Tag: pubmed

J Thorac Oncol. 2021 May 26:S1556-0864(21)02174-2. doi: 10.1016/j.jtho.2021.05.003. Online ahead of print.

ABSTRACT

INTRODUCTION: Stage III non-small cell lung cancer (NSCLC) is a heterogeneous disease requiring a multi-modal management approach. We conducted a real-world, global study to characterise patients, treatment patterns, and their associated clinical outcomes for stage III NSCLC.

METHODS: KINDLE was a retrospective study in patients with stage III NSCLC (American Joint Committee on Cancer, 7^th edition) diagnosed between January 2013 and December 2017, with at least nine months of documented follow-up since index diagnosis. In addition to descriptive statistics, Kaplan-Meier methodology evaluated survival estimates; two-sided 95% confidence interval (CI) intervals were computed. Cox proportional hazard model was used for univariate and multi-variate analyses.

RESULTS: A total of 3151 patients from more than 100 centres across 19 countries from Asia, Middle East and Africa, and Latin America were enrolled. Median age was 63.0 years (range 21.0-92.0); 76.5% were males, 69.2% had a smoking history, 53.7% had adenocarcinoma and 21.4% underwent curative resection. Of >25 treatment regimens, concurrent chemoradiotherapy (cCRT) was the most common (29.4%). The overall median progression-free survival (mPFS; 95% CI) and median overall survival (mOS) were 12.5 months (12.06-13.14) and 34.9 months (32.00-38.01), respectively. Significant associations (p<0.05) were observed for mPFS and mOS with respect to gender, region, smoking status, stage, histology, and Eastern Cooperative Oncology Group (ECOG) status. In univariate and multi-variate analyses, younger age, stage IIIA, better ECOG status, cCRT, and surgery as initial therapy predicted better mOS.

CONCLUSIONS: KINDLE reveals the diversity in treatment practices and outcomes in stage III NSCLC in a real-world setting in the pre-immuno-oncology era. There is a high unmet medical need, necessitating novel approaches to optimise outcomes.

PMID:34051381 | DOI:10.1016/j.jtho.2021.05.003

Eur J Trauma Emerg Surg. 2021 May 29. doi: 10.1007/s00068-021-01704-1. Online ahead of print.

ABSTRACT

PURPOSE: Open reduction and internal fixation (ORIF) are commonly utilized for the repair of distal radius fractures (DRF). While general anesthesia (GA) is typically administered for ORIF, recent studies have also demonstrated promising results with the usage of regional anesthesia (RA) in the surgical treatment of distal radius fractures. This study will compare complication rates between the use of RA versus GA for ORIF of DRFs.

METHODS: A multi-institutional surgical registry was utilized to identify patients who had undergone ORIF for DRFs from 2005 to 2018-these patients were stratified into GA and RA cohorts. Patients were matched utilizing coarsened-exact-matching (CEM) to compare postoperative outcomes and rates of 30-day complications were compared between the two cohorts.

RESULTS: Upon CEM-matching, 1191 patients receiving RA were matched to 9250 patients who had received GA, with a multivariate imbalance measure (L1) statistic of < 0.001. In the matched-cohort analysis, no significant differences were observed in rates of any complication (all p ≥ 0.083). On multivariate regression analyses, RA was not associated with increased risk for any complication (p = 0.445), minor complications (p = 0.093), major complications (p = 0.758), unplanned reoperations (p = 0.355), unplanned readmissions (p = 0.799), or mortality (p = 0.579).

CONCLUSION: With similar safety profiles, RA is a safe and reasonable alternative to GA when managing DRFs surgically. RA may be the preferred anesthetic technique for ORIF of DRFs in patients at high risk with GA, such as those with reactions to GA in the past or with significant cardiopulmonary risk factors.

PMID:34050773 | DOI:10.1007/s00068-021-01704-1

J Clin Endocrinol Metab. 2021 May 29:dgab377. doi: 10.1210/clinem/dgab377. Online ahead of print.

ABSTRACT

BACKGROUND: Age at natural menopause (ANM) is an important index for women’s health. Either early or late ANM is associated with a series of adverse outcomes later in life. Despite being an inheritable trait, its genetic determinant has not yet been fully understood.

METHODS: Aiming to better characterize the genetic architecture of ANM, we conducted genome-wide association study (GWAS) meta-analyses in European-specific as well as trans-ancestry samples by using GWAS summary statistics from the following 3 large studies: the Reproductive Genetics Consortium (ReproGen, N=69,626), the UK Biobank cohort (UKBB, N=111,593) and the BioBank Japan Project (BBJ, N=43,861), followed by a series of bioinformatical assessments and functional annotations.

RESULTS: By integrating the summary statistics from the 3 GWAS of up to 225,200 participants, this largest meta-analysis identified 49 novel loci and 3 secondary signals that were associated with ANM at the genome-wide significance level (P<5×10 -8). No population specificity or heterogeneity was observed at most of the associated loci. Functional annotations prioritized 90 candidate genes at the newly identified loci. Among the 26 traits that were genetically correlated with ANM, hormone replacement therapy (HRT) exerted a causal relationship, implying a causal pattern by which HRT was determined by ANM.

CONCLUSION: Our findings improved our understanding of the etiology of female menopause, as well as shed light on potential new therapies for abnormal menopause.

PMID:34050765 | DOI:10.1210/clinem/dgab377

Knee Surg Sports Traumatol Arthrosc. 2021 May 29. doi: 10.1007/s00167-021-06621-9. Online ahead of print.

ABSTRACT

PURPOSE: This study aimed to investigate preoperative sports participation and postoperative clinical outcomes including a return to sports (RTS) after hybrid closed-wedge high tibial osteotomy (CWHTO) for medial compartment osteoarthritis of the knee. Characteristic of Hybrid CWHTO was defined as extra-articular lateral closed and medial open wedge osteotomy.

METHODS: The patients who underwent hybrid CWHTO from January 2016 to December 2018 were retrospectively reviewed and divided them into sports and non-sports groups. The preoperative demographic and radiographic characteristics were compared in both groups. And the clinical outcomes including the Japanese Orthopaedic Association (JOA) score, visual analogue scale (VAS), Lysholm score, University of California at Los Angeles (UCLA) activity score, and RTS in the sports group were also investigated. Statistical analysis was performed for comparisons among the preoperative factors between the two groups. Influence of sports impact and bone union of fibular osteotomy was also statistically investigated for RTS.

RESULTS: Of the 161 knees (129 patients; 46 males, 83 females), 20 knees (16 patients; 13 males, 3 females; 12.3%) belonged to sports group. Although there were no significant differences regarding the age and radiographic parameters, there were significant differences in the body mass index and proportion of males between both groups. The JOA, VAS, Lysholm, and UCLA activity scores significantly improved after surgery. RTS was 80% at a mean duration of 7.2 ± 3.1 months. RTS in the high-impact sports group was significantly lower than that in the low-impact sports group (high-impact 60% vs. low-impact 100%, p = 0.043). There was no significant difference in RTS regarding bone union after fibular osteotomy.

CONCLUSION: The clinical outcomes including RTS were satisfactory in patients with hybrid CWHTO.

LEVEL OF EVIDENCE: IV.

PMID:34050769 | DOI:10.1007/s00167-021-06621-9

Stat Med. 2021 May 29. doi: 10.1002/sim.9082. Online ahead of print.

ABSTRACT

This article proposes a powerful method to compare two samples. The proposed method handles comparison of data by drawing inference from ROC curve model parameters. The method estimates parameters from a linear model framework on the empirical sensitivities and specificities. The consistent ROC parameters are then used to give a more powerful test than existing methods in several situations. In addition, we present a comprehensive statistic based on the Cauchy combination, which works well in all scenarios considered in this article. We also offer an efficient one-layer wild permutation procedure to calculate the P-value of our statistic. The method is particularly useful when the underlying continuous biomarker results are non-normal. We illustrate the proposed methods in a neonatal audiology diagnostic example.

PMID:34050680 | DOI:10.1002/sim.9082

J Periodontol. 2021 May 29. doi: 10.1002/JPER.21-0254. Online ahead of print.

ABSTRACT

BACKGROUND: The long-term outcomes of demineralized porcine bone matrix (DPBM) in combination with enamel matrix protein derivative (EMD) for the treatment of one-wall intrabony defects have not yet been evaluated. Therefore, this study aimed to assess the clinical, radiographic, and patient-reported outcomes of regenerative therapy using DPBM with EMD (test group) in comparison with DPBM alone (control group) for the treatment of one-wall intrabony defects in the molar regions.

METHODS: Thirty-four patients (control group, n = 18, and test group, n = 16) were available at the 4-year follow-up assessment. Clinical (probing pocket depth and clinical attachment level [CAL]), radiographic (defect depth and width), and patient-reported (Oral Health Impact Profile [OHIP]-14) parameters were evaluated at baseline, 2 years, and 4 years after regenerative treatment.

RESULTS: Both treatment modalities, with and without adjunctive use of EMD, resulted in significant improvement of clinical (mean gain in CAL of 1.58 ± 1.34 mm), radiographic (mean defect width fill of 2.41 ± 0.90 mm), and oral health-related quality of life outcomes at 2 years after regenerative treatment of one-wall intrabony defects (P < 0.001), which has been sustained over a 4-year follow-up period. Particularly, OHIP-14 scores revealed a statistically significant reduction in physical pain, psychological discomfort, and physical disability (P < 0.05).

CONCLUSIONS: The clinical, radiographic, and patient-reported outcomes were significantly improved when DPBM was used in the regenerative treatment, but no additional benefits were observed with the adjunctive use of EMD. This article is protected by copyright. All rights reserved.

PMID:34050681 | DOI:10.1002/JPER.21-0254

Bioinformatics. 2021 May 29:btab417. doi: 10.1093/bioinformatics/btab417. Online ahead of print.

ABSTRACT

MOTIVATION: Currently, most genome-wide association studies (GWAS) are studies of a single disease against controls. However, an individual is often affected by more than one condition. For example, coronary artery disease (CAD) is often comorbid with type 2 diabetes (T2DM). Similarly, it is clinically meaningful to study patients with one disease but without a related comorbidity. For example, obese T2DM may have different pathophysiology from non-obese T2DM.

RESULTS: We developed a statistical framework (CombGWAS) to uncover susceptibility variants for comorbid disorders (or a disorder without comorbidity), using GWAS summary statistics only. In essence, we mimicked a case-control GWAS in which the cases are affected with comorbidities or a disease without comorbidity. We extended our methodology to analyze continuous traits with clinically meaningful categories (e.g. lipids), and combination of more than 2 traits.We verified the feasibility and validity of our method by applying it to simulated scenarios and four cardiometabolic (CM) traits. In total, we identified 384 and 587 genomic risk loci respectively for 6 comorbidities and 12 CM disease ‘subtypes’ without a relevant comorbidity. Genetic correlation analysis revealed that some subtypes may be biologically distinct from others. Further Mendelian randomization analysis showed differential causal effects of different subtypes to relevant complications. For example, we found that obese T2DM is causally related to increased risk of CAD (p=2.62E-11).

AVAILABILITY: The R code is available at: https://github.com/LiangyingYin/CombGWAS.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:34050728 | DOI:10.1093/bioinformatics/btab417

Neuro Oncol. 2021 May 29:noab133. doi: 10.1093/neuonc/noab133. Online ahead of print.

ABSTRACT

BACKGROUND: Antibody drug conjugates (ADCs) targeting the epidermal growth factor receptor (EGFR), such as depatuxizumab mafodotin (Depatux-M), is a promising therapeutic strategy for glioblastoma (GBM) but recent clinical trials did not demonstrate a survival benefit. Understanding the mechanisms of failure for this promising strategy is critically important.

METHODS: PDX models were employed to study efficacy of systemic vs intracranial delivery of Depatux-M. Immunofluorescence and MALDI-MSI were performed to detect drug levels in the brain. EGFR levels and compensatory pathways were studied using quantitative flow cytometry, Western blots, RNAseq, FISH and phosphoproteomics.

RESULTS: Systemic delivery of Depatux-M was highly effective in nine of 10 EGFR-amplified heterotopic PDXs with survival extending beyond one year in eight PDXs. Acquired resistance in two PDXs (GBM12 and GBM46) was driven by suppression of EGFR expression or emergence of a novel short-variant of EGFR lacking the epitope for the Depatux-M antibody. In contrast to the profound benefit observed in heterotopic tumors, only two of seven intrinsically sensitive PDXs were responsive to Depatux-M as intracranial tumors. Poor efficacy in orthotopic PDXs was associated with limited and heterogeneous distribution of Depatux-M into tumor tissues, and artificial disruption of the BBB or bypass of the BBB by direct intracranial injection of Depatux-M into orthotopic tumors markedly enhanced the efficacy of drug treatment.

CONCLUSIONS: Despite profound intrinsic sensitivity to Depatux-M, limited drug delivery into brain tumor may have been a key contributor to lack of efficacy in recently failed clinical trials.

PMID:34050676 | DOI:10.1093/neuonc/noab133

J Periodontol. 2021 May 29. doi: 10.1002/JPER.20-0842. Online ahead of print.

ABSTRACT

BACKGROUND: This study evaluated the effects of infrared light laser therapy (ILLT) on ligature-induced periodontitis in rats using micro-computed tomography (micro-CT), histology, fibroblast migration, and viability analysis.

METHODS: Forty-eight rats were randomly distributed into three groups: control (no periodontitis), PDC (periodontitis without laser therapy), and PD+L (periodontitis with laser therapy). Periodontitis was induced by ligature placement for four weeks. The 12-week-old rats (baseline) were subjected to laser treatment and euthanized 30 days after. After treatment, the mandibular first molars were prepared for micro-CT scanning, and histological sections were assessed as to the cementoenamel junction, alveolar bone crest, and polymorphonuclear (PMN) cell infiltration. In vitro assays were carried out to examine NIH/3T3 fibroblast viability after laser therapy.

RESULTS: Migration and cell viability assays revealed that the ILLT maintained fibroblast cell viability with 4 J/cm² , reaching 100% healing. The control group (at baseline and 30 days) presented a statistically significant difference from the PDC group at 30 days in terms of distance from the cementoenamel junction to the alveolar bone crest (CEJ-ABC). The PD+L group showed a statistically substantial difference from the PDC group at 30 days in terms of trabecular thickness (Tb.Th), degree of anisotropy (DA), and closed porosity percentage (Po%).

CONCLUSION: Infrared light laser therapy seemed to preserve the bone structure in the in vivo periodontitis induction model at 30 days and did not reduce cell viability or increase fibroblast migration in vitro. The ILLT provides positive effects on mandibular bone microstructure. This article is protected by copyright. All rights reserved.

PMID:34050677 | DOI:10.1002/JPER.20-0842

Int J Med Educ. 2021 May 27;12:94-100. doi: 10.5116/ijme.609d.4db0.

ABSTRACT

OBJECTIVES: To explore potential disparities in representation of Racially Minoritised (RM) persons and women in leadership roles in London Medical Schools compared to their RM and female student populations.

METHODS: General Medical Council’s Medical School Annual Return 2017-18 data and official leadership team webpages were used to determine percentages of RM and female students and percentages of RM and women leaders in London medical schools. Student and leadership team percentages were then compared using chi-squared tests to assess statistically significant differences.

RESULTS: The percentage of RM persons filling leadership roles in London medical schools combined was statistically significantly less than the percentage of RM persons that compose the combined student body (8.6% (N=81) versus 60.2% (N=8786, χ²(1, N=8,867)=88.83, p<0.001). There was no statistically significant difference between the percentage of women filling leadership roles and the percentage of women in the combined student body (43.4% (N = 83) versus 52.5% (N=9026, χ²(1, N=9,109) =2.85, p=0.0913).

CONCLUSIONS: Results mirror the underrepresentation of RM persons in leadership positions throughout the National Health Service (NHS) and in higher education but reflect the improved representation of women in leadership positions seen at the NHS board level. Greater effort is necessary to rectify RM representation within London medical school leadership teams. This is especially imperative given that racially similar role models for RM students are an important predictor in determining academic and future success.

PMID:34050640 | DOI:10.5116/ijme.609d.4db0