Thyroid cancer is the predominant endocrine-related malignancy. ST6 β-galactoside α2,6-sialyltransferase 1 (ST6GAL1) has been studied in various types of cancers; however, the expression and function of ST6GAL1 in thyroid cancer has not been investigated so far. Previously, we conducted two genome-wide association studies and have identified the association of the ST6GAL1 gene with plasma thyroglobulin (Tg) levels. Since Tg levels are altered in thyroid pathologies, in the current study, we wanted to evaluate the expression of ST6GAL1 in thyroid cancer tissues. We performed an immunohistochemical analysis using human thyroid tissue from 89 patients and analyzed ST6GAL1 protein expression in papillary thyroid cancer (including follicular variant and microcarcinoma) and follicular thyroid cancer in comparison to normal thyroid tissue. Additionally, ST6GAL1 mRNA levels from The Cancer Genome Atlas (TCGA, n = 572) and the Genotype-Tissue Expression (GTEx) project (n = 279) were examined. The immunohistochemical analysis revealed higher ST6GAL1 protein expression in all thyroid tumors compared to normal thyroid tissue. TCGA data revealed increased ST6GAL1 mRNA levels in both primary and metastatic tumors versus controls. Notably, the follicular variant of papillary thyroid cancer exhibited significantly higher ST6GAL1 mRNA levels than classic papillary thyroid cancer. High ST6GAL1 mRNA levels significantly correlated with lymph node metastasis status, clinical stage, and reduced survival rate. ST6GAL1 emerges as a potential cancer-associated glycosyltransferase in thyroid malignancies, offering valuable insights into its diagnostic and prognostic significance.

This systematic review assesses current molecular targeted therapies for glioblastoma multiforme (GBM), a challenging condition with limited treatment options. Using PRISMA methodology, 166 eligible studies, involving 2526 patients (61.49% male, 38.51% female, with a male-to-female ratio of 1.59/1), were analyzed. In laboratory studies, 52.52% primarily used human glioblastoma cell cultures (HCC), and 43.17% employed animal samples (mainly mice). Clinical participants ranged from 18 to 100 years, with 60.2% using combined therapies and 39.8% monotherapies. Mechanistic categories included Protein Kinase Phosphorylation (41.6%), Cell Cycle-Related Mechanisms (18.1%), Microenvironmental Targets (19.9%), Immunological Targets (4.2%), and Other Mechanisms (16.3%). Key molecular targets included Epidermal Growth Factor Receptor (EGFR) (10.8%), Mammalian Target of Rapamycin (mTOR) (7.2%), Vascular Endothelial Growth Factor (VEGF) (6.6%), and Mitogen-Activated Protein Kinase (MEK) (5.4%). This review provides a comprehensive assessment of molecular therapies for GBM, highlighting their varied efficacy in clinical and laboratory settings, ultimately impacting overall and progression-free survival in GBM management.

As the global population grows, we are witnessing rapid urbanization and the development of industry and agriculture. Novel, largely toxic substances are being used in agriculture to improve yields. All of this has led to the generation of large amounts of pollutants that need to be disposed of and treated. Irresponsible behavior and discharges into nature and river channels not clearly defined by law or sanctioned, certainly have an environmental impact. The Drina River Basin occupies parts of the territories of four countries. It is one of the most important drainage areas in the West Balkans. It calls for international cooperation in many areas, such as public water supply, irrigation, hydropower generation, and the like. However, in order to achieve such cooperation, all the countries that “steward” the resource need to commit to water quality conservation and protection. The DPSIR approach proposed by the Water Framework Directive of the European Union is followed to identify major pressures (pollution sources) in the Serbian part of the Drina River Basin. The pressures are grouped into several categories and described in detail.

AIMS The aim of this study was to estimate cutoff values of mid-upper arm circumference (MUAC) and calf circumference (CC) for reduced muscle mass and analyze their accuracy in identifying malnutrition among individuals of 65 years of age or older in Bosnia and Herzegovina. MATERIALS AND METHODS The study is a secondary analysis dataset assessing nutritional risk and malnutrition among 446 community-dwellers and nursing home residents in Bosnia and Herzegovina. Malnutrition assessment included phenotypic criterions (weight loss, low body mass index, and reduced muscle mass) and etiologic criterions (inadequate food intake, disease-related inflammation, or albumin levels) according to recommendations of the Global Leadership Initiative on Malnutrition (GLIM). Receiver operating curves were used to calculate MUAC and CC's cutoff values as compared to the Mini Nutritional Assessment (MNA). RESULTS The optimal cutoff value for MUAC in men was 24 cm (AUC = 0.910, sensitivity 100%, specificity 77%), and in women 23 cm (AUC = 0.792, sensitivity 64%, specificity 83%). Optimal cutoff value of CC in men was 31 cm (AUC = 0.818, sensitivity 100%, specificity 67%) and in women 29 cm (AUC = 0.882, sensitivity 86%, specificity 74%). Two hundred fifty nine elderly individuals were categorized as malnourished/at risk for malnutrition per MNA. The prevalence of malnutrition based on GLIM criteria ranged from 19% to 30%. CONCLUSIONS The study suggested that MUAC and CC may be used as the alternative indicators of muscle mass when other assessment methods are unavailable. Future validation and reliability studies for GLIM using anthropometric parameters as a proxy of reduced muscle mass are needed.

This study aimed to investigate the effect of lifestyle intervention (LSI) on diagnosed infertility in overweight and obese women. A systematic review and meta-analysis were conducted. A literature search was performed on the following databases from September 2022 to December 2022: PubMed, Web of Science, and SPORTDiscus. The inclusion criteria were the following: women between 18 and 45 years of age, BMI over 25.0 kg/m2, diagnosed with infertility, a weight loss intervention, and control group part of RCTs. In total, 15 studies were identified and included. The meta-analysis shows a beneficial effect of LSI on reducing weight, waist circumference, and BMI and increasing infertility. A significantly beneficial effect of lifestyle intervention on weight reduction was observed for participants who initially had a higher BMI, while a non-significant effect was observed for individuals with a BMI above 35 kg/m2. The meta-analysis showed a beneficial effect of lifestyle intervention on ovulation incidence and sex hormone-binding globulin. The lifestyle intervention group had 11.23 times more ovulatory incidence than the control group, which in turn increased the ability to conceive. As robust evidence for the effect of lifestyle interventions on infertility in obese and overweight women was found, it is advised to integrate similar interventions into future infertility treatment processes.

ETHNOPHARMACOLOGICAL RELEVANCE The medicinal plants Salvia officinalis, Trifolium pratense, Agrimonia eupatoria, Cichorium intybus and Vinca minor are traditionally used for the prevention and treatment of numerous diseases, including diabetes. AIM OF THE STUDY Type 2 diabetes (T2D) is one of the most common diseases nowadays, often accompanied by oxidative stress and microbial infections. The aim of our work was to examine the antidiabetic, antioxidant, and antimicrobial properties of ethanol extracts of five medicinal plants for the purpose of their possible use in the treatment of T2D. MATERIALS AND METHODS The polyphenolic profile of the plant extracts was analyzed by Ultra-High Performance Liquid Chromatography with a diode array detector configured with a triple quadrupole mass spectrometer (UHPLC/DAD/(-)HESI-MS2). In vitro antidiabetic activity of extracts was determined by measuring the percentage of α-amylase and α-glucosidase inhibition. The antioxidant activity of the extract was determined by different spectrophotometric methods, while the antimicrobial activity was determined by agar dilution and disc diffusion methods. RESULTS A. eupatoria extract contains the highest percentage of flavonoids (94%, with isoquercetin, vitexin, and rutin as the most abundant) in relation to the concentration of total phenolic compounds and exhibits excellent antidiabetic, antioxidant, and antimicrobial activity. S. officinalis extract contains 60% flavonoids (predominately cirismaritin and epigallocatechin gallate) and 40% phenolic acids (with rosmarinic acid being the most abundant from this group) and exhibits weak antidiabetic activity, significant antioxidant activity, and excellent antibacterial activity. A 45% percentage of flavonoids (with isoquercetin as the most abundant one) and 55% of phenolic acids (with ferulic acid as the most abundant) were measured in the extract of T. pratense, which had excellent antidiabetic activity but weaker antioxidant and antimicrobial activity. A similar percentage of flavonoids (52%, with epigallocatechin gallate in the highest concentration) and phenolic acids (48%, with chlorogenic acid as the most abundant) was measured in the extract of C. intybus which showed moderate antidiabetic, antioxidant, and antimicrobial properties. The extract of V. minor was the richest in phenolic acids (80%, with the most abundant chlorogenic acid), which resulted in weaker antidiabetic and antioxidant activities (except for Fe2+ chelating ability) and antimicrobial activity. CONCLUSION The results indicate that specific phenolic compounds are responsible for the different biological activities of the plant extracts. Among the investigated plants, the extract of A. eupatoria has the greatest potential for applications in the treatment of T2D.

For over two decades, the acronym PAPA syndrome has been used to describe an autoinflammatory condition caused by missense mutations in the PSTPIP1 (proline-serine-threonine phosphatase interacting protein 1) gene and clinically characterized by the presence of pyogenic arthritis, pyoderma gangrenosum (PG), and acne (1,2). Due to the involvement of the PSTPIP1 gene in the regulation of innate immunity, mutations of this gene cause abnormal activation of inflammasomes, complexes of NLRP3/ASC/caspase-1 proteins. As a result, production of interleukin-1β, a key molecule that triggers synthesis of cytokines necessary for the recruitment of neutrophils, is significantly increased (2,3). Additionally, the levels of other pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ) and interleukin 17 (IL-7) are also elevated, which further disrupts inflammatory mechanisms in the microenvironment (4). Since hyperproduction of IL-1 and other involved cytokines is the predominant event in the pathogenesis, these molecules are promising targets in the treatment of PAPA syndrome. Corticosteroids and biologics are currently the most commonly used agents for inducing and hastening remission of symptoms (5). A substantial step forward in the treatment of PAPA syndrome has been the introduction of medications blocking the cytokines crucial in the pathogenesis of this disorder, with TNF-α and IL-1 inhibitors being the most frequent choice of such biological therapy (6). We report the case of a 22-year-old male patient with PAPA syndrome who was referred to our department 18 months ago due to exacerbation of skin changes. Initial presentation and subsequent evolution of disease in this patient matched the typical clinical pattern of PAPA syndrome. The first symptoms occurred at the age of two in the form of unspecific joint disease that was diagnosed as juvenile idiopathic arthritis. Subsequently, in the early adolescence the patient presented with new skin changes manifesting as severe acne and persistent pyoderma gangrenosum-like ulcers. At the same time, severity of joint involvement gradually decreased. After the characteristic phenotype of the disease had fully developed, suspicion of possible syndromic origin of symptoms arose. For this reason, genetic analysis was performed as requested by attending pediatricians at the University Clinical Center in Sarajevo, and E250Q mutation of the PSTPIP1 gene was detected. Thus, the diagnosis of PAPA syndrome was confirmed. Throughout the duration of the disease, several types of medication had been introduced in the treatment with varying success. Earliest joint symptoms were alleviated with non-steroidal anti-inflammatory drugs, while repeated courses of corticosteroids were the mainstay of the therapy during a decade-long period. As a consequence of prolonged steroid therapy, growth disorder, among various other side-effects, had been especially pronounced. Acting as a classic steroid-sparing immunosuppressive agent, methotrexate had also been part of the patient's treatment regimen. Lastly, biologics, including both TNF-α and IL-a inhibitors, had been separately administered as the remaining treatment options. However, adalimumab expressed a predominant effect on joint symptoms, whereas re-activation of previously undetected Hepatitis-B infection occurred during the subsequent therapy with anakinra. Due to this adverse reaction, anakinra treatment was discontinued. At the initial examination, the patient presented with multiple erythematous, partially excoriated papules and nodules, along with residual post-inflammatory hyperpigmented patches and scars on the skin of the whole back, chest, shoulders, and upper arms (Figure 1, Figure 2). The presence of postoperative scars on the elbows, resulting from previously performed surgical procedures of persistently affected joints with the goal of achieving pain relief and functional improvement, was also observed. Several smaller ulcers with undermined edges (Figure 3), as well as residual hyperpigmentation and cicatrices (Figure 4) were visible on the lower extremities. Additionally, the patient reported appearance of pustules and non-healing ulcers after minor trauma, which corresponds to the pathergy phenomenon, a common feature of PAPA syndrome. In contrast to the severity of cutaneous changes, the joint symptoms were mild. After thorough assessment of the patient's medical history and current condition, a multi-agent regimen was initiated, consisting of adalimumab, isotretinoin, and prednisone. Regular check-ups during the 12 months of treatment showed that the applied agents stabilized the patient's condition, alleviated more severe and acute skin changes, and slowed down further exacerbation of symptoms. Due to the rarity of PAPA syndrome, data on its treatment is scarce. Official guidelines are non-existing, and available information is based on case reports, case series, and a few smaller retrospective studies (5,7). In general, response to therapy remains inconsistent between patients, despite introduction of novel drugs. Furthermore, single treatment regimens are often not equally effective for all manifestations of the disease, which in a number of cases results in the administration of multi-agent treatment (2). As described in our case report, we opted for a multi-agent regimen not only due to specific individual role of each drug in the treatment of PAPA syndrome but also because of the possible augmented effect of combined therapy. Initially, a short course of systemic corticosteroid (prednisone 30 mg/day for 3 weeks) was introduced in order to alleviate acute symptoms until other agents started showing their effects. The initial dose of administered corticosteroid was gradually tapered by 5 mg every week and soon discontinued. Adalimumab (40 mg every 2 weeks for 12 months) was chosen since its previous administration was without significant adverse effects and with more acceptable end results, unlike therapy with anakinra (8). In addition, TNF-α inhibitors, such as adalimumab, etanercept, and infliximab, have been generally regarded as a more effective treatment option for cutaneous changes, while anakinra, an anti-IL-1 agent, has been more beneficial in alleviating joint symptoms (9-11). Since the skin of our patient was significantly more affected than the joints, adalimumab was a preferred option for biological treatment. Finally, isotretinoin (0.5 mg/kg/day for 6 months) also found a place in our multi-agent therapy plan as a specific, supportive treatment agent for acne (12). Due to the fact that our national health insurance system covered the costs of treatment with TNF-α inhibitors for only 12 months, adalimumab had to be discontinued after the end of this period. Episodes of acute exacerbation that the patient experienced after the cessation of multi-agent regimen were addressed with systemic corticosteroids and symptomatic therapy. Based on case reports, corticosteroids are usually one of the first agents to be administered in patients diagnosed with PAPA syndrome. They are frequently effective in alleviating joint symptoms, but, on the other hand, high doses of corticosteroids can worsen acne lesions (6). Moreover, due to the multiple side-effects of corticosteroids, such as electrolyte abnormalities, hypertension, hyperglycemia, osteoporosis, growth suppression, and adrenal insufficiency (13), a steroid-sparing agent is typically introduced into treatment together with or after corticosteroid therapy. A substantial step forward in the treatment of PAPA syndrome has been achieved with the introduction of medications targeting cytokines crucial in the pathogenesis of this disorder. The two most commonly used groups of such biological drugs have been those that block TNF-α and IL-1. A longer lasting improvement of symptoms has been achieved in a number of cases with both types of agents. Since other medications have often failed to establish long-term control of PAPA syndrome, such effects can be seen as a valuable accomplishment (6,14). Regardless of this observation, the response to treatment still differs between patients. More variable effects have been documented for IL-1 inhibitors, such as anakinra, while TNF-α inhibitors, such as adalimumab, infliximab, and etanercept, have been associated with more steady responses (4,6,10). The inconsistent effect of biologic therapies could be explained by the fact that PSTPIP1 protein is involved in various biochemical processes in different cells of the immune system. Thuse, none of the medications has an adequate spectrum of activity to control all involved immunological pathways (5,15). Overall, due to scarcity of valid information and guidelines, there is an increasing need for multicentric randomized controlled trials that would provide evidence-based data on effective treatment options for PAPA syndrome. Despite the rarity of this disorder, extensive research should be performed in order to discover therapies that could successfully manage all different manifestations of PAPA syndrome. Consequently, such efforts and breakthroughs would lead to decreased mortality and improved quality of life for patients suffering from this debilitating disease. The case described herein shows that PAPA syndrome can remain undiagnosed for longer periods of time, resulting in delayed treatment. Furthermore, the available therapeutic options are not sufficient to achieve long-term remission in many patients. Thus, continuous and comprehensive research is vital for ensuring adequate care of patients with PAPA syndrome.

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance. Analysis of HbA1c and FPG levels across 117 population-based studies demonstrates regional variation in prevalence of previously undiagnosed screen-detected diabetes using one or both measures and suggests that use of elevated FPG alone could underestimate diabetes prevalence in low- and middle-income countries.

Medicines can be taken by various routes of administration. These can impact the effects and perceptions of medicines. The literature about individuals' preferences for and perceptions of the different routes of administration is sparse, but indicates a potential influence of culture. Our aim was to determine: (i) any association between one's culture and one's preferred route of medicine administration and (ii) individual perceptions of pain, efficacy, speed of action and acceptability when medicines are swallowed or placed in the mouth, under the tongue, in the nose, eye, ear, lungs, rectum, vagina, on the skin, or areinjected. A cross-sectional, questionnaire-based survey of adults was conducted in 21 countries and regions of the world, namely, Tunisia, Ghana, Nigeria, Turkey, Ethiopia, Lebanon, Malta, Brazil, Great Britain, United States, India, Serbia, Romania, Portugal, France, Netherlands, Japan, South Korea, Hong Kong, mainland China and Estonia, using the Inglehart–Welzel cultural map to ensure coverage across all cultures. Participants scored the pain/discomfort, efficacy, speed of onset and acceptability of the different routes of medicine administration and stated their preferred route. Demographic information was collected. A total of 4435 participants took part in the survey. Overall, the oral route was the most preferred route, followed by injection, while the rectal route was the least preferred. While the oral route was the most preferred in all cultures, the percentage of participants selecting this route varied, from 98% in Protestant Europe to 50% in the African-Islamic culture. A multinomial logistic regression model revealed a number of predictors for the preferred route. Injections were favoured in the Baltic, South Asia, Latin America and African-Islamic cultures while dermal administration was favoured in Catholic Europe, Baltic and Latin America cultures. A marked association was found between culture and the preference for, and perceptions of the different routes by which medicines are taken. This applied to even the least favoured routes (vaginal and rectal). Only women were asked about the vaginal route, and our data shows that the vaginal route was slightly more popular than the rectal one.

Clinoidal meningiomas are meningiomas arising from or in the vicinity of the anterior clinoid process.1 Despite advanced microsurgical techniques, clinoidal meningiomas remain challenging.2 Extradural anterior clinoidectomy with optical unroofing remains an important tool in skull base surgery, which provides a safe operative corridor, facilitating greater extent of resection and enhancing overall outcome, particularly visual function.2-13 A 66-year-old female presented with history of visual disturbances. MRI revealed dural-based tumor consistent with a large left clinoidal meningioma, with tumor wrapping (encircling) around left trunk and internal carotid artery (ICA) bifurcation, elevating the left middle cerebral artery M1 segment, and invading the left optic canal. Left cranio-orbital craniotomy with pretemporal exposure was used.1,9 High-speed diamond drill with irrigation completed the extradural anterior clinoidectomy and optical canal unroofing. Use of 1mm Kerrison rongeur should be used with utmost care. The tumor was unwrapped via meticulous piecemeal removal. Final dissection and ICA unwrapping was done when the tumor was debulked enough that dissecting it off the artery was safe and under less tension. Due to its obscurity, final decompression of the left optic nerve with incision and opening of the falciform ligament was performed at the end of the procedure.10 Postoperative neuro-ophthalmologic exam showed grossly unchanged left visual field with some visual acuity improvement. Resection of tumor encircling the ICA has been described previously14; however, to the best of our knowledge, this is the first video describing removal of tumor surrounding ICA ("unwrapping") the left ICA trunk and its bifurcation. The patient consented to publication.

Abstract Idiopathic dilatation of the right atrium is a rare condition with an unknown etiology. It is characterized by a significant enlargement of the right atrium without the presence of other valvopathies, intracardiac shunts, or pulmonary hypertension. This report presents the case of a 50-year-old woman with a significantly enlarged right atrium that was identified at birth; however, a definitive diagnosis was made later in life. The patient did not have any genetic diseases. Through the help of regular follow-up, anticoagulant therapy, previous radio-frequency ablation, and antiarrhythmic medications, she was able to carry a pregnancy to full term and live a regular life.