KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.

BACKGROUND AND AIMS: Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). Herein, the pathologic phenotype in transgenic LQT1 rabbits is rescued using a novel KCNQ1 suppression-replacement (SupRep) gene therapy. METHODS: KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection (1E10 vg/kg). To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. RESULTS: KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared to LQT1 controls, leading to levels similar to WT (LQT1-UT vs. LQT1-SupRep, P < .0001, LQT1-SupRep vs. WT, P = ns). Under ß-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. CONCLUSIONS: This study provides the first animal-model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalized the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1.

Single procedure tibialis anterior tendon shortening in combination with Achilles tendon lengthening in unilateral cerebral palsy improves swing phase dorsiflexion in gait.

Purpose: Tibialis anterior tendon shortening combined with tendon Achilles lengthening showed satisfactory short- and long-term outcomes for pes equinus treatment. This retrospective study aimed to evaluate the effectiveness of a single tibialis anterior tendon shortening-tendon Achilles lengthening procedure for treating pes equinus, in a homogeneous unilateral cerebral palsy patient group. Methods: Gait analysis was conducted on 22 unilateral cerebral palsy patients (mean age at surgery = 13.3 years, standard deviation = 3 years) before and within 2.5 years (standard deviation = 0.61 years) after the tibialis anterior tendon shortening-tendon Achilles lengthening procedure. Primary outcome measures included foot drop occurrence in swing, foot dorsiflexion and the first ankle rocker presence compared to healthy reference data. Movement analysis profile and gait profile score were also calculated for the entire gait cycle. The clinical exam and the A2 peak ankle power were analyzed. Statistical analysis used the paired Wilcoxon's sign rank test (p < 0.05). Results: Post-operatively, significant improvements were observed in ankle dorsiflexion during swing (p = 0.0006) and reduced foot drop in swing (p = 0.0107). The occurrence of a first ankle rocker did not significantly change (p = 0.1489). Significant improvements in gait profile score and movement analysis profile for all joints and planes indicate overall gait quality improvement. The foot progression changed significantly (p = 0.0285), with a greater external orientation. Nineteen out of 22 patients were able to quit wearing their ankle foot orthoses. Conclusion: Tibialis anterior tendon shortening and tendon Achilles lengthening combination yielded positive outcomes, showing increased foot dorsiflexion, first ankle rocker presence, and overall improved gait quality. These findings support the effectiveness of this surgical approach for treating pes equinus in children with unilateral spastic cerebral palsy.

Revisiting Childhood-Onset Systemic Lupus Erythematosus.

Childhood-onset systemic lupus erythematosus (cSLE) is a chronic autoimmune disease with a multisystemic involvement diagnosed during childhood. The disease is marked by the production of autoantibodies targeting self-antigens, often before symptoms emerge. The presentation, clinical course, and outcome vary significantly among patients with cSLE. The onset of cSLE can be at any age during childhood while a diagnosis of cSLE before the age of 5 years is rare and raises a suspicion of monogenic lupus. Childhood-onset systemic lupus erythematosus affects various organs and systems, most frequently presenting with mucocutaneous, musculoskeletal, renal, and neuropsychiatric manifestations. Multiple disease flares can be seen during the disease course. Childhood-onset systemic lupus erythematosus causes significant morbidity and mortality. Children and adolescents with cSLE show higher disease activity and damage, and more aggressive immunosuppressive treatments are needed compared to adultonset SLE. Early diagnosis can be difficult due to the insidious onset with nonspecific symptoms. Disease activity and damage measures aim to ensure an accurate evaluation of disease status. A multidisciplinary approach and individualized disease management are important. Disease management is complex including the control of disease activity, the reduction of flares and damage, and a limitation of drug toxicity while improving the health-related quality of life in patients with cSLE.

Recurrence pattern and its risk factors in patients with resected pancreatic ductal adenocarcinoma - A retrospective analysis of 272 patients.

BACKGROUND: The aim of this study was to investigate the patterns of recurrence and their associated risk factors in patients who underwent resection for pancreatic carcinoma. METHODS: This retrospective study included 272 patients, who underwent Ro/R1-resection of PDAC from 2005 to 2020 at the University Hospital Erlangen. Risk factors for different recurrence patterns and the prognostic value of recurrence pattern on the overall survival after recurrence were evaluated. RESULTS: 61 % of the patients experienced recurrence, mostly within the first 12 postoperative months (62 %) and in the form of metastases (87 %). The median overall survival from recurrence was 9.2 months. The preoperative absence of diabetes and the presence of lymph node metastasis were independent risk factors for recurrence and a preoperative CA19-9 exceeding 97 U/ml for early recurrence. Additionally, lymph node metastases were associated with a higher risk of metastatic recurrence. Early recurrence, but not the site of recurrence, was identified as an independent prognostic factor for worse overall survival from recurrence. CONCLUSION: The occurrence of recurrence and especially of early and metastatic recurrence are associated with a worse overall survival. Patients lacking preoperative diabetes, having high preoperative CA19-9 values and lymph node metastases are particularly at risk for (early) recurrence.

Return to Driving Following Moderate-to-Severe Traumatic Brain Injury: A TBI Model System Longitudinal Investigation.

OBJECTIVE: To examine longitudinal patterns of return to driving (RTD), driving habits, and crash rates associated with moderate-to-severe traumatic brain injury (TBI). SETTING: Eight TBI Model System sites. PARTICIPANTS: Adults (N = 334) with TBI that required inpatient acute rehabilitation with follow-up of 197 and 218 at 1 and 2 years post-injury, respectively. Data collection at 2 years occurred almost exclusively during the pandemic, which may have affected results. DESIGN: Longitudinal and observational. MAIN MEASURES: Driving survey completed during rehabilitation and at phone follow-up 1 and 2 years after injury. RESULTS: The rate of RTD was 65% at 1-year follow-up and 70% at 2-year follow-up. RTD at both follow-up time points was positively associated with family income. The frequency of driving and distance driven were diminished compared to before injury. Limitation of challenging driving situations (heavy traffic, bad weather, and at night) was reported at higher rates post-injury than before injury. Crash rates were 14.9% in the year prior to injury (excluding crashes that resulted in TBI), 9.9% in the first year post-injury, and 6% during the second year. CONCLUSION: RTD is common after TBI, although driving may be limited in terms of frequency, distance driven, and avoiding challenging situations compared to before injury. Incidence of crashes is higher than population-based statistics; however, those who sustain TBI may be at higher risk even prior to injury. Future work is needed to better identify characteristics that influence the likelihood of crashes post-TBI.

Sleep quality and the cortisol and alpha-amylase awakening responses in adolescents with depressive disorders.

BACKGROUND: Depressive disorders in adolescents affect all aspects of life and impose a very large burden of disease. Sleep is frequently affected by depression and is crucial for facing challenges during development. One of the postulated reasons for depression-induced sleep disruption is dysregulation of the physiological stress system. AIMS: To investigate the links of adolescent depressive disorders with subjective sleep quality, objective sleep quality, and the course of cortisol and alpha-amylase after awakening. METHOD: We compared subjective sleep quality (via daily questionnaires) and objective sleep quality (via actigraphy measurement) of 35 adolescents with depressive disorders and 29 healthy controls over 7 consecutive days. In addition, saliva samples were collected on 3 days to examine cortisol and alpha-amylase patterns after awakening. RESULTS: No significant differences in cortisol or alpha-amylase awakening responses were observed between participants with depressive disorders and healthy controls. We found severe reductions in subjective sleep quality in the depression group (Z = -5.19, P < 0.001, d = 1.80) and a prolonged actigraphy-measured sleep onset latency (Z = -2.42, P = 0.015, d = 0.64) compared with controls. Reductions in subjective sleep quality were partially correlated with objective sleep measures (sleep onset latency: r = -0.270, P = 0.004, sleep efficiency: r = 0.215, P = 0.017). CONCLUSIONS: Sleep onset latency seems to aggravate depressive symptoms and to have an important role in perception of sleep quality. Adolescents with depressive disorders should be supported regarding the establishment of good sleep hygiene and avoiding activities that may impede falling asleep.

Fasting induces metabolic switches and spatial redistributions of lipid processing and neuronal interactions in tanycytes.

The ependyma lining the third ventricle (3V) in the mediobasal hypothalamus plays a crucial role in energy balance and glucose homeostasis. It is characterized by a high functional heterogeneity and plasticity, but the underlying molecular mechanisms governing its features are not fully understood. Here, 5481 hypothalamic ependymocytes were cataloged using FACS-assisted scRNAseq from fed, 12h-fasted, and 24h-fasted adult male mice. With standard clustering analysis, typical ependymal cells and ß2-tanycytes appear sharply defined, but other subpopulations, ß1- and α-tanycytes, display fuzzy boundaries with few or no specific markers. Pseudospatial approaches, based on the 3V neuroanatomical distribution, enable the identification of specific versus shared tanycyte markers and subgroup-specific versus general tanycyte functions. We show that fasting dynamically shifts gene expression patterns along the 3V, leading to a spatial redistribution of cell type-specific responses. Altogether, we show that changes in energy status induce metabolic and functional switches in tanycyte subpopulations, providing insights into molecular and functional diversity and plasticity within the tanycyte population.

Does it need an app? - Differences between app-guided breathing and natural relaxation in adolescents after acute stress.

A key component of stress management and biofeedback training is the use of relaxation exercises, such as slow/deep breathing (6 breaths/minute) in heart coherence exercises (HCEs). Breathing exercises are also increasingly being integrated into smartphones as part of health apps, though their effectiveness in adolescents after acute stress has rarely been validated scientifically. The aim of the current study was to investigate the effectiveness of an app-guided HCE (n = 36) after an acute stress situation (Trier Social Stress Test) compared with natural relaxation (n = 37), among healthy adolescents (aged 11-17 years). Endocrine, autonomic, and psychological stress parameters (cortisol, alpha-amylase, heart rate, heart rate variability, mood) were examined in 73 adolescents (46 female, 27 male; Mage = 13.86, SDage = 1.87). Significant group differences were found in heart rate variability, with higher values in the low frequency band and low-to-high frequency ratio for the HCE condition, possibly indicating improved physiological functions through the stimulation of vagal tone and baroreflex. The use of a general breathing technique (natural and app-guided) also resulted in stronger relaxation reactions in cortisol when controlling for the previous stronger stress reactivity. On the other hand, app-guided slow breathing without a long training may be experienced as more uncomfortable during relaxation. The integration of breathing exercises in health apps for adolescents appears to be useful, offering a helpful and low-threshold coping/relaxation strategy during acute stress situations. Further studies should examine the benefits of app-guided breathing exercises in both psychiatric samples and the general population across a wide age range.

Homocysteine contributes to atherogenic transformation of the aorta in rabbits in the absence of hypercholesterolemia.

Atherosclerosis, the leading cause of cardiovascular disease, cannot be sufficiently explained by established risk factors, including cholesterol. Elevated plasma homocysteine (Hcy) is an independent risk factor for atherosclerosis and is closely linked to cardiovascular mortality. However, its role in atherosclerosis has not been fully clarified yet. We have previously shown that rabbits fed a diet deficient in B vitamins and choline (VCDD), which are required for Hcy degradation, exhibit an accumulation of macrophages and lipids in the aorta, aortic stiffening and disorganization of aortic collagen in the absence of hypercholesterolemia, and an aggravation of atherosclerosis in its presence. In the current study, plasma Hcy levels were increased by intravenous injections of Hcy into balloon-injured rabbits fed VCDD (VCDD+Hcy) in the absence of hypercholesterolemia. While this treatment did not lead to thickening of aortic wall, intravenous injections of Hcy into rabbits fed VCDD led to massive accumulation of VLDL-triglycerides as well as significant impairment of vascular reactivity of the aorta compared to VCDD alone. In the aorta intravenous Hcy injections into VCDD-fed rabbits led to fragmentation of aortic elastin, accumulation of elastin-specific electron-dense inclusions, collagen disorganization, lipid degradation, and autophagolysosome formation. Furthermore, rabbits from the VCDD+Hcy group exhibited a massive decrease of total protein methylated arginine in blood cells and decreased creatine in blood cells, serum and liver compared to rabbits from the VCDD group. Altogether, we conclude that Hcy contributes to atherogenic transformation of the aorta not only in the presence but also in the absence of hypercholesterolemia.

Multi-omics analysis of overexpressed tumor-associated proteins: gene expression, immunopeptide presentation, and antibody response in oropharyngeal squamous cell carcinoma, with a focus on cancer-testis antigens.

Introduction: The human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets. Materials and methods: Snap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins). Results: 183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR<0.05). Low concordance (r=0.25; p<0.0001) was found between upregulated mRNA and class I TAP. The specific mode of correlation of TAP was found to be dependent on clinical parameters. A lack of correlation was observed both between mRNA and class II TAP, as well as between class II tumor-unique TAP (TAP-U) presentation and antibody response (AR) levels. Discussion: This study demonstrates that focusing exclusively on gene transcript levels fails to capture the full extent of TAP presentation in OPSCC. Furthermore, our findings reveal that although CTA are presented at relatively low levels, a few CTA TAP-U show potential as targets for immunotherapy.

Biomarker Changes in Response to Tofacitinib Treatment in Patients with Polyarticular Course Juvenile Idiopathic Arthritis.

OBJECTIVE: Examine levels of candidate blood-based biomarkers (CBB) in juvenile idiopathic arthritis (JIA) treated with tofacitinib. METHODS: JIA patients who participated in clinical trial NCT02592434 received tofacitinib from baseline to week 18. Serial serum samples were assayed for CBB (S100A8/9, S100A12, IL-18, SAA, resistin, VEGF, Angiopoietin-1, Angiopoietin-2, MMP8, MMP2, TIMP1, Leptin, CXCL9, sIL2R, ICAM-1, sTNFr, IL-6, IL-23, MCP1, CCL18, and CCL20). Association of CBB with JIA response to treatment from baseline to week 18 were assessed. RESULTS: This study included 166 patients with polyarticular-course JIA. Paired serum samples from 143 patients were available at both baseline and week 18. There were 35% (50/143) of patients with a JIA-American College of Rheumatology 90 (JIA-ACR90) level improvement while 90/121/137 (63%/85%/96%) achieved JIA-ACR70/50/30 improvement at wk18. Despite small numerical differences by JIA category, there were no baseline CBB values that independently predicted a decrease in JADAS-27 or JIA-ACR90 response by week 18. Decrease in resistin level (baseline to week 18) was significantly associated with wk18 improvement in JADAS-27 and JIA-ACR90 response, after adjusting for age, sex, JIA disease duration and baseline resistin [(r2 0.79, SE, 0.070, p<0.01 and OR(95%CI) = 1.134(1.018, 1.264)]. HLA-B27 positivity was significantly associated with not achieving a JIA-ACR90 response at week 18 (p=0.0097). CONCLUSION: Among the CBB included, only resistin was significantly associated with treatment response, and no CBB was identified that forecasts JIA improvement after initiation of tofacitinib. The association of HLA-B27 positivity with lower response to tofacitinib in JIA is intriguing and merits further study.

Nurse Well-Being and Patient-Specific Outcomes: A Scoping Review.

BACKGROUND: The health and well-being of the nursing workforce has received recent attention due to nurse attrition and the critical nurse shortages projected across the country. A nurse's well-being may impact patient outcomes. PURPOSE: The purpose of this scoping review was to assess the association between nurse well-being factors and specific patient outcomes. METHODS: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) PRISMA Scoping Review protocol and 2020 reporting guidelines were utilized in this review. RESULTS: Staffing, environment, physical health, and mental health of nurses were correlated to specific adverse patient outcomes among the 97 articles included in the final review. The majority of the articles reported significant findings. CONCLUSIONS: Patient outcomes were reviewed as discrete events in the articles examined. With mixed results found on key patient outcomes, future research requires more in-depth investigation into the role nurse well-being has on patient outcomes.

Single-cell RNA sequencing comparison of CD4+, CD8+ and TCR-γδ+ cutaneous T-cell lymphomas reveals subset-specific molecular phenotypes.

BACKGROUND: Malignant clones of primary cutaneous T-cell lymphomas (CTCL) can show a CD4, CD8 or TCR-γδ phenotype, but their individual impact on tumor biology and skin lesion formation remains ill-defined. OBJECTIVES: To perform a comprehensive molecular characterization of CD4+ vs. CD8+ and TCR-γ/δ+ CTCL lesions. METHODS: We performed scRNA-seq of 18 CTCL skin biopsies to compare classic CD4+ advanced-stage mycosis fungoides (MF) with TCR-γ/δ+MF and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti's lymphoma). RESULTS: Malignant clones of TCR-γ/δ+MF and Berti's lymphoma showed similar clustering patterns distinct from CD4+MF, along with increased expression of cytotoxic markers such as NKG7, CTSW, GZMA, and GZMM. Only advanced-stage CD4+MF clones expressed central memory T-cell markers (SELL, CCR7, LEF1), alongside B1/B2 blood involvement, whereas TCR-γ/δ+MF and Berti's lymphoma harbored a more tissue-resident phenotype (CD69, CXCR4, NR4A1) without detectable cells in the blood. CD4+MF and TCR-γ/δ+MF skin lesions harbored strong type 2 immune activation across myeloid cells, while Berti's lymphoma was more skewed towards type 1 immune responses. Both CD4+MF and TCR-γ/δ+MF lesions showed upregulation of keratinocyte hyperactivation markers such as S100As and KRT16 genes. This increase was entirely absent in Berti's lymphoma, possibly reflecting an aberrant keratinocyte response to invading tumor cells, that could contribute to the formation of the typical ulcero-necrotic lesions within this entity. CONCLUSIONS: Our scRNAseq profiling study reveals specific molecular patterns associated with distinct CTCL subtypes.

Identification of a DNA methylation episignature for recurrent constellations of embryonic malformations.

The term "recurrent constellations of embryonic malformations" (RCEM) is used to describe a number of multiple malformation associations that affect three or more body structures. The causes of these disorders are currently unknown, and no diagnostic marker has been identified. Consequently, providing a definitive diagnosis in suspected individuals is challenging. In this study, genome-wide DNA methylation analysis was conducted on DNA samples obtained from the peripheral blood of 53 individuals with RCEM characterized by clinical features recognized as VACTERL and/or oculoauriculovertebral spectrum association. We identified a common DNA methylation episignature in 40 out of the 53 individuals. Subsequently, a sensitive and specific binary classifier was developed based on the DNA methylation episignature. This classifier can facilitate the use of RCEM episignature as a diagnostic biomarker in a clinical setting. The study also investigated the functional correlation of RCEM DNA methylation relative to other genetic disorders with known episignatures, highlighting the common genomic regulatory pathways involved in the pathophysiology of RCEM.

Cephalosporin Allergy: Updates on Diagnostic Testing.

PURPOSE OF REVIEW: Cephalosporins are one of the most prescribed antibiotics worldwide and are implicated in a wide range of hypersensitivity reactions (HSR). This review summarizes recent updates in cephalosporin hypersensitivity with a focus on diagnostic testing. RECENT FINDINGS: Reported testing strategies to evaluate different immediate and delayed cephalosporin HSR have included skin testing, in vitro testing, and diagnostic drug challenges. However, the diagnostic performance of in vivo and in vitro tests remains unclear across different hypersensitivity endotypes; adequately powered studies investigating the true positive and negative predictive value of these diagnostic modalities are needed using the reference standard of drug challenges to define cephalosporin hypersensitivity. Refinement of diagnostic testing should be guided by growth in our understanding of cephalosporin antigenic determinants. This growth will be crucial in driving further clarification of cross-reactivity between cephalosporins, and potentially delineating streamlined evaluation processes resulting in reduced unnecessary antibiotic avoidance.

Compounding Trade Association Issues Ketamine, Office Pay Best Practices APC Also Updated Position Statements on Constructive Transfer and Peptide Compounding.

The Alliance for Pharmacy Compounding recently released four resource documents aimed at shaping compounding best practices and regulatory compliance.

Impact of PM2.5 exposure in old age and its interactive effect with smoking on incidence of diabetes.

PURPOSE: To determine the impact of PM2.5 exposure in old age and its interactive effect with smoking on incident diabetes. METHODS: A total of 2766 participants aged ≥60 years in China were interviewed at baseline for disease risk factors in 2001-03 and were then followed up for 10 years to document incident diabetes. They were assessed for daily PM2.5 exposure in 2005. Multivariate Cox regression models were used to examine the association of PM2.5 exposure with incident diabetes and interactive effect between PM2.5 and smoking on incident diabetes. RESULTS: During the cohort follow-up, 176 participants developed diabetes. The incidence of diabetes increased with PM2.5 exposure; the multiple-adjusted hazard ratio (HR) of diabetes was 2.27 (95 % CI 1.36-3.77) in participants with PM2.5 at ≥62.0 µg/m3 compared to those with <62.0 µg/m3. There was a significant interaction effect of PM2.5 with smoking on increased risk of diabetes. The adjusted HR for participants exposed to PM2.5 levels ≥62.0 µg/m3 who smoked was 4.39 (95 % CI 1.72-11.21), while for non-smokers it was 1.65 (95 % CI 0.88-3.09), compared to those with <62.0 µg/m3. CONCLUSIONS: Exposure to PM2.5 in old age was associated with an increased incidence of diabetes and smoking enhanced the impact of PM2.5 on diabetic risk. These findings underscore the urgent need for air quality improvement measures and smoking cessation programs to mitigate the risk of diabetes in aging populations.

Redisplacement rate after bony hip reconstructive surgery in nonambulatory patients with cerebral palsy: a systematic review and meta-analysis.

Purpose: Up to 90% of nonambulatory patients with cerebral palsy (CP) experience hip displacement during their lifetime. Reconstructive surgery is recommended. Redisplacement rate is an outcome parameter. Methods: In a systematic literature review (MEDLINE, Embase and CENTRAL databases) until January 2023 we searched for reports with redisplacement rates after bony hip reconstructive surgery in nonambulatory patients. Quantitative data synthesis, subgroup analysis and meta-regression with moderators were carried out. Results: The pooled mean redisplacement rate was 16% (95% CI: 12-21%) with a prediction interval of 3-51% (Q: 149; df: 32; P < 0.001; I2: 78%; τ2: 0.67 and τ: 0.82) in 28 studies (1540 hips). Varus derotation osteotomy (VDRO) alone showed a higher redisplacement rate than VDRO + pelvic osteotomy (30% vs 12%, P < .0001). Mean age in the VDRO-alone subgroup was 7.1 years and in the combined group 9.5 years (P = .004). In meta-regression, lower redisplacement rates were observed with higher preoperative migration index (MI) (correlation coefficient: -0.0279; P = .0137), where comprehensive surgery was performed. Variance in true effects are explained by type of bone surgery (57%), preoperative MI (11%), age (5%) and MI for definition of failure (20%). No significant reduction in the redisplacement rate could be observed over the mid-years of studies (1977-2015). Conclusion: Our pooled data support the more extensive surgical approach in patients with high preoperative MI and emphasize the superiority of combined surgery. Studies should report a coordinated set of parameters and outcome classifications according to internationally accepted gradings to reduce redisplacement in future.

Intravenous Golimumab in Children with Polyarticular-Course Juvenile Idiopathic Arthritis: Long-term Extension of an Open-label, Phase 3 Study.

OBJECTIVE: Report pharmacokinetics, immunogenicity, clinical effect, and safety of intravenous golimumab in children with active polyarticular-course juvenile idiopathic arthritis (pcJIA) who participated in the GO-VIVA study open-label long-term extension (LTE) through Week 252. METHODS: GO-VIVA participants who continued intravenous golimumab (80 mg/m2 every 8 weeks) after Week 52 were included. Pharmacokinetics and safety were assessed through Week 244 (last dose) and Week 252, respectively, and clinical response through Week 116. Clinical outcomes included JIA American College of Rheumatology (ACR) responses and clinical Juvenile Arthritis Disease Activity Score based upon 10 joints (cJADAS-10). Binary outcomes used nonresponder imputation; other descriptive analyses used observed data. RESULTS: Of 112/127 (88.2%) participants entering the LTE, 69 completed the Week-252 visit. Median steady-state trough golimumab concentrations were generally maintained from Weeks 52 through 244 (range, 0.3-0.6 µg/mL). Anti-golimumab antibody rates were consistent through Week 52 (39.2% [49/125]) and Week 244 (44.8% [56/125]). Week-52 JIA ACR 30/50/70/90 response rates (75.6% [96/127]/74.0% [94/127]/65.4% [83/127]/48.8% [62/127], respectively) were generally maintained through Week 116 (72.4% [92/127]/71.7% [91/127]/63.8% [81/127]/50.4% [64/127], respectively), when the median cJADAS-10 was 1.6 and 56.7% (72/127) of participants achieved JADAS-10 ≤5 (minimal disease activity). Rates (per 100 patient-years) of serious adverse events and serious infections through Week 252 were 7.7 and 3.9, respectively. CONCLUSION: GO-VIVA LTE participants experienced adequate pharmacokinetic exposure and stable safety and immunogenicity. The majority of participants experienced no more than minimal residual disease activity. Data suggest intravenous golimumab treatment provided durable clinical response through Week 116, with an acceptable benefit-risk profile.

Evaluation of score-based tertiary triage policies during the COVID-19 pandemic: simulation study with real-world intensive care data.

OBJECTIVE: The explicit prohibition of discontinuing intensive care unit (ICU) treatment that has already begun by the newly established German Triage Act in favor of new patients with better prognoses (tertiary triage) under crisis conditions may prevent saving as many patients as possible and therefore may violate the international well-accepted premise of undertaking the "best for the most" patients. During the COVID-19 pandemic, authorities set up lockdown measures and infection-prevention strategies to avoid an overburdened health-care system. In cases of situational overload of ICU resources, when transporting options are exhausted, the question of a tertiary triage of patients arises. METHODS: We provide data-driven analyses of score- and non-score-based tertiary triage policies using simulation and real-world electronic health record data in a COVID-19 setting. Ten different triage policies, for example, based on the Simplified Acute Physiology Score (SAPS II), are compared based on the resulting mortality in the ICU and inferential statistics. RESULTS: Our study shows that score-based tertiary triage policies outperform non-score-based tertiary triage policies including compliance with the German Triage Act. Based on our simulation model, a SAPS II score-based tertiary triage policy reduces mortality in the ICU by up to 18 percentage points. The longer the queue of critical care patients waiting for ICU treatment and the larger the maximum number of patients subject to tertiary triage, the greater the effect on the reduction of mortality in the ICU. CONCLUSION: A SAPS II score-based tertiary triage policy was superior in our simulation model. Random allocation or "first come, first served" policies yield the lowest survival rates, as will adherence to the new German Triage Act. An interdisciplinary discussion including an ethical and legal perspective is important for the social interpretation of our data-driven results.