Tag: statistics

JAMA Netw Open. 2023 Jan 3;6(1):e2249422. doi: 10.1001/jamanetworkopen.2022.49422.

ABSTRACT

IMPORTANCE: Improved, efficient, and acceptable treatments are needed for combat-related posttraumatic stress disorder (PTSD).

OBJECTIVE: To determine the efficacy of 2 compressed prolonged exposure (PE) therapy outpatient treatments for combat-related PTSD.

DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted among military personnel and veterans at 4 sites in Texas from 2017 to 2019. Assessors were blinded to conditions. Data were analyzed from November 2020 to October 2022.

INTERVENTIONS: The interventions were massed-PE, which included 15 therapy sessions of 90 minutes each over 3 weeks, vs intensive outpatient program PE (IOP-PE), which included 15 full-day therapy sessions over 3 weeks with 8 treatment augmentations. The IOP-PE intervention was hypothesized to be superior to massed-PE.

MAIN OUTCOMES AND MEASURES: Coprimary outcomes included the Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) (CAPS-5) and the PTSD Checklist for DSM-5 (PCL-5) administered at baseline and posttreatment follow-ups. Measures ranged from 0 to 80, with higher scores indicating greater severity. Diagnostic remission and reliable change were secondary outcomes.

RESULTS: Among 319 military personnel and veterans screened, 234 were randomized (mean [SD] age, 39.20 [7.72] years; 182 [78%] male participants), with 117 participants randomized to IOP-PE and 117 participants randomized to massed-PE. A total of 61 participants (26%) were African American, 58 participants (25%) were Hispanic, and 102 participants (44%) were White; 151 participants (65%) were married. Linear mixed-effects models found that CAPS-5 scores decreased in both treatment groups at the 1-month follow-up (IOP-PE: mean difference, -13.85 [95% CI, -16.47 to -11.23]; P < .001; massed-PE: mean difference, -14.13 [95% CI, -16.63 to -11.62]; P < .001). CAPS-5 change scores differed from 1- to 6-month follow-ups (mean difference, 4.44 [95% CI, 0.89 to 8.01]; P = .02). PTSD symptoms increased in massed-PE participants during follow-up (mean difference, 3.21 [95% CI, 0.65 to 5.77]; P = .01), whereas IOP-PE participants maintained treatment gains (mean difference, 1.23 [95% CI, -3.72 to 1.27]; P = .33). PCL-5 scores decreased in both groups from baseline to 1-month follow-up (IOP-PE: mean difference, -21.81 [95% CI, -25.57 to -18.04]; P < .001; massed-PE: mean difference, -19.96 [95% CI, -23.56 to -16.35]; P < .001) and were maintained at 6 months (IOP-PE: mean change, -0.21 [95% CI, -3.47 to 3.06]; P = .90; massed-PE: mean change, 3.02 [95% CI, -0.36 to 6.40]; P = .08). Both groups had notable PTSD diagnostic remission at posttreatment (IOP-PE: 48% [95% CI, 36% to 61%] of participants; massed-PE: 62% [95% CI, 51% to 73%] of participants), which was maintained at 6 months (IOP-PE: 53% [95% CI, 40% to 66%] of participants; massed-PE: 52% [95% CI, 38% to 66%] of participants). Most participants demonstrated reliable change on the CAPS-5 (61% [95% CI, 52% to 69%] of participants) and the PCL-5 (74% [95% CI, 66% to 81%] of participants) at the 1-month follow-up.

CONCLUSIONS AND RELEVANCE: These findings suggest that PE can be adapted into compressed treatment formats that effectively reduce PTSD symptoms.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03529435.

PMID:36602803 | DOI:10.1001/jamanetworkopen.2022.49422

JAMA Netw Open. 2023 Jan 3;6(1):e2249591. doi: 10.1001/jamanetworkopen.2022.49591.

ABSTRACT

IMPORTANCE: The addition of consolidative durvalumab to chemoradiation has improved disease control and survival in locally advanced non-small cell lung cancer (NSCLC). However, there remains a need to identify biomarkers for response to this therapy to allow for risk adaptation and personalization.

OBJECTIVES: To evaluate whether TMB or other variants associated with radiation response are also associated with outcomes following definitive chemoradiation and adjuvant durvalumab among patients with locally advanced unresectable NSCLC.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included consecutive patients with unresectable locally advanced NSCLC treated with chemoradiation and adjuvant durvalumab between November 2013 and March 2020 who had prospective comprehensive genomic profiling. This study was completed at a multisite tertiary cancer center. The median (IQR) follow-up time was 26 (21-36) months. Statistical analysis was conducted from April to October 2022.

EXPOSURES: Patients were grouped into TMB-high (≥10 mutations/megabase [mt/Mb]) and TMB-low (<10 mt/Mb) groups and were additionally evaluated by the presence of somatic alterations associated with radiation resistance (KEAP1/NFE2L2) or radiation sensitivity (DNA damage repair pathway).

MAIN OUTCOMES AND MEASURES: The primary outcomes were 24-month local-regional failure (LRF) and progression-free survival (PFS).

RESULTS: In this cohort study of 81 patients (46 [57%] male patients; median [range] age, 67 [45-85] years), 36 patients (44%) had TMB-high tumors (≥10 mt/Mb). Patients with TMB-high vs TMB-low tumors had markedly lower 24-month LRF (9% [95% CI, 0%-46%] vs 51% [95% CI, 36%-71%]; P = .001) and improved 24-month PFS (66% [95% CI, 54%-84%] vs 27% [95% CI, 13%-40%]; P = .003). The 24-month LRF was 52% (95% CI, 25%-84%) among patients with KEAP1/NFE2L2-altered tumors compared with 27% (95% CI, 17%-42%) among patients with KEAP1/NFE2L2-wildtype tumors (P = .05). On Cox analysis, only TMB status was associated with LRF (hazard ratio [HR], 0.17; 95% CI, 0.03-0.64; P = .02) and PFS (HR, 0.45; 95% CI, 0.21-0.90; P = .03). Histology, disease stage, Eastern Cooperative Oncology Group status, programmed cell death ligand 1 expression, and pathogenic KEAP1/NFE2L2, KRAS, and DNA damage repair pathway alterations were not significantly associated with LRF or PFS.

CONCLUSIONS AND RELEVANCE: In this cohort study, TMB-high status was associated with improved local-regional control and PFS after definitive chemoradiation and adjuvant durvalumab. TMB status may facilitate risk-adaptive radiation strategies in unresectable locally advanced NSCLC.

PMID:36602799 | DOI:10.1001/jamanetworkopen.2022.49591

JAMA Netw Open. 2023 Jan 3;6(1):e2249674. doi: 10.1001/jamanetworkopen.2022.49674.

ABSTRACT

IMPORTANCE: Merkel cell carcinoma (MCC) is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence. Cytotoxic chemotherapy and checkpoint inhibitors provide treatment options in the metastatic setting; however, there are no approved or standard of care targeted therapy treatment options.

OBJECTIVE: To identify actionable alterations annotated by the OncoKB database therapeutic evidence level in association with tumor mutation burden (TMB).

DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective, cross-sectional study using data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange, a multicenter international cancer consortium database. Patients with MCC were enrolled in participating institutions between 2017 and 2022. Data from version 11.0 of the database were released in January 2022 and analyzed from April to June 2022.

MAIN OUTCOMES AND MEASURES: The main outcome was the percentage of patients with high TMB and OncoKB level 3B and 4 alterations.

RESULTS: A total of 324 tumor samples from 313 patients with MCC (107 women [34.2%]; 287 White patients [91.7%]; 7 Black patients [2.2%]) were cataloged in the database. The median (range) number of alterations was 4.0 (0.0-178.0), with a mean (SD) of 13.6 (21.2) alterations. Oncogenic alterations represented 20.2% of all alterations (862 of 4259 alterations). Tissue originated from primary tumor in 55.0% of patients (172 patients) vs metastasis in 39.6% (124 patients). TMB-high (≥10 mutations per megabase) was present in 26.2% of cases (82 patients). Next-generation sequencing identified 55 patients (17.6%) with a level 3B variation for a Food and Drug Administration-approved drug for use in a biomarker-approved indication or approved drug in another indication. An additional 8.6% of patients (27 patients) had a level 4 variation. Actionable alterations were more common among high TMB cases, with 37 of 82 patients (45.1%) harboring level 3 alterations compared with only 18 of 231 patients (7.8%) with low TMB. The most common level 3B gene variants included PIK3CA (12 patients [3.8%]), BRCA1/2 (13 patients [4.2%]), ATM (7 patients [2.2%]), HRAS (5 patients [1.6%]), and TSC1/2 (6 patients [1.9%]). The most common level 4 variants include PTEN (13 patients [4.1%]), ARID1A (9 patients [2.9%]), NF1 (7 patients [2.2%]), and CDKN2A (7 patients [2.2%]). Copy number alterations and fusions were infrequent. In 61.0% of cases (191 cases), a PanCancer pathway was altered, and 39.9% (125 cases) had alterations in multiple pathways. Commonly altered pathways were RTK-RAS (119 patients [38.0%]), TP53 (103 patients [32.9%]), cell cycle (104 patients [33.2%]), PI3K (99 patients [31.6%]), and NOTCH (93 patients [29.7%]). In addition, oncogenic DNA mismatch repair gene alterations were present in 8.0% of cases (25 patients).

CONCLUSIONS AND RELEVANCE: In this cross-sectional retrospective study of alterations and TMB in MCC, a minority of patients had potentially actionable alterations. These findings support the investigation of targeted therapies as single agent or in combination with immunotherapy or cytotoxic chemotherapy in selected MCC populations.

PMID:36602798 | DOI:10.1001/jamanetworkopen.2022.49674

JAMA Netw Open. 2023 Jan 3;6(1):e2249720. doi: 10.1001/jamanetworkopen.2022.49720.

ABSTRACT

IMPORTANCE: Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel.

OBJECTIVE: To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022.

INTERVENTIONS: Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks.

MAIN OUTCOMES AND MEASURES: The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis.

RESULTS: A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01834235.

PMID:36602796 | DOI:10.1001/jamanetworkopen.2022.49720

Int J Comput Dent. 2023 Jan 5;0(0):1-22. doi: 10.3290/j.ijcd.b3759621. Online ahead of print.

ABSTRACT

AIM: The purpose of this investigation was to evaluate the accuracy of root canal length determination in dependence of CBCT acquisition protocol and evaluating the influence of additional superimposed computerized optical impressions.

MATERIALS AND METHODS: CBCT scans with low-dose (LD) and high-definition (HD) protocols and computerized optical impressions of thirty extracted human molars were acquired. The Sicat Endo software (Sicat, Bonn, Germany) was used for CBCT root canal length (RCL) measurements with (LD+, HD+) and without (LD-, HD-) a superimposed optical impression. To evaluate the accuracy, absolute differences between test groups and the actual root canal length (ARCL) were calculated and statistically analyzed using the Wilcoxon-Rank-Sum-Test.

RESULTS: Absolute differences between the ARCL and the tested measurement methods varied significantly (p<0.05). Both, higher resolution and additionally superimposed computerized optical impression improved measurement accuracy. Mean differences compared to the ARCL were 0.26 mm (HD+), 0.34 mm (HD-), 0.43 (LD+) and 0.66mm (LD-). 93.4% of all measurements in the HD+ group were within the limits of ±0.5 mm.

CONCLUSIONS: Both resolution and superimposition of additional computerized optical impressions have a significant influence on root canal length measurements using CBCT.

PMID:36602786 | DOI:10.3290/j.ijcd.b3759621

Int J Comput Dent. 2023 Jan 5;0(0):1-14. doi: 10.3290/j.ijcd.b3759607. Online ahead of print.

ABSTRACT

AIM: The aim of this in vitro study was the evaluation of the in-vitro performance and fracture force of 3D-printed anterior implant-supported temporary partial dentures (TPD) with different filler content.

MATERIALS AND METHODS: Identical anterior resin-based TPDs (tooth situation 11-13; n=8 per material) were 3D-printed of methacrylate resins with different filler content. A cartridge polymethacrylate (PMMA) material was used as a reference. After temporary cementation, combined thermal cycling and mechanical loading (TCML) was performed on all restorations to mimic clinical application. Behavior during TCML and fracture force was determined and failures were analyzed. Data were statistically investigated (Kolmogorov- Smirnov-test, one-way-ANOVA; post-hoc-Bonferroni, Kaplan-Meier-survival, α=0.05).

RESULT: Failure during TCML varied between three failures and total failure during loading time. Mean survival time varied between 93±206 x10³ cycles and 329±84 x10³ cycles. Significant different survival cycles between individual materials could be determined (Log Rank test Mantel Cox: Chi2 21,861, df =4, p<0.001). A correlation between filler level and survival cycles could be found (Pearson: 0.186, p=0.065). Fracture values of the surviving TPDs varied between 499 N and 835 N. Failures were characterized by fracture of the connector (n=24) followed by fractures at the abutment (n=10).

CONCLUSION: TDPs showed different filler-dependent survival. Individual 3D-printed materials provided comparable or even better performance than a standard cartridge system, and might be sufficient for temporary application of at least half a year.

PMID:36602785 | DOI:10.3290/j.ijcd.b3759607

JAMA Oncol. 2023 Jan 5. doi: 10.1001/jamaoncol.2022.6288. Online ahead of print.

ABSTRACT

IMPORTANCE: Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known.

OBJECTIVE: To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials.

DESIGN, SETTING, AND PARTICIPANTS: In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022.

MAIN OUTCOMES AND MEASURES: Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses.

RESULTS: The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature-adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99).

CONCLUSIONS AND RELEVANCE: Results of this study suggest that multiple B-cell-related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

PMID:36602784 | DOI:10.1001/jamaoncol.2022.6288

Inhal Toxicol. 2023 Jan 5:1-16. doi: 10.1080/08958378.2022.2164388. Online ahead of print.

ABSTRACT

OBJECTIVE: The air quality index (AQI) forecasts are one of the most important aspects of improving urban public health and enabling society to remain sustainable despite the effects of air pollution. Pollution control organizations deploy ground stations to collect information about air pollutants. Establishing a ground station all-around is not feasible due to the cost involved. As an alternative, satellite-captured data can be utilized for AQI assessment. This study explores the changes in AQI during various COVID-19 lockdowns in India utilizing satellite data. Furthermore, it addresses the effectiveness of state-of-the-art deep learning and statistical approaches for forecasting short-term AQI.

MATERIALS AND METHODS: Google Earth Engine (GEE) has been utilized to capture the data for the study. The satellite data has been authenticated against ground station data utilizing the beta distribution test before being incorporated into the study. The AQI forecasting has been explored using state-of-the-art statistical and deep learning approaches like VAR, Holt-Winter, and LSTM variants (stacked, bi-directional, and vanilla).

RESULTS: AQI ranged from 100 to 300, from moderately polluted to very poor during the study period. The maximum reduction was recorded during the complete lockdown period in the year 2020. Short-term AQI forecasting with Holt-Winter was more accurate than other models with the lowest MAPE scores.

CONCLUSIONS: Based on our findings, air pollution is clearly a threat in the studied locations, and it is important for all stakeholders to work together to reduce it. The level of air pollutants dropped substantially during the different lockdowns.

PMID:36602767 | DOI:10.1080/08958378.2022.2164388

Vector Borne Zoonotic Dis. 2023 Jan 4. doi: 10.1089/vbz.2022.0054. Online ahead of print.

ABSTRACT

Background: Flaviviruses are agents with high zoonotic potential of importance to human health. They are transmitted by mosquitoes of the Culicidae family, and birds act as host-amplifiers. Birds, mammals, and humans are susceptible hosts to infection. Methods: In this study, West Nile virus (WNV), flavivirus, infection was studied in 37 serum samples from 22 hens on Easter Island, Chile. Results: WNV was detected by ELISA (ID Screen® West Nile Competition Multi-Species). We report absence of antibodies to WNV, and to related viruses of the Japanese Encephalitis Virus serocomplex, and, therefore, absence of infection across the sample. Conclusion: This is the first evaluation of its type carried out in Chile, and represents a positive result for public health at Easter Island.

PMID:36602757 | DOI:10.1089/vbz.2022.0054

Environ Sci Pollut Res Int. 2023 Jan 5. doi: 10.1007/s11356-022-24700-3. Online ahead of print.

ABSTRACT

This study examines the impact of information and communication technologies (ICT), GDP growth, population, and globalization on the environmental quality of 31 Asian economies (i.e., categorized as lower middle-income, upper middle-income, and high-income groups Asian economies). This analysis employed the time series data from 1990 to 2018. The robust second-generation econometric technologies are used in this analysis. This study applied the Environmental Kuznets curve (EKC) premises under the extended “STIRPAT model” to add population and GDP (per capita) and information technologies (ICTs) by employing ecological footprint. To estimate, the estimators of this study used the CS-ARDL estimates, and for robustness check, this study used the augmented mean group (AMG) test. The co-integration test found the long-run association between ecological footprint and its main determinants. The results of CS-ARDL have confirmed the imperative role of information technologies in mitigating the ecological footprint in the higher, upper-middle, and lower-middle-income economies of Asian economies. The statistical findings of this study are robust to diagnostic tests and alternative estimation proxies and techniques. Moreover, policymakers need to identify the direction of the information technology-ecological footprint nexus through cooperation in combating climate change with financial assistance in the ICT sector.

PMID:36602742 | DOI:10.1007/s11356-022-24700-3