First validation of the childhood lupus low disease activity state (cLLDAS) definition in a real-life longitudinal cSLE cohort.

OBJECTIVES: To validate the childhood lupus low disease activity state (cLLDAS) definition in cSLE by describing differences in time to reach first adult LLDAS (aLLDAS) versus cLLDAS. Secondly, to analyse positive and negative predictors for maintaining cLLDAS for at least 50% of follow-up time (cLLDAS-50) and for the occurrence of damage. METHODS: Prospective longitudinal data from a cSLE cohort were analysed. Used definitions were: aLLDAS according to Franklyn, cLLDAS by cSLE treat-to-target (T2T) Task Force, disease activity score by SLEDAI -2 K and damage by SLICC damage index. RESULTS: Fifty cSLE patients were studied, with a median follow-up of 3.1 years. Each patient reached aLLDAS and cLLDAS at least once. Mean time to reach first aLLDAS/cLLDAS was 8.2/9.0 months, respectively. For 22/42 patients the mean steroid-dose related delay to reach first cLLDAS was 6.2 months. 58% of patients were able to maintain cLLDAS-50. Time to first cLLDAS (OR 0.8, p = 0.013) and higher number of flares (OR 0.374, p = 0.03) were negative predictors to maintain cLLDAS-50. Damage occurred in 34% of patients (23.5% steroid-related), in 64.7% within one year after diagnosis. African/Afro-Caribbean ethnicity, neuropsychiatric involvement and ever use of a biologic were significant predictors for damage. CONCLUSION: Time to reach cLLDAS in cSLE differs from time to (a)LLDAS, which validates the new cLLDAS definition. Attaining cLLDAS-50 was difficult in real-life. This cohort shows the high risk for early damage in cSLE. T2T with earlier focus on steroid-tapering and starting steroid-sparing drugs seems important to prevent (steroid-related) damage in cSLE.

Prevalence and Predictors of Young-Onset Colorectal Neoplasia: Insights From a Nationally Representative Colonoscopy Registry.

BACKGROUND & AIMS: A disturbing increase in early-onset colorectal cancer (EOCRC) has prompted recent guidelines to recommend lowering the colorectal cancer (CRC) screening starting age from 50 to 45 years old for average-risk individuals. Little is known about the prevalence of colorectal neoplasia in individuals between 45 and 49 years old, or even younger, in the United States. We analyzed a large, nationally representative data set of almost 3 million outpatient colonoscopies to determine the prevalence of, and risk factors for, colorectal neoplasia among patients aged 18 to 54. METHODS: Findings from high-quality colonoscopies were analyzed from AMSURG ambulatory endoscopy centers (ASCs) that report their results in the GI Quality Improvement Consortium (GIQuIC) Registry. Logistic regression was used to identify risk factors for EOCRC. RESULTS: Increasing age, male sex, White race, family history of CRC, and examinations for bleeding or screening were all associated with higher odds of advanced premalignant lesions (APLs) and CRC. Among patients aged 45 to 49, 32% had any neoplasia, 7.5% had APLs, and 0.58% had CRC. Rates were almost as high in those aged 40 to 44. Family history of CRC portended neoplasia rates 5 years earlier. Rates of APLs were higher in American Indian/Alaskan Natives, but lower among Blacks, Asians, and Hispanics, compared with White counterparts. The prevalence of any neoplasia and APL gradually increased between 2014 and 2019, in all age groups. CONCLUSIONS: These data provide support for lowering the screening age to 45 for all average-risk individuals. Early messaging to patients and providers in the years leading up to age 45 is warranted, especially in those with a family history of CRC.

Pharmacodynamics of rituximab in paediatric immune mediated diseases: B cell depletion and repopulation, effects on immunoglobulin levels and risk for infections.

OBJECTIVES: Rituximab (RTX), used for treatment in paediatric immune-mediated diseases, can lead to hypogammaglobulinaemia and thus to an increased risk of infection, but data on these adverse effects in children are scarce. We aimed to describe the pharmacodynamics of RTX by time to B cell repopulation in paediatric immune-mediated diseases and to assess whether low post-RTX immunoglobulin levels were associated with frequency and severity of infections. METHODS: Data of children with autoimmune diseases (AID), immune dysregulation (ID), haematological diseases (HD) and renal diseases (RD), including immunoglobulin levels pre-/post-RTX and occurrence of infections, who had received RTX at our centre were retrospectively collected. B cell depletion was defined as B cells <10 cells/µl. RESULTS: Post-RTX B cell depletion was achieved in 45/49 patients. In 30/45 patients with B cell repopulation, median time to repopulation was 166 days (IQR 140-224): AID group (n=9) (183 days (IQR 156-239), ID group (n=6) 170 days (IQR 128-184), HD group (n=7) 139 days (IQR 127-294), RD group (n=7) 160 days (IQR 121-367). Severe infections leading to hospitalisation occurred in 7/52 (13.5%) patients: ID (n=3), HD (n=1), RD (n=3). After RTX treatment, 13/52 patients (25%) had low IgG levels for their age at least once, 11/13 had an infection during low IgG but only 2/13 had a severe infection. Low IgG was not associated with severe infection (p=0.459). CONCLUSIONS: Time to B cell repopulation post-RTX ranged individually but did not significantly differ between paediatric patient groups. Severe infections were non-frequent and not associated with low (post-RTX) IgG levels.

Sonographic reference values for median nerve cross-sectional area: A meta-analysis of data from healthy individuals.

Objective: Establish median nerve CSA reference values and identify patient-level factors impacting diagnostic thresholds. Methods: Studies were identified through a robust search of multiple databases, and quality assessment was conducted using a modified version of the National Institute of Health Study Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A meta-analysis was performed to identify normative values stratified by anatomic location. A meta-regression was conducted to examine heterogeneity effects of age, sex, and laterality. Results: The meta-analysis included 73 studies; 41 (56.2%) were high quality. The median nerve CSA [95% CI] was 6.46mm2 [6.09-6.84], 8.68mm2 [8.22-9.13], and 8.60mm2 [8.23-8.97] at the proximal forearm, the carpal tunnel inlet, and the proximal carpal tunnel, respectively. Age was positively associated with CSA at the level of proximal carpal tunnel (ß=0.03mm2, p=0.047). Men (9.42mm2, [8.06-10.78]) had statistically larger proximal tunnel CSA (p = 0.03) as compared to women (7.71mm2, [7.01-8.42]). No difference was noted in laterality. Conclusion: A reference value for median nerve CSA in the carpal tunnel is 8.60mm2. Adjustments may be required in pediatrics or older adults. The diagnostic threshold of 10.0mm2 for male patients should be cautiously applied as the upper limit of normative averages surpasses this threshold.

Rarities in rare: illuminating the microvascular and dermal status in juvenile localised scleroderma. A case series.

OBJECTIVES: To assess the (structural and functional) characteristics of the microvascular and dermal status in juvenile localised scleroderma (jLoS), using novel non-invasive standardised research tools commonly used in adult systemic sclerosis (SSc). METHODS: Ten consecutive patients with a confirmed jLoS diagnosis were studied cross-sectionally in this two-centre case series. For each patient, the most prominent lesion (i.e., "target lesion") was chosen for further examination of the centre, edge and contralateral unaffected site. High-frequency ultrasonography was used to determine dermal thickness, durometer for skin hardness, and laser speckle contrast analysis (LASCA) for a dynamical evaluation of the microcirculation. The structure of the microcirculation was evaluated at the nailfolds of the 2nd-5th finger bilaterally, using nailfold videocapillaroscopy (NVC). RESULTS: 6 linear and 4 plaque subtype jLoS lesions were included. Dermal thickness was thinner at the centre of the "target lesions" vs. the edges (p<0.001) and control sites (p<0.001). Skin hardness was harder at the centre of the "target lesions" vs. the edges (p=0.012) and control sites (p=0.003). A higher perfusion was found in the centre of the "target lesion" (124.87±66.40 PU) vs. the edges (87.27±46.40 PU; p<0.001) and control sites (67.85±37.49; p<0.001). Of note, all patients had a "non-scleroderma" pattern on NVC. CONCLUSIONS: This case series suggests the supportive value of both microcirculatory and dermal assessments of skin lesions using novel non-invasive research tools, adopted from adult SSc, for (j)LoS.

Nailfold capillary abnormalities in childhood-onset systemic lupus erythematosus: a cross-sectional study compared with healthy controls.

OBJECTIVES: For selection of high-risk systemic lupus erythematosus (SLE) patients it is necessary to obtain indicators of disease severity that predict disease damage. As in systemic sclerosis, nailfold capillary abnormalities could be such a biomarker in SLE. The primary objective of this cross-sectional study is to describe capillary abnormalities in childhood-onset SLE (cSLE) cohort (onset < 18 years) and compare them with matched healthy controls. The secondary objective is to correlate the observed capillary abnormalities with demographical variables in both cohorts and with disease-specific variables in cSLE patients. METHODS: Healthy controls were matched for ethnic background, age and gender. Videocapillaroscopy was performed in eight fingers with 2-4 images per finger. Quantitative and qualitative assessments of nailfold capillaroscopy images were performed according to the definitions of the EULAR study group on microcirculation in Rheumatic Diseases. RESULTS: Both groups (n = 41 cSLE-patients and n = 41 healthy controls) were comparable for ethnic background (p = 0.317). Counted per mm, cSLE-patients showed significantly more 'giants' (p = 0.032), 'abnormal capillary shapes' (p = 0.003), 'large capillary hemorrhages' (p < 0.001) and 'pericapillary extravasations' (p < 0.001). Combined 'abnormal capillary shapes and pericapillary extravasations' (in the same finger) were detected in 78% (32/41 patients). By qualitative analysis, 'microangiopathy' was detected in 68.3% (28/41) and a 'scleroderma pattern' in 17.1% (7/41) of the cSLE-patients (without scleroderma symptoms). The difference of percentage positive anti-RNP antibodies in the group with or without a scleroderma pattern was not significant (p = 0.089). The number of 'abnormal capillary shapes per mm' was significantly correlated with treatment-naivety. The number of 'large pathological hemorrhages per mm' was significantly correlated with SLEDAI score and presence of nephritis. Compared to healthy controls, 'pericapillary extravasations' were found in significantly higher numbers per mm (p < 0.001) as well as in percentage of patients (p < 0.001). CONCLUSIONS: Our observations confirm that giants, abnormal capillary morphology and capillary hemorrhages are also observed in cSLE, as was already known for adults with SLE. Number of capillary hemorrhages in cSLE was significantly correlated with disease activity. A high frequency and total amount of "pericapillary extravasations" was observed in cSLE patients, possibly revealing a new subtype of capillary hemorrhage that might reflect endothelial damage in these pediatric patients.

Reliable detection of subtypes of nailfold capillary haemorrhages in childhood-onset systemic lupus erythematosus.

OBJECTIVES: In systemic lupus erythematosus (SLE), it is necessary to obtain biomarkers that predict cardiovascular complications due to premature atherosclerosis, which is related to endothelial dysfunction. Nailfold capillary abnormalities might be a biomarker for endothelial dysfunction. In adults and children with SLE, nailfold capillary haemorrhages have shown to be significantly correlated with disease activity. Recently, different subtypes of capillary haemorrhages have been described in childhood-onset SLE (cSLE). The aim of the current study was to assess the inter- and intra-rater reliability of observations of different subtypes of haemorrhages in cSLE patients. METHODS: Five raters blindly evaluated 140 capillaroscopy images from 35 cSLE-patients (diagnosed according to the 2012 SLICC criteria). The images were assessed qualitatively (present or absent) and quantitatively (total number) on four different subtypes of haemorrhages: 1) punctate extravasations, 2) perivascular haemorrhage, 3) large confluent haemorrhage and 4) non-definable. As subgroups 1) and 2) were interpreted as a continuous spectrum, a post-hoc analysis with "merged" (mean) kappa/ICC was additionally calculated as one sub-group. RESULTS: Qualitative assessment showed a kappa 0.65 (95% CI: 0.60-0.70) for "punctate extravasations and perivascular haemorrhages merged" and a kappa 0.78 (95% CI: 0.72-0.83) for large confluent haemorrhages. For the quantitative assessment, ICC was 0.82 (95% CI: 0.76-0.87) for the "merged groups" and ICC 0.93 (95% CI: 0.91-0.95) for large confluent haemorrhages. CONCLUSIONS: Our study shows that different subtypes of capillary haemorrhages in cSLE-patients could be reliably reproduced by different raters. This confirms our recent observation of perivascular extravasations as a subgroup of capillary haemorrhage in cSLE that might reflect endothelial dysregulation.

A feasibility study using time-driven activity-based costing as a management tool for provider cost estimation: lessons from the national TB control program in Zimbabwe in 2018.

BACKGROUND: Insufficient cost data and limited capacity constrains the understanding of the actual resources required for effective TB control. This study used process maps and time-driven activity-based costing to document TB service delivery processes. The analysis identified the resources required to sustain TB services in Zimbabwe, as well as several opportunities for more effective and efficient use of available resources. METHODS: A multi-disciplinary team applied time-driven activity-based costing (TDABC) to develop process maps and measure the cost of clinical pathways used for Drug Susceptible TB (DS-TB) at urban polyclinics, rural district and provincial hospitals, and community based targeted screening for TB (Tas4TB). The team performed interviews and observations to collect data on the time taken by health care worker-patient pairs at every stage of the treatment pathway. The personnel's practical capacity and capacity cost rates were calculated on five cost domains. An MS Excel model calculated diagnostic and treatment costs. FINDINGS: Twenty-five stages were identified in the TB care pathway across all health facilities except for community targeted screening for TB. Considerable variations were observed among the facilities in how health care professionals performed client registration, taking of vital signs, treatment follow-up, dispensing medicines and processing samples. The average cost per patient for the entire DS-TB care was USD324 with diagnosis costing USD69 and treatment costing USD255. The average cost for diagnosis and treatment was higher in clinics than in hospitals (USD392 versus USD256). Nurses in clinics were 1.6 time more expensive than in hospitals. The main cost components were personnel (USD130) and laboratory (USD119). Diagnostic cost in Tas4TB was twice that of health facility setting (USD153 vs USD69), with major cost drivers being demand creation (USD89) and sputum specimen transportation (USD5 vs USD3). CONCLUSION: TDABC is a feasible and effective costing and management tool in low-resource settings. The TDABC process maps and treatment costs revealed several opportunities for innovative improvements in the NTP under public health programme settings. Re-engineering laboratory testing processes and synchronising TB treatment follow-up with antiretroviral treatments could produce better and more uniform TB treatments at significantly lower cost in Zimbabwe.

Contrast-Enhanced Ultrasound Imaging of Breast Masses: Adjunct Tool to Decrease the Number of False-Positive Biopsy Results.

OBJECTIVES: This pilot study evaluated use of contrast-enhanced ultrasound (CEUS) to reduce the number of benign breast masses recommended for biopsy. METHODS: This prospective study included 131 consenting women, from October 2016 to June 2017, with American College of Radiology Breast Imaging Reporting and Data System category 4a, 4b, and 4c masses detected by mammography, conventional ultrasound (US), or both. Contrast-enhanced US examinations (using intravenous injection of perflutren lipid microspheres or sulfur hexafluoride lipid-type A microspheres) were performed before biopsy. Qualitative and quantitative CEUS parameters were compared with reference standard histopathologic results from biopsy of 131 masses. RESULTS: There were 109 benign, 6 high-risk, and 16 malignant masses, with a median size of 12 mm (range, 4 to 48 mm) on conventional US imaging. Of 131 masses, 93 (71%) enhanced on CEUS imaging, including 73 of 109 (67%) benign, 6 of 6 (100%) high-risk, and 14 of 16 (87.5%) malignant. Thirty-eight lesions did not enhance, including 36 of 109 (33%) benign and 2 of 16 (12.5%) malignant. Prediction models using recursive petitioning revealed that CEUS may reduce 31% (95% confidence interval, 23%, 40%) of benign biopsies for masses that are: nonenhancing with circumscribed margins or enhancing with an oval shape and homogeneous enhancement. Quantitative parameters indicated that benign masses had the longest time to peak (P = .078), highest time-to-peak ratio of mass to background (P = .036), lowest peak intensity (P = .021), and smallest difference in peak intensity between the mass and background (P = .079) compared to high-risk and malignant lesions. CONCLUSIONS: Contrast-enhanced US may be a valuable modality that can be used to predict benign pathologic results of breast masses, thereby reducing the number of biopsies.

Hand therapy interventions, outcomes, and diagnoses evaluated over the last 10 years: A mapping review linking research to practice.

STUDY DESIGN: Mapping review. INTRODUCTION: Although published literature and evidence to support medical practice is becoming more abundant, it is not known how well available evidence supports the full spectrum of hand therapy practice. PURPOSE OF THE STUDY: The aim of this mapping review was to identify strengths and/or gaps in the available literature as compared with the hand therapy scope of practice to guide future research. METHODS: A systematic search and screening was conducted to identify evidence published from 2006 to 2015. Descriptive data from 191 studies were extracted, and the diagnoses, interventions, and outcomes used in the literature were compared with the hand therapy scope of practice. RESULTS: Osteoarthritis, tendon surgeries, and carpal tunnel syndrome were most frequently studied. Exercise, education, and orthotic interventions were most common, each used in more than 100 studies; only 12 studies used activity-based interventions. Primary outcome measures included range of motion, pain/symptoms, strength, and functional status. DISCUSSION: Abundant high-quality research exists for a portion of the hand therapy scope of practice; however, there is a paucity of evidence for numerous diagnoses and interventions. CONCLUSIONS: More evidence is needed for complex diagnoses and activity-based interventions as well as behavioral and quality-of-care outcomes. LEVEL OF EVIDENCE: Not applicable.

Identification of Aberrant Muscle Bellies in the Carpal Tunnel using Sonography.

Musculoskeletal sonography is being widely used for evaluation of structures within the carpal tunnel. While some anatomical variants, such as bifurcated median nerves and persistent median arteries, have been well documented, limited literature describes the sonographic appearance of aberrant muscle bellies within the carpal tunnel. Multiple examples of the sonographic appearance of flexor digitorum superficialis and lumbrical muscle bellies extending into the carpal tunnel are provided. Techniques for static image acquisition and analysis are discussed, and the use of dynamic imaging to confirm which specific muscle belly is involved is described. Knowledge of the potential presence of muscle bellies in these images and ability to identify these structures is vital to avoid misclassification or misdiagnosis as abnormal pathology. The case examples are situated among current published evidence regarding how such anomalies may be related to the development of pathologies, such as carpal tunnel syndrome.

Predominance of triple wild-type and IGF2R mutations in mucosal melanomas.

BACKGROUND: Primary mucosal melanoma (MM) is a rare subtype of melanoma that arises from melanocytes in the mucosa. MM has not been well profiled for mutations and its etiology is not well understood, rendering current treatment strategies unsuccessful. Hence, we investigated mutational landscape for MM to understand its etiology and to clarify mutations that are potentially relevant for MM treatment. METHODS: Forty one MM and 48 cutaneous melanoma (CM) tissues were profiled for mutations using targeted deep next-generation sequencing (NGS) for 89 cancer-related genes. A total of 997 mutations within exons were analyzed for their mutational spectrum and prevalence of mutation, and 685 non-synonymous variants were investigated to identify mutations in individual genes and pathways. PD-L1 expression from 21 MM and 18 CM were assessed by immunohistochemistry. RESULTS: Mutational spectrum analysis revealed a lower frequency of UV-induced DNA damage in MM than in CM (p = 0.001), while tobacco exposure was indicated as a potential etiologic factor for MM. In accordance with low UV damage signatures, MM demonstrated an overall lower number of mutations compared to CM (6.5 mutations/Mb vs 14.8 mutations/Mb, p = 0.001), and less PD-L1 expression (p = 0.003). Compared to CM, which showed frequent mutations in known driver genes (BRAF 50.0%, NRAS 29.2%), MM displayed lower mutation frequencies (BRAF; 12.2%, p < 0.001, NRAS; 17.1%), and was significantly more enriched for triple wild-type (no mutations in BRAF, RAS, or NF1, 70.7% vs 25.0%, p < 0.001), IGF2R mutation (31.7% vs 6.3%, p = 0.002), and KIT mutation (9.8% vs 0%, p = 0.042). Of clinical relevance, presence of DCC mutations was significantly associated with poorer overall survival in MM (log-rank test, p = 0.02). Furthermore, mutational spectrum analysis distinguished primary anorectal MM from CM metastasized to the bowel (spectrum analysis p < 0.001, number of mutations p = 0.002). CONCLUSIONS: These findings demonstrated a potential etiologic factor and driver mutation for MM and strongly suggested that MM initiation or progression involves distinct molecular-mechanisms from CM. This study also identified mutational signatures that are clinically relevant for MM treatment.

Accuracy of Contrast-Enhanced Ultrasound Compared With Magnetic Resonance Imaging in Assessing the Tumor Response After Neoadjuvant Chemotherapy for Breast Cancer.

OBJECTIVES: This pilot study compared contrast enhanced ultrasound (US) with contrast-enhanced magnetic resonance imaging (MRI) in assessing the treatment response in patients with breast cancer receiving preoperative neoadjuvant chemotherapy (NAC). METHODS: This prospective Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study included 30 patients, from January 2014 to October 2015, with invasive breast cancer detected by mammography, conventional US imaging, or both and scheduled for NAC. Informed consent was obtained. Contrast-enhanced US (perflutren lipid microspheres, 10 µL/kg) and MRI (gadopentetate dimeglumine, 0.1 mmol/kg) scans were performed at baseline before starting NAC and after completing NAC before surgery. Results of the imaging techniques were compared with each other and with histopathologic findings obtained at surgery using the Spearman correlation. Tumor size and enhancement parameters were compared for 15 patients with contrast-enhanced US, MRI, and surgical pathologic findings. RESULTS: The median tumor size at baseline was 3.1 cm on both contrast-enhanced US and MRI scans. The Spearman correlation showed strong agreement in tumor size at baseline between contrast-enhanced US and MRI (r = 0.88; P < .001) but less agreement in tumor size after NAC (r = 0.66; P = .004). Trends suggested that contrast-enhanced US (r = 0.75; P < .001) had a better correlation than MRI (r = 0.42; P = .095) with tumor size at surgery. Contrast-enhanced US was as effective as MRI in predicting a complete pathologic response (4 patients; 75.0% accuracy for both) and a non-complete pathologic response (11 patients; 72.7% accuracy for both). CONCLUSIONS: Contrast enhanced US is a valuable imaging modality for assessing the treatment response in patients receiving NAC and had a comparable correlation as MRI with breast cancer size at surgery.

Radiologist's role in breast cancer staging: providing key information for clinicians.

Breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer, and the 5-year survival rate is largely dependent on disease stage. The American Joint Committee on Cancer (AJCC) staging system for breast cancer (7th edition) provides a tumor-node-metastasis (TNM) classification scheme for breast cancer that is important for determining prognosis and treatment. Ascertaining the correct stage of breast cancer can be challenging, and the importance of the radiologist's role has increased over the years. The radiologist should understand how breast cancer stage is assigned and should be familiar with the AJCC's TNM classification scheme. The authors review the AJCC's TNM staging system for breast cancer with emphasis on clinical and preoperative staging, the different imaging modalities used in staging, and the key information that should be conveyed to clinicians. Radiologic information that may alter stage, prognosis, or treatment includes tumor size; number of tumor lesions; total span of disease; regional nodal status (axillary levels I-III, internal mammary, supraclavicular); locoregional invasion (involvement of the pectoralis muscle, skin, nipple, or chest wall); and distant metastases to bone, lung, brain, and liver, among other anatomic structures.

Perinatal administration of Saccharomyces cerevisiae UFMG A-905 prevents asthma development in the offspring of mice.

Asthma prevalence has been increasing in communities that become more urbanised. Our previous results showed that Saccharomyces cerevisiae UFMG A-905 prevented the development of asthma symptoms and characteristics in a dose-dependent manner. Perinatal programming theory proposes that early exposure to some stimuli may have a protective effect in adult life. The aim of this study was to evaluate the effects of perinatal administration of S. cerevisiae UFMG A-905 in the prevention of asthma in the offspring of mice. S. cerevisiae UFMG A-905 was cultured in YPD broth medium and administered to three groups of mice: before conception, during gestation and lactation (CGL group); during gestation and lactation (GL group); and only during lactation (L group). The offspring of these animals were sensitised and challenged with ovalbumin. Two control groups received saline in the same periods. After, in vivo measurements of airway hyperresponsiveness (AHR) were performed. Total and differential cell count in bronchoalveolar lavage (BAL); ELISA for interleukin (IL)-4, IL-5, IL-10, IL-13, and IL-17A in the lung homogenate or BAL; and ELISA for ovalbumin (OVA)-specific immunoglobulin E (IgE) were performed. The animals of the CGL, GL, and L group, when compared to the OVA group, presented a significant reduction of AHR ( P < 0.01), levels of IL-5 ( P < 0.001) in BAL, and IL-4 ( P < 0.05) and IL-13 ( P < 0.01) in the lung homogenate. Serum IgE levels were significantly higher ( P < 0.05) in CGL and GL groups when compared to the OVA group, but not in the L group. Only in the group L, there was a significant decrease in the number of total cells ( P < 0.01) and eosinophils ( P < 0.05). Perinatal administration of S. cerevisiae UFMG A-905 prevented the development of asthma-like characteristics and may be an option for asthma management. The protective effects on the offspring were more prominent when the yeast was given during lactation.

Learning from serum markers reflecting endothelial activation: longitudinal data in childhood-onset systemic lupus erythematosus.

OBJECTIVES: In childhood-onset SLE (cSLE), patients have an increased risk of premature atherosclerosis. The pathophysiological mechanisms for this premature atherosclerosis are not yet completely understood, but besides traditional risk factors, the endothelium plays a major role. The first aim of this study was to measure levels of SLE-associated markers involved in endothelial cell (EC) function and lipids in a cSLE cohort longitudinally in comparison with healthy controls (HC). Next aim was to correlate these levels with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and nailfold capillaroscopic patterns. METHODS: Blood serum samples, videocapillaroscopy images and patient characteristics were collected in a multicentre longitudinal cSLE cohort and from age and sex comparable HC. Disease activity was evaluated by SLEDAI. A total of 15 EC markers and six lipids were measured in two longitudinal cSLE samples (minimum interval of 6 months) and in HC. Nailfold videocapillaroscopy images were scored according to the guidelines from the EULAR Study Group on Microcirculation in Rheumatic Diseases. RESULTS: In total, 47 patients with cSLE and 42 HCs were analysed. Median age at diagnosis was 15 years (IQR 12-16 years). Median time between t=1 and t=2 was 14.5 months (IQR 9-24 months). Median SLEDAI was 12 (IQR 6-18) at t=1 and 2 (IQR 1-4) at t=2. Serum levels of angiopoietin-2, CCL2, CXCL10, GAS6, pentraxin-3, thrombomodulin, VCAM-1 and vWF-A2 were elevated in cSLE compared with HC at t=1. While many elevated EC markers at t=1 normalised over time after treatment, several markers remained significantly increased compared with HC (angiopoietin-2, CCL2, CXCL10, GAS6, thrombomodulin and VCAM-1). CONCLUSION: In serum from patients with cSLE different markers of endothelial activation were dysregulated. While most markers normalised during treatment, others remained elevated in a subset of patients, even during low disease activity. These results suggest a role for the dysregulated endothelium in early and later phases of cSLE, possibly also during lower disease activity. TRIAL REGISTRATION NUMBER: NL60885.018.17.

Population Pharmacokinetics of Adalimumab in Juvenile Idiopathic Arthritis Patients: A Retrospective Cohort Study Using Clinical Care Data.

BACKGROUND AND OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. MATERIALS AND METHODS: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. RESULTS: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. CONCLUSIONS: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.

Induction of dsRNA-activated protein kinase links mitochondrial unfolded protein response to the pathogenesis of intestinal inflammation.

OBJECTIVE: Inflammatory bowel diseases (IBDs) feature multiple cellular stress responses, including endoplasmic reticulum (ER) unfolded protein responses (UPRs). UPRs represent autoregulatory pathways that adjust organelle capacity to cellular demand. A similar mechanism, mitochondrial UPR (mtUPR), has been described for mitochondria. ER UPR in intestinal epithelial cells (IECs) contributes to the development of intestinal inflammation, and since mitochondrial alterations and dysfunction are implicated in the pathogenesis of IBDs, the authors characterised mtUPR in the context of intestinal inflammation. METHODS: Truncated ornithine transcarbamylase was used to selectively induce mtUPR in a murine IEC line. Dextran sodium sulphate (DSS) was administered to PKR (double-stranded-RNA-activated protein kinase) knockout mice to induce IEC stress in vivo and to test for their susceptibility to DSS-induced colitis. Expression levels of the mitochondrial chaperone chaperonin 60 (CPN60) and PKR were quantified in IECs from patients with IBDs and from murine models of colitis using immunohistochemistry and Western blot analysis. RESULTS: Selective mtUPR induction by truncated ornithine transcarbamylase transfection triggered the phosphorylation of eukaryotic translation initiation factor (eIF) 2α and cJun through the recruitment of PKR. Using pharmacological inhibitors and small inhibitory RNA, the authors identified mtUPR-induced eIF2α phosphorylation and transcription factor activation (cJun/AP1) as being dependent on the activities of the mitochondrial protease ClpP and the cytoplasmic kinase PKR. Pkr(-/-) mice failed to induce CPN60 in IECs upon DSS treatment at early time points and subsequently showed an almost complete resistance to DSS-induced colitis. Under inflammatory conditions, primary IECs from patients with IBDs and two murine models of colitis exhibited a strong induction of the mtUPR marker protein CPN60 associated with enhanced expression of PKR. CONCLUSION: PKR integrates mtUPR into the disease-relevant ER UPR via eIF2α phosphorylation and AP1 activation. Induction of mtUPR and PKR was observed in IECs from murine models and patients with IBDs. The authors' results indicate that PKR might link mitochondrial stress to intestinal inflammation.

Modeling extracurricular activity participation with physical and mental health in college students over time.

Objective: To describe extracurricular activity participation and explore its relationship with college students' health. Participants: 159 college students majoring in dental hygiene or occupational therapy. Methods: Data were collected prospectively at baseline, one- and two-year follow-ups. Self-reported participation in extracurricular activities over the past six months was grouped into eight categories: Fitness, Sports, Creative arts, Leisure, Social, Work, Caregiving, and Animal care. Physical and mental health were measured using SF-36, a valid tool measuring general health. Results: Participation in fitness, sports, creative arts, and work significantly decreased at one-year and two-year follow-ups (p < 0.01). Work/volunteer activity participation was associated with poorer physical health (ß = -1.4, 95% CI: (-2.2, -0.5), p < 0.01), but a change from nonparticipation to some participation in work/volunteer activity was associated with better mental health (ß = 2.6, 95% CI (0.3, 4.9), p = 0.04). Conclusions: Educators should consider the potential impact of maintaining extracurricular activities on college students' health when designing academic courses.

Case Report: Anastrozole as a monotherapy for pre-pubertal children with non-classic congenital adrenal hyperplasia.

Most children with non-classic congenital adrenal hyperplasia (NC-CAH) due to 21-hydroxylase deficiency are asymptomatic and do not require cortisol replacement therapy unless they develop symptoms of hyperandrogenemia. The current practice is to treat symptomatic children with hydrocortisone aimed at suppressing excess adrenal androgen production irrespective of the child's level of endogenous cortisol production. Once on hydrocortisone therapy, even children with normal cortisol production require stress dosing. Some children with NC-CAH may present with premature adrenarche, growth acceleration, and advanced bone age, but with no signs of genital virilization and normal endogenous cortisol production. In these cases, an alternative therapy to hydrocortisone treatment that does not impact the hypothalamic-pituitary-adrenal axis, but targets increased estrogen production and its effects on bone maturation, could be considered. Aromatase inhibitors (AIs), which block the aromatization of androgen to estrogen, have been used off-label in men with short stature to delay bone maturation and as an adjunct therapy in children with classic CAH. The use of AI as a monotherapy for children with NC-CAH has never been reported. We present three pre-pubertal female children with a diagnosis of NC-CAH treated with anastrozole monotherapy after presenting with advanced bone age, early adrenarche, no signs of genital virilization, and normal peak cortisol in response to ACTH stimulation testing. Bone age z-scores normalized, and all three reached or exceeded their target heights. Monotherapy with anastrozole can be an effective alternative in slowing down bone maturation and improving height outcomes in children with NC-CAH and normal adrenal cortisol production.