Tag: statistics

BJU Int. 2021 Aug 10. doi: 10.1111/bju.15566. Online ahead of print.

ABSTRACT

OBJECTIVES: To investigate gene alterations as diagnostic and prognostic markers in upper tract urothelial carcinoma (UTUC).

PATIENTS AND METHODS: Patients with UTUC who underwent nephroureterectomy in 2005-2012 were followed until November 2020. DNA was extracted from paraffin-embedded tumour tissue. Next-generation sequencing using a 388-gene panel was performed. First a blinded analysis using principal component analysis and hierarchical clustering was used to search for patterns of mutations. Then a comparative analysis using ANOVA was used to search for mutations enriched in groups of various grade, stage and survival. In addition, careful manual annotation was used to identify pathogenic mutations overrepresented in tumours of high grade/stage and/or poor survival.

RESULTS: 39 patients were included. All tumour stages and grades were represented in the cohort. The median follow-up was 10.6 years. Eleven patients died from UTUC during the follow-up time. Tumour mutational burden showed a statistically significant correlation with stage, grade and stage + grade. G1, G2 and G3 tumours had different mutational patterns. Patients who died from UTUC had pathogenic mutations in specific genes e.g. TP53 and HRAS. Patients with TaG1 tumours with a known pathogenic FGFR3 mutation did not die of UTUC.

CONCLUSION: The genetic analysis was highly concordant with histopathological features and added prognostic information in some cases. Thus, results from genomic profiling may contribute to the choice of treatment and follow-up regimens in the future.

PMID:34375486 | DOI:10.1111/bju.15566

BJU Int. 2021 Aug 10. doi: 10.1111/bju.15567. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess whether bacillus Calmette-Guérin (BCG) responsiveness after initiation of an adequate BCG treatment (at least five of six instillations of induction and at least two of three instillations of maintenance) impacts oncological outcomes in patients with CIS of the bladder treated with BCG immunotherapy.

PATIENTS AND METHODS: Data were available for 193 patients with bladder CIS with or without associated cTa/cT1 disease who received an adequate BCG treatment between 2008 and 2015. Bladder biopsies were performed at 6 months and patients were then stratified as either BCG responsive (negative biopsies) or BCG unresponsive (positive biopsies). Inverse probability weighting (IPW)-adjusted Kaplan-Meier and IPW-adjusted Cox regression were performed to compare progression-free survival (PFS), radical cystectomy-free survival (RCFS), overall survival OS, and cancer-specific survival (CSS) in the two groups.

RESULTS AND LIMITATIONS: Comparing the BCG-responsive and BCG-unresponsive groups, IPW-adjusted Kaplan-Meier analysis revealed, respectively, a PFS of 9 months (IQR 5-15) vs 48.5 months (IQR 28-77) (p=0.001), an RCFS of 11 months (IQR 9-15) vs 49 months (IQR 24-76) (p<0.001), and a CSS of 25 months (IQR 13-60) vs 109 months (IQR 78-307) (p=0.004). On IPW-adjusted Cox regression analysis, BCG-unresponsive patients had a worse PFS (HR 3.40, 95% CI 1.59-7.27), RCFS (HR 3.52, 95% CI 1.77-7), and CSS (HR 4.42, 95% CI 1.95-10.01). We found no significant differences for OS.

CONCLUSION: Using an IPW method we found that lack of response after initiation of an adequate BCG treatment has prognostic implications beyond identification of complete response in patients with CIS. BCG-unresponsive patients, satisfying the novel definition of BCG unresponsive, showed a poor PFS, RCFS, and CSS. In this setting, the patients should be counseled regarding radical cystectomy as a first option or enrolled in a clinical trial if they refuse radical cystectomy or are unfit for surgery.

PMID:34375494 | DOI:10.1111/bju.15567

Med Educ. 2021 Aug 10. doi: 10.1111/medu.14606. Online ahead of print.

ABSTRACT

CONTEXT: Although many medical schools seek to improve diversity, they grapple with the challenge of how to weight the scores of different admission methods to achieve a balance between obtaining high predictiveness and ensuring diversity in the selected student pool. Yet, in large-scale employment settings, substantial progress has been made on this front: Pareto-optimization has been introduced as an elegant statistical tool to assist decision makers in determining the weights assigned to selection methods in advance (before the selection has taken place) so that a selection system is designed to achieve an optimal balance as reflected by the trade-off that one outcome (e.g., predictiveness) cannot be improved without harm to the other outcome (e.g., diversity).

AIMS: This paper reviews the theory and research evidence about Pareto-optimization and explains how Pareto-optimization permits medical schools to better balance predictiveness and diversity in medical admission systems.

METHODS: After reviewing common weighting schemes (unit, regression-based, and ad hoc weighting) and their drawbacks, we introduce the theory and logic of Pareto-optimization for better balancing predictiveness and diversity. To this end, we also offer an illustrative example. Next, we review the mathematical basis and available research evidence regarding Pareto-optimization. Finally, we discuss potential criticisms (i.e., complexity, legal concerns).

CONCLUSIONS: Compared to traditional unit weighting, regression-based weighting, and ad hoc weighting, Pareto-optimization leads to substantial increases in diversity intake (up to three times more), while keeping the predictiveness of the selection methods at the same level. Moreover, the Pareto-optimization is robust to sampling variability and variability of the input selection parameters.

PMID:34375476 | DOI:10.1111/medu.14606

Clin Exp Pharmacol Physiol. 2021 Aug 10. doi: 10.1111/1440-1681.13570. Online ahead of print.

ABSTRACT

This study investigated the impact of intra-renal angiotensin 1-7 (Ang (1-7)) infusion on renal excretory function in a rat model of hypertension. Eleven-week-old spontaneously hypertensive rats (SHRs, n=7) and Han Wistar controls (NCR, n=7) were anaesthetised with sodium pentobarbital (60mg/kg i.p.) and prepared for the measurement of mean arterial pressure (MAP) and left renal function during renal interstitial infusion of Ang (1-7) (50ng/min). The kidneys were harvested, the renal cortex and medulla separated, prepared for measurement of Ang II and Ang (1-7) and Western blot determination of AT1 and Mas receptor protein expression. MAP, glomerular filtration rate (GFR), urine flow (UF) and absolute sodium excretion (UNaV) were 109±16mmHg, 4.4±1.0ml/min/kg, 102±16µl/min/kg and 16±3µmol/min/kg, respectively in the NCR and 172±24mmHg, 3.4±0.7ml/min/kg, 58±30μl/min/kg and 8.6±4.8μmol/min/kg respectively in the SHR. Ang (1-7) increased UF (31%), U_Na V (50%) and FENa⁺ (22%) in the NCR group (all P<0.05) but had no effect on GFR in either group. The magnitudes of the Ang (1-7)-induced increases in UF and U_Na V were significantly blunted in the SHR group (model×drug P<0.05). Renal cortical AT1:Mas receptor expression ratio was significantly higher in the SHR group (P<0.05) but renal Ang II and Ang (1-7) levels were not statistically different between groups. The Ang (1-7) induced increases in sodium and water excretion were impaired in the SHR group in the context of an unstimulated RAS. The decrease in responsiveness of the SHR kidney to Ang (1-7) appears to be associated with higher levels of AT1 receptor expression in the renal cortex.

PMID:34375480 | DOI:10.1111/1440-1681.13570

Int Endod J. 2021 Aug 10. doi: 10.1111/iej.13606. Online ahead of print.

ABSTRACT

AIM: To evaluate if treatment with resiniferatoxin (RTX) is capable of lowering the plasma levels of PGE₂ and TNF-α, as well as histopathological parameters in inflammation of pulp tissue in a mouse experimental model.

METHODOLOGY: Ten groups of six BALB/c mice were formed as follows: healthy group (H_C ), healthy group treated with RTX (H_RTX ), two groups with pulp inflammation at 14 and 18 hours (PI₁₄ /PI₁₈ ); six groups with pulpal inflammation plus treatment with Ibuprofen (IBU₁₄ /IBU₁₈ ), dexamethasone (DEX₁₄ /DEX₁₈ ) and resiniferatoxin (RTX₁₄ /RTX₁₈ ) at 14 and 18 hours, respectively. Pulpal inflammation was induced through occlusal exposure of the pulp of the maxillary first molar. The plasma levels of PGE₂ and TNF-α and the histological parameters of the pulp tissue of the H_C and H_RTX groups were evaluated at the time of acquiring the animals. In the other groups, the plasma levels of PGE₂ and TNF-α and the histopathological parameters were evaluated at 14 and 18 hours after pulp damage. Plasma levels of PGE₂ and TNF-α were quantified by ELISA assay and the histopathological parameters were evaluated by H/E staining. Statistical significance was determined by one-way analysis of variance (ANOVA) to test for overall differences between group means.

RESULTS: A significant increase (*p<0.05) in plasma levels of PGE₂ and TNF-α occurred 14 and 18 hours after pulp damage. In addition, treatment with RTX significantly decreased (*p<0.05) the plasma levels of PGE₂ and TNF-α at 14 and 18 hours after pulp damage, as well as the infiltrate of inflammatory cells at 18 hours after pulp damage, similarly to treatment with ibuprofen and dexamethasone.

CONCLUSION: It was possible to detect systemic levels of PGE₂ and TNF-α at 14 and 18 hours after pulp damage. Likewise, treatment with RTX was associated with an anti-inflammatory effect similar to treatment with ibuprofen and dexamethasone. These findings place resiniferatoxin as a therapeutic alternative in the treatment of inflammatory diseases in Dentistry.

PMID:34375451 | DOI:10.1111/iej.13606

Pharmacoepidemiol Drug Saf. 2021 Aug 10. doi: 10.1002/pds.5338. Online ahead of print.

ABSTRACT

In the causal analysis of observational data, the positivity assumption requires that all treatments of interest be observed in every patient subgroup. Violations of this assumption are indicated by nonoverlap in the data in the sense that patients with certain covariate combinations are not observed to receive a treatment of interest, which may arise from contraindications to treatment or small sample size. In this paper, we emphasize the importance and implications of this often-overlooked assumption. Further, we elaborate on the challenges nonoverlap poses to estimation and inference and discuss previously proposed methods. We distinguish between structural and practical violations and provide insight into which methods are appropriate for each. To demonstrate alternative approaches and relevant considerations (including how overlap is defined and the target population to which results may be generalized) when addressing positivity violations, we employ an electronic health record-derived data set to assess the effects of metformin on colon cancer recurrence among diabetic patients. This article is protected by copyright. All rights reserved.

PMID:34375473 | DOI:10.1002/pds.5338

J Am Geriatr Soc. 2021 Aug 10. doi: 10.1111/jgs.17416. Online ahead of print.

ABSTRACT

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multi-organ failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors (PAMPs). Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty, obesity/diabetes, osteoporosis, and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here an NIH-funded, multi-center, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials. This article is protected by copyright. All rights reserved.

PMID:34375437 | DOI:10.1111/jgs.17416

Eur J Clin Invest. 2021 Aug 10:e13663. doi: 10.1111/eci.13663. Online ahead of print.

ABSTRACT

BACKGROUND: There is still a lack of consensus on the efficacy of convalescent plasma (CP) treatment in COVID-19 patients. We performed a systematic review and meta-analysis to investigate the efficacy of CP vs standard treatment/non-CP on clinical outcomes in COVID-19 patients.

METHODS: Cochrane Library, PubMed, Embase, and ClinicalTrial.gov were searched from December 2019 to 16^th July 2021, for data from clinical trials and observational studies. The primary outcome was all-cause mortality. Risk estimates were pooled using a random-effect model. Risk of bias was assessed by Cochrane Risk of Bias tool for clinical trials and Newcastle-Ottawa Scale for observational studies.

RESULTS: In total, 18 peer-review clinical trials, 3 preprints, and 26 observational studies met the inclusion criteria. In the meta-analysis of 18 peer-reviewed trials, CP use had a 31% reduced risk of all-cause mortality compared to standard treatment use (pooled risk ratio [RR]=0.69, 95% confidence interval [CI]: 0.56-0.86, p=0.001, I² =50.1%). Based on severity and region, CP treatment significantly reduced risk of all-cause mortality in patients with severe and critical disease and studies conducted in Asia, pooled RR=0.61, 95% CI: 0.47-0.81, p=0.001, I² =0.0%, pooled RR=0.67, 95% CI: 0.49-0.92, p=0.013, I² =0.0%, and pooled RR=0.62, 95% CI: 0.48- 0.80, p<0.001, I² =20.3%, respectively. The meta-analysis of observational studies showed the similar results to the clinical trials.

CONCLUSIONS: CP use was associated with reduced risk of all-cause mortality in severe or critical COVID-19 patients. However, the findings were limited with a moderate degree of heterogeneity. Further studies with well-designed and larger sample size are needed.

PMID:34375445 | DOI:10.1111/eci.13663

Vet Rec. 2021 Aug 10:e775. doi: 10.1002/vetr.775. Online ahead of print.

ABSTRACT

BACKGROUND: Farm management practices have a major impact on nematode population dynamics. The presented study aimed to understand current nematode management practices on UK sheep farms; with a particular focus on Nematodirus battus because of the changing epidemiology, and emerging anthelmintic resistance observed in this species.

METHODS: A 42 question online survey covering grazing management, farm demographics and parasite control strategies was developed and distributed to the farming community in 2016. Analysis of the 187 completed questionnaires explored regional variations in practices.

RESULTS: Uptake of recommendations was variable, particularly quarantine practices and monitoring tools. Results also highlighted variation in the epidemiology of N. battus; respondents in the north (Scotland, north-west and north-east England) typically reported N. battus in spring with a perception of more severe clinical symptoms than those from the south (Midlands, Wales, south-east and south-west England; p = 0.03). Farms in the south observed greater changes in the timing of disease (p = 0.006) with N. battus being reported throughout the year on some holdings and more frequent use of faecal egg count monitoring (p = 0.006).

CONCLUSIONS: Control of N. battus infection is challenging and ‘one-size-fits-all’ advice is not applicable; however, the information gathered will enable the development of effective, adaptable control strategies.

PMID:34375447 | DOI:10.1002/vetr.775

J Clin Endocrinol Metab. 2021 Aug 10:dgab591. doi: 10.1210/clinem/dgab591. Online ahead of print.

ABSTRACT

PURPOSE: Although homocysteine accumulation is a reported risk factor for several age-related disorders, little is known on its relationship with osteoarthritis (OA). We therefore investigated for associations of homocysteine and C677T polymorphism in methylenetetrahydrofolate reductase (MTHFR), which is involved in homocysteine clearance, with the development and progression of spinal OA, through a combined cross-sectional and longitudinal cohort study.

METHODS: A total of 1306 Japanese postmenopausal outpatients participating in the Nagano Cohort Study were followed for a 9.7-year mean period. Cross-sectional multiple logistic regression for spinal OA prevalence at registration by serum homocysteine level was performed with adjustment for confounders. In addition to Kaplan-Meier analysis, multivariate Cox regression was employed to examine the independent risk of MTHFR C677T variant for spinal OA progression.

RESULTS: Multivariate regression analysis revealed a significant association between homocysteine and spinal OA prevalence (odds ratio 1.38; 95% confidence interval [CI] 1.14-1.68). Kaplan-Meier curves showed a gene dosage effect of the T allele in MTHFR C677T polymorphism on the accelerated progression of spinal OA severity (P = 0.003). A statistically significant independent risk of the T allele for spinal OA advancement was validated by Cox regression analysis. Respective adjusted hazard ratios for the CT/TT and TT genotypes were 1.68 (95% CI 1.16-2.42) and 1.67 (95% CI 1.23-2.28).

CONCLUSIONS: Circulating homocysteine and C677T variant in MTHFR are associated with the prevalence rate and ensuing progression, respectively, of spinal OA. These factors may represent potential interventional targets to prevent OA development and improve clinical outcomes.

PMID:34375425 | DOI:10.1210/clinem/dgab591