Nevin Manimala

Probl Endokrinol (Mosk). 2022 Nov 3;68(6):110-120. doi: 10.14341/probl13166.

ABSTRACT

BACKGROUND: Adrenocortical adenomas are often followed with steroid hormones hyperproduction, and therefore determination of their concentration plays an important role in the differential diagnosis of adrenal diseases. Steroid profiling by tandem mass spectrometry is one of the main diagnostic methods in steroidogenesis characterization. Currently plasma and urinary steroid profiling is of particular interest in differential diagnosis and subtyping patients with adrenocortical adenomas.

AIM: Steroid profiling of pediatric patients with adrenal diseases (incidentalomas, ACTH-secreting pituitary adenoma, ACTH-independent Cushing syndrome, premature adrenarche).

MATERIALS AND METHODS: We conducted a retrospective analysis of steroid profile of 41 pediatric patients with adrenal diseases who were observed between 2005 and 2020 at the Endocrinology Research Centre.

RESULTS: All patients were divided into groups due to diagnosis: with ACTH-secreting pituitary adenoma [n=7], ACTH-independent Cushing syndrome (autonomous cortisol secretion by an adrenal adenoma) [n=4], with incidentaloma [n=7] and premature adrenarche [n=23]. In group of patients with ACTH-independent Cushing syndrome identified statistically significant higher levels of 11-deoxycortisol (р=0, 0035) and significant lower levels of 17-hydroxypregnenolone (р=0, 0026) and DHEA (р=0, 0047) compared to other groups. Statistically significant differences in steroid profiles between other groups were not identified.

CONCLUSION: Results of our study steroid profiling can be used as additional differential diagnosis method in patients with adrenocortical adenomas with or without hormonal hyperproduction (ACTH-independent Cushing syndrome and incidentaloma). Further studies are needed to identify steroid markers for subtyping pediatric adrenal diseases.

PMID:36689716 | DOI:10.14341/probl13166

Probl Endokrinol (Mosk). 2023 Jan 24;68(6):89-109. doi: 10.14341/probl13165.

ABSTRACT

BACKGROUND: There is enough evidence of the negative impact of excess weight on the formation and progression of res piratory pathology. Given the continuing SARS-CoV-2 pandemic, it is relevant to determine the relationship between body mass index (BMI) and the clinical features of the novel coronavirus infection (NCI).

AIM: To study the effect of BMI on the course of the acute SARS-COV-2 infection and the post-covid period.

MATERIALS AND METHODS: AKTIV and AKTIV 2 are multicenter non-interventional real-world registers. The АКТИВ registry (n=6396) includes non-overlapping outpatient and inpatient arms with 6 visits in each. The АКТИВ 2 registry (n=2968) collected the data of hospitalized patients and included 3 visits. All subjects were divided into 3 groups: not overweight (n=2139), overweight (n=2931) and obese (n=2666).

RESULTS: A higher BMI was significantly associated with a more severe course of the infection in the form of acute kidney injury (p=0.018), cytokine storm (p<0.001), serum C-reactive protein over 100 mg/l (p<0.001), and the need for targeted therapy (p<0.001) in the hospitalized patients. Obesity increased the odds of myocarditis by 1,84 times (95% confidence interval [CI]: 1,13-3,00) and the need for anticytokine therapy by 1,7 times (95% CI: 1,30-2,30).The patients with the 1st and 2nd degree obesity, undergoing the inpatient treatment, tended to have a higher probability of a mortality rate. While in case of morbid obesity patients this tendency is the most significant (odds ratio – 1,78; 95% CI: 1,13-2,70). At the same time, the patients whose chronical diseases first appeared after the convalescence period, and those who had certain complaints missing before SARS-CoV-2 infection, more often had BMI of more than 30 kg/m2 (p<0,001).Additionally, the odds of death increased by 2,23 times (95% CI: 1,05-4,72) within 3 months after recovery in obese people over the age of 60 yearsCONCLUSION. Overweight and/or obesity is a significant risk factor for severe course of the new coronavirus infection and the associated cardiovascular and kidney damage Overweight people and patients with the 1st and 2nd degree obesity tend to have a high risk of death of SARS-CoV-2 infection in both acute and post-covid periods. On top of that, in case of morbid obesity patients this tendency is statistically significant. Normalization of body weight is a strategic objective of modern medicine and can contribute to prevention of respiratory conditions, severe course and complications of the new coronavirus infection.

PMID:36689715 | DOI:10.14341/probl13165

Probl Endokrinol (Mosk). 2023 Jan 8;68(6):76-88. doi: 10.14341/probl13172.

ABSTRACT

BACKGROUND: Adrenocortical cancer (ACC) is an orphan malignant tumor of the adrenal cortex with a predominantly poor prognosis and an aggressive clinical course. Nowadays, mitotane is a non-alternative drug in the treatment of ACC. The search for prognostic parameters that determine the sensitivity of ACC to ongoing treatment is currently an urgent task. Expression levels of the large subunit of ribonucleotide reductase M1 (RRM1), cytochrome P450 2W1 (CYP2W1), and sterol- O-acyltransferase-1 (SOAT1) are considered as potential predictors of response to mitotane therapy.

AIM: To assess the immunohistochemical expression of RRM1, CYP2W1 and SOAT1 in ACC as markers of clinical outcomes and response to the therapy with mitotane.

MATERIALS AND METHODS: The study included 62 patients older than 17 years of age with a diagnosis of ACC confirmed histologically and immunohistochemically. Mitotane therapy was initiated in 29 patients in the postoperative period, 33 patients were under dynamic observation without concomitant drug treatment. Antibodies to RRM1, CYP2W1, SOAT1 were used diluted in accordance with recommendations of firms-manufacturers for immunohistochemical detection.

RESULTS: In the group of patients with low and moderate RRM1, CYP2W1 and SOAT1 immunoreactivity in the tumor and no antitumor therapy, a better DFS was noted (p=0.037, p=0.020 and p=0.001, respectively) compared to the group of patients receiving mitotane therapy at this level of marker expression. With high immunoreactivity of the markers, no statistically significant differences in DFS were found.

CONCLUSION: Consistent with the findings in our study, low expression of RRM1, CYP2W1 and SOAT1 was associated with worse DFS with antitumor therapy. The results of the work indicate the need to assess the levels of immunoreactivity of these markers in patients with ACC before starting treatment with mitotane in order to predict the efficiency of therapy.

PMID:36689714 | DOI:10.14341/probl13172

Probl Endokrinol (Mosk). 2022 Oct 12;68(6):43-48. doi: 10.14341/probl13151.

ABSTRACT

BACKGROUND: Pregnancy is a condition with important structural and physiological changes in the thyroid gland. In this regard, experts of thyroid associations have recommended developing specific reference intervals taking into account the natural and socio-geographical characteristics of the region under study.

AIM: To conduct an epidemiological analysis and evaluate TSH reference intervals in pregnant women living in the central regions of the Russian Federation with mild iodine deficiency.

MATERIALS AND METHODS: We have conducted the observational multicenter cross-sectional study included 2008 healthy pregnant women at different trimesters of pregnancy, from three regions of the Russian Federation (Moscow, Ivanovo and Smolensk). We assessed the level of thyroid-stimulating hormone, antibodies to thyroid peroxidase, antibodies to serum thyroglobulin, the level of iodine concentration in the morning portion of urine (cerium arsenic method) and we have conducted a questionnaire (date birth and gestational age). Women with elevated titers of anti-TPO and/or anti-TG antibodies were excluded from the study (245 women). As a result, we assessed high and medium levels of TSH and its overestimation with iodine sufficiency in pregnant women. The results are presented using the calculation of 2.5 and 97.5 percentiles.

RESULTS: We confirmed the presence of iodine deficiency in the study areas. The median concentration of iodine in the urine was: in Moscow 106 μg/l, in Ivanovo 119 μg/l, in Smolensk 134 μg/l. Pregnant women were divided into 2 groups according to iodine adequacy. In the group with optimal iodine supply, the level of TSH was 0,006-3,36 in the 1st trimester, 0,20-3,74 in the 2nd trimester, and 0,33-3,68 mIU/L in the 3rd trimester. In the group with mild iodine deficiency – in the 1st trimester it was 0,11-3,00, in the 2nd trimester 0,22-3,78, in the 3rd trimester 0,07-3,04 mIU/l. Statistical analysis of the data revealed that when comparing the level of TSH by trimester, depending on the place of residence, no statistical difference was found (p = 0,239).

CONCLUSION: We obtained that the level of TSH in healthy pregnant women living in the central regions of the Russian Federation does not exceed 3.8 mIU/l in all trimesters.

PMID:36689710 | DOI:10.14341/probl13151

Probl Endokrinol (Mosk). 2022 Aug 15;68(6):30-42. doi: 10.14341/probl13144.

ABSTRACT

AIM: To determine significant factors affecting the survival of patients with ectopic ACTH syndrome (EAS).

MATERIALS AND METHODS: A multi-center, observational study with a retrospective analysis of patients with EAS. The end point of the study was the fatal outcome of patients from various causes. In order to identify predictors of survival or mortality, univariate and multifactorial Cox regression analyses were carried out. ROC-analysis was used to determine the prognostic threshold values of individual predictors. The survival analysis was carried out using the Kaplan-Mayer method. Statistical data processing was carried out by using IBM SPSS Statistics 23.

RESULTS: The age of patients at the time of diagnosis ranged from 12 to 76 years (Me 40 years [28;54]). The age of the studied population was 55 years [38; 64] for women and 42 years [32; 54] for men. The median period of observation was 50 months [13;91], with a maximum follow-up of 382 months. 92 patients (60,9%) had bronchopulmonary NET, 17 (11,3%) – thymic carcinoid, 8 – pancreatic NET, 5 -pheochromocytoma, 1- cecum NET, 1- appendix carcinoid tumor, 1 – medullary thyroid cancer and 26 (17,2%) patients had an occult NET. The primary tumor was removed in 101 patients (66,9%). Bilateral adrenalectomy was performed in 42 (27,8%) cases. Metastases were revealed in 23,2% (n=35) of patients. Relapse of the disease was observed in 24,4%, long-term remission was preserved in 64 patients (74,4%). Death occurred in 42 patients (28%). The average age of survivors was 47,0±15,2 versus 53,5±15,6 years for the deceased (p=0,022). The average survival time from diagnosis for the deceased was 32 months, Me 16,5 months [7;54]. Multivariate analysis revealed that the following factors have a direct impact on survival: age of diagnosis ≥51 years (OR 4,493; 95% CI 2,056-9,818, p<0,001), bronchopulmonary neuroendocrine tumor (NET) (OR 0,281; 95% CI 0,119-0,665, p=0,004), the presence of distant metastases (OR 2,489; 95% CI 1,141-5,427, p=0,022), late-night salivary cortisol (LNSC) ≥122,2 nmol/L (OR 2,493; 95% CI 1,014-6,128, p=0,047).

CONCLUSION: The prognosis of patients with EAS is influenced by the age of diagnosis, NET localization, distant metastases and level of LNSC. The most common cause of ectopic ACTH syndrome was bronchopulmonary NET which was associated with the best survival rate.

PMID:36689709 | DOI:10.14341/probl13144

Probl Endokrinol (Mosk). 2022 Jul 31;68(6):12-21. doi: 10.14341/probl12892.

ABSTRACT

BACKGROUND: The issues of monitoring the effectiveness of iodine deficiency prevention programs are an important component in the process of iodine elimination. Neonatal thyrotropin (TSH) has been used as a criterion for the severity of iodine deficiency since 1994, however, the question of the “cut-off point” of the neonatal TSH level has been widely discussed in the recent literature.

AIM: Evaluate the criterion for neonatal hyperthyroidism above 5 mIU/l from the perspective of monitoring iodine deficiency and establish a «cut-off point» on the model of healthy pregnant women with adequate iodine status.

MATERIALS AND METHODS: A prospective study was conducted in a population of pregnant women in the city of Tyumen, with the formation of observation groups according to the level of iodine excretion in the urine – the main group (with adequate iodine status throughout the entire gestation period) and the comparison group (women with iodine levels less than 150 μg/l). The results of neonatal screening for congenital hypothyroidism in children of women participating in the study were evaluated. The frequency of neonatal TSH above 5mIU/l was assessed in the observation groups. ROC-analysis was performed and a «cut-off point» of the level of neonatal TSH was established as an indicator of iodine deficiency.

RESULTS: The median urinary iodine concentration in the population of pregnant women in Tyumen was 159.05 μg/l, the incidence of goiter was 0.38%, the incidence of neonatal hyperthyroidism above 5 mIU/l was 2.88%, which characterizes adequate iodine intake in the pregnant population women. The frequency of neonatal TSH above 5 mIU/l in newborns from women from the main group was 1.47%, and in the comparison group – 9.3% (p = 0.076). ROC analysis revealed a threshold value of neonatal TSH of 2.77 mIU/l at the cut-off point, which corresponded to the highest value of the Youden index. Urinary iodine concentrations greater than 150 μg/l were predicted for nTSH values below this value.

CONCLUSION: Analysis of databases of neonatal screening for congenital hypothyroidism makes it possible to effectively, quickly and at minimal cost annually assess the iodine status in the population. The established «cut-off point» of neonatal TSH in the model of healthy pregnant women with adequate iodine intake in our work is 2.77 mIU/l, the absence of statistically significant differences in the incidence of neonatal hyperthyroidism above 5 mIU/l from women with different iodine status during pregnancy indicate the need to revise the existing threshold of 5 mIU/l and may be an incentive to conduct large-scale studies in regions with different iodine supply.

PMID:36689707 | DOI:10.14341/probl12892

Prosthet Orthot Int. 2022 Dec 28. doi: 10.1097/PXR.0000000000000201. Online ahead of print.

ABSTRACT

BACKGROUND: Prostheses are a primary rehabilitative intervention for people after lower limb amputation. To appropriately measure the effectiveness of prosthetic interventions, valid and reliable measures of prosthetic mobility are required. The Prosthetic Limb Users Survey of Mobility (PLUS-M) is a promising instrument for measuring prosthesis users’ mobility. However, German translations of the PLUS-M short forms have not yet been validated.

OBJECTIVES: Rasch validation of the German translation of the PLUS-M short forms in people with lower limb amputation.

STUDY DESIGN: This study is based on a cross-sectional survey of prosthesis-using lower limb amputees from a nation-wide cohort.

METHODS: PLUS-M data (the 7-item and the 12-item shortforms; PLUS-M-7 and PLUS-M-12, respectively) from 194 lower limb prosthesis users were subjected to Rasch analysis, an advanced statistical method for assessing if the measurement properties of a questionnaire comply with a wide spectrum of psychometric requirements.

RESULTS: Analysis showed appropriate rating scale functioning, good internal construct validity (item fit), unidimensionality, and good targeting of the PLUS-M-7 and PLUS-M-12 short forms. Moreover, the greater conditional measurement precision of PLUS-M-12 (regarding higher test information and lower standard error of mobility estimates) was quantified.

CONCLUSIONS: Rasch analysis of the German translation of both PLUS-M short forms showed good psychometric qualities. In addition, our study showed that test scores from the PLUS-M-12 are more accurate. Therefore, the PLUS-M-12 is recommended for individual-level clinical applications (e.g., classification or change assessment).

PMID:36689667 | DOI:10.1097/PXR.0000000000000201

Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2218663120. doi: 10.1073/pnas.2218663120. Epub 2023 Jan 23.

ABSTRACT

Complex systems can exhibit sudden transitions or regime shifts from one stable state to another, typically referred to as critical transitions. It becomes a great challenge to identify a robust warning sufficiently early that action can be taken to avert a regime shift. We employ landscape-flux theory from nonequilibrium statistical mechanics as a general framework to quantify the global stability of ecological systems and provide warning signals for critical transitions. We quantify the average flux as the nonequilibrium driving force and the dynamical origin of the nonequilibrium transition while the entropy production rate as the nonequilibrium thermodynamic cost and thermodynamic origin of the nonequilibrium transition. Average flux, entropy production, nonequilibrium free energy, and time irreversibility quantified by the difference in cross-correlation functions forward and backward in time can serve as early warning signals for critical transitions much earlier than other conventional predictors. We utilize a classical shallow lake model as an exemplar for our early warning prediction. Our proposed method is general and can be readily applied to assess the resilience of many other ecological systems. The early warning signals proposed here can potentially predict critical transitions earlier than established methods and perhaps even sufficiently early to avert catastrophic shifts.

PMID:36689655 | DOI:10.1073/pnas.2218663120

J Chem Theory Comput. 2023 Jan 23. doi: 10.1021/acs.jctc.2c00976. Online ahead of print.

ABSTRACT

The dynamics of molecules are governed by rare event transitions between long-lived (metastable) states. To explore these transitions efficiently, many enhanced sampling protocols have been introduced that involve using simulations with biases or changed temperatures. Two established statistically optimal estimators for obtaining unbiased equilibrium properties from such simulations are the multistate Bennett acceptance ratio (MBAR) and the transition-based reweighting analysis method (TRAM). Both MBAR and TRAM are solved iteratively and can suffer from long convergence times. Here, we introduce stochastic approximators (SA) for both estimators, resulting in SAMBAR and SATRAM, which are shown to converge faster than their deterministic counterparts, without significant accuracy loss. Both methods are demonstrated on different molecular systems.

PMID:36689637 | DOI:10.1021/acs.jctc.2c00976

Medwave. 2023 Jan 23;23(1):e2592. doi: 10.5867/medwave.2023.01.2592.

ABSTRACT

Introduction: The SARS-CoV-2 pandemic has affected the entire population, especially vulnerable people with risk factors, such as people over 65 years. Globally and nationally, health protection measures were established to reduce transmission and the impact of the disease on the healthcare system, such as using face masks, hand washing, and social distancing, among others. This led to restrictions on activities outside the home, which affected the cognitive sphere of the population, especially people over 65 years of age. Objective: To demonstrate that social isolation causes changes in the cognitive status of people over 65 years of age. Methods: A longitudinal study was conducted from 2019 to 2020, with the participation of 37 older adults in a parish club of support activities who voluntarily agreed to participate by signing the informed consent form. The Folstein Mini-Mental State Examination was administered to all of them at two points in the study: before the pandemic and after six months of strict social isolation established as a control measure for the SARS-CoV-2 pandemic. We looked for cognitive status differences during this period and studied qualitative-quantitative sociodemographic variables. Results: The club members were older people, predominantly women. Mean age of the participants was 75.4 years; 89.2% had little schooling (less than ten years of formal education). Identified prevalent diseases were arterial hypertension and type-2 diabetes mellitus. In the first evaluation, six out of thirty-seven participants had slight cognitive deficits (16.2%), all females; there were no cases of cognitive impairment; the rest had normal cognitive status (31 out of 37, or 83.8%). After the second evaluation (at the end of strict isolation due to the pandemic), we observed that 11 (29.7%) participants had slight cognitive deficits (ten female and one male), which represents an increase of 13.5%. In addition, four participants (10.8%) showed mild cognitive impairment, all females. Such changes were statistically significant (p-value < 0.05). We conclude that social isolation due to the SARS-CoV-2 pandemic was related to changes in the cognitive status of the elderly.

PMID:36689629 | DOI:10.5867/medwave.2023.01.2592