Predicting mucosal inflammation in IBD patients using patient-reported symptom scores and a faecal calprotectin home test: protocol for a multicentre prospective validation study.

INTRODUCTION: Crohn's disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) with a relapsing-remitting nature. With adequate non-invasive prediction of mucosal inflammation, endoscopies can be prevented and treatment optimised earlier for better disease control. We aim to validate and recalibrate commonly used patient-reported symptom scores combined with a faecal calprotectin (FC) home test as non-invasive diagnostic tool for remote monitoring of IBD, both in daily practice and in a strict trial setting. Endoscopy will be used as the gold standard. METHODS AND ANALYSIS: In this multicentre prospective validation study, adult IBD patients are asked to fill out questionnaires regarding disease activity (Monitor IBD At Home, mobile Health Index, Manitoba IBD Index, IBD control and patient-HBI/patient-Simple Clinical Colitis Activity Index), perform a FC home test and collect a stool sample for routine laboratory FC measurement, before the start of the bowel preparation for the ileocolonoscopy. Endoscopic disease activity will be scored according to the simplified endoscopic score for Crohn's disease (CD) for CD patients or Ulcerative Colitis Endoscopic Index for Severity and Mayo Endoscopic Subscore for ulcerative colitis patients. The main study outcome is the diagnostic test accuracy of the various patient-reported scores to assess mucosal inflammation in combination with a FC home test. ETHICS AND DISSEMINATION: This study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 03 March 2021 (METC 20-085) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT05886322.

Minimally modified human blood coagulation factor X to bypass direct factor Xa inhibitors.

BACKGROUND: Direct oral factor (F)Xa inhibitors are widely used as alternatives to conventional vitamin K antagonists in managing venous thromboembolism and nonvalvular atrial fibrillation. Unfortunately, bleeding-related adverse events remain a major concern in clinical practice. In case of bleeding or emergency surgery, rapid-onset reversal agents may be required to counteract the anticoagulant activity. OBJECTIVES: The ability of FXa variants to bypass the direct oral FXa inhibitors was assessed. METHODS: Human FXa variants were generated through substitution of phenylalanine 174 (F174) for either alanine, isoleucine, or serine. FXa variants were stably expressed in HEK293 cells and purified to homogeneity using ion-exchange chromatography. RESULTS: F174-substituted human FX variants demonstrated efficacy in restoring thrombin generation in plasma containing direct FXa inhibitors (apixaban, rivaroxaban, edoxaban). Their ability to bypass the anticoagulant effects stems from a significantly reduced sensitivity for the direct FXa inhibitors due to a decrease in binding affinity determined using molecular dynamics simulations and free energy computation. Furthermore, F174 modification resulted in a partial loss of inhibition by tissue factor pathway inhibitor, enhancing the procoagulant effect of F174-substituted FX. Consequently, the F174A- and F174S-substituted FX variants effectively counteracted the effects of 2 widely used anticoagulants, apixaban and rivaroxaban, in plasma of atrial fibrillation and venous thromboembolism patients. CONCLUSION: These human FX variants have the potential to serve as a rescue reversal strategy to overcome the effect of direct FXa inhibitors in case of life-threatening bleeding events or emergency surgical interventions.

The association between vaginal hygiene practices and spontaneous preterm birth: A case-control study.

BACKGROUND: Spontaneous preterm birth (SPTB) is a major cause of neonatal morbidity and mortality worldwide and defining its risk factors is necessary to reduce its prevalence. Recent studies have pointed out that bacterial vaginosis, a disturbance in the vaginal microbiome, is associated with SPTB. It is hypothesized that vaginal hygiene practices can alter the vaginal microbiome and are therefore associated with SPTB, but there are no studies investigating this matter. METHODS AND FINDINGS: A case-control study was conducted between August 2018 and July 2021 in two affiliated university medical centers in Amsterdam, the Netherlands. We included a total of 79 women with a SPTB and compared them with 156 women with a term birth. Women with uterine anomalies, a history of cervical surgery or major congenital anomalies of the fetus were excluded. All participants filled in a questionnaire about vaginal washing with water, soap or gel, the use of intravaginal douches and vaginal steaming, both before and during pregnancy. Most women washed vaginally with water, 144 (61.3%) women before pregnancy and 135 (57.4%) women during pregnancy. A total of 43 (18.3%) washed with soap before and 36 (15.3%) during pregnancy. Before pregnancy, 40 (17.0%) women washed with vaginal gel and 27 (11.5%) during pregnancy. We found that the use of vaginal gel before pregnancy (aOR 2.29, 95% CI: 1.08-4.84) and even more during pregnancy, was associated with SPTB (aOR 3.45, 95% CI: 1.37-8.67). No association was found between washing with water or soap, intravaginal douching, or vaginal steaming and SPTB. CONCLUSIONS: Our findings suggest that the use of vaginal gel is associated with SPTB. Women should be informed that vaginal use of gels might not be safe.

Control Crohn Safe with episodic adalimumab monotherapy as first-line treatment study (CoCroS): study protocol for a randomised controlled trial.

INTRODUCTION: Crohn's disease (CD) is a chronic inflammatory bowel disease with a heterogeneous clinical presentation, relapse rate and treatment response. At present, no markers are available to adequately predict disease course at diagnosis. To prevent overtreatment of patients with a relative mild disease course, a step-up approach starting with corticosteroids is usually applied. Timely introduction of potentially disease modifying drugs and tight control of mucosal inflammation are crucial to prevent disease-related complications in patients with a complex disease course. We hypothesise that episodic treatment with adalimumab monotherapy in combination with close monitoring after drug discontinuation improves long-term outcome and reduces drug-related side effects, while preventing overtreatment. METHODS AND ANALYSIS: In this pragmatic multicentre randomised controlled trial, newly diagnosed CD patients or CD patients with a flare, naïve to thiopurines and biologicals, will be included and randomised 1:1 to open-label episodic (ie, 24 weeks) adalimumab monotherapy or step-up care starting with corticosteroids. The primary outcome is the number of yearly quarters of corticosteroid free clinical (Monitor Inflammatory Bowel Disease At Home score ≤3) and biochemical (C reactive protein within normal range and faecal calprotectin ≤200 µg/g) remission at week 96. Secondary outcomes are total healthcare costs, cumulative corticosteroid dose, proportion of patients with endoscopic remission at week 24, corticosteroid-free clinical remission, time to remission and patient-reported outcome measures on quality of life, (work) disability and treatment adherence. Safety outcomes are drug-related and disease-related adverse events and disease progression on MRI-enterography at week 96. ETHICS AND DISSEMINATION: This study is approved by the Medical Research Ethics Committee of azM/UM in Maastricht dated 21 August 2019 (METC18-076) and is monitored by the Clinical Trial Centre Maastricht according to Good Clinical Practice guidelines. Written informed consent will be obtained from all patients. Study results will be published in international peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT03917303.

Bilateral breast implant associated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): A case report.

INTRODUCTION: An estimated 30.000 breast implants are placed in the Netherlands annually. An increasing amount of reports have linked implants to the rare anaplastic large cell lymphoma (ALCL). Other implant-related lymphomas, such as those of B-cell lineage, are much rarer. PRESENTATION OF CASE: A 62-year-old female presented with pain and Baker grade III capsular contraction of the right breast. Subpectorally placed textured anatomical implants had been in situ for 26 years after cosmetic augmentation. Magnetic Resonance Imaging (MRI) showed bilateral implant leakage. Explantation of both implants confirmed bilateral leakage after which symptoms went into remission. Three months later our patient noticed an erythematous area, scar swelling and serous fluid leakage on the lateral side of the inframammary fold of the right breast. Siliconomas were excised bilaterally together with a partial capsulectomy on the left. Histopathology and immunohistochemical analysis showed monotonous small cell B-lymphocytic infiltration (CD20+, CD5+, CD23+, ALK-) in both capsules, highly suggestive for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). DISCUSSION: CLL/SLL are classified as nearly the same disease. The primary difference is the localization; CLL is found the bone marrow and blood whereas SLL is predominantly in the lymph nodes and spleen. There are no previous descriptions of bilateral CLL/SLL found in periprosthetic capsules. CONCLUSION: Breast implants are increasingly linked to various malignancies. In most cases, including our patient, implant explantation together with long-term follow-up suffices. MRI yields additional value in early stage diagnosis. More research is required to further optimize multidisciplinary care and improve patient outcomes.

Higher Plasma Sclerostin and Lower Wnt Signaling Gene Expression in White Adipose Tissue of Prediabetic South Asian Men Compared with White Caucasian Men.

BACKGROUND: South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is associated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians. METHODS: Ten Dutch South Asian men with prediabetes and overweight or obesity and 10 matched Dutch white Caucasians were included. Blood samples were assayed for the Wnt inhibitor sclerostin. Subcutaneous white adipose tissue (WAT) and skeletal muscle biopsies were assayed for Wnt and insulin signaling gene expression with quantitative reverse transcription polymerase chain reaction (Clinicaltrials.gov NCT02291458). RESULTS: Plasma sclerostin was markedly higher in South Asians compared with white Caucasians (+65%, P<0.01). Additionally, expression of multiple Wnt signaling genes and key insulin signaling genes were lower in WAT in South Asians compared with white Caucasians. Moreover, in WAT in both ethnicities, Wnt signaling gene expression strongly positively correlated with insulin signaling gene expression. In skeletal muscle, WNT10B expression in South Asians was lower, but expression of other Wnt signaling and insulin signaling genes was comparable between ethnicities. Wnt and insulin signaling gene expression also positively correlated in skeletal muscle, albeit less pronounced. CONCLUSION: South Asian men with overweight or obesity and prediabetes have higher plasma sclerostin and lower Wnt signaling gene expression in WAT compared with white Caucasians. We interpret that reduced Wnt signaling could contribute to impaired insulin signaling in South Asians.

Long-Term Follow-Up Study of Young Adults Treated for Unilateral Complete Cleft Lip, Alveolus, and Palate by a Treatment Protocol Including Two-Stage Palatoplasty: Speech Outcomes.

BACKGROUND: No consensus exists on the optimal treatment protocol for orofacial clefts or the optimal timing of cleft palate closure. This study investigated factors influencing speech outcomes after two-stage palate repair in adults with a non-syndromal complete unilateral cleft lip and palate (UCLP). METHODS: This was a retrospective analysis of adult patients with a UCLP who underwent two-stage palate closure and were treated at our tertiary cleft centre. Patients ≥17 years of age were invited for a final speech assessment. Their medical history was obtained from their medical files, and speech outcomes were assessed by a speech pathologist during the follow-up consultation. RESULTS: Forty-eight patients were included in the analysis, with a mean age of 21 years (standard deviation, 3.4 years). Their mean age at the time of hard and soft palate closure was 3 years and 8.0 months, respectively. In 40% of the patients, a pharyngoplasty was performed. On a 5-point intelligibility scale, 84.4% received a score of 1 or 2; meaning that their speech was intelligible. We observed a significant correlation between intelligibility scores and the incidence of articulation errors (P<0.001). In total, 36% showed mild to moderate hypernasality during the speech assessment, and 11%-17% of the patients exhibited increased nasalance scores, assessed through nasometry. CONCLUSIONS: The present study describes long-term speech outcomes after two-stage palatoplasty with hard palate closure at a mean age of 3 years old. We observed moderate long-term intelligibility scores, a relatively high incidence of persistent hypernasality, and a high pharyngoplasty incidence.

Adnexal masses in children, adolescents and women of reproductive age in the Netherlands: A nationwide population-based cohort study.

OBJECTIVE: To provide an accurate incidence of adnexal masses in children and young women which can significantly improve the performance of current risk prediction models. METHODS: We used the PALGA database, a nationwide network and registry of histopathology and cytopathology, as the primary source of our study. Reports on ovarian histology of girls, years 1991-2014, and women aged 21-39, years 2011-2013, were included. Reports were labeled using the WHO-classification and classified as benign, borderline malignant, or malignant. Surgical procedure was scored separately. RESULTS: Included were 11,595 patients. The incidence of adnexal masses increased exponentially with age, from 0.43 per 100,000womenyears at age 1 to 152 per 100,000womenyears at age 35. A (borderline) malignancy was found in 898 (7.7%) patients, ratios between benign and malignant masses varied with age and were lowest in premenarchal children. Histology varied widely with surface epithelial tumors (35.1%), germ cell tumors (29.8%), and other cysts, tumors and tumorlike lesions (32.8%) being evenly distributed while sex cord stromal tumors were rare and only represented 2.3%. The proportion of malignancies was 6.3% in germ cell tumors while the type of malignant germ cell tumor was dependent on age. Oophorectomy was more often performed in the premenarchal age group and in women approaching the end of their reproductive age. CONCLUSION: Our results show that adnexal masses in different age groups do not only differ in histological subgroups but also in malignancy rate which is of high value in presurgical risk evaluation.

Insulin-like growth factor 1 receptor expression and IGF1R 3129G > T polymorphism are associated with response to neoadjuvant chemotherapy in breast cancer patients: results from the NEOZOTAC trial (BOOG 2010-01).

BACKGROUND: The insulin-like growth factor 1 (IGF-1) pathway is involved in cell growth and proliferation and is associated with tumorigenesis and therapy resistance. This study aims to elucidate whether variation in the IGF-1 pathway is predictive for pathologic response in early HER2 negative breast cancer (BC) patients, taking part in the phase III NEOZOTAC trial, randomizing between 6 cycles of neoadjuvant TAC chemotherapy with or without zoledronic acid. METHODS: Formalin-fixed paraffin-embedded tissue samples of pre-chemotherapy biopsies and operation specimens were collected for analysis of IGF-1 receptor (IGF-1R) expression (n = 216) and for analysis of 8 candidate single nucleotide polymorphisms (SNPs) in genes of the IGF-1 pathway (n = 184) using OpenArray® RealTime PCR. Associations with patient and tumor characteristics and chemotherapy response according to Miller and Payne pathologic response were performed using chi-square and regression analysis. RESULTS: During chemotherapy, a significant number of tumors (47.2 %) showed a decrease in IGF-1R expression, while in a small number of tumors an upregulation was seen (15.1 %). IGF-1R expression before treatment was not associated with pathological response, however, absence of IGF-1R expression after treatment was associated with a better response in multivariate analysis (P = 0.006) and patients with a decrease in expression during treatment showed a better response to chemotherapy as well (P = 0.020). Moreover, the variant T allele of 3129G > T in IGF1R (rs2016347) was associated with a better pathological response in multivariate analysis (P = 0.032). CONCLUSIONS: Absent or diminished expression of IGF-1R after neoadjuvant chemotherapy was associated with a better pathological response. Additionally, we found a SNP (rs2016347) in IGF1R as a potential predictive marker for chemotherapy efficacy in BC patients treated with TAC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01099436 . Registered April 6, 2010.

Microfractionation revisited: a 1536 well high resolution screening assay.

The aim of the here presented study was to combine high performance liquid chromatography with plate reader technology in order to overcome certain drawbacks of integrated online systems as well as offline plate reader approaches. The described method combines an "at-line" enzyme assay for the simultaneous bioactivity determination with parallel QTOF MS data acquisition for analyte identification. All biochemical reagents are added in an online mode directly to the column effluent (postcolumn addition/mixing), and the complete screening assay mixture is subsequently microfractionated into a 1536 well plate. The screening of a natural extract fortified with two well-known Protein Kinase A inhibitors and the identification of an inhibitor in a natural extract showed the applicability of the approach to detect bioactive compounds in low concentrations in a complex mixture. The described mode of operation utilizes today's plate reader technology to its full capacity and directly hyphenates it to a high resolution separation technique which has not been shown before. Furthermore, it allows coupling of a microbore HPLC with a biochemical screening assay without compromising resolution and overcomes problems associated with the 1536 well format.