CD69 controls the uptake of L-tryptophan through LAT1-CD98 and AhR-dependent secretion of IL-22 in psoriasis.

The activation marker CD69 is expressed by skin γδ T cells. Here we found that CD69 controlled the aryl hydrocarbon receptor (AhR)-dependent secretion of interleukin 22 (IL-22) by γδ T cells, which contributed to the development of psoriasis induced by IL-23. CD69 associated with the aromatic-amino-acid-transporter complex LAT1-CD98 and regulated its surface expression and uptake of L-tryptophan (L-Trp) and the intracellular quantity of L-Trp-derived activators of AhR. In vivo administration of L-Trp, an inhibitor of AhR or IL-22 abrogated the differences between CD69-deficient mice and wild-type mice in skin inflammation. We also observed LAT1-mediated regulation of AhR activation and IL-22 secretion in circulating Vγ9(+) γδ T cells of psoriatic patients. Thus, CD69 serves as a key mediator of the pathogenesis of psoriasis by controlling LAT1-CD98-mediated metabolic cues.

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).

Targeting YAP-mediated HSC death susceptibility and senescence for treatment of liver fibrosis.

BACKGROUND AND AIMS: Liver fibrosis results from the accumulation of myofibroblasts (MFs) derived from quiescent HSCs, and yes-associated protein (YAP) controls this state transition. Although fibrosis is also influenced by HSC death and senescence, whether YAP regulates these processes and whether this could be leveraged to treat liver fibrosis are unknown. APPROACH AND RESULTS: YAP activity was manipulated in MF-HSCs to determine how YAP impacts susceptibility to pro-apoptotic senolytic agents or ferroptosis. Effects of senescence on YAP activity and susceptibility to apoptosis versus ferroptosis were also examined. CCl 4 -treated mice were treated with a ferroptosis inducer or pro-apoptotic senolytic to determine the effects on liver fibrosis. YAP was conditionally disrupted in MFs to determine how YAP activity in MF-HSC affects liver fibrosis in mouse models. Silencing YAP in cultured MF-HSCs induced HSC senescence and vulnerability to senolytics, and promoted ferroptosis resistance. Conversely, inducing HSC senescence suppressed YAP activity, increased sensitivity to senolytics, and decreased sensitivity to ferroptosis. Single-cell analysis of HSCs from fibrotic livers revealed heterogeneous sensitivity to ferroptosis, apoptosis, and senescence. In mice with chronic liver injury, neither the ferroptosis inducer nor senolytic improved fibrosis. However, selectively depleting YAP in MF-HSCs induced senescence and decreased liver injury and fibrosis. CONCLUSION: YAP determines whether MF-HSCs remain activated or become senescent. By regulating this state transition, Yap controls both HSC fibrogenic activity and susceptibility to distinct mechanisms for cell death. MF-HSC-specific YAP depletion induces senescence and protects injured livers from fibrosis. Clarifying determinants of HSC YAP activity may facilitate the development of novel anti-fibrotic therapies.

Targeting senescent hepatocytes using the thrombomodulin-PAR1 inhibitor vorapaxar ameliorates NAFLD progression.

BACKGROUND AND AIMS: Senescent hepatocytes accumulate in parallel with fibrosis progression during NASH. The mechanisms that enable progressive expansion of nonreplicating cell populations and the significance of that process in determining NASH outcomes are unclear. Senescing cells upregulate thrombomodulin-protease-activated receptor-1 (THBD-PAR1) signaling to remain viable. Vorapaxar blocks the activity of that pathway. We used vorapaxar to determine if and how THBD-PAR1 signaling promotes fibrosis progression in NASH. APPROACH AND RESULTS: We evaluated the THBD-PAR1 pathway in liver biopsies from patients with NAFLD. Chow-fed mice were treated with viral vectors to overexpress p16 in hepatocytes and induce replicative senescence. Effects on the THBD-PAR1 axis and regenerative capacity were assessed; the transcriptome of p16-overexpressing hepatocytes was characterized, and we examined how conditioned medium from senescent but viable (dubbed "undead") hepatocytes reprograms HSCs. Mouse models of NASH caused by genetic obesity or Western diet/CCl 4 were treated with vorapaxar to determine effects on hepatocyte senescence and liver damage. Inducing senescence upregulates the THBD-PAR1 signaling axis in hepatocytes and induces their expression of fibrogenic factors, including hedgehog ligands. Hepatocyte THBD-PAR1 signaling increases in NAFLD and supports sustained hepatocyte senescence that limits effective liver regeneration and promotes maladaptive repair. Inhibiting PAR1 signaling with vorapaxar interrupts this process, reduces the burden of 'undead' senescent cells, and safely improves NASH and fibrosis despite ongoing lipotoxic stress. CONCLUSION: The THBD-PAR1 signaling axis is a novel therapeutic target for NASH because blocking this pathway prevents accumulation of senescing but viable hepatocytes that generate factors that promote maladaptive liver repair.

Intraoperative image-guidance during robotic surgery: is there clinical evidence of enhanced patient outcomes?

BACKGROUND: To date, the benefit of image guidance during robot-assisted surgery (IGS) is an object of debate. The current study aims to address the quality of the contemporary body of literature concerning IGS in robotic surgery throughout different surgical specialties. METHODS: A systematic review of all English-language articles on IGS, from January 2013 to March 2023, was conducted using PubMed, Cochrane library's Central, EMBASE, MEDLINE, and Scopus databases. Comparative studies that tested performance of IGS vs control were included for the quantitative synthesis, which addressed outcomes analyzed in at least three studies: operative time, length of stay, blood loss, surgical margins, complications, number of nodal retrievals, metastatic nodes, ischemia time, and renal function loss. Bias-corrected ratio of means (ROM) and bias-corrected odds ratio (OR) compared continuous and dichotomous variables, respectively. Subgroup analyses according to guidance type (i.e., 3D virtual reality vs ultrasound vs near-infrared fluoresce) were performed. RESULTS: Twenty-nine studies, based on 11 surgical procedures of three specialties (general surgery, gynecology, urology), were included in the quantitative synthesis. IGS was associated with 12% reduction in length of stay (ROM 0.88; p = 0.03) and 13% reduction in blood loss (ROM 0.87; p = 0.03) but did not affect operative time (ROM 1.00; p = 0.9), or complications (OR 0.93; p = 0.4). IGS was associated with an estimated 44% increase in mean number of removed nodes (ROM 1.44; p < 0.001), and a significantly higher rate of metastatic nodal disease (OR 1.82; p < 0.001), as well as a significantly lower rate of positive surgical margins (OR 0.62; p < 0.001). In nephron sparing surgery, IGS significantly decreased renal function loss (ROM 0.37; p = 0.002). CONCLUSIONS: Robot-assisted surgery benefits from image guidance, especially in terms of pathologic outcomes, namely higher detection of metastatic nodes and lower surgical margins. Moreover, IGS enhances renal function preservation and lowers surgical blood loss.

Safety of biologic therapy in combination with methotrexate in moderate to severe psoriasis: a cohort study from the BIOBADADERM registry.

BACKGROUND: Safety is an important consideration in decisions on treatment for patients with moderate-to-severe psoriasis and the study of drug safety is the main purpose of the BIOBADADERM registry. The combination of a biologic agent and a conventional systemic drug [generally methotrexate (MTX)] is a common treatment in clinical practice. However, there is a paucity of evidence from real-world practice on the safety of such combination regimens in the treatment of psoriasis. OBJECTIVES: The primary objective of this study was to ascertain whether the use of regimens combining biologic drugs with MTX in the management of moderate-to-severe psoriasis increases the risk of adverse events (AEs) or serious AEs (SAEs). We compared monotherapy using tumour necrosis factor (TNF), interleukin (IL)-17 and IL-23 inhibitors with the use of the same drugs in combination with MTX. METHODS: Using data from the BIOBADADERM registry, we compared biologic monotherapies with therapies that were combined with MTX. We estimated adjusted incidence rate ratios (aIRR) using a random effects Poisson regression with 95% confidence intervals for all AEs, SAEs, infections and serious infections and other AEs by system organ class. RESULTS: We analysed data from 2829 patients and 5441 treatment cycles, a total of 12 853 patient-years. The combination of a biologic with MTX was not associated with statistically significant increases in overall risk of AEs or SAEs in any treatment group. No increase in the total number of infections or serious infections in patients receiving combined therapy was observed for any group. However, treatment with a TNF inhibitor combined with MTX was associated with an increase in the incidence of gastrointestinal AEs (aIRR 2.50, 95% CI 1.57-3.98; P < 0.002). CONCLUSIONS: The risk of AEs and SAEs was not significantly increased in patients with moderate-to-severe psoriasis receiving different classes of biologic drugs combined with MTX compared with those on biologic monotherapy.

Augmentation of a Transosseous-Equivalent Repair in Posterosuperior Nonacute Rotator Cuff Tears With a Bioinductive Collagen Implant Decreases the Retear Rate at 1 Year: A Randomized Controlled Trial.

PURPOSE: To determine whether the addition of a bioinductive collagen implant (BCI) over a transosseous equivalent (TOE) repair of medium-to-large posterosuperior rotator cuff tears improves the healing rate determined by magnetic resonance imaging (MRI) at 12-month follow-up. METHODS: A Level I randomized controlled trial was performed in 124 subjects with isolated, symptomatic, reparable, full-thickness, medium-to-large posterosuperior nonacute rotator cuff tears, with fatty infiltration ≤2. These were randomized to 2 groups in which an arthroscopic posterosuperior rotator cuff tear TOE repair was performed alone (Control group) or with BCI applied over the TOE repair (BCI group). The primary outcome was the retear rate (defined as Sugaya 4-5) determined by MRI at 12 months of follow-up. Secondary outcomes were characteristics of the tendon (Sugaya grade and thickness of the healed tendon) and clinical outcomes (pain levels, EQ-5D-5L, American Shoulder and Elbow Surgeons, and Constant-Murley scores) at 12 months of follow-up. RESULTS: Of the 124 randomized patients, 122 (60 in the BCI group and 62 in the Control group) were available for MRI evaluation 12.2 ± 1.02 months after the intervention. There were no relevant differences in preoperative characteristics. Adding the BCI reduced the retear rate (8.3% [5/60] in the BCI group vs 25.8% [16/62] in the Control group, P = .010; relative risk of retear of 0.32 [95% confidence interval 0.13-0.83]). Sugaya grade was also better in the BCI group (P = .030). There were no differences between groups in the percentage of subjects who reached the MCID for CMS (76.7% vs 81.7%, P = .654) or American Shoulder and Elbow Surgeons (75% vs 80%, P = .829), in other clinical outcomes or in complication rates at 12.4 ± 0.73 (range 11.5-17) months of follow-up. CONCLUSIONS: Augmentation with a BCI of a TOE repair in a medium-to-large posterosuperior rotator cuff tear reduces the retear rate at 12-month follow-up by two-thirds, yielding similar improvements in clinical outcomes and without increased complication rates. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

Pityriasis Rubra Pilaris: A Multicentric Case Series of 65 Spanish Patients.

INTRODUCTION: PRP is a rare entity of unknown etiopathogenesis. Lack of clinical practice guidelines makes management challenging for clinicians. OBJECTIVE: To add our experience to the corpus evidence on PRP. METHODS: This was a retrospective, descriptive, and multicentric study of 65 patients with PRP, the largest European case series of patients with PRP ever reported. RESULTS: PRP was more prevalent in men with a mean age of 51 years, yet erythrodermic forms presented in older patients (mean age, 61 years).Six (75%) pediatric patients and 10 (60%) non-erythrodermic adults controlled their disease with topical corticosteroids. However, 26 (68%) erythrodermic patients required biologic therapy as the last and effective therapy for a mean 6.5 months to achieve complete response. CONCLUSION: Our study showed a statistical difference in terms of outcome and response to treatment between children, or patients with limited disease and patients who develop erythroderma.

Secukinumab demonstrates superiority over narrow-band ultraviolet B phototherapy in new-onset moderate to severe plaque psoriasis patients: Week 52 results from the STEPIn study.

BACKGROUND: Biologic treatments have been studied mainly in patients with a long-term history of psoriasis and previous treatment failures. OBJECTIVES: The purpose of this primary analysis of the STEPIn study is to determine whether early intervention with secukinumab in patients with new-onset moderate to severe plaque psoriasis is superior to standard of care treatment with narrow band ultraviolet B (nb-UVB) phototherapy. METHODS: The STEPIn study is a randomized, open-label, multicentre study to investigate early intervention with 52 weeks of secukinumab 300 mg administered subcutaneously versus standard treatment with nb-UVB phototherapy in patients with new-onset (≤12 months) moderate to severe plaque psoriasis (NCT03020199). The primary and additional secondary endpoints were ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) at Week 52 and Investigator's Global Assessment (IGA mod 2011) 0/1 response at Week 52, respectively. RESULTS: In the secukinumab and nb-UVB study arms, 77/80 and 76/80 randomized patients received at least one dose of study treatment, respectively. The primary endpoint was achieved: 91.1% (70/77) of patients achieved a PASI 90 response at Week 52 in the secukinumab arm versus 42.3% (32/76) in the nb-UVB arm (p < 0.0001, odds ratio [OR] estimate [95% confidence intervals, CI] = 16.3 [5.6, 46.9]). The additional secondary endpoint was also achieved: 85.7% of patients achieved an IGA 0/1 response at Week 52 in the secukinumab arm versus 36.8% in the nb-UVB arm (p < 0.0001). The safety data were consistent with the safety profiles of secukinumab and nb-UVB with no new or unexpected safety signals. CONCLUSIONS: Secukinumab was superior to nb-UVB in treating patients with new-onset moderate to severe plaque psoriasis. The high and sustained skin clearance observed indicates that biologic treatment for psoriasis may be more effective if used early in the disease course.

Tildrakizumab improves high burden skin symptoms, impaired sleep and quality of life of moderate-to-severe plaque psoriasis patients in conditions close to clinical practice.

BACKGROUND: Tildrakizumab (TIL) is an interleukin (IL)-23p19 inhibitor for the treatment of moderate-to-severe plaque psoriasis with long-term efficacy and safety demonstrated in Phase III trials. Studies conducted in conditions closer to clinical practice are needed. OBJECTIVES: The TRIBUTE study (open-label, Phase IV) assessed the efficacy and impact on health-related quality of life (HRQoL) of TIL 100 mg in adult moderate-to-severe psoriasis patients (naïve to IL-23/Th17 pathway inhibitors) in conditions similar to clinical practice. METHODS: Key efficacy measure was Psoriasis Area Severity Index (PASI). HRQoL was evaluated using the Dermatology Life Quality Index (DLQI) and Skindex-16. Additional patient-reported outcomes included Pain-, Pruritus- and Scaling-Numerical Rating Scale (NRS), Medical Outcome Study (MOS)-Sleep, Work Productivity and Activity Impairment (WPAI), Patient Benefit Index (PBI) and Treatment Satisfaction Questionnaire for Medication (TSQM). RESULTS: One hundred and seventy-seven patients were enrolled (six patients did not complete the study). After 24 weeks, the proportion of patients achieving PASI scores ≤ 3, PASI 75, PASI 90 and DLQI 0/1 was 88.4%, 92.5%, 74.0% and 70.4%, respectively. Skindex-16 overall score improved (mean absolute change from baseline, MACB [95%CI]: -53.3 [-58.1, -48.5]). Significant benefits (MACB [95%CI]) were found on pruritus-, pain- and scaling-NRS scores (-5.7 [-6.1, -5.2], -3.5 [-4.1, -3.0] and -5.7 [-6.2, -5.2], respectively), MOS-Sleep (-10.4 [-13.3, -7.4] Sleep problems Index II) and WPAI (-36.4 [-42.6, -30.2] activity impairment, -28.2 [-34.7, -21.7] productivity loss, -27.0 [-32.9, -21.1] presenteeism and -6.8 [-12.1, -1.5] absenteeism). 82.7% of patients reported PBI ≥ 3 and the mean (SD) global TSQM score was high (80.5 [18.5]). Only one serious treatment-emergent adverse event was reported (not-related to TIL). CONCLUSIONS: TIL 100 mg treatment after 24 weeks in conditions close to real clinical practice showed a quick and high improvement in psoriasis signs and HRQoL. Patient reported improvements in sleep outcomes and work productivity, relevant benefits and high treatment satisfaction. The safety profile was favourable and consistent with Phase III trials.

Effectiveness and safety of tildrakizumab for the treatment of psoriasis in real-world settings at 24 weeks: A retrospective, observational, multicentre study by the Spanish Psoriasis Group.

BACKGROUND: Tildrakizumab is a humanized, IgG1/κ antibody that interacts with the p19 subunit of interleukin 23. It is approved for the treatment of moderate-to-severe plaque psoriasis. Real-world evidence on the effectiveness and safety of tildrakizumab is limited. OBJECTIVES: To assess the effectiveness and safety of tildrakizumab at 24 weeks in patients with moderate-to-severe plaque psoriasis in routine clinical practice. METHODS: Retrospective, observational, multicentre study including adult patients with moderate-to-severe plaque psoriasis treated with tildrakizumab under real-life conditions. Patient data were extracted from anonymized electronic medical records. Statistical analysis was performed using SPSS22. RESULTS: A total of 190 patients were included. About 53.9% were men with a mean age of 51.45 (SD 3.9) and a mean BMI of 29.13 (SD 6.21). About 79.8% (132 out of 190) of patients had previously received biological therapy (BT) and 17.3% (33 out of 191) had psoriatic arthritis. Baseline PASI was 10.7 (SD 6.53). Up to 109 patients reached Week 24 and at this point mean baseline PASI decreased to 1.7 (SD 4.8), representing an 88.79% mean PASI reduction. At 6 months, 87.1% and 40.3% of the treated patients achieved PASI ≤3 and ≤1, respectively. At Week 24 mean BSA decreased from 13.2 (SD 10.07) to 1.6 (SD 4.40) and mean DLQI went from 12.5 (SD 7.12) to 1.2 (SD 3.27). Multivariate analysis showed no differences when effectiveness was correlated with gender, obesity, psoriatic arthritis or prior exposure to BT. The rate of adverse events (AE) was 5.9% (11 out of 190), where infections were the most frequent AE (4 out of 11). One patient suffered a haemorrhagic ictus and one patient died due to causes unrelated to the study. CONCLUSION: Tildrakizumab was effective and safe in a large cohort of patients with moderate-to-severe plaque psoriasis treated in a routine clinical setting.

Cyst formation and bony ingrowth inside coil-type open-architecture anchors used for arthroscopic remplissage: a volumetric computed tomographic study of 50 anchors.

BACKGROUND: The use of anchors in the proximal humerus during arthroscopic surgery can cause localized bone loss due to osteolysis and cyst formation. The purpose of this study was to use computed tomography (CT) to evaluate the incidence of implant-related bone loss and cyst formation after implantation of polyetheretherketone (PEEK) coil-type open-architecture anchors during remplissage for the management of Hill-Sachs defects (HSDs) in patients with shoulder instability. METHODS: This was a single-cohort, observational study with a minimum of 12 months of follow-up. Subjects undergoing arthroscopic instability surgery with HSD requiring remplissage were included. The volume of the bone defects and the degree of bony ingrowth into the anchor were measured on CT images. RESULTS: Thirty-one participants (28 males, 3 females; mean age 29.4 years, standard deviation [SD] 10.6) in whom 50 anchors (4.5-mm Healicoil PEEK double-loaded anchors) were used were evaluated with a CT performed at a mean of 14.1 (SD 3.74) months after surgery. Full bony ingrowth inside the anchor was found in 15 anchors (30%, range 17.8%-44.5%); clear ossification with a thin lucent rim was found in 10 anchors (20%, range 10.0%-33.7%); discontinuous ossification was found in 8 anchors (16%, range 7.2%-29.1%); and no ossification was observed inside 17 anchors (34%, range 21.2%-48.7%). Regarding bone defect size, no bone defect was identified in 15 anchors (30%, 95% CI 17.9%-44.6%), a partial bone defect was found in 17 anchors (34%, 95% CI 21.2%-48.7%), hole enlargement was found in 17 anchors (34%, 95% CI 21.2%-48.7%), and 1 anchor caused a cyst larger than twice the size of the hole made for anchor insertion (2%, 95% CI 0.1%-8.6%). At the 1-year evaluation, none of the participants presented recurrence or residual apprehension. CONCLUSION: The use of PEEK coil-type open-architecture anchors for remplissage during instability surgery caused large cystic lesions in less than 10% of anchors. There was full bony ingrowth in one-third of anchors, and partial cancellous bone ingrowth occurred in another third of anchors.

Retrospective Case-Control Study Genes Related to Bone Metabolism That Justify the Condition of Periodontal Disease and Failure of Dental Implants in Patients with down Syndrome.

Down syndrome patients show success rates in dental implants much lower than those observed in the general population. This retrospective case-control study aimed to identify possible genes that are related to the regulation of inflammatory responses and bone metabolism related to periimplantitis and implant loss, as well as genes related to bone quality. This process involved using the functional analysis of the gene expression software Transcriptome Analysis Console (TAC version 4.0 Applied BiosystemsTM, Thermo Fisher Scientific, Waltham, MA, USA) and a search for possible candidate genes involved. The focus was placed on the 93 genes related to periodontitis, periimplantitis, bone loss, implant loss, and genes related to bone quality and regulators underlying the establishment and maintenance of osseointegration. Five genes showed statistically significant results (p < 0.05) in our comparison. Four of them, IL1B (p = 0.023), IL1RN (p = 0.048), BGLAP (p = 0.0372) and PTK2 (p = 0.0075) were down-regulated in the periodontal disease and implant rejection group, and only one was overexpressed: FOXO1A (p = 0.0552). The genes with statistically significant alterations described in this article determine that the group of Down syndrome patients with periodontal disease and implant failure is a group of patients genetically susceptible to suffering from both conditions together.

Secukinumab demonstrates efficacy, safety, and tolerability upon administration by 2 ml autoinjector in adult patients with plaque psoriasis: 52-week results from MATURE, a randomized, placebo-controlled trial.

Convenient administration is an important factor for treatment adherence in patients with psoriasis. MATURE study reports the efficacy, safety, tolerability, and pharmacokinetics (PKs) of secukinumab 300 mg 2 ml autoinjector (AI) from MATURE trial (NCT03589885). Eligible patients were randomized to secukinumab 300 mg 2 ml AI or 2× 1 ml prefilled syringe (PFS) or placebo. The co-primary endpoints were psoriasis area and severity index (PASI) 75 and investigator's global assessment (IGA) 0/1 response rates at Week 12 versus placebo. Other endpoints included PASI90/100 response, dermatology life quality index (DLQI) 0/1, PKs, 2 ml AI usability rated using self-injection assessment questionnaire (SIAQ), and safety. The study met both co-primary and secondary endpoints (p < 0.0001). Secukinumab 300 mg 2 ml AI and 2× 1 ml PFS treatments led to superior PASI75/90/100 (2 ml AI: 95.1%/75.6%/43.9%; 2× 1 mL PFS: 83.2%/62.6%/37.5% and placebo: 10%/5.0%/0.0%, respectively), IGA, and DLQI 0/1 responses compared with placebo, and efficacy was sustained through 52 weeks. SIAQ results showed high usability of self-injection with 2 mL AI device. No new safety signals were observed. Study design may bias the interpretation of safety profile after Week 12, due to different exposure of secukinumab versus placebo. Secukinumab 300 mg administered with the 2 mL AI demonstrated superior efficacy over placebo, good tolerability, and convenient administration.

Secukinumab is effective and safe in the long-term treatment of plaque psoriasis in a daily practice setting: Multicenter study in 384 Spanish patients.

The aim of the study was to assess the long-term effectiveness and safety of secukinumab in Spanish patients with moderate-to-severe psoriasis in a daily practice setting. Nationwide multicenter, observational, retrospective, non-interventional, single-cohort study including patients who initiated treatment with secukinumab in daily clinical practice conditions. Subjects were followed for a minimum of 3 months and a maximum of 24 months. Psoriasis Area Severity Index (PASI), Body Surface Area and Physician's Global Assessments were collected at baseline and months 3, 6, 12, 18 and 24 during treatment. Adverse events and reasons for secukinumab withdrawal were collected and classified for analyses. A total of 384 patients were enrolled in the study. Median PASI declined rapidly from 14.3 at baseline to 2.7 at month 3, 2.1 at month 12, and remained low (2.8) at month 24. Within the group of patients with PASI ≥10 at baseline (n = 278), 58.3%, 60.4% and 56.5% achieved a PASI90 response at months 3, 12 and 24, respectively. As for absolute PASI, 86.5%, 69.5%, 42.7% and 37% achieved PASI <5, < 3, < 1 and 0, respectively, at month 3. Secukinumab was more effective in biologic-naïve patients and in those with lower Body Mass Index. Secukinumab presented a good long-term safety profile. Secukinumab was effective and safe in a routine clinical setting, in a large cohort of patients with moderate-to-severe plaque psoriasis, in the short-, medium- and long-term (up to 24 months).

Assessment of isolated glenohumeral range of motion in patients with adhesive capsulitis can help predict failure of conservative treatment: a pilot study.

PURPOSE: To prospectively evaluate a cohort of patients with adhesive capsulitis and identify predictors of failure of conservative treatment in the first 2 months of therapy. METHODS: This was a single-cohort, prospective observational study that included 20 participants (13 females/7 males; median age of 51.8 years [interquartile range: 8.65]) with primary adhesive capsulitis managed conservatively and evaluated clinically every month for at least 2 years of follow-up (29 [5] months). The evaluation included stage of the disease, treatment applied, radiological findings, pain levels and range of motion (active and passive ROM in the four planes and isolated glenohumeral passive ROM in abduction [GH-ABD], external rotation [GH-ER] and internal rotation). The main outcome assessed was failure of conservative treatment defined as the need for surgery and persistent pain or CMS below 70 points at the 1-year follow-up. RESULTS: Seven patients (7/20, 35%) were considered to have failed conservative treatment because they required arthroscopic capsular release 5.2 (2.1) months after the initial diagnosis. Of all the clinical and epidemiological variables, absence of improvement during the first 2 months in isolated glenohumeral ROM abduction and external rotation predicted failure of conservative treatment: improvement in GH-ABD (10° or more) occurred in 10/13 patients in the conservative treatment group and in 1/7 patients in the surgery group (p = 0.017). Improvement in GH-ER (10° or more) occurred in 9/13 patients in the conservative treatment group and in 0/7 patients in the surgery group (p = 0.005). CONCLUSIONS: Precise assessment of isolated glenohumeral ROM in patients with adhesive capsulitis can help identify patients in which conservative treatment might fail. In this study, patients who did not experience early improvements in isolated glenohumeral ROM often required surgery. LEVEL OF EVIDENCE: III (Prospective cohort study).

Intra- and inter-operator concordance of the resonance frequency analysis. A cross-sectional and prospective clinical study.

OBJECTIVE: Resonance frequency analysis (RFA) provides an evaluation of implant stability over time. This analysis is a non-invasive, precise, and objective method. Several studies compare the RFA system with other devices. However, few investigations analyze repeatability and reproducibility between different operators. The aim of this study was to evaluate the intra- and inter-operator concordance of the Osstell® ISQ. MATERIAL AND METHODS: RFA measurements were performed with Osstell® ISQ in a total of 37 implants placed in 21 patients. At the time of implant placement, 6 measurements per implant were taken by three different experienced operators. Three measurements were carried out consecutively and three by removing and placing the SmartPeg-Osstell® to assess intra-operator and inter-operator agreement. RESULTS: Intra-operator concordance according to the intraclass correlation coefficient (ICC) showed high concordance. The ICC values were higher than 0.9 (p < 0.0001) for consecutive measures and alternative measures, being almost perfect of Landis & Koch classification. For inter-operator concordance The ICC was 0.709 (p < 0.0001) and 0.670 (p < 0.0001) for consecutive and alternative measures, respectively, both estimates being in the substantial category. In torque and ISQ values, no statistically significant differences were observed when operators and measurements were compared. CONCLUSIONS: Osstell® ISQ system was stable both in intra-operator and inter-operator measurements. This device has excellent repeatability and reproducibility, demonstrating reliability to measure the stability of dental implants. CLINICAL RELEVANCE: Resonance frequency analysis (RFA) is a non-invasive, objective, and reliable diagnostic method to determine the ideal moment to load the implant, as well as to predict possible failures.

Endocytosis of the glutamate transporter 1 is regulated by laforin and malin: Implications in Lafora disease.

Lafora disease (LD) is a fatal rare type of progressive myoclonus epilepsy that appears during early adolescence. The disease is caused by mutations in EPM2A or EPM2B genes, which encode laforin, a glucan phosphatase, and malin, an E3-ubiquitin ligase, respectively. Although the exact roles of laforin and malin are still not well understood, it is known that they work as a complex in which laforin recruits targets that will be ubiquitinated by malin. Recently, we suggested that the type of epilepsy that accompanies LD could be due to deficiencies in the function of the astrocytic glutamate transporter GLT-1. We described that astrocytes from LD mouse models presented decreased levels of GLT-1 at the plasma membrane, leading to increased levels of glutamate in the brain parenchyma. In this work, we present evidence indicating that in the absence of a functional laforin/malin complex (as in LD cellular models) there is an alteration in the ubiquitination of GLT-1, which could be the cause of the reduction in the levels of GLT-1 at the plasma membrane. On the contrary, overexpression of the laforin/malin complex promotes the retention of GLT-1 at the plasma membrane. This retention may be due to the direct ubiquitination of GLT-1 and/or to an opposite effect of this complex on the dynamics of the Nedd4.2-mediated endocytosis of the transporter. This work, therefore, presents new pieces of evidence on the regulation of GLT-1 by the laforin/malin complex, highlighting its value as a therapeutic target for the amelioration of the type of epilepsy that accompanies LD.

Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), the hepatic correlate of the metabolic syndrome, is a major risk factor for hepatobiliary cancer (HBC). Although chronic inflammation is thought to be the root cause of all these diseases, the mechanism whereby it promotes HBC in NAFLD remains poorly understood. Herein, we aim to evaluate the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis. METHODS: We use murine NAFLD models, liver biopsies from patients with NAFLD, human liver cancer registry data, and studies in liver cancer cell lines. RESULTS: Our results confirm the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis, supporting a model whereby chronic inflammation suppresses hepatocyte expression of ESRP2, an RNA splicing factor that directly targets and activates NF2, a tumor suppressor that is necessary to constrain YAP/TAZ activation. The resultant loss of NF2 function permits sustained YAP/TAZ activity that drives hepatocyte proliferation and de-differentiation. CONCLUSION: Herein, we report on a novel mechanism by which chronic inflammation leads to sustained activation of YAP/TAZ activity; this imposes a selection pressure that favors liver cells with mutations enabling survival during chronic oncogenic stress. LAY SUMMARY: Non-alcoholic fatty liver disease (NAFLD) increases the risk of hepatobiliary carcinogenesis. However, the underlying mechanism remains unknown. Our study demonstrates that chronic inflammation suppresses hepatocyte expression of ESRP2, an adult RNA splicing factor that activates NF2. Thus, inactive (fetal) NF2 loses the ability to activate Hippo kinases, leading to the increased activity of downstream YAP/TAZ and promoting hepatobiliary carcinogenesis in chronically injured livers.