Category: Nevin Manimala

Adv Ther. 2024 Feb 16. doi: 10.1007/s12325-023-02728-2. Online ahead of print.

ABSTRACT

INTRODUCTION: Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population.

METHODS: Thromboembolic events with onset before and after week 12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase 3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset.

RESULTS: Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5 g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98-4.46) showed a trend towards increased risk of thromboembolic events before week 12, and high rate of hemoglobin decline was associated with events after week 12 (< – 0.5 g/dL/week; OR 3.73; 95% CI 1.68-8.27) as compared to stable hemoglobin levels (≥ – 0.1 to < 0.1 g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10 g/dL: adjusted OR 1.91; 95% CI 1.04-3.50; vs ≥ 12 g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95% CI 1.71-8.39; vs ≥ 30%) before event onset were associated with events after week 12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%.

CONCLUSIONS: Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article.

TRIAL REGISTRATION: NCT02278341, NCT02273726, NCT02052310, NCT02174731.

PMID:38363466 | DOI:10.1007/s12325-023-02728-2

Hum Nat. 2024 Feb 16. doi: 10.1007/s12110-024-09467-5. Online ahead of print.

ABSTRACT

Many studies in Western societies show a pattern of discriminative grandparental investment as follows: maternal grandmothers (MGMs) > maternal grandfathers (MGFs) > paternal grandmothers (PGMs) > paternal grandfathers (PGFs). This pattern is in line with the expectation from evolutionary reasoning. Yet whether or not this pattern applies in China is in question. The present study was based on a questionnaire survey at a university in Central China (N = 1,195). Results show that (1) when grandparent-grandchild residential distance during grandchildren’s childhood is controlled, in the case of grandsons and granddaughters as a whole and granddaughters only, both grandparental caregiving and grandchildren’s emotional closeness to grandparents display a rank order of MGM > MGF > PGM > PGF, but in the case of grandsons only, this order is not statistically significant. (2) There are stable relationships between grandparental caregiving/grandchildren’s emotional closeness and residential distance/similarity in appearance. (3) The effects of residential distance on either PGFs’ or PGMs’ caregiving exceed those on either MGFs’ or MGMs’. (4) The PGF and PGM prefer grandsons to granddaughters in their caregiving, whereas the MGF and MGM do not have a sex preference, and (5) the fact that the PGF and PGM invest more in grandsons than in granddaughters does not depend on grandsons’ duration of living in a rural area. Our results suggest that (1) in general, the Chinese display a pattern of differential grandparental investment predicted by an evolutionary perspective, (2) the evolutionary perspective that combines the two factors of paternal uncertainty and sex-specific reproductive strategies is applicable to grandparental investment in China, and (3) the traditional son-preference culture also plays some role in affecting grandparental investment in China, though the roles of culture and urban-rural cultural difference should not be exaggerated.

PMID:38363458 | DOI:10.1007/s12110-024-09467-5

Int Ophthalmol. 2024 Feb 16;44(1):88. doi: 10.1007/s10792-024-02932-1.

ABSTRACT

PROPOSE: This study aimed to compare the diagnostic accuracy of MR dacryocystography (MRD) and dacryoscintigraphy (DSG) in the diagnosis of acquired epiphora related to NLDO. A total of 15 patients with acquired epiphora and suspected NLDO were included in this study.

METHODS: All patients underwent MRD and DSG examinations. MRD was performed using a 3-Tesla magnetic resonance imaging (MRI) scanner, while DSG involved injection of a radiotracer into the lacrimal drainage system followed by DSG. The results of both imaging methods were compared with the reference standard that was a combination of clinical examination findings and surgical exploration.

RESULTS: The results of this study showed that no abnormal findings were observed in MR-DCG in patients before the Valsalva maneuver. However, after the Valsalva maneuver, stenosis/obstruction at the canal surface was observed in all 15 patients diagnosed by DSG, giving a sensitivity of 100% for canal stenosis. Moreover, the results revealed that among these 15 patients, 9 showed stenosis or simultaneous obstruction at the level of the canal and lacrimal sac, but MR-DCG showed these lesions in only 9 patients, giving a sensitivity of 60%. The specificity of MRD and DSG were 85% and 76.7%, respectively. There was a statistically significant difference in the sensitivity of MRD and DSG (p < 0.05).

CONCLUSION: This study demonstrated that MRD has a higher diagnostic accuracy in the diagnosis of acquired epiphora associated with NLDO compared to DSG. MRD showed significantly higher sensitivity and specificity than DSG. Therefore, MRD can be considered as the preferred imaging modality in the diagnosis of acquired epiphora due to NLDO. By accurately identifying the underlying cause of NLDO, MRD can help determine the most appropriate treatment approach for patients and lead to better outcomes.

PMID:38363448 | DOI:10.1007/s10792-024-02932-1

Cell Mol Neurobiol. 2024 Feb 16;44(1):22. doi: 10.1007/s10571-024-01456-7.

ABSTRACT

Calcitonin gene-related peptide (CGRP) is synthesized and secreted by trigeminal ganglion neurons, and is a key neuropeptide involved in pain and immune regulation. This study investigates the expression of CGRP in the trigeminal ganglion (TG) and its regulatory role in the polarization of macrophages in rats with temporomandibular arthritis. A rat model of temporomandibular arthritis was established using CFA. Pain behavior was then observed. Temporomandibular joint (TMJ) and the TG were collected, and immunohistochemistry, immunofluorescence (IF) staining, and RT-qPCR were used to examine the expression of CGRP and macrophage-related factors. To investigate the impact of CGRP on macrophage polarization, both CGRP and its antagonist, CGRP 8-37, were separately administered directly within the TG. Statistical analysis revealed that within 24 h of inducing temporomandibular arthritis using CFA, there was a significant surge in CD86 positive macrophages within the ganglion. These macrophages peaked on the 7th day before beginning their decline. In this context, it’s noteworthy that administering CGRP to the trigeminal ganglion can prompt these macrophages to adopt the M2 phenotype. Intriguingly, this study demonstrates that injecting the CGRP receptor antagonist (CGRP 8-37) to the ganglion counteracts this shift towards the M2 phenotype. Supporting these in vivo observations, we found that in vitro, CGRP indeed fosters the M2-type polarization of macrophages. CGRP can facilitate the conversion of macrophages into the M2 phenotype. The phenotypic alterations of macrophages within the TG could be instrumental in initiating and further driving the progression of TMJ disorders.

PMID:38363424 | DOI:10.1007/s10571-024-01456-7

Environ Monit Assess. 2024 Feb 16;196(3):272. doi: 10.1007/s10661-024-12408-5.

ABSTRACT

Magnetic proxy approaches proved to be efficient for potentially toxic elements (PTEs) pollution assessment when targeting forests or areas with a homogenous background where anthropogenic magnetic signals could be easily distinguished. Here, we present a multidisciplinary approach for magnetic susceptibility ([Formula: see text]) and HM assessment in a complex area in the Nile Delta, where geogenic input, land use, and various industries with different fly ash and surface water emissions interfere. Statistical analysis discriminates between the effects of lithologic elements and the concentrations of toxic anthropogenic elements. The studied elements are classified into lithogenic and anthropogenic-related (HMs, Au industry, and fertilizers industry) groups with maximum contamination levels of eight anthropogenic-related and highly toxic PTEs (Cu, Zn, Mo, Cd, Sb, Pb, Hg, and As) in the Akrasha industrial area (pollution load index = 15.84). Considering the whole data set, the numerical correlation of [Formula: see text] with most PTE concentrations and the pollution load index (PLI) is weak, while it is moderate to strong with lithogenic elements. However, a comparison of lithogenic elements and PTE concentrations along with x-values in two separate clusters supports the correspondence of lithology with elevated x-values in silt and clay-rich soil samples as well as HM concentration in industrial sandy soils. Correspondence between magnetic maps and chemistry data with land use reflects the potential of magnetic proxy methods for qualitative PTE pollution pre-delineation of the polluted spots, provided that lithological conditions are carefully considered.

PMID:38363423 | DOI:10.1007/s10661-024-12408-5

EJNMMI Res. 2024 Feb 16;14(1):19. doi: 10.1186/s13550-024-01078-6.

ABSTRACT

BACKGROUND: Mutations in the epidermal growth factor receptor (EGFR) kinase domain are common in non-small cell lung cancer. Conventional tyrosine kinase inhibitors target the mutation site in the ATP binding pocket, thereby inhibiting the receptor’s function. However, subsequent treatment resistance mutations in the ATP binding site are common. The EGFR allosteric inhibitor, EAI045, is proposed to have an alternative mechanism of action, disrupting receptor signaling independent of the ATP-binding site. The antibody cetuximab is hypothesized to increase the number of accessible allosteric pockets for EAI045, thus increasing the potency of the inhibitor. This work aimed to gain further knowledge on pharmacokinetics, the EGFR mutation-targeting potential, and the influence of cetuximab on the uptake by radiolabeling EAI045 with carbon-11 and tritium.

RESULTS: 2-(5-fluoro-2-hydroxyphenyl)-2-((2-iodobenzyl)amino)-N-(thiazol-2-yl)acetamide and 2-(5-fluoro-2-hydroxyphenyl)-N-(5-iodothiazol-2-yl)-2-(1-oxoisoindolin-2-yl)acetamide were synthesized as precursors for the carbon-11 and tritium labeling of EAI045, respectively. [¹¹C]EAI045 was synthesized using [¹¹C]CO in a palladium-catalyzed ring closure in a 10 ± 1% radiochemical yield (decay corrected to end of [¹¹C]CO₂ production), > 97% radiochemical purity and 26 ± 1 GBq/µmol molar activity (determined at end of synthesis) in 51 min. [³H]EAI045 was synthesized by a tritium-halogen exchange in a 0.2% radiochemical yield, 98% radiochemical purity, and 763 kBq/nmol molar activity. The ability of [¹¹C]EAI045 to differentiate between L858R/T790M mutated EGFR expressing H1975 xenografts and wild-type EGFR expressing A549 xenografts was evaluated in female nu/nu mice. The uptake was statistically significantly higher in H1975 xenografts compared to A549 xenografts (0.45 ± 0.07%ID/g vs. 0.31 ± 0.10%ID/g, P = 0.0166). The synergy in inhibition between EAI045 and cetuximab was evaluated in vivo and in vitro. While there was some indication that cetuximab influenced the uptake of [³H]EAI045 in vitro, this could not be confirmed in vivo when tumor-bearing mice were administered cetuximab (0.5 mg), 24 h prior to injection of [¹¹C]EAI045.

CONCLUSIONS: EAI045 was successfully labeled with tritium and carbon-11, and the in vivo results indicated [¹¹C]EAI045 may be able to distinguish between mutated and non-mutated EGFR in non-small cell lung cancer mouse models. Cetuximab was hypothesized to increase EAI045 uptake; however, no significant effect was observed on the uptake of [¹¹C]EAI045 in vivo or [³H]EAI045 in vitro in H1975 xenografts and cells.

PMID:38363422 | DOI:10.1186/s13550-024-01078-6

Skeletal Radiol. 2024 Feb 16. doi: 10.1007/s00256-024-04609-3. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the CT features of incidental rib enhancement (RE) and to summarize the CT characteristics for distinguishing the RE from sclerotic metastasis (SM) in patients with malignancies.

MATERIAL AND METHODS: This retrospective observational study enrolled 79 patients with RE (involved 133 ribs) during October 2014 and December 2021. Another 53 patients with SM (160 SM) in the same period were selected randomly for comparison. The location, enhancement patterns of RE were reviewed. The CT values of RE regions and SM were measured and statistically analyzed.

RESULTS: Most REs (70 patients, 88.6%) were in the 1st to 6th ribs. 50 patients had solitary RE and 29 with multiple REs in a regional distribution. All the REs were closely connected to the intercostal venous plexus (ICVP) ipsilateral to the injection site. No visible abnormalities on unenhanced scans were detected in all REs. One hundred and twenty REs (90.2%) had nodular/patchy enhancement. The CT value of RE regions in the venous phase was lower than that in the arterial phase (589.8 ± 344.2 HU versus 1188.5 ± 325.3 HU, p < 0.001). During the venous phase, most REs (125, 94.0%) shrank or disappeared. SM appeared similar on both contrast-enhanced and unenhanced scans in terms of shape and CT values.

CONCLUSION: The RE demonstrated characteristic CT features. The manifestations of nodular/patchy enhancement in the arterial phase, decreased density and shrinkage or disappearance during the venous phase, and no abnormality on unenhanced scans, as well as a close connection with the ICVP, may help differentiate RE from SM.

PMID:38363418 | DOI:10.1007/s00256-024-04609-3

Arch Gynecol Obstet. 2024 Feb 16. doi: 10.1007/s00404-024-07376-7. Online ahead of print.

ABSTRACT

BACKGROUND: Critical aortic stenosis (AS) in fetuses may progress to hypoplastic left heart syndrome (HLHS) with need for postnatal single ventricular (SV) palliation. Fetal aortic valvuloplasty (FAV) is performed to achieve postnatal biventricular (BV) circulation. However, the impact of FAV on fetal myocardial function is difficult to measure. Prediction of postnatal circulatory status and, therefore, counseling is challenging.

METHODS: Retrospective study of fetuses with critical AS who underwent FAV. Global Longitudinal Peak Systolic Strain (GLPSS) of the left ventricle (LV) and right ventricle (RV) were retrospectively analyzed before and after intervention. Fisher’s Exact Test and Mann-Whitney-U Test were used for univariant statistical analysis.

RESULTS: 23 fetuses with critical AS were included. After intervention fetuses demonstrated more negative LV-GLPSS mean values post- vs. pre-intervention (- 5.36% vs. – 1.57%; p < 0.05). RV-GLPSS was decreased in all fetuses, there was no peri-interventional change. 20 fetuses were born alive. Postnatally, 10 had BV and 10 SV circulation. Improved post-interventional LV-GLPSS strain values correlated with BV outcome (p < 0.05). Pre-interventional continuous LV-GLPSS values correlated with postnatal SV vs. BV outcome (p < 0.05).

CONCLUSION: In some fetuses, LV myocardial function assessed by speckle tracking echocardiography (STE) improves after FAV. Improved post-interventional LV-GLPSS correlates with biventricular postnatal outcome. Furthermore, pre-interventional LV- and RV-GLPSS correlate with postnatal outcome. Further studies are needed to asses, if pre-interventional STE parameters might predict which fetuses will benefit from FAV with postnatal BV circulation.

PMID:38363396 | DOI:10.1007/s00404-024-07376-7

Eur J Pediatr. 2024 Feb 16. doi: 10.1007/s00431-024-05464-z. Online ahead of print.

ABSTRACT

Recent research links early weight changes (EWC) with bronchopulmonary dysplasia (BPD) in preterm neonates, while lung ultrasound score (LUS) has shown promise in predicting BPD. We aimed to explore the correlation between LUS and EWC as markers of extravascular lung edema and to investigate the correlation between LUS and EWC in preterm infants with respiratory distress syndrome regarding future BPD development. This secondary analysis of a prospective study involved infants ≤ 28 weeks gestation. Enrolled infants underwent lung ultrasound assessment on postnatal days 3, 7 and 14, measuring LUS. EWC was computed on the same time points. Infants were classified as either having BPD or not. Descriptive statistics, correlation coefficient, and area under the receiver operating characteristic (AUROC) curve analysis were utilized. Of 132 infants, 70 (53%) had BPD. Univariate analysis revealed statistically significant differences in LUS and EWC at days 3, 7, and 14 between BPD and no-BPD groups (p < 0.001). A statistically significant but weak positive correlation existed between LUS and EWC (r0.37, r0.29, r0.24, and p < 0.01) at postnatal days 3, 7, and 14, respectively. AUROC analysis indicated LUS having superior predictive capacity for the need for invasive mechanical ventilation at day 14 as well as the later BPD development compared to EWC (p < 0.0001).

CONCLUSION: In a cohort of extreme preterm infants, our study revealed a positive yet weak correlation between LUS and EWC, suggesting that EWC was not the major contributing to the evolving chronic lung disease.

WHAT IS KNOWN: • Recent evidence links Early Weight-Changes with bronchopulmonary dysplasia in preterm neonates. • Lung ultrasound score has shown promise in early prediction of the subsequent development of bronchopulmonary dysplasia in preterm infants. No studies have examined the correlation between Early Weight-Changes and Lung ultrasound score in preterm infants during first 2 weeks after birth.

WHAT IS NEW: • Our study demonstrated a positive and statistically significant correlation between early LUS and EWC, indicating their potential role as early predictors for the subsequent development of BPD in extreme preterm infants. • The weak correlation between the two parameters may stem from the possible restricted influence of EWC, given that it may not be the primary factor contributing to the evolving chronic lung disease.

PMID:38363393 | DOI:10.1007/s00431-024-05464-z

Bull Math Biol. 2024 Feb 16;86(3):32. doi: 10.1007/s11538-024-01257-5.

ABSTRACT

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found: JAK2 V617F and one in the TET2 gene. Whether one mutation is present influences how the other subsequent mutation will affect the regulation of gene expression. In other words, when a patient carries both mutations, the order of when they first arose has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation, the Moran process, and Markov chain models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. Combined, these observations are used to shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

PMID:38363386 | DOI:10.1007/s11538-024-01257-5