. The up mutation gained increased expression especially in the fruit pedicel through a 579-bp sequence deletion in its 5' upstream region, resulting in the phenotype of pendent fruit. The function of Up was confirmed by virus-induced gene silencing. Taken together, these findings constitute a cornerstone for understanding the domestication and differentiation of a key horticultural crop.

Single-cell atlas of craniogenesis uncovers SOXC-dependent, highly proliferative, and myofibroblast-like osteodermal progenitors.

The mammalian skull vault is essential to shape the head and protect the brain, but the cellular and molecular events underlying its development remain incompletely understood. Single-cell transcriptomic profiling from early to late mouse embryonic stages provides a detailed atlas of cranial lineages. It distinguishes various populations of progenitors and reveals a high expression of SOXC genes (encoding the SOX4, SOX11, and SOX12 transcription factors) early in development in actively proliferating and myofibroblast-like osteodermal progenitors. SOXC inactivation in these cells causes severe skull and skin underdevelopment due to the limited expansion of cell populations before and upon lineage commitment. SOXC genes enhance the expression of gene signatures conferring dynamic cellular and molecular properties, including actin cytoskeleton assembly, chromatin remodeling, and signaling pathway induction and responsiveness. These findings shed light onto craniogenic mechanisms and SOXC functions and suggest that similar mechanisms could decisively control many developmental, adult, pathological, and regenerative processes.

Single-cell analysis identifies the interaction of altered renal tubules with basophils orchestrating kidney fibrosis.

Inflammation is an important component of fibrosis but immune processes that orchestrate kidney fibrosis are not well understood. Here we apply single-cell sequencing to a mouse model of kidney fibrosis. We identify a subset of kidney tubule cells with a profibrotic-inflammatory phenotype characterized by the expression of cytokines and chemokines associated with immune cell recruitment. Receptor-ligand interaction analysis and experimental validation indicate that CXCL1 secreted by profibrotic tubules recruits CXCR2+ basophils. In mice, these basophils are an important source of interleukin-6 and recruitment of the TH17 subset of helper T cells. Genetic deletion or antibody-based depletion of basophils results in reduced renal fibrosis. Human kidney single-cell, bulk gene expression and immunostaining validate a function for basophils in patients with kidney fibrosis. Collectively, these studies identify basophils as contributors to the development of renal fibrosis and suggest that targeting these cells might be a useful clinical strategy to manage chronic kidney disease.

Quantification and morphological characterization of microfibers emitted from textile washing.

Microplastics are a subject of growing interest as they are a potential threat for living organisms. Textile microfibers (MFs) are an important microplastics sub-group that have been reported as a major source of microplastics release into the environment. This pollution occurs mainly during the washing of synthetic garments. However, standardized methods to quantify and characterize these MFs are scarce. This study proposes a new analytical protocol to characterize these MFs in number and size by means of filtration techniques, optical and electronic microscopy and automatic image post-processing. This approach was developed and validated on effluents from washing machines produced in different conditions (5 different garments, sequential cycles, and presence or not of detergent). Among the analyzed effluents, it was found that 40 to 75% of microfibers have a length comprised between 50 and 200 µm, with average microfiber diameters ranging from 8 to 17 µm depending on the type of textile. The emission range of microfibers was estimated to be between 220,000 to 2,820,000 microfibers per kg of textile depending on the type of garment and the washing conditions. The counting method developed is adapted to a certain range of textiles, such as 100% polyester fleece jackets (PET-1), 100% smooth polyester T-shirt (PET-2) and 100% acrylic sweater (PAN), and is not affected by the presence of detergent. The proposed method of characterization of these MFs lengths can also be extrapolated to the counting of other objects that have a similar morphology to the analyzed fibers. Hence, it can be helpful to develop new testing capture technologies and, thus, contribute to the enhancement of filtering techniques of several pollutants.

Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome.

BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.

A double-blind randomized, multicenter, placebo-controlled study of itopride in functional dyspepsia postprandial distress syndrome.

BACKGROUND: Itopride, a mixed D2 antagonist and cholinesterase inhibitor, has prokinetic effects on gastric motility. The Leuven Postprandial Distress Scale is a validated patient-reported outcome instrument for functional dyspepsia (FD) postprandial distress syndrome (PDS). We aimed to use the LPDS to assess treatment outcome in PDS and PDS/EPS (epigastric pain syndrome). METHODS: Patients with PDS, with or without non-predominant EPS symptoms, were enrolled in an 8-week double-blind placebo-controlled multi-center trial with itopride (100 mg t.i.d.). Patients completed LPDS diaries and questionnaires to assess treatment response. Mann-Whitney test and mixed models were used. RESULTS: One hundred patients (79% females, 39.1 ± 1.5 yo) were included. No significant difference was observed between treatment arms (p = 0.6). Compared to baseline, itopride treatment significantly improved the LPDS score (p = 0.001) and all individual symptoms (p < 0.0001). In the placebo arm, this was only the case for belching and epigastric pain (p < 0.05). In an exploratory analysis, outcomes in "pure" PDS (n = 45) and overlapping PDS/EPS (n = 55) patients were assessed and showed that the latter subgroup has the largest benefit with itopride compared to placebo (p = 0.03). CONCLUSION: Using the LPDS score in a pilot controlled trial in FD, itopride shows no therapeutic benefit over placebo after 8 weeks of treatment. In an exploratory post hoc analysis, itopride but not placebo was associated with improvement of symptoms compared to baseline, and this was most prominent in patients with overlapping PDS/EPS. The efficacy of itopride in this subgroup needs to be evaluated in a large study using the same outcome measure. (clinialtrials.org ref.: NCT04647955).

Mass fractal dimension from 2D microscopy images via an aggregation model with variable compactness.

Microscopy-image analysis provides precious information on size and structure of colloidal aggregates and agglomerates. The structure of colloids is often characterized using the mass fractal dimension d f $d_f$ , which is different from the two-dimensional (2D) fractal dimension d p $d_p$ that can be computed from microscopy images. In this work, we propose to use a recent morphological aggregation model to find a relationship between 2D image fractal dimension and 3D mass fractal dimension of aggregates and agglomerates. Our case study is represented by scanning transmission electron microscopy images of boehmite colloidal suspensions. The behaviour of the computed d f $d_f$ at different acid and base concentration shows a fair agreement with the results of small angle x-ray scattering and with the literature, enabling to use the d f $d_f$ versus d p $d_p$ relationship to study the impact of the composition of the colloidal suspension on the density of colloidal aggregates and agglomerates.

Boehmite powder is often employed for the manufacturing of γ $\gamma$ -alumina catalyst carriers and absorbents. This process involves boehmite colloidal particles coagulation, the size and shape of the particles affect the porosity of the final solid. As there is a high interest in tuning the porosity via the synthesis parameters, this work is aimed at the use of microscopy analysis to evaluate the mass fractal dimension of boehmite aggregates and agglomerates formed under controlled physical chemical conditions (acid and alkaline content and Brownian motion). Since the mass fractal dimension cannot be directly computed on binary two-dimensional images, a recently developed morphological model has been used to generate three-dimensional clusters characterized by a certain mass fractal dimension d f $d_f$ , the projection of the clusters leads to the estimation on the projected fractal dimension d p $d_p$ , being related to the slope on a bi-logarithmic plot perimeter versus area. According to the morphological model, the higher the d f $d_f$ , the lower the d p $d_p$ . The relationship between d f $d_f$ and d p $d_p$ has been used to estimate the mass fractal dimension from STEM images of boehmite suspensions. The trend of d f $d_f$ with respect to the acid and alkaline content in the suspensions agrees with small angle X-ray scattering measurement and with the literature.

SoxD genes are required for adult neural stem cell activation.

The adult neurogenic niche in the hippocampus is maintained through activation of reversibly quiescent neural stem cells (NSCs) with radial glia-like morphology (RGLs). Here, we show that the expression of SoxD transcription factors Sox5 and Sox6 is enriched in activated RGLs. Using inducible deletion of Sox5 or Sox6 in the adult mouse brain, we show that both genes are required for RGL activation and the generation of new neurons. Conversely, Sox5 overexpression in cultured NSCs interferes with entry in quiescence. Mechanistically, expression of the proneural protein Ascl1 (a key RGL regulator) is severely downregulated in SoxD-deficient RGLs, and Ascl1 transcription relies on conserved Sox motifs. Additionally, loss of Sox5 hinders the RGL activation driven by neurogenic stimuli such as environmental enrichment. Altogether, our data suggest that SoxD genes are key mediators in the transition of adult RGLs from quiescence to an activated mitotic state under physiological situations.

The INRAE Centre for Vegetable Germplasm: Geographically and Phenotypically Diverse Collections and Their Use in Genetics and Plant Breeding.

The French National Research Institute for Agriculture, Food and the Environment (INRAE) conserves and distributes five vegetable collections as seeds: the aubergine* (in this article the word aubergine refers to eggplant), pepper, tomato, melon and lettuce collections, together with their wild or cultivated relatives, are conserved in Avignon, France. Accessions from the collections have geographically diverse origins, are generally well-described and fixed for traits of agronomic or scientific interest and have available passport data. In addition to currently conserving over 10,000 accessions (between 900 and 3000 accessions per crop), the centre maintains scientific collections such as core collections and bi- or multi-parental populations, which have also been genotyped with SNP markers. Each collection has its own merits and highlights, which are discussed in this review: the aubergine collection is a rich source of crop wild relatives of Solanum; the pepper, melon and lettuce collections have been screened for resistance to plant pathogens, including viruses, fungi, oomycetes and insects; and the tomato collection has been at the heart of genome-wide association studies for fruit quality traits and environmental stress tolerance.

A transcriptional biosensor to monitor single cancer cell therapeutic responses by bioluminescence microscopy.

When several life-prolonging drugs are indicated for cancer treatment, predictive drug-response tumor biomarkers are essential to guide management. Most conventional biomarkers are based on bulk tissue analysis, which cannot address the complexity of single-cell heterogeneity responsible for drug resistance. Therefore, there is a need to develop alternative drug response predictive biomarker approaches that could directly interrogate single-cell and whole population cancer cell drug sensitivity. In this study, we report a novel method exploiting bioluminescence microscopy to detect single prostate cancer (PCa) cell response to androgen receptor (AR)-axis-targeted therapies (ARAT) and predict cell population sensitivity. Methods: We have generated a new adenovirus-delivered biosensor, PCA3-Cre-PSEBC-ITSTA, which combines an integrated two-step transcriptional amplification system (ITSTA) and the activities of the prostate cancer antigen 3 (PCA3) and modified prostate-specific antigen (PSEBC) gene promoters as a single output driving the firefly luciferase reporter gene. This system was tested on PCa cell lines and on primary PCa cells. Single cells, exposed or not to ARAT, were dynamically imaged by bioluminescence microscopy. A linear discriminant analysis (LDA)-based method was used to determine cell population sensitivities to ARAT. Results: We show that the PCA3-Cre-PSEBC-ITSTA biosensor is PCa-specific and can dynamically monitor single-cell AR transcriptional activity before and after ARAT by bioluminescence microscopy. After biosensor transduction and bioluminescence microscopy single-cell luminescence dynamic quantification, LDA analysis could discriminate the cell populations overall ARAT sensitivity despite heterogeneous single-cell responses. Indeed, the biosensor could detect a significant decrease in AR activity following exposure to conventional ARAT in hormone-naive primary PCa cells, while in castration-resistant PCa patients, treatment response correlated with the observed clinical ARAT resistance. Conclusion: The exploitation of bioluminescence microscopy and multi-promoter transcriptionally-regulated biosensors can aptly define the overall treatment response of patients by monitoring live single cell drug response from primary cancer tissue. This approach can be used to develop predictive biomarkers for drug response in order to help clinicians select the best drug combinations or sequences for each patient.

Attachment and Childhood Maltreatment as Moderators of Treatment Outcome in a Randomized Clinical Trial for Provoked Vestibulodynia.

BACKGROUND: Although distal developmental factors, such as attachment and childhood maltreatment (CM), are associated with the occurrence, severity, and adjustment to provoked vestibulodynia (PVD)-the most prevalent form of vulvodynia-no studies to date have examined whether these variables are related to treatment efficacy in the context of PVD. Attachment and CM may act as moderating variables when examining different treatment modalities, whereby individuals with more insecure attachment orientations (anxiety/avoidance) or a history of CM may benefit less from treatments with higher interpersonal contexts, such as sex and couple therapy-a recommended treatment for PVD. AIM: The present randomized clinical trial (RCT) examined attachment and CM as predictors and moderators of sexual satisfaction, distress, and function at post-treatment and 6-month follow-up while comparing 2 treatments for PVD: Topical lidocaine, and a novel cognitive behavioral couple therapy focused on women's pain and partners' sexuality. METHODS: One hundred eight women with PVD were randomized to a 12-week treatment of either lidocaine or couple therapy. Women completed questionnaires at pretreatment, post-treatment, and at a 6-month follow-up. OUTCOMES: (1) Global Measure of Sexual Satisfaction; (2) Female Sexual Distress Scale-Revised; (3) Female Sexual Function Index. RESULTS: Both attachment and CM were significant moderators of treatment outcomes. At either post-treatment or 6-month follow-up, in the couple therapy condition, women with greater attachment avoidance had poorer outcomes on sexual distress, satisfaction and function, whereas women with higher levels of CM had poorer outcomes on sexual satisfaction and sexual function, compared to women in the lidocaine condition. CLINICAL IMPLICATIONS: Although these novel findings need further replication, they highlight the importance for clinicians to take into account distal factors, for instance, attachment and CM, when treating sexual difficulties such as PVD, as these variables may affect more interpersonal dimensions of treatment (eg, trust, compliance, etc.) and ultimately, treatment progress. STRENGTHS & LIMITATIONS: Using a rigorous RCT study design and statistical approach, this study is the first to examine attachment and CM as moderators in the treatment of sexual difficulties. It is however limited by the use of self-report measures, and further studies are necessary to validate the generalizability of current results to other sexual difficulties. CONCLUSION: Findings support the role of interpersonal factors in the treatment of PVD and indicate that short-term psychological interventions, such as couple therapy, may be less beneficial for women with antecedents of CM and attachment insecurity. V Charbonneau-Lefebvre, M-P Vaillancourt-Morel, NO Rosen, et al. Attachment and Childhood Maltreatment as Moderators of Treatment Outcome in a Randomized Clinical Trial for Provoked Vestibulodynia. J Sex Med 2022;19:479-495.