Search Results (197)

Background/Objectives: The effect of metformin on the secretory function of thyrotropic cells is sex-dependent. The current study aimed to investigate whether the impact of this drug on activity of the hypothalamic–pituitary–thyroid axis in women is impacted by the androgen status of patients. Methods: The study population included 48 levothyroxine-naïve reproductive-aged women with subclinical hypothyroidism and prediabetes receiving 3.0 g of metformin daily. Women with (n = 24) and without (n = 24) polycystic ovary syndrome were matched for age, insulin sensitivity, TSH, and reasons for thyroid hypofunction. Circulating levels of glucose, glycated hemoglobin, insulin, TSH, thyroid hormones, gonadotropins, androgens, estradiol, SHBG, prolactin, ACTH, and IGF-1 were measured before metformin treatment and six months later. Results: At entry, women with and without polycystic ovary syndrome differed in LH, LH/FSH ratio, androgens, and estradiol. The decrease in TSH, fasting glucose and glycated hemoglobin, and the improvement in insulin sensitivity were less pronounced in women with than in women without polycystic ovary syndrome. In each group, there were no differences in the impact on TSH and thyroid hormones between patients with subclinical hypothyroidism of autoimmune and non-autoimmune origin. The changes in TSH inversely correlated with total testosterone and free androgen index. Only in women with coexisting polycystic ovary syndrome, did metformin slightly reduce LH, LH/FSH ratio, testosterone, and free androgen index. Conclusions: The results suggest that concurrent polycystic ovary syndrome attenuates metformin action on TSH secretion, which can be explained by increased androgen production. Moreover, the drug seems to alleviate PCOS-associated changes in the activity of the reproductive axis. Full article

Background and Objectives: Type 2 diabetes mellitus (T2DM) is associated with subclinical cardiovascular changes, such as increased arterial stiffness and myocardial dysfunction. Vitamin D deficiency has been recognized as a potential contributing factor to vascular disease; however, its impact on early cardiac changes associated with T2DM remains poorly understood. Our aim was to evaluate the association between serum levels of 25-hydroxyvitamin D3 [25(OH)D3], arterial stiffness, and left ventricular global longitudinal strain (LV GLS) in patients with T2DM who do not have a clinically evident cardiovascular disease. Material and methods: This cross-sectional study evaluated the carotid intima–media thickness (IMT), aortic pulse wave velocity (PWVao), LV GLS, and serum 25(OH)D3 levels in patients diagnosed with T2DM (n = 65) compared to healthy control subjects (n = 55). Independent predictors of arterial stiffness were identified by a multivariate logistic regression analysis. Results: Patients with T2DM showed a significant increase in IMT and PWVao, a reduction in LV GLS, and low levels of 25(OH)D3 compared to subjects in the control group (all p < 0.05). Both vitamin D deficiency and T2DM were found to be independently associated with an increased arterial stiffness, with odds ratios of 2.4 and 4.8, respectively. A significant inverse relationship was identified between 25(OH)D3 levels and markers of arterial stiffness, as well as LV GLS, suggesting a possible association between the vitamin D status and the early onset of cardiovascular dysfunction. Conclusions: Patients with T2DM show early signs of heart and blood vessel problems, even with an ejection fraction that remains within normal limits. There is a significant correlation between vitamin D deficiency and increased arterial stiffness, along with impaired LV GLS, indicating its possible involvement in cardiovascular complications associated with diabetes. These findings support the utility of integrating vascular, myocardial, and vitamin D assessments in early cardiovascular risk stratification for T2DM patients. Full article

Background/Objectives: Atypical sensory processing is increasingly recognized as a transdiagnostic dimension of neurodevelopmental disorders (NDDs), with critical implications for emotional and behavioral regulation. This study aimed to identify distinct sensory profiles in preschool children with NDDs and to examine their associations with emotional–behavioral and cognitive/developmental functioning. Methods: A total of 263 children (aged 21–71 months) diagnosed with autism spectrum disorder (ASD), language disorder (LD), or other NDDs (ONDD) were recruited. Sensory processing was assessed using the SPM-P, emotional–behavioral functioning was assessed via the CBCL 1½–5, and cognitive/developmental levels were assessed through standardized instruments. Latent profile analysis (LPA) was conducted to identify sensory subtypes. Group comparisons and multinomial logistic regression were used to examine profile characteristics and predictors of profile membership. Results: Three sensory profiles emerged: (1) Multisystemic Sensory Dysfunction (20.1%), characterized by pervasive sensory and emotional difficulties, primarily observed in ASD; (2) Typical Sensory Processing (44.9%), showing normative sensory and emotional functioning, predominantly LD; and (3) Mixed Subclinical Sensory Processing (35%), with subclinical-range scores across multiple sensory and emotional domains, spanning all diagnoses. Higher cognitive functioning and fewer internalizing symptoms significantly predicted membership in the typical profile. A gradient of symptom severity was observed across profiles, with the Multisystemic group showing the most pronounced emotional–behavioral impairments. Conclusions: Distinct sensory–emotional phenotypes were identified across diagnostic categories, supporting a dimensional model of neurodevelopment. Sensory profiles were strongly associated with emotional functioning, independently of diagnostic status. Early sensory assessment may therefore offer clinically meaningful insights into emotional vulnerability and inform targeted interventions in preschool populations with NDDs. Full article

Background: Histologic chorioamnionitis (HCA) is a placental inflammatory condition characterized by neutrophilic infiltration of the fetal membranes, often occurring without overt clinical signs or symptoms. Risk factors include prolonged labor, premature rupture of membranes (PROM) exceeding 12 h, nulliparity, labor dystocia, and lower socioeconomic status. Although HCA frequently presents as a subclinical condition, its early diagnosis remains challenging. Nevertheless, HCA is associated with an increased risk of maternal and neonatal morbidity, including early-onset neonatal sepsis, cerebral palsy, and long-term neurodevelopmental impairment. We report the case of a 29-year-old primigravida at 40 + 0 weeks of gestation, admitted for decreased fetal movements. Discussion: Cardiotocographic (CTG) monitoring revealed a “zigzag pattern” in the absence of maternal fever, leukocytosis, or tachycardia. Due to the CTG findings suggestive of possible fetal compromise, in addition to reduced fetal movements, an emergency cesarean section was performed. Intraoperative findings included heavily meconium-stained amniotic fluid, then the examination of the placenta confirmed acute HCA with a maternal inflammatory response, without evidence of fetal inflammatory response. Conclusion: This case highlights the crucial role of CTG abnormalities, particularly the “zigzag pattern,” as an early marker of subclinical intrauterine inflammation. Early recognition of such patterns may facilitate timely intervention and improve perinatal outcomes in cases of histologic chorioamnionitis. Full article

Fundus autofluorescence (FAF) is a non-invasive retinal imaging technique that helps visualize naturally occurring fluorophores, such as lipofuscin, and provides valuable insight into retinal diseases—particularly inherited retinal diseases (IRDs). FAF is especially useful in detecting subclinical or early-stage IRDs and in monitoring disease progression over time. In Stargardt disease, areas of decreased autofluorescence correlate with disease progression and have been proposed as a biomarker for future clinical trials. FAF can also help differentiate Stargardt disease from other macular dystrophies. In retinitis pigmentosa, hyperautofluorescent rings are a common feature on FAF and serve as an important marker for disease monitoring, especially as changes align with those seen on other imaging modalities. FAF is valuable in tracking progression of choroideremia and may help identify disease carrier status. FAF has also improved the characterization of mitochondrial retinopathies such as maternally inherited diabetes and deafness. As a rapid and widely accessible imaging modality, FAF plays a critical role in both diagnosis and longitudinal care of patients with IRDs. Full article

Hypocalcemia is common in dairy cows within the first 72 h post-calving, and can be either clinical or subclinical. Early detection is critical, but traditional laboratory tests are time-consuming and cow-side tests remain costly. A classic symptom of hypocalcemia is reduced ear skin temperature, which has been explored as a diagnostic tool in a previous study, but was not recommended at the end. Additionally, ambient temperature was found to strongly influence ear skin temperature, complicating diagnosis. The present study investigates infrared thermography of the ear as a potential non-invasive method for helping in the detection of hypocalcemia in Holstein cows. In order to differ from the previous study, with the goal of improving diagnosis accuracy, this research analyzed the entire ear temperature using infrared imaging software. Ambient temperature was factored in by categorizing samples into two groups based on air temperature: colder (−1.6 to 14.6 °C) and hotter (15.3 to 31.2 °C). Forty-two cows were monitored during the perinatal period, with blood samples and thermographic images taken twice a day until 48 h after calving. This study found that the median surface temperature of the ear correlated strongly with environmental temperature (r = 0.806, p < 0.001) and weakly with blood ionized calcium levels (r = 0.310, p < 0.01). In colder air temperatures, ear surface temperature was significantly different between healthy and hypocalcemic cows (p = 0.014). Logistic regression models were used to assess ionized calcium status based on different combinations of ear surface temperature, its difference from air temperature, and days in milk. In hotter air temperatures, only ear surface temperature, with no other covariates, was able to generate a valid model (p = 0.029). In colder air temperatures, multiple combinations of those variables generated valid models (p < 0.05), with the difference between ear and air temperature, together with days in milk, performing the best. Thus, this study concluded that ear surface temperature obtained through infrared thermography, while not promising for warmer environments, does show application potential for helping in the detection of hypocalcemia in colder environments. Full article

Background: Multidrug-resistant bacteria (MDRB) represent a significant challenge in intensive care units (ICUs), as they limit treatment options, prolong hospital stays, and escalate healthcare costs. Respiratory ICUs are particularly affected due to the high prevalence of chronically ill patients with recurrent infections. Understanding the impact of culture positivity and MDRB on clinical outcomes and readmission rates is essential for enhancing patient care and addressing the growing burden of antimicrobial resistance. Methods: This retrospective study was conducted in a specialized respiratory ICU at a tertiary care hospital between 1 January 2019, and 1 January 2020. A total of 695 ICU admissions were analyzed, with patients grouped based on readmission status and culture results. Demographic, clinical, and laboratory data were reviewed. Statistical analyses were performed using appropriate tests, with p-values ≤ 0.05 considered statistically significant. Results: Among the 519 unique patients, 65 experienced ICU readmissions. Male patients were significantly more likely to be readmitted (p = 0.008). Culture positivity was predominantly observed in respiratory samples, with Klebsiella spp. identified as the most common pathogen. MDRB prevalence exceeded 60% in both groups, significantly prolonging ICU stays (p = 0.013). However, no significant differences in survival rates were observed between MDRB-positive and MDRB-negative groups. Notably, patients with readmissions had lower C-reactive protein (CRP) levels both during admission and at discharge compared to non-readmitted patients (p = 0.004). This paradox may reflect a subclinical inflammatory response associated with bacterial colonization rather than active infection, particularly in patients with chronic respiratory diseases. Conclusions: MDRB infections and culture positivity are key contributors to prolonged ICU stays, resulting in increased healthcare costs. Implementing effective strategies to manage MDRB infections is critical for improving outcomes in respiratory ICUs and reducing associated risks. This study underscores the growing burden of MDRB and highlights the importance of enhanced antimicrobial stewardship in respiratory ICUs. Full article

Background/Objectives: Trace minerals (TMs), both essential and toxic, are integral to human physiology, participating in enzymatic reactions, oxidative balance, immune function, and the modulation of chronic disease risk. Despite their importance, imbalances due to deficiencies or toxic exposures are widespread globally. While low-income countries often face overt deficiencies and environmental contamination, middle- and high-income populations increasingly deal with subclinical deficits and chronic toxic metal exposure. This review aims to explore the relevance of serum as a matrix for evaluating TM status across diverse clinical and epidemiological, geographic, and demographic settings. Methods: A narrative literature review was conducted focusing on the physiological roles, health impacts, and current biomarker approaches for key essential (e.g., zinc, copper, selenium) and toxic (e.g., lead, mercury, cadmium, arsenic) trace elements. Particular emphasis was placed on studies utilizing serum analysis and on recent advances in multi-element detection using inductively coupled plasma mass spectrometry (ICP-MS). Results: Serum was identified as a versatile and informative matrix for TM assessment, offering advantages in terms of clinical accessibility, biomarker reliability, and capacity for the simultaneous quantification of multiple elements. For essential TMs, serum levels reflect nutritional status with reasonable accuracy. For toxic elements, detection depends on instrument sensitivity, but serum can still provide valuable exposure data. The method’s scalability supports applications ranging from public health surveillance to individualized patient care. Conclusions: Serum trace mineral analysis is a practical and scalable approach for nutritional assessment and exposure monitoring. Integrating it into clinical practice and public health strategies can improve the early detection of imbalances, guide interventions such as nutritional supplementation, dietary modifications, and exposure mitigation efforts. This approach also supports advanced personalized nutrition and preventive care. Full article

Previous research has linked both endothelial protein changes and vitamin D with infertility. This study was undertaken to investigate the association of proteins associated with endothelial function and vitamin D status in the luteal phase at day 21 in a group of non-obese women prior to in vitro fertilization (IVF) with either unexplained infertility (UI) or male factor infertility (MFI). Twenty-five non-obese Caucasian women from a UK academic center with MFI (n = 14) and UI (n = 11) were recruited. Blood was withdrawn at day 21 of the menstrual cycle at the time of mock embryo transfer. Vitamin D parameters were measured by tandem mass spectroscopy. Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 20 protein markers of endothelial dysfunction. Baseline demographics did not differ between groups and parameters of response following IVF did not differ. Vitamins D₂ and D₃, and 1,25 Vitamin D₃ did not differ between groups. In UI, markers of endothelial activation/dysfunction were investigated; vascular cell adhesion molecule 1 (VCAM-1) decreased and this is associated with endothelial stress; vascular endothelial growth factor (VEGF) decreased and this may suggest impaired endometrial angiogenesis; while intercellular adhesion molecule 1 (ICAM-3) increased (p < 0.05) and is associated with increased immunological activity. A marker of vascular integrity, angiopoietin-1, increased while soluble angiopoietin-1 receptor (sTie-2) decreased (p < 0.05), suggesting increased vascular development. Endothelial markers of inflammation, coagulation, and endothelial progenitor cells were unchanged. Vitamin D and its metabolites show no relationship to UI, but endothelial activation/dysfunction and vascular integrity changes in VCAM-1, VEGF, sICAM-3, angiopoietin-1, and sTie-2 may contribute to UI, though the mechanisms through which they work require further evaluation; however, these protein changes have been associated with endometriosis, raising the suggestion that subclinical/undiagnosed endometriosis may have contributed to UI in these subjects. Full article

Background: Vitamin D is a steroid hormone, essential for the immune system and bone health. Since the sun is meant to provide at least 80% of daily vitamin D requirements, the COVID-19 pandemic is likely to have induced a considerable influence on calcium metabolism. Methods: We analyzed data from 1138 children, seen in an outpatient pediatric endocrinology clinic from 2022–2023. Vitamin D status was classified as deficiency if 25(OH)D ≤ 20 ng/mL, insufficiency < 30 ng/mL, and sufficiency ≥ 30 ng/mL. Results: Overall, 60.8% of children had vitamin D deficiency or insufficiency worsened with age (p < 0.005), and with adolescent males having higher 25(OH)D concentrations than females (p < 0.05). A negative correlation was found between 25(OH)D and BMI SDS (R² = 0.02, p < 0.001), and 25(OH)D concentrations varied seasonally, decreasing in winter. Subclinical hyperparathyroidism [parathyroid hormone (PTH) > 45 pg/mL) and normal calcium] was found in 21.5% of children, with 73.5% of them being vitamin D deficient or insufficient. A negative correlation between PTH and 25(OH)D was observed, with PTH plateauing at 25(OH)D above 40 ng/mL (p < 0.001). Conclusions: Compared to the pre-pandemic data (2016–2018), with only 5.1% of children having subclinical hyperparathyroidism (p < 0.001), these findings suggest a marked deterioration in vitamin D status and calcium metabolism in children, with possible unforeseen consequences for bone, immune, and general health. Full article

Background/Objectives: Hypothyroidism and thyroid autoimmunity have a negative effect on women’s sexual health, which is only partially reversed by thyroid hormone substitution. Sexual functioning in thyroid disorders after delivery has been poorly researched. The aim of our study was to compare the effect of levothyroxine on sexual response and depressive symptoms in women with postpartum thyroiditis (PPT) and different vitamin D status. Methods: The study population consisted of three matched groups of women with the hypothyroid phase of PPT: two groups with subclinical and one with overt thyroid hypofunction. Each group included similar numbers of women with normal and low vitamin D status. For the following six months, one group of women with subclinical hypothyroidism and all women with overt thyroid hypofunction received levothyroxine. At the beginning and at the end of the study, all participants completed questionnaires evaluating female sexual function (FSFI) and depressive symptoms (BMI-II). The remaining outcomes of interest included thyroid antibody titers, and the serum levels of 25-hydroxyvitamin D, TSH, free thyroid hormones, sex hormones, and prolactin. Results: Before levothyroxine substitution, women with overt and subclinical disease differed in the total FSFI score, all domain scores, and the overall BDI-II score. Within each study group, domain scores for desire were greater in women with vitamin D sufficiency than in those with vitamin D deficiency/insufficiency. Testosterone and estradiol levels were lower in women with overt than in women with subclinical hypothyroidism, while the opposite relationship was found for prolactin. Levothyroxine treatment improved all domains of female sexual function and reduced the total BDI-II score in both patients with overt and subclinical hypothyroidism and normal vitamin D status. In women with vitamin D deficiency/insufficiency, the impact of this agent was limited to arousal, lubrication, and sexual satisfaction. Levothyroxine replacement reduced thyroid antibody titers only in women with normal vitamin D status. The impact on testosterone was limited to women with normal vitamin D status, and was more pronounced in women with overt than subclinical disease. The effect on estradiol and prolactin, observed only in overt disease, was unrelated to vitamin D status. The increase in sexual functioning correlated with the following: 25-hydroxyvitamin D levels (in vitamin D-deficient/insufficient women); the impact on thyroid peroxidase antibodies, free triiodothyronine and testosterone (for desire and arousal); and the changes in the overall BDI-II score. Five years later, the quality of life was better in vitamin D-sufficient women receiving levothyroxine in the postpartum period. Conclusions: Low vitamin D status attenuates the impact of levothyroxine on female sexual function and depressive symptoms in women with the hypothyroid phase of PPT. Full article

Background/Objectives: Metformin inhibits secretory function of overactive thyrotrophs, gonadotrophs, and lactotrophs. The clinical significance of an excess of high-molecular-weight prolactin (macroprolactinemia) remains unclear. The aim of the current study was to investigate for the first time whether macroprolactinemia determines the pituitary effects of this drug. Methods: This single-center prospective case–control study included two groups of postmenopausal women with subclinical hypothyroidism, who were matched for age, insulin sensitivity, and plasma concentrations of gonadotropins and TSH. Group A enrolled women with normal prolactin status, while group B included women with macroprolactinemia. Owing to concomitant type 2 diabetes or prediabetes, all the participants received metformin for six months. The outcomes of interest included glucose homeostasis markers (fasting glucose, glycated hemoglobin, and HOMA-IR), plasma prolactin (total and monomeric), macroprolactin, other pituitary hormones (FSH, LH, TSH, and ACTH), and peripheral hormones (estradiol, free thyroid hormones, and IGF-1). Results: Before metformin treatment, the study groups differed only in concentrations of total prolactin and macroprolactin. Metformin decreased FSH and TSH and tended to decrease LH only in group A, and the strength of this effect showed correlations with the baseline levels of these hormones, the degree of improvement in insulin sensitivity, and the macroprolactin content (only in group B). The decrease in fasting glucose, glycated hemoglobin, and HOMA-IR was more pronounced in group A than group B. There were no differences between the pretreatment and posttreatment values of total prolactin, monomeric prolactin, macroprolactin, ACTH, estradiol, free thyroid hormones, and IGF-1. Conclusions: The obtained results suggest that macroprolactinemia may counteract the pituitary effects of metformin. Full article

Toxic oil syndrome (TOS) is a multisystemic disease that emerged in Spain in 1981 due to the ingestion of aniline-adulterated rapeseed oil fraudulently sold as olive oil. Although neurological sequelae, including cognitive deficits, have been documented in long-term survivors, it remains unclear whether TOS leads to chronic or progressive neurodegeneration. In this case-control study, we measured blood concentrations of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau 217 (pTau217) in 50 individuals with clinically confirmed TOS and 50 matched healthy controls. Biomarkers were quantified using ultrasensitive immunoassay platforms (Quanterix SIMOA SR-X and Fujirebio Lumipulse G600II). Group differences were evaluated using non-parametric tests, and multiple linear regression was applied to assess associations between biomarkers and clinical variables. While NfL levels were slightly higher in TOS patients (p = 0.025), no significant group differences were observed for pTau217 or GFAP. Age was a consistent predictor of biomarker levels, particularly for GFAP and pTau217, and female sex was independently associated with higher GFAP concentrations. Lower educational attainment was linked to increased NfL levels. Clinical status (TOS vs. control) did not significantly predict biomarker concentrations in any model. These findings suggest no evidence of overt or ongoing neurodegeneration in long-term TOS survivors as detected by current blood biomarkers. However, the possibility of subtle, compartmentalized, or slowly evolving neurotoxic processes cannot be excluded. Future longitudinal studies incorporating serial biomarker assessments, advanced neuroimaging, and oxidative stress markers are warranted to clarify the long-term neurological consequences of TOS and to detect subclinical trajectories of delayed neurotoxicity in this population. Full article

Summary-data-based Mendelian randomization (SMR) analysis identified a novel cis-expression quantitative loci (cis-eQTL) associated with the upregulation of the expression of the early growth response factor 4 (EGR4) gene in animals with paratuberculosis (PTB)-associated multifocal lesions, which has been suggested to be modulating the NF-kβ-induced proinflammatory immune response to Mycobacterium avium subsp. paratuberculosis (Map) infection. To confirm these findings and to study the role of EGR4 expression in PTB resilience, the number of EGR4-expressing cells were analysed in paraffin-fixed gut tissues and regional lymph nodes of naturally Map-infected Holstein Friesian cows with focal, multifocal (subclinical and clinical), and diffuse lesions (intermediate and multibacillary), and in controls without lesions by quantitative anti-EGR4 immunohistochemistry. Subclinical animals with multifocal lesions showed a significantly higher number of EGR4-positive cells and were sacrificed at a significantly older average age than the remaining groups (p < 0.001 in all cases). We hypothesize that EGR4 could be mitigating the negative impact of Map infection on host clinical status through its involvement in three molecular mechanisms that promote resilience: (i) limiting NF-kβ-mediated proinflammatory responses, (ii) controlling tissue damage, acting as a brake on T-cell proliferation and cytokine production, and (iii) favouring tissue repair through interaction with epidermal growth factor receptor (EGFR). Full article

Background/Objectives: The gonadotropin-lowering effects of metformin were found to be more pronounced in the case of coexisting hyperthyroidism and absent in patients with hypovitaminosis D. Thus, the aim of the current study was to determine whether vitamin D status determines pituitary effects of metformin in individuals with thyroid hyperfunction and elevated gonadotropin levels. Methods: This prospective cohort study included three matched groups of postmenopausal women with hyperthyroidism and prediabetes: women with 25-hydroxyvitamin D levels between 50 and 75 nmol/L (uncompensated vitamin D insufficiency), women with 25-hydroxyvitamin D levels between 75 and 150 nmol/L receiving exogenous calciferol due to previously diagnosed vitamin D deficiency/insufficiency (compensated vitamin D deficiency/insufficiency), and calciferol-naïve subjects with 25-hydroxyvitamin D levels between 75 and 150 nmol/L (the control group). Over the entire study period (six months), all the women were treated with metformin. At the beginning and at the end of this study, we determined 25-hydroxyvitamin D, glucose homeostasis markers, gonadotropins, estradiol, progesterone, TSH, free thyroid hormones, prolactin, ACTH, and IGF-1. Results: Before metformin treatment, except for the 25-hydroxyvitamin D levels, there were no between-group differences in the investigated markers. In all the study groups, metformin reduced plasma glucose, HOMA1-IR, glycated hemoglobin, and FSH, but these effects were more pronounced in both groups of women with normal vitamin D status than in women with uncompensated vitamin D insufficiency. The decrease in LH concentration was observed only in patients with compensated vitamin D deficiency/insufficiency and in the control group. There were no differences between the baseline and follow-up levels of the remaining hormones. The impact of metformin on gonadotropin concentrations positively correlated with their baseline values, free thyroid hormone levels, 25-hydroxyvitamin D levels, and metformin-induced changes in HOMA1-IR. Conclusions: Our findings suggest that low vitamin D status impairs the gonadotropin-lowering effects of metformin in individuals with hyperthyroidism. Full article