Tag: pubmed

Nat Commun. 2023 Dec 9;14(1):8177. doi: 10.1038/s41467-023-44031-2.

ABSTRACT

Counteracting the overactivation of glucocorticoid receptors (GR) is an important therapeutic goal in stress-related psychiatry and beyond. The only clinically approved GR antagonist lacks selectivity and induces unwanted side effects. To complement existing tools of small-molecule-based inhibitors, we present a highly potent, catalytically-driven GR degrader, KH-103, based on proteolysis-targeting chimera technology. This selective degrader enables immediate and reversible GR depletion that is independent of genetic manipulation and circumvents transcriptional adaptations to inhibition. KH-103 achieves passive inhibition, preventing agonistic induction of gene expression, and significantly averts the GR’s genomic effects compared to two currently available inhibitors. Application in primary-neuron cultures revealed the dependency of a glucocorticoid-induced increase in spontaneous calcium activity on GR. Finally, we present a proof of concept for application in vivo. KH-103 opens opportunities for a more lucid interpretation of GR functions with translational potential.

PMID:38071198 | DOI:10.1038/s41467-023-44031-2

Sci Rep. 2023 Dec 9;13(1):21855. doi: 10.1038/s41598-023-49029-w.

ABSTRACT

In this paper, we aim to present a powerful approach for the approximate results of multi-dimensional diffusion problems with time-fractional derivatives. The fractional order is considered in the view of the Caputo fractional derivative. In this analysis, we develop the idea of the Yang homotopy perturbation transform method (YHPTM), which is the combination of the Yang transform (YT) and the homotopy perturbation method (HPM). This robust scheme generates the solution in a series form that converges to the exact results after a few iterations. We show the graphical visuals in two-dimensional and three-dimensional to provide the accuracy of our developed scheme. Furthermore, we compute the graphical error to demonstrate the close-form analytical solution in the comparison of the exact solution. The obtained findings are promising and suitable for the solution of multi-dimensional diffusion problems with time-fractional derivatives. The main advantage is that our developed scheme does not require assumptions or restrictions on variables that ruin the actual problem. This scheme plays a significant role in finding the solution and overcoming the restriction of variables that may cause difficulty in modeling the problem.

PMID:38071195 | DOI:10.1038/s41598-023-49029-w

Dig Liver Dis. 2023 Dec 8:S1590-8658(23)01071-X. doi: 10.1016/j.dld.2023.11.030. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Despite its growing popularity, endoscopic submucosal dissection (ESD) for colorectal neoplasms is still technically challenging. The factors contributing to the failure of ESD are not yet comprehensively elucidated. Therefore, this systematic review was conducted to explore the potential risk factors associated with unsuccessful colorectal ESD.

METHODS: A comprehensive search of Medline and Embase databases was conducted to identify relevant publications from inception until March 14, 2023. Unsuccessful ESD was defined as cases involving incomplete resection or the occurrence of adverse events, such as perforation and delayed bleeding.

RESULTS: Among the 2067 citations initially identified, a total of 23 cohort studies and 16 case-control studies met the inclusion criteria. Following meta-analyses, several significant risk factors for incomplete resection were identified, including lesion diameter ≥40 or 50 mm, right-side colonic location, deeper submucosal invasion, and severe fibrosis. Similarly, lesion diameter ≥40 or 50 mm and severe fibrosis emerged as risk factors for perforation. However, no individual factor was found to be statistically associated with delayed bleeding.

CONCLUSIONS: This meta-analysis identified risk factors correlated with incomplete resection and adverse events following ESD. The findings provide valuable insights that can guide clinical decision-making, aiding gastroenterologists in accurately identifying high-risk individuals.

PMID:38071178 | DOI:10.1016/j.dld.2023.11.030

Endeavour. 2023 Dec 8:100902. doi: 10.1016/j.endeavour.2023.100902. Online ahead of print.

ABSTRACT

Although much scholarship on nineteenth and twentieth century mathematics has focused on processes of professionalization, historical mathematicians themselves rarely experienced their lives as neatly divisible into the professional and the private. Taking marriage as a focal point, this introduction brings the fruitful historiography of gender, collaborative couples, and domesticity in science into a broader conversation with the history of mathematics. By historicizing marriage and its relationship to mathematical careers, we lay the groundwork for the special issue which uncovers the myriad ways in which spousal collaboration and support have been central to mathematical work.

PMID:38071174 | DOI:10.1016/j.endeavour.2023.100902

Ophthalmic Physiol Opt. 2023 Dec 9. doi: 10.1111/opo.13260. Online ahead of print.

ABSTRACT

PURPOSE: There is uncertainty about the effect of increased neonatal protein intake on neurodevelopmental outcomes following preterm birth. The aim of this study was to assess the effect of a change in neonatal nutrition protocol at a major tertiary neonatal intensive care unit intended to increase protein intake on ophthalmic and visual development in school-age children born very preterm.

METHODS: The study cohort comprised children (n = 128) with birthweight <1500 g or gestational age < 30 weeks born at Auckland City Hospital before (OldPro group, n = 55) and after (NewPro group, n = 73) a reformulation of parenteral nutrition that resulted in increased total protein intake during the first postnatal week and decreased carbohydrate, total parenteral fluid and sodium intake. Clinical and psychophysical vision assessments were completed at 7 years’ corrected age, including visual acuity, global motion perception (a measure of dorsal stream function), stereoacuity, ocular motility and ocular health. Composite measures of favourable overall visual, binocular and functional visual outcomes along with individual vision measures were compared between the groups using logistic and linear regression models.

RESULTS: Favourable overall visual outcome did not differ between the two groups. However, global motion perception was better in the NewPro group (p = 0.04), whereas the OldPro group were more likely to have favourable binocular visual outcomes (60% vs. 36%, p = 0.02) and passing stereoacuity (p = 0.02).

CONCLUSIONS: These results indicate subtle but complex associations between early neonatal nutrition after very preterm birth and visual development at school age.

PMID:38069619 | DOI:10.1111/opo.13260

Am J Ind Med. 2023 Dec 9. doi: 10.1002/ajim.23556. Online ahead of print.

ABSTRACT

BACKGROUND: Working from home (WFH) may affect health behaviors and mental health. The coronavirus disease-2019 (COVID-19) pandemic saw many US employees transition to WFH, which has persisted in various job sectors and significantly impacted employees. However, its effects on health outcomes have remained unclear. We aimed to explore the characteristics and health outcomes of, and health-related differences between, WFH and not-WFH groups.

METHODS: Using the 2021 California Health Interview Survey data, we analyzed health behaviors (smoking, alcohol consumption, and fruit-related nutrition) and the mental health status of 12,438 individuals using descriptive statistics, Pearson’s χ² test, and regressions.

RESULTS: A total of 39% were WFH and 61% were not-WFH. Overall, the WFH group had worse health behaviors and mental health than the not-WFH group. Age was associated with smoking in both groups (WFH: b = 0.37; not-WFH: b = 0.35), but with fruit-related nutrition only in the WFH group. Household income and occupation were associated with alcohol consumption in both groups. Age (WFH: b = -1.58; not-WFH: b = -1.39), household income (WFH: b = -0.75; not-WFH: b = -0.34), and job duration (WFH: b = -0.34; not-WFH: b = -0.40) were associated with mental health in both groups; those who were younger and had lower household incomes and job durations had worse mental health.

CONCLUSION: Health management is a clear necessity for the WFH group. Irrespective of WFH status, young workers with shorter than 5 years’ job duration reported mental distress, highlighting a need for distress assessment and management for the young workforce.

PMID:38069590 | DOI:10.1002/ajim.23556

J Sleep Res. 2023 Dec 9:e14118. doi: 10.1111/jsr.14118. Online ahead of print.

ABSTRACT

Diagnostic manuals describe insomnia disorder (ID) characterised by fatigue and sleepiness as diurnal consequences of nocturnal symptoms. However, patients with ID do not frequently report sleepiness in the clinical setting. The present study aimed to investigate subjective sleepiness in ID measured through the Epworth Sleepiness Scale (ESS) and its independence towards daytime functioning and fatigue, and to evaluate cognitive behavioural therapy for insomnia (CBT-I) improvement in daytime consequences and their relationship to sleepiness and fatigue. We retrospectively collected the ESS evaluation in a large sample of 105 healthy controls (HCs), 671 patients with ID, and 602 patients with sleep disorders characterised by excessive daytime sleepiness (EDS). Moreover, we conducted a pre-post evaluation of the ESS in a sub-sample of patients with ID who underwent CBT-I. Component 2 of the Insomnia Severity Index and Profile of Mood States-Fatigue Inertia Scale was used to evaluate daytime functioning and fatigue. Patients with ID reported ESS levels comparable to that observed in HCs and significantly lower than the EDS group. No significant correlation arose between ESS and the diurnal impact of the disorder, suggesting the independence between daytime functioning and sleepiness in ID. Contrarily, insomnia severity and diurnal impact significantly correlated with fatigue. Data showed a statistically significant increase in sleepiness after CBT-I, despite significantly improving daytime consequences and fatigue. Although diagnostic manuals report sleepiness and fatigue as daytime consequences of sleep symptoms in patients with ID, these retrospective data indicate a dissociation between these entities. This evidence aligns with the core feature of ID: the hyperarousal status that pervades patients also during wakefulness.

PMID:38069577 | DOI:10.1111/jsr.14118

Int J Lab Hematol. 2023 Dec 9. doi: 10.1111/ijlh.14213. Online ahead of print.

ABSTRACT

INTRODUCTION: Flow cytometry-based paroxysmal nocturnal hemoglobinuria (PNH) testing involves utilization of monoclonal antibodies against GPI-linked proteins and FLAER. The ability of FLAER to bind to a wide variety of GPI-linked structures and to be utilized across different leukocyte subsets is remarkable. We hypothesize that FLAER as a standalone reagent may be equally effective for detecting PNH clones. The present study intends to compare the results of a FLAER alone-based strategy to the recommended FLAER+GPI-linked protein-based approach for applicability in clinical settings.

METHODS: EDTA-anticoagulated blood samples from patients for PNH workup were tested for PNH by multiparametric flow cytometry. A conventional panel comprising gating markers (CD45 for WBC, CD15 for granulocytes, and CD64 for monocytes) and a combination of FLAER and GPI-linked markers, such as CD24 and CD14, henceforth referred to as the “routine panel,” was employed. Second, a “FLAER-only panel” comprising the gating markers and FLAER alone (excluding the GPI-linked markers CD24 and CD14) was set up. The samples were processed using the lyse-wash-stain-wash technique, and events were acquired on BC Navios Ex flow cytometer (Beckman Coulter, Inc., USA) and analyzed on Kaluza Software 2.1. The presence of a PNH clone was reported at a value of ≥0.01%.

RESULTS: A total of 209 patients were tested. Both panels found a PNH clone in 20.1% of patients (n = 42/209) with a 100% concordance rate. The PNH clone range for granulocytes was 0.01%-89.68%, and for monocyte was 0.04%-96.09% in the routine panel. The range in the FLAER-only panel for granulocytes was 0.01%-89.61%, and for monocytes, it was 0.01%-96.05%. Pearson correlation statistics revealed a significant correlation between the size of the PNH clone of granulocytes and monocytes among the two panels tested (granulocytes r = 0.9999, p < 0.0001, 95% CI = 0.9999 to 1.000; monocytes r = 0.9974, p < 0.0001, 95% CI = 0.9966-0.9980).

CONCLUSION: Based on our results, FLAER as a standalone marker is specific and sensitive for identifying PNH clones in granulocytes and monocytes, even for high-sensitivity PNH assay. The proposed “FLAER-only panel” panel is efficient and cost-effective for highly sensitive PNH testing in two different cell lineages, especially in resource-limited clinical settings.

PMID:38069562 | DOI:10.1111/ijlh.14213

Cancer Med. 2023 Dec 9. doi: 10.1002/cam4.6779. Online ahead of print.

ABSTRACT

BACKGROUND: Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors.

METHODS: Patients with ALL aged 3-18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or ≥three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2.

RESULTS: We included 105 patients, 61% were boys. Median age was 5.3 years (range: 3-18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28-0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22-0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96-0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2-3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2.

CONCLUSION: Physical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course.

PMID:38069550 | DOI:10.1002/cam4.6779

Trop Med Int Health. 2023 Dec 8. doi: 10.1111/tmi.13958. Online ahead of print.

ABSTRACT

BACKGROUND: Uganda has one of the highest rates of cervical cancer in the world. Many women are diagnosed and treated with advanced stages of the disease. With only one facility offering comprehensive cervical cancer care in Uganda, many women are required to travel significant distances and spend time away from their homes to receive cervical cancer care. It is important to understand the burden of time away from home while attending treatment because it can inform the expansion of cervical cancer treatment programmes. The aim of this mixed-methods paper is to describe how the distance to cervical cancer treatment locations impacts women in Uganda.

METHODS: Women were recruited from 19 September, 2022, to 17 January, 2023, at the Uganda Cancer Institute (UCI) and the cancer clinic at Jinja Regional Referral Hospital (JRRF). Women were eligible for the study if they were (i) aged ≥18 years with a histopathologic diagnosis of cervical cancer; (ii) being treated at the UCI or JRRF for cervical cancer; and (iii) able to provide consent to participate in the study in English, Luganda, Lusoga, Luo, or Runyankole. All participants completed a quantitative survey and a selected group was sampled for semi-structured interviews. Data were analysed using the convergent parallel mixed-methods approach. Descriptive statistics were reported for the quantitative data and qualitative data using an inductive-deductive thematic analysis approach.

RESULTS: In all, 351 women participated in the quantitative section of the study and 24 in the qualitative. The quantitative and qualitative findings largely aligned and supported one another. Women reported travelling up to 14 h to receive treatment and 20% noted that they would spend three or more nights away from home during their current visit. Major themes of the qualitative include means of transportation, spending the night away from home, and financial factors.

CONCLUSION: Our findings show that travelling to obtain cervical cancer care can be a significant burden for women in Uganda. Approaches should be considered to reduce this burden such as additional satellite cervical cancer clinics or subsidised transportation options.

PMID:38069532 | DOI:10.1111/tmi.13958