Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells.

Maintenance of stemness is tightly linked to cell cycle regulation through protein phosphorylation by cyclin-dependent kinases (CDKs). However, how this process is reversed during differentiation is unknown. We report here that exit from stemness and differentiation of pluripotent cells along the neural lineage are controlled by CDC14, a CDK-counteracting phosphatase whose function in mammals remains obscure. Lack of the two CDC14 family members, CDC14A and CDC14B, results in deficient development of the neural system in the mouse and impairs neural differentiation from embryonic stem cells (ESCs). Mechanistically, CDC14 directly dephosphorylates specific proline-directed Ser/Thr residues of undifferentiated embryonic transcription Factor 1 (UTF1) during the exit from stemness, triggering its proteasome-dependent degradation. Multiomic single-cell analysis of transcription and chromatin accessibility in differentiating ESCs suggests that increased UTF1 levels in the absence of CDC14 prevent the proper firing of bivalent promoters required for differentiation. CDC14 phosphatases are dispensable for mitotic exit, suggesting that CDC14 phosphatases have evolved to control stemness rather than cell cycle exit and establish the CDK-CDC14 axis as a critical molecular switch for linking cell cycle regulation and self-renewal.

Spider mite herbivory induces an abscisic acid-driven stomatal defense.

Arthropod herbivory poses a serious threat to crop yield, prompting plants to employ intricate defense mechanisms against pest feeding. The generalist pest two-spotted spider mite (Tetranychus urticae) inflicts rapid damage and remains challenging due to its broad target range. In this study, we explored the Arabidopsis (Arabidopsis thaliana) response to T. urticae infestation, revealing the induction of abscisic acid (ABA), a hormone typically associated with abiotic stress adaptation, and stomatal closure during water stress. Leveraging a FRET-based ABA biosensor (nlsABACUS2-400n), we observed elevated ABA levels in various leaf cell types post-mite feeding. While ABA's role in pest resistance or susceptibility has been debated, an ABA-deficient mutant exhibited increased mite infestation alongside intact canonical biotic stress signaling, indicating an independent function of ABA in mite defense. We established that ABA-triggered stomatal closure effectively hinders mite feeding and minimizes leaf cell damage through genetic and pharmacological interventions targeting ABA levels, ABA signaling, stomatal aperture, and density. This study underscores the critical interplay between biotic and abiotic stresses in plants, highlighting how the vulnerability to mite infestation arising from open stomata, crucial for transpiration and photosynthesis, reinforces the intricate relationship between these stress types.

Gastrointestinal bleeding due to disseminated histoplasmosis in a patient under anti-TNF treatment.

A 62-year-old woman, originally from Peru, with rheumatoid arthritis under treatment with anti-tumor necrosis factor (anti-TNF) therapy, was admitted due to constitutional syndrome and suspicion of neoplasia. Computed tomography (CT) scan revealed involvement of three segments of the colon, ascites, and likely peritoneal implants. Ascitic fluid analysis showed elevated adenosine deaminase (ADA) levels and lymphocytosis. The patient presented with hematemesis and hematochezia with hemodynamic instability. Upper gastrointestinal endoscopy identified an extensive ulcer in the middle esophagus with a granular base, elevated and defined edges, indeterminate for malignancy and without blood residues. Colonoscopy also revealed multiple extensive ulcers in the transverse colon, with whitish bases and thickened and necrotic-looking surrounding mucosal edges. Histology showed granulomas and yeast-like fungal structures with methenamine silver staining in both tissues, consistent with disseminated histoplasmosis. Antifungal treatment was initiated with good clinical evolution.

Evaluation of the transition from intravenous to subcutaneous vedolizumab in patients with inflammatory bowel disease. / Valoración de la transición de vedolizumab intravenoso a subcutáneo en pacientes con enfermedad inflamatoria intestinal.

AIMS: The aim of the study is to evaluate the clinical and biochemical response of inflammatory bowel disease patients treated with vedolizumab, 16 weeks after transitioning from intravenous (iv) to subcutaneous (sc). METHODS: An observational, prospective, single-center cohort study was performed. Patients with inflammatory bowel disease and maintenance treatment with vedolizumab, stable for at least 4 months, were offered to switch to sc formulation. At the same time of treatment administration a blood test was performed, with vedolizumab levels and fecal calprotectin. RESULTS: Forty-three patients were included, 12 of them (27.9%) chose to transition to sc formulation. All included patients remained in remission during follow-up. At week 16 no significant differences were found in terms of calprotectin levels in patients on iv treatment (mean 146.6±SD 45.9) vs. sc (159.26±53.9) (p=0.9). Vedolizumab serum levels at week 16 were higher in the sc group (22,364.3±5141.6) vs. iv (11,425.9±1514.2) (p=0.009). At week 16, 9 (75%) of the patients in the sc group were highly satisfied with the medication and 11 (91.7%) considered it easy to administer. Four patients (12.9%) in the iv group and 2 (16.6%) in the sc group presented mild adverse effects. The 2 cases (100%) of the sc group the adverse event was local inflammation at the injection site. CONCLUSION: In our experience, vedolizumab sc is a convenient alternative to iv administration. Vedolizumab serum levels in patients who transitioned to sc were higher than iv formulation.

Spanish Cross-Cultural Adaptation and Validation of the Kerlan-Jobe Orthopaedic Clinic Shoulder and Elbow Score.

CONTEXT: There are no available questionnaires in Spanish that assess the function and performance of shoulder and elbow in overhead sports. The Kerlan-Jobe Orthopaedic Clinic (KJOC) score is a reference tool for this purpose. We aimed to cross-culturally adapt and investigate its measurement properties in Spanish overhead athletes. DESIGN: Cross-cultural adaptation followed the steps of direct translation, back translation, comprehensibility analysis, and review by the Committee of Experts. Then, symptomatic and asymptomatic overhead athletes were invited to complete an electronic version of the Spanish adaptation (KJOC-Sp). The structural validity was evaluated through an exploratory factor analysis with principal axis factoring. Hypotheses were tested for known-groups and convergent validity, studying the correlation with the Shoulder Pain and Disability Index and the Disabilities of the Arm, Shoulder, and Hand Sports Module questionnaires in symptomatic athletes. Cronbach alpha was calculated for internal consistency and intraclass correlation coefficient (ICC)2,1 for test-retest reliability. Floor and ceiling effects and time to completion were also calculated. RESULTS: The KJOC-Sp maintained the content of the original version and was adapted to the new population. One hundred participants (41 females and 59 males) with a mean age of 22.4 (5.9) years participated in the study of measurement properties. The factor analysis revealed a 1-factor solution. Symptomatic participants scored significantly lower than asymptomatic, with a large effect size (P < .001; r = .67). Correlations were of -.60 (P < .05) with the Shoulder and Pain Disability Index questionnaire and -0.66 (P < .05) with the Disabilities of the Arm, Shoulder, and Hand Sports Module questionnaire. Cronbach alpha was .98 (95% confidence interval, .97-.98) and the ICC2,1 was .96 (95% confidence interval .93-.98). No floor or ceiling effects were observed among the symptomatic athletes, while mean time to completion was 121 seconds. CONCLUSION: The KJOC-Sp is equivalent to the original score, aside from valid and reliable, without floor or ceiling effects in symptomatic athletes and with a low time consumption.

Hydroxynitrile lyase defends Arabidopsis against Tetranychus urticae.

Plant-pest interactions involve multifaceted processes encompassing a complex crosstalk of pathways, molecules, and regulators aimed at overcoming defenses developed by each interacting organism. Among plant defensive compounds against phytophagous arthropods, cyanide-derived products are toxic molecules that directly target pest physiology. Here, we identified the Arabidopsis (Arabidopsis thaliana) gene encoding hydroxynitrile lyase (AtHNL, At5g10300) as one gene induced in response to spider mite (Tetranychus urticae) infestation. AtHNL catalyzes the reversible interconversion between cyanohydrins and derived carbonyl compounds with free cyanide. AtHNL loss- and gain-of-function Arabidopsis plants showed that specific activity of AtHNL using mandelonitrile as substrate was higher in the overexpressing lines than in wild-type (WT) and mutant lines. Concomitantly, mandelonitrile accumulated at higher levels in mutant lines than in WT plants and was significantly reduced in the AtHNL overexpressing lines. After mite infestation, mandelonitrile content increased in WT and overexpressing plants but not in mutant lines, while hydrogen cyanide (HCN) accumulated in the three infested Arabidopsis genotypes. Feeding bioassays demonstrated that the AtHNL gene participated in Arabidopsis defense against T. urticae. The reduced leaf damage detected in the AtHNL overexpressing lines reflected the mite's reduced ability to feed on leaves, which consequently restricted mite fecundity. In turn, mites upregulated TuCAS1 encoding ß-cyanoalanine synthase to avoid the respiratory damage produced by HCN. This detoxification effect was functionally demonstrated by reduced mite fecundity observed when dsRNA-TuCAS-treated mites fed on WT plants and hnl1 mutant lines. These findings add more players in the Arabidopsis-T. urticae interplay to overcome mutual defenses.

The membrane-associated protein 17 (MAP17) is up-regulated in response to empagliflozin on top of RAS blockade in experimental diabetic nephropathy.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to delay diabetic kidney disease (DKD) progression on top of the standard of care with the renin-angiotensin system (RAS) blockade. The molecular mechanisms underlying the synergistic effect of SGLT2i and RAS blockers is poorly understood. We gave a SGLT2i (empagliflozin), an angiotensin-converting enzyme inhibitor (ramipril), or a combination of both drugs for 8 weeks to diabetic (db/db) mice. Vehicle-treated db/db and db/m mice were used as controls. At the end of the experiment, mice were killed, and the kidneys were saved to perform a differential high-throughput proteomic analysis by mass spectrometry using isobaric tandem mass tags (TMT labeling) that allow relative quantification of the identified proteins. The differential proteomic analysis revealed 203 proteins differentially expressed in one or more experimental groups (false discovery rate < 0.05 and Log2 fold change ≥ ±1). Fourteen were differentially expressed in the kidneys from the db/db mice treated with empagliflozin with ramipril. Among them, MAP17 was up-regulated. These findings were subsequently validated by Western blot. The combined therapy of empagliflozin and ramipril up-regulated MAP17 in the kidney of a diabetic mice model. MAP17 is a major scaffolding protein of the proximal tubular cells that places transporters together, namely SGLT2 and NHE3. Our results suggest that SGLT2i on top of RAS blockade may protect the kidney by boosting the inactivation of NHE3 via the up-regulation of key scaffolder proteins such as MAP17.

Endothelin Receptor Antagonists in Kidney Disease.

Endothelin (ET) is found to be increased in kidney disease secondary to hyperglycaemia, hypertension, acidosis, and the presence of insulin or proinflammatory cytokines. In this context, ET, via the endothelin receptor type A (ETA) activation, causes sustained vasoconstriction of the afferent arterioles that produces deleterious effects such as hyperfiltration, podocyte damage, proteinuria and, eventually, GFR decline. Therefore, endothelin receptor antagonists (ERAs) have been proposed as a therapeutic strategy to reduce proteinuria and slow the progression of kidney disease. Preclinical and clinical evidence has revealed that the administration of ERAs reduces kidney fibrosis, inflammation and proteinuria. Currently, the efficacy of many ERAs to treat kidney disease is being tested in randomized controlled trials; however, some of these, such as avosentan and atrasentan, were not commercialized due to the adverse events related to their use. Therefore, to take advantage of the protective properties of the ERAs, the use of ETA receptor-specific antagonists and/or combining them with sodium-glucose cotransporter 2 inhibitors (SGLT2i) has been proposed to prevent oedemas, the main ERAs-related deleterious effect. The use of a dual angiotensin-II type 1/endothelin receptor blocker (sparsentan) is also being evaluated to treat kidney disease. Here, we reviewed the main ERAs developed and the preclinical and clinical evidence of their kidney-protective effects. Additionally, we provided an overview of new strategies that have been proposed to integrate ERAs in kidney disease treatment.

Effectiveness of ultrasound in the differential diagnosis of ileitis detected by computed tomography.

CASE REPORT A 86-year-old man with a recent history of stent placement for infrarenal aortic aneurysm arrives to the emergency department with abdominal pain. Computed tomography (CT) is performed to rule out complications of the endovascular procedure. The CT showed a loop of ileum with decreased caliber, fat trabeculation and hypervascularity causing proximal dilatation. No signs of ischemia or complications related to the prosthesis were observed. He was admitted to our service due to findings of non-specific ileitis. An intestinal ultrasound was performed and revealed a short segment of proximal ileum with pathological wall thickening with an intraluminal birefringent filamentary hyperechoic material (foreign body), which crossed all the layers of the wall. In the following days serial ultrasounds were performed showing that the foreign body remained in the same location and it was decided to perform surgery. During surgery the foreign body turned out to be a blister which conditioned an ileitis. Finally, intestinal resection was performed and the patient presented good clinical evolution. DISCUSSION The most validated technique for the diagnosis of foreign bodies is CT (1). However, intestinal ultrasound could help in its identification, especially for the non-radiopaque ingested material. On the other hand, it is especially useful in the pediatric age, where exposure to ionizing radiation should be avoided (2,3). In our case, it allowed not only to establish the diagnosis immediately but also to evaluate the evolutionary behavior of the same in terms of its mobilization or detection of local complications.

Black esophagus.

A 76-year-old man with multiple cardiovascular risk factors (hypertension, DM2, LD, smoker) and severe peripheral arterial disease (iliofemoral bypass, supracondylar amputation) came to the emergency with coffee ground emesis and mild anemia. Urgent gastroscopy showed diffuse circumferential black mucosa covered by fibrin affecting the middle and distal esophageal third. Acute esophageal necrosis is a rare cause of gastrointestinal bleeding that should be suspected in patients with cardiovascular risk factors with an image of a black esophagus that is abruptly interrupted at the EGJ.

Influence of biologic therapy on cardiovascular risk factors in patients with inflammatory bowel disease. / Influencia del tratamiento biológico en los factores de riesgo cardiovascular de los pacientes con enfermedad inflamatoria intestinal.

INTRODUCTION: Chronic immune-mediated diseases, including inflammatory bowel disease (IBD), present an increased risk of developing early atherosclerosis and cardiovascular events (CVE) at early age. OBJECTIVE: To describe the baseline and 1-year cardiovascular profile of patients with IBD according to the biologic treatment received, taking into account the inflammatory activity. PATIENTS AND METHODS: It is a retrospective, observational study that included 374 patients. Cardiovascular risk factors (CVRF) and CVE were collected at the baseline visit and at one-year follow-up to describe the cardiovascular risk according to the biological treatment received, also assessing clinical and biological remission. RESULTS: A total of 374 patients were included: 146 (38.73%) were treated with Infliximab, 128 (33.95%) with adalimumab, 61 (16.18%) with ustekinumab and 42 (11.14%) with vedolizumab. The changes in blood glucose levels are [86.31mg/dL (84.57-88.06) vs. 89.25mg/dL (87.54-90.96), P=.001] for those treated with antiTNFα and [86.52mg/dL (83.48-89.55) vs. 89.44mg/dL (85.77-93.11), P=.11] in the other group. In the group treated with antiTNFα total cholesterol values at baseline visit are [169.40mg/dL (164.97-173.83) vs. 177.40mg/dL (172.75-182.05) at one year of treatment, P=<.001], those of HDL [50.22mg/dL (48.39-52.04) vs. 54.26mg/dL (52.46-56.07), P=<.001] and those of triglycerides [114.77mg/dL (106.36-123.18) vs. 121.83mg/dL (112.11-131.54), P=.054]. Regarding weight, an increase was observed, both in those patients treated with antiTNFα [71.39kg (69.53-73.25) vs. 72.87kg (71.05-74.70), P<.001], and in the group treated with ustekinumab and vedolizumab [67.59kg (64.10-71.08) vs. 69.43kg (65.65-73.04), P=.003]. Concerning CVE, no significant differences were observed neither according to the drug used (p=0.36), nor according to personal history of CVE (P=.23) nor according to inflammatory activity (P=.46). CONCLUSIONS: Our results on a real cohort of patients with IBD treated with biologic drugs show a better control of certain cardiovascular parameters such as CRP or HDL, but a worsening of others such as total cholesterol or triglycerides, regardless of the treatment. Therefore, it is possibly the disease control and not the therapeutic target used, the one that affect the cardiovascular risk of these patients.

Pdx1 Is Transcriptionally Regulated by EGR-1 during Nitric Oxide-Induced Endoderm Differentiation of Mouse Embryonic Stem Cells.

The transcription factor, early growth response-1 (EGR-1), is involved in the regulation of cell differentiation, proliferation, and apoptosis in response to different stimuli. EGR-1 is described to be involved in pancreatic endoderm differentiation, but the regulatory mechanisms controlling its action are not fully elucidated. Our previous investigation reported that exposure of mouse embryonic stem cells (mESCs) to the chemical nitric oxide (NO) donor diethylenetriamine nitric oxide adduct (DETA-NO) induces the expression of early differentiation genes such as pancreatic and duodenal homeobox 1 (Pdx1). We have also evidenced that Pdx1 expression is associated with the release of polycomb repressive complex 2 (PRC2) and P300 from the Pdx1 promoter; these events were accompanied by epigenetic changes to histones and site-specific changes in the DNA methylation. Here, we investigate the role of EGR-1 on Pdx1 regulation in mESCs. This study reveals that EGR-1 plays a negative role in Pdx1 expression and shows that the binding capacity of EGR-1 to the Pdx1 promoter depends on the methylation level of its DNA binding site and its acetylation state. These results suggest that targeting EGR-1 at early differentiation stages might be relevant for directing pluripotent cells into Pdx1-dependent cell lineages.

Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice.

Treatments with sodium-glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin-angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.

Comparative transcriptomics reveals hidden issues in the plant response to arthropod herbivores.

Plants experience different abiotic/biotic stresses, which trigger their molecular machinery to cope with them. Besides general mechanisms prompted by many stresses, specific mechanisms have been introduced to optimize the response to individual threats. However, these key mechanisms are difficult to identify. Here, we introduce an in-depth species-specific transcriptomic analysis and conduct an extensive meta-analysis of the responses to related species to gain more knowledge about plant responses. The spider mite Tetranychus urticae was used as the individual species, several arthropod herbivores as the related species for meta-analysis, and Arabidopsis thaliana plants as the common host. The analysis of the transcriptomic data showed typical common responses to herbivory, such as jasmonate signaling or glucosinolate biosynthesis. Also, a specific set of genes likely involved in the particularities of the Arabidopsis-spider mite interaction was discovered. The new findings have determined a prominent role in this interaction of the jasmonate-induced pathways leading to the biosynthesis of anthocyanins and tocopherols. Therefore, tandem individual/general transcriptomic profiling has been revealed as an effective method to identify novel relevant processes and specificities in the plant response to environmental stresses.

Clock Genes Disruption in the Intensive Care Unit.

BACKGROUND: Intensive care unit (ICU) environment disrupts the circadian rhythms due to environmental and other nonphotic synchronizers. The main purpose of this article is to establish whether critically patients have desynchronization at the molecular level after 1 week of stay in the ICU. METHODS: The rhythm of Clock, Bmal1, Cry1, and Per2 genes in neuro-ICU patients (n = 11) on the first day after admission in the unit (1 day) and 1 week later (1 week) was studied, 4 time points throughout the day, at 6, 12, 18, and 24 hours. Human whole blood samples were obtained from neuro-ICU patients. The total RNA was isolated and each sample was reverse transcribed to complementary DNA and quantitative polymerase chain reaction (PCRq) was performed. The possible rhythm was studied using Fourier Series. RESULTS: After 1 week, the clock gene rhythmicity completely disappeared. Messenger RNA (mRNA) expression for the 4 clock genes was shown rhythmicity at the first day after admission in the ICU. Circadian rhythmicity for none of them was observed but rather, ultradian rhythmicity was found. The expression of Clock, Bmal1, and Per2 mRNA after 1 week was similar in the 4-time point studies without significant fluctuation among the 4 time points analyzed. DISCUSSION: Rhythmic mRNA expression is present at the first day after admission in the ICU. However, ICU stay during 1 week affects the molecular machinery of the biological clock generating chronodisruption. Circadian disruption is associated with the risk of several pathologies, thus, it seems to be clear that ICU stay in constant conditions could adversely affect patient evolution and probably, circadian resynchronization restoring clock gene expression could lead to a better clinical evolution of the patient. CONCLUSIONS: Clock genes disruption is observed in neuro-ICU patients. Light therapy as well as melatonin treatment could reduce the impact of ICU stay period in biological clock, thereby improving patients' recovery.

Tin and silver recovery from wave soldering dross.

This work proposes a method for the recovery of tin and silver from wave soldering dross produced during the manufacture of printed circuit boards. Samples of wave soldering dross were first subjected to carbothermic reduction to obtain an ingot containing the above metals plus other elements. This ingot was then subjected to electrorefining at different densities of electrical current, electrolyte flow rate, and cathode-anode separation distance, to determine the optimum conditions for recovering pure tin. Under such conditions, 82 wt% of the tin in the ingot was recovered at a purity of 99.94%. After subjecting ingots to continuous electrorefining under optimum conditions for 845 h, the slime collected at the anode was removed for the recovery of silver. This slime was subjected to thin-layer leaching with concentrated nitric acid. The leachate produced was subjected to copper-cementation; the silver adhering to the copper rod was collected by washing. This process recovered 92% of the silver in the wave soldering dross ingot at a purity of >99.6%. Some 99% of the copper entering the leachate from the copper rod during cementation was recovered by liquid-liquid extraction with 40% LIX84 (dissolved in EXXOL D100). This method could provide a rapid, inexpensive means of recovering pure tin and silver from wave soldering dross.

Applicability of in vitro methods to study patulin bioaccessibility and its effects on intestinal membrane integrity.

In human health risk assessment, ingestion of food is considered a major route of exposure to many contaminants, although the total amount of an ingested contaminant (external dose) does not always reflect the quantity available for the body (internal dose). In this study, two in vitro methods were applied to study bioaccessibility and intestinal membrane integrity of cells exposed to patulin, a mycotoxin with significant public health risk. Seven artificially contaminated fruit juices were assayed in the presence or absence of a standard meal, showing a significant difference for bioaccessibility values between contaminated samples alone (mean 27.65 ± 13.50%) and combinations with a standard meal (mean 7.89 ± 4.03%). Different concentrations of patulin (PAT) and cysteine (CYS) (protector agent) were assayed in Caco-2 cells monolayers. At 95 µM, PAT produced a marked decrease in transepithelial electrical resistance (TEER). This effect was significantly reduced when 400 µM and 4000 µM CYS was added to the cells. Combined use of in vitro digestion models with other techniques using intestinal cell lines, such as in vitro intestinal absorption models that use Caco-2 cells, may offer a more comprehensive model of what is occurring during digestion and absorption processes. The study of beneficial effects of protective agents would also be enhanced.

Incidence and Course of Joint Inflammation Associated with Inflammatory Bowel Disease in Patients Undergoing Treatment with Vedolizumab/Ustekinumab: The VEDUSTAR Study.

BACKGROUND: The role of ustekinumab (UST) and vedolizumab (VDZ) in the extraintestinal joint manifestations of inflammatory bowel disease (IBD) remain unclear, and most existing studies are retrospective. The aim of this prospective study was to analyze the incidence of new-onset joint disease or the worsening of pre-existing IBD-associated joint disease in patients treated with UST and VDZ. METHODS: The study population comprised IBD patients with previous spondyloarthritis (SpA) or new-onset arthropathy undergoing treatment with VDZ or UST. RESULTS: Eighty patients were referred to rheumatology because of previous SpA or onset of symptoms. Most patients (90%) were anti-TNF experienced. Two patients with previous SpA (2/22; 9%) experienced a flare-up (one with UST and one with VDZ), and two patients with VDZ developed SpA during follow-up (2/58; 3%). Only one of these four patients did not have gastrointestinal symptoms, and VDZ was discontinued because of joint symptoms. The other three patients had concomitant intestinal activity, and treatment was not discontinued. CONCLUSION: Our experience shows that treatment with UST and VDZ did not worsen joint disease in patients with SpA. Most remained stable or improved. In addition, poor control of IBD in patients with joint flare-ups could be the main cause of worsening SpA.

The biobehavioural pain and movement questionnaire (BioPMovQ): development and psychometric validation of a new questionnaire.

Objective: The purpose of this research was to design and psychometrically validate a new instrument (the Biobehavioural Pain and Movement Questionnaire/BioPMovQ), which assesses the relationship between pain and various factors related to motor behaviour from a biobehavioural perspective. Methods: A mixed-method design combining a qualitative study with an observational and cross-sectional study was employed to develop (content validity) and psychometrically validate (construct validity, reliability and concurrent/discriminant validity) a new instrument. A total of 200 patients with chronic musculoskeletal pain were recruited. Results: According to the exploratory factor analysis, the final version of the BioPMovQ consists of 16 items distributed across 4 subscales (1, disability, 2, self-efficacy for physical activity; 3, movement avoidance behaviours; and 4, self-perceived functional ability), all with an eigen value greater than 1, explaining 55.79% of the variance. The BioPMovQ showed high internal consistency (Cronbach's α = 0.82; McDonald's ω = 0.83). The intraclass correlation coefficient was 0.86 (95% confidence interval 0.76 to 0.91), which was considered to demonstrate excellent test-retest reliability. The standard error of measurement and minimal detectable change were 3.43 and 8.04 points, respectively. No floor or ceiling effects were identified. There was a positive, significant and moderate magnitude correlation with the Graded Chronic Pain Scale (r = 0.54), kinesiophobia (r = 0.60), pain catastrophising (r = 0.44) and chronic pain self-efficacy (r = -0.31). Conclusion: The BioPMovQ showed good psychometric properties. Based on the findings of this study, the BioPMovQ can be used in research and clinical practice to assess patients with chronic musculoskeletal pain.

Ranking COMMPS chemical substances by an improved POT/RLE approach.

The combined monitoring-based and modeling-based priority setting (COMMPS) provides a procedure for the identification of priority hazardous substances outlined in the Working Document (ENV/191000/01 of January 16, 2001). This procedure is based on scoring a set of criteria which individually make substances more or less hazardous. The way scores are weighted and combined has been established by a panel of experts. Different authors outlined how such a procedure might be affected by subjectiveness of judgment, and alternative solutions based on partial order theory (POT) and random linear extensions (RLE) have been suggested. This method consists of generating a set of RLE and of averaging the rank given to each substance, so that a total order could be determined. Any POT/RLE approach must face the issue of covering as much as possible the space of linear extensions that, in the case of the 85 substances considered by COMMPS, becomes extremely large, and an exhaustive generation of linear extension is not feasible. Therefore, having a faster algorithm would help to consider a larger number of linear extensions in a given time frame. In this paper, we discuss this problem, and we outline a possible solution.