bluuebunny/crossref_metadata_2025 huggingface dataset:
Progestin plus metformin improves outcomes in patients with endometrial hyperplasia and early endometrial cancer more than progestin alone: a meta-analysis
Authors: Shao Fengping , Li Yinguang , Zhao Yunhe
Published: June 2023

Objective

Progestin based therapy is the preferred option for fertility-sparing treatment of reproductive-age women with preserved fertility in endometrial hyperplasia (EH) or early endometrial cancer (EEC). Our objective was to investigate whether metformin could enhance the efficacy of progestin-based therapies by meta-analysis.

Methods

We conducted a meta-analysis of randomized or non-randomized controlled trials by searching of PubMed, Embase, Web of science, and Cochrane database from inception to November 8, 2022. The results of enrolled studies were pooled using meta-analysis to estimate the effect of progestin plus metformin on remission, recurrence, pregnancy rate and live birth rate.

Results

In the analysis of progestin administered systemically or locally, complete response (CR) was significantly higher in progestin plus metformin versus progestin alone in the EH group (pooled OR 2.08, 95% CI 1.29 to 3.34, P=0.003), in the EEC group (pooled OR 1.86, 95% CI 1.13 to 3.05, P=0.01), but not in EEC and EH group (pooled OR 1.46, 95% CI 0.97 to 2.21, P=0.07). In the analysis of progestin administered systemically, complete response was improved in progestin plus metformin versus progestin alone, in the EH group (pooled OR 2.47, 95% CI 1.45 to 4.21, P=0.0009), in the EEC group (pooled OR 2.09, 95% CI 1.18 to 3.71, P=0.01), and in the EEC and EH group (pooled OR 2.03, 95% CI 1.16 to 3.54, P=0.01). The relapse rates of patients with EEC and EH were not different (pooled OR 0.54, 95% CI 0.24 to 1.20, P=0.13). For obstetric outcomes, the addition of metformin improved pregnancy rate (pooled OR 1.55, 95% CI 0.99 to 2.42, P=0.05), but not live birth rate (pooled OR 0.95, 95% CI 0.45 to 2.01, P=0.89).

Conclusion

For fertility-sparing management, compared to progestin alone, the outcomes of patients with endometrial hyperplasia and early endometrial cancer were more improved with progestin plus metformin because progestin plus metformin increases the rate of remission and pregnancy.
Osteogenesis of bone marrow mesenchymal stem cell in hyperglycemia
Authors: Luo Meng , Zhao Zhihe , Yi Jianru
Published: June 2023

Diabetes mellitus (DM) has been shown to be a clinical risk factor for bone diseases including osteoporosis and fragility. Bone metabolism is a complicated process that requires coordinated differentiation and proliferation of bone marrow mesenchymal stem cells (BMSCs). Owing to the regenerative properties, BMSCs have laid a robust foundation for their clinical application in various diseases. However, mounting evidence indicates that the osteogenic capability of BMSCs is impaired under high glucose conditions, which is responsible for diabetic bone diseases and greatly reduces the therapeutic efficiency of BMSCs. With the rapidly increasing incidence of DM, a better understanding of the impacts of hyperglycemia on BMSCs osteogenesis and the underlying mechanisms is needed. In this review, we aim to summarize the current knowledge of the osteogenesis of BMSCs in hyperglycemia, the underlying mechanisms, and the strategies to rescue the impaired BMSCs osteogenesis.
Changes in glucose metabolism among recipients with diabetes 1 year after kidney transplant: a multicenter 1-year prospective study
Authors: Bang Jun Bae , Oh Chang-Kwon , Kim Yu Seun , Kim Sung Hoon , Yu Hee Chul , Kim Chan-Duck , Ju Man Ki , So Byung Jun , Lee Sang Ho , Han Sang Youb , Jung Cheol Woong , Kim Joong Kyung , Ahn Hyung Joon , Lee Su Hyung , Jeon Ja Young
Published: June 2023

Background

Diabetes mellitus is a common and crucial metabolic complication in kidney transplantation. It is necessary to analyze the course of glucose metabolism in patients who already have diabetes after receiving a transplant. In this study, we investigated the changes in glucose metabolism after transplantation, and a detailed analysis was performed on some patients whose glycemic status improved.

Methods

The multicenter prospective cohort study was conducted between 1 April 2016 and 31 September 2018. Adult patients (aged 20 to 65 years) who received kidney allografts from living or deceased donors were included. Seventy-four subjects with pre-transplant diabetes were followed up for 1 year after kidney transplantation. Diabetes remission was defined as the results of the oral glucose tolerance test performed one year after transplantation and the presence or absence of diabetes medications. After 1-year post-transplant, 74 recipients were divided into the persistent diabetes group (n = 58) and the remission group (n = 16). Multivariable logistic regression was performed to identify clinical factors associated with diabetes remission.

Results

Of 74 recipients, 16 (21.6%) showed diabetes remission after 1-year post-transplant. The homeostatic model assessment for insulin resistance numerically increased in both groups throughout the first year after transplantation and significantly increased in the persistent diabetes group. The insulinogenic index (IGI30) value significantly increased only in the remission group, and the IGI30 value remained low in the persistent diabetes group. In univariate analysis, younger age, newly diagnosed diabetes before transplantation, low baseline hemoglobin A1c, and high baseline IGI30 were significantly associated with remission of diabetes. After multivariate analysis, only newly diagnosed diabetes before transplantation and IGI30 at baseline were associated with remission of diabetes (34.00 [1.192–969.84], P = 0.039, and 17.625 [1.412–220.001], P = 0.026, respectively).

Conclusion

In conclusion, some kidney recipients with pre-transplant diabetes have diabetes remission 1 year after transplantation. Our prospective study revealed that preserved insulin secretory function and newly diagnosed diabetes at the time of kidney transplantation were favorable factors for which glucose metabolism did not worsen or improve 1 year after kidney transplantation.
Molecular data suggests a Pliocene – Early Pleistocene divergence date for the common and pygmy hippopotamus
Authors: Kardos Michael C. , Velmurugan Sindhu , Janecka Jan E.
Published: June 2023

Hippopotamid phylogeny has proven difficult to resolve with proposed relationships between extant and fossil species receiving mixed levels of support. Of particular interest is the divergence between the two extant hippopotamid species, the well-known common hippopotamus (Hippopotamus amphibius) and the enigmatic pygmy hippopotamus (Choeropsis liberiensis). Previous studies have relied on morphological and fossil evidence to identify the ancestral species at the core of this divergence and its timing. In this study, we assembled a molecular matrix of 26 nuclear gene sequences from 11 ungulate species with two primates as an outgroup. We used a Bayesian relaxed molecular clock approach to reconstruct a calibrated time tree for Cetartiodactyla and estimate the divergence date between the common and pygmy hippopotamus. While previous morphological studies have estimated this event to have occurred sometime during the Late Miocene (between 11.6 and 5.3 million years ago), our nuclear gene-based estimates suggest a more recent split of about 4.04 Ma (95% confidence interval: 8.31–1.97 Ma) via RelTime-ML or 2.4 Ma (95% confidence interval: 3.1–1.6 Ma) via MCMCTree. These more recent estimates correspond with the Early Pliocene – Early Pleistocene sub-epochs and align most closely with the results of previous genomic studies. We discuss how our results compare with previous estimates based on both morphological and molecular studies, some of which extend the predicted range of this divergence date even further back in time. Our results suggest a different path of evolution for the understudied pygmy hippopotamus and reveal that morphological evidence alone may not resolve the correct hippopotamid phylogenetic and time trees. We suggest that the common and pygmy hippopotamus may be phylogenetically closer than once believed. Our results also call for further studies to develop a combined approach incorporating both molecular and morphological evidence to reach a consensus on the evolutionary patterns and timing that led to modern hippopotamid evolution.
Small non-coding RNAs encoded by RNA viruses: old controversies and new lessons from the COVID-19 pandemic
Authors: Ruivinho Carolina , Gama-Carvalho Margarida
Published: June 2023

The recurring outbreaks caused by emerging RNA viruses have fostered an increased interest in the research of the mechanisms that regulate viral life cycles and the pathological outcomes associated with infections. Although interactions at the protein level are well-studied, interactions mediated by RNA molecules are less explored. RNA viruses can encode small non-coding RNAs molecules (sncRNAs), including viral miRNAs (v-miRNAs), that play important roles in modulating host immune responses and viral replication by targeting viral or host transcripts. Starting from the analysis of public databases compiling the known repertoire of viral ncRNA molecules and the evolution of publications and research interests on this topic in the wake of the COVID-19 pandemic, we provide an updated view on the current knowledge on viral sncRNAs, with a focus on v-miRNAs encoded by RNA viruses, and their mechanisms of action. We also discuss the potential of these molecules as diagnostic and prognostic biomarkers for viral infections and the development of antiviral therapies targeting v-miRNAs. This review emphasizes the importance of continued research efforts to characterize sncRNAs encoded by RNA viruses, identifies the most relevant pitfalls in the study of these molecules, and highlights the paradigm changes that have occurred in the last few years regarding their biogenesis, prevalence and functional relevance in the context of host-pathogen interactions.
Evaluation of plasma IL-21 as a potential biomarker for type 1 diabetes progression
Authors: Schroderus Anna-Mari , Poorbaugh Josh , McElyea Samantha , Beasley Stephanie , Zhang Lin , Näntö-Salonen Kirsti , Rintamäki Reeta , Pihlajamäki Jussi , Knip Mikael , Veijola Riitta , Toppari Jorma , Ilonen Jorma , Benschop Robert J. , Kinnunen Tuure
Published: June 2023

IL-21 is a multifunctional cytokine linked with the pathophysiology of several autoimmune diseases, including type 1 diabetes. In this study, our aim was to examine plasma IL-21 levels in individuals at different stages of type 1 diabetes progression. We measured plasma IL-21 levels, as well as levels of other key pro-inflammatory cytokines (IL-17A, TNF-α and IL-6), from 37 adults with established type 1 diabetes and 46 healthy age-matched adult controls, as well as from 53 children with newly diagnosed type 1 diabetes, 48 at-risk children positive for type 1 diabetes-associated autoantibodies and 123 healthy age-matched pediatric controls using the ultrasensitive Quanterix SiMoA technology. Adults with established type 1 diabetes had higher plasma IL-21 levels compared to healthy controls. However, the plasma IL-21 levels showed no statistically significant correlation with clinical variables, such as BMI, C-peptide, HbA1c, or hsCRP levels, evaluated in parallel. In children, plasma IL-21 levels were almost ten times higher than in adults. However, no significant differences in plasma IL-21 levels were detected between healthy children, autoantibody-positive at-risk children, and children with newly diagnosed type 1 diabetes. In conclusion, plasma IL-21 levels in adults with established type 1 diabetes were increased, which may be associated with autoimmunity. The physiologically high plasma IL-21 levels in children may, however, reduce the potential of IL-21 as a biomarker for autoimmunity in pediatric subjects.
Panax quinquefolius polysaccharides ameliorate ulcerative colitis in mice induced by dextran sulfate sodium
Authors: Ren Duo-duo , Chen Ke-Cheng , Li Shan-shan , Zhang Yan-ting , Li Zhi-man , Liu Shuang , Sun Yin-shi
Published: June 2023

This study aimed to investigate the ameliorative effect of the polysaccharides of Panax quinquefolius (WQP) on ulcerative colitis (UC) induced by dextran sulfate sodium (DSS) in mice and to explore its mechanism. Male C57BL/6J mice were randomly divided into the control group (C), model group (DSS), positive control mesalazine (100 mg/kg, Y) group, and low (50 mg/kg, L), medium (100 mg/kg, M) and high dose (200 mg/kg, H) of WQP groups. The UC model was induced by free drinking water with 2.5% DSS for 7 days. During the experiment, the general condition of the mice was observed, and the disease activity index (DAI) was scored. The conventional HE staining was used to observe pathological changes in mice’s colon, and the ELISA method was used to detect the levels of interleukin-6 (IL-6), IL-4, IL-8, IL-10, IL-1β and tumor necrosis factor-α (TNF-α) in mice’s colon. The changes in gut microbiota in mice were detected by high-throughput sequencing; the concentration of short-chain fatty acids (SCFAs) was determined by gas chromatography; the expression of related proteins was detected by Western blot. Compared with the DSS group, the WQP group showed a significantly lower DAI score of mice and an alleviated colon tissue injury. In the middle- and high-dose polysaccharides groups, the levels of pro-inflammatory cytokines IL-6, IL-8, IL-1β and TNF-α in the colonic tissue were significantly decreased (P<0.05), while the levels of IL-4 and IL-10 were significantly increased (P<0.05). The 16S rRNA gene sequencing results showed that different doses of WQP could regulate the composition and diversity of gut microbiota and improve its structure. Specifically, at the phylum level, group H showed an increased relative abundance of Bacteroidetes and a decreased relative abundance of Firmicutes compared with the DSS group, which was closer to the case in group C. At the family level, the relative abundance of Rikenellaceae in L, M and H groups increased significantly, close to that in group C. At the genus level, the relative abundance of Bacteroides, Shigella and Oscillospira in the H group increased significantly, while that of Lactobacillus and Prevotella decreased significantly. The high-dose WQP group could significantly increase the contents of acetic acid, propionic acid, butyric acid, and total SCFAs. Different doses of WQP also increased the expression levels of tight junction proteins ZO-1, Occludin and Claudin-1. To sum up, WQP can regulate the gut microbiota structure of UC mice, accelerate the recovery of gut microbiota, and increase the content of Faecal SCFAs and the expression level of tight junction proteins in UC mice. This study can provide new ideas for the treatment and prevention of UC and theoretical references for the application of WQP.
NOD2 in monocytes negatively regulates macrophage development through TNFalpha
Authors: Chauvin Camille , Alvarez-Simon Daniel , Radulovic Katarina , Boulard Olivier , Laine William , Delacre Myriam , Waldschmitt Nadine , Segura Elodie , Kluza Jérome , Chamaillard Mathias , Poulin Lionel F.
Published: June 2023

Objective

It is believed that intestinal recruitment of monocytes from Crohn’s Disease (CD) patients who carry NOD2 risk alleles may repeatedly give rise to recruitment of pathogenic macrophages. We investigated an alternative possibility that NOD2 may rather inhibit their differentiation from intravasating monocytes.

Design

The monocyte fate decision was examined by using germ-free mice, mixed bone marrow chimeras and a culture system yielding macrophages and monocyte-derived dendritic cells (mo-DCs).

Results

We observed a decrease in the frequency of mo-DCs in the colon of Nod2-deficient mice, despite a similar abundance of monocytes. This decrease was independent of the changes in the gut microbiota and dysbiosis caused by Nod2 deficiency. Similarly, the pool of mo-DCs was poorly reconstituted in a Nod2-deficient mixed bone marrow (BM) chimera. The use of pharmacological inhibitors revealed that activation of NOD2 during monocyte-derived cell development, dominantly inhibits mTOR-mediated macrophage differentiation in a TNFα-dependent manner. These observations were supported by the identification of a TNFα-dependent response to muramyl dipeptide (MDP) that is specifically lost when CD14-expressing blood cells bear a frameshift mutation in NOD2.

Conclusion

NOD2 negatively regulates a macrophage developmental program through a feed-forward loop that could be exploited for overcoming resistance to anti-TNF therapy in CD.
Self-assembled ferritin nanoparticles displaying PcrV and OprI as an adjuvant-free Pseudomonas aeruginosa vaccine
Authors: Li Yuhang , Pu Ruixue , Zhang Yi , Zhang Yiwen , Wei Yujie , Zeng Sheng , Gao Chen , Wang Ying , Yin Daijiajia , Zhang Yueyue , Wan Jiqing , Zou Quanming , Gu Jiang
Published: June 2023

Introduction

Serious infections of Pseudomonas aeruginosa (PA) in hospitals and the emergence and increase of multidrug resistance have raised an urgent need for effective vaccines. However, no vaccine has been approved to date. One possible reason for this is the limited immune response due to the lack of an efficient delivery system. Self-assembled ferritin nanoparticles are good carriers of heterogeneous antigens, which enhance the activation of immunological responses.

Methods

In this study, two well-studied antigen candidates, PcrV and OprI, were selected and connected to the ferritin nanoparticle by the Spytag/SpyCatcher system to generate the nanovaccine rePO-FN.

Results

Compared to recombinant PcrV-OprI formulated with aluminum adjuvants, intramuscular immunization with adjuvant-free rePO-FN induced quick and efficient immunity and conferred protection against PA pneumonia in mice. In addition, intranasal immunization with adjuvant-free rePO-FN enhanced protective mucosal immunity. Moreover, rePO-FN exhibited good biocompatibility and safety.

Discussion

Our results suggest that rePO-FN is a promising vaccine candidate, as well as, provide additional evidence for the success of ferritin-based nanovaccines.
The role of interleukin-18 and interleukin-18 binding protein in K/BxN serum transfer-induced arthritis
Authors: Fauteux-Daniel Sebastien , Merlo Pich Laura M. , Girard-Guyonvarc’h Charlotte , Caruso Assunta , Rodriguez Emiliana , Gabay Cem
Published: June 2023

Background

Interleukin-18 is a proinflammatory cytokine, the activity of which is regulated by its natural inhibitor, IL-18 binding protein (IL-18BP). Elevated circulating levels of IL-18 have been observed in patients with systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still’s disease (AOSD), two conditions associated with dysregulated innate immune responses. This study examines the expression and function of IL-18 and IL-18BP in K/BxN serum transfer arthritis (STA), a model that is uniquely dependent on innate immune responses.

Methods

Naïve and serum transfer-induced arthritis (STA) wild-type (WT) mice were used to examine the articular levels of IL-18 and IL-18BP mRNA by RT-qPCR. The cellular sources of IL-18BP in the joints were determined by using Il18bp-tdTomato reporter knock-in mice. The incidence and severity of arthritis, including mRNA levels of different cytokines, were compared in IL-18BP or IL-18 knock-out (KO) mice and their WT littermates.

Results

IL-18 and IL-18BP mRNA levels were significantly increased in arthritic as compared to normal joints. Synovial neutrophils, macrophages, and endothelial cells represented the cellular sources of IL-18BP in arthritic joints, whereas IL-18BP production was limited to endothelial cells in non-inflamed joints. The incidence and severity of arthritis were similar in IL-18BP KO and IL-18 KO compared to their WT littermates. Transcript levels of different inflammatory cytokines were not different in the two KO mouse lines compared to WT mice.

Conclusion

Although IL-18 and IL-18BP levels were increased in arthritic joints, our results show that the IL-18/IL-18BP balance is not involved in the regulation of STA.
Prediction of medication-related osteonecrosis of the jaws using machine learning methods from estrogen receptor 1 polymorphisms and clinical information
Authors: Choi Seo-Yong , Kim Jin-Woo , Oh Sang-Hyeon , Cheon Seunghyun , Yee Jeong , Kim Sun-Jong , Gwak Hye Sun , Chung Jee-Eun
Published: June 2023

Objective

The purpose of this study was to evaluate the effect of estrogen receptor 1 (ESR1) polymorphisms on the development of medication-related osteonecrosis of the jaws (MRONJ) in women with osteoporosis.

Methods

A total of 125 patients taking bisphosphonates was evaluated the relationship between MRONJ occurrence and single nucleotide polymorphisms (SNPs) of ESR1. Clinical information was collected, including current age, treatment duration, and comorbidity. Univariate and Multivariable regression analyzes were performed to evaluate the independent predictive factors for MRONJ occurrence. Predictive models were constructed using machine learning methods such as Lasso regression, Random forest (RF), and Support vector machine (SVM). The area under the receiver-operating curve (AUROC) was used to evaluate the performance of a binary classifier.

Result

Two SNPs of ESR1 (rs4870056 and rs78177662) were significantly associated with MRONJ development. Patients with variant allele (A) of rs4870056 showed 2.45 times (95% CI, 1.03–5.87) the odds of MRONJ occurrence compared to those with wild-type homozygote (GG) after adjusting covariates. Additionally, carriers with variant allele (T) of rs78177662 had higher odds than those with wild-type homozygote (CC) (adjusted odds ratio (aOR), 2.64, 95% CI, 1.00–6.94). Among demographic variables, age ≥ 72 years (aOR, 3.98, 95% CI, 1.60–9.87) and bisphosphonate exposure ≥48 months (aOR, 3.16, 95% CI, 1.26–7.93) were also significant risk factors for MRONJ occurrence. AUROC values of machine learning methods ranged between 0.756–0.806 in the study.

Conclusion

Our study showed that the MRONJ occurrence was associated with ESR1 polymorphisms in osteoporotic women.
Cardiovascular events in delayed presentation of HIV: the prospective PISCIS cohort study
Authors: Martín-Iguacel Raquel , Vazquez-Friol Mari Carmen , Burgos Joaquin , Bruguera Andreu , Reyes-Urueña Juliana , Moreno-Fornés Sergio , Aceitón Jordi , Díaz Yesika , Domingo Pere , Saumoy Maria , Knobel Hernando , Dalmau David , Borjabad Beatriz , Johansen Isik Somuncu , Miro Jose M. , Casabona Jordi , Llibre Josep M.
Published: June 2023

Objectives

People with HIV (PWH) have a higher cardiovascular risk than the general population. It remains unclear, however, whether the risk of cardiovascular disease (CVD) is higher in late HIV presenters (LP; CD4 ≤ 350 cells/μL at HIV diagnosis) compared to PWH diagnosed early. We aimed to assess the rates of incident cardiovascular events (CVEs) following ART initiation among LP compared to non-LP.

Methods

From the prospective, multicentre PISCIS cohort, we included all adult people with HIV (PWH) initiating antiretroviral therapy (ART) between 2005 and 2019 without prior CVE. Additional data were extracted from public health registries. The primary outcome was the incidence of first CVE (ischemic heart disease, congestive heart failure, cerebrovascular, or peripheral vascular disease). The secondary outcome was all-cause mortality after the first CVE. We used Poisson regression.

Results

We included 3,317 PWH [26 589.1 person/years (PY)]: 1761 LP and 1556 non-LP. Overall, 163 (4.9%) experienced a CVE [IR 6.1/1000PY (95%CI: 5.3–7.1)]: 105 (6.0%) LP vs. 58 (3.7%) non-LP. No differences were observed in the multivariate analysis adjusting for age, transmission mode, comorbidities, and calendar time, regardless of CD4 at ART initiation [aIRR 0.92 (0.62–1.36) and 0.84 (0.56–1.26) in LP with CD4 count <200 and 200– ≤ 350 cells/μL, respectively, compared to non-LP]. Overall mortality was 8.5% in LP versus 2.3% in non-LP (p < 0.001). Mortality after the CVE was 31/163 (19.0%), with no differences between groups [aMRR 1.24 (0.45–3.44)]. Women vs. MSM and individuals with chronic lung and liver disease experienced particularly high mortality after the CVE [aMRR 5.89 (1.35–25.60), 5.06 (1.61–15.91), and 3.49 (1.08–11.26), respectively]. Sensitivity analyses including only PWH surviving the first 2 years yielded similar results.

Conclusion

CVD remains a common cause of morbidity and mortality among PWH. LP without prior CVD did not exhibit an increased long-term risk of CVE compared with non-LP. Identifying traditional cardiovascular risk factors is essential for CVD risk reduction in this population.
Changes in musculoskeletal disease activity and patient-reported outcomes in patients with psoriatic arthritis treated with ixekizumab: results from a real-world US cohort
Authors: Tillett William , Birt Julie , Cavanaugh Cristi , Jung Yoojin , Vadhariya Aisha , Ross Sarah , Paulus Jessica , Lubrano Ennio
Published: June 2023

Introduction

Ixekizumab has demonstrated efficacy in pivotal trials in patients with psoriatic arthritis (PsA), both those naïve to prior biologic therapy and those with prior inadequate response or intolerance to biologics; however, minimal information is currently available on the effectiveness of ixekizumab in routine clinical practice. The objective of this study was to investigate the clinical effectiveness of ixekizumab for the treatment of PsA over 6- and 12-month follow-up periods in a real-world setting.

Methods

This retrospective cohort study included patients who initiated treatment with ixekizumab from the OM1 PremiOMTM PsA dataset, a dataset of over 50,000 patients with claims and electronic medical record (EMR) data. Changes in musculoskeletal outcomes, such as tender and swollen joint count and patient-reported pain, as well as physician and patient global assessment, as measured using the Clinical Disease Activity Index (CDAI), and Routine Assessment of Patient Index Data 3 (RAPID3) were summarized at 6 and 12 months. The RAPID3, CDAI score, and their individual components were assessed in multivariable regressions adjusting for age, sex, and baseline value. The results were stratified by biologic disease-modifying antirheumatic drug (bDMARD) status (naïve vs. experienced) and monotherapy status (monotherapy vs. combination therapy with conventional synthetic DMARDs). Changes in a 3-item composite score derived from a physician global assessment, patient global assessment, and patient-reported pain score were summarized.

Results

Among the 1,812 patients identified receiving ixekizumab, 84% had prior bDMARD treatment and 82% were monotherapy users. All outcomes improved at 6 and 12 months. For RAPID3, the mean (SD) change at 6 and 12 months was −1.2 (5.5) and −1.2 (5.9), respectively. Patients overall, bDMARD experienced, and monotherapy patients achieved statistically significant mean change in CDAI and all components from baseline to 6 and 12 months in adjusted analyses. Patients experienced an improvement in the 3-item composite score at both time points.

Conclusion

Treatment with ixekizumab was associated with improvements in musculoskeletal disease activity and PROs as assessed by several outcome measures. Future research should assess ixekizumab's clinical effectiveness in the real world across all PsA domains using PsA-specific endpoints.
Modifications in cellular viability, DNA damage and stress responses inflicted in cancer cells by copper-64 ions
Authors: Serban Radu M. , Niculae Dana , Manda Gina , Neagoe Ionela , Dobre Maria , Niculae Dragoș A. , Temelie Mihaela , Mustăciosu Cosmin , Leonte Radu A. , Chilug Livia E. , Cornoiu Maria R. , Cocioabă Diana , Stan Miruna , Dinischiotu Anca
Published: June 2023

Due to combined therapeutical emissions, a high linear energy transfer Auger-electrons with the longer ranged β− particles, 64Cu-based radiopharmaceuticals raise particular theragnostic interest in cancer, by joined therapeutic and real-time PET imaging properties. The in vitro study aimed to investigate the biological and molecular background of 64CuCl2 therapy by analyzing the damages and stress responses inflicted in various human normal and tumor cell lines. Colon (HT29 and HCT116) and prostate carcinoma (DU145) cell lines, as well as human normal BJ fibroblasts, were treated up to 72 h with 2–40 MBq/mL 64CuCl2. Radioisotope uptake and retention were assessed, and cell viability/death, DNA damage, oxidative stress, and the expression of 84 stress genes were investigated at various time points after [64Cu]CuCl2 addition. All the investigated cells incorporated 64Cu ions similarly, independent of their tumoral or normal status, but their fate after exposure to [64Cu]CuCl2 was cell-dependent. The most striking cytotoxic effects of the radioisotope were registered in colon carcinoma HCT116 cells, for which a substantial decrease in the number of metabolically active cells, and an increased DNA damage and oxidative stress were registered. The stress gene expression study highlighted the activation of both death and repair mechanisms in these cells, related to extrinsic apoptosis, necrosis/necroptosis or autophagy, and cell cycle arrest, nucleotide excision repair, antioxidant, and hypoxic responses, respectively. The in vitro study indicated that 40 MBq/mL [64Cu]CuCl2 delivers a therapeutic effect in human colon carcinoma, but its use is limited by harmful, yet lower effects on normal fibroblasts. The exposure of tumor cells to 20 MBq/mL [64Cu]CuCl2, might be used for a softer approach aiming for a lower radiotoxicity in normal fibroblasts as compared to tumor cells. This radioactive concentration was able to induce a persistent decrease in the number of metabolically active cells, accompanied by DNA damage and oxidative stress, associated with significant changes in stress gene expression in HCT116 colon cancer cells.
Species-level microbiota of ticks and fleas from Marmota himalayana in the Qinghai-Tibet Plateau
Authors: Dong Lingzhi , Li Yaben , Yang Caixin , Gong Jian , Zhu Wentao , Huang Yuyuan , Kong Mimi , Zhao Lijun , Wang Feifei , Lu Shan , Pu Ji , Yang Jing
Published: June 2023

Introduction

Ticks and fleas, as blood-sucking arthropods, carry and transmit various zoonotic diseases. In the natural plague foci of China, monitoring of Yersinia pestis has been continuously conducted in Marmota himalayana and other host animals, whereas other pathogens carried by vectors are rarely concerned in the Qinghai-Tibet Plateau.

Methods

In this study, we investigated the microbiota of ticks and fleas sampling from M. himalayana in the Qinghai-Tibet Plateau, China by metataxonomics combined with metagenomic methods.

Results

By metataxonomic approach based on full-length 16S rDNA amplicon sequencing and operational phylogenetic unit (OPU) analyses, we described the microbiota community of ticks and fleas at the species level, annotated 1,250 OPUs in ticks, including 556 known species and 492 potentially new species, accounting for 48.50% and 41.71% of the total reads in ticks, respectively. A total of 689 OPUs were detected in fleas, consisting of 277 known species (40.62% of the total reads in fleas) and 294 potentially new species (56.88%). At the dominant species categories, we detected the Anaplasma phagocytophilum (OPU 421) and potentially pathogenic new species of Wolbachia, Ehrlichia, Rickettsia, and Bartonella. Using shotgun sequencing, we obtained 10 metagenomic assembled genomes (MAGs) from vector samples, including a known species (Providencia heimbachae DFT2), and six new species affliated to four known genera, i.e., Wolbachia, Mumia, Bartonella, and Anaplasma. By the phylogenetic analyses based on full-length 16S rRNA genes and core genes, we identified that ticks harbored pathogenic A. phagocytophilum. Moreover, these potentially pathogenic novel species were more closely related to Ehrlichia muris, Ehrlichia muris subsp. eauclairensis, Bartonella rochalimae, and Rickettsia limoniae, respectively. The OPU 422 Ehrlichia sp1 was most related to Ehrlichia muris and Ehrlichia muris subsp. eauclairensis. The OPU 230 Bartonella sp1 and Bartonella spp. (DTF8 and DTF9) was clustered with Bartonella rochalimae. The OPU 427 Rickettsia sp1 was clustered with Rickettsia limoniae.

Discussion

The findings of the study have advanced our understanding of the potential pathogen groups of vectors in marmot (Marmota himalayana) in the Qinghai-Tibet Plateau.
Structural diversity among Acinetobacter baumannii K-antigens and its implication in the in silico serotyping
Authors: Roshini Janardhanaachari , Patro L. Ponoop Prasad , Sundaresan Sruthi , Rathinavelan Thenmalarchelvi
Published: June 2023

Acinetobacter baumannii is an emerging opportunistic pathogen. It exhibits multi-, extreme-, and pan-drug resistance against several classes of antibiotics. Capsular polysaccharide (CPS or K-antigen) is one of the major virulence factors which aids A. baumannii in evading the host immune system. K-antigens of A. baumannii exploit the Wzx/Wzy-dependent pathway that involves 13 different proteins for its assembly and transport onto the outer membrane. A total of 64 (out of 237 K-locus(KL) types) known K-antigen sugar repeating structures are discussed here and are classified into seven groups based on their initial sugars, QuiNAc4NAc, GalNAc, GlcNAc, Gal, QuiNAc/FucNAc, FucNAc, and GlcNAc along with Leg5Ac7Ac/Leg5Ac7R. Thus, the corresponding seven initializing glycosyltransferases (ItrA1, ItrA2, ItrA3, ItrA4, ItrB1, ItrB3, and ItrA3 along with ItrB2) exhibit serotype specificity. The modeled 3D-structural repository of the 64 K-antigens can be accessed at https://project.iith.ac.in/ABSD/k_antigen.html. The topology of K-antigens further reveals the presence of 2-6 and 0-4 sugar monomers in the main and side chains, respectively. The presence of negatively (predominant) or neutrally charged K-antigens is observed in A. baumannii. Such diversity in the K-antigen sugar composition provides the K-typing specificity (viz., 18–69% in terms of reliability) for Wza, Wzb, Wzc, Wzx, and Wzy proteins involved in the Wzx/Wzy-dependent pathway. Interestingly, the degree of uniqueness of these proteins among different K-types is estimated to be 76.79%, considering the 237 reference sequences. This article summarizes the A. baumannii K-antigen structural diversity and creation of a K-antigen digital repository and provides a systematic analysis of the K-antigen assembly and transportation marker proteins.
Dysregulated NAD(H) homeostasis associated with ciprofloxacin tolerance in Escherichia coli investigated on a single-cell level with the Peredox [NADH:NAD+] biosensor
Authors: Urbaniec Joanna , Sanderson-Smith Martina , McFadden Johnjoe , Hai Faisal I. , Hingley-Wilson Suzanne M.
Published: June 2023

Introduction

Antibiotic persistence (subpopulation tolerance) occurs when a subpopulation of antibiotic sensitive cells survives prolonged exposure to a bactericidal concentration of an antibiotic, and is capable of regrowth once the antibiotic is removed. This phenomenon has been shown to contribute to prolonged treatment duration, infection recurrence, and accelerated development of genetic resistance. Currently, there are no biomarkers which would allow for segregation of these antibiotic-tolerant cells from the bulk population prior to antibiotic exposure, limiting research on this phenomenon to retrograde analyses. However, it has been previously shown that persisters often have a dysregulated intracellular redox homeostasis, warranting its investigation as a potential marker for antibiotic tolerance. Furthermore, it is currently unknown whether another antibiotic tolerant subpopulation - viable but non-culturable cells (VBNCs), are simply persisters with extreme lag phase, or are formed through separate pathways. VBNCs similarly to persisters remain viable following antibiotic exposure, however, are not capable of regrowth in standard conditions.

Methods

In this article we employed an NADH:NAD+ biosensor (Peredox) to investigate NADH homeostasis of ciprofloxacin-tolerant E. coli cells on a single-cell level. [NADH:NAD+] was used as a proxy for measuring intracellular redox homeostasis and respiration rate.

Results and Discussion

First, we demonstrated that ciprofloxacin exposure results in a high number of VBNCs, several orders of magnitude higher than persisters. However, we found no correlation in the frequencies of persister and VBNC subpopulations. Ciprofloxacin-tolerant cells (persisters & VBNCs) were actively undergoing respiration, although at a significantly lower rate on average when compared to the bulk population. We also noted significant heterogeneity on a single-cell level within the subpopulations, however were unable to segregate persisters from VBNCs based on these observations alone. Finally, we showed that in the highly-persistent strain of E. coli, E. coli HipQ, ciprofloxacin-tolerant cells have a significantly lower [NADH:NAD+] ratio than tolerant cells of its parental strain, providing further link between disturbed NADH homeostasis and antibiotic tolerance.
Temporal and spatial changes in rhizosphere bacterial diversity of mountain Rhododendron mucronulatum
Authors: Wang Sirui , Zhou Tiantian , Zhao Hewen , Zhang Kezhong , Cui Jinteng
Published: June 2023

To better conserve the ecology of the wild Rhododendron mucronulatum range, we studied the rhizosphere microenvironment of R. mucronulatum in Beijing’s Yunmeng Mountain National Forest Park. R. mucronulatum rhizosphere soil physicochemical properties and enzyme activities changed significantly with temporal and elevational gradients. The correlations between soil water content (SWC), electrical conductivity (EC), organic matter content (OM), total nitrogen content (TN), catalase activity (CAT), sucrose-converting enzyme activity (INV), and urease activity (URE) were significant and positive in the flowering and deciduous periods. The alpha diversity of the rhizosphere bacterial community was significantly higher in the flowering period than in the deciduous period, and the effect of elevation was insignificant. The diversity of the R. mucronulatum rhizosphere bacterial community changed significantly with the change in the growing period. A network analysis of the correlations revealed stronger linkages between the rhizosphere bacterial communities in the deciduous period than in the flowering period. Rhizomicrobium was the dominant genus in both periods, but its relative abundance decreased in the deciduous period. Changes in the relative abundance of Rhizomicrobium may be the main factor influencing the changes in the R. mucronulatum rhizosphere bacterial community. Moreover, the R. mucronulatum rhizosphere bacterial community and soil characteristics were significantly correlated. Additionally, the influence of soil physicochemical properties on the rhizosphere bacterial community was larger than that of enzyme activity on the bacterial community. We mainly analyzed the change patterns in the rhizosphere soil properties and rhizosphere bacterial diversity of R. mucronulatum during temporal and spatial variation, laying the foundation for further understanding of the ecology of wild R. mucronulatum.
Translocator protein in the rise and fall of central nervous system neurons
Authors: Cheung Garett , Lin Yiqi Christina , Papadopoulos Vassilios
Published: June 2023

Translocator protein (TSPO), a 18 kDa protein found in the outer mitochondrial membrane, has historically been associated with the transport of cholesterol in highly steroidogenic tissues though it is found in all cells throughout the mammalian body. TSPO has also been associated with molecular transport, oxidative stress, apoptosis, and energy metabolism. TSPO levels are typically low in the central nervous system (CNS), but a significant upregulation is observed in activated microglia during neuroinflammation. However, there are also a few specific regions that have been reported to have higher TSPO levels than the rest of the brain under normal conditions. These include the dentate gyrus of the hippocampus, the olfactory bulb, the subventricular zone, the choroid plexus, and the cerebellum. These areas are also all associated with adult neurogenesis, yet there is no explanation of TSPO’s function in these cells. Current studies have investigated the role of TSPO in microglia during neuron degeneration, but TSPO’s role in the rest of the neuron lifecycle remains to be elucidated. This review aims to discuss the known functions of TSPO and its potential role in the lifecycle of neurons within the CNS.
Sex differences in acute telestroke care: more to the story
Authors: Sevilis Theresa , Avila Amanda , McDonald Mark , Fowler Mariecken , Chalfin Renata , Amir Murtaza , Heath Gregory , Zaman Mohammed , Avino Lorianne , Boyd Caitlyn , Gao Lan , Devlin Thomas
Published: June 2023

Background

Previous studies have shown sex differences in stroke care. Female patients have both lower thrombolytic treatment rates with OR reported as low as 0.57 and worse outcomes. With updated standards of care and improved access to care through telestroke, there is potential to reduce or alleviate these disparities.

Methods

Acute stroke consultations seen by TeleSpecialists, LLC physicians in the emergency department in 203 facilities (23 states) from January 1, 2021 to April 30, 2021 were extracted from the Telecare by TeleSpecialists™ database. The encounters were reviewed for demographics, stroke time metrics, thrombolytics candidate, premorbid modified Rankin Score, NIHSS score, stroke risk factors, antithrombotic use, admitting diagnosis of suspected stroke, and reason not treated with thrombolytic. The treatment rates, door to needle (DTN) times, stroke metric times, and variables of treatment were compared for females and males.

Results

There were 18,783 (10,073 female and 8,710 male) total patients included. Of the total, 6.9% of females received thrombolytics compared to 7.9% of males (OR 0.86, 95% CI 0.75–0.97, p = 0.006). Median DTN times were shorter for males than females (38 vs. 41 min, p < 0.001). Male patients were more likely to have an admitting diagnosis of suspected stroke, p < 0.001. Analysis by age showed the only decade with significant difference in thrombolytics treatment rate was 50–59 with increased treatment of males, p = 0.047. When multivariant logistic regression analysis was performed with stroke risk factors, NIHSS score, age, and admitting diagnosis of suspected stroke, the adjusted odds ratio for females was 0.9 (95% CI 0.8, 1.01), p = 0.064.

Conclusion

While treatment differences between sexes existed in the data and were apparent in univariate analysis, no significant difference was seen in multivariate analysis once stroke risk factors, age, NIHSS score and admitting diagnosis were taken into consideration in the telestroke setting. Differences in rates of thrombolysis between sexes may therefore be reflective of differences in risk factors and symptomatology rather than a healthcare disparity.
Case report: Reversible brain atrophy with low titer anti-amphiphysin antibodies related to gastric adenocarcinoma
Authors: Amano Ryota , Kim Yeon-Jeong , Yoshida Toshikazu , Hara Makoto , Nakajima Hideto , Ohtsuka Toshihisa , Yazawa Masanobu
Published: June 2023

Amphiphysin (AMPH) autoimmunity is associated with a variety of neurological complications, including encephalitis, peripheral neuropathy, myelopathy, and cerebellar syndrome. Its diagnosis is based on clinical neurological deficits and the presence of serum anti-AMPH antibodies. Active immunotherapy, such as intravenous immunoglobulins, steroids, and other immunosuppressive therapies, has been reported to be effective in most patients. However, the extent of recovery varies depending on the case. Herein, we report the case of a 75-year-old woman with semi-rapidly progressive systemic tremors, visual hallucinations, and irritability. Upon hospitalization, she developed a mild fever and cognitive impairment. Brain magnetic resonance imaging (MRI) showed semi-rapidly progressive diffuse cerebral atrophy (DCA) over 3 months, while no clear abnormal intensities were observed. The nerve conduction study revealed sensory and motor neuropathy in the limbs. The fixed tissue-based assay (TBA) failed to detect antineuronal antibodies; however, based on commercial immunoblots, the presence of anti-AMPH antibodies was suspected. Therefore, serum immunoprecipitation was performed, which confirmed the presence of anti-AMPH antibodies. The patient also had gastric adenocarcinoma. High-dose methylprednisolone, and intravenous immunoglobulin were administered and tumor resection was performed, resulting in resolution of the cognitive impairment and improvement in the DCA on the post-treatment MRI. After immunotherapy and tumor resection, the patient's serum was analyzed using immunoprecipitation, which showed a decrease in the level of anti-AMPH antibodies. This case is noteworthy because the DCA showed improvement after immunotherapy and tumor resection. Additionally, this case demonstrates that negative TBA with positive commercial immunoblots do not necessarily indicate false positive results.
The accuracy of ultrasound-guided fine-needle aspiration and core needle biopsy in diagnosing axillary lymph nodes in women with breast cancer: a systematic review and meta-analysis
Authors: Zheng Haining , Zhao Rui , Wang Wei , Liu Xiaona , Wang Xiaoqing , Wen Chaoyang , Ren Yubo
Published: June 2023

Background

This study evaluates the diagnostic accuracy of ultrasound-guided fine needle aspiration (US-FNA) and core needle biopsy (US-CNB) for detecting axillary lymph nodes in women with breast cancer.

Methods

Eligible studies and pertinent literature resources were identified in Cochrane, PubMed, Embase, CNKI, VIP, and Wanfang databases using subject-specific keywords. Study outcomes were tested for heterogeneity, and meta-analyses were performed to estimate sensitivity, specificity, and diagnostic odds ratios (DORs). The summary receiver operating characteristic (SROC) curve analysis was also performed.

Results

A total of 22 studies involving 3,548 patients were included to evaluate the diagnostic accuracy of US-FNA and 11 studies involving 758 patients were included to evaluate the diagnostic accuracy of US-CNB in identifying axillary lymph nodes in women with breast cancer. The accuracy of US-FNA in identifying suspicious axillary lymph nodes was as follows: overall sensitivity, 79% (95% CI: 73%–84%); global specificity, 96% (95% CI: 92%–98%); overall positive likelihood ratio, 18.55 (95% CI: 10.53–32.69); overall negative likelihood ratio, 0.22 (95% CI: 0.17–0.28); DOR, 71.68 (95% CI: 37.19–138.12); and the area under the SROC curve, 0.94 (95% CI: 0.92–0.96). The accuracy of US-CNB in identifying suspicious axillary lymph nodes was as follows: overall sensitivity, 85% (95% CI: 81%–89%); global specificity, 93% (95% CI: 87%–96%); overall positive likelihood ratio, 11.88 (95% CI: 6.56–21.50); overall negative likelihood ratio, 0.16 (95% CI: 0.12–0.21); overall DOR, 66.83 (95% CI: 33.28–134.21), and the area under SROC curve 0.96 (95% CI: 0.94–0.97).

Conclusions

The results indicate that both US-FNA and US-CNB have high accuracy for suspicious axillary lymph nodes.
CTNNB1-related neurodevelopmental disorder mimics cerebral palsy: case report
Authors: Lee Jaewoong , Yoo Jaeeun , Lee Seungok , Jang Dae-Hyun
Published: June 2023

While somatic gain-of-function mutations in the CTNNB1 gene cause diverse malignancies, germline loss-of-function mutations cause neurodevelopmental disorders or familial exudative vitreoretinopathy. In particular, CTNNB1-related neurodevelopmental disorders have various phenotypes, and a genotype-phenotype relationship has not been established. We report two patients with CTNNB1-related neurodevelopmental disorder whose clinical features were similar to those of cerebral palsy, hindering diagnosis.