Membrane Curvature Promotes ER-PM Contact Formation via Junctophilin-EHD Interactions.

Contact sites between the endoplasmic reticulum (ER) and the plasma membrane (PM) play a crucial role in governing calcium regulation and lipid homeostasis. Despite their significance, the factors regulating their spatial distribution on the PM remain elusive. Inspired by observations in cardiomyocytes, where ER-PM contact sites concentrate on tubular PM invaginations known as transverse tubules (T-tubules), we hypothesize that the PM curvature plays a role in ER-PM contact formation. Through precise control of PM invaginations, we show that PM curvatures locally induce the formation of ER-PM contacts in cardiomyocytes. Intriguingly, the junctophilin family of ER-PM tethering proteins, specifically expressed in excitable cells, is the key player in this process, while the ubiquitously expressed extended synaptotagmin 2 does not show a preference for PM curvature. At the mechanistic level, we find that the low complexity region (LCR) and the MORN motifs of junctophilins can independently bind to the PM, but both the LCR and MORN motifs are required for targeting PM curvatures. By examining the junctophilin interactome, we identify a family of curvature-sensing proteins, Eps15-homology domain containing proteins (EHDs), that interact with the MORN_LCR motifs and facilitate junctophilins' preferential tethering to curved PM. These findings highlight the pivotal role of PM curvature in the formation of ER-PM contacts in cardiomyocytes and unveil a novel mechanism for the spatial regulation of ER-PM contacts through PM curvature modulation.

Peri-ankle muscles architecture and performance changes in patients with chronic ankle instability: A retrospective cross-sectional study.

This study aimed to identify changes in the architecture and performance of the peri-ankle muscles in patients with chronic ankle instability (CAI) and investigate the relationship between them. In total, 17 subjects were evaluated retrospectively. Each subject underwent anthropometric and isokinetic test, and peroneus longus (PL) and brevis (PB), medial gastrocnemius (MGCM), and tibialis anterior (TA) ultrasound imaging were performed at rest and maximum voluntary contraction (MVC) conditions. Regarding muscle architectural variables, the pennation angle (PA) of the MGCM at rest and the PA of the TA, MGCM, and PL in MVC were significantly reduced on the injured side compared to the intact side. There were no significant differences in muscle thickness of PL, PB, MGCM, and TA observed between intact and injured side during both rest and MVC. Regarding muscle performance parameters, significant decreased were observed in the muscle strength for both limbs in all four directions under the two different conditions. A secondary finding was that the relative PA ratio of the TA showed moderate correlation with the relative dorsiflexion ratio at 30°/s. These findings can provide opportunities to better understand how injuries in patients with CAI may be related to changes in ankle and foot function.

Extended genome-wide association study employing the African genome resources panel identifies novel susceptibility loci for Alzheimer's disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. METHODS: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. RESULTS: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, P = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. DISCUSSION: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. HIGHLIGHTS: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at P < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.

Impact of upadacitinib induction and maintenance therapy on health-related quality of life, fatigue, and work productivity in patients with moderately-to-severely active Crohn's disease.

BACKGROUND AND AIMS: Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. METHODS: Clinical responders to upadacitinib 45 mg in U-EXCEL and U-EXCEED induction trials were re-randomized 1:1:1 to upadacitinib 30 mg, 15 mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. RESULTS: Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements (all p≤0.001) in IBDQ response (71.0% vs 50.2%), IBDQ remission (44.2% vs 23.7%), and FACIT-Fatigue (42.0% vs 27.0%) were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment (52.1% vs 38.1%, p≤0.05) was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. CONCLUSIONS: In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

Feasibility of low contrast volume and low injection flow rate in CT pulmonary angiography.

BACKGROUND: Computed Tomography Pulmonary Angiography (CTPA) is currently the gold standard for diagnosing Pulmonary Embolism (PE), with a high flowrate (>4.5ml/s) for contrast media (CM) administration recommended for sufficient pulmonary artery opacification. However, this may not be achievable for patients with challenging IV access. AIM: To determine if a low volume CM, low flowrate (LVLF) CTPA protocol produces images of similar image quality compared to a standard protocol in two aspects, in terms of peak arterial enhancement through the quantitative measurement of Hounsfield unit (HU) and based on subjective overall image quality. METHODS: Retrospective collection of 151 patients who underwent CTPA via 320 slice multi-detector CT due to clinical suspicion of PE. 80 patients underwent the standard protocol, with a fixed flowrate of 4.5ml/s and 50ml of CM, while 71 patients underwent the LVLF protocol with up to a 37% and 30% reduction in flowrate and CM administered, respectively. Two independent radiographers measured the attenuation of multiple pulmonary arteries in HU, with ≥200HU being considered diagnostic. Overall image quality was also reviewed using a 5-point close-ended questionnaire by two independent radiologists. RESULTS: There was no significant difference in terms of attenuation measured in HU for the seven regions of interest (main pulmonary trunk, right and left pulmonary arteries, right and left lobar arteries, and right and left subsegmental arteries (RSA and LSA)) between the LVLF and standard CTPA protocol. Similarly, there were no significant differences in the overall image quality score obtained from standard and LVLF protocols reported by both radiologists. CONCLUSION: The LVLF protocol can achieve similar enhancement and subjective image quality as the standard CTPA protocol, potentially allowing for further optimisation in the CM dosage.

Cancer pain self-management interventions in adults: scoping review.

BACKGROUND: The predominant trend in cancer treatment now leans towards outpatient care, placing the responsibility of pain management largely on the patients themselves. Moreover, a significant portion of treatment for advanced cancer occurs in the home environment, so patient self-management becomes increasingly crucial for the effective treatment of cancer pain. OBJECTIVES: To map self-management for pain in patients with cancer at all phases of the disease before examining the potential of pain self-care interventions for ill patients with cancer. METHODS: A search was conducted on six electronic databases to locate studies published in English, from 2013 to 2023. We followed Arskey and O'Malley's Scoping Reviews guidelines. RESULTS: This study thoroughly examined the provision of cancer pain self-management by healthcare professionals and identified four intervention types from 23 studies. Education emerged as the most prevalent form of self-management for cancer pain. CONCLUSION: Guiding patients in managing their pain effectively, starting from their hospitalisation and extending to their discharge.

Perceptions and self-management of a healthy diet among middle-aged adults with risk of stroke in North China: a qualitative exploration.

OBJECTIVE: Although stroke is prevalent among older people, there is a rising incidence among the younger subpopulations, particularly middle-aged adults. A healthy diet is one of the key modifiable factors to primary prevention of stroke among these subpopulations, yet there is limited understanding of the dietary habits among middle agers who have the risk factor(s) but no occurrence of stroke. This study aims to explore the views on perceptions and the self-management of middle-aged adults at risk of stroke on a healthy diet and to identify the enablers and barriers that could inform the future development of dietary interventions. DESIGN: This study used an interpretive descriptive qualitative design, employing semistructured purposive sampling for focus group discussions. Thematic analysis was conducted on the transcribed interviews and field notes, facilitated by NVivo 12.0 Plus software. SETTING: Community settings in Zhengzhou City, Henan Province. PARTICIPANTS: Middle-aged adults (aged 45-59) were identified as at risk of stroke due to the presence of one or more modifiable risk factors. RESULT: A total of seven focus group discussions were audio recorded. Four main themes emerged, which were: (1) cognitive understanding of a healthy diet; (2) dietary practices; (3) knowledge acquisition and (4) barriers to dietary adherence. CONCLUSIONS: The middle-aged adults at risk of stroke were generally aware of the risk and attempted to practise healthy eating. The existing educational programmes on following a healthy diet in the prevention of disease need to be made more comprehensible, accessible and equitable, especially for those from socioeconomically disadvantaged communities.

Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase 3 Clinical Trials (Measure Up 1 and 2).

INTRODUCTION: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. METHODS: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). RESULTS: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. CONCLUSIONS: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1­2 weeks. The extent of the improvements increased through weeks 4­6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis.

The complete chloroplast genome sequence and phylogenetic analysis of Asplenium antiquum Makino 1929, an Endangered species in Korea.

Asplenium antiquum Makino 1929 is one of the Endangered endemic species on the Korean Peninsula. The complete chloroplast of A. antiquum is 150,690 bp in length with typical quadripartite structure comprised of large single-copy region of (83,166 bp), a small single copy region (21,932 bp), and two inverted repeat regions, each 22,796 bp in length. 114 genes were detected in the chloroplast genome of A. antiquum, comprising 84 protein-encoding genes, 26 tRNA genes, and 4 rRNA genes. The phylogenetic analysis revealed a monophyletic relationship, placing A. antiquum as a sister to voth A. Prolongatum and A. nidus, forming a subclade of Asplenium species within the Aspleniaceae family. The genomic data obtained from this study will serve as valuable information for the species' genetic classification of Asplenium.

Multimodality Imaging of Bi-Coronary and Aortic to Pulmonary Fistulas With Saccular Aneurysms.

A 69-year-old man had fistulas arising from the left main, conus and aortic arch complicated by 2 saccular aneurysms with one draining into the pulmonic trunk seen during computed tomography and invasive angiography. These were treated conservatively but required repeat computed tomography and cardiac magnetic resonance imaging 2 years later for new heart failure.

MicroRNAs and Other Non-Coding RNAs as Regulators, Biomarkers, and Therapeutic Targets.

Over the past few decades, the field of RNA research in molecular and cellular biology has undergone a dramatic transformation [...].

Engineering of an EPHA2-Targeted Monobody for the Detection of Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) is the third most common cancer worldwide, and is second only to lung cancer with respect to cancer-related deaths. Noninvasive molecular imaging using established markers is a new emerging method to diagnose CRC. The human ephrin receptor family type-A 2 (hEPHA2) oncoprotein is overexpressed at the early, but not late, stages of CRC. Previously, we reported development of an E1 monobody that is specific for hEPHA2-expressing cancer cells both in vitro and in vivo. Herein, we investigated the ability of the E1 monobody to detect hEPHA2 expressing colorectal tumors in a mouse model, as well as in CRC tissue. MATERIALS AND METHODS: The expression of hEPHA2 on the surface of CRC cells was analyzed by western blotting and flow cytometry. The targeting efficacy of the E1 monobody for CRC cells was examined by flow cytometry, and immunofluorescence staining. E1 conjugated to the Renilla luciferase variant 8 (Rluc8) reporter protein was used for in vivo imaging in mice. Additionally, an enhanced green fluorescence protein (EGFP) conjugated E1 monobody was used to check the ability of the E1 monobody to target CRC tissue. RESULTS: The E1 monobody bound efficiently to hEPHA2-expressing CRC cell lines, and E1 conjugated to the Rluc8 reporter protein targeted tumor tissues in mice transplanted with HCT116 CRC tumor cells. Finally, E1-EGFP stained tumor tissues from human CRC patients, showing a pattern similar to that of an anti-hEPHA2 antibody. CONCLUSION: The E1 monobody has utility as an EPHA2 targeting agent for the detection of CRC.

Perceptions and attitudes of dental students and dentists in South Korea toward artificial intelligence: a subgroup analysis based on professional seniority.

BACKGROUND: This study explored dental students' and dentists' perceptions and attitudes toward artificial intelligence (AI) and analyzed differences according to professional seniority. METHODS: In September to November 2022, online surveys using Google Forms were conducted at 2 dental colleges and on 2 dental websites. The questionnaire consisted of general information (8 or 10 items) and participants' perceptions, confidence, predictions, and perceived future prospects regarding AI (17 items). A multivariate logistic regression analysis was performed on 4 questions representing perceptions and attitudes toward AI to identify highly influential factors according to position, age, sex, residence, and self-reported knowledge level about AI of respondents. Participants were reclassified into 2 subgroups based on students' years in school and 4 subgroups based on dentists' years of experience. The chi-square test or Fisher's exact test was used to determine differences between dental students and dentists and between subgroups for all 17 questions. RESULTS: The study included 120 dental students and 96 dentists. Participants with high level of AI knowledge were more likely to be interested in AI compared to those with moderate or low level (adjusted OR 24.345, p < 0.001). Most dental students (60.8%) and dentists (67.7%) predicted that dental AI would complement human limitations. Dental students responded that they would actively use AI in almost all cases (40.8%), while dentists responded that they would use AI only when necessary (44.8%). Dentists with 11-20 years of experience were the most likely to disagree that AI could outperform skilled dentists (50.0%), and respondents with longer careers had higher response rates regarding the need for AI education in schools. CONCLUSIONS: Knowledge level about AI emerged as the factor influencing perceptions and attitudes toward AI, with both dental students and dentists showing similar views on recognizing the potential of AI as an auxiliary tool. However, students' and dentists' willingness to use AI differed. Although dentists differed in their confidence in the abilities of AI, all dentists recognized the need for education on AI. AI adoption is becoming a reality in dentistry, which requires proper awareness, proper use, and comprehensive AI education.

Sunlight enhanced the formation of tribromomethane from benzotriazole degradation during the sunlight/free chlorine treatment in the presence of bromide.

The coexistence of free chlorine and bromide under sunlight irradiation (sunlight/FC with Br-) is unavoidable in outdoor seawater swimming pools, and the formation of brominated disinfection byproducts could act more harmful than chlorinated disinfection byproducts. In this study, benzotriazole was selected as a model compound to investigate the degradation rate and the subsequent formation of disinfection byproducts via sunlight/FC with Br- process. The rate constants for the degradation of benzotriazole under pseudo first order conditions in sunlight/FC with Br- and sunlight/FC are 2.3 ± 0.07 × 10-1 min-1 and 6.0 ± 0.7 × 10-2 min-1, respectively. The enhanced degradation of benzotriazole can be ascribed to the generation of HO•, bromine species, and reactive halogen species (RHS) during sunlight/FC with Br-. Despite the fact that sunlight/FC with Br- process enhanced benzotriazole degradation, the reaction results in increasing tribromomethane (TBM) formation. A high concentration (37.8 µg/L) of TBM was detected in the sunlight/FC with Br-, which was due to the reaction of RHS. The degradation of benzotriazole was notably influenced by the pH value (pH 4 - 11), the concentration of bromide (0 - 2 mM), and free chlorine (1 - 6 mg/L). Furthermore, the concentration of TBM increased when the free chlorine concentrations increased, implying the formation potential of harmful TBM in chlorinated seawater swimming pools.

Comparison of the 2022 world health organization classification and international consensus classification in myelodysplastic syndromes/neoplasms.

In 2022, two novel classification systems for myelodysplastic syndromes/neoplasms (MDS) have been proposed: the International Consensus Classification (ICC) and the 2022 World Health Organization (WHO-2022) classification. These two contemporary systems exhibit numerous shared features but also diverge significantly in terminology and the definition of new entities. Thus, we retrospectively validated the ICC and WHO-2022 classification and found that both systems promoted efficient segregation of this heterogeneous disease. After examining the distinction between the two systems, we showed that a peripheral blood blast percentage ≥ 5% indicates adverse survival. Identifying MDS/acute myeloid leukemia with MDS-related gene mutations or cytogenetic abnormalities helps differentiate survival outcomes. In MDS, not otherwise specified patients, those diagnosed with hypoplastic MDS and single lineage dysplasia displayed a trend of superior survival compared to other low-risk MDS patients. Furthermore, the impact of bone marrow fibrosis on survival was less pronounced within the ICC framework. Allogeneic transplantation appears to improve outcomes for patients diagnosed with MDS with excess blasts in the ICC. Therefore, we proposed an integrated system that may lead to the accurate diagnosis and advancement of future research for MDS. Prospective studies are warranted to validate this refined classification.

A Modified eCura System to Stratify the Risk of Lymph Node Metastasis in Undifferentiated-Type Early Gastric Cancer After Endoscopic Resection.

PURPOSE: The original eCura system was designed to stratify the risk of lymph node metastasis (LNM) after endoscopic resection (ER) in patients with early gastric cancer (EGC). We assessed the effectiveness of a modified eCura system for reflecting the characteristics of undifferentiated-type (UD)-EGC. MATERIALS AND METHODS: Six hundred thirty-four patients who underwent non-curative ER for UD-EGC and received either additional surgery (radical surgery group; n=270) or no further treatment (no additional treatment group; n=364) from 18 institutions between 2005 and 2015 were retrospectively included in this study. The eCuraU system assigned 1 point each for tumors >20 mm in size, ulceration, positive vertical margin, and submucosal invasion <500 µm; 2 points for submucosal invasion ≥500 µm; and 3 points for lymphovascular invasion. RESULTS: LNM rates in the radical surgery group were 1.1%, 5.4%, and 13.3% for the low- (0-1 point), intermediate- (2-3 points), and high-risk (4-8 points), respectively (P-for-trend<0.001). The eCuraU system showed a significantly higher probability of identifying patients with LNM as high-risk than the eCura system (66.7% vs. 22.2%; McNemar P<0.001). In the no additional treatment group, overall survival (93.4%, 87.2%, and 67.6% at 5 years) and cancer-specific survival (99.6%, 98.9%, and 92.9% at 5 years) differed significantly among the low-, intermediate-, and high-risk categories, respectively (both P<0.001). In the high-risk category, surgery outperformed no treatment in terms of overall mortality (hazard ratio, 3.26; P=0.015). CONCLUSIONS: The eCuraU system stratified the risk of LNM in patients with UD-EGC after ER. It is strongly recommended that high-risk patients undergo additional surgery.

Pharmacokinetic analysis of antiviral drug ritonavir across the blood-brain barrier and its interaction with Scutellaria baicalensis using multisite microdialysis in rats.

Ritonavir, an excellent inhibitor of CYP3A4, has recently been combined with nirmatrelvir to form Paxlovid for the treatment of severe acute respiratory syndrome coronavirus 2 infections. The root of Scutellaria baicalensis Georgi (S. baicalensis), a traditional Chinese medicinal (TCM) herb commonly used to treat heat/inflammation in the lung and digestive tracts, which are major organs targeted by viral infections, contains flavones that can influence the CYP3A metabolism pathway. To investigate the ability of ritonavir to cross the bloodbrain barrier (BBB) and its potential herb-drug interactions with an equivalent TCM clinical dose of S. baicalensis, multisite microdialysis coupled with an LCMS/MS system was developed using rat model. Pretreatment with S. baicalensis extract for 5 days, which contains less flavones than those used in previous studies, had a significant influence on ritonavir, resulting in a 2-fold increase in the total concentration of flavones in the blood and brain. Treatment also boosted the maximum blood concentration of flavones by 1.5-fold and the maximum brain concentration of flavones by 2-fold, all the while exerting no noticeable influence on the transfer ratio across the bloodbrain barrier. These experimental results demonstrated that the use of a typical traditional Chinese medicinal dose of S. baicalensis is sufficient to influence the metabolic pathway and synergistically increase the concentration of ritonavir in rats.

Early and Sustained Improvements in Symptoms and Quality of Life with Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: 52-Week Results from Two Phase III Randomized Clinical Trials (Measure Up 1 and Measure Up 2).

BACKGROUND: Atopic dermatitis is a chronic inflammatory disease characterized by increased itch, skin pain, poor sleep quality, and other symptoms that negatively affect patient quality of life. Upadacitinib, an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, is approved to treat moderate-to-severe atopic dermatitis. OBJECTIVE: We aimed to evaluate the effect of upadacitinib on patient-reported outcomes over 52 weeks in adults and adolescents with moderate-to-severe atopic dermatitis. METHODS: Data from two phase III monotherapy trials of upadacitinib (Measure Up 1, NCT03569293; Measure Up 2, NCT03607422) were integrated. Changes in pruritus, pain, other skin symptoms, sleep, quality of life, mental health, and patient impression were evaluated. Patient-reported outcome assessments included the Worst Pruritus Numerical Rating Scale, Patient-Oriented Eczema Measure, Dermatology Life Quality Index, Atopic Dermatitis Symptom Scale, Atopic Dermatitis Impact Scale, Hospital Anxiety and Depression Scale, SCORing Atopic Dermatitis index, Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment. Minimal clinically important differences, achievement of scores representing minimal disease burden, and the change from baseline were evaluated in patients who received upadacitinib through week 52 and in patients who received placebo through week 16. RESULTS: This analysis included 1609 patients (upadacitinib 15 mg, N = 557; upadacitinib 30 mg, N = 567; placebo, N = 485). Baseline demographics and disease characteristics were generally similar across all arms. The proportion of patients treated with upadacitinib reporting improvements in itch increased rapidly by week 1, increased steadily through week 8, and was sustained through week 52. Patients receiving upadacitinib also experienced improvements in pain and other skin symptoms by week 1, which continued through week 16; improvements were maintained through week 52. Patient reports of improved sleep increased rapidly from baseline to week 1, increased steadily through week 32, and were sustained through week 52. Patients experienced quality-of-life improvements through week 8, which were maintained through week 52. By week 1, patients in both upadacitinib groups experienced rapid improvements in emotional state, and by week 12, patients also achieved meaningful improvements in anxiety and depression. Improvements in mental health continued steadily through week 32 and were maintained through week 52. Patients treated with upadacitinib 30 mg generally experienced improvements in patient-reported outcomes earlier than those treated with upadacitinib 15 mg. Through week 16, patients receiving upadacitinib experienced greater improvements versus those receiving placebo in all assessed patient-reported outcomes. CONCLUSIONS: Adults and adolescents with moderate-to-severe atopic dermatitis treated with once-daily upadacitinib 15 or 30 mg experienced early improvements in itch, pain, other skin symptoms, sleep, quality of life, and mental health that were sustained through week 52. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifiers NCT03569293 (13 August 2018) and NCT03607422 (27 July 2018).

Atopic dermatitis, or eczema, is a condition that causes painful itchy dry skin, which is burdensome for patients and has a negative impact on quality of life. These symptoms frequently lead to disruption of daily activities such as school and work, decreased self-confidence, social isolation, anxiety, depression, and sleep disturbance. Symptoms of atopic dermatitis, such as itch and sleep disturbance, can only be assessed by patients. Therefore, it is important to consider patients' perceptions of their symptoms and the related impact on their quality of life, especially when evaluating treatment benefits. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. In two clinical trials (Measure Up 1 and Measure Up 2), we investigated how treatment with upadacitinib (15-mg or 30-mg dose) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis would impact their symptoms and quality of life over a 1-year period. We measured changes over time in patients' assessments of itch, pain, other skin-related symptoms, sleep, daily activities, emotional state, mental health, and overall quality of life. Patients treated with upadacitinib experienced improvements in symptoms of atopic dermatitis and quality of life within the first 1­2 weeks of treatment. These improvements continued to steadily increase in the following weeks and lasted through 1 year of treatment. In conclusion, once-daily treatment with upadacitinib 15 or 30 mg led to early and lasting improvements in the well-being of patients with atopic dermatitis.

Unusual Coincidence: Concurrent Cast Nephropathy and Lymphoma Infiltration in an Influenza A-Associated Acute Kidney Injury.

Acute kidney injury (AKI) poses a substantial challenge in the management of lymphoma patients and is frequently associated with diverse causative factors. Herein, we report an illustrative case involving a 47-year-old male with influenza A infection who developed severe AKI, which was incongruent with his medical history. Laboratory investigations disclosed aberrant immunoglobulin levels and urinary protein excretion, prompting further evaluation. A renal biopsy revealed the presence of infiltrating lymphoid cells and cast nephropathy, raising suspicion of an underlying hematological disorder. A comprehensive diagnostic workup, including positron emission tomography imaging and bone marrow biopsy, culminated in the definitive diagnosis of splenic marginal zone lymphoma. This case highlights the crucial significance of including lymphoma-associated kidney disorders in the evaluation of unexplained AKI, particularly when encountering unconventional clinical and laboratory results. Swift and precise intervention is of utmost importance in attaining positive results in these rare and complex clinical situations. This study underscores the persistent concern of AKI in lymphoma patients, with lymphocytic infiltration and cast nephropathy as notable elements contributing to the intricate nature of this condition.