Category: Statistics

Neurochem Res. 2022 Jun 18. doi: 10.1007/s11064-022-03636-7. Online ahead of print.

ABSTRACT

Myocardial infraction (MI) is the principal risk factor for the onset of heart failure (HF). Investigations regarding the physiopathology of MI progression to HF have revealed the concerted engagement of other tissues, such as the autonomic nervous system and the medulla oblongata (MO), giving rise to systemic effects, important in the regulation of heart function. Cardiac sympathetic afferent denervation following application of resiniferatoxin (RTX) attenuates cardiac remodelling and restores cardiac function following MI. While the physiological responses are well documented in numerous species, the underlying molecular responses during the initiation and progression from MI to HF remains unclear. We obtained multi-tissue time course proteomics with a murine model of HF induced by MI in conjunction with RTX application. We isolated tissue sections from the left ventricle (LV), MO, cervical spinal cord and cervical vagal nerves at four time points over a 12-week study. Bioinformatic analyses consistently revealed a high statistical enrichment for metabolic pathways in all tissues and treatments, implicating a central role of mitochondria in the tissue-cellular response to both MI and RTX. In fact, the additional functional pathways found to be enriched in these tissues, involving the cytoskeleton, vesicles and signal transduction, could be downstream of responses initiated by mitochondria due to changes in neuronal pulse frequency after a shock such as MI or the modification of such frequency communication from the heart to the brain after RTX application. Development of future experiments, based on our proteomic results, should enable the dissection of more precise mechanisms whereby metabolic changes in neuronal and cardiac tissues can effectively ameliorate the negative physiological effects of MI via RTX application.

PMID:35716295 | DOI:10.1007/s11064-022-03636-7

Environ Sci Pollut Res Int. 2022 Jun 18. doi: 10.1007/s11356-022-21391-8. Online ahead of print.

ABSTRACT

Polycyclic aromatic hydrocarbons (PAHs) are widely existing organic pollutants in the environment, and their persistence in the environment makes us have to pay continuous attention to their health effects. However, since the American Heart Association updated its definition of hypertension in 2017, few studies have explored the relationship. This study aimed to investigate the relationship between PAH exposure and hypertension after the updated definition of hypertension and explore whether body mass index (BMI) moderates this relationship. A total of 6332 adult participants from the 2009-2016 National Health and Nutrition Examination Survey (NHANES) were examined. Multiple logistic regression and restricted cubic splines were used to analyze the association between urinary polycyclic aromatic hydrocarbon metabolites and hypertension, and the dose-response relationship. Weighted quantile sum (WQS) regression was applied to blood pressure to reveal multiple exposure effects and the relative weights of each PAH. The prevalence of hypertension in the study population was 48.52%. There was a positive dose-response relationship between high exposure to 1-hydroxynaphthalene, 2&3-hydroxyphenanthrene, and the risk of hypertension. Naphthalene metabolites accounted for the most significant proportion of systolic blood pressure, and phenanthrene metabolites accounted for the most significant proportion of diastolic blood pressure. Obese individuals with high PAH exposure were at greater risk for hypertension than individuals with low PAH exposure and normal BMI. Higher prevalence rate and stronger association of metabolites with outcomes were obtained in the general population of the USA under the new guideline. High levels of exposure to PAHs were positively associated with the risk of hypertension, and these effects were modified by BMI.

PMID:35716300 | DOI:10.1007/s11356-022-21391-8

J Patient Rep Outcomes. 2022 Jun 18;6(1):69. doi: 10.1186/s41687-022-00476-5.

ABSTRACT

INTRODUCTION: Thirst is a powerfully distressing sensation that occurs most frequently in the immediate postoperative period. Postoperative thirst is prevalent, the moderate-to-severe type is estimated to affect 53.2-69.8% of patients and causes significant patient discomfort.

OBJECTIVE: The objective of this study was to assess the prevalence, and factors associated with postoperative thirst among surgical patients in PACU at the University of Gondar Comprehensive Specialized Hospital from April 20 to June 27, 2021.

METHODS: An institution-based cross-sectional study was conducted at the University of Gondar Comprehensive Specialized Hospital. A total of 424 participants were included in the study. Statistical analysis had performed using SPSS 26.00 version statistical software. Binary logistic regression analysis was performed to identify the association between the prevalence of postoperative thirst and independent variables and only variables with p-value < 0.2 were entered into the multivariable analysis. The strength of the association was presented by odds ratio and 95% Confidence interval. P-value < 0.05 was considered statistically significant.

RESULT: The prevalence of postoperative thirst among postsurgical patients was 59% (95% CI = 54.74-64.13). Inadequate preloading (Adjusted odes ratio (AOR) = 2.137 95% CI 1.260-3.624), prolonged Nil Per Os (NPO) time (AOR = 13.80 95% CI 2.93-65.37), general anesthesia (AOR = 3.90 95% CI 3.56-11.25), and axillary body temperature ≥ 37.5 °C (AOR = 8.07 95% CI 3.63-17.96) were significantly associated with postoperative thirst. Low room temperature (< 20 °C) was protective for the occurrence of postoperative thirst (AOR = 0.162 95% CI 0.37-0.707).

CONCLUSION AND RECOMMENDATIONS: The prevalence of postoperative thirst remains high and need commitment in close monitoring of PACU patients and immediate intervention. We also urge that high-level, ongoing research be conducted in this area, as postoperative thirst is a very common problem with a lot to discover.

PMID:35716262 | DOI:10.1186/s41687-022-00476-5

Target Oncol. 2022 Jun 18. doi: 10.1007/s11523-022-00887-w. Online ahead of print.

ABSTRACT

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers with an estimated prevalence of less than 1% across all solid tumors. Tropomyosin receptor kinase inhibitors (TRKis) block the constitutively activated tyrosine receptor kinase (TRK) fusion protein produced in NTRK gene fusion positive (NTRK+) tumors from downstream signaling. Tropomyosin receptor kinase inhibitors are now first-line (1L) or subsequent treatment options for TRK fusion cancers.

OBJECTIVE: This study assessed timing of NTRK gene fusion testing and treatment modifications among patients with TRK fusion cancers.

PATIENTS AND METHODS: This was a one-time physician questionnaire with a retrospective, multisite patient chart abstraction of oncology practices in the USA. From June to September 2020, medical oncologists from the Oncology Provider Extended Network (OPEN) who treated patients with NTRK+ advanced/metastatic solid tumors abstracted information into electronic case report forms (eCRFs) for adult patients with advanced/metastatic solid tumors and a NTRK+ tumor test result with a known fusion partner. Use of NTRK testing in routine clinical practice among patients with advanced/metastatic solid tumors was assessed. Data included demographic, clinical, and NTRK gene fusion testing characteristics. Responses were summarized using descriptive statistics.

RESULTS: Twenty-eight community-based medical oncologists who had managed or treated 148 patients with advanced/metastatic TRK fusion cancer between 01/01/2016 and 12/31/2019 completed the survey. Lung (27%), thyroid (18%), salivary gland (14%), and colorectal (12%) were the most commonly reported tumor types. A majority (68%) tested NTRK status prior to 1L initiation; testing after disease progression on 1L (36%), 2L (25%), and 3L (21%) was also noted. Most oncologists (96%) reported no difficulty interpreting NTRK reports. Nearly all (96%) indicated using next-generation sequencing (NGS) for determining NTRK status. The majority (57%) indicated that age, tumor type, and performance status did not impact NTRK testing decisions. Less than half (46%) include TRKi therapy following NTRK+ determination. NTRK testing guidelines were commonly reviewed by physicians (89%).

CONCLUSION AND RELEVANCE: Among patients with advanced/metastatic TRK fusion cancer, medical oncologists reported testing for NTRK fusions at diagnosis or prior to 1L. Future research should elucidate why fewer than half of oncologists surveyed (46%) would not use TRKis after NTRK+ status confirmation, assess clinical practices among NTRK+ patients, and characterize treatment patterns and clinical outcomes in real-world settings.

PMID:35716252 | DOI:10.1007/s11523-022-00887-w

Matern Child Health J. 2022 Jun 18. doi: 10.1007/s10995-022-03454-x. Online ahead of print.

ABSTRACT

OBJECTIVES: Frenotomy is performed in breast fed infants who experience difficulty in latching after failed conservative management for ankyloglossia or tongue-tie. Though parents sometimes enquire about massage after frenotomy, neither published evidence nor clinical consensus supports this. The aim of our study was to assess if there was significant difference in breast feeding or recurrence rate between those infants who had post frenotomy massage and those who did not.

METHODS: A retrospective study was conducted in a tertiary Children’s hospital from January 2018 to December 2018. The tongue-tie service consisted of five pediatric surgical consultants, three of whom routinely advice post frenotomy massage. As a result, we had two groups to compare -massage and non-massage group. Total sample size (n = 599) consisted of those who were advised massage (n = 282) and those who were not advised massage (n = 317).

RESULTS: Overall recurrence rate was 4/599 (0.66%) and this did not achieve statistical significance between the two groups. Breast feeding rates were also similar in both the groups. However, it is interesting to note that only 43.5% of those advised massage adhered to the massage regimen.

CONCLUSIONS: Improvement in breast feeding and recurrence after frenotomy were similar between massage and non-massage groups. This confirms the lack of any additional benefit of post frenotomy massage. This study assists clinicians with decision making not to advise massage as it is unlikely to benefit infants with tongue-tie.

PMID:35716239 | DOI:10.1007/s10995-022-03454-x

J Clin Immunol. 2022 Jun 18. doi: 10.1007/s10875-022-01298-2. Online ahead of print.

ABSTRACT

Pathogenic RIPK1 variants have been described as the cause of two different inborn errors of immunity. Biallelic loss-of-function variants cause the recessively inherited RIPK1 deficiency, while monoallelic variants impairing the caspase-8-mediated RIPK1 cleavage provoke a novel autoinflammatory disease (AID) called cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome. The aim of this study was to characterize the pathogenicity of two novel RIPK1 variants located at the cleavage site of caspase-8 detected in patients with dominantly-inherited, early-onset undefined AID. RIPK1 genotyping was performed by Sanger and next-generation sequencing. Clinical and analytical data were collected from medical charts, and in silico and in vitro assays were performed to evaluate the functional consequences. Genetic analyses identified two novel heterozygous RIPK1 variants at the caspase-8 cleavage site (p.Leu321Arg and p.Asp324Gly), which displayed a perfect intrafamilial phenotype-genotype segregation following a dominant inheritance pattern. Structural analyses suggested that these variants disrupt the normal RIPK1 structure, probably making it less accessible to and/or less cleavable by caspase-8. In vitro experiments confirmed that the p.Leu321Arg and p.Asp324Gly RIPK1 variants were resistant to caspase-8-mediated cleavage and induced a constitutive activation of necroptotic pathway in a similar manner that previously characterized RIPK1 variants causing CRIA syndrome. All these results strongly supported the pathogenicity of the two novel RIPK1 variants and the diagnosis of CRIA syndrome in all enrolled patients. Moreover, the evidences here collected expand the phenotypic and genetic diversity of this recently described AID, and provide interesting data about effectiveness of treatments that may benefit future patients.

PMID:35716229 | DOI:10.1007/s10875-022-01298-2

J Comput Aided Mol Des. 2022 Jun 18. doi: 10.1007/s10822-022-00460-7. Online ahead of print.

ABSTRACT

The main protease (M^pro) of SARS-Cov-2 is the essential enzyme for maturation of functional proteins implicated in viral replication and transcription. The peculiarity of its specific cleavage site joint with its high degree of conservation among all coronaviruses promote it as an attractive target to develop broad-spectrum inhibitors, with high selectivity and tolerable safety profile. Herein is reported a combination of three-dimensional quantitative structure-activity relationships (3-D QSAR) and comparative molecular binding energy (COMBINE) analysis to build robust and predictive ligand-based and structure-based statistical models, respectively. Models were trained on experimental binding poses of co-crystallized M^pro-inhibitors and validated on available literature data. By means of deep optimization both models’ goodness and robustness reached final statistical values of r²/q² values of 0.97/0.79 and 0.93/0.79 for the 3-D QSAR and COMBINE approaches respectively, and an overall predictiveness values of 0.68 and 0.57 for the SDEP_PRED and AAEP metrics after application to a test set of 60 compounds covered by the training set applicability domain. Despite the different nature (ligand-based and structure-based) of the employed methods, their outcome fully converged. Furthermore, joint ligand- and structure-based structure-activity relationships were found in good agreement with nirmatrelvir chemical features properties, a novel oral M^pro-inhibitor that has recently received U.S. FDA emergency use authorization (EUA) for the oral treatment of mild-to-moderate COVID-19 infected patients. The obtained results will guide future rational design and/or virtual screening campaigns with the aim of discovering new potential anti-coronavirus lead candidates, minimizing both time and financial resources. Moreover, as most of calculation were performed through the well-established web portal 3d-qsar.com the results confirm the portal as a useful tool for drug design.

PMID:35716228 | DOI:10.1007/s10822-022-00460-7

Qual Life Res. 2022 Jun 18. doi: 10.1007/s11136-022-03169-0. Online ahead of print.

ABSTRACT

PURPOSE: Mixture item response theory (MixIRT) models can be used to uncover heterogeneity in responses to items that comprise patient-reported outcome measures (PROMs). This is accomplished by identifying relatively homogenous latent subgroups in heterogeneous populations. Misspecification of the number of latent subgroups may affect model accuracy. This study evaluated the impact of specifying too many latent subgroups on the accuracy of MixIRT models.

METHODS: Monte Carlo methods were used to assess MixIRT accuracy. Simulation conditions included number of items and latent classes, class size ratio, sample size, number of non-invariant items, and magnitude of between-class difference in item parameters. Bias and mean square error in item parameters and accuracy of latent class recovery were assessed.

RESULTS: When the number of latent classes was correctly specified, the average bias and MSE in model parameters decreased as the number of items and latent classes increased, but specification of too many latent classes resulted in modest decrease (i.e., < 10%) in the accuracy of latent class recovery.

CONCLUSION: The accuracy of MixIRT model is largely influenced by the overspecification of the number of latent classes. Appropriate choice of goodness-of-fit measures, study design considerations, and a priori contextual understanding of the degree of sample heterogeneity can guide model selection.

PMID:35716223 | DOI:10.1007/s11136-022-03169-0

Breast Cancer Res Treat. 2022 Jun 18. doi: 10.1007/s10549-022-06641-0. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the clinical role of tumor-associated macrophages, including foamy (FM) and hemosiderin-laden macrophages (HLM) in the tumor bed (TB) of triple-negative breast cancer (TNBC) post-neoadjuvant chemotherapy (NACT).

METHODS: We conducted a pathologic review of 129 women, diagnosed with TNBC between 2002 and 2016 at our institute. The residual cancer burden (RCB) was calculated. We estimated the percentage of tumor-infiltrating lymphocytes (TILs) in the core needle biopsy (CNB), and FM, HLM, and TILs (in TB) [the combined cells are designated as tumor-associated mononuclear cells (TAMNC)]. The information on patient demographics, chemotherapy regimen, recurrence-free survival (RFS), and overall survival (OS) was extracted from the medical records.

RESULTS: Pathologic complete response (pCR) was achieved in 34.1% of the women. TILs (10% increment in CNB) only were associated with pCR in the multivariable analysis [odds ratio 1.04 (1.02, 1.06) (p = 0.0003)]. Immune cells associated with better OS included TAMNC (≤ 30%) [hazard ratio (HR) 4.32 (1.93, 9.66) (p = 0.0004)], and FM (0%) [HR 2.30 (1.06, 4.98) (p = 0.036)]. While increased HLM (10% increment) was statistically significant with HR 0.93 and 95% CI (0.88 to 0.98) (p = 0.0061), using a cutoff of 0%, HLM (0%: negative vs. ≥ 1%: positive) achieved only borderline significance with HR 2.05 (0.98, 4.31) (p = 0.058). Similarly, these immune cells were also associated with better RFS: TAMNC (≤ 30%) [HR 4.57 (2.04, 10.21) (p = 0.0002)], FM (0%) [HR 2.80 (1.23, 6.35) (p = 0.014)], and HLM (0%) [HR 2.34 (1.07, 5.11) (p = 0.03)]. TILs (in TB) were not associated with any clinical outcomes.

CONCLUSIONS: Although TILs may play a role in the response to NACT, they may not be critical to the prognosis after NACT. Instead, FM and HLM may assume this role. More studies are warranted.

PMID:35716216 | DOI:10.1007/s10549-022-06641-0

J Ophthalmic Inflamm Infect. 2022 Jun 18;12(1):18. doi: 10.1186/s12348-022-00297-z.

ABSTRACT

OBJECTIVES: This study aimed to evaluate the retinal and choroidal changes in the macular region of patients with Coronavirus Disease 2019 (COVID-19) using structural spectral-domain optical coherence tomography (SD-OCT) analysis.

METHODS: This cross-sectional observational case-control study included patients recovered from COVID-19. The COVID-19 in all participants was confirmed using the reverse transcription-polymerase chain reaction (RT-PCR) technique. The participants had mild to moderate degree of disease without a history of hospitalization, steroid usage, or blood saturation below 92%. Macular SD-OCT was performed at least two weeks and up to one month after recovery from systemic COVID-19. Quantitative and qualitative changes detected by macular SD-OCT imaging were evaluated in COVID-19 recovered patients and compared with the results of age-matched normal controls.

RESULTS: Participants in this study included 30 cases (60 eyes) and 60 healthy controls (120 eyes). In total, 17 (28.3%) eyes in patient group showed at least one abnormal finding indicated by macular SD-OCT imaging included hyperreflective lesions in different retinal layers. In addition, dilated choroidal vessels and retinal pigment epitheliopathy were evident in 41 (68.3.6%) and 4 (6.6%) eyes in patient group, respectively, and their OCT findings resembled those with pachychoroid spectrum. No statistically significant differences were observed in retinal layers or retinal volume between the two groups. The mean ± SD subfoveal choroidal thickness (SFCT) was determined at 380.3 ± 12.40 μm, which was significantly thicker than that in control group (310.7 ± 57.5 μm) (P < 0.001).

CONCLUSION: Regarding retinal thickness, no significant change was observed in different retina layers of patients with COVID-19; however, there were striking qualitative changes, such as hyperreflective lesions in different retinal layers. The evaluation of choroidal structure and thickness demonstrated remarkable abnormal pachyvessels and significant thickening of the SFCT but the clinical significance of these findings is unknown.

PMID:35716213 | DOI:10.1186/s12348-022-00297-z