Clinical Activity Research Articles

The Role of Intra-Articular Injection of Autologous Platelet Rich Plasma versus Corticosteroids in Treatment of Synovitis in Lumbar Facet Joint Disease

Abstract Background Low back pain (LBP) is an extremely common health problem and lumbar facet joint (FJ) disease is one of its main causes. Intra-articular injection of FJ is one of the vital therapeutic methods for FJ disease. Corticosteroids (CS) are the most commonly used injected drugs; however, previous studies have indicated that it has limited ability in long-term relief of LBP. Aim of the Work to compare the efficacy of intra-articular injection of platelet rich plasma (PRP) versus CS in improving MRI detected synovitis in correlation to clinical complaints of the patients with lumbar FJ syndrome. Patients and Methods Thirty patients with lumbar FJ syndrome divided into two equal groups: Group ‘I’ injected with PRP and Group ‘II’ with CS. The patients were comparatively assessed pre and post the intervention according to; number of tender lumbar FJs on palpation, maximum active lumbar extension range of motion, LBP visual analogue score (VAS), functional disability questionnaires - Roland Morris disability questionnaire (RMQ) and Oswestry disability index (ODI) - and MRI lumbar FJ detected synovitis and their grading. Results Both study groups showed statistical significant improvement in all mentioned parameters at 3 month follow up, there was no statistically significant difference between the results of both groups, however, PRP injected joints showed better performance regarding MRI synovitis grade in all lumbar FJ levels as compared to those injected with CS. Conclusion Both PRP and CS injections were determined to be effective in improvement of MRI detected FJ synovitis concurrently with improving clinical parameters, pain and functional activities of the patients at 3 months follow-up. However, PRP showed superior effect in improving MRI detected synovitis grade, therefore may be a better treatment option for longer duration efficacy and fewer side effects. TRN NCT04860531- 1/3/2021

Impact of Race on the Efficacy and Safety of Tofacitinib in Rheumatoid Arthritis: Post Hoc Analysis of Pooled Clinical Trials.

Racial disparities in disease activity, clinical outcomes, and treatment survival persist despite advancements in rheumatoid arthritis (RA) therapies and clinical management. In this post hoc analysis of pooled data from the tofacitinib global clinical program, we evaluated the impact of race on the efficacy and safety of tofacitinib in patients with RA. Data were pooled from 15 phase 2-3b/4 studies of patients with RA treated with tofacitinib 5 or 10mg twice daily, adalimumab, or placebo. Outcomes were stratified by self-reported patient race (White/Black/Asian/Other). Efficacy outcomes to month 12 included: American College of Rheumatology (ACR)20/50/70 responses, Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] low disease activity (LDA) rates, least squares (LS) mean change from baseline (∆) in CDAI, DAS28-4 (ESR), Health Assessment Questionnaire-Disability Index (HAQ-DI), and Pain [Visual Analog Scale (VAS)]. Odds ratios (ORs; 95% CI) versus placebo, and placebo-adjusted ∆LS means were calculated for active treatments using logistic regression model and mixed-effect model of repeated measurements, respectively. Safety outcomes were assessed throughout. A total of 6355 patients were included (White, 4145; Black, 213; Asian, 1348; Other, 649). For tofacitinib-treated patients, ORs for ACR20/50/70 responses and CDAI/DAS28-4(ESR) LDA rates through month 3 were generally numerically higher for White/Asian/Other versus Black patients. Across active treatments, trends toward higher placebo-adjusted improvements from baseline in CDAI, DAS28-4 (ESR), HAQ-DI, and Pain (VAS) were observed in Asian/Other versus White/Black patients. Numerically higher placebo responses in Black versus White/Asian/Other patients were generally observed across outcomes through month 12. Safety outcomes were mostly similar across treatment/racial groups. In patients with RA, tofacitinib was efficacious across racial groups with similar safety outcomes; observed racial differences potentially reflect patient demographics or regional practice disparities. ClinicalTrials.gov identifiers: NCT00147498; NCT00413660; NCT00550446; NCT00603512; NCT00687193; NCT01164579; NCT00976599; NCT01359150; NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01039688; NCT02187055.

Role of CXCL-10 as a Biomarker for Rheumatoid Arthritis

Abstract Background CXCL-10 has been detected within sera, synovial fluid, and synovial tissue in patients with RA and identified as a pro-inflammatory chemokine that mediate leukocyte trafficking and modulate innate and adaptive immune responses. It plays a critical role in the inflammatory response and is involved in several biological processes. Objective To evaluate the predicative significance of chemokine CXCL10 in rheumatoid arthritis (RA) and to focus on its relation to disease activity. Patients and Methods A case control study included 30 patients; were diagnosed with RA, and 30 healthy controls. Clinical examination was done for all patients. Measurement of serum CXCL10 level was done by ELISA, while assessment of disease activity in patients was done using disease activity score (DAS-28). Serum levels of CXCL10 were significantly higher in RA patients than controls. Results Serum level of CXCL-10 was ranging from 349–1380 pg/ml with a mean of 784.6 ± 152.2 in RA patients, which was very high level compared to control group the serum level was ranging from 137 – 476.8 pg/ml with a mean of 338.1 ± 125.5. The difference was statistically highly significant (p < 0.001). AUC for CXCL-10 was 0.951 and the 95% CI was ≤ 1. The cutoff point of CXCL-10 was 450 pg/mL were able to differentiate between RA patients and control group. Most of RA patients (70%) were on methotrexate with dose ranged from 12.5–25 mg per week. Thirty-five (58.3%) patients were on steroids with dose 5-20 mg per day. Comparison of CXCL-10 levels in patients with different grades of disease activity had a statistically significant difference between different grades. Conclusion Our study supports the critical role of CXCL10 in the RA inflammatory cascade. The correlation of CXCL10 with clinical disease activity suggests that CXCL10 plays a central role in RA inflammation and may serve as a disease activity marker in RA. CXCL10 has a significant role as a biomarker for prediction of RA.

Venetoclax resistance in acute lymphoblastic leukemia is characterized by increased mitochondrial activity and can be overcome by co-targeting oxidative phosphorylation

Deregulated apoptosis signaling is characteristic for many cancers and contributes to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Apoptosis is controlled by different pro- and anti-apoptotic molecules. Inhibition of anti-apoptotic molecules like B-cell lymphoma 2 (BCL-2) has been developed as therapeutic strategy. Venetoclax (VEN), a selective BCL-2 inhibitor has shown clinical activity in different lymphoid malignancies and is currently evaluated in first clinical trials in BCP-ALL. However, insensitivity to VEN has been described constituting a major clinical concern. Here, we addressed and modeled VEN-resistance in BCP-ALL, investigated the underlying mechanisms in cell lines and patient-derived xenograft (PDX) samples and identified potential strategies to overcome VEN-insensitivity. Leukemia lines with VEN-specific resistance were generated in vitro and further characterized using RNA-seq analysis. Interestingly, gene sets annotated to the citric/tricarboxylic acid cycle and the respiratory electron transport chain were significantly enriched and upregulated, indicating increased mitochondrial metabolism in VEN-resistant ALL. Metabolic profiling showed sustained high mitochondrial metabolism in VEN-resistant lines as compared to control lines. Accordingly, primary PDX-ALL samples with intrinsic VEN-insensitivity showed higher oxygen consumption and ATP production rates, further highlighting that increased mitochondrial activity is a characteristic feature of VEN-resistant ALL. VEN-resistant PDX-ALL showed significant higher mitochondrial DNA content and differed in mitochondria morphology with significantly larger and elongated structures, further corroborating our finding of augmented mitochondrial metabolism upon VEN-resistance. Using Oligomycin, an inhibitor of the complex V/ATPase subunit, we found synergistic activity and apoptosis induction in VEN-resistant BCP-ALL cell lines and PDX samples, demonstrating that acquired and intrinsic VEN-insensitivity can be overcome by co-targeting BCL-2 and the OxPhos pathway. These findings of reprogrammed, high mitochondrial metabolism in VEN-resistance and synergistic activity upon co-targeting BCL-2 and oxidative phosphorylation strongly suggest further preclinical and potential clinical evaluation in VEN-resistant BCP-ALL.

Final Results From a Phase I Trial and Expansion Cohorts of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced/Metastatic Genitourinary Tumors.

Cabozantinib and nivolumab (CaboNivo) alone or with ipilimumab (CaboNivoIpi) have shown promising efficacy and safety in patients with metastatic urothelial carcinoma (mUC), metastatic renal cell carcinoma (mRCC), and rare genitourinary (GU) tumors in a dose-escalation phase I study. We report the final data analysis of the safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the phase I patients and seven expansion cohorts. This is an investigator-initiated, multicenter, phase I trial. CaboNivo doublet expansion cohorts included (1) mUC, (2) mRCC, and (3) adenocarcinoma of the bladder/urachal; CaboNivoIpi triplet expansion cohorts included (1) mUC, (2) mRCC, (3) penile cancer, and (4) squamous cell carcinoma of the bladder and other rare GU tumors (ClinicalTrials.gov identifier: NCT02496208). The study enrolled 120 patients treated with CaboNivo (n = 64) or CaboNivoIpi (n = 56), with a median follow-up of 49.2 months. In 108 evaluable patients (CaboNivo n = 59; CaboNivoIpi n = 49), the ORR was 38% (complete response rate 11%) and the median duration of response was 20 months. The ORR was 42.4% for mUC, 62.5% for mRCC (n = 16), 85.7% for squamous cell carcinoma of the bladder (n = 7), 44.4% for penile cancer (n = 9), and 50.0% for renal medullary carcinoma (n = 2). Grade ≥ 3 treatment-related adverse events occurred in 84% of CaboNivo patients and 80% of CaboNivoIpi patients. CaboNivo and CaboNivoIpi demonstrated clinical activity and safety in patients with multiple GU malignancies, especially clear cell RCC, urothelial carcinoma, and rare GU tumors such as squamous cell carcinoma of the bladder, small cell carcinoma of the bladder, adenocarcinoma of the bladder, renal medullary carcinoma, and penile cancer.

Neoadjuvant short-course radiotherapy followed by camrelizumab and chemotherapy in locally advanced rectal cancer (UNION): early outcomes of a multicenter randomized phase III trial

Neoadjuvant short-course radiotherapy (SCRT) followed by CAPOX and camrelizumab (a programmed cell death protein 1 monoclonal antibody) has shown potential clinical activity for locally advanced rectal cancer (LARC) in a phase II trial. This study aimed to further confirm the efficacy and safety of SCRT followed by CAPOX and camrelizumab compared to long-course chemoradiotherapy (LCRT) followed by CAPOX alone as neoadjuvant treatment for LARC. In this randomized, phase III trial, patients with T3-4/N+ rectal adenocarcinoma were randomly assigned (1 : 1) to receive SCRT or long-course chemoradiotherapy (LCRT), followed by two cycles of camrelizumab and CAPOX or CAPOX alone, respectively. After surgery, each arm underwent either six cycles of camrelizumab and CAPOX, followed by up to 17 doses of camrelizumab, or six cycles of CAPOX. The primary endpoint was pathological complete response (pCR) rate (ypT0N0) assessed by a blinded independent review committee. Key secondary endpoints tested hierarchically were 3-year event-free survival (EFS) rate and overall survival (OS). Between July 2021 and March 2023, the intention-to-treat population comprised 113 patients in the experimental arm and 118 patients in the control arm, with surgery carried out in 92% and 83.9%, respectively. At data cut-off (11 July 2023), the pCR rates were 39.8% [95% confidence interval (CI) 30.7% to 49.5%] in the experimental arm compared to 15.3% (95% CI 9.3% to 23.0%) in the control arm (difference, 24.6%; odds ratio, 3.7; 95% CI 2.0-6.9; P < 0.001). In each arm, surgical complication rates were 40.0% and 40.8%, and grade ≥3 treatment-related adverse events were 29.2% and 27.2%. Three-year EFS rate and OS continue to mature. In LARC patients, neoadjuvant SCRT followed by camrelizumab plus CAPOX demonstrated a significantly higher pCR rate than LCRT followed by CAPOX, with a well-tolerated safety profile. SCRT followed by camrelizumab and chemotherapy can be recommended as a neoadjuvant treatment modality for these patients.

Measuring pharmacy clinical workload in the emergency department: Current status and a plan for action

BackgroundInpatient pharmacy productivity workload ratios historically encompass dispensing functions including numbers of medication orders verified, dispensed, and billed for and full-time equivalents (FTEs) but do not include pharmacy clinical activities. Clinical pharmacy activities are difficult to capture because they generally require manual documentation and vary among health systems. The emergency medicine pharmacists’ (EMPs) role adds additional complexity to capturing clinical activities given that bedside response and verbal recommendations are difficult to capture outside of manual documentation. It is unknown how many health systems use EMP-specific workload metrics. ObjectivesThe purpose of our survey was to determine the percentage of hospital pharmacies that use EMP-specific workload metrics, to describe workload metrics used by EMPs and to quantify time spent on clinical activities, and to describe methods for implementing EMP metrics. MethodsA 13-item questionnaire was developed, pretested, and sent to EMPs practicing in hospitals in the United States through 2 EMP national committee e-mail listservs. Survey completion online included questions on hospital characteristics, number of EMP FTEs, clinical services provided and time spent on these tasks, and current workload metrics used. ResultsFull responses to the survey were received from 100 pharmacists, with an overall response rate of 9.8%. Workload metrics specific to EMP activities were used by 15.1% of responders. Workload metrics were used but not tailored to EMP activities for 43% of responders, and 41.9% responded that no metrics were used whatsoever. Ten responders provided commentary on types of EMP activities tracked, which included bedside response for critical patients, culture callback, drug information and dosing, time to antibiotic administration, and medication histories. No universal software for metric tracking was identified. ConclusionA survey of EMP clinical services and workload metrics indicated that although 43% of responders use non-EMP-specific metrics, only 15.1% reported workload metrics that capture EMP clinical activities.

Phenotypic subgroup in serologically active clinically quiescent systemic lupus erythematosus: A cluster analysis based on CSTAR cohort

Serologically active clinically quiescent (SACQ) is a state within systemic lupus erythematosus (SLE) characterized by elevated serologic markers without clinical activity. The heterogeneity in SACQ patients poses challenges in disease management. This multicenter prospective study aimed to identify distinct SACQ subgroups and assess their utility in predicting organ damage. SACQ was defined as a sustained period of at least 6months with persistent serologic activity, marked by positive anti-double-stranded DNA (dsDNA) antibodies and/or hypocomplementemia, and without clinical activity. Cluster analysis was employed, utilizing 16 independent components to delineate phenotypes. Among the 4,107 patients with SLE, 990 (24.1%) achieved SACQ within 2.0± 2.3 years on average. Over a total follow-up of 7,105.1 patient years, 340 (34.3%) experienced flares, and 134 (13.5%) developed organ damage. Three distinct SACQ subgroups were identified. Cluster 1 (n= 219, 22.1%) consisted predominantly of elderly males with a history of major organ involvement at SLE diagnosis, showing the highest risk of severe flares (16.4%) and organ damage (27.9%). Cluster 2 (n= 279, 28.2%) was characterized by milder disease and a lower risk of damage accrual (5.7%). Notably, 86 patients (30.8%) in cluster 2 successfully discontinued low-dose glucocorticoids, with 49 of them doing so without experiencing flares. Cluster 3 (n= 492, 49.7%) featured the highest proportion of lupus nephritis and a moderate risk of organ damage (11.8%), with male patients showing significantly higher risk of damage (hazard ratio [HR]= 4.51, 95% confidence interval [CI], 1.82-11.79). This study identified three distinct SACQ clusters, each with specific prognostic implications. This classification could enhance personalized management for SACQ patients. This work was funded by the National Key R&D Program (2021YFC2501300), the Beijing Municipal Science& Technology Commission (Z201100005520023), the CAMS Innovation Fund (2021-I2M-1-005), and National High-Level Hospital Clinical Research Funding (2022-PUMCH-D-009).

Evaluating Safety and Clinical Activity of Front-line Treatment with Cadonilimab plus Chemotherapy in Advanced/Metastatic Nonsmall Cell Lung Cancer Harboring STK11 Genetic Aberration: A Protocol of Phase II Study

BackgroundCadonilimab is a first-in-class bispecific PD-1/CTLA-4 antibody. Serine/threonine kinase (STK11) mutation was shown to be related to low PD-L1 expression and objective response rate (ORR) in nonsmall cell lung cancer (NSCLC), resulting in poor progression-free survival (PFS) and overall survival (OS). Herein, we hypothesized that combining cadonilimab with chemotherapy could enhance antitumor immunity and extend survival in these patients. Consequently, we designed this study to explore the clinical activity and safety of cadonilimab combined with chemotherapy in patients with advanced/metastatic NSCLC harboring STK11 alteration. Trial designThis single-center, open-label, single-arm phase II trial is conducted at the first affiliated hospital of Guangzhou Medical University. Treatment-naïve advanced/metastatic NSCLC patients harboring STK11 mutation will be enrolled in this study. Eligible patients will receive either cadonilimab (10mg/kg on Day 1) plus pemetrexed (500 mg/m2) and carboplatin (AUC = 5) for nonsquamous NSCLC or abraxane (100 mg/m2) and carboplatin (AUC = 5) for squamous NSCLC for 4 cycles, followed by maintenance therapy (cadonilimab plus pemetrexed or abraxane). The treatment will be discontinued when disease progression, intolerability to cadonilimab, and/or chemotherapy occurs. Measurable lesions were assessed according to the Response Evaluation Criteria in Solid Tumors (1.1). The main endpoint is ORR and safety. Subordinate endpoints include PFS, disease control rate, and duration of response. ResultsThe study commenced enrolment in September 2023, with preliminary findings regarding the primary endpoint anticipated by January 2025.

Matrix-Assisted Autologous Chondrocyte Transplantation for the Treatment of Patellofemoral Chondral Lesions: Long-term Results at a Minimum 15-Year Follow-up.

A few studies have documented the long-term results of chondrocyte-based procedures for the treatment of patellofemoral cartilage lesions, but specific results are lacking after matrix-assisted autologous chondrocyte transplantation (MACT) for patellar and trochlear lesions. To document the clinical results of MACT for the treatment of patellar and trochlear chondral defects at long-term follow-up. Cohort study; Level of evidence, 3. A total of 44 patients were prospectively evaluated after MACT for patellofemoral lesions. There were 24 patients affected by patellar lesions, 16 by trochlear lesions, and 4 with both patellar and trochlear defects. Clinical outcomes were analyzed using the International Knee Documentation Committee (IKDC) subjective form, EuroQol visual analog scale, and Tegner score for sport activity level before surgery and at follow-up time points of 5, 10, and a minimum of 15 years (mean final follow-up, 17.6 ± 1.6 years). A Kaplan-Meier survival analysis was performed to examine the survival to failure. Failure was defined as the need for a second surgery because of the persistence of symptoms related to the primary defect. An overall significant improvement was documented from baseline to the last follow-up. The IKDC subjective score improved in the trochlear group from 41.0 ± 13.3 at baseline to 83.9 ± 21.6 at 5 years (P < .005), remaining stable up to the final follow-up (81.3 ± 20.5). In the patellar group, the IKDC subjective score improved from 36.1 ± 14.4 at baseline to 72.3 ± 17.5 at 5 years (P < .005), remaining stable up to the final follow-up (62.0 ± 20.3). Patients with trochlear lesions presented higher IKDC subjective scores compared with those with patellar lesions at 5 (P = .029), 10 (P = .023), and ≥15 years (P = .006) of follow-up. Similar trends were documented for the Tegner score, while no differences were documented for the EuroQol visual analog scale score between patellar and trochlear lesions. There were 4 failures (9.1%) during the follow-up period. The Kaplan-Meier survival analysis did not show statistically significant differences between trochlear and patellar lesions. This hyaluronic acid-based MACT technique offered positive and durable clinical outcomes with a low failure rate at long-term follow-up in patients affected by patellofemoral cartilage lesions. However, trochlear and patellar lesions demonstrated a notable difference in terms of clinical findings and sport activity level, with significantly higher results for patients with trochlear lesions but less satisfactory outcomes for patients with patellar lesions.

Discussion of the classification of pediatric drug clinical trials in children's hospitals in China.

This study aimed to gain insights into pediatric clinical trials conducted in children's hospitals in China and provide valuable references for the development of children's hospitals and the research and development of pediatric drugs. A comprehensive search was performed on the Chinese Clinical Trial Registry (Chi CTR) and ChinaDrugTrials.org.cn to collect information on all clinical trials involving subjects under 18 years, including those conducted in children's hospitals. The retrieval period was extended until 31 December 2022. A total of 459 pediatric clinical trials were collected, comprising 299 from Chi CTR and 160 from the Drug Clinical Trial Registration and Information Publicity Platform (Information Platform). Post-marketing drug studies and phase III clinical trials accounted for the majority of research stages. These trials covered a wide range of diseases/systems, with a particular focus on respiratory system disorders, tumors, endocrine disorders, and nutritional or metabolic diseases. Chemical drugs constituted the most extensively studied category, while traditional Chinese medicine/natural drugs received comparatively less attention. Clinical trial activities were primarily geographically focused on the eastern coastal regions of China, with multicenter trials being the most predominant. Ethics committee approval was obtained for 427 studies. The pediatric clinical trials conducted by children's hospitals in China have shown an overall upward trend; however, there is limited research focusing on traditional Chinese medicine, along with significant regional and institutional imbalances. Furthermore, there is still room for improvement regarding ethical review processes. It is recommended that children's hospitals enhance their scientific research capabilities while optimizing resource allocation to meet medical service demands effectively. Additionally, fostering more research-focused children's hospitals will contribute to the high-quality development of children's health in China.

Association of nutritional intake with clinical and imaging activity in pediatric multiple sclerosis

Background: Understanding nutrition’s role in multiple sclerosis (MS) can guide recommendations and intervention-based studies. Objective: Evaluate the association between nutrition and pediatric-onset MS outcomes. Methods: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase. Results: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07–1.86), and risk of T2 progression by 40% (1.40, 1.12–1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60–0.95), 45% (0.55, 0.32–0.96), and 15% (0.84, 0.74–0.96), respectively. No associations were found with EDSS. Conclusion: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation.

Relationship of serum and dietary vitamin D with high cardiometabolic risk in Mexican systemic lupus erythematosus patients: A cross-sectional study.

Objetive: Serum and dietary vitamin D could influence clinical disease activity and cardiometabolic outcomes in systemic lupus erythematosus (SLE). This study aimed to assess the relationship of serum and dietary vitamin D with cardiometabolic risk in Mexican SLE patients and healthy subjects (HS).Methods: 224 SLE patients and 201 HS were included in this cross-sectional study. Serum calcidiol was measured using a competitive enzyme-linked immunosorbent assay (ELISA). Vitamin D dietary intake was assessed by collecting three 24h food records. Dietary patterns (DPs) were identified using principal component analysis (PCA). Cardiometabolic status was analyzed through biochemical measurements and cardiometabolic indexes.Results: Calcidiol deficiency (<20 ng/mL) was associated with 1.66-fold higher risk of excess weight by body mass index (BMI) (≥25 kg/m2) (p = .02), 2.25-fold higher risk to low high-density lipoprotein-cholesterol (HDL-C) (<40 mg/dL) (p < .001), and 1.74-fold higher risk to high triglycerides (TG) ≥150 mg/dL (p = .02). Inadequate vitamin D dietary intake was associated with 1.92-fold higher risk of presenting non-healthy waist circumference (WC) (>80 cm) (p < .01), 2.05-fold higher risk of android waist to hip ratio (WHR ≥85) (p < .01), and 1.72-fold higher risk to excess weight (p = .02). Non-adherence to a DP rich in vitamin D food sources was associated with higher WC, WHR, triglycerides, and lower high-density lipoprotein-cholesterol (HDL-C); furthermore, in HS, non-adherence to the DP rich in vitamin D food sources provided 2.11-fold higher risk to calcidiol deficiency.In Cconclusion: A pattern of Calcidiol deficiency, inadequate vitamin D dietary intake, and non-adherence to a DP rich in vitamin D food sources was related to high cardiometabolic risk in SLE patients and HS.

The Rate of Re-treatment in Patients Treated with Teprotumumab: A Multicenter Study of 119 Patients with 1 Year of Follow-up

Objective or PurposeTo determine the rate of retreatment in patients who receive a full course of teprotumumab therapy for Thyroid Eye Disease (TED) and drivers of retreatment. DesignMulti center, retrospective study SubjectsAll patients who received a full course of treatment and had available data at 1 year post initial treatment were included. MethodsCharts were reviewed for the following information: age, gender, months since diagnosis of TED, smoking status, prior treatments. Further, the clinical activity score (CAS), proptosis and the Gorman diplopia score were reviewed at baseline, at the end of the first course and at baseline for the second course in those who received it. A logistic regression model was created to review the drivers of retreatment. Main Outcome MeasuresRate of retreatment and the drivers of retreatment. Results119 patients were included from 3 centers across the US. The overall retreatment rate was 24% (29/119). There was no difference between the 3 sites (p = 0.6). In univariate analyses, at baseline, there was no difference in proptosis (p = 0.07), diplopia score (p = 0.4) or duration of TED (p = 0.4), between retreated and non-retreated patients. From the retreated group, 82% had a significant proptosis response (≥ 2 mms reduction from baseline) following their initial course, while 68% of patients had a clinically significant proptosis response in the non-retreated group (p = 0.16). The use of other treatments prior to the first infusion of teprotumumab and baseline thyroid dysfunction, were not significantly different between the retreated and non-retreated groups (p = 0.06 and 0.09, respectively). The mean (SD) difference between the end of first treatment and at baseline prior to second treatment (in those who received it) was 2 (2) for CAS, 2 mms (4) for proptosis and 1 (1) for diplopia. Age as the only significant driver of retreatment (p < 0.05). Retreated patients were 7 years older than their non retreated counterparts (age 60 vs 53 (p < 0.05). ConclusionsIn patients receiving a full course of teprotumumab therapy, the rate of retreatment is 24%. Age is the only driver of retreatment.

Using the electronic health record to provide audit and feedback in medical student clerkships.

This article focuses on the role of the electronic health record (EHR) to generate meaningful formative feedback for medical students in the clinical setting. Despite the scores of clinical data housed within the EHR, medical educators have only just begun to tap into this data to enhance student learning. Literature to-date has focused almost exclusively on resident education. Development of EHR auto-logging and triggered notifications are discussed as specific use cases in providing enhanced feedback for medical students. By incorporating predictive and prescriptive analytics into the EHR, there is an opportunity to create powerful educational tools which may also support general clinical activity. This article explores the possibilities of EHR as an educational resource. This serves as a call to action for educators and technology developers to work together on creating health record user-centric tools, acknowledging the ongoing work done to improve student-level attribution to patients. EHR analytics and tools present a novel approach to enhancing clinical clerkship education for medical students.

Phase 1b study to assess the safety, tolerability, and clinical activity of pamiparib in combination with temozolomide in patients with locally advanced or metastatic solid tumors.

Pamiparib is a potent, selective, poly (ADP-ribose) polymerase 1/2 inhibitor that demonstrates synthetic lethality in cells with breast cancer susceptibility gene mutations or other homologous recombination deficiency. This two-stage phase 1b study (NCT03150810) assessed pamiparib in combination with temozolomide (TMZ) in adult patients with histologically confirmed locally advanced and metastatic solid tumors. Oral pamiparib 60 mg was administered twice daily. During the dose-escalation stage, increasing doses of TMZ (40-120 mg once daily pulsed or 20-40 mg once daily continuous) were administered to determine the recommended dose to be administered in the dose-expansion stage. The primary objectives were to determine safety and tolerability, maximum tolerated/administered dose, recommended phase 2 dose and schedule, and antitumor activity of pamiparib in combination with TMZ. Pharmacokinetics of pamiparib and TMZ and biomarkers were also assessed. Across stages, 139 patients were treated (dose escalation, n = 66; dose expansion, n = 73). The maximum tolerated dose of TMZ, which was administered during dose expansion, was 7-day pulsed 60 mg once daily. The most common treatment-emergent adverse events (TEAEs) were anemia (dose escalation, 56.1%; dose expansion, 63.0%), nausea (dose escalation, 54.5%; dose expansion, 49.3%), and fatigue (dose escalation, 48.5%; dose expansion, 47.9%). In the dose-escalation stage, four patients experienced dose-limiting toxicities (three neutropenia and one neutrophil count decreased). No TEAEs considered to be related to study drug treatment resulted in death. Antitumor activity was modest, indicated by confirmed overall response rate (dose escalation, 13.8%; dose expansion, 11.6%), median progression-free survival (3.7 and 2.8 months), and median overall survival (10.5 and 9.2 months). Administration of combination therapy did not notably impact pamiparib or TMZ pharmacokinetics. Pamiparib in combination with TMZ had a manageable safety profile. Further investigation of the efficacy of this combination in tumor types with specific DNA damage repair deficiencies is warranted.

[Translated article] Hospital pharmacy towards 2030

Hospital Pharmacy is today a profession marked by therapeutic advances, with a proactive attitude, focussed on people and their health. The evolution of processes is constant, with the full presence of digitalisation, robotisation, and even artificial intelligence, in an environment that also requires the efficient and sustainable use of these tools. In this context, it is necessary to have a roadmap that guides the advancement of the profession and Hospital Pharmacy Services.Continuing with the philosophy of the 2020 initiative which, with the slogan “Towards the future, safely”, defined the strategic lines to advance in the improvement of Hospital Pharmacy practice, the Spanish Society of Hospital Pharmacy wanted to raise the challenges the profession is currently facing and with a view to 2030.With this strategic planning objective, 20 challenges have been identified and developed, which cover the different areas of action and involvement of Hospital Pharmacy and which cover clinical activities, transversal aspects, training, and research, as well as areas related to people and to the organisations or health systems. For each of them, the objectives, standards, tools, and resources have been defined. It is also planned to provide tools that facilitate monitoring of implementation and the impact on the profession, patients, and the environment.

Subcutaneous Injections of Triamcinolone Acetonide for Upper Eyelid Retraction and Swelling Associated with Thyroid Eye Disease: A Retrospective Case Series Study.

To evaluate the efficacy of subcutaneous injection of triamcinolone acetonide (SCTA) in treating upper eyelid retraction and swelling in patients with thyroid eye disease (TED). This case series included consecutive patients (aged 16-69 years, monitored from June 2012 to December 2015) with TED-related eyelid symptom and without an enlarged extraocular muscle on magnetic resonance imaging (MRI). SCTA (0.5 mL, 40 mg/mL) was administered to target the orbital fat around the levator palpebrae superioris (LPS) muscle. Patients who did not exhibit improvement after the first trial received an additional injection. Follow-up was conducted for 12 months with 3-month intervals. Eyelid retraction, eyelid swelling, and eyelid lag were evaluated at each follow-up visit. In total, 116 eyelids of 102 patients were analyzed. SCTA led to significant improvement in 93% of eyes (108/116), disappearance of eyelid symptoms (74%, 87%, and 73% in retraction, swelling, and lag, respectively), and improvement of scores (from 1.64 to 0.12, 1.32 to 0.26, and 1.72 to 0.30, respectively). Improvement in eyelid symptoms was observed in eight eyes; however, additional steroid therapy was required in these cases due to the emergence of other extraocular muscle inflammation. Additional injection was required in 39.8% of patients. The clinical activity score was lower in the single SCTA group than in the multiple SCTA group (1.5 vs 0.9; p < 0.01). However, the levels of thyroid-stimulating hormone receptor antibody and MRI findings were not significantly different between the two groups. No elevation in intraocular pressure was observed. Eight female patients experienced menstrual disorder. SCTA effectively reduced LPS muscle enlargement and fat tissue swelling in patients with TED. A single SCTA was sufficient in almost 60% of the patients; nevertheless, follow-up is necessary to detect early signs of orbital inflammation even in eyelid-symptom-improved patients.

Long-Term Efficacy of Teprotumumab in Thyroid Eye Disease: Follow-Up Outcomes in Three Clinical Trials.

Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responsesfrom the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.

Imaging-based detection of anterior chamber inflammation: a comparative diagnostic accuracy study

PurposeWe investigated the impact of operator parameters on the diagnostic performance of danterior segment optical coherence tomography (AS-OCT) in anterior uveitis. DesignProspective comparative diagnostic analysis. MethodsSetting: Single site.Study Population: Children aged under 18 years with anterior uveitis, recruited consecutively.Observation Procedures: Index testing: Optovue RTVue80 AS-OCT using ‘low-volume’ (LV, horizontal and vertical cross-sections) and ‘high-volume’ (HV, 68 horizontal cross-sections) protocols. Reference testing: slit lamp examination with anterior chamber inflammation graded using standardisation of uveitis nomenclature (SUN).Main Outcome Measure: Index test performance metrics (sensitivity, specificity, likelihood ratios), utility for ‘ruling-in’ and ‘ruling-out’ disease (positive / negative predictive values, PPV/NPV), receiver operating characteristic (ROC) curves to explore the impact of different imaging derived metrics, multivariable multilevel regression analyses to quantify correlation of index to reference testing, and repeatability indices across protocols. Results40 children (77 eyes: 51 eyes at SUN grade 0, 10 at SUN0.5+, 8 at SUN1+, 8 SUN≥2+ or higher) were included. There was high repeatability across protocols (0.98, p<0.001, 95% CI 0.75-1.0). OCT resulted in strong predictive values for ‘ruling-out’ (LV-scan NPV 82.9%, 95% CI 71.5 - 90.4%; HV-scan NPV 100%, 95% CI 3% to 100%), and but less predictive value for ‘ruling-in’ SUN≥0.5+ (LV-scan PPV 52.8% 95% CI 41.5 - 63.7%; HV-scan PPV 34.2%, 95% CI 33.3 to 35.1%). Detection of more than 1 cell within a cross sectional scan was strongly suggestive of clinical activity, with area under the curve of 0.76 (95% CI 0.62 - 0.89) for SUN≥0.5+, and 0.85 (95% CI 0.73- 0.98), for the detection of SUN≥1+. Cell count correlated with SUN grades at higher levels of inflammation (SUN≥2+ both protocols, SUN≥1+ HV-scans). There was an independent positive association between age and AS-OCT cell (adjusted correlation coefficient 0.2 cells for each additional year of age). ConclusionsOperator dependent factors impact the diagnostic and quantification performance of AS-OCT for anterior chamber inflammation. However, the strong, ‘dose-respondent’ correlation of low-volume protocols with SUN grading promises clinical utility without the storage and analysis burden of high-volume approaches. Further work will involve exploration of the need for age-specific image metric interpretation.