Datasets:

wasifis

/

citation_prompting-ex

like 0

BACKGROUND: Huntingtons disease is a complex neurodegenerative hereditary disease with symptoms in all domains of a persons functioning. It begins after a healthy start in life and leads through the relentless progression over many years to complete care dependency and finally death. To date, the disease is incurable. The long progressive complex nature of the disease demands multiple disciplines for treatment and care of patient and family. These health care providers need inter- and multidisciplinary collaboration to persevere and be efficacious in this devastating disease trajectory. DISCUSSION: The position paper outlines current knowledge and experience alongside the experience and consensus of a recognised group of HD multidisciplinary experts. Additionally the patients voice is clear and calls for health care providers with a holistic view on patient and family. Building long-term trust is a cornerstone of the network around the patient. This paper describes a managed care network comprising all the needed professionals and services. In the health care system, the role of a central coordinator or case manager is of key importance but lacks an appropriate guideline. Other disciplines currently without guidelines are general practitioners, nurses, psychologists, and social workers. Guidelines for neurologists, psychiatrists, geneticists, occupational therapists, speech and language therapists, physiotherapists, dieticians, and dentists are being discussed. Apart from all these profession-specific guidelines, distinctive inter- and multidisciplinary collaboration requirements must be met. CONCLUSIONS AND RECOMMENDATIONS: The complex nature of Huntingtons disease demands multidisciplinary treatment and care endorsed by international regulations and the lay association. Available guidelines as reviewed in this paper should be used, made available by a central body, and updated every 3-5\xa0years. Time needs to be invested in developing missing guidelines but the lack of this proof should not prevent the doing of good care. , Huntington’s disease is a complex neurodegenerative hereditary disease with symptoms in all domains of a person’s functioning. It begins after a healthy start in life and leads through the relentless progression over many years to complete care dependency and finally death. To date, the disease is incurable. The long progressive complex nature of the disease demands multiple disciplines for treatment and care of patient and family. These health care providers need inter- and multidisciplinary collaboration to persevere and be efficacious in this devastating disease trajectory. The position paper outlines current knowledge and experience alongside the experience and consensus of a recognised group of HD multidisciplinary experts. Additionally the patient’s voice is clear and calls for health care providers with a holistic view on patient and family. Building long-term trust is a cornerstone of the network around the patient. This paper describes a managed care network comprising all the needed professionals and services. In the health care system, the role of a central coordinator or case manager is of key importance but lacks an appropriate guideline. Other disciplines currently without guidelines are general practitioners, nurses, psychologists, and social workers. Guidelines for neurologists, psychiatrists, geneticists, occupational therapists, speech and language therapists, physiotherapists, dieticians, and dentists are being discussed. Apart from all these profession-specific guidelines, distinctive inter- and multidisciplinary collaboration requirements must be met. The complex nature of Huntingtons disease demands multidisciplinary treatment and care endorsed by international regulations and the lay association. Available guidelines as reviewed in this paper should be used, made available by a central body, and updated every 3–5\xa0years. Time needs to be invested in developing missing guidelines but the lack of this ‘proof’ should not prevent the ‘doing’ of good care. , Huntingtons disease (HD) is an autosomal neurodegenerative disease that involves movement disorders, cognitive impairments, and psychiatric symptoms. It is characterized by\xa0regionally selective cortical degeneration that proceeds from posterior to anterior cortical region which explains its heterogeneity. At present, the psychiatric symptoms of HD are mostly managed by antidepressant such as selective serotonin reuptake inhibitors or selective nor-epinephrine reuptake inhibitors, and atypical antipsychotics. Currently, there are no efficient pharmacological treatment available for HD. Thus, in order to avoid this void in effective pharmacotherapy, further supplemental and alternative approaches are being explored for the management of problems associated with HD. A literature review was performed using the databases PubMed and Google Scholar identifying clinical studies that were set to ameliorate the symptoms associated with HD. On critical analysis, it was found that alternative treatment modalities like music therapy, video games, Yoga, Physical therapy, and exercise-based programs have a potential and possible role in improving the symptoms of HD at varied degrees. , Huntington’s disease (HD) is a progressive autosomal dominant genetic disease, which typically manifests in adulthood with movement disorder, cognitive decline, and psychiatric changes(1). Its overall survival after clinical diagnosis is around 20 years(2). There are currently no disease-modifying interventions available (3), but several clinical trials are underway and planned in the next few years to explore novel therapeutic approaches to treating this disease(4-6). In preparation for such trials, biomarkers are needed – especially prognostic, pharmacodynamic, efficacy and safety biomarkers., Huntingtons disease (HD) is a genetic disease caused by expanded CAG repeat tract in exon 1 of the HTT gene that codes for huntingtin. Since the first symptoms of the disease the average life expectancy is 15-20 years, when the symptoms resulting from neurodegeneration are progressing. Therefore, there is a great demand for an effective HD treatment method. Various therapeutic strategies are being developed based on mechanisms of gene expression silencing, including DNA editing techniques. Here, we present the most important currently tested approaches, with particular emphasis on strategies based on the use of antisense oligonucleotides (ASO), RNA interference (RNAi) technology and CRISPR-Cas9. Currently ongoing clinical trials as well as different pharmacological agents are discussed. , Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded cytosine-adenine-guanine triplet repeat in the huntingtin gene. The current diagnosis is based on the presence of typical motor signs in combination with a positive gene test. The motor onset of the disease is usually between 30 and 50 years of age, and the disease then progresses over around 20 more years. Nonmotor symptoms and signs such as cognitive decline, metabolic dysfunction, sleep disturbances, as well as psychiatric symptoms are common and can occur many years before motor onset. Psychiatric symptoms include irritability, apathy, depression, anxiety, and OCD. Although there exist no disease-modifying treatment, available pharmacologic drugs often offer significant symptom relief and improve quality of life. Today, there are only two drugs that are approved by the US Food and Drug Association for the treatment of HD. These are the dopamine-depleting drugs tetrabenazine and deutetrabenazine that both target motor symptoms. The current status of best clinical practice for HD is based on expert opinions as well as evidence and/or experience of treating similar symptoms in other conditions. In this chapter, we provide an overview of the complex clinical manifestations of HD and the commonly used psychopharmacologic treatments.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Tisotumab vedotin-tftv (Tivdak) has received accelerated approval to treat adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.Ocular adverse effects occurred in 60% of patients in clinical trials. To minimize this risk, nurses should follow the guidelines for premedication and required eye care., Cervical cancer is one of the most common gynecological malignancies. At present, cytotoxic chemotherapeutic drugs and immunotherapy are the main therapeutic options for recurrent and metastatic cervical cancer. Tisotumab vedotin is an antibody-drug conjugate (ADC) and a potential novel treatment for cervical carcinoma. Tisotumab vedotin targets tissue factor (TF), which is highly expressed on the surface of cervical cancer cells, by delivering the cytotoxic agent monomethyl auristatin E (MMAE) directly into tumor cells. Currently, the U.S. Food and Drug Administration (FDA) has approved tisotumab vedotin for the treatment of adult female patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This article reviews the results of preclinical studies and clinical trials of tisotumab vedotin. The findings suggest that tisotumab vedotin can induce clinically significant and long-lasting remission with controllable and tolerable safety in the difficult-to-treat group of cervical cancer patients., Tisotumab vedotin (Tivdakâ„¢) is an antibody-drug conjugate comprising a fully human monoclonal antibody specific for tissue factor (TF-011) conjugated to monomethyl auristatin E (MMAE) that has been engineered to target tissue factor expressing tumours. Based on the results of a phase II trial, tisotumab vedotin has been granted accelerated approval in the USA for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This article summarizes the milestones in the development of tisotumab vedotin leading to this first approval., OBJECTIVE: To review and compare the pharmacology, efficacy, and safety of the novel tissue factor antibody-drug conjugate, tisotumab vedotin. DATA SOURCES: Literature search was performed through PubMed MEDLINE, Google Scholar, ClinicalTrials.gov, and the Food and Drug Administration. DATA SUMMARY: Tisotumab vedotin, a novel tissue factor antibody-drug conjugate, was granted accelerated approval by the US FDA on 20 September 2021 for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Tisotumab vedotin demonstrated clinical efficacy in a number of solid tumors in innovaTV 201 and more specifically in cervical cancer in the pivotal phase 2 innovaTV 204. In the single-arm innovaTV 204 study, 101 patients with recurrent or metastatic cervical cancer received intravenous tisotumab vedotin at the recommended dose of 2\u2005mg/kg every 3 weeks until disease progression or unacceptable toxicity. The independent review committee confirmed an objective response rate of 24% with 7% complete responses and 17% partial responses. Tisotumab vedotin is associated with several notable adverse events with data from innovaTV 204 including ocular toxicity, hemorrhage, and peripheral neuropathy. Ninety-two percent of patients experienced treatment-related adverse events with 28% experiencing an adverse event of grade 3 or higher. CONCLUSIONS: Metastatic cervical cancer has a high risk of relapse with few effective second-line therapeutic options. Current guidelines recommend single agent tisotumab vedotin as a possible option. Ongoing trials will further define its place in therapy., Tisotumab vedotin (TV) is an antibody-drug conjugate used for the treatment of adult patients with recurrent or metastatic cervical cancer. TV comprised of a monoclonal antibody against tissue factor and monomethyl auristatin E (MMAE), a potent inhibitor of cell division. The innovaTV-201 and innovaTV-204/GO30xx/ENGOT-cx6 trials showed that TV has clinically meaningful and durable antitumor activity in pretreated patients with recurrent or metastatic cervical cancer. The innovaTV-204 trial showed that TV monotherapy resulted in an objective response rate of 24% (including 7% and 17% complete and partial responses, respectively). In September 2021, the US Food and Drugs Administration (FDA) granted accelerated approval to TV for the treatment of recurrent or metastatic cervical cancer patients with disease progression on or after chemotherapy. The ongoing randomized, open-label Phase 3 innovaTV-301/ENGOTcx12/GOG-30xx trial will assess the effect of TV in pre-treated recurrent or metastatic cervical cancer. Meanwhile, the phase 1b/2 trial ENGOT Cx8/GOG 3024/innovaTV-205 is testing other possible combination between TV and other treatments. TV is characterized by a promising antitumor activity and an acceptable safety profile. Moreover, the preliminary data highlighted the feasibility of using TV in first line. In the first line, TV in combination with carboplatin or pembrolizumab provides an ORR of 55% and 41%, respectively Although the effect of adding TV to the current standard of care in first-line (carboplatin plus pembrolizumab) is still under evaluation, we expected to observe impressive results in the cervical cancer population.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

PURPOSE: This study analysed the relationship between caregiver-related factors (dental knowledge, attitude, behaviour, and health status) and early childhood caries. ?It aimed to explore better intervention methods for reducing caries prevalence in preschool children. MATERIALS AND METHODS: This cross-sectional investigation was carried out in Zhejiang, China. A total of 1344 guardians (parents and grandparents) paired with their children aged 3-5 years old were enrolled. The guardians completed structured questionnaires, which included their attitude, knowledge level and oral health status. The children received dental examinations. All of the data ?were analysed with R software. Chi-squared and Fishers exact tests were used to analyse different variables. Multinomial logistic regression with stepwise procedures and curve fitting was used to explore the relationship between guardians risk factors and the level of early childhood caries. RESULTS: Guardians have a great influence on the incidence of early childhood dental caries. ?When guardians pay attention to oral health and have a good command of relevant knowledge, then the risk of early dental caries in children is low (p = 0.027). The guardians dental problems?, e.g. dental caries (p = 0.0002), gingival bleeding problems (p = 0.049) and chewing discomfort experience (p = 0.049), demonstrated ?statistically significant correlations with early childhood caries levels?. CONCLUSION: Guardians attitudes, knowledge, and oral health status ?had a statistically significant relationship with the level of early childhood caries? in their children/grandchildren. Instead of instructing schoolchildren about oral health, multiple-level dental knowledge instruction of guardians is needed to prevent early childhood caries. , OBJECTIVES: Tooth brushing with fluoride toothpaste has a major effect on the reduction in dental caries. However, among young children, tooth brushing requires skill and motivation from caregivers and is not widely practised. To find a more effective way to train caregivers, Protection-Motivation Theory (PMT)-based educational programmes were compared with the basic one with regard to the incremental caries rate in children, caregivers motivation and caregivers awareness. METHODS: In a quasi-experimental study, 9- to18-month-old children and their caregivers (N\xa0=\xa0102) were allocated to PMT or control groups. The PMT group received PMT-based oral health education programme while the control group received public hospitals current one. Childrens caries status and motivation and awareness among caregivers were measured. Mann-Whitney U test was used to find out the difference between control and test groups. RESULTS: After 12\xa0months, the PMT group showed lower dmft, dmfs and incremental caries rate compared with control. Chi-square test showed the control group was at more risk of developing additional dental caries (RR 2.23, 95% C.I.: 1.41-3.54, p\xa0<\xa00.001), and when early carious lesions were included (RR 2.40, 95% C.I.: 1.56-3.69, p\xa0<\xa00.001). In terms of motivation and awareness among caregivers, the PMT group rated their perception of disease severity and belief in self-efficacy significantly higher than the control group. CONCLUSIONS: PMT-based education programmes encourage suitable motivation and awareness that changes oral healthcare behaviour of caregivers, relating to decreased incremental caries rate in infants and toddlers comparing with regular health education methods. , OBJECTIVE: To evaluate the effectiveness of an intervention to improve young childrens oral health-related behaviours and caregiver knowledge. METHODS: This paper reports on findings from a cluster randomized controlled trial, 12\xa0months after of baseline, conducted in Pelotas, Southern Brazil. Two Primary Healthcare Centers (PHCs) and 170 caregiver-child dyads were assigned to an intervention group, and two PHCs and 174 dyads were assigned to a control group. Childrens oral hygiene behaviours, sugar consumption and use of dental services were the outcomes analysed as well as changes in caregiver knowledge. The impact of the intervention was assessed using multilevel mixed-effects model regressions and the change rate ratios (IRR) were expressed. RESULTS: There were positive and significant changes in favour of the intervention group in childrens oral hygiene behaviours, use of dental services, and caregivers knowledge of oral health. For example, children in the intervention group were more likely to have brushed with fluoride toothpaste at least two times a day (IRR 1.43, 95% CI 1.06-1.92), to have brushed their teeth before bedtime (IRR 1.37, 95% CI 1.02-1.84), and to have used dental services for preventive care (IRR 2.54, 95% CI 2.02-3.19) than children in the control group. CONCLUSION: This intervention had positive effects on childrens oral health-related behaviours and caregivers oral health knowledge. , Objectives: The aim of the present study was to compare the perception of caregivers regarding the oral health status of children and adolescents with cerebral palsy (CP) and those with typical development. Study Design: Study group (SG) was composed of 35 children and adolescents with a clinical diagnosis of CP and their caregivers. Control group (CG) was composed of 35 individuals with typical development (matched with the SG for age, sex and caries activity) and their caregivers. Questionnaire was administered to caregivers addressing the oral health of individuals under their care. Caries activity, dmft/DMFT index, visible plaque index (VPI) and occlusal characteristics were determined. Results: Statistically significant differences were found in the perceptions of dental problems (p = 0.004) and gingival bleeding (p = 0.013). Individuals in SG whose caregivers perceived dental problems had a higher mean VPI (50.84 ± 5.11%) than those in CG (27.97 ± 6.50%). The mean dmft/DMFT in the SG was 2.77 ± 3.20. Class II molar relationship, overjet and anterior open bite were more prevalent in the SG. Conclusion: Caregivers of children/adolescents with CP perceive more oral problems, such as visible plaque, gingival bleeding and malocclusion, than caregivers of children/ adolescents with typical development., Objectives\u3000Early diagnosis and treatment are particularly important for children who have dental caries. It has been reported that some children are not taken to a dental clinic even though they are diagnosed with dental caries at school dental check-ups. The purpose of this study is to investigate factors related to the passive attitude of caregivers regarding dental care visits when elementary and junior high school children are diagnosed with dental caries.Methods\u3000A cross-sectional study was conducted utilizing data from the 2016 Adachi Child Health Impact of Living Difficulty (A-CHILD) study. A questionnaire was administered to 1,994 parents of 4th and 6th grade students in elementary school, and 8th grade students in junior high school. Out of the 1,994 parents, 1,652 (83%) responded. Caregivers were asked whether they take their child to the dental clinic immediately if their child is diagnosed with dental caries. Those who answered cannot take immediately were defined as caregivers with a passive attitude towards dental care visits. Their reasoning was further probed by the questionnaire. The validity of the answer (i.e., taking their child to the dental clinic) was assessed with the child\s untreated dental caries obtained from the results from the school dental health checkup. The number of children excluded in the analysis due to a lack of information on dental caries and/or the attitude of the parents was 1,613. A logistic regression analysis was performed to investigate the association between passive attitude on dental care visit and demographic factors (e.g., child\s sex, grade, number of siblings, and household members), lifestyle (e.g., time home for caregiver, grandparent co-residence, skipping breakfast, snacking habits, sugar-sweetened beverage intake, frequency of teeth brushing, and parent-child relationship), and socioeconomic status (e.g., annual household income, educational attainment of caregiver, employment status of caregiver).Results\u3000In total, 269 (16.7%) caregivers reported a passive attitude for the dental care visit of their child. The most frequent reason was I don\t have time to take my child to the dental clinic (172 people, 55.8%). The passive attitude by the caregivers was associated with untreated decay for the child (P<0.001). The passive attitude of the caregiver on the dental care visit was associated with lower maternal educational attainment, skipping breakfast for the child, and lower frequency of brushing teeth. In elementary school children, the passive attitude of the caregiver on the dental care visit was also significantly associated with maternal employment, later time of getting home by the mother and a lack of interaction with children by the caregiver.Conclusion\u3000The passive attitude of the caregiver as pertaining to the dental care visit of the child was associated with maternal socioeconomic background. Health promotion activities considering maternal socioeconomic background is needed., Because most data on oral health do not include infants and toddlers, we aimed to describe the oral health behaviors of low-income children younger than 3 years and determine factors associated with child tooth brushing. We obtained data from the Coordinated Oral Health Promotion Chicago study, which included 420 families with children aged 6 to 36 months and their caregivers in Cook County, Illinois. We assessed child frequency of brushing from caregiver reports and objectively determined child dental plaque scores. Significant factors associated with tooth brushing frequency and dental plaque score were identified using the Least Absolute Shrinkage and Selection Operator variable selection. Mean child age was 21.5 (SD, 6.9) months, and only 45% of caregivers brushed their children’s teeth twice per day or more. The mean plaque score was 1.9 (SD, 0.6), indicating high levels of plaque. Child brushing frequency was higher when children were older; used the correct toothpaste amount; brushed for a longer duration; and when caregivers brushed their own teeth more frequently, had more help with the overall care of the child’s teeth, and had family to help. Child brushing frequency was lower for caregivers with more interference from activities of daily life. Children whose caregivers had more adult help with child brushing had better plaque scores; worse plaque scores were seen in children with higher sugary beverage and food consumption and lower household incomes. The tooth brushing behaviors of young children are strongly associated with those of their parents and with the level of family support for brushing. Interventions to improve brushing in young children should focus on the entire family.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752., Background: The optimal strategy for the treatment of recurrent and/or advanced endometrial cancer is still undefined. Recently, despite the lack of any predictive biomarker, the combination of pembrolizumab with lenvatinib has improved survival outcomes. We here report the long-term management of lung toxicity in a patient with endometrial cancer, and we critically review the current therapeutic options for this disease. Results: A patient with heavily pretreated endometrial cancer took pembrolizumab plus lenvatinib for 1 year, achieving a persistent partial response with a time to treatment failure of 18 months, despite relevant lung toxicity that did not affect the remarkable overall clinical benefit. A systematic review of this combination underlines the efficacy outcome despite toxicity. Interestingly, the literature review on lung toxicity suggested the role of anti-angiogenetic agents in the pathogenesis of lung cavitation, probably related to direct treatment activity, and disclosed a potential radiological sign predictive of the activity of anti-angiogenetic agents. Conclusion: We underline the efficacy of pembrolizumab plus lenvatinib in the current treatment landscape of endometrial cancer, underscoring the relevance of a correct management of toxicity., One of the most promising developments in therapy for acute myeloid leukemia (AML) in recent years has been the combination of hypomethylating agents (HMA, either decitabine or 5-azacytidine) with the Bcl-2 inhibitor venetoclax (VEN). Although both classes of drugs have single-agent activity in AML, the combination has resulted in high rates of complete remission (CR) both in the frontline and relapsed settings suggesting synergy between these two agents. Recent data have suggested that CR\u2009+\u2009CR with incomplete count recovery rate may exceed 70% for frontline VEN-HMA. Moreover, this activity has been observed across various genetic subtypes of AML including those known to have very poor response to conventional chemotherapy. Although VEN has only recently obtained FDA approval for treatment of AML, there has been increasing on and off-label use of this combination given its striking efficacy and excellent toxicity profile. In this article, we summarize the current available data on this combination and offer practical guidelines for management of patients receiving VEN-HMA. Our recommendations are based on protocol guidelines, published data from clinical trials as well as from analysis of real world evidence from patients treated with this combination., Patients with Myelodysplastic Syndromes (MDS) and secondary Acute Myeloid Leukemia (sAML) have a very poor prognosis after failure of hypomethylating agents (HMA). Stem cell transplantation is the only effective salvage therapy, for which only a limited number of patients are eligible due to age and comorbidity. Combination therapy of venetoclax and azacitidine (5-AZA) seems to be a promising approach in myeloid malignancies, but data from patients with HMA failure are lacking. Furthermore, a considerable concern of combination regimens in elderly AML and MDS patients is the toxicity on the remaining healthy hematopoiesis. Here, we report in vitro data showing the impact of venetoclax and 5-AZA, alone or in combination, in a larger cohort of MDS/sAML patients (n\u2009=\u200921), even after HMA failure (n\u2009=\u200913). We especially focused on the effects on healthy hematopoiesis and the impact on colony forming capacity as a parameter for long-term effects. To the best of our knowledge, we show for the first time that venetoclax in combination with capped dose of 5-AZA targets cell malignancies, while sparing healthy hematopoiesis. The online version of this article (10.1186/s40164-019-0133-1) contains supplementary material, which is available to authorized users., Higher-risk Myelodysplastic Syndromes/Neoplasms (MDS) represent an ongoing therapeutic challenge, with few effective therapies, many of which may have limited use in this older patient population often with considerations around comorbidities. Outside of transplant, azacitidine and decitabine remain the only disease-modifying therapies, and are palliative in nature. Recent interest has grown in extending combination chemotherapies used to treat acute myeloid leukemia (AML) to patients with MDS, including novel combination chemotherapy doublets and triplets. In this review, we discuss considerations around combination chemotherapy in MDS, specifically as relates to study design, appropriate endpoints, supportive considerations, and how to integrate these into the current treatment paradigm. New therapies in MDS are desperately needed but also require considerations particular to this unique patient population.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

OBJECTIVE: The clinical use of mesenchymal\xa0stem cells (MSCs) in regenerative medicine either in\xa0tissue repair or tissue reconstruction has given highly interesting results thanks to their particular nature. Sources that have attracted the attention of medical scientists from where stem cells (SCs) in adults could be obtained are different and, dental tissues have certainly become an optimal source of MSCs. Dental tissue is a main reservoir of two types of MSCs dental\xa0bud (DBSCs) that constitute the immature\xa0precursor\xa0of the tooth and dental pulp (DPSCs) that are derived from dental inner pulp and partly from dental follicle tissue and can differentiate into several cell phenotypes as osteoblast, chondrocyte, hepatocytes, cardiomyocytes, neuron and β cells. PATIENTS AND METHODS: Normal impacted third molars and tooth buds were collected from adults and adolescents underwent to extractions for orthodontic reasons. The expression of the five stemness genes Nanog, OCT4, Sox2, c-Myc and Klf4 were investigated by qRT-PCR in two different dental stem/progenitor cells: dental pulp stem cells (DPSCs) and stem cells from dental bud (DBSCs), differentiated toward osteoblastic phenotype and not. RESULTS: Both DPSCs and DBSCs are easy to access and we found their expression of the typical mesenchymal stemness makers and osteogenic capacity due to the effective presence of embryonic gene regulators like Nanog, OCT4, Sox2, c-Myc and Klf4. Both DBSCs and DPSCs could represent a valid tool in\xa0regenerative medicine and translational applications. CONCLUSIONS: The results depicted here provide, for the first time to our knowledge, a comparative outcome about the stemness properties generated from accessible tissues such as DPSCs and DBSCs. These two types of SCs showed few different distinctive genetic traits supposedly in relation to their origin, location and stage of maturation. Certainly these SCs reserve solid potential for human clinical application in autologous procedure for bone, hard tissue and soft tissue regeneration, easy to isolate, ready availability, high-biocompatibility and safety and no ethical restrictions., Dental stem cells have been isolated from the medical waste of various dental tissues. They have been characterized by numerous markers, which are evaluated herein and differentiated into multiple cell types. They can also be used to generate cell lines and iPSCs for long-term in vitro research. Methods for utilizing these stem cells including cellular systems such as organoids or cell sheets, cell-free systems such as exosomes, and scaffold-based approaches with and without drug release concepts are reported in this review and presented with new pictures for clarification. These in vitro applications can be deployed in disease modeling and subsequent pharmaceutical research and also pave the way for tissue regeneration. The main focus herein is on the potential of dental stem cells for hard tissue regeneration, especially bone, by evaluating their potential for osteogenesis and angiogenesis, and the regulation of these two processes by growth factors and environmental stimulators. Current in vitro and in vivo publications show numerous benefits of using dental stem cells for research purposes and hard tissue regeneration. However, only a few clinical trials currently exist. The goal of this review is to pinpoint this imbalance and encourage scientists to pick up this research and proceed one step further to translation., Dental stem cell is a kind of stem cell isolated from dental hard tissue or periodontal tissue, including dental pulp stem cell, stem cell from human exfoliated deciduous teeth, stem cell from root apical papilla, periodontal ligament stem cell, dental follicle progenitor cell, and so on. As seed cell, dental stem cell provides safe and efficient cell source for nerve tissue engineering research. The review aims to introduce the characteristics of these dental stem cells in promoting the regeneration and preparation of nerve and the clinical application., Tissue engineering has become a research hotspot regarding periodontal bone regeneration in recent years. Generally, stem cells used in periodontal tissue engineering are derived from healthy dental tissues, while restricted due to the strict indication of tooth extraction and limited sources. Stem cells in inflamed dental tissues mainly derive from inflamed pulp, periapical and periodontal tissues. Stem cells in inflamed dental tissues are abundant and retain most of the basic characteristics of stem cell compared with the ones derived from healthy dental tissues, which can be a promising source of stem cells for periodontal bone regeneration. In this review, we summarize the current application and prospect of stem cells in inflamed dental tissues on periodontal bone regeneration, and then discuss their feasibility as seed cells, in order to provide a reference for future research and clinical application of stem cells in inflamed dental tissues., Stem cell-based therapies remain at the forefront of tissue engineering and regenerative medicine because stem cells are a unique cell source with enormous potential to treat incurable diseases and even extend lifespans. The search for the best stem cell candidates continues to evolve and in recent years, dental stem cells have received significant attention due to their easy accessibility, high plasticity, and multipotential properties. Dental stem cells have been the subject of extensive research in both animal models and human clinical trials over the past two decades, and have demonstrated significant potential in ocular therapy, bone tissue engineering, and, of course, therapeutic applications in dentistry such as regenerative endodontics and periodontal tissue regeneration. These new sources of cells may be advantageous for cellular therapy and the advancement of regenerative medicine strategies, such as allogeneic transplantation or therapy with extracellular vesicles (EVs), which are functional nanoscale membrane vesicles produced by cells. This chapter discusses the accumulating research findings on cell-based regenerative therapy utilizing dental stem cells and their derived EVs, which could be a viable tool for the treatment of a variety of diseases and hence extremely valuable to mankind in the long run.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

The aim of this study was to evaluate the root canal preparation and apical enlargement of molar root canals with rotary or reciprocating heat-treated nickel-titanium instruments, by using micro-computed tomography (micro-CT). Mesial root canals (n=48) of mandibular molars, with a curvature between 20° and 40°, were prepared with ProDesign Logic 25.01 and 25.06 in rotary motion, or ProDesign R 25.06 in reciprocating motion . Apical enlargement was performed with PDL35.01 and PDL35.05 or PDR35.05. Scanning with 9 µm resolution was performed before and after preparation, and, after apical enlargement, by using micro-CT. The percentage of volume increase, debris and untouched root canal surface, transportation, centralization and preparation time were analyzed. ANOVA and Tukey or Kruskall-Wallis and Dunn statistical tests were conducted (α=.05). PDL promoted a higher apical percentage of volume increase, and lower percentage of debris and untouched root canal surface than PDR 25.06 preparation in entire canal and in all thirds (P<.05). Apical enlargement with PDL 35.05 and PDR 35.05 produced a higher percentage of volume increase in the apical region in relation to the initial preparation (P<.05). PDR 35.05 and PDL 35.05 showed similar results in relation to percentage of debris and untouched root canal surface in entire canal and in all thirds (P>.05). Centralization and transportation showed no difference (P>.05). PDR required less time to perform preparation and apical enlargement (P<.05). The apical enlargement 35.05 with CM heat-treatment instruments using reciprocating and rotary motion reduced the percentage of debris and untouched root canal surface, without causing deviations or procedural errors. The protocol of greater apical enlargement favors the cleaning of the root canals in both kinematics. Preparation by the reciprocating system was faster than by the rotary system., INTRODUCTION: The purpose of this study was to evaluate root canal preparation and apical enlargement of curved canals using rotary heat-treated and heat/surface-treated systems by micro-computed tomographic imaging. METHODS: Curved mesial root canals (n = 48) of mandibular molars (20°-40°) were prepared using ProDesign Logic (PDL; Easy Equipamentos Odontológicos, Belo Horizonte, MG, Brazil) 25/.01 and 25/.06 or HyFlex EDM 10/.05, HyFlex CM 20/.04, and HFEDM 25/.08. Apical enlargement was performed using PDL 40/.05 or HFEDM 40/.04. Scanning (9 μm) was performed before and after preparation and after apical enlargement using micro-computed tomographic imaging. Volume, percentage of volume increase, debris, untouched root canal surface, and centering ability were analyzed. Statistical analysis was performed using Mann-Whitney, Wilcoxon, and unpaired t tests (α = .05). RESULTS: HFEDM promoted a higher volume increase of the root canals than PDL after preparation and after apical enlargement (P < .05). The apical enlargement promoted a significant decrease in debris and untouched surface in both groups (P < .05). The percentage of debris and untouched surface were similar between HFEDM and PDL after preparation and after apical enlargement (P > .05). Both systems promoted centered canals (P > .05). CONCLUSIONS: HFEDM instruments promoted greater volume of the root canal than PDL. However, the cleaning ability of the instruments was similar. The apical increase up to size 40 with both instruments provided less debris and untouched surfaces and allowed centralization of the curved root canals., This study evaluated the long-term clinical outcomes of single-visit root canal treatments with apical enlargement on patients with necrotic pulp tissue retrospectively. A total of 137 teeth with necrotic pulp tissue which underwent single-visit root canal treatments were included. The root canals were shaped up until the apical constriction, which was determined by an apex locator. The outcomes were evaluated by two independent and calibrated endodontists clinically and radiographically. Teeth were dichotomized into healed (PAI ≤ 2, no signs or symptoms) and nonhealed (PAI > 2, with/without signs or symptoms) groups. Each patients preoperative PAI and lesion size were recorded to evaluate the preoperative periapical status as well as several other prognostic factors. Statistical analyses were performed (p = 0.05) on ninety teeth. The mean observation time was 60 months. Out of ninety teeth, 87 (96.7%) were healed and 3 (3.3%) were nonhealed. No correlations were found between the prognostic factors and the outcomes (p > 0.05). Cohens kappa and Gwets agreement coefficient scores between the preoperative PAI scores and preoperative lesion sizes showed good agreements, with values of 0.834 and 0.898, respectively. Apical enlargement is a viable treatment option for single-visit root canal treatments. , The aim of this study was to evaluate the foraminal enlargement and its influence on microcrack formation and apical transportation in root canals with apical curvature. Eighteen maxillary lateral incisors with apical curvature were selected by using micro-CT images. Root canals were randomly divided in two groups (n\u2009=\u20099) according to root canal preparation using two working lengths: 1\xa0mm short of the apical foramen (control group) and 1\xa0mm beyond the apical foramen (foraminal enlargement). For both groups Reciproc Blue R40 was used for root canal instrumentation. Specimens were scanned by nano-CT (UniTOM HR) before and after root canal preparation. Percentage, length, and width of microcracks, and apical transportation were assessed. Kappa, chiâ€_x0090_square and McNemar tests were used for qualitative analyses while paired and unpaired t-test were used for quantitative analyses (α\u2009=\u20090.05). For both groups, rather similar and low percentages of microcracks were observed before root canal preparation (P\u2009>\u20090.05). The foraminal enlargement promoted new microcracks, not observed in the control group. An increase in microcrack length was observed when the foraminal enlargement was performed (P\u2009<\u20090.05). Higher apical transportation was observed when foraminal enlargement was performed (P\u2009<\u20090.05). Foraminal enlargement using a heat-treated reciprocating file size 40 promoted microcracks and higher apical transportation than root canal preparation up to 1\xa0mm short of apical foramen., Upon completion of the root canal preparation to an apical size of either 6% size 20 or 25, apical patency was checked using a size 10 K-file (ManiCo. , Tokyo, Japan). Root canal filling was done using a greater taper single gutta-percha cone (DiaDentGroup, Seoul, Korea), along with a zinc oxide eugenol-basedcement (Prime Dental Products, Thane, India). A post-operative radiograph was taken to ensure the canals were filled tothe working length and there was no extrusion of filling material into the periapical tissues. All the patients were prescribed paracetamol 500 mg as analgesics but the patients were advised to only take them in the event of significant pain. The occlusion was not relieved in this study.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Objective: To summarize the clinical features, surgical methods, and prognosis of bucket-handle meniscal tears (BHMTs), and provide guidance for clinical treatment. Methods: The clinical data of 91 BHMTs patients (91 knees), who met the selection criteria and were admitted between January 2015 and January 2021, was retrospectively analyzed. There were 68 males and 23 females. Age ranged from 16 to 58 years with an average of 34.4 years. The injury was caused by sports in 68 cases, traffic accident in 15 cases, and falls or sprains in 8 cases. There were 49 cases of left knee injury and 42 cases of right knee injury. The time from the onset of symptoms to the admission ranged from 1 day to 13 months (median, 18 days), including >1 month in 35 cases and ≤1 month in 56 cases. Medial BHMTs occurred in 52 cases and lateral BHMTs in 39 cases. There were 36 cases with ACL rupture and 12 cases with discoid meniscus. The knee extension was limited more than 10° in 55 cases. According to the condition of meniscus injury, the meniscus suture with Inside-out combined with All-inside techniques (54 cases) or meniscoplasty (37 cases) under arthroscopy were selected. ACL reconstruction was performed in all patients with ACL rupture with autogenous hamstring tendon. Postoperative complications were observed. International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner score were used to evaluate knee function, and clinical failure was recorded. Results: Two patients developed intermuscular venous thrombosis, which improved after oral anticoagulant therapy. No vascular injury, postoperative infection, joint stiffness, or other complications occurred in all patients. All patients were followed up 24-95 months, with a median of 64 months. A total of 12 cases (13.19%) failed the operation and were re-operated or given oral anti-inflammatory analgesics and rehabilitation therapy. At last follow-up, IKDC score and Lysholm score of 91 patients significantly increased when compared with those before operation ( P<0.05), while Tegner score significantly decreased ( P<0.05). The above indexes of patients treated with meniscus suture and meniscoplasty were also significantly different from those before operation ( P<0.05). Conclusion: BHMTs occurs mostly in young men and is one of the important reasons for the limitation of knee extension after trauma. Arthroscopic meniscus suture and meniscoplasty can obtain good effectiveness according to individual conditions of patients. But the latter can better preserve the shape and function of meniscus, and theoretically can obtain better long-term outcomes, which needs to be confirmed by further research with larger sample size., PURPOSE: In regions of the world where resources can limit medical care (limited-resource settings, LRS), most meniscal tears are often treated with meniscectomy. A simple, low-cost option for meniscal repair has been developed. We sought to evaluate patient reported outcomes (PROMs) and clinical failure rates of bucket handle meniscus tears (BHTs) treated with meniscal repair in a LRS. METHODS: We prospectively enrolled patients over 18 who were treated for BHT with meniscal repair in a LRS. Meniscal repair was primarily accomplished using an outside-in technique. Pre-injury and final follow-up PROMs were recorded. Clinical failure was defined as the need for re-operation or symptoms that prevented the patient from returning to recreational activities or work responsibilities. RESULTS: Nineteen patients with a mean age of 25.4\xa0years were eligible. Two patients sustained a clinical failure (10.5%). At mean follow-up of 40.6\xa0months, there was significant improvement in all PROMs from baseline. Subgroup analysis revealed no significant difference in the failure group compared to the success group in number of knots used, pre-injury Tegner score, number of devices used, suture type, or technique. CONCLUSION: Bucket-handle meniscal tears can be repaired using a low-cost technique resulting in satisfactory healing rates and excellent outcomes., INTRODUCTION: While open repair of horizontal meniscal tears in young active patients has shown good results at mid- and long-term follow-up, complex horizontal tears (cleavage associated with meniscal flaps) are often treated by arthroscopic subtotal meniscectomy. The aim of this study was to evaluate long-term outcomes after arthroscopic removal of meniscal flaps associated with an open meniscal repair for treating complex lesions in young active patients. The hypothesis was that this salvage procedure would be efficient in such rare cases. METHODS: Fourteen patients underwent an arthroscopic partial meniscectomy associated with an open meniscal repair to treat a painful complex horizontal meniscal cleavage between 2005 and 2010. There were two females and 12 males with a median age of 28.4\xa0years (range 15-48\xa0years). Patients were assessed by KOOS and IKDC scores, return to sport and the need for a secondary meniscectomy. RESULTS: Thirty patients were evaluated at a median follow-up of 8.5\xa0years (range 7-12\xa0years). One patient required revision of a partial meniscectomy and one other a meniscal replacement (15% failure rate). All other patients showed improvement with regard to their symptoms and returned to sports, ten (91%) of them at the same level. The mean IKDC subjective score was 86.1 (±\u200910.9). The mean KOOS scores were: pain 91.4 (±\u20097.5), symptoms 91.4 (±\u200910.2), daily activity 97.1 (±\u20094), sports 84.4 (±\u200920.7) and quality of life 84 (±\u200914.2). For six patients, scores at median follow-up of 2.6\xa0years were available and compared to newly obtained data. IKDC score at 8.6\xa0years follow-up was not significantly different. KOOS scores for daily activity and sports were maintained. CONCLUSIONS: Even in the presence of a complex lesion, horizontal cleavage can be repaired in young patients with good subjective and objective outcomes and a low rate of long-term failure as with other meniscal lesions in young active patients. LEVEL OF EVIDENCE: IV., To identify and summarize literature related to the association between mechanical symptoms (catching and locking of the knee), the presence of meniscal tear, and outcomes after arthroscopic surgery. We searched PubMed and hand-searched reference lists for relevant articles and selected 38 for analysis. Mechanical symptoms appear to have modest sensitivity (ranging 0.32–0.69), specificity (ranging 0.45–0.74) and positive predictive value (ranging 0.75–0.81) for meniscal tear. There is also very little evidence to suggest that those with mechanical symptoms experience better outcomes after arthroscopic surgery. Our examination of the literature does not support the hypothesis that mechanical symptoms are related to the presence of meniscal tear or portend better outcomes after arthroscopic surgery., Meniscal tears are one of the most common knee injuries. Partial meniscectomy and meniscal repair are the most common treatment options in the setting of an unstable meniscal tear. Standard MR diagnostic criteria of a meniscal tear may be normal findings postoperatively. The diagnosis of a recurrent or residual meniscal tear after prior meniscal surgery is primarily based on the visualization of surfacing high meniscal T2-weighted signal. After meniscectomy of greater than 25%, or meniscal repair, MR arthrography may be of benefit in the accurate evaluation of a possible residual or recurrent meniscal tear.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Betel quid chewing increased the risk of oral cancer and oral submucous fibrosis , an oral premalignant disorder with malignant transformation potential. BQ components such as areca nut , trauma by coarse AN fiber, catechin, copper, alkaloids, stimulated reactive oxygen species , inflammation and cytotoxicity are suggested to be the contributing factors. They may induce tissue inflammation, proliferation of fibroblasts and collagen deposition, myofibroblast differentiation and contraction, collagen cross-links and inhibit collagen phagocytosis, finally leading to the development of OSMF and oral cancer. These events are mediated by BQ components-induced changes of extracellular matrix turnover via regulation of TGF-β1, plasminogen activator inhibitor-1 (PAI-1), cystatin, lysyl oxidase and tissue inhibitors of metalloproteinases and metalloproteinases . Genetic susceptibility is also involved in these disease processes. Further understanding the molecular mechanisms of BQ-induced OSMF and oral cancer can be helpful for future disease prevention and treatment., Areca nut chewing is one of the major risk factors for oral cancer, with large-magnitude risks reported in studies comparing betel quid chewers and never users, and it has been evaluated as a group 1 carcinogen by the International Agency for Research on Cancer. Data from a high-quality meta-analysis examining risk estimates are presented in summary form with additional information from more recent studies (pooled adjusted relative risk, 7.9; 95% CI, 7.1 to 8.7). The risk of oral cancer increases in a dose-response manner with the daily number of quids consumed and the number of years chewing. In the Indian subcontinent and in Taiwan, approximately half of oral cancers reported are attributed to betel quid chewing (population attributable fraction, 53.7% for residents in Taiwan and 49.5% for the Indian population), a disease burden that could be prevented. Oral leukoplakia and oral submucous fibrosis are 2 main oral potentially malignant disorders caused by areca nut chewing that can progress to oral cancer with continued use. Ex-chewers seem to demonstrate lower risks than current chewers, but the impact of areca nut cessation on oral cancer risk has not been scientifically evaluated on the basis of randomized controlled studies. These data strongly reconfirm that betel quid chewing, primarily areca nut use, should be taken into account in assessing the cancer risk of South Asian, East Asian populations and Pacific Islanders for the development of oral cancer., BACKGROUND: Chewing betel nuts can increase the risk of periodontal disease severity and potentially become malignant in the oral cavity. OBJECTIVE: This study aimed to investigate the effect of the duration and frequency of betel quid chewing behaviour on periodontitis severity and the life quality of people in Tanini Village, Kupang Regency, Indonesia. METHODS: The type of this study was an analytic observational study with a cross-sectional design. We used a questionnaire to obtain sociodemographic data. Oral Health Survey Basic Methods were used to measure debris index, plaque index, bleeding on probing, loss of attachment, and pocket depth. Behaviour and quality of life were measured by questionnaire and WHOQOL-BREF method as well. RESULTS: The largest number of respondents were male. Duration of chewing had a significant relationship with the frequency of chewing and periodontal status. Periodontitis was higher compared to all categories. The lifestyle of the community greatly influenced their behaviour in betel nut chewing and also affected the severity of their periodontitis and OHIs significantly. CONCLUSION: The lifestyle of betel nut chewing of the people in Tanini Village, greatly influences their behaviour. Prolonged and excessive use of betel nut induced significant adverse effects on human health. The longer and more often chew betel or areca nut, the higher the incidence of periodontitis, which significantly affects the quality of life as there is a possibility of the development of carcinogenesis, particularly in the oral cavity., Over the years, betel quid chewing and tobacco use have attracted considerable interest as they are implicated as the most likely causative risk factors of oral and esophageal cancers. Although areca nut use and betel quid chewing may lead to apoptosis, chronic exposure to areca nut and slaked lime may promote pre-malignant and malignant transformation of oral cells. The putative mutagenic and carcinogenic mechanisms may involve endogenous nitrosation of areca and tobacco alkaloids as well as the presence of direct alkylating agents in betel quid and smokeless tobacco. Metabolic activation of carcinogenic N-nitrosamines by phase-I enzymes is required not only to elicit the genotoxicity via the reactive intermediates but also to potentiate the mutagenicity with the sporadic alkylations of nucleotide bases, resulting in the formation of diverse DNA adducts. Persistent DNA adducts provides the impetus for genetic and epigenetic lesions. The genetic and epigenetic factors cumulatively influence the development and progression of disorders such as cancer. Accumulation of numerous genetic and epigenetic aberrations due to long-term betel quid (with or without tobacco) chewing and tobacco use culminates into the development of head and neck cancers. We review recent evidence that supports putative mechanisms for mutagenicity and carcinogenicity of betel quid chewing along with tobacco (smoking and smokeless) use. The detailed molecular mechanisms of the extent of accumulation and patterns of genetic alterations, indicative of the prior exposure to carcinogens and alkylating agents because of BQ chewing and tobacco use, have not yet been elucidated., The habit of smoking and chewing tobacco is associated with various types of oral mucosal lesions and conditions, many of which pose a potential threat to cancer growth. The present study aims to evaluate the prevalence of potentially malignant lesions and oral cancer in North India and to identify the associated risk factors. A cross-sectional study was carried out in the Department of Oral Medicine and Radiology Rama Dental College Hospital and research center Kanpur over a period of 5 years with1,10,625 patients. Participants were divided into study group with a positive history of the chewing habit as well as oral lesions and control group who had a positive history of habits with no oral lesions. Detailed case history and clinical examination were carried out under visible light by trained professionals to assess any oral mucosal changes. The study group consisted of 76.31% males and 23.69% females. In total, 84.34% participants in the study group were literate. However, 57.56% subjects were having oral submucous fibrosis, 23.7% were having leukoplakia, 13.12% were having Lichen planus, and 5.62% were having oral cancer. Results from the present study indicate that tobacco smoking, chewing of betel quid with and/or without tobacco chewing are the major risk factors for PML and oral cancer.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

CLINICAL PHARMACOLOGY Nedocromil sodium is a mast cell stabilizer. Nedocromil sodium inhibits the release of mediators from cells involved in hypersensitivity reactions. Decreased chemotaxis and decreased activation of eosinophils have also been demonstrated. In vitro studies with adult human bronchoalveolar cells showed that nedocromil sodium inhibits histamine release from a population of mast cells having been defined as belonging to the mucosal sub type and inhibits beta-glucuronidase release from macrophages. Pharmacokinetics and Bioavailability Nedocromil sodium exhibits low systemic absorption. When administered as a 2% ophthalmic solution in adult human volunteers, less than 4% of the total dose was systemically absorbed following multiple dosing. Absorption is mainly through the nasolacrimal duct rather than through the conjunctiva. It is not metabolized and is eliminated primarily unchanged in urine (70%) and feces (30%)., asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV 1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV 1 , daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-neededâ€_x009d_ β-agonist requirements. In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated see Warnings and Precautions (5.4) . montelukast-fig2.jpg 14.2 Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older) The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo\xad-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8, asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV 1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV 1 , daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-neededâ€_x009d_ β-agonist requirements. In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated see Warnings and Precautions (5.4) . montelukast-fig2.jpg 14.2 Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older) The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo\xad-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8, asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV 1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV 1 , daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-neededâ€_x009d_ β-agonist requirements. In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated see Warnings and Precautions (5.4) . Figure2 14.2 Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older) The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo\xad-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and, asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV 1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV 1 , daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-neededâ€_x009d_ β-agonist requirements. In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated see Warnings and Precautions (5.4) . Figure2 14.2 Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults, Adolescents, and Pediatric Patients 6 years of age and older) The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo‑-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

BACKGROUND: Whether improved glucose control with hybrid closed-loop therapy can preserve C-peptide secretion as compared with standard insulin therapy in persons with new-onset type 1 diabetes is unclear. METHODS: In a multicenter, open-label, parallel-group, randomized trial, we assigned youths 10.0 to 16.9 years of age within 21 days after a diagnosis of type 1 diabetes to receive hybrid closed-loop therapy or standard insulin therapy (control) for 24 months. The primary end point was the area under the curve (AUC) for the plasma C-peptide level (after a mixed-meal tolerance test) at 12 months after diagnosis. The analysis was performed on an intention-to-treat basis. RESULTS: A total of 97 participants (mean ±SD age, 12±2 years) underwent randomization: 51 were assigned to receive closed-loop therapy and 46 to receive control therapy. The AUC for the C-peptide level at 12 months (primary end point) did not differ significantly between the two groups (geometric mean, 0.35 pmol per milliliter interquartile range, 0.16 to 0.49 with closed-loop therapy and 0.46 pmol per milliliter interquartile range, 0.22 to 0.69 with control therapy; mean adjusted difference, -0.06 pmol per milliliter 95% confidence interval {CI}, -0.14 to 0.03). There was not a substantial between-group difference in the AUC for the C-peptide level at 24 months (geometric mean, 0.18 pmol per milliliter interquartile range, 0.06 to 0.22 with closed-loop therapy and 0.24 pmol per milliliter interquartile range, 0.05 to 0.30 with control therapy; mean adjusted difference, -0.04 pmol per milliliter 95% CI, -0.14 to 0.06). The arithmetic mean glycated hemoglobin level was lower in the closed-loop group than in the control group by 4 mmol per mole (0.4 percentage points; 95% CI, 0 to 8 mmol per mole 0.0 to 0.7 percentage points) at 12 months and by 11 mmol per mole (1.0 percentage points; 95% CI, 7 to 15 mmol per mole 0.5 to 1.5 percentage points) at 24 months. Five cases of severe hypoglycemia occurred in the closed-loop group (in 3 participants), and one occurred in the control group; one case of diabetic ketoacidosis occurred in the closed-loop group. CONCLUSIONS: In youths with new-onset type 1 diabetes, intensive glucose control for 24 months did not appear to prevent the decline in residual C-peptide secretion. (Funded by the National Institute for Health and Care Research and others; CLOuD ClinicalTrials.gov number, NCT02871089.)., : Following a diagnosis of type 1 diabetes (T1D), persisting C-peptide secretion leads to improved glycemic control and outcomes. Residual β-cell function is often assessed with serial mixed-meal tolerance tests, but these tests do not correlate well with clinical outcomes. Herein, we instead use β-cell glucose sensitivity (βGS) to assess changes in β-cell function, incorporating insulin secretion for a given serum glucose into the assessment of β-cell function. We evaluated changes in βGS in individuals enrolled in the placebo arm of 10 T1D trials performed at diabetes onset. We found that βGS showed a more rapid decline in children, as compared with adolescents and adults. Individuals in the top quartile of βGS baseline distribution had a slower rate in loss of glycemic control time over time. Notably, half of this group were children and adolescents. Finally, to identify predictors of glycemic control throughout follow-up, we ran multivariate Cox models and found that incorporating βGS significantly improved the overall model. Taken together, these data suggest that βGS may be of great utility in predicting those more likely to have a more robust clinical remission and may be of use in design of new-onset diabetes clinical trials and in evaluating response to therapies. ARTICLE HIGHLIGHTS: We undertook this study to better predict β-cell loss following type 1 diabetes diagnosis. We set out to answer whether β-cell glucose sensitivity (βGS) improves means to evaluate β-cell function postdiagnosis and whether βGS correlates with clinical outcomes. We found that βGS declines faster in children, subjects in the top baseline quartile of βGS exhibit slower β-cell decline (half are children), and incorporating βGS into multivariate Cox models for glycemic improves the model. The implications of our findings are that βGS predicts those likely to have robust clinical remissions and may help with clinical trials design., Management of newly diagnosed type 1 diabetes (T1D) in children and adolescents is challenging for patients, families and healthcare professionals. The objective of this study is to determine whether continued intensive metabolic control using hybrid closed-loop (CL) insulin delivery following diagnosis of T1D can preserve C-peptide secretion, a marker of residual beta-cell function, compared with standard multiple daily injections (MDI) therapy. The study adopts an open-label, multicentre, randomised, parallel design, and aims to randomise 96 participants aged 10–16.9 years, recruited within 21 days of diagnosis with T1D. Following a baseline mixed meal tolerance test (MMTT), participants will be randomised to receive 24 months treatment with conventional MDI therapy or with CL insulin delivery. A further 24-month optional extension phase will be offered to all participants to continue with the allocated treatment. The primary outcome is the between group difference in area under the stimulated C-peptide curve (AUC) of the MMTT at 12 months post diagnosis. Analyses will be conducted on an intention-to-treat basis. Key secondary outcomes are between group differences in time spent in target glucose range (3.9–10 mmol/L), glycated haemoglobin (HbA1c) and time spent in hypoglycaemia (<3.9 mmol/L) at 12 months. Secondary efficacy outcomes include between group differences in stimulated C-peptide AUC at 24 months, time spent in target glucose range, glucose variability, hypoglycaemia and hyperglycaemia as recorded by periodically applied masked continuous glucose monitoring devices, total, basal and bolus insulin dose, and change in body weight. Cognitive, emotional and behavioural characteristics of participants and parents will be evaluated, and a cost–utility analysis performed to support adoption of CL as a standard treatment modality following diagnosis of T1D. Ethics approval has been obtained from Cambridge East Research Ethics Committee. The results will be disseminated by peer-reviewed publications and conference presentations. NCT02871089; Pre-results., Background: C-peptide is used as an important indicator of residual insulin secretion in patients diagnosed with type 1 diabetes mellitus (T1DM) and treated with insulin. Aim:We have aimed to monitor the serum C-peptide (CP) levels during the first three years after diagnosis of T1DM in a cohort of children admitted to the Diabetes Department of M. S. Curie Emergency Clinical Hospital for Children, Bucharest, Romania, and to investigate the factors that could influence the rate of decline in its secretion. Method:We conducted a longitudinal, retrospective cohort study on a group of 215 children and adolescents who met the inclusion criteria and were monitored in our clinic over the course of a long period of time. We analyzed several parameters, including fasting serum CP values at diagnosis and yearly throughout T1DM evolution, the severity of diabetic ketoacidosis (DKA) at onset, HbA1c at diagnosis, family history of T1DM/T2DM, patient gender and presence of concurrent acute infectious disease at diagnosis, with the purpose of evaluating their influence on the preservation of endogenous insulin secretion. Based on serum CP value measured three years after T1DM onset, patients were divided into two groups: group 1, with low insulin residual secretion (CP < 0.6 ng/mL), and group 2, with preserved insulin residual secretion (CP ≥0.6 ng/mL) Results:At the moment of diagnosis, patients in group 1 were younger than those in group 2 (6.03 ± 3.54 years and 9.76 ± 2.75 years, respectively). The proportion of children with diabetic ketoacidosis (DKA) at onset was greater in group 1 (68% of patients) than group 2, in which the majority of subjects (60%) did not have DKA. The C-peptide value at diagnosis was significantly lower (0.55 ± 0.36 ng/mL) among patients in group 1 than those in group 2 (1.11 ± 0.59 ng/mL). In group 1 there was a higher proportion of patients (65%) with acute infectious disease at onset. Family history of T1DM/T2DM was associated with a more rapid decline in CP values. Our data showed no correlation between CP levels monitored for three years and HbA1c at diagnosis and no association with the gender of each patient. Conclusion:Patients with higher CP concentrations at diagnosis maintained increased values (> 0.6 ng/mL) three years after disease onset. Younger children had a faster decline of CP secretion during the first three years following diabetes diagnosis. In patients with severe symptoms (DKA) and associated infectious disease at onset, a risk of rapid CP decline was found., High-residual C-peptide in longer-duration type 1 diabetes (T1D) is associated with fewer hypoglycemic events and reduced glycemic variability. Little is known about the impact of C-peptide close to diagnosis. Using continuous glucose monitoring (CGM) data from a study of newly diagnosed adults with T1D, we aimed to explore if variation in C-peptide close to diagnosis influenced glycemic variability and risk of hypoglycemia. We studied newly diagnosed adults with T1D who wore a Dexcom G4 CGM for 7 days as part of the Exercise in Type 1 Diabetes (EXTOD) study. We examined the relationship between peak stimulated C-peptide and glycemic metrics of variability and hypoglycemia for 36 CGM traces from 23 participants. For every 100 pmol/L-increase in peak C-peptide, the percentage of time spent in the range 3.9 to 10 mmol/L increased by 2.4% (95% CI, 0.5-4.3), P\u2005=\u2005.01) with a reduction in time spent at level 1 hyperglycemia (>\u200510 mmol/L) and level 2 hyperglycemia (>\u200513.9 mmol/L) by 2.6% (95% CI, –4.9 to –0.4, P\u2005=\u2005.02) and 1.3% (95% CI, –2.7 to –0.006, P\u2005=\u2005.04), respectively. Glucose levels were on average lower by 0.19 mmol/L (95% CI, –0.4 to 0.02, P\u2005=\u2005.06) and SD reduced by 0.14 (95% CI, –0.3 to –0.02, P\u2005=\u2005.02). Hypoglycemia was not common in this group and no association was observed between time spent in hypoglycemia (P\u2005=\u2005.97) or hypoglycemic risk (P\u2005=\u2005.72). There was no association between peak C-peptide and insulin dose–adjusted glycated hemoglobin A_1c (P\u2005=\u2005.45). C-peptide is associated with time spent in the normal glucose range and with less hyperglycemia, but not risk of hypoglycemia in newly diagnosed people with T1D.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Differential diagnosis of bacterial meningitis (BM) and viral meningitis (VM) is a critical clinical challenge, as the early and accurate identification of the causative agent determines the appropriate treatment regimen and markedly improves patient outcomes. Clinical and experimental studies have demonstrated that the pathogen and the host immune response contribute to mortality and neurological sequelae. As BM is associated with the activation of an inflammatory cascade, the patterns of pro- and anti-inflammatory cytokines/chemokines (CTs/CKs) present in the cerebrospinal fluid (CSF) in response to the immune assault may be useful as sensitive markers for differentiating BM from VM. In the present study, the ability of CTs/CKs in the CSF to differentiate between BM and VM was investigated. For this, biochemical markers and CT/CK profiles were analysed in 145 CSF samples, divided into three groups: BM (n=61), VM (n=58) and the control group (C; n=26) comprising patients with meningism. The CSF concentrations of monocyte chemoattractant protein-1, interleukin (IL)-8, IL-1β, IL-6, macrophage inflammatory protein-1α (MIP-1α), epithelial-neutrophil activating peptide, IL-10, tumour necrosis factor-α (TNF-α), proteins and white blood cells were significantly higher and the CSF glucose level was significantly lower in the BM group compared with the VM and C groups (P<0.01). Correlation analysis identified 28 significant correlations between various CTs/CKs in the BM group (P<0.01), with the strongest positive correlations being for TNF-α/IL-6 (r=0.75), TNF-α/MIP-1α (r=0.69), TNF-α/IL-1β (r=0.64) and IL-1β/MIP-1α (r=0.64). To identify the optimum CT/CK patterns for predicting and classifying BM and VM, a dataset of 119 BM and VM samples was divided into training (n=90) and testing (n=29) subsets for use as input for a Random Forest (RF) machine learning algorithm. For the 29 test samples (15 BM and 14 VM), the RF algorithm correctly classified 28 samples, with 92% sensitivity and 93% specificity. The results show that the patterns of CT/CK levels in the CSF can be used to aid discrimination of BM and VM., Meningitis is defined as the inflammation of the meninges that is most often caused by various bacterial and viral pathogens, and is associated with high rates of mortality and morbidity. Early detection of bacterial meningitis is essential to appropriate antibiotic therapy. Alterations in immunologic biomarkers levels have been considered the diagnostic approach in medical laboratories for the identifying of infections. The early increasing immunologic mediators such as cytokines and acute phase proteins (APPs) during bacterial meningitis have made they significant indicators for laboratory diagnosis. Immunology biomarkers showed wide variable sensitivity and specificity values that influenced by different reference values, selected a certain cutoff point, methods of detection, patient characterization and inclusion criteria, as well as etiology of meningitis and time of CSF or blood specimens collection. This study provides an overview of different immunologic biomarkers as diagnostic markers for the identification of bacterial meningitis and their efficiencies in the differentiating of bacterial from viral meningitis. , Biomarkers of inflammation such as sedimentation rate, C-reactive protein and procalcitonin are used in daily clinical practice for the diagnosis, prognosis and follow-up of patients with fever or inflammatory syndrome. The purpose of this article is to summarize the current knowledge about these main biological tests and to discuss new biomarkers and new assay approaches such as multiplex technology., OBJECTIVES: Meningitis is a medical emergency with permanent disabilities and high mortality worldwide. We aimed to determine causative microorganisms and potential markers for differentiation between bacterial and viral meningitis. METHODOLOGY: Adult patients with acute meningitis were subjected to lumber puncture. Cerebrospinal fluid (CSF) microorganisms were identified using Real-time PCR. PCT and CRP levels, peripheral and CSF-leucocyte count, CSF-protein and CSF-glucose levels were assessed. RESULTS: Out of 80 patients, infectious meningitis was confirmed in 75 cases; 38 cases were bacterial meningitis, 34 cases were viral meningitis and three cases were mixed infection. Higher PCT, peripheral and CSF-leukocytosis, higher CSF-protein and lower CSF-glucose levels were more significant in bacterial than viral meningitis patients. Neisseria meningitides was the most frequent bacteria and varicella-zoster virus was the most common virus. Using ROC analyses, serum PCT and CSF-parameters can discriminate bacterial from viral meningitis. Combined ROC analyses of PCT and CSF-protein significantly improved the effectiveness in predicting bacterial meningitis (AUC of 0.998, 100%sensitivity and 97.1%specificity) than each parameter alone (AUC of 0.951 for PCT and 0.996 for CSF-protein). CONCLUSION: CSF-protein and serum PCT are considered as potential markers for differentiating bacterial from viral meningitis and their combination improved their predictive accuracy to bacterial meningitis., Differential diagnosis between bacterial and viral meningitis is crucial. In our study, to differentiate bacterial vs. viral meningitis, three machine learning (ML) algorithms (multiple logistic regression (MLR), random forest (RF), and naïve-Bayes (NB)) were applied for the two age groups (0–14 and >14 years) of patients with meningitis by both conventional (culture) and molecular (PCR) methods. Cerebrospinal fluid (CSF) neutrophils, CSF lymphocytes, neutrophil-to-lymphocyte ratio (NLR), blood albumin, blood C-reactive protein (CRP), glucose, blood soluble urokinase-type plasminogen activator receptor (suPAR), and CSF lymphocytes-to-blood CRP ratio (LCR) were used as predictors for the ML algorithms. The performance of the ML algorithms was evaluated through a cross-validation procedure, and optimal predictions of the type of meningitis were above 95% for viral and 78% for bacterial meningitis. Overall, MLR and RF yielded the best performance when using CSF neutrophils, CSF lymphocytes, NLR, albumin, glucose, gender, and CRP. Also, our results reconfirm the high diagnostic accuracy of NLR in the differential diagnosis between bacterial and viral meningitis., The identification of CSF biomarkers for bacterial meningitis can potentially improve diagnosis and understanding of pathogenesis, and the differentiation from viral CNS infections is of particular clinical importance. Considering that substantial changes in CSF metabolites in CNS infections have recently been demonstrated, we compared concentrations of 188 metabolites in CSF samples from patients with bacterial meningitis (n = 32), viral meningitis/encephalitis (n = 34), and noninflamed controls (n = 66). Metabolite reprogramming in bacterial meningitis was greatest among phosphatidylcholines, and concentrations of all 54 phosphatidylcholines were significantly (p = 1.2 × 10^−25–1.5 × 10^−4) higher than in controls. Indeed, all biomarkers for bacterial meningitis vs. viral meningitis/encephalitis with an AUC ≥ 0.86 (ROC curve analysis) were phosphatidylcholines. Four of the five most accurate (AUC ≥ 0.9) phosphatidylcholine biomarkers had higher sensitivity and negative predictive values than CSF lactate or cell count. Concentrations of the 10 most accurate phosphatidylcholine biomarkers were lower in meningitis due to opportunistic pathogens than in meningitis due to typical meningitis pathogens, and they correlated most strongly with parameters reflecting blood–CSF barrier dysfunction and CSF lactate (r = 0.73–0.82), less so with CSF cell count, and not with blood CRP. In contrast to the elevated phosphatidylcholine concentrations in CSF, serum concentrations remained relatively unchanged. Taken together, these results suggest that increased free CSF phosphatidylcholines are sensitive biomarkers for bacterial meningitis and do not merely reflect inflammation but are associated with local disease and a shift in CNS metabolism.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Extrapulmonary tuberculosis (TB) presents unique diagnostic and therapeutic challenges. The site of involvement can vary widely, with common sites including the lymph nodes, pleura, skin, ear, nose and throat, genitourinary system, pericardium, gastrointestinal tract, bones and joints, and central nervous system. Clinical manifestations of extrapulmonary TB are diverse and often non-specific. Diagnosis is based on a combination of clinical suspicion, imaging, histopathology, and microbiology. Treatment of extrapulmonary TB generally follows similar principles to pulmonary TB, but the duration of treatment depends on the site of involvement and the extent of the disease. Increased awareness among healthcare providers is essential for the timely recognition and effective management of extrapulmonary TB cases., Diagnosis of tuberculosis, and especially the diagnosis of extrapulmonary tuberculosis, still faces challenges in clinical practice. There are several reasons for this. Methods based on the detection of Mycobacterium tuberculosis (Mtb) are insufficiently sensitive, methods based on the detection of Mtb-specific immune responses cannot always differentiate active disease from latent infection, and some of the serological markers of infection with Mtb are insufficiently specific to differentiate tuberculosis from other inflammatory diseases. New tools based on technologies such as flow cytometry, mass spectrometry, high-throughput sequencing, and artificial intelligence have the potential to solve this dilemma. The aim of this review was to provide an updated overview of current efforts to optimize classical diagnostic methods, as well as new molecular and other methodologies, for accurate diagnosis of patients with Mtb infection., Aim: Diagnosis of extrapulmonary tuberculosis (EPTB) is difficult, and a rapid and dependable diagnostic test is urgently needed. Methods: A nano-based assay, SYBR Green magnetic bead-coupled gold nanoparticle-based real-time immuno-polymerase chain reaction (MB-AuNP-RT-I-PCR) was studied for the quantitative detection of Mycobacterium tuberculosis MPT-64+CFP-10 proteins in clinically suspected EPTB patients. Results: A wide range (270\xa0fg/ml-9.9\xa0ng/ml) of MPT-64+CFP-10 was quantified by MB-AuNP-RT-I-PCR in EPTB cases, whereas magneto-ELISA demonstrated a narrow range (1.8-10\xa0ng/ml). Furthermore, high sensitivity (88.2%) and specificity (100%) were attained by MB-AuNP-RT-I-PCR in EPTB (n\xa0=\xa051) and non-TB control (n\xa0=\xa049) subjects, respectively. Both MB-AuNP-I-PCR/magneto-ELISA exhibited significantly lower (p\xa0<\xa00.05-0.01) sensitivities than MB-AuNP-RT-I-PCR. Conclusion: The MB-AuNP-RT-I-PCR described herein\xa0shows good diagnostic accuracy, which may translate into a credible diagnostic kit., INTRODUCTION: Diagnosis of extrapulmonary tuberculosis (EPTB) is an arduous task owing to different anatomical locations, unusual clinical presentations, and sparse bacillary load in clinical specimens. Although GeneXpert® MTB/RIF is a windfall in TB diagnostics including EPTB, it yields low sensitivities but high specificities in many EPTB specimens. To further improve the sensitivity of GeneXpert®, GeneXpert® Ultra, a fully nested real-time PCR targeting IS6110, IS1081 and rpoB (Rv0664) has been endorsed by the WHO (2017), wherein melt curve analysis is utilized to detect rifampicin-resistance (RIF-R). AREA COVERED: We described the assay chemistry/work design of Xpert Ultra and evaluated its performance in several EPTB types, that is, TB lymphadenitis, TB pleuritis, TB meningitis, and so on, against the microbiological reference standard or composite reference standard. Notably, Xpert Ultra exhibited better sensitivities than Xpert, but mostly at the compensation of specificity values. Moreover, Xpert Ultra exhibited low false-negative and false-positive RIF-R results, compared with Xpert. We also detailed other molecular tests, that is, Truenat MTBTM/TruPlus, commercial real-time PCR, line probe assay, and so on, for EPTB diagnosis. EXPERT OPINION: A combination of clinical features, imaging, histopathological findings, and Xpert Ultra are adequate for definite EPTB diagnosis so as to initiate an early anti-tubercular therapy., Extrapulmonary tuberculosis (EPTB) poses diagnostic challenges due to the paucibacillary nature of the disease. The immunochemistry-based MPT64 antigen detection test (MPT64 test) has shown promising results for diagnosing EPTB in previous studies performed in low-resource settings, with higher sensitivity than microscopy and culture. The aim of this study was to investigate the performance of the MPT64 test in a routine clinical setting in a high-income low TB prevalence country. Extrapulmonary samples sent for TB diagnostics to microbiology and pathology laboratories at three regional tertiary care hospitals in Norway in a one-year period were included and subjected to the MPT64 test in parallel to the routine TB diagnostic tests. Samples from 288 patients were included and categorised as confirmed TB cases (n\xa0=\u200926), clinically diagnosed TB cases (n\xa0=\u20095), non-TB cases (n\xa0=\u2009243) and uncategorised (n\xa0=\u200914), using a composite reference standard (CRS). In formalin-fixed biopsies, the sensitivity (95% CI) of the MPT64 test, microscopy, PCR-based tests pooled, and culture was 37% (16–62), 20% (4–48), 37% (16–62) and 50% (23–77), respectively, against the CRS. The MPT64 test showed a good positive predictive value (88%) and an excellent specificity (99, 95% CI 92–100) in formalin-fixed biopsies. In fine-needle aspirates, pus and fluid samples, the test performance was lower. The MPT64 test was implementable in pathology laboratories as part of routine diagnostics, and although the sensitivity of the MPT64 test was not better than culture in this setting, the test supplements other rapid diagnostic methods, including microscopy and PCR-based tests, and can contribute to strengthen the diagnosis of EPTB in formalin-fixed biopsies in the absence of culture confirmation.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Major depressive (MDD) and anxiety disorders are among the most prevalent and devastating disorders. Comorbidity represents the normative clinical course, with particular high rates between MDD and Generalized Anxiety Disorder (GAD) (lifetime comorbidity 70-90%) 1. Together with the high comorbidity rates, a strong overlap in symptomatology, genetic and risk factors 1 led to a continuous debate about the nosological and neurobiological uniqueness of GAD and MDD 2., Major depression, as well as other depressive disorders, is commonly comorbid with other medical illnesses, particularly chronic and systemic medical illnesses. The co-occurrence of the disorders is so common that it challenges our notions of the meaning of comorbidity and our desire to neatly separate psychiatric and medical illnesses. The overlap between symptoms of physical illness and the neurovegetative symptoms of major depression and the initial normative emotional response to physical illness add to the challenge of accurate diagnosis and timely treatment of depression in the medically ill. We review the literature on the comorbidity of depression and the various medical illnesses, including diagnostic and treatment approaches. The differential diagnosis for major depression among medically ill patients should include delirium and medication-induced symptoms. We suggest that major depression itself may be best conceptualized as a systemic illness whose pathophysiology overlaps with other systemic medical illnesses. The initial treatment strategies for major depression in medical illness are like those for the general population; however, the comorbid medical illnesses may interfere with remission. To illustrate these points, we describe a patient with clinical characteristics covered in this review who experienced major depression as well as several chronic illnesses, including hypersensitivity pneumonitis, multiple sclerosis, chronic pain due to degenerative joint disease, and diabetes mellitus., The comorbidity of depression and anxiety is a major global health problem. A 2015 report examining response patterns of 74,000 adults across 27 World Mental Health surveys in 24 countries showed a very high comorbidity between a diagnosis of lifetime DSM-IV1 major depressive disorder and a diagnosis of any anxiety disorder in the past 12 months or lifetime anxiety disorder at similar rates in high-income and mid- to low-income countries. In addition, the report highlighted that almost 70% of people with lifetime depression and anxiety first developed anxiety and that the course and burden of lifetime depression comorbid with anxiety was usually more impairing than depression without anxiety.2., Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Using genetic data, this study elucidates biological mechanisms, key risk factors, and causal pathways underlying the comorbidity. We show that CVDs share a large proportion of their genetic risk factors with MDD. Multivariate genome-wide association analysis of the shared genetic liability between MDD and CVD revealed seven novel loci and distinct patterns of tissue and brain cell-type enrichments, suggesting a role for the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic, and psychosocial risk factors. Finally, we found support for causal effects of genetic liability to MDD on CVD risk, but not vice versa, and demonstrated that the causal effects are partly explained by metabolic and psychosocial factors. The distinct signature of MDD-CVD comorbidity aligns with the idea of an immunometabolic sub-type of MDD more strongly associated with CVD than overall MDD. In summary, we identify plausible biological mechanisms underlying MDD-CVD comorbidity, as well as key modifiable risk factors for prevention of CVD in individuals with MDD., : Major depression disorder (MDD) and bipolar disorder (BD) are usual comorbidities in patients with substance use disorders (SUD), a condition known as dual disorder (DD). MDD, BD and SUD are associated with cognitive impairment, potentially leading to a greater functional impairment in the context of DD. OBJECTIVES: To review the existing data on the cognitive impairment in DD patients with comorbid MDD or BD, considering the influence of the depressive symptomatology. METHODS: Following the PRISMA protocol 19 studies were selected from the last 17 years, 13 of which focused on BD, five on MDD and one included both diagnoses. RESULTS: Studies based in BD+SUD showed that the most affected cognitive domains were attention and executive functions, but not all of them found a greater impairment due to the comorbidity. While fewer studies were found for depression, MDD+SUD works point to a similar impairment cognitive pattern. Furthermore, depression improvement could be associated to better cognitive performance. LIMITATIONS: More standardized research is needed regarding the influence of depression on cognitive performance of DD patients, especially on those with comorbid MDD. Factors such as main substance, abstinence, or MDD/BD-related variables should be considered. Unstudied factors, like gender or circadian rhythms, are proposed to improve knowledge in this area. CONCLUSIONS: Current studies suggest that DD could potentiate cognitive impairment in BD, MDD and SUD. However, additional research is needed to improve the understanding of comorbidity to apply more individualized therapies in the treatment of these patients, considering the interference of their neurocognitive functioning.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Oral diseases are largely preventable. However, as the number of older adults is expected to increase, along with the high cost and various barriers to seeking continuous professional care, a sustainable approach is needed to assist older adults in maintaining their oral health. Mobile health technologies may facilitate oral disease prevention and management through oral health education. This review aims to provide an overview of existing evidence on using mHealth to promote oral health through education among older adults. A literature search was performed across five electronic databases. A total of five studies were identified, which provided low to moderate evidence to support using mHealth among older adults. The selected studies showed that mHealth could improve oral health management, oral health behavior, and oral health knowledge among older adults. However, more quality studies regarding using mHealth technologies in oral health management, oral health behavior, and oral health knowledge among older adults are needed., Purpose: The purpose of this study was to investigate the effects of a professional oral health care program on the oral health status and salivary flow of elderly people living in nursing homes.Methods: Elderly residents aged ≥ 65 years, living in a nursing home, were randomly assigned to either a one-week interval, two-week interval, or control group, and received an oral health intervention accordingly over a period of 12 weeks. Plaque index, tongue coating, gingival index, and salivary flow rate were compared before and after the oral health intervention within and between the groups.Results: The plaque, tongue coating, and gingival indices of the participants who received the oral health intervention decreased significantly; while the salivary flow rate significantly increased. Plaque, tongue coating, and gingival indices decreased most significantly in the one-week interval group, followed by the two-week interval group, relative to the control. The salivary flow rate increased most significantly in the one-week interval group, followed by the two-week interval group.Conclusion: A professional oral health care program is effective for improving the oral health and salivation of elderly residents in nursing homes and the effect was found to be greater with interventions provided at one-week intervals. Oral health care professionals, including dentists and dental hygienists, must regularly monitor and manage the oral health of elderly residents., P u r p o s e: Oral health and diseases are significant components of general health. However, oral health-care remains at the lowest of older patients\ priorities. The inability to obtain dental care can result in progression of dental disease, leading to a diminished quality of life and overall health. Teledentistry provides an opportunity to improve the quality of oral health services. The aim of our narrative review was to analyze the usefulness of teledentistry as a part of telemedicine to improve oral health in the elderly. Materials/Methods: The PubMed database search was done for: teledentistry, oral health, oral- health related diseases, elderly, older adults. R e s u l t s: The applicability of TD has been demonstrated from children to older adults. Older adults have many obstacles in getting oral health care, including low income, lack health insurance, frailty, anxiety, depression, mobility problems or other handicaps. Available data suggests that the usefulness of TD in the provision of oral care in elderly people living in residential aged care facilities. Moreover, TD procedures were found to be as accurate as traditional face-to-face dental examinations, they was cost-effective and well accepted among patients and caregivers. C o n c l u s i o n s: TD might be a very useful tool for professional education, improving access and patient satisfaction of dental care. However, such TD modes would be difficult to widely implementation in community-dwelling older people who cannot access dental care. The ongoing Patient centric solution for smart and sustainable healthcare project will add to the intelligent oral health solutions., Sustainable oral care of the elderly requires a holistic view of aging, which must extend far beyond the narrow field of dental expertise to help reduce the effects of sociobiological changes on oral health in good time. Digital technologies now extend into all aspects of daily life. This review summarizes the diverse digital opportunities that may help address the complex challenges in Gerodontology. Systemic patient management is at the center of these descriptions, while the application of digital tools for purely dental treatment protocols is deliberately avoided., These nurses leverage technology to improve health.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

What is the efficacy of digital cognitive behavioral therapy compared with standard treatment among pregnant women with insomnia symptoms? In this randomized clinical trial of 208 pregnant women with insomnia symptoms, digital cognitive behavioral therapy for the treatment of insomnia was associated with statistically significantly greater improvements in insomnia symptom severity, sleep efficiency, global sleep quality, insomnia caseness, depressive symptoms, and anxiety symptoms compared with standard treatment. Digital cognitive behavioral therapy is an effective, scalable, safe, and acceptable intervention for improving insomnia symptoms during pregnancy. Despite the prevalence and adverse consequences of prenatal insomnia, a paucity of research is available regarding interventions to improve insomnia symptoms during pregnancy. To test the efficacy of digital cognitive behavioral therapy for insomnia (CBT-I) compared with standard treatment among pregnant women with insomnia symptoms. This randomized clinical trial enrolled pregnant women from November 23, 2016, to May 22, 2018. Of the 2258 women assessed for eligibility using an online self-report questionnaire, 208 were randomized to receive digital CBT-I (n\u2009=\u2009105) or standard treatment (n\u2009=\u2009103) for insomnia. Participants were pregnant up to 28 weeks’ gestation, and they either had elevated insomnia symptom severity or met the criteria for insomnia caseness as determined by self-report questionnaires. Participants completed outcome measures at 10 weeks (postintervention) and 18 weeks (follow-up) after randomization. All study visits were completed remotely, and the intervention was delivered digitally. Data were analyzed between December 12, 2018, and July 2, 2019. Digital CBT-I consisted of 6 weekly sessions of approximately 20 minutes each. Standard treatment reflected standard care. Women receiving standard treatment had no limits placed on the receipt of nonstudy treatments, including medication and psychotherapy. All outcomes were assessed remotely using self-report questionnaires administered via online survey. The primary outcome was the change in insomnia symptom severity (measured by the Insomnia Severity Index) from baseline to postintervention. Secondary outcomes were sleep efficiency and nightly sleep duration (defined by sleep diary), global sleep quality (measured by the Pittsburgh Sleep Quality Index), depressive symptom severity (measured by the Edinburgh Postnatal Depression Scale), and anxiety symptom severity (measured by the Generalized Anxiety Disorder Scale-7). For each outcome, we also examined the change from baseline to follow-up. The 208 participants had a mean (SD) age of 33.6 (3.7) years and a mean (SD) gestational age of 17.6 (6.3) weeks at baseline. Most of the participants were white (138 66.3%), married or cohabiting (196 94.2%), had a college degree (180 86.5%), and earned $100\u2009000 or more per year (141 67.8%). Women randomized to receive digital CBT-I experienced statistically significantly greater improvements in insomnia symptom severity from baseline to postintervention compared with women randomized to receive standard treatment (time-by-group interaction, difference\u2009=\u2009−0.36; 95% CI, −0.48 to −0.23; χ^2\u2009=\u200929.8; P\u2009<\u2009.001; d\u2009=\u2009−1.03). Improvements from baseline to postintervention for all secondary outcomes, with the exception of sleep duration, were statistically significant. A similar pattern of results was evident for the change from baseline to follow-up. In this trial, digital CBT was an effective, scalable, safe, and acceptable intervention for improving insomnia symptoms during pregnancy. ClinicalTrials.gov identifier: NCT02805998 This randomized clinical trial examines the efficacy of digital cognitive behavioral therapy for insomnia compared with standard treatment among pregnant women with insomnia symptoms., OBJECTIVE: Randomized controlled trials (RCTs) of digitally delivered Cognitive Behavioral Therapy for insomnia (CBT-I) have demonstrated reductions in insomnia severity, depression symptoms, anxiety symptoms, and suicidal ideation. The present study aimed to evaluate the effectiveness of self-guided, digital CBT-I to improve sleep-specific outcomes. METHOD: An RCT of Australian adults with insomnia and depressive symptoms (N\u2009=\u20091149) compared SHUTi, a digital CBT-I intervention, with HealthWatch, an attention-matched control internet program, at baseline, posttest (9\u2009weeks) and at 6-, 12-, and 18-month follow-ups. Online sleep diaries were used to derive measures of sleep-onset latency (SOL), wake after sleep onset (WASO), sleep efficiency (SE), number of awakenings, sleep quality, and total sleep time (TST). RESULTS: Participants in the SHUTi condition had greater improvements at posttest compared with control for: SOL, WASO, SE, number of awakenings, and sleep quality. These improvements were sustained at every follow-up (p\u2009<\u2009.02 for all outcomes except TST, in which statistically significant increases were observed only at 12- and 18-months). CONCLUSIONS: Digitally delivered CBT-I produced lasting improvements in sleep outcomes among adults with insomnia and depressive symptoms. Findings provide further evidence of long-term improvements associated with a digital therapeutic for insomnia, compared to an attention-control condition., To evaluate the effects of digital cognitive behavior therapy for insomnia (dCBT-I) delivered during pregnancy on subjective sleep outcomes, depressive symptoms, and anxiety symptoms through 6 months postpartum. People up to 28 weeks gestation (N = 208) with insomnia were randomized to 6 weekly sessions of dCBT-I or standard care. We report follow-up data at 3 and 6 months postpartum. The primary outcome was insomnia symptom severity. Secondary sleep outcomes included global sleep quality and insomnia caseness. Mental health outcomes included depressive and anxiety symptom severity. We evaluated between-condition differences in change from baseline for each postpartum timepoint and categorical outcomes. dCBT-I participants did not experience significantly greater improvements in insomnia symptom severity relative to standard care participants, but they did experience higher rates of insomnia remission and lower rates of insomnia caseness at 6 months postpartum. dCBT-I participants experienced greater improvements in depressive symptom severity from baseline to both postpartum timepoints, and in anxiety symptom severity from baseline to 3 months postpartum. The proportion of participants with probable major depression at 3 months postpartum was significantly higher among standard care (18%) than dCBT-I (4%, p = 0.006) participants; this between-condition difference was pronounced among the subset (n = 143) with minimal depressive symptoms at baseline (18% vs 0%). dCBT-I use during pregnancy leads to enduring benefits for postpartum insomnia remission. Findings provide strong preliminary evidence that dCBT-I use during pregnancy may prevent postpartum depression and anxiety, which is notable when considering the high frequency and importance of these problems. Clinical Trials: ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02805998, NCT02805998., Despite high rates of prenatal insomnia, efficacious treatment options for this population are quite limited. Early evidence from randomized controlled trials (RCTs) support the efficacy of face-to-face cognitive-behavioral therapy for insomnia (CBTI) for prenatal insomnia. Yet, as many patients are unable to access this specialist-driven care, a critical need exists to increase its accessibility. This RCT examined the efficacy internet-based digital CBTI in pregnant women with insomnia. Single-site RCT. A total of 91 pregnant women (29.03 ± 4.16 years) nearing/entering the third trimester who screened positive for clinical insomnia on the Insomnia Severity Index (ISI) were randomized to digital CBTI or digital sleep education control. The ISI, Pittsburgh Sleep Quality Index (PSQI), Edinburgh Postnatal Depression Scale (EPDS), and Pre-Sleep Arousal Scale’s Cognitive factor (PSAS-C) served as study outcomes, which were collected before treatment and after treatment during pregnancy, then six weeks after childbirth. From pre to posttreatment, CBTI patients reported reductions in ISI (−4.91 points, p < 0.001) and PSQI (−2.98 points, p < 0.001) and increases in nightly sleep duration by 32 min (p = 0.008). Sleep symptoms did not change during pregnancy in the control group. After childbirth, CBTI patients, relative to controls, slept longer by 40 min per night (p = 0.01) and reported better sleep maintenance. No pre or postnatal treatment effects on depression or cognitive arousal were observed. Digital CBTI improves sleep quality and sleep duration during pregnancy and after childbirth. To better optimize outcomes, CBTI should be tailored to meet the changing needs of women as the progress through pregnancy and early parenting. Insomnia and Rumination in Late Pregnancy and the Risk for Postpartum Depression. clinicaltrials.gov. Registration: NCT03596879., Background: Symptoms of insomnia are common in new mothers and have been associated with a range of negative maternal and child outcomes. Despite this, interventions to improve maternal postpartum sleep remain scarce. Cognitive Behavioural Therapy (CBT) and Light Dark Therapy (LDT) represent two promising interventions for insomnia symptoms and associated daytime consequences such as fatigue. This randomised controlled trial examines whether CBT and LDT improve maternal insomnia symptoms as the primary outcome and maternal sleep disturbance, mood, fatigue, and sleepiness as secondary outcomes. This protocol paper outlines the development, design, and implementation of the trial. Methods: Participants are an Australian community-sample of 90 first-time mothers who are 4–12 months postpartum with self-reported symptoms of insomnia (Insomnia Severity Index scores ≥ 8). Exclusion criteria include current severe sleep/psychiatric disorders, unsettled infant sleep behaviour, sleep-affecting medication use, and photosensitivity. Eligible women are randomised into a CBT (strategies targeting sleep, worries, fatigue, and relaxation), LDT, or a treatment-as-usual control condition. Interventions are therapist-assisted and personalised through two telephone calls and include a series of automated intervention emails delivered over 6 weeks. Primary and secondary outcomes are assessed at four time points: baseline, intervention mid-point, post-intervention, and 1-month post-intervention. Discussion: If found effective, these interventions could represent efficacious, safe, and inexpensive treatments for improving postpartum insomnia and mitigate its negative impact on maternal well-being. Interventions tested are highly scalable and can be integrated into postpartum care and made available to the broader community. ANZCTR trial registration: Accessible at: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12618000842268.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

OBJECTIVES: Orthognathic surgery is gaining importance as an aesthetic procedure. The aim of this work is the first case report of a simultaneous rhinoplasty and orthognathic surgery, using a nasal spine implant. CASE REPORT: This is a retrospective study based on the CARE guideline. A nasal spine implant was virtually planned and printed in polyetheretherketone (PEEK) to correct a nasal deviation and enable a rhinoplasty in the same surgical time. Both the surgeon and the patient were very satisfied with the clinical result. CONCLUSIONS: Virtually planned and printed nasal spine implant is feasible. A helpful method to support rhinoplasty in orthognathic surgery to avoid deviations in the tip of the nose or asymmetries in the nostrils., Orthognathic surgery is a well-recognized method to correct dentofacial deformities. The main goal of orthognathic surgery is to improve soft tissue change. Soft tissue changes to the nose have been well documented. Simultaneous rhinoplasty during orthognathic surgery can be performed to correct existing inherent nasal deformities and also the unfavorable changes that arose from the maxillary surgery. Challenges for concurrent nasal surgery with jaw surgery include preoperative, perioperative, and postoperative which can be overcome with meticulous planning and experience. In complex cases, rhinoplasty can be staged in the last 6\xa0months after the orthognathic surgery., Rhinoplasty typically is not considered a part of the repertoire facial rejuvenation surgery but the same involutional changes that affect the other structures of the face also impact the nose and midface. Comparatively little has been written about nasal rejuvenation. Rhinoplasty may be an under-recognized but a useful adjunct to the rejuvenation of the aging face. The aging nose presents unique pathology due to the involutional changes that affect the cartilage and supporting structures. A comprehensive facial rejuvenation plan should address these progressive effects., BACKGROUND: Nasal aesthetics can be significantly affected by the interdependence of the surrounding bone and soft tissues of the face. These include the maxilla, septum, frontal bone, mandible, and the soft tissues and cartilage surrounding the nose. Therefore, it is pertinent to analyze and address these critical relationships of the nose in order to achieve a successful rhinoplasty. This work seeks to describe the battery of adjunct procedures available to supplement a rhinoplasty. Furthermore, each preoperative finding or indication for the adjunct is described in an algorithmic fashion. METHODS: A literature search using PubMed, Google Scholar, and a university library database was performed to locate papers describing adjunctive procedures to rhinoplasty. Indications and preoperative analysis were extracted from each paper. If the indication or finding was unclear, supplementary literature describing rhinoplasty and adjunctive analysis were sought in order to supplement our findings. RESULTS: Sixteen papers in total described adjunctive procedures for rhinoplasty. Each work highlighted a procedure or set of procedures on a surrounding facial feature including the forehead, brow, cheeks, lips, and chin, and neck. In total, 13 adjunct procedures for rhinoplasty are described with their respective indications. Additional literature and techniques were researched to clarify indicated procedures. CONCLUSION: The ability to correctly understand the critical relationships of the nose can help the surgeon correctly recognize the indication for a rhinoplasty adjunct procedure, leading to better aesthetic balance and surgical outcomes. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., INTRODUCTION: Cleft patients often need orthognathic surgery to correct maxillary hypoplasia and rhinoplasty to correct nasal deformity. Rhinoplasty can be performed as a staged procedure after orthognathic surgery or simultaneously with maxillary osteotomy. AIM: The authors evaluated need for and complications of staged and simultaneous rhinoplasties in patients with different cleft types undergoing maxillary osteotomy. PATIENTS AND METHODS: This retrospective study examined 99 (54 females) consecutive nonsyndromic patients with cleft lip/palate 23 bilateral cleft lip and palate (BCLP), 51 unilateral cleft lip and palate (UCLP), and 25 cleft palate (CP) with a mean age of 17.8 (range: 11.5-45.3) years who had undergone Le Fort I maxillary advancement or bimaxillary osteotomy at the Cleft Palate and Craniofacial Center, Helsinki University Hospital, Finland, between 2002 and 2016. Medical charts were accessed through the hospitals archives and database. RESULTS: Of patients who underwent maxillary osteotomy, 45% (45/99) needed rhinoplasty (14 BCLP, 27 UCLP, and 4 CP). A significant difference (P<0.01) existed in the need for rhinoplasty between different cleft types, those with BCLP and UCLP needing the most operations (60% and 53%). In 20 patients (20%), rhinoplasty was performed simultaneously with maxillary osteotomy, and in 25 patients (25%) in a second operation after osteotomy. The overall complication rate was 14%. No difference existed in complication rate in patients with or without simultaneous rhinoplasty. CONCLUSIONS: Of cleft patients who underwent maxillary osteotomy, 45% needed rhinoplasty. Patients with BCLP and UCLP needed rhinoplasty most often. Staged and simultaneous procedures were almost equally common with similar complication rates.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Antiresorptive drugs, such as the bisphosphonates and the RANKL inhibitor denosumab, are currently the most widely used osteoporosis medications. These drugs increase bone mineral density (BMD) and reduce the risk of vertebral (by 40-70%), nonvertebral (by 25-40%) and hip fractures (by 40-53%) in postmenopausal women with osteoporosis. Due to the risk of rare side-effects, the use of bisphosphonates has been limited to up to 10\xa0years with oral bisphosphonates and 6\xa0years with intravenous zoledronic acid. Despite their well-proven efficacy and safety, few women at high risk of fracture are started on treatment. Case finding strategies, such as fracture risk-based screening in primary care using the fracture risk assessment tool (FRAX) and Fracture Liaison Services, have proved effective in increasing treatment rates and reducing fracture rates. Recently, anabolic therapy with teriparatide was demonstrated to be superior to the bisphosphonate risedronate in preventing vertebral and clinical fractures in postmenopausal women with vertebral fracture. Treatment with the sclerostin antibody romosozumab increases BMD more profoundly and rapidly than alendronate and is also superior to alendronate in reducing the risk of vertebral and nonvertebral fracture in postmenopausal women with osteoporosis. For patients with severe osteoporosis and high fracture risk, bisphosphonates alone are unlikely to be able to provide long-term protection against fracture and restore BMD. For those patients, sequential treatment, starting with a bone-building drug (e.g. teriparatide), followed by an antiresorptive, will likely provide better long-term fracture prevention and should be the golden standard of future osteoporosis treatment., OBJECTIVE: To review the comparative effectiveness of osteoporosis treatments, including the bone anabolic agents, abaloparatide and romosozumab, on reducing the risk of fractures in postmenopausal women, and to characterise the effect of antiosteoporosis drug treatments on the risk of fractures according to baseline risk factors. DESIGN: Systematic review, network meta-analysis, and meta-regression analysis of randomised clinical trials. DATA SOURCES: Medline, Embase, and Cochrane Library to identify randomised controlled trials published between 1 January 1996 and 24 November 2021 that examined the effect of bisphosphonates, denosumab, selective oestrogen receptor modulators, parathyroid hormone receptor agonists, and romosozumab compared with placebo or active comparator. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials that included non-Asian postmenopausal women with no restriction on age, when interventions looked at bone quality in a broad perspective. The primary outcome was clinical fractures. Secondary outcomes were vertebral, non-vertebral, hip, and major osteoporotic fractures, all cause mortality, adverse events, and serious cardiovascular adverse events. RESULTS: The results were based on 69 trials (>80\u2009000 patients). For clinical fractures, synthesis of the results showed a protective effect of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab compared with placebo. Compared with parathyroid hormone receptor agonists, bisphosphonates were less effective in reducing clinical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). Compared with parathyroid hormone receptor agonists and romosozumab, denosumab was less effective in reducing clinical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An effect of all treatments on vertebral fractures compared with placebo was found. In the active treatment comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab were more effective than oral bisphosphonates in preventing vertebral fractures. The effect of all treatments was unaffected by baseline risk indicators, except for antiresorptive treatments that showed a greater reduction of clinical fractures compared with placebo with increasing mean age (number of studies=17; β=0.98, 95% confidence interval 0.96 to 0.99). No harm outcomes were seen. The certainty in the effect estimates was moderate to low for all individual outcomes, mainly because of limitations in reporting, nominally indicating a serious risk of bias and imprecision. CONCLUSIONS: The evidence indicated a benefit of a range of treatments for osteoporosis in postmenopausal women for clinical and vertebral fractures. Bone anabolic treatments were more effective than bisphosphonates in the prevention of clinical and vertebral fractures, irrespective of baseline risk indicators. Hence this analysis provided no clinical evidence for restricting the use of anabolic treatment to patients with a very high risk of fractures. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019128391., Bisphosphonates are widely used in the treatment of osteoporosis in postmenopausal women and older men. In clinical trials they have been shown to reduce fractures in women with osteoporosis and there is increasing evidence that they are also effective in women with osteopenia, in whom the majority of fractures occur. In addition to their role as initial therapy in individuals at increased risk of fracture, bisphosphonates are used as sequential therapy after treatment with anabolic drugs. There are no head-to head studies to compare the anti-fracture efficacy of different bisphosphonates, but there is limited evidence that zoledronate treatment results in greater increases in BMD than risedronate or alendronate. This, together with the need for less frequent administration of zoledronate, supports its wider use in clinical practice, particularly if longer dosing intervals than those currently recommended are shown to be effective., Osteoporosis affects a significant number of postmenopausal women in the United States. Screening\xa0is performed using clinical assessments and bone mineral density scans via dual x-ray absorptiometry. Oral therapy is indicated to prevent pathologic fractures in those deemed at increased risk following screening.\xa0Bisphosphonates including\xa0alendronate, ibandronate, and risedronate\xa0are currently first-line oral therapeutics in fracture prevention following the diagnosis of osteoporosis. Hormonal therapies\xa0include estrogen-containing therapies, selective estrogen receptor modulators, and other compounds that mimic the effects of estrogen such as tibolone. Lifestyle modifications such as supplementation and physical activity may also contribute to the prevention of osteoporosis and are used as adjuncts to therapy following diagnosis. These therapeutics are limited primarily by their adverse effects. Treatment regimens should be tailored based on significant risk factors demonstrated by patients, adverse effects, and clinical response to treatment. The most severe risk factors relevant to pharmacological selection involve hormone replacement therapies, where concern for venous thrombosis, coronary artery disease, breast, and uterine cancer exist. Bisphosphonates are most commonly associated with gastrointestinal discomfort which may be mitigated with proper administration. Although adverse effects exist, these medications have proven to be efficacious in the prevention of vertebral and non-vertebral fractures in post-menopausal women. Fracture risk should be weighed against the risk of adverse events associated with each of the regimens, with clinical judgment dictating the treatment approach centered around patient goals and experiences., To provide a summarized state of the art of the relative efficacy and rapidity of action of pharmacological treatments to prevent imminent osteoporotic fractures. We reviewed metanalyses (MA) and network metaanalyses (NMA) published during the last 10\xa0years concerning the pharmacological treatment of osteoporosis. We compared the anti-fracture efficacy and the rapidity of action of various agents versus placebo and versus risedronate. All bisphosphonates decrease the incidence of vertebral fractures compared with placebo. Ibandronate is the only one without demonstrated efficacy against non-vertebral and hip fractures. Zoledronate, denosumab and anabolic therapy are associated with a higher fracture risk reduction than oral bisphosphonates. Compared with risedronate, which significantly reduces the rate of hip fractures, zoledronate, denosumab, teriparatide, abaloparatide and romosozumab are more efficient for vertebral fractures but not for non-vertebral or hip fractures reduction. No studies have compared bone anabolic treatments with zoledronate or denosumab. Oral bisphosphonates significantly reduce fracture risk only after more than one year of therapy. A faster reduction of fracture risk is observed with zoledronate and denosumab, or with anabolic agents. For denosumab and anabolic agents, a sequential treatment is required to keep gains after treatment withdrawal. In patients at high risk of imminent fracture, starting therapy with potent antiresorptive agents or with an anabolic agent seems most appropriate to promptly reduce the fracture risk. Available NMA/MA suggest that, compared to zoledronate and denosumab, anabolic agents have a higher efficacy for vertebral fractures but head-to-head studies are lacking. •The concept of imminent fracture has implications for the choice of therapy•We reviewed metanalyses and network metaanalyses published in the last 10\xa0years•We compared the efficacy and rapidity of treatments to prevent imminent fractures•Potent antiresorptive and anabolic agents are most appropriate to promptly reduce fracture risk•Anabolic agents seem to be more efficient to reduce vertebral fracture risk The concept of imminent fracture has implications for the choice of therapy We reviewed metanalyses and network metaanalyses published in the last 10\xa0years We compared the efficacy and rapidity of treatments to prevent imminent fractures Potent antiresorptive and anabolic agents are most appropriate to promptly reduce fracture risk Anabolic agents seem to be more efficient to reduce vertebral fracture risk The concept of imminent fracture has implications for the choice of therapy We reviewed metanalyses and network metaanalyses published in the last 10\xa0years We compared the efficacy and rapidity of treatments to prevent imminent fractures Potent antiresorptive and anabolic agents are most appropriate to promptly reduce fracture risk Anabolic agents seem to be more efficient to reduce vertebral fracture risk

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

PURPOSE: Treatment of hyperprolactinemia with ergoline dopamine agonists (DAs) can be complicated by intolerance and resistance. This study examines the efficacy and tolerability of the non-ergot dopamine agonist ropinirole for the long-term treatment of hyperprolactinemia. METHODS: Twelve hyperprolactinemic women were treated with ropinirole in a 6 month open-label dose escalation trial; 7/12 continued treatment in an extension study for up to 17 months. Ropinirole doses were up-titrated to achieve normal prolactin levels, restore menses, and eliminate galactorrhea. RESULTS: Two of 12 subjects were DA naïve; 6/12 were ergot DA intolerant; 1/12 had known ergot DA resistance. Baseline prolactin levels were 126.2\u2009±\u200941.4\u2005ng/mL (SEM). Ropinirole was up-titrated from 0.125-0.25\u2005mg QHS to a median total daily dose (TDD) of 2\u2005mg/d (1-4\u2005mg/d (IQR). Prolactin normalization was achieved in 50% of subjects (5 with microadenomas and 1 with idiopathic hyperprolactinemia) at a median effective TDD of 1\u2005mg/d. Of the patients achieving prolactin normalization, 83% were ergot DA intolerant. A persistent partial biochemical response (prolactin reduction >50% from baseline) was achieved in 17% of subjects. During treatment, menses resumed in 67% of amenorrheic subjects; galactorrhea resolved in 67%. Mild adverse effects were reported in 92% of subjects; however, ropinirole was not discontinued due to intolerance even among the 50% of subjects with a prior history of ergot DA intolerance and resultant medication discontinuation. CONCLUSION: These data demonstrate the efficacy and tolerability of ropinirole for the treatment of hyperprolactinemia in patients with microprolactinomas and idiopathic hyperprolactinemia and suggest ropinirole may represent a novel therapeutic alternative for treating hyperprolactinemic disorders in patients with ergot DA intolerance.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Background/Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) is categorized into three subtypes: overweight/obese (OW), lean/normal weight with metabolic abnormalities, and diabetes mellitus (DM). We investigated whether fibrotic burden in liver differs across subtypes of MAFLD patients. Methods: This cross-sectional multicenter study was done in cohorts of subjects who underwent a comprehensive medical health checkup between January 2014 and December 2020. A total of 42,651 patients with ultrasound-diagnosed fatty liver were included. Patients were classified as no MAFLD, OW-MAFLD, lean-MAFLD, and DM-MAFLD. Advanced liver fibrosis was defined based on the nonalcoholic fatty liver disease fibrosis score (NFS) or fibrosis-4 (FIB-4) index. Results: The mean age of the patients was 50.0 years, and 74.1% were male. The proportion of patients with NFS-defined advanced liver fibrosis was the highest in DM-MAFLD (6.6%), followed by OW-MAFLD (2.0%), lean-MAFLD (1.3%), and no MAFLD (0.2%). The proportion of patients with FIB-4-defined advanced liver fibrosis was the highest in DM-MAFLD (8.6%), followed by lean-MAFLD (3.9%), OW-MAFLD (3.0%), and no MAFLD (2.0%). With the no MAFLD group as reference, the adjusted odds ratios (95% confidence intervals) for NFS-defined advanced liver fibrosis were 4.46 (2.09 to 9.51), 2.81 (1.12 to 6.39), and 9.52 (4.46 to 20.36) in OW-MAFLD, lean-MAFLD, and DM-MAFLD, respectively, and the adjusted odds ratios for FIB-4-defined advanced liver fibrosis were 1.03 (0.78 to 1.36), 1.14 (0.82 to 1.57), and 1.97 (1.48 to 2.62) in OW-MAFLD, lean-MAFLD, and DM-MAFLD. Conclusions: Fibrotic burden in the liver differs across MAFLD subtypes. Optimized surveillance strategies and therapeutic options might be needed for different MAFLD subtypes., INTRODUCTION: nonalcoholic fatty liver disease (NAFLD) is a complex disorder resulting from intricate relationships with diverse cardiometabolic risk factors and environmental factors. NAFLD may result in severe chronic liver damage and potentially declining liver function. AREAS COVERED: Accumulated knowledge over the last decade indicates that the disease trajectory presents substantial heterogeneity. In addition, overlapping features with the diseases of the metabolic syndrome, combined with heterogeneity in disease mechanisms, further complicates NAFLD diagnosis and prognosis, and hampers progress in biomarker and pharmacological discoveries. Here, we explore solving the heterogeneous clinical landscape of NAFLD by cluster analysis of molecular signatures that serve as a proxy for disease stratification into molecular sub-types. First, we collected information on NAFLD and metabolic syndrome-associated protein-coding genes by data mining the literature. Next, we performed pathways enrichment and cluster analyses to decipher and dissect the different patterns of phenotypic heterogeneity. Our approach showed unique biological pathways for every clinical subtype/group, namely NAFLD + obesity, NAFLD + arterial hypertension, NAFLD + dyslipidemia, and NAFLD + type 2 diabetes. EXPERT OPINION: Patients with NAFLD may be benefited by a better understanding of the disease biology, which involves dissection of the molecular sub-phenotypes that drive the disease progression. , Non-alcoholic steatohepatitis (NASH) is a condition characterized by inflammation and hepatic injury/fibrosis caused by the accumulation of ectopic fats in the liver. Recent advances in lipidomics have allowed the identification and characterization of lipid species and have revealed signature patterns of various diseases. Here, we describe a lipidomics workflow to assess the lipid profiles of liver homogenates taken from a NASH mouse model. The protocol described below was used to extract and analyze the metabolites from the livers of mice with NASH by liquid chromatography-mass spectrometry (LC-MS); however, it can be applied to other tissue homogenate samples. Using this method, over 1,000 species of lipids from five classes can be analyzed in a single run on the LC-MS. Also, partial elucidation of the identity of neutral lipid (triacylglycerides and diacylglycerides) aliphatic chains can be performed with this simple LC-MS setup. Key features Over 1,000 lipid species (sphingolipids, cholesteryl esters, neutral lipids, phospholipids, fatty acids) are analyzed in one run. Analysis of liver lipids in non-alcoholic steatohepatitis (NASH) mouse model. Normal-phase chromatography coupled to a triple quadrupole mass spectrometer., BACKGROUND: Fatty liver disease is a common condition caused by excess fat in the liver. It consists of two types: Alcoholic Fatty Liver Disease, also called alcoholic steatohepatitis, and Non-Alcoholic Fatty Liver Disease (NAFLD). As per epidemiological studies, fatty liver encompasses 9% to 32% of the general population in India and affects overweight people. OBJECTIVE: An Optimized Support Vector Machine with Support Vector Regression model is proposed to evaluate the volume of liver fat by image analysis (LFA-OSVM-SVR). METHOD: The input computed tomography (CT) liver images are collected from the Chennai liver foundation and Liver Segmentation (LiTS) datasets. Here, input datasets are pre-processed using Gaussian smoothing filter and bypass filter to reduce noise and improve image intensity. The proposed U-Net method is used to perform the liver segmentation. The Optimized Support Vector Machine is used to classify the liver images as fatty liver image and normal images. The support vector regression (SVR) is utilized for analyzing the fat in percentage. RESULTS: The LFA-OSVM-SVR model effectively analyzed the liver fat from CT scan images. The proposed approach is activated in python and its efficiency is analyzed under certain performance metrics. CONCLUSION: The proposed LFA-OSVM-SVR method attains 33.4%, 28.3%, 25.7% improved accuracy with 55%, 47.7%, 32.6% lower error rate for fatty image classification and 30%, 21%, 19.5% improved accuracy with 57.9%, 46.5%, 31.76% lower error rate for normal image classificationthan compared to existing methods such as Convolutional Neural Network (CNN) with Fractional Differential Enhancement (FDE) (CNN-FDE), Fully Convolutional Networks (FCN) and Non-negative Matrix Factorization (NMF) (FCN-NMF), and Deep Learning with Fully Convolutional Networks (FCN) (DL-FCN)., BACKGROUND: Fatty liver, or steatosis, is a condition of excess accumulation of lipids, mainly under form of triglycerides (TG), in the liver, and it is the hallmark of non-alcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disorder world-wide and it has frequently been associated with obesity, hyperlipidemia and insulin resistance. Free fatty acids (FA) are the major mediators of hepatic steatosis; patients with NAFLD have elevated levels of circulating FA that correlate with disease severity. METHODS: Steatosis is a reversible condition that can be resolved with changed behaviors, or that can progress towards more severe liver damages such as steatohepatitis (NASH), fibrosis and cirrhosis. In NAFLD, FA of exogenous or endogenous origin accumulate in the hepatocytes and trigger liver damages. Excess TG are stored in cytosolic lipid droplets (LDs) that are dynamic organelles acting as hubs for lipid metabolism. RESULTS: In the first part of this review, we briefly reassumed the main classes of FA and their chemical classification as a function of the presence and number of double bonds, their metabolic pathways and effects on human health. Then, we summarized the main genetic and diet-induced animal models of NAFLD, as well as the cellular models of NAFLD. CONCLUSIONS: In recent years, both the diet-induced animal models of NAFLD as well as the cellular models of NAFLD have found ever more application to investigate the mechanisms involved in NAFLD, and we referred to their advantages and disadvantages., Fatty liver, which has been continuously becoming more common in a number of patients, is the most common liver disease. For detailed analysis, a useful model for fatty liver is needed and fish are considered as a potential candidate. We assessed through direct observation of the liver, which is the most conventional method for non-invasive analysis of progression in fatty liver. By using transparent medaka (Oryzias latipes), we were able to observe changes in fat deposition in the liver. An analysis of the progression of fatty liver using ultrasound showed a significant increase in echo intensity, which indicates that this is a useful examination method. In addition, we clarified a metabolite profile in the medaka liver fed a high-fat diet (HFD), which had not previously been shown in detail. This medaka model, allowing non-invasive and repetitive assessment, is a useful model for the analysis of diseases that cause fatty liver in which changes in detailed metabolites are identified. Summary: Our medaka model allows for non-invasive and repetitive assessment and is useful in the analysis of fatty liver in which changes in detailed metabolites are identified.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Background: Non-alcoholic fatty liver disease (NAFLD) is a predominant health condition across the world due to its rising prevalence and association with various metabolic disorders. Intermittent fasting (IF) has attracted increasing attention as a dietary approach to addressing weight management and enhancing metabolic well-being, and its potential effects on NAFLD have been a topic of growing research interest. Aim: This review aims to critically evaluate the current evidence on IFs impact on NAFLD, including the mechanisms underlying the observed effects in older adults (65+). Methods: A comprehensive search of Clinicaltrials.gov was conducted to identify relevant studies that investigated the effects of IF on NAFLD in older adults (65+). Data on study design, sample size, intervention details, and outcomes related to NAFLD were extracted and analyzed. Results: As of April 12th, 2023, there were 1304 clinical trials on NAFLD. Most of these were interventional studies. The investigation focused on completed studies and found that limited clinical trials were identified with limited interventional measures. Only five out of the 1304 studies on NAFLD involved IF. Basic and advanced outcome measures were examined. Conclusion: Although some studies suggest that IF may have potential benefits for NAFLD, the evidence is still limited and inconclusive. , Background: Weight loss by lifestyle modification is the cornerstone therapy of non-alcoholic fatty liver disease (NAFLD). Intermittent fasting has shown favorable effects on body weight (BW) and relevant indicators of NAFLD in several reports. Objective: To estimate the effects of intermittent fasting on adults with NAFLD. Materials and methods: Literature searches were conducted on PubMed, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov from inception to May 10, 2021. Results: A total of six studies involving 417 patients with NAFLD were included. In the meta-analysis, there were significant differences in BW, body mass index (BMI), alanine aminotransferase (ALT), and aspartate transaminase (AST) between the control and fasting group. Up to now, there is no significant difference in triglycerides (TG), total cholesterol (TC), and other metabolic parameters between the two groups. Conclusions: Intermittent fasting is beneficial for weight management and liver enzyme improvement, but long-term feasibility and safety of intermittent fasting should be conducted in further studies., We review the underlying mechanisms and potential benefits of intermittent fasting (IF) from animal models and recent clinical trials. Numerous variations of IF exist, and study protocols vary greatly in their interpretations of this weight loss trend. Most human IF studies result in minimal weight loss and marginal improvements in metabolic biomarkers, though outcomes vary. Some animal models have found that IF reduces oxidative stress, improves cognition and delays aging. Additionally, IF has anti-inflammatory effects, promotes autophagy, and benefits the gut microbiome. The benefit-to-harm ratio varies by model, IF protocol, age at initiation, and duration. We provide an integrated perspective on potential benefits of IF as well as key areas for future investigation. In clinical trials, caloric restriction and IF result in similar degrees of weight loss and improvement in insulin sensitivity. Although these data suggest that IF may be a promising weight loss method, IF trials have been of moderate sample size and limited duration. More rigorous research is needed., OBJECTIVE: Intermittent fasting (IF) is a nutritional intervention with significant metabolic effects on the liver that are not yet fully understood. The aim of this study was to investigate the effects of IF on body mass, lipid profile, glucose metabolism, liver lipogenesis, β-oxidation, and inflammation. METHODS: We used cellular and molecular techniques to investigate the effects of IF on 3-mo-old male C57 BL/6 mice that were fed control (10% kcal fat), high-fat (HF; 50% kcal fat), or high-fructose (HFr; 50% kcal fructose) diets for 8 wk. Half of the animals were submitted to IF (1 d fed, 1 d fast) for an additional 4 wk. RESULTS: Although food intake on the fed day did not differ between the groups, mice in the HF and HFr groups showed diminished body mass, total cholesterol, and triacylglycerol levels. Also, plasma adiponectin increased in the HFr group and leptin decreased in the HF mice. Oral glucose tolerance test and insulin were ameliorated by IF, regardless of the diet consumed (HF or HFr), and decreased hepatic lipogenesis and increased β-oxidation markers, resulting in a reduction of the hepatic steatosis and inflammation. CONCLUSIONS: There were beneficial effects of IF even with the continuity of the obesogenic diet and proinflammatory diet in mice. It is recommended that based on the beneficial effects of IF on glucose and liver metabolism and inflammation that IF be a coadjutant factor in the treatment of hepatic metabolic issues and steatosis., PURPOSE OF REVIEW: We review the underlying mechanisms and potential benefits of intermittent fasting (IF) from animal models and recent clinical trials. RECENT FINDINGS: Numerous variations of IF exist, and study protocols vary greatly in their interpretations of this weight loss trend. Most human IF studies result in minimal weight loss and marginal improvements in metabolic biomarkers, though outcomes vary. Some animal models have found that IF reduces oxidative stress, improves cognition, and delays aging. Additionally, IF has anti-inflammatory effects, promotes autophagy, and benefits the gut microbiome. The benefit-to-harm ratio varies by model, IF protocol, age at initiation, and duration. We provide an integrated perspective on potential benefits of IF as well as key areas for future investigation. In clinical trials, caloric restriction and IF result in similar degrees of weight loss and improvement in insulin sensitivity. Although these data suggest that IF may be a promising weight loss method, IF trials have been of moderate sample size and limited duration. More rigorous research is needed., Scope: Intermittent fasting (IF) has been extensively reported to promote improved energy homeostasis and metabolic switching. While IF may be a plausible strategy to ameliorate the epidemiological burden of disease in many societies, our understanding of the underlying molecular mechanisms behind such effects is still lacking. The present study has sought to investigate the relationship between IF and changes in gene expression. We focused on the liver, which is highly sensitive to metabolic changes due to energy status. Mice were randomly assigned to ad libitum feeding or IF for 16 hours per day or for 24 hours on alternate days for 3 months, after which genome-wide transcriptome analysis of the liver was performed using RNA sequencing. Our findings revealed that IF caused robust transcriptomic changes in the liver that led to a complex array of metabolic changes. We also observed that the IF regimen produced distinct profiles of transcriptomic changes, highlighting the significance of temporally different periods of energy restriction. Our results suggest that IF can regulate metabolism via transcriptomic mechanisms and provide insight into how genetic interactions within the liver might lead to the numerous metabolic benefits of IF.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Background: Berberine effectively alleviates non-alcoholic fatty liver disease (NAFLD). Nevertheless, the mechanism is incompletely comprehended. It has been reported that SIRT1 mediates lipid metabolism in liver and berberine promotes the expression of SIRT1 in hepatocytes. We hypothesized that SIRT1 mediated the effect of berberine on NAFLD. Methods: The effects of berberine on NAFLD were evaluated in C57BL/6J mice fed a high-fat diet (HFD) and in mouse primary hepatocytes and cell lines exposed to palmitate. The change of fatty acid oxidation (FAO) and the activity of CPT1A were observed in HepG2 cells. Quantitative real-time polymerase chain reaction and Western blot were employed to observe the expression of SIRT1 and lipid metabolism-related molecules. The interaction between SIRT1 and CPT1A was investigated by using co-immunoprecipitation assay in HEK293T cells. Results: Berberine treatment attenuated hepatic steatosis, reduced triglyceride (190.1\u2009±\u200911.2\u2009μmol/g liver vs 113.6\u2009±\u20097.6\u2009μmol/g liver, P\u2009<\u20090.001) and cholesterol (11.3\u2009±\u20092.5\u2009μmol/g liver vs 6.3\u2009±\u20090.4\u2009μmol/g liver, P\u2009<\u20090.001) concentration in the liver, and improved lipid and glucose metabolism disorders compared with the HFD group. The expression of SIRT1 was reduced in the liver of NAFLD patients and mouse models. Berberine increased the expression of SIRT1 and promoted the protein level of CPT1A and its activity in HepG2 cells. SIRT1 overexpression mimicked the effect of berberine on reducing triglyceride levels in HepG2 cells, whereas SIRT1 knock-down attenuated the effect of berberine. Mechanistically, berberine increased the expression of SIRT1. SIRT1 deacetylated CPT1A at the Lys675 site, which suppressed its ubiquitin-dependent degradation, thereby promoting FAO and alleviating non-alcoholic liver steatosis. Conclusions: Berberine promoted SIRT1 deacetylation of CPT1A at the Lys675 site, which reduced the ubiquitin-dependent degradation of CPT1A and ameliorated non-alcoholic liver steatosis., The incidence of Non-Alcoholic Fatty Liver Disease (NAFLD) has been rapidly increasing during the last decade. It is a relevant health problem that affects 25% of the general population. NAFLD involves an extensive array of clinical conditions. So far, no approved pharmacological therapy for NAFLD has been developed. Multiple bioactive compounds have been proposed to treat NAFLD. One of the most promising is Berberine (BBR). Its pleiotropic effect positively impacts various cardiometabolic aspects. In this review, we summarize NAFLD, its metabolic and cardiovascular complications, the hepatoprotective effects of BBR due to its broad spectrum of pharmacological effects, and the potential role of BBR in NAFLD therapy. BBR ameliorates NAFLD by affecting numerous abnormalities. It inhibits lipogenesis and gluconeogenesis, improves insulin resistance and lipid profile, and modulates gut microbiota. The exact mechanism underlying these effects is not yet entirely explained. A growing amount of evidence confirming the positive effects of BBR on multiple metabolic pathways, such as lipids and glucose metabolism, energy homeostasis, or gut microbiota modulation, allows us to speculate about the importance of this natural bioactive substance for NAFLD therapy., OBJECTIVES: To compare the effect of berberine and bicyclol on patients with nonalcoholic fatty liver disease (NAFLD). METHODS: Chinese nonalcoholic and non-viral hepatitis patients with a hepatic lipid content > 13% and nonalcoholic fatty liver disease activity score (NAS) ≥ 2 were treated with 500 mg berberine thrice daily, together with dietary modification (low-fat diet) and Tai Chi exercise for 4\xa0months (BT cohort; n =\xa0112), or 25 mg bicyclol thrice daily plus dietary modification and Tai Chi exercise for 4\xa0months (CT cohort, n =\xa0145), or dietary modification and Tai Chi exercise for 4\xa0months (DT cohort, n =\xa0128). RESULTS: Patients in the BT and the CT cohorts had improved anthropometric measurements (weight, height, body mass index, and waist-to-hip ratio), biochemical parameters (blood sugar, lipid profile, and liver functions tests), liver/spleen computed tomography findings, and liver biopsy results after 4\xa0months of intervention (p <\xa00.05 for all). Bicyclol decreased the NAS in the CT cohort to a significantly greater degree than berberine in the BT cohort (p <\xa00.0001, q =\xa03.879). Patients in the DT cohort had reduced body mass index and waist-to-hip ratio (p <\xa00.05 for both). During the 4-month intervention, patients in the BT cohort had abdominal distension, mild diarrhea, constipation, nausea, and dyspepsia; patients in the CT cohort had dizziness and abdominal distension. CONCLUSIONS: Berberine or bicyclol plus dietary modification and Tai Chi exercise could control NAFLD without serious adverse effects. Dietary modification and Tai Chi exercise alone for 4\xa0months are insufficient for the management of NAFLD. It is possible to reduce body weight by administering berberine or bicyclol., Background and Aims: The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC–MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR’s beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation., This study aimed to explore the therapeutic effects and underlying mechanism of berberine (BBR) on the non-alcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD). Rats were randomly divided into the following 4 groups: control (normal diet), model (HFD), polyene phosphatidylcholine HFD+PPC, and BBR (HFD+BBR) group. The NAFLD models were prepared by feeding with HFD for 12 weeks. The liver tissues were observed by oil red O staining. H&E staining was used to detect pathological changes in the liver tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were detected by an automatic biochemical analyzer. ELISA was performed to observe the inflammatory cytokines (TNF-α, IL-6, and IL-1β) expressions. The levels of TLR4, MyD88, and NF-κB p65 were analyzed using western blot and qRT-PCR, respectively. The nuclear translocation levels of NF-κB in the primary liver cells were measured using flow cytometry. BBR could significantly alleviate the liver tissue steatosis and inflammatory cell infiltration; reduce the NAFLD activity scores and serum levels of ALT, AST, TC, and LDL-C; decrease the levels of TNF-α, IL-6, and IL-1β, and reduce the expression of TLR4, MyD88, and NF-κB in the liver tissues. BBR could also reverse the nuclear translocation of NF-κB in the primary liver cells. BBR alleviated the progress of NAFLD and liver damage, which might contribute to inhibit the nuclear translocation of NF-κB via the TLR4/MyD88/NF-κB pathway., Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide. Recent studies have shown that the Angptl2 pathway mediated hepatic inflammatory response plays an important role in the progression of nonalcoholic fatty liver disease. Our study investigated the possible molecular mechanisms of berberine (BBR) in the treatment of the liver inflammatory response in the livers of rats with high-fat diet-induced NAFLD via the Angptl2 pathway. At the end of 12\u2009weeks, compared with the control group rats, the high-fat- diet group rats showed obvious pathological and biochemical changes. The levels of pro-infalmmatory cytokines (CCL2, TNF-α) were increased, the infiltration of inflammatory cells (CCR2) was elevated, and the hepatic mRNA and protein levels of Angptl2, NF-κB and Foxo1 were increased to different degrees. Nevertheless, following treatment with BBR, liver tissue pathology, biochemical data, and Angptl2 pathway-related genes expression were significantly ameliorated. Our findings demonstrate that BBR might attenuate the liver inflammatory response in the livers of rats with high-fat diet-induced NAFLD through the regulation of the Angptl2 pathway.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Activation of the innate immune system through toll-like receptors (TLRs) has been repeatedly demonstrated in non-alcoholic fatty liver disease (NAFLD) and several TLRs have been shown to contribute. Myeloid differentiation primary response 88 (MyD88) is as an adapter protein for the activation of TLRs and bridges TLRs to NF-κB-mediated inflammation in macrophages. However, whether myeloid cell MyD88 contributes to NAFLD are largely unknown. To test this approach, we generated macrophage-specific MyD88 knockout mice and show that these mice are protected against high-fat diet (HFD)-induced hepatic injury, lipid accumulation, and fibrosis. These protective effects were associated with reduced macrophage numbers in liver tissues and surpassed inflammatory responses. In cultured macrophages, saturated fatty acid palmitate utilizes MyD88 to activate NF-κB and induce inflammatory and fibrogenic factors. In hepatocytes, these factors may cause lipid accumulation and a further elaboration of inflammatory cytokines. In hepatic stellate cells, macrophage-derived factors, especially TGF-β, cause activation and hepatic fibrosis. We further show that pharmacological inhibition of MyD88 is also able to reduce NAFLD injury in HFD-fed mice. Therefore, our study has provided empirical evidence that macrophage MyD88 participates in HFD-induced NAFLD and could be targeted to prevent the development and progression of NAFLD/NASH., OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), which often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC depend on inflammatory signaling, whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways. METHODS: Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition, and DEN-induced HCC. To this end, we performed dietary and chemical interventions in mice that were analyzed via single nucleus sequencing, gene expression and histochemical methods. Ultimately, we verified our mouse results in human patient samples. RESULTS: We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis, independent of its role in the NFκB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans. CONCLUSIONS: Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients., CONTEXT: Inflammatory and immune pathways play a crucial role in the pathophysiology of non-alcoholic fatty liver disease (NAFLD). Sitagliptin blocks the dipeptidyl peptidase-4 (DPP-4) enzyme, mechanisms that alter inflammatory pathways and the innate immune system, and by which Sitagliptin affects the pathogenesis of NAFLD werent previously discussed. OBJECTIVE: This study aims to understand the interaction between Sitagliptin and innate immune response in order to meliorate NAFLD. METHODS: Thirty- two Wistar male albino rats were categorised into four groups. Rats have received a standard diet or a high-fat diet either with or without Sitagliptin. Serum HMGB1, protein and mRNA expressions of hepatic TLR4 and NF-κB, inflammatory cytokines, and histopathological changes were analysed. RESULTS: An ameliorative action of Sitagliptin in NAFLD was demonstrated via decreasing HMGB1-mediated TLR4/NF-κB signalling in order to suppress inflammation and reduce insulin resistance. CONCLUSION: Sitagliptin may in fact prove to be a beneficial therapeutic intervention in NAFLD. , The pathogenesis of NAFLD is complex and diverse, involving multiple signaling pathways and cytokines from various organs. Hepatokines, stellakines, adipokines, and myokines secreted by hepatocytes, hepatic stellate cells, adipose tissue, and myocytes play an important role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributes to the progression of NAFLD by mediating liver inflammation, immune response, hepatocyte death, and later compensatory proliferation. In this review, we first discuss the crosstalk and interaction between hepatokines, stellakines, adipokines, and myokines and NF-κB in NAFLD. The characterization of the crosstalk of NF-κB with these factors will provide a better understanding of the molecular mechanisms involved in the progression of NAFLD. In addition, we examine new expert management opinions for NAFLD and explore the therapeutic potential of silymarin in NAFLD/NASH., Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention., The progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) is linked to systemic inflammation. Currently, two of the aspects that need further investigation are diagnosis and treatment of NASH. In this sense, the aim of this study was to assess the relationship between circulating levels of cytokines, hepatic expression of toll-like receptors (TLRs), and degrees of NAFLD, and to investigate whether these levels could serve as noninvasive biomarkers of NASH. The present study assessed plasma levels of cytokines in 29 normal-weight women and 82 women with morbid obesity (MO) (subclassified: normal liver (n = 29), simple steatosis (n = 32), and NASH (n = 21)). We used enzyme-linked immunosorbent assays (ELISAs) to quantify cytokine and TLR4 levels and RTqPCR to assess TLRs hepatic expression. IL-1β, IL-8, IL-10, TNF-α, tPAI-1, and MCP-1 levels were increased, and adiponectin levels were decreased in women with MO. IL-8 was significantly higher in MO with NASH than in NL. To sum up, high levels of IL-8 were associated with the diagnosis of NASH in a cohort of women with morbid obesity. Moreover, a positive correlation between TLR2 hepatic expression and IL-8 circulating levels was found.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

We explored the shared pathophysiological mechanisms between COVID-19 and non-alcoholic fatty liver disease (NAFLD) by integrating multi-omics data. We studied common genetic risk factors and underlying biological processes using functional enrichment analysis. To understand the sex-specific pathways involved in the clinical course of SARS-CoV-2 infection, we processed sex-stratified data from COVID-19 genome-wide association datasets. We further explored the transcriptional signature of the liver cells in healthy and COVID-19 tissue specimens. We also integrated genetic and metabolomic information. We found that COVID-19 and NAFLD share biological disease mechanisms, including pathways that regulate the inflammatory and lipopolysaccharide response. Single-cell transcriptomics revealed enrichment of complement-related pathways in Kupffer cells, syndecan-mediated signalling in plasma cells, and epithelial-to-mesenchymal transition in hepatic stellate cells. The strategy of pathway-level analysis of genomic and metabolomic data uncovered l-lactic acid, Krebs cycle intermediate compounds, arachidonic acid and cortisol among the most prominent shared metabolites., Activation of the innate immune system through toll-like receptors (TLRs) has been repeatedly demonstrated in non-alcoholic fatty liver disease (NAFLD) and several TLRs have been shown to contribute. Myeloid differentiation primary response 88 (MyD88) is as an adapter protein for the activation of TLRs and bridges TLRs to NF-κB-mediated inflammation in macrophages. However, whether myeloid cell MyD88 contributes to NAFLD are largely unknown. To test this approach, we generated macrophage-specific MyD88 knockout mice and show that these mice are protected against high-fat diet (HFD)-induced hepatic injury, lipid accumulation, and fibrosis. These protective effects were associated with reduced macrophage numbers in liver tissues and surpassed inflammatory responses. In cultured macrophages, saturated fatty acid palmitate utilizes MyD88 to activate NF-κB and induce inflammatory and fibrogenic factors. In hepatocytes, these factors may cause lipid accumulation and a further elaboration of inflammatory cytokines. In hepatic stellate cells, macrophage-derived factors, especially TGF-β, cause activation and hepatic fibrosis. We further show that pharmacological inhibition of MyD88 is also able to reduce NAFLD injury in HFD-fed mice. Therefore, our study has provided empirical evidence that macrophage MyD88 participates in HFD-induced NAFLD and could be targeted to prevent the development and progression of NAFLD/NASH., The pathogenesis of NAFLD is complex and diverse, involving multiple signaling pathways and cytokines from various organs. Hepatokines, stellakines, adipokines, and myokines secreted by hepatocytes, hepatic stellate cells, adipose tissue, and myocytes play an important role in the occurrence and development of nonalcoholic fatty liver disease (NAFLD). The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) contributes to the progression of NAFLD by mediating liver inflammation, immune response, hepatocyte death, and later compensatory proliferation. In this review, we first discuss the crosstalk and interaction between hepatokines, stellakines, adipokines, and myokines and NF-κB in NAFLD. The characterization of the crosstalk of NF-κB with these factors will provide a better understanding of the molecular mechanisms involved in the progression of NAFLD. In addition, we examine new expert management opinions for NAFLD and explore the therapeutic potential of silymarin in NAFLD/NASH., Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL-1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome-caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of proinflammatory cytokines. Also, neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention., Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Pathways responsible for the activation of IL1 family cytokines are key in the development of NAFLD but underlying mechanisms are not fully understood. Many studies have focused on the inflammasome/caspase-1 pathway and have shown that this pathway is an important inducer of inflammation in NAFLD. However, this pathway is not solely responsible for the activation of pro-inflammatory cytokines. Also neutrophil serine proteases (NSPs) are capable of activating cytokines and recent studies reported that these proteases also contribute to NAFLD. These studies provided, for the first time, evidence that this inflammasome-independent pathway is involved in NAFLD. In our opinion, these new insights open up new approaches for therapeutic intervention., To analyze expression of members of the Toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor (NF)-κB signaling pathway in the heart and liver in a rat model of type 2 diabetes mellitus (T2DM). Our overall goal was to understand the underlying pathophysiological mechanisms. We measured fasting blood glucose (FBG) and insulin (FINS) in a rat model of T2DM. Expression of members of the TLR4/MyD88/NF-κB signaling pathway as well as downstream cytokines was investigated. Levels of mRNA and protein were assessed using quantitative real-time polymerase chain reaction and western blotting, respectively. Protein content of tissue homogenates was assessed using enzyme-linked immunosorbent assays. Diabetic rats had lower body weights, higher FBG, higher FINS, and higher intraperitoneal glucose tolerance than normal rats. In addition, biochemical indicators related to heart and liver function were elevated in diabetic rats compared with normal rats. TLR4 and MyD88 were involved in the occurrence of T2DM as well as T2DM-related heart and liver complications. TLR4 caused T2DM-related heart and liver complications through activation of NF-κB. TLR4/MyD88/NF-κB signaling induces production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1, leading to the heart- and liver-related complications of T2DM.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Many people living with diabetes also have non-alcoholic fatty liver disease (NAFLD). Interleukin-6 (IL-6) is involved in both diseases, interacting with both membrane-bound (classical) and circulating soluble receptors (trans-signaling). We investigated whether secretion of IL-6 trans-signaling co-receptors are altered in NAFLD by diabetes, and whether this might associate with the severity of fatty liver disease. Secretion patterns were investigated using human hepatocyte, stellate and monocyte cell lines. Associations with liver pathology were investigated in two patient cohorts: 1) biopsy-confirmed NASH and 2) class 3 obesity. We found that exposure of stellate cells to high glucose and palmitate increased IL-6 and sgp130 secretion. In line with this, plasma sgp130 in both patient cohorts positively correlated with HbA1c, and subjects with diabetes had higher circulating levels of IL-6 and trans-signaling co-receptors. Plasma sgp130 strongly correlated with liver stiffness and was significantly increased in subjects with F4 fibrosis stage. Monocyte activation was associated with reduced sIL-6R secretion. These data suggest that the hyperglycemia and hyperlipidemia can directly impact IL-6 trans-signaling, and that this may be linked to enhanced severity of NAFLD in patients with concomitant diabetes., Interleukin (IL)-6 has been studied since its discovery for its role in health and diseases. It is one of the most important pro-inflammatory cytokines. IL-6 was reported as an exacerbating factor in coronavirus disease. In recent years, it has become clear that the function of muscle-derived IL-6 is different from what has been reported so far. Exercise is accompanied by skeletal muscle contraction, during which, several bioactive substances, collectively named myokines, are secreted from the muscles. Many reports have shown that IL-6 is the most abundant myokine. Interestingly, it was indicated that IL-6 plays opposing roles as a myokine and as a pro-inflammatory cytokine. In this review, we discuss why IL-6 has different functions, the signaling mode of hyper-IL-6 via soluble IL-6 receptor (sIL-6R), and the involvement of soluble glycoprotein 130 in the suppressive effect of hyper-IL-6. Furthermore, the involvement of a disintegrin and metalloprotease family molecules in the secretion of sIL-6R is described. One of the functions of muscle-derived IL-6 is lipid metabolism in the liver. However, the differences between the functions of IL-6 as a pro-inflammatory cytokine and the functions of muscle-derived IL-6 are unclear. Although the involvement of myokines in lipid metabolism in adipocytes was previously discussed, little is known about the direct relationship between nonalcoholic fatty liver disease and muscle-derived IL-6. This review is the first to discuss the relationship between the function of IL-6 in diseases and the function of muscle-derived IL-6, focusing on IL-6 signaling and lipid metabolism in the liver., Interleukin (IL)-25 is a cytokine that has previously been shown to have a protective role against nonalcoholic fatty liver disease (NAFLD), which is associated with the induction of M2 macrophage differentiation. However, the direct relationships between IL-25 expression regulation, M2 induction and NAFLD remain unknown. In this study, we demonstrate that IL-25 promotes hepatic macrophage differentiation into M2a macrophages both in\xa0vivo and in\xa0vitro via the IL-13/STAT6 pathway. M2 macrophages that were differentiated in\xa0vitro were able to ameliorate high-fat diet HFD-induced hepatic steatosis. Furthermore, we found that IL-25 treatment, both in\xa0vitro and in\xa0vivo, promotes direct binding of STAT6 to the IL-25 gene promoter region. This binding of STAT6 in response to IL-25 treatment also resulted in the increase of IL-25 expression in hepatocytes. Together, these findings identify IL-25 as a protective factor against HFD-induced hepatic steatosis by inducing an increase\xa0of IL-25 expression in hepatocytes and through promotion of M2a macrophage production., Interleukin 6 (IL-6) is a cytokine that is involved in divers immune responses and implicated in a number of diseases. However, this cytokine has other non-immune functions. Within this review, we highlight selected effects on metabolic pathways, which are mediated, controlled or modified by the IL-6. Importantly, putting spotlight on such concepts could allow us to classify IL-6 among the metabolic hormones and further study it to both deepen our knowledge on disorders involving metabolic or energy imbalances such as obesity and develop novel therapeutic strategies. Furthermore, potential explanations related to IL-6 roles in both physiology and pathology as well as relevant implications and applications on both research and therapeutic fields are also pointed as consequences of the involvement of IL-6 in the energy and metabolic homeostasis via its endocrine roles., BACKGROUND: Pro-inflammatory cytokines are associated with systemic inflammatory responses. OBJECTIVE: To investigate the levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in patients with non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) compared to healthy individuals. METHODS: This case-control study was conducted on 30 patients with NAFL, 30 patients with NASH, and 30 healthy volunteers. The plasma level of IL-1β, IL-6, and TNF-α were determined by ELISA, and biochemical parameters were measured using colorimetric methods. RESULTS: IL-1β and IL-6 levels were significantly higher in patients with NASH compared with NAFL and control group. However, TNF-α levels had no significant variations in NAFL and NASH patients compared to the control group (p=0.903 and p=0.960, respectively). CONCLUSION: Results showed that the levels of ALT activity and pro-inflammatory cytokines were higher in patients with NASH compared to control and NAFL subjects; Therefore, steatosis and inflammation develop as a result of excessive pro-inflammatory factors in NASH., Non-alcoholic fatty liver disease (NAFLD) is closely associated with metabolic diseases like type 2 diabetes and obesity. In recent decades, accumulating evidence has revealed that the hepatokines, proteins mainly secreted by the liver, play important roles in the development of NAFLD by acting directly on the lipid and glucose metabolism. As a member of organokines, the hepatokines establish the communication between the liver and the adipose, muscular tissues. In this review, we summarize the current understanding of the hepatokines and how they modulate the pathogenesis of metabolic disorders especially NAFLD.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Diabetes mellitus is considered as an autoimmune inflammatory and age-related disease. As an important immune organ, the thymus is involved in the immune response and inflammatory response process. Therefore, there may be a link between changes in thymus function and diabetes. Based on previous studies, we hypothesized that thymus dysfunction due to aging and other reasons leads to changes in the generation of various inflammatory-immune cells and inflammatory cytokines that regulate insulin resistance, and then participates in the development of diabetes and its complications. Therefore, thymus may be a key factor in diabetes and complications, and it may be a promising therapeutic strategy to improve the thymus function for patients with diabetes. The purpose of this review is to summarize and discuss recent advances in the influence of thymus function on diabetes, especially its potential mechanisms., Background: Inflammation, along with aging processes, contributes to the development of insulin resistance , but the roles of different inflammatory and other cytokines in this process remain unclear. Thus, we aimed to analyze the association between several plasma cytokines with IR as evaluated by the metabolic score for insulin resistance, METS-IR. Methods: We measured the plasma concentrations of thirty cytokines from a cohort of older persons and analyzed their role as independent factors for IR. We used regression analyses adjusted for known IR-associated factors (including age, gender, cholesterol levels, and BMI) to find the determinants of IR. Results: The study evaluated 132 subjects, mostly women (82F/50M), slightly overweight, and with a mean age of 78.5 ± 6.5 years. In the overall population, IL-15 significantly and negatively correlates with METS-IR (r = −0.183, p = 0.036). A regression model showed that the association between IL-15 and METS-IR was significantly modulated by gender and BMI (R^2: 0.831). Only in women, EGF, Eotaxin and MCP-1 significantly correlated with METS-IR even after controlling by age (EGF, r = 0.250 p = 0.025; Eotaxin, r = 0.276 p = 0.13; MCP-1, r = 0.237, p = 0.033). Furthermore, regression models showed that these molecules were associated with METS-IR and were strongly mediated by BMI. Conclusions: Our results indicate the association between cytokines and IR has to be interpreted in a gender-specific manner. In women, EGF, Eotaxin, and MCP-1 circulating levels are associated with METS-IR being BMI a significant mediator. Understanding the role of gender in the relationship between cytokines and IR will help to define individualized preventive and treatment interventions to reduce the risk of age-related metabolic disorders., Insulin has an important regulatory effect on the heart, and the important regulatory effect of insulin on the heart is the regulation of substrate utilization. Studies have shown that aging is closely related to insulin resistance, and aging is thought to be one of the underlying causes of insulin resistance. Additionally, chronic inflammation is a major risk factor for aging and aging-related diseases. How to delay or reverse insulin resistance caused by aging is an important scientific problem. In the current study, we used cardiomyocyte cell lines and isolated heart cells as an in vitro model, and aged mice as in vivo model to study the effect of KAT7 on insulin resistance, and results showed that knockdown or inhibiting KAT7 can significantly increase the insulin sensitivity in vivo and in vitro. In addition, the knockdown of KAT7 could reduce inflammation and oxidative stress caused by aging. These findings indicate that KAT7 can be used as one of the potential targets for the treatment of insulin resistance caused by aging., OBJECTIVE: The morbidity and prevalence of type 2 diabetes mellitus are increasing in the elderly population. Interleukin 37 (IL-37) play important roles in anti-inflammatory and anti-bacteria immune responses, but its role in the development of type 2 DM in the elderly is unclear. Therefore, we investigated whether IL-37 is associated with type 2 DM in the elderly and the underlying mechanism. METHODS: Hospitalized patients (aged 65-95 years) with recently diagnosed type 2 diabetes mellitus were studied retrospectively and compared with healthy subjects without glucose metabolism abnormalities. A diabetic mouse model was established by feeding ob/ob mice (C57BL/6) a high-fat, carbohydrate-free diet. Plasma glucose and insulin levels were determined by glucose oxidase assay and radioimmunoassay, respectively. The IL-37 expression level was determined by real-time PCR, western blot and ELISA (Enzyme-linked immunoassay). RESULTS: Statistic analysis showed that the IL-37 level was significantly associated with type 2 DM and insulin resistance in the elderly. The patients were then divided into insulin therapy sensitive and resistant group according to their response to insulin therapy. Data showed that the IL-37 was highly expressed in the insulin therapy sensitive group. And this was related to the less severe gut microbiota dysbiosis. In the mice model, overexpressing the IL-37 could suppress the gut microbiota dysbiosis and also the diabetes development. CONCLUSION: Thus our results showed that higher IL-37 was associated with increased insulin sensitive in elderly type 2 DM patients through suppressing the gut microbiota dysbiosis.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.

Low-grade inflammation is a major player in obesity and the metabolic syndrome predicting development of type 2 diabetes (T2DM). The interleukin-1 receptor antagonist (IL-1Ra) is a vital and natural anti-inflammatory factor and mediator in glucose homeostasis disturbances. The predictive role is independent of multiple confounders, and elevated levels appear few years before T2DM. The role of IL-1Ra is important for accumulated risk factors, dysregulated metabolism and glucose homeostasis, and dietary interventions. Longitudinal and cross-sectional population study cohorts have enabled the approximation of IL-1Ra limit values for metabolic dysregulation and guide further analysis as a potential biomarker. The limit value of IL-1Ra is reaching 400 pg/mL with prediabetes and before T2DM. However, subjects with metabolic syndrome are suggested to have lower limit values, especially among men. Future research may evaluate the role of IL-1Ra in actual glucose homeostasis together with routine fasted laboratory tests, such as glucose and C-reactive protein instead of the oral glucose tolerance test. The significance of intermediate low IL-1Ra levels in metabolic abnormalities should be further analyzed. It is possible to specify the impact of multiple lifestyle and metabolic parameters together with age and sex. IL-1Ra could be studied in multiple approaches including interventional studies of metabolic diseases., Interleukin-1 (IL-1) is a key player in the immune response to pathogens due to its role in promoting inflammation and recruiting immune cells to the site of infection. In tuberculosis , tight regulation of IL-1 responses is critical to ensure host resistance to infection while preventing immune pathology. In the mouse model of Mycobacterium tuberculosis infection, both IL-1 absence and overproduction result in exacerbated disease and mortality. In humans, several polymorphisms in the IL1B gene have been associated with increased susceptibility to TB. Importantly, M. tuberculosis itself has evolved several strategies to manipulate and regulate host IL-1 responses for its own benefit. Given all this, IL-1 appears as a promising target for host-directed therapies in TB. However, for that to succeed, more detailed knowledge on the biology and mechanisms of action of IL-1 in vivo, together with a deep understanding of how host-M. tuberculosis interactions modulate IL-1, is required. Here, we discuss the most recent advances in the biology and therapeutic potential of IL-1 in TB as well as the outstanding questions that remain to be answered., Metabolic abnormalities such as obesity, insulin resistance, and type 2 diabetes mellitus are known to be associated with adipose tissue inflammation and impaired secretion of cytokines. Anti-inflammatory cytokine interleukin-4 (IL-4) was found to promote insulin sensitivity, glucose tolerance, and reduce lipid accumulation in vivo through multiple mechanisms, including direct regulation of lipolysis in adipocytes. However, little is known about its role in adipocyte glucose metabolism. This study reveals that IL-4 upregulates glucose uptake in adipocytes without additional activation of the insulin-dependent IRS1 (insulin receptor substrate 1)-Akt (protein kinase B) pathway. Moreover, the main transcription factor STAT6 (signal transducer and activator of transcription 6), regulated by IL-4, was not involved in adipocyte glucose uptake. The proteomic results showed that IL-4 upregulates expression of proteins involved in mitochondrial biogenesis, renewal, and glucose oxidation. Our study provides a new hypothesis, explaining protective effects of IL-4 against metabolic abnormalities through activation of adipocytes glucose utilization and maintenance of mitochondrial function under metabolic overload conditions., Type 1 diabetes (T1D) is a metabolic disease associated with systemic low-grade inflammation and macrophage reprogramming. There is evidence that this inflammation depends on the increased systemic levels of leukotriene B4 found in T1D mice, which shifts macrophages towards the proinflammatory (M1) phenotype. Although T1D can be corrected by insulin administration, over time T1D patients can develop insulin resistance that hinders glycemic control. Here, we sought to investigate the role of leukotrienes in a metabolically active tissue such as muscle, focusing on the insulin signaling pathway and muscle-associated macrophage profiles. Type 1 diabetes was induced in the 129/SvE mouse strain by streptozotocin in mice deficient in the enzyme responsible for LT synthesis (5LO^−/−) and the LT-sufficient wild type . The response to insulin was evaluated by the insulin tolerance test , insulin concentration by ELISA, and Akt phosphorylation by western blotting. The gene expression levels of the insulin receptor and macrophage markers Stat1, MCP-1, Ym1, Arg1, and IL-6 were evaluated by qPCR, and that of IL-10 by ELISA. We observed that after administration of a single dose of insulin to diabetic mice, the reduction in glycemia was more pronounced in 5LO^−/− than in WT mice. When muscle homogenates were analyzed, diabetic 5LO^−/− mice showed a higher expression of the insulin receptor gene and higher Akt phosphorylation. Moreover, in muscle homogenates from diabetic 5LO^−/− mice, the expression of anti-inflammatory macrophage markers Ym1, Arg1, and IL-10 was increased, and the relative expression of the proinflammatory cytokine IL-6 was reduced compared with WT diabetic mice. These results suggest that LTs have an impact on the insulin receptor signaling pathway and modulate the inflammatory profile of muscle-resident macrophages from T1D mice.

Create a suitable heading for the given text and return it in the following JSON format: {"Title": ""}.