Tag: nevin manimala

J Comput Aided Mol Des. 2023 Jul 27. doi: 10.1007/s10822-023-00518-0. Online ahead of print.

ABSTRACT

When designing peptide ligands based on the structure of a protein receptor, it can be very useful to narrow down the possible binding positions and bound conformations of the ligand without the need to choose its amino acid sequence in advance. Here, we construct and benchmark a tool for this purpose based on a recently reported statistical energy model named SCUBA (Sidechain-Unknown Backbone Arrangement) for designing protein backbones without considering specific amino acid sequences. With this tool, backbone fragments of different local conformation types are generated and optimized with SCUBA-driven stochastic simulations and simulated annealing, and then ranked and clustered to obtain representative backbone fragment poses of strong SCUBA interaction energies with the receptor. We computationally benchmarked the tool on 111 known protein-peptide complex structures. When the bound ligands are in the strand conformation, the method is able to generate backbone fragments of both low SCUBA energies and low root mean square deviations from experimental structures of peptide ligands. When the bound ligands are helices or coils, low-energy backbone fragments with binding poses similar to experimental structures have been generated for approximately 50% of benchmark cases. We have examined a number of predicted ligand-receptor complexes by atomistic molecular dynamics simulations, in which the peptide ligands have been found to stay at the predicted binding sites and to maintain their local conformations. These results suggest that promising backbone structures of peptides bound to protein receptors can be designed by identifying outstanding minima on the SCUBA-modeled backbone energy landscape.

PMID:37498491 | DOI:10.1007/s10822-023-00518-0

Infection. 2023 Jul 27. doi: 10.1007/s15010-023-02078-9. Online ahead of print.

ABSTRACT

PURPOSE: Posaconazole is an antifungal drug currently being used for prophylaxis and treatment of invasive fungal infections such as aspergillosis. To date, therapeutic drug monitoring (TDM) of posaconazole is recommended with the use of oral suspension, but the potential need of TDM with the use of IV formulations is rising. Therefore, we aimed to investigate the pharmacokinetics of IV posaconazole in critically ill patients.

METHODS: In a prospective study, we analysed 168 consecutivelly collected posaconazole levels from 10 critically ill patients drawn during a 7 day curse. Posaconazole concentrations were measured using a chromatographic method. Demographic and laboratory data were collected, and the data was analysed using descriptive statistics.

RESULTS: We included 168 posaconazole levels, resulting in a median trough of 0.62 [0.29-1.05] mg/L with 58% not reaching the suggested target of 0.5 mg/L for fungal prophylaxis. Moreover, 74% of the trough levels were under the target of 1 mg/L which is proposed for the treatment of aspergillosis.

CONCLUSION: Posaconazole exposure is highly variable in critically ill patients resulting in potentially insufficient drug concentrations in many cases. TDM is highly recommended to identify and avoid underexposure.

TRIAL REGISTRATION NUMBER: NCT05275179, March 11, 2022.

PMID:37498488 | DOI:10.1007/s15010-023-02078-9

Updates Surg. 2023 Jul 27. doi: 10.1007/s13304-023-01598-1. Online ahead of print.

ABSTRACT

Liver transplantation (LT) represents the best cure for several acute and chronic liver diseases. Several studies reported excellent mid-term survivals after LT. However, lesser evidence has been reported on very long (10- and 20-year) follow-up results. This study aims to analyze the monocentric LT experience of the Sapienza University of Rome to identify the pre-operatively available parameters limiting a 10-year post-transplant survival. A total of 491 patients transplanted between 1982 and 2012 were enrolled. The cohort was split into two groups, namely the Short Surviving Group (< 10 years; n = 228, 46.4%) and the Long Surviving Group (≥ 10 years; n = 263, 53.6%). Several differences were reported between the two groups regarding initial liver function, surgical techniques adopted, and immunosuppression. Four variables emerged as statistically relevant as independent risk factors for not reaching at least 10 years of follow-up: recipient age (OR = 1.02; P = 0.01), donor age (OR = 1.01; P = 0.03), being transplanted during the eighties (OR = 6.46; P < 0.0001) and nineties (OR = 2.63; P < 0.0001), and the UNOS status 1-2A (OR = 2.62; P < 0.0001). LT confirms to be an extraordinary therapy for several severe liver diseases, consenting to reach in half of the transplanted cases even more than 20 years of follow-up. The initial liver function and the donor and recipient ages are relevant in impacting long-term survival after transplantation. A broad commitment from many professional groups, including surgeons, hepatologists, and anesthesiologists, is necessary. The achievement of excellent results in terms of long-term survival is proof of the effectiveness of this multidisciplinary collaboration.

PMID:37498485 | DOI:10.1007/s13304-023-01598-1

Ir J Med Sci. 2023 Jul 27. doi: 10.1007/s11845-023-03478-4. Online ahead of print.

ABSTRACT

OBJECTIVE: High levels of insulin-like growth factor 1 (IGF-1) in patients with acromegaly cause structural and functional changes specific to the disease. These changes lead to mortality if the disease is not treated. Circadian blood pressure (BP) rhythm as measured by 24-h ambulatory blood pressure monitoring (ABPM) can change with a decrease in BP during sleep and a sudden increase in wakefulness.

AIM: We aim to evaluate the relationship between changes in BP and IGF-1 levels in patients with acromegaly.

METHODS: Patients who were diagnosed with acromegaly and the patient group with hypertension were included. Serum biochemistry parameters, serum IGF-1 level and ABPM follow-ups were compared in these patients.

RESULTS: In our study, 30 patients with acromegaly and 30 patients with hypertension without acromegaly were included. Thirty of the patients were male and 30 were female. There was a statistically significant difference between the groups in terms of IGF-1(p = < 0.001) and GH(p = 0.004). There was no significant difference between patients’ office systolic/diastolic BP measurements, day/night, systolic/diastolic BP measurements and all systolic/diastolic BP measurements in ambulatory blood pressure follow-ups. There was a significant difference in morning blood pressure surge(p = < 0.001). A statistically significant difference was found between the acromegaly patient groups with MBPS below and above 25 mmHg in terms of IGF-1 (p = 0.025) and platelet levels (p = 0.004).

CONCLUSION: As a result, cardiovascular disease risks can be predicted in patients with high serum IGF-1 levels by planning ambulatory blood pressure in the early period.

PMID:37498476 | DOI:10.1007/s11845-023-03478-4

Environ Geochem Health. 2023 Jul 27. doi: 10.1007/s10653-023-01698-2. Online ahead of print.

ABSTRACT

Changes in the concentrations of PM₁₀-bound potentially toxic elements (PTEs) during the COVID-19 lockdown period and after the revocation of restrictions were analyzed using the data received at the Aerosol Complex of Moscow State University in April-July 2020. During the lockdown, the input of biomass combustion products enriched in PTEs from the Moscow region hindered the decrease in pollutant concentrations. After the introduction of the self-isolation regime, lower concentrations of most PTEs occurred due to the decrease in anthropogenic activity and the rainy meteorological conditions. After the revocation of restrictive measures, the PTE concentrations began to increase. Multivariate statistical analysis (APCA-MLR) identified the main sources of atmospheric pollutants as urban dust, non-exhaust traffic emissions, and combustion and exhaust traffic emissions. PM₁₀ particles were significantly enriched with Sb, Cd, Sn, Bi, S, Pb, Cu, Mo, and Zn. The total non-carcinogenic and carcinogenic risks, calculated according to the U.S. EPA model, decreased by 24% and 23% during the lockdown; after the removal of restrictions, they increased by 61% and 72%, respectively. The study provides insight into the PTE concentrations and their main sources at different levels of anthropogenic impact.

PMID:37498434 | DOI:10.1007/s10653-023-01698-2

J Community Genet. 2023 Jul 27. doi: 10.1007/s12687-023-00658-8. Online ahead of print.

ABSTRACT

The decision for genetic testing in children is usually taken by their parents or caregivers, and may be influenced by sociocultural and ethical concerns. This study evaluateds the perspectives of Nigerian parents towards genetic testing of their children with genetic eye diseases parental willingness for genetic testing in their children, and its determinants, in a hospital setting in Nigeria. This cross-sectional, hospital-based study was conducted at the Eye clinic, University College Hospital, Ibadan. The participants were 42 parents of children with genetic eye diseases purposively recruited from April to July 2021. The main variables of interest were overall willingness to test, and willingness to test given ten different scenarios. Summary statistics were performed, and determinants of willingness to test (parental sociodemographic and children’s clinical characteristics) were assessed using Fischer’s exact test. All the participants expressed willingness to test when presented with six of the ten scenarios.However, slightly fewer (83-95%) proportions were willing to test for the other four scenarios (out-of-pocket payment, if test will reveal a systemic association, if test may confirm a diagnosis with no current treatment, and prenatal testing). Willingness to test was not significantly associated with the determinants tested. Thirty-nine (93%) would join a support group, 38 (91%) would inform a family member at risk, and 28 (67%) would be unwilling to have more children if there wais a risk to future offspring. This study demonstrated a high degree of parental willingness for genetic testing of their children. This is important evidence that can guide policy and planning of ophthalmic genetics services.

PMID:37498433 | DOI:10.1007/s12687-023-00658-8

Environ Sci Pollut Res Int. 2023 Jul 27. doi: 10.1007/s11356-023-28902-1. Online ahead of print.

ABSTRACT

Metals exposure has gained increasing attention in the hypertension prevention. However, previous studies have focused on the impacts of single or separated metals on hypertension, and the critical metals contributing to the prevalence of hypertension are still under discussion. We collected data from 5092 participants across three consecutive National Health and Nutrition Examination Survey (NHANES) circles (2011-2016). Weighted logistic regression, weighted quantile sum (WQS) regression, quantile-based g-computation (QGC), and Bayesian kernel machine regression (BKMR) analyses were conducted to evaluate the combined and individual effects of 15 urinary metals, as well as to identify the critical metals on the development of hypertension. In our study, the weighted prevalence of hypertension was 37.9%, and the average age was 47.42 years. Manganese, uranium and tin were found as the independent risk factors for hypertension, while barium, lead, and thallium were found to have protective effects against hypertension. Lead, barium, tungsten, uranium, and tin were determined as critical elements for the prediction of hypertension. No significant interaction relationship was detected between multiple metals. There might be potential positive combined effects of urinary metal mixture on hypertension. Tungsten, uranium, and tin were positively associated with hypertension while lead and barium were negatively associated with hypertension. The underlying mechanisms of urinary metal exposure on the risk of hypertension deserve further investigations.

PMID:37498425 | DOI:10.1007/s11356-023-28902-1

Environ Monit Assess. 2023 Jul 27;195(8):1001. doi: 10.1007/s10661-023-11587-x.

ABSTRACT

Air pollution is the change in air composition that disrupts human health and environmental balance. Although natural and anthropogenic processes include crustal movements, photosynthesis, and plant and animal emissions, other sources of contamination also include industrial operations, transportation activities, household resources, and the chemical and metal industries. Thus, biomonitoring can be employed as a quick, affordable, and efficient method for estimating air pollution. In this study, some inorganic pollutants were detected using olive trees (Olea europaea L.) at eleven different points, depending on the traffic density in Artvin, Turkey. Trace element concentrations (Cr, Ti, Fe, Ni, Co, Cu, Zn, Pb, Al, and Mn) were measured in soil once a year and seasonally in plant samples with ICP-OES. Furthermore, basic component analyses total carbon (TC), total nitrogen (TN), total hydrogen (TH), and total sulfur (TS) were done with an elemental analyzer, total chlorophyll contents with a portable chlorophyll meter, and morphological and particle-based plant analyses with SEM-EDS. The pollution levels of these metals were calculated using the enrichment factor (EF) and geoaccumulation index (I_geo) parameters. Furthermore, the accuracy and validity tests of the analyses for trace metals were tested by applying certified reference materials (CRM) (ERM-CD281) for the plant samples and CRM (LGC-6187) for soil samples. Results indicated that soil trace element pollution distributions were ranked according to the following descending order: Fe (37,873.33 mg/kg) > Al (13,300 mg/kg) > Mn (1101.33 mg/kg) > Ti (353.5 mg/kg) > Zn (252.86 mg/kg) > Cu (87.77 mg/kg) > Cr (30.52 mg/kg) > Pb (19.65 mg/kg) > Ni (17.07 mg/kg) > Co (7.65 mg/kg). Moreover, air pollution from anthropogenic sources substantially increased average trace metal concentrations and sulfur emissions in autumn and winter. The average highest values of Fe (321.08 mg/kg) > Al (304.05 mg/kg) > Mn (32.75 mg/kg) > Zn (31.01 mg/kg) > Cu (17.92 mg/kg) > Ti (11.07 mg/kg) Cr (2.57 mg/kg) > Ni (17.07 mg/kg) were found in leaf samples taken from the roadside in autumn and winter. According to the EF and I_geo values, the main polluting trace elements in the soil were Zn, Cu, and Pb, while in the plant, these were detected as Fe, Al, Ti, Cr, Ni, and Cu. Kruskal-Wallis and correlation analysis statistically supported this relationship among metals. Results show that olive leaves are an effective bioindicator for detecting urban air pollution.

PMID:37498404 | DOI:10.1007/s10661-023-11587-x

Neurol Sci. 2023 Jul 27. doi: 10.1007/s10072-023-06975-7. Online ahead of print.

ABSTRACT

BACKGROUND: Evusheld (EVS) was authorized by FDA and EMA as pre-exposure prophylaxis (PrEP) in people at high risk of severe Covid-19 outcomes, including people with Multiple Sclerosis (pwMS) on B-cell depleting (BCD) therapies-such as Ocrelizumab (OCR). In this population, no data on possible adverse drug reactions (ADRs) to EVS, B-lymphocytes (CD20 +) counts pre- and post-EVS injection, and comparison of percentage increase of IgG antibodies directed against SARS-CoV-2 trimeric spike protein (anti-TSP IgG) post-EVS and Covid-19 vaccine was available. The aim of this study was to better characterize the efficacy and safety profile of EVS in pwMS on BCD agents.

METHODS: 17 pwMS on OCR agreed to receive EVS as PrEP for Covid-19. Sera samples were collected before the first dose of Covid-19 vaccine (T0), 4 weeks after the second dose (T1), 4 weeks after third dose (T2), immediately before (T3) and 4 weeks after (T4) EVS.

RESULTS: Covid-19 vaccine ADRs were mild-to-moderate, whereas no ADRs were reported after EVS injection. A significant increase of anti-TSP IgG was found only at T0-T1 (Z = -3.059, p = .002) and T3-T4 (Z = -3.621, p < .001) time-points. The median percentage increase between T3-T4 was significantly higher with respect to the T0-T1(Z = -3.296, p = .001) and T1-T2 (Z = -3.059, p = .002) time-points.

CONCLUSIONS: These results further support EVS safety and efficacy in boosting anti-TSP IgG titers in pwMS on OCR, with a statistically greater increase than that observed after completion of a full Covid-19 vaccine cycle, plus a booster dose.

PMID:37498399 | DOI:10.1007/s10072-023-06975-7

Clin Exp Rheumatol. 2023 Jul 24. doi: 10.55563/clinexprheumatol/srma43. Online ahead of print.

ABSTRACT

OBJECTIVES: The prevalence and outcome of mixed connective tissue disease-associated pulmonary arterial hypertension (MCTD-PAH) has not been well understood. Our aim was to review the current knowledge on the prevalence, severity, and mortality of MCTD-PAH. We also aimed to examine the prevalence trend of MCTD-PAH over the years.

METHODS: PubMed/Medline, Embase, Scopus and Web of Science electronic databases were searched for the published randomised controlled clinical trials (RCTs) and observational/original studies on PAH in patients with MCTD from January 1972 to December 2020.

RESULTS: The results were pooled using random-effects meta-analysis based on DerSimonian and Laird method. A total of 983 patients from eight studies were included in the meta-analysis (K=8, n=983). Pooled prevalence of PAH in MCTD patients was 12.53% [95% CI 8.30-18.48%] with significant level statistical heterogeneity (tau2=0.30, tau=0.55, i2 83.3%, H=2.13 Q(df,7)=31.90, p=0.001). There was no association between PAH and female gender or age. The percentage of deaths in MCTD patients due to PAH varied and reached up to 81.8%.

CONCLUSIONS: This is the first systematic review and meta-analysis investigating the prevalence of PAH in patients with MCTD and it revealed an overall prevalence of PAH in patients with MCTD of 12.53%. Our results showed trends of reduced prevalence of MCTD-PAH over last four decade, reconfirmed the lower prevalence rate in recent studies, but revealed an increased mortality rate. We also determined the low impact of the age, gender, and interstitial lung disease on MCTD-PAH.

PMID:37497727 | DOI:10.55563/clinexprheumatol/srma43