Identifying Candidate Biomarkers of Clinical Response to Ustekinumab in Psoriasis

The development and use of biologic drugs, including ustekinumab, secukinumab, adalimumab and newer anti-interleukin (IL)-23p19 biologics, have revolutionised treatment for the immune-mediated inflammatory skin disease, psoriasis. Ustekinumab targets the shared IL-12/IL-23p40 subunit, while anti-IL-23p19 biologics target the specific IL-23p19 subunit. Both forms of biologics prevent the binding of IL-23 to its receptor, inhibiting the translocation of Signal Transducer and Activator of Transcription 3 (STAT3) and downstream IL-17A expression. In turn, secukinumab blocks IL-17A and adalimumab blocks tumour necrosis factor (TNF). Although highly effective, clinical response is variable with up to 30% of patients failing to achieve a satisfactory clinical response, namely a 75% reduction in Psoriasis Area Severity Index (PASI75). Hence, there is a need to identify predictive biomarkers of response to biologics.Mechanistic biomarkers i.e., associated with the drug’s mechanism of action, are considered more accurate biomarkers. Moreover, their identification in the blood would prove advantageous as they would be easy-to-access and implement in clinical settings. Therefore, we hypothesized that biomarkers predictive of response to biologics targeting the IL-23/IL-17A axis could be identified among IL-23-responsive cells within peripheral blood mononuclear cells (PBMCs).As a first step, we developed an imaging-flow cytometry assay to quantify IL-23-induced STAT3 translocation in healthy volunteer PBMCs and identified mucosal-associated invariant T (MAIT) cells and CD8+CCR6+CD161+Vα7.2- T cells to be IL-23-responsive. Next, we identified the optimum IL-23 concentration to induce STAT3 translocation and established a threshold to reproducibly define positive translocation. Additionally, we confirmed the robustness of this assay by measuring STAT3 translocation in PBMCs over time with no fluctuations.Having optimised an experimental assay, we measured IL-23-induced STAT3 translocation in PBMCs of psoriasis patients before (baseline week (Wk)0) and during (Wk1, Wk4 and Wk12) ustekinumab therapy. Clinical response was assessed as PASI75 and residual disease at Wk12. Within MAIT cells, STAT3 translocation was significantly lower in PASI75 non-responders compared to responders at Wk0 (p&lt;0.05, FDR&lt;0.05) and highly predictive of PASI75 outcome in Receiver Operating Characteristic (ROC) curve analysis, yielding 87.5% specificity and 100% sensitivity.To investigate a clinically scalable alternative to STAT3 translocation as a predictive biomarker, we measured cytokine production in PBMCs of ustekinumab-treated psoriasis patients. The frequency of IL-17A-producing CD8+ T cells significantly decreased after Wk12 of ustekinumab treatment in PASI75 responders (p&lt;0.05), but not in non-responders. However, no differences with potential predictive value were identified at Wk0.After identifying IL-23-induced STAT3 translocation as a potential biomarker predictive of response to ustekinumab, we also assessed STAT3 translocation in psoriasis patients prior receiving treatment with adalimumab and secukinumab. We observed no difference in STAT3 translocation between adalimumab PASI75 non-responders and responders. However, STAT3 translocation was significantly lower (p&lt;0.05) in MAIT cells of secukinumab PASI75 non-responders than responders at Wk0. Next, we validated IL-23-induced STAT3 translocation as a predictive biomarker by applying the previously determined ROC cut-off to an independent ustekinumab-treated patient cohort.Finally, we investigated the ability of IL-23-induced STAT3 translocation to predict clinical response to newer anti-IL-23p19 biologics. PASI75 clinical response was accurately predicted in 8/10 patients undergoing treatment with anti-IL23p19 biologics, highlighting the predictive potential of this biomarker in the context of newer biologics targeting IL-23.Taken together, we have identified IL-23-induced STAT3 translocation in MAIT cells as a candidate predictive biomarker of response to biologics targeting the IL-23/IL-17 axis. Future work should involve refining the clinical feasibility of this biomarker by investigating STAT3 phosphorylation as an alternative. Finally, this biomarker has potential for further validation in clinical trials, with the aim to be utilised for patient stratification.<br/

Multimodal Pain Management for Older Adults in Primary Care

Persistent pain affects 50% to 75% of adults of the age of 65 and it is often underreported and undertreated in primary care. This manuscript discusses how nurse practitioners and other primary care providers can manage persistent pain in older adults utilizing nonpharmacological methods in addition to standard pharmacological treatments

Safe Injection Facilities in the Tenderloin: Starting with Operational Plans

There are over 90 safe injection facilities (SIFs) in at least 11 countries around the world, except in the United States. SIFs are spaces where people who inject drugs (PWID) can bring their pre-obtained drugs in a hygienic space and use them under supervision. The goal of these sites is to reduce the harmful effects of injection drug use and refer PWID to other medical, social, and treatment services. The Safer Inside Coalition, a community-driven health initiative, in the Tenderloin district of San Francisco recommended opening a SIF in the Tenderloin to improve the health of the community and individual drug users. The purpose of this project was to develop an operational plan for a SIF. Based on a literature review and coalition meetings, two operational plan models were developed – a centralized model and an integrated model. These were compiled in a report for community organizations to review to assess feasibility of implementing these services in the Tenderloin district. Further development needs to be done to work out more specific details based on the model that is chosen and the needs of the community

The molecular mechanisms of duodenal and placental iron absorption during pregnancy

During pregnancy duodenal iron absorption, placental transfer, and the release of iron from stores in the mothers liver, are increased to meet the requirements of the developing foetus. The regulatory mechanisms co-ordinating these events are for the first time illustrated here. Various proteins, notably hepcidin and hfe, have been implicated as having a role in iron homeostasis. By quantitating the expression of hepcidin and the duodenal iron transporters: DMT1, Tfr1, Dcytb and Ireg1, in mice raised on iron-deficient and iron-loaded diets, this study confirms that hepcidin expression is positively regulated by body iron status and negatively regulates duodenal DMTI. A parallel study in hfe knockout mice, demonstrates inappropriately low hepcidin expression and elevated duodenal DMT1 levels. This provides a possible explanation for the liver iron loading characteristic of hereditary haemochromatosis. The expression of hepcidin is studied in pregnant rats and is shown to decrease during the final trimester when duodenal and placental iron transfer is maximal. This decrease is preceded by a reduction in liver iron stores and subsequent reduction in hepcidin expression. Iron supplementation to pregnant dams, increases liver iron status and hepcidin expression, this corresponds with a decrease in duodenal and placental DMT1 expression, whilst iron deficiency during this period, increases both duodenal and placental uptake. This implies that the increase in duodenal iron absorption observed during pregnancy is, at least in part, a consequence of reduced liver iron stores. Using an in vitro model of the placental syncytiotrophoblast, DMT1 is localised to endosomal compartments, but not co-localised with either Tfr1 or Ireg1. Hepcidin is demonstrated to bind to the plasma membrane of these cells and reduce the uptake of diferric-transferrin. These results provide new insight into the molecular processes of iron homeostasis and implicate a regulatory role for hepcidin, not only in duodenal, but also in placental iron uptake

Patterns of inflammation, microstructural alterations, and sodium accumulation define multiple sclerosis subtypes after 15 years from onset

MRI; Machine learning; Multiple sclerosisRessonància magnètica; Aprenentatge automàtic; Esclerosi múltipleResonancia magnética; Aprendizaje automático; Esclerosis múltipleIntroduction: Conventional MRI is routinely used for the characterization of pathological changes in multiple sclerosis (MS), but due to its lack of specificity is unable to provide accurate prognoses, explain disease heterogeneity and reconcile the gap between observed clinical symptoms and radiological evidence. Quantitative MRI provides measures of physiological abnormalities, otherwise invisible to conventional MRI, that correlate with MS severity. Analyzing quantitative MRI measures through machine learning techniques has been shown to improve the understanding of the underlying disease by better delineating its alteration patterns. Methods: In this retrospective study, a cohort of healthy controls (HC) and MS patients with different subtypes, followed up 15 years from clinically isolated syndrome (CIS), was analyzed to produce a multi-modal set of quantitative MRI features encompassing relaxometry, microstructure, sodium ion concentration, and tissue volumetry. Random forest classifiers were used to train a model able to discriminate between HC, CIS, relapsing remitting (RR) and secondary progressive (SP) MS patients based on these features and, for each classification task, to identify the relative contribution of each MRI-derived tissue property to the classification task itself. Results and discussion: Average classification accuracy scores of 99 and 95% were obtained when discriminating HC and CIS vs. SP, respectively; 82 and 83% for HC and CIS vs. RR; 76% for RR vs. SP, and 79% for HC vs. CIS. Different patterns of alterations were observed for each classification task, offering key insights in the understanding of MS phenotypes pathophysiology: atrophy and relaxometry emerged particularly in the classification of HC and CIS vs. MS, relaxometry within lesions in RR vs. SP, sodium ion concentration in HC vs. CIS, and microstructural alterations were involved across all tasks.This project has received funding under the European Union's Horizon 2020 Research and Innovation Programme under grant agreement No. 634541. FG received the support of a fellowship from “la Caixa” Foundation (ID 100010434). The fellowship code is “LCF/BQ/PR22/11920010”. FG has also received support from the Beatriu de Pinós (2020 BP 00117) programme, funded by the Secretary of Universities and Research (Government of Catalonia). BK, FP, and OC are supported by the National Institute of Health Research Biomedical Research Centre at UCL and UCLH. EPSRC grants EP/M020533/1 and EP/J020990/01, MRC MR/T046422/1 and MR/T046473/1, Wellcome Trust award 221915/Z/20/Z, and the NIHR UCLH BRC support DCA's work in this area. CGWK also receives funding from Horizon 2020 [Research and Innovation Action Grants Human Brain Project 945539 (SGA3)], BRC (#BRC704/CAP/CGW), MRC (#MR/S026088/1), and Ataxia UK

Human Placental Arterial Distensibility, Birth Weight, and Body Size Are Positively Related to Fetal Homocysteine Concentration

Methionine demethylation during metabolism generates homocysteine (Hcy) and its remethylation requires folate and cobalamin. Elevated Hcy concentrations are associated with vascular-related complications of pregnancy, including increased vascular stiffness, predictive of clinical vascular disease. Maternal and fetal total Hcy (tHcy) concentrations are positively related, yet the influence of Hcy on fetoplacental vascular function in normal pregnancy has not been examined. We hypothesized that Hcy alters fetoplacental vascular characteristics with influences on fetal growth outcomes. We investigated (1) placental chorionic plate artery distensibility and neonatal blood pressure in relation to umbilical plasma tHcy; (2) relationships between cord venous (CV) and cord arterial (CA) plasma tHcy, folate, and cobalamin concentrations; and (3) tHcy associations with birth weight and anthropometric measurements of body size as indices of fetal growth in normal pregnancies with appropriate weight-for-gestational age newborns. Maternal plasma tHcy, folate, and cobalamin concentrations were consistent with published data. Placental chorionic plate artery distensibility index (β; measure of vessel stiffness) was inversely related to CA tHcy, yet neonatal blood pressure was not significantly affected. CV and CA tHcy concentrations were positively related and CV tHcy negatively related to CV cobalamin but not folate. CV tHcy concentration positively related to birth weight, corrected birth weight per-centile, length, head circumference, and mid-arm circumference of newborns. CV cobalamin was inversely related to fetal growth indices but not to folate concentration. Our study demonstrates a potential relationship between fetal tHcy and placental artery distensibility, placing clinical relevance to cobalamin in influencing Hcy concentration and maintaining low vascular resistance to facilitate nutrient exchange favorable to fetal growth