Tag: nevin manimala

PLoS Genet. 2021 Aug 17;17(8):e1009728. doi: 10.1371/journal.pgen.1009728. Online ahead of print.

ABSTRACT

Dosage compensation equalizes X-linked expression between XY males and XX females. In male fruit flies, expression levels of the X-chromosome are increased approximately two-fold to compensate for their single X chromosome. In testis, dosage compensation is thought to cease during meiosis; however, the timing and degree of the resulting transcriptional suppression is difficult to separate from global meiotic downregulation of each chromosome. To address this, we analyzed testis single-cell RNA-sequencing (scRNA-seq) data from two Drosophila melanogaster strains. We found evidence that the X chromosome is equally transcriptionally active as autosomes in somatic and pre-meiotic cells, and less transcriptionally active than autosomes in meiotic and post-meiotic cells. In cells experiencing dosage compensation, close proximity to MSL (male-specific lethal) chromatin entry sites (CES) correlates with increased X chromosome transcription. We found low or undetectable levels of germline expression of most msl genes, mle, roX1 and roX2 via scRNA-seq and RNA-FISH, and no evidence of germline nuclear roX1/2 localization. Our results suggest that, although dosage compensation occurs in somatic and pre-meiotic germ cells in Drosophila testis, there might be non-canonical factors involved in the dosage compensation mechanism. The single-cell expression patterns and enrichment statistics of detected genes can be explored interactively in our database: https://zhao.labapps.rockefeller.edu/gene-expr/.

PMID:34403408 | DOI:10.1371/journal.pgen.1009728

Eur J Endocrinol. 2021 Aug 1:EJE-21-0552.R1. doi: 10.1530/EJE-21-0552. Online ahead of print.

ABSTRACT

OBJECTIVE: Polycystic ovary syndrome is diagnosed based on clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, as obesity and insulin-resistance. MicroRNAs have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical-tools.

METHODS: A case-control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean; non-PCOS/obese; PCOS/lean; and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800-human-miRNA panel, followed by targeted-qPCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs and build classification algorithms, considering PCOS and obesity as major categories.

RESULTS: The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial LASSO-Regression and decision-tree models were built to reliably discriminate PCOS vs. non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers.

CONCLUSIONS: We define herein a robust method for molecular classification of PCOS, based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS, but also discrimination between PCOS and obesity.

PMID:34403358 | DOI:10.1530/EJE-21-0552

J Biopharm Stat. 2021 Aug 17:1-21. doi: 10.1080/10543406.2021.1918140. Online ahead of print.

ABSTRACT

The use of real-world data became more and more popular in the pharmaceutical industry. The impact of real-world evidence is now well emphasized by the regulatory authorities. Indeed, the analysis of this type of data can play a key role for treatment efficacy and safety. The aim of this work is to assess various methods and give guidance on the comparisons of drugs, mostly with respect to time-to-event data, in non-randomized studies with potentially confounding variables. For that purpose, several statistical methodologies are compared based on simulation studies. These methodologies belong to family classes of methods that are widely used for this type of problem: regression, matching, weighting and subclassification methods. The evaluation criteria used to compare methods performances are the relative bias, the mean square error, the coverage probability and the width of the confidence interval. In this paper, we consider different scenarios of dataset features in order to study the effect of the sample size, the number of covariates and the magnitude of the treatment effect on the statistical methodologies performances. These statistical analyses are conducted within a proportional hazard model framework. Furthermore, we highlight the advantage of using techniques to identify relevant covariates for time-to-event outcomes by comparing two variable selection methods under a frequentist and a Bayesian inference. Based on simulation results, recommendations on each of the family of methods are provided to guide decision making.

PMID:34403296 | DOI:10.1080/10543406.2021.1918140

Eur J Endocrinol. 2021 Aug 1:EJE-21-0475.R2. doi: 10.1530/EJE-21-0475. Online ahead of print.

ABSTRACT

OBJECTIVE: The diagnosis of growth hormone deficiency (GHD) in children is not always straightforward because IGF-1 or GH stimulation tests may not be able to discriminate GHD from constitutional delay of growth and puberty (CDGP) or other causes of short stature.

DESIGN: Boys and girls, n=429, (0.7 – 16 years old) that attended our department for short stature, participated in this study. They were followed up for an average period of 9 years (4-15). At the end of follow up, a definitive diagnosis was assigned to each individual, and all the components of ternary complex (IGF-1, IGFBP-3, ALS and IGF-1/IGFBP-3 ratio) were evaluated as biomarkers for the respective diagnosis.

RESULTS: All components of ternary complex were tightly correlated with each other and positively related to age. IGF-1, IGFBP-3, ALS, and IGF-1/IGFBP-3 ratio differed significantly between GHD and normal groups. IGF-1 and ALS levels were lower in GHD compared to children with familial short stature, while IGF-1 and IGF-1/IGFBP-3 ratio was significantly lower in GHD compared to children with CDGP. IGF-1 and IGF-1/IGFBP-3 Receiver Operating Curves (ROC) cutoff points were unable to discriminate between GHD and normal or between GHD and CDGP groups.

CONCLUSION: Despite the tight correlation among all components of the ternary complex, each one shows a statistically significant diagnosis-dependent alteration. There is a superiority of IGF-1, ALS and IGF-1/IGFBP-3 ratio in the distinction between GHD and CDGP or GHD and normal groups but without usable discriminating power, making thus auxology the primary criterion of establishing the diagnosis.

PMID:34403357 | DOI:10.1530/EJE-21-0475

Acta Oncol. 2021 Aug 17:1-10. doi: 10.1080/0284186X.2021.1962972. Online ahead of print.

ABSTRACT

BACKGROUND: With increased survival among patients with metastatic melanoma and limited time with health care providers, patients are expected to assume a more active role in managing their treatment and care. Activated patients have the knowledge, skills, and confidence to make effective solutions to self-manage health. The use of patient-reported outcomes (PRO) could have the potential to enhance patient activation. However, PRO-based interventions that facilitate an activation in patients with metastatic melanoma are lacking and warranted.

MATERIAL AND METHODS: In this prospective non-randomized controlled, clinical trial, patients with metastatic melanoma were assigned to either the intervention (systematic feedback and discussion of PRO during consultation) given at one hospital or the control group (treatment as usual) if they received treatment from two other hospitals in Denmark. The primary outcome was the patient activation measure (PAM), which reflects self-management. Secondary outcomes were health-related quality of life (HRQoL), self-efficacy, and Patient-Physician interaction. Outcomes were measured at baseline, and after 3, 6, and 12 months. The analysis of the effect from baseline to 12 months employed mixed-effects modeling.

RESULTS: Between 2017 and 2019, patients were allocated to either the intervention group (n = 137) or the control group (n = 142). We found no significant difference in the course of patient activation between the two groups over time. The course of HRQoL was statistically significantly improved by the intervention compared to the control group. Especially, females in the intervention group performed better than males. The other secondary outcomes were not improved by the intervention.

CONCLUSION: The intervention did not improve knowledge, skills, and confidence for self-management for patients with metastatic melanoma. Neither did it improve coping self-efficacy nor perceived efficacy in Patient-Physician interaction. However, the results suggest that the intervention can have a significant impact on HRQoL and in particular social and emotional well-being among the females.

PMID:34403293 | DOI:10.1080/0284186X.2021.1962972

Metabolomics. 2021 Aug 16;17(9):74. doi: 10.1007/s11306-021-01822-2.

ABSTRACT

INTRODUCTION: To study metabolic signatures can be used to identify predictive biomarkers for a patient’s therapeutic response.

OBJECTIVES: We hypothesized that the characterization of a patients’ metabolic profile, utilizing one-dimensional nuclear magnetic resonance (¹H-NMR), may predict a response to tocilizumab in patients with rheumatoid arthritis (RA).

METHODS: 40 active RA patients meeting the 2010 ACR/EULAR classification criteria initiating treatment with tocilizumab were recruited. Clinical outcomes were determined at baseline, and after six and twelve months of treatment. EULAR response criteria at 6 and 12 months to categorize patients as responders and non-responders. Blood was collected at baseline and after six months of tocilizumab therapy. ¹H-NMR was used to acquire a spectra of plasma samples. Chenomx NMR suite 8.5 was used for metabolite identification and quantification. SPSS v.27 and MetaboAnalyst 4.0 were used for statistical and pathway analysis.

RESULTS: Isobutyrate, 3-hydroxybutyrate, lysine, phenylalanine, sn-glycero-3-phosphocholine, tryptophan and tyrosine were significantly elevated in responders at the baseline. OPLS-DA at baseline partially discriminated between RA responders and non-responders. A multivariate diagnostic model showed that concentrations of 3-hydroxybutyrate and phenylalanine improved the ability to specifically predict responders classifying 77.1% of the patients correctly. At 6 months, levels of methylamine, sn-glycero-3-phosphocholine and tryptophan tended to still be low in non-responders.

CONCLUSION: The relationship between plasma metabolic profiles and the clinical response to tocilizumab suggests that ¹H-NMR may be a promising tool for RA therapy optimization. More studies are needed to determine if metabolic profiling can predict the response to biological therapies in RA patients.

PMID:34402961 | DOI:10.1007/s11306-021-01822-2

Graefes Arch Clin Exp Ophthalmol. 2021 Aug 17. doi: 10.1007/s00417-021-05340-8. Online ahead of print.

ABSTRACT

PURPOSE: To investigate the clinical profile and visual outcomes of infectious endophthalmitis in children at a single tertiary hospital in France, and propose an evidence-based protocol for management.

METHODS: This is a retrospective monocentric study that involved children with a history of endophthalmitis between January 2008 and January 2020. The clinical characteristics, etiology, microbiological spectrum from aqueous/vitreous tab, anatomical and visual outcomes, and management were analyzed. The Fischer and chi-square tests were used in the statistical evaluation.

RESULTS: Twenty-six children were eligible for inclusion. The mean patients age at presentation was 4.2 years (range, 8 days-14.3 years). With regard to etiology, patients were divided into posttraumatic group (n = 7 (26.9%)), postoperative group (n = 15 (57.7%)), endogenous group (n = 3 (11.5%)), and infectious corneal ulcer group (n = 1 (3.9%)). Time-to-onset of symptoms was highest in children ≤ 3 years old and in the postoperative subgroup who had at least one glaucoma procedure. Microbiology results showed growth in 12/26 (46.2%). The most common microorganism identified was Streptococcus pneumoniae (5/12 (41.7%)). The antibiotic regimen varied depending on age, organism, and sensitivities. The final visual outcomes were 20/200 or better in 11/26 (42.3%) eyes, and 13/26 (50.0%) eyes had no light perception. Twelve of twenty-six (46.2%) eyes ended up with phthisis bulbi.

CONCLUSION: Pediatric endophthalmitis is a rare but devastating condition with poor visual prognosis, requiring prompt recognition and treatment. Despite aggressive management with antibiotics and vitrectomy, the visual prognosis is generally poor. A protocol for management with an adapted systemic antibiotic therapy is proposed in order to improve outcomes.

PMID:34402964 | DOI:10.1007/s00417-021-05340-8

Childs Nerv Syst. 2021 Aug 17. doi: 10.1007/s00381-021-05326-1. Online ahead of print.

ABSTRACT

PURPOSE: To review the use of different valve types in infants with hydrocephalus, in doing so, determining whether an optimal valve choice exists for this patient cohort.

METHODS: We conducted (1) a literature review for all studies describing valve types used (programmable vs. non-programmable, valve size, pressure) in infants (≤ 2 years) with hydrocephalus, (2) a review of data from the pivotal BASICS trial for infant patients and (3) a separate, institutional cohort study from Alder Hey Children’s Hospital NHS Foundation Trust. The primary outcome was any revision not due to infection.

RESULTS: The search identified 19 studies that were included in the review. Most did not identify a superior valve choice between programmable and non-programmable, small compared to ultra-small, and differential pressure compared to flow-regulating valves. Five studies investigated a single-valve type without a comparator group. The BASICS data identified 391 infants, with no statistically significant difference between gravitational and programmable subgroups. The institutional data from our tertiary referral centre did not reveal any significant difference in failure rate between valve subtypes.

CONCLUSION: Our review highlights the challenges of valve selection in infant hydrocephalus, reiterating that the concept of an optimal valve choice in this group remains a controversial one. While the infant-hydrocephalic population is at high risk of valve failure, heterogeneity and a lack of direct comparison between valves in the literature limit our ability to draw meaningful conclusions. Data that does exist suggests at present that there is no difference in non-infective failure rate are increasing in number, with the British valve subtypes in infant hydrocephalus, supported by both the randomised trial and institutional data in this study.

PMID:34402954 | DOI:10.1007/s00381-021-05326-1

Pediatr Radiol. 2021 Aug 17. doi: 10.1007/s00247-021-05128-2. Online ahead of print.

ABSTRACT

BACKGROUND: Since coronavirus disease 2019 (COVID-19) was declared a worldwide pandemic in March 2020, many authors have noted the collateral damage on non-COVID-19-related illnesses. These indirect effects of the pandemic have resulted in people presenting later and with more severe stages of disease, even if their diagnoses are not directly related to SARS-CoV-2, the virus that causes COVID-19.

OBJECTIVE: We studied these indirect effects of COVID-19 on the imaging workup and outcomes for pediatric patients at our center who had acute appendicitis during the pandemic.

MATERIALS AND METHODS: We performed a retrospective review of cases in children ≤18 years who were evaluated for acute appendicitis during the same period, March 1 to May 31, in both 2019 and 2020. We compared demographic and clinical data as well as surgical and pathological findings, and we graded imaging findings according to severity. Differences in patient outcomes were assessed using the Wilcoxon rank sum test and the Pearson chi-square test.

RESULTS: The total number of pediatric patients evaluated with imaging for acute appendicitis dropped by 43% between 2019 and 2020 (298 vs. 169), but the total number of children treated remained similar (59 vs. 51). There was proportionate use of US and CT in each timeframe but a higher percentage of positive imaging findings in 2020 (50/169, 29.6% vs. 56/298, 18.7% in 2019, P=0.04). There were more imaging examinations with features of complicated appendicitis among positive cases (9/51, 18% vs. 5/59, 8% in 2019, P=0.08) and more pathologically proven perforated cases during the pandemic (14/51, 27% vs. 6/59, 10% in 2019, P=0.11), although these results did not reach statistical significance. There were no changes in surgical management, vital signs, laboratory values, length of stay or complication rates.

CONCLUSION: There was a large drop in the number of pediatric patients imaged for acute appendicitis during the acute phase of the COVID-19 pandemic despite similar numbers of patients treated. The utilization trends of US vs. CT remained stable between time periods. The differences in imaging findings and perforation rates were less pronounced compared to other published studies.

PMID:34402958 | DOI:10.1007/s00247-021-05128-2

Arch Orthop Trauma Surg. 2021 Aug 17. doi: 10.1007/s00402-021-04120-7. Online ahead of print.

ABSTRACT

INTRODUCTION: Complex orthopaedic procedures, such as iliosacral screw (ISS) fixations, can take advantage of surgical navigation technology to achieve accurate results. Although the impact of surgical navigation on outcomes has been studied, no studies to date have quantified how the design of the targeting display used for navigation affects ISS targeting performance. However, it is known in other contexts that how task information is displayed can have significant effects on both accuracy and time required to perform motor tasks, and that this can be different among users with different experience levels. This study aimed to investigate which visualization techniques helped experienced surgeons and inexperienced users most efficiently and accurately align a surgical tool to a target axis.

METHODS: We recruited 21 participants and conducted a user study to investigate five proposed 2D visualizations (bullseye, rotated bullseye, target-fixed, tool-fixed in translation, and tool-fixed in translation and rotation) with varying representations of the ISS targets and tool, and one 3D visualization. We measured the targeting accuracy achieved by each participant, as well as the time required to perform the task using each of the visualizations.

RESULTS: We found that all 2D visualizations had equivalent translational and rotational errors, with mean translational errors below 0.9 mm and rotational errors below 1.1[Formula: see text]. The 3D visualization had statistically greater mean translational and rotational errors (4.29 mm and 5.47[Formula: see text], p < 0.001) across all users. We also found that the 2D bullseye view allowed users to complete the simulated task most efficiently (mean 30.2 s; 95% CI 26.4-35.7 s), even when combined with other visualizations.

CONCLUSIONS: Our results show that 2D bullseye views helped both experienced orthopaedic trauma surgeons and inexperienced users target iliosacral screws accurately and efficiently. These findings could inform the design of visualizations for use in a surgical navigation system for screw insertions for both training and surgical practice.

PMID:34402930 | DOI:10.1007/s00402-021-04120-7