Burosumab Efficacy and Safety in Patients with X-Linked Hypophosphatemia: Systematic Review and Meta-analysis of Real-World Data.

To assess the efficacy and safety of burosumab in children and adults with X-linked hypophosphatemia based on real-world evidence. MEDLINE (via PubMed) and Cochrane Library were searched until 18 October 2023 for single-arm (before-after) studies. Registries including Clinicaltrials.gov, EU Clinical Trials, WHO International Clinical Trials Registry Platform, and conference abstracts. The outcomes were a change in serum phosphorus concentrations and change in RSS, a change in serum ALP, bone-specific ALP, a change in the ratio of Tubular maximum reabsorption of Phosphate to Glomerular Filtrate rate, a change in serum 1,25(OH)2D and 25(OH)2D concentrations, change in height Z-score, McMaster Universities Osteoarthritis Index (WOMAC) and safety outcomes. An inverse variance random-effects meta-analysis was applied for data synthesis. Fifteen studies (289 participants) were included. Burosumab treatment improved serum phosphate concentrations [mean difference 0.88 mg/dl, 95% confidence interval 0.70 to 1.07, I2 = 92%), Rickets Severity score (mean difference - 1.86, 95% confidence interval - 2.5 to - 1.21, I2 = 71%), serum alkaline phosphate concentrations (mean difference - 1.86, 95% confidence interval - 2.5 to - 1.21, I2 = 71%), serum 1,25(OH)2D concentrations (mean difference 18.91 pg/ml, 95% confidence interval 6.39 to 31.43, I2 = 96%) and renal phosphate reabsorption (mean difference 1.22 mg/dl, 95% confidence interval 0.70 to 1.74, I2 93%). Burosumab treatment improved overall clinical and laboratory findings in patients with X-linked hypophosphatemia.

A New Technique with Scleral Grooves for Sutureless Scleral Fixation of the Carlevale Intraocular Lens.

INTRODUCTION: A novel technique is described employing scleral grooves to facilitate sutureless scleral fixation of the Carlevale intraocular lens (CIL). We describe its use in a series of 47 patients with aphakia. METHODS: A retrospective study of all patients with aphakia who underwent CIL implantation with the new technique by a single surgeon during 1 year. The novelty of this technique consists in the creation of two partial-thickness linear sclerotomies (grooves), 180° apart, 2 mm from and parallel to the limbus. In the middle of each groove a full-thickness sclerotomy is performed to facilitate externalization of the CIL anchors. The groove allows the anchor to plug the full-thickness sclerotomy and to rest within the sclera without protrusion. Reported outcomes include pre-operative/post-operative visual acuity, post-operative spherical equivalent and surgical complications. Follow-up was a minimum of 6 months. RESULTS: Forty-eight eyes of 47 patients with aphakia with a mean age of 74 years (range 31-90 years) are included. The commonest causes of aphakia were intraocular lens (IOL) subluxation,with or without exfoliation (54.2%), complicated cataract surgery (29.2%), crystalline lens luxation (6.3%) and trauma (4.1%). All CILs inserted with the new technique stayed successfully in situ during follow-up. Median pre-operative best-corrected visual acuity (0.75 logMAR; range 0.1-2.7) significantly improved to 0.5 logMAR post-operatively (p < 0.001). Moreover, 78% and 65% of the operated cases were within 1.0 and 0.5 diopters, respectively, from intended refraction. The most common complications were transient cystoid macular oedema (8.3%) and transient intraocular pressure rise (8.3%), all of which resolved within 2 months. CONCLUSIONS: The proposed modification of sutureless scleral fixation of the CIL appears safe and effective. In our experience it is less time consuming and easier to perform than previous techniques and may therefore offer a useful future option.

Contraceptive counseling: Shared decision on contraceptive choices.

The promising results achieved in male hormonal contraceptive trials over the last decades suggest that new male contraceptives could hit the market soon. In shared decision-making counseling, couples and their healthcare provider collaborate to make decisions about contraception choices. This model of contraceptive counseling could aid men in taking responsibility for contraception and women in trusting their partners in family planning. The shared decision-making process in contraceptive counseling requires partners to provide input on their preferences, values, and desires, while healthcare professionals share medical knowledge and evidence-based information.It has been proven that this method leads to higher adherence and satisfaction. To ensure that contraceptive counseling is inclusive, fair, and supportive of different reproductive experiences and needs, it is crucial to incorporate the Reproductive Justice Framework into counseling.

Structural basis of MALAT1 RNA maturation and mascRNA biogenesis.

The metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) long noncoding RNA (lncRNA) has key roles in regulating transcription, splicing, tumorigenesis, etc. Its maturation and stabilization require precise processing by RNase P, which simultaneously initiates the biogenesis of a 3' cytoplasmic MALAT1-associated small cytoplasmic RNA (mascRNA). mascRNA was proposed to fold into a transfer RNA (tRNA)-like secondary structure but lacks eight conserved linking residues required by the canonical tRNA fold. Here we report crystal structures of human mascRNA before and after processing, which reveal an ultracompact, quasi-tRNA-like structure. Despite lacking all linker residues, mascRNA faithfully recreates the characteristic 'elbow' feature of tRNAs to recruit RNase P and ElaC homolog protein 2 (ELAC2) for processing, which exhibit distinct substrate specificities. Rotation and repositioning of the D-stem and anticodon regions preclude mascRNA from aminoacylation, avoiding interference with translation. Therefore, a class of metazoan lncRNA loci uses a previously unrecognized, unusually streamlined quasi-tRNA architecture to recruit select tRNA-processing enzymes while excluding others to drive bespoke RNA biogenesis, processing and maturation.

Integrative transcriptomic and proteomic profiling of the effects of cell confluency on gene expression.

In this study we examine the impact of cell confluency on gene expression. We focused on Argonaute (AGO) protein dynamics and associated gene and protein expression in HEK293, A375, and SHSY5Y cell lines. As a consequence of cell confluency, AGO2 protein translocates into the nucleus. Therefore, we generated transcriptomic data using RNA sequencing to compare gene expression in subconfluent versus confluent cells, which highlighted significant alterations in gene regulation patterns directly corresponding to changes in cell density. Our study also encompasses miRNA profiling data obtained through small RNA sequencing, revealing miRNA expressional changes dependent on cellular confluency, as well as cellular localization. Finally, we derived proteomic data from mass spectrometry analyses following AGO1-4 immunoprecipitation, providing a comprehensive view of AGO interactome in both nuclear and cytoplasmic compartments under varying confluency. These datasets offer a detailed exploration of the cellular and molecular dynamics, influenced by cell confluency, presenting a valuable resource for further research in cellular biology, particularly in understanding the basic mechanisms of cell density in cancer cells.

Mechanical reinforcement from two-dimensional nanofillers: model, bulk and hybrid polymer nanocomposites.

Thanks to their intrinsic properties, multifunctionality and unique geometrical features, two-dimensional nanomaterials have been used widely as reinforcements in polymer nanocomposites. The effective mechanical reinforcement of polymers is, however, a multifaceted problem as it depends not only on the intrinsic properties of the fillers and the matrix, but also upon a number of other important parameters. These parameters include the processing method, the interfacial properties, the aspect ratio, defects, orientation, agglomeration and volume fraction of the fillers. In this review, we summarize recent advances in the mechanical reinforcement of polymer nanocomposites from two-dimensional nanofillers with an emphasis on the mechanisms of reinforcement. Model, bulk and hybrid polymer nanocomposites are reviewed comprehensively. The use of Raman and photoluminescence spectroscopies is examined in light of the distinctive information they can yield upon stress transfer at interfaces. It is shown that the very diverse family of 2D nanofillers includes a number of materials that can attribute distrinctive features to a polymeric matrix, and we focus on the mechanical properties of both graphene and some of the most important 2D materials beyond graphene, including boron nitride, molybdenum disulphide, other transition metal dichalcogenides, MXenes and black phosphorous. In the first part of the review we evaluate the mechanical properties of 2D nanoplatelets in "model" nanocomposites. Next we examine how the performance of these materials can be optimised in bulk nanocomposites. Finally, combinations of these 2D nanofillers with other 2D nanomaterials or with nanofillers of other dimensions are assessed thoroughly, as such combinations can lead to additive or even synergistic mechanical effects. Existing unsolved problems and future perspectives are discussed.

Menopause and metabolic dysfunction-associated steatotic liver disease.

Nonalcoholic fatty liver disease, recently proposed to be renamed metabolic dysfunction-associated steatotic liver disease, is a highly prevalent disease (25-30 % of the global general population) whose prevalence increases after menopause. Apart from the rates of simple steatosis, the severity of the disease (e.g., hepatic fibrosis) increases after menopause. Menopause is associated with higher abdominal adiposity and dysmetabolism of carbohydrate and lipid metabolism, which may contribute to the development and severity of metabolic dysfunction-associated steatotic liver disease and the higher cardiovascular risk observed after menopause. The association between menopause and metabolic dysfunction-associated steatotic liver disease renders menopausal hormone therapy an appealing way to reverse hepatic disease in parallel with the benefits of menopausal hormone therapy in other tissues. In this regard, most animal studies have shown a beneficial effect of estrogens on metabolic dysfunction-associated steatotic liver disease. Still, clinical studies are few, and their data are conflicting. The effect of menopausal hormone therapy on metabolic dysfunction-associated steatotic liver disease may be distinct among estrogen monotherapies and the combinations of estrogens and progestogens. It may also depend on the type of progestogen and the route of administration. However, more studies specifically designed for these aims are needed to draw secure conclusions. This review summarizes the data related to the association between menopause and metabolic dysfunction-associated steatotic liver disease, as well as between menopausal hormone therapy and metabolic dysfunction-associated steatotic liver disease, with a special focus on clinical studies.

Effect of DASH vs. mediterranean diet accompanied by a salt restriction on metabolic syndrome and cardiometabolic risk factors in adults with high normal blood pressure or grade 1 hypertension: secondary analyses of a randomized controlled trial.

OBJECTIVE: Lifestyle interventions are recommended as the first-line treatment to control metabolic syndrome components and improve cardiometabolic risk factors. However, studies directly comparing the cardiometabolic effects of the Dietary Approaches to Stop Hypertension (DASH) vs. the Mediterranean diet (MedDiet) accompanied by salt restriction are currently lacking. Thus, with the present secondary analyses of a randomized trial, we aimed to assess the cardiometabolic effects of a 3-month intensive dietary intervention implementing salt restriction alone or on top of the DASH and MedDiet compared to no/minimal intervention in never drug-treated adults with high normal blood pressure (BP) or grade 1 hypertension. METHODS: We randomly assigned individuals to the control group (CG, n = 60), salt restriction group (SRG, n = 60), DASH diet with salt restriction group (DDG, n = 60), or MedDiet with salt restriction group (MDG, n = 60). RESULTS: According to the intention-to-treat analysis, the DDG and the MDG had lower odds ratio (OR) (95% CI) of metabolic syndrome [0.29 (0.12, 0.72), and 0.15 (0.06, 0.41), respectively] compared to the CG. Moreover, the MDG had lower odds of metabolic syndrome compared to the SRG and lower odds of elevated BP levels than the DDG and the SRG. Moreover, total and LDL-cholesterol, fasting glucose, HbA1c, and systolic/diastolic BP were reduced in all three intervention groups compared to the CG. CONCLUSION: On a background of salt restriction, the MedDiet was superior in BP reduction, but the DASH and MedDiet reduced the prevalence of metabolic syndrome to the same extent.

A Comparative Study and Prediction of the Ex Vivo Permeation of Six Vaginally Administered Drugs across Five Artificial Membranes and Vaginal Tissue.

The theoretical interpretation of the vaginal permeability phenomenon, the evaluation of the suitability of five artificial membranes, and the prediction of the behaviors of vaginal drugs were the main objectives of this study. Franz vertical diffusion cells and different validated HPLC methods were used to measure the permeability of six vaginally administered drugs (econazole, miconazole, metronidazole, clindamycin, lidocaine, and nonoxynol-9). This study was performed (in vitro) on different membranes of polyvinylidene fluoride (PVDF), plain cellulose or cellulose impregnated with isopropyl myristate (IPM), and cellulose combined with PVDF or IPM. The results were compared with those obtained from cow vaginal tissue (ex vivo), where cellulose was proven to be the best simulant. According to the permeability profiles (Papp), the water solubility of the drugs was considered a necessary criterion for their transport in the membranes or in the tissue, while the size was important for their penetration. Furthermore, it was found that polar compounds show clear superiority when penetrating cellulose or tissue, while non-polar ones show superiority when penetrating the lipophilic PVDF membrane. Finally, a successful attempt was made to predict the Papp values (|Papp-predPapp| < 0.005) of the six drugs under study based on a PLS (Partial Least Squares) in silico simulation model.

Hypogonadism and nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD), recently proposed to be renamed to metabolic dysfunction-associated steatotic liver disease (MASLD), is a major global public health concern, affecting approximately 25-30% of the adult population and possibly leading to cirrhosis, hepatocellular carcinoma, and liver transplantation. The liver is involved in the actions of sex steroids via their hepatic metabolism and production of the sex hormone-binding globulin (SHBG). Liver disease, including NAFLD, is associated with reproductive dysfunction in men and women, and the prevalence of NAFLD in patients with hypogonadism is considerable. A wide spectrum of possible pathophysiological mechanisms linking NAFLD and male/female hypogonadism has been investigated. As therapies targeting NAFLD may impact hypogonadism in men and women, and vice versa, treatments of the latter may affect NAFLD, and an insight into their pathophysiological pathways is imperative. This paper aims to elucidate the complex association between NAFLD and hypogonadism in men and women and discuss the therapeutic options and their impact on both conditions.

Food Cravings and Obesity in Women with Polycystic Ovary Syndrome: Pathophysiological and Therapeutic Considerations.

Polycystic ovary syndrome (PCOS), the most common endocrine disorder in women of reproductive age, constitutes a metabolic disorder frequently associated with obesity and insulin resistance (IR). Furthermore, women with PCOS often suffer from excessive anxiety and depression, elicited by low self-esteem due to obesity, acne, and hirsutism. These mood disorders are commonly associated with food cravings and binge eating. Hypothalamic signaling regulates appetite and satiety, deteriorating excessive food consumption. However, the hypothalamic function is incapable of compensating for surplus food in women with PCOS, leading to the aggravation of obesity and a vicious circle. Hyperandrogenism, IR, the reduced secretion of cholecystokinin postprandially, and leptin resistance defined by leptin receptors' knockout in the hypothalamus have been implicated in the pathogenesis of hypothalamic dysfunction and appetite dysregulation. Diet modifications, exercise, and psychological and medical interventions have been applied to alleviate food disorders, interrupting the vicious circle. Cognitive-behavioral intervention seems to be the mainstay of treatment, while the role of medical agents, such as GLP-1 analogs and naltrexone/bupropion, has emerged.

Investigation of Health-Related Quality of Life, Anxiety and Satisfaction in Patients with Pulmonary Embolism.

BACKGROUND: Features of post-traumatic stress disorder and anxiety may be present in pulmonary embolism (PE) patients, along with impaired quality of life (QoL). We aim to evaluate health-related QoL, anxiety and satisfaction with life in patients with PE. METHODS: Patients with PE were enrolled during their follow-up. All participants completed the Short Form 36 (SF-36) questionnaire, the State-Trait Anxiety Inventory (STAI) X1 and X2 forms, and the Satisfaction with Life Scale (SWLS). RESULTS: 92 PE patients were included (mean age ± SD = 62.50 ± 15.33 years, 56.5% males). The median values of the SF-36 subscales were below the corresponding values of the Greek general population (besides the mental health (MH) subscale). Mean STAIX1 levels were 37.05 ± 11.17 and mean STAIX2 levels were 39.80 ± 10.47. Mean SWLS levels were 23.31 ± 6.58. According to multiple linear regression analysis, the MH and general health subscales were predictive of SWLS levels (F (10.76) = 10.576, p < 0.001, R2 = 0.581). The MH score (ß = -0.242, p < 0.01) and STAIX1 level (ß = 0.312, p < 0.001) (F (9.77) = 26.445, p < 0.001, R2 = 0.756) were predictive of STAIX2. CONCLUSIONS: Patients with PE exhibit slight satisfaction with life, borderline anxiety and impaired HRQoL.

OPTORER: A Dynamic Routing and Touring Service for Indoors and Outdoor Tours.

This paper introduces a new routing and touring service both for outdoor and indoor places of touristic and cultural interest designed to be used in the wider area of Attica, Greece. This service is the result of the work performed in OPTORER (OPTORER: OPtimal rouTing and explOration of touRistic and cultural arEas of interest within Attica given personalized adaptive preferences, promoted underlying purpose, and interactive experience), project, and it aspires to offer a range of innovative and thematic routes to several specified points of interest in the selected area of Attica, encouraging the combination of indoor and outdoor routes in a single tour. The aim is to optimize the user experience while promoting specific, user-centric features, with safety and social welfare being a priority for every designed tour, resulting in enhancing the touristic experience in the area. Using a common smartphone device, as well as common wearable devices (i.e., smartwatches), the OPTORER service will provide an end-to-end solution by developing the algorithms and end-user applications, together with an orchestration platform responsible for managing, operating, and executing the service that produces and presents to the end user results derived from solving dynamically complex optimization problems.

EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Evaluation of 3D-Printed Solid Microneedles Coated with Electrosprayed Polymeric Nanoparticles for Simultaneous Delivery of Rivastigmine and N-Acetyl Cysteine.

In the current study, coated microneedle arrays were fabricated by means of digital light processing (DLP) printing. Three different shapes were designed, printed, and coated with PLGA particles containing two different actives. Rivastigmine (RIV) and N-acetyl-cysteine (NAC) were coformulated via electrohydrodynamic atomization (EHDA), and they were incorporated into the PLGA particles. The two actives are administered as a combined therapy for Alzheimer's disease. The printed arrays were evaluated regarding their ability to penetrate skin and their mechanical properties. Optical microscopy and scanning electron microscopy (SEM) were employed to further characterize the microneedle structure. Confocal laser microscopy studies were conducted to construct 3D imaging of the coating and to simulate the diffusion of the particles through artificial skin samples. Permeation studies were performed to investigate the transport of the drugs across human skin ex vivo. Subsequently, a series of tape strippings were performed in an attempt to examine the deposition of the APIs on and within the skin. Light microscopy and histological studies revealed no drastic effects on the membrane integrity of the stratum corneum. Finally, the cytocompatibility of the microneedles and their precursors was evaluated by measuring cell viability (MTT assay and live/dead staining) and membrane damages followed by LDH release.

The association of vasomotor symptoms with fracture risk and bone mineral density in postmenopausal women: a systematic review and meta-analysis of observational studies.

BACKGROUND/AIMS: Vasomotor symptoms (VMS) adversely affect postmenopausal quality of life. However, their association with bone health has not been elucidated. This study aimed to systematically review and meta-analyze the evidence regarding the association of VMS with fracture risk and bone mineral density (BMD) in peri- and postmenopausal women. METHODS: A literature search was conducted in PubMed, Scopus and Cochrane databases until 31 August 2023. Fracture, low BMD (osteoporosis/osteopenia) and mean change in lumbar spine (LS) and femoral neck (FN) BMD were assessed. The results are presented as odds ratio (OR) and mean difference (MD), respectively, with a 95% confidence interval (95% CI). The I2 index quantified heterogeneity. RESULTS: Twenty studies were included in the qualitative and 12 in the quantitative analysis (n=49,659). No difference in fractures between women with and without VMS was found (n=5, OR 1.04, 95% CI 0.93-1.16, I2 16%). However, VMS were associated with low BMD (n=5, OR 1.54, 95% CI 1.42-1.67, I2 0%). This difference was evident for LS (MD -0.019 g/cm2, 95% CI -0.03 to -0.008, I2 85.2%), but not for FN BMD (MD -0.010 g/cm2, 95% CI -0.021 to 0.001, I2 78.2%). These results were independent of VMS severity, age and study design. When the analysis was confined to studies that excluded menopausal hormone therapy use, the association with BMD remained significant. CONCLUSIONS: The presence of VMS is associated with low BMD in postmenopausal women, although it does not seem to increase fracture risk.

Morphometric Analysis of the Thymic Epithelial Cell (TEC) Network Using Integrated and Orthogonal Digital Pathology Approaches.

The thymus, a central primary lymphoid organ of the immune system, plays a key role in T cell development. Surprisingly, the thymus is quite neglected with regards to standardized pathology approaches and practices for assessing structure and function. Most studies use multispectral flow cytometry to define the dynamic composition of the thymus at the cell population level, but they are limited by lack of contextual insight. This knowledge gap hinders our understanding of various thymic conditions and pathologies, particularly how they affect thymic architecture, and subsequently, immune competence. Here, we introduce a digital pathology pipeline to address these challenges. Our approach can be coupled to analytical algorithms and utilizes rationalized morphometric assessments of thymic tissue, ranging from tissue-wide down to microanatomical and ultrastructural levels. This pipeline enables the quantitative assessment of putative changes and adaptations of thymic structure to stimuli, offering valuable insights into the pathophysiology of thymic disorders. This versatile pipeline can be applied to a wide range of conditions that may directly or indirectly affect thymic structure, ranging from various cytotoxic stimuli inducing acute thymic involution to autoimmune diseases, such as myasthenia gravis. Here, we demonstrate applicability of the method in a mouse model of age-dependent thymic involution, both by confirming established knowledge, and by providing novel insights on intrathymic remodeling in the aged thymus. Our orthogonal pipeline, with its high versatility and depth of analysis, promises to be a valuable and practical toolset for both basic and translational immunology laboratories investigating thymic function and disease.

Proteomics in Patients with Fibromyalgia Syndrome: A Systematic Review of Observational Studies.

PURPOSE OF REVIEW: Fibromyalgia syndrome (FMS) is a disease of unknown pathophysiology, with the diagnosis being based on a set of clinical criteria. Proteomic analysis can provide significant biological information for the pathophysiology of the disease but may also reveal biomarkers for diagnosis or therapeutic targets. The present systematic review aims to synthesize the evidence regarding the proteome of adult patients with FMS using data from observational studies. RECENT FINDINGS: An extensive literature search was conducted in MEDLINE/PubMed, CENTRAL, and clinicaltrials.gov from inception until November 2022. The study protocol was published in OSF. Two independent reviewers evaluated the studies and extracted data. The quality of studies was assessed using the modified Newcastle-Ottawa scale adjusted for proteomic research. Ten studies fulfilled the protocol criteria, identifying 3328 proteins, 145 of which were differentially expressed among patients with FMS against controls. The proteins were identified in plasma, serum, cerebrospinal fluid, and saliva samples. The control groups included healthy individuals and patients with pain (inflammatory and non-inflammatory). The most important proteins identified involved transferrin, α-, ß-, and γ-fibrinogen chains, profilin-1, transaldolase, PGAM1, apolipoprotein-C3, complement C4A and C1QC, immunoglobin parts, and acute phase reactants. Weak correlations were observed between proteins and pain sensation, or quality of life scales, apart from the association of transferrin and a2-macroglobulin with moderate-to-severe pain sensation. The quality of included studies was moderate-to-good. FMS appears to be related to protein dysregulation in the complement and coagulation cascades and the metabolism of iron. Several proteins may be dysregulated due to the excessive oxidative stress response.