One-sided Confidence Interval Research Articles

Tests and confidence bands for multiple one-sided comparisons

One-sided inference should be used in some applications, but Stata has limited support for one-sided tests and confidence intervals for a single compari­son and almost no support for one-sided tests and confidence bands for multiple comparisons. In this article, we provide an introduction to one-sided tests and confidence intervals for a single hypothesis and to one-sided tests and confidence intervals for multiple comparisons. We also discuss extensions of the sotable com­mand introduced in Drukker (2023, Stata Journal 23: 518-544) to cover one-sided tests and confidence bands for a single comparison and for multiple comparisons. We also provide examples of how to use sotable to perform multiple tests against values other than zero and how to perform multiple tests after commands like margins and nlcom that support the post option.

A Retrospective Multicentric Study of 52 Nasal and Trans-nasal Implants in 31 Severe Atrophic Patients to Reduce Anterior Cantilever Bending in Full Arch Implant-supported Fixed Rehabilitation.

Severe anterior maxillary atrophy offers few implant-supported rehabilitation solutions to Quad Zygoma characterized by a wide anterior cantilever. One of the possible alternatives to consider before the quad zygoma is the extra-long nasal/trans-nasal implant placement. This retrospective multicentric study shows the predictability of nasal/transnasal implant placement in patients affected by severe anterior maxilla atrophy, with residual anatomical features that indicate this surgery. This specific remote anchorage can often be safely involved in immediate loading with other remote anchorages, such as zygoma and pterygoid implants. In this rehabilitation, it's mandatory to reduce the instability of the frameworks and mechanical stress that could unfavorably affect the implant's prognosis due to the overloading derived from anterior bending. In this retrospective multicentric study, 52 nasal or trans-nasal implants were inserted in 31 atrophic anterior maxillas (Cawood and Howell's class V-VI). All implants were successful after the healing period; even if 27 nasal implants reached an insertional torque equal to or greater than 50 n/cm2, the threshold value estimated to be able to support an immediate load. All 52 implants were successful, so the proportion of success was 100%, with a 97.5% one-sided confidence interval of 88.8-100%. The success rate is achieved only if at least two of the following criteria are met: 1) a greater torque than 50 Ncm as a minimum sufficient condition to plan immediate loading; 2) after a healing period of 16 weeks, the secondary stability is clinically and radiographically evaluated to exclude possible coronal bone resorption: this condition allows the successive prosthetic finalization; 3) the possibility of carrying out a full arch rehabilitation with minimal anterior spread. Insertion torque was <50 Newton centimeters (Ncm) in 14 patients (45%) and 50 Ncm in 17 (55%). Mechanical load was delayed in the former and immediate in the latter. The proportion of torque <50 Ncm was higher in men than in women (69% versus 28%, p=0.033). Immediate torque was not significantly affected by age. Although the sample is not extremely numerically significant, it conveys a clear and significant clinical, surgical indication as never before in the literature; we can state that nasal/trans nasal implants have been very useful in reducing the anterior cantilever and overcoming the anatomical limitations affecting conventional Quad Zygoma.

Nivolumab for mismatch-repair-deficient or hypermutated gynecologic cancers: a phase 2 trial with biomarker analyses

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7–100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5–100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6–87.1%). At the median follow-up of 42.1 months (range, 8.9–59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9–89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+ cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745.

Evaluating the Efficacy and Safety of Hemofence (Thorombin Cross-Linked Sodium Hyaluronate Gel Matrix) in Hemostasis for Intractable Exudative Bleeding in Spinal Surgery: A Multicenter, Randomized, Phase III Clinical Trial.

To demonstrate the noninferiority of the novel hemostatic agent, Hemofence (BMI Korea Co., Ltd., thrombin cross-linked sodium hyaluronate gel matrix) compared to the established agent, Floseal Hemostatic Matrix (Baxter, thrombin-gelatin matrix) in achieving hemostasis for spinal surgeries, with secondary objectives to assess additional efficacy and safety. This clinical trial was a multicenter, randomized, subject-blinded, active-controlled, parallel-group, phase 3 study. Investigational drugs were administered to the first and second bleeding sites of each participant (or only to the first site if a second site was absent), evaluating hemostasis success rate within 10 minutes and the time to achieve hemostasis. Subsequent visits were conducted for safety assessments. For noninferiority test, a 97.5% one-sided confidence interval (CI) was used; the test group was deemed noninferior if the lower limit exceeded -10%. This trial showed a 97.10% success rate in the test group and 96.05% in the control group for primary efficacy. The 95% CI (-4.90% to 7.44%) confirmed the test drug's noninferiority. Time to hemostasis showed no significant difference between groups. All adverse events, adverse drug reactions, and serious adverse events were statistically similar between groups (p=1.000, p=0.243, and p=0.966, respectively). A novel hemostatic agent, Hemofence, demonstrated an efficacy and safety profile comparable to that of Floseal.

Phase II trial of domatinostat (4SC-202) in combination with avelumab in patients with previously treated advanced mismatch repair proficient oesophagogastric and colorectal adenocarcinoma: EMERGE

Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC. Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively. Patients (n= 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n= 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D. Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage2. NCT03812796 (registered 23rd January 2019).

The eROSITA upper limits

Context. The soft X-ray instrument eROSITA on board the Spectrum-Roentgen-Gamma (SRG) observatory has successfully completed four of the eight planned all-sky surveys, detecting almost one million X-ray sources during the first survey (eRASS1). The catalog of this survey will be released as part of the first eROSITA data release (DR1). Aims. Based on X-ray aperture photometry, we provide flux upper limits for eRASS1 in several energy bands. We cover galactic longitudes between 180° ≲ l ≲ 360° (eROSITA-DE). These data are crucial for studying the X-ray properties of variable and transient objects, as well as non-detected sources in the eROSITA all-sky survey data. Methods. We performed aperture photometry on every pixel of the SRG/eROSITA standard pipeline data products for all available sky tiles in the single detection band (0.2–2.3 keV). Simultaneously, we performed the same analysis in the three-band detection at soft (0.2–0.6 keV), medium (0.6–2.3 keV), and hard (2.3–5.0 keV) energy bands. Based on the combination of products for the individual bands, we are also able to provide aperture photometry products and flux upper limits for the 0.2–5.0 keV energy band. The upper limits were calculated based on a Bayesian approach that utilizes detected counts and background within the circular aperture. Results. The final data products consist of tables with the aperture photometry products (detected counts, background counts, and exposure time), a close-neighbor flag, and the upper flux limit based on an absorbed power-law spectral model (Γ = 2.0, NH = 3 × 1020 cm−2). The upper limits are calculated using the one-sided 3σ confidence interval (CL) of a normal distribution, representing CL = 99.87%. The aperture photometry products allow for an easy computation of upper limits at any other confidence interval and spectral model. These data are stored in a database with hierarchical indexes in order to offer a fast query option. Conclusions. We provide a detailed description of the process of retrieving SRG/eROSITA upper limits for a large set of input positions, as well as of the eROSITA data, the X-ray aperture photometry, the upper limit calculation, and the final data products. The eROSITA upper flux limits represent either the maximum flux of potential non-detections or the 3σ upper flux uncertainty of detected sources. We emphasize the importance of choosing the right spectral model that ought to match the spectral shape of the source of interest: the wrong spectral model can produce discrepancies of up to 30% in the final flux upper limit value. We also describe the architecture of the database and the web tool, which are designed to handle large queries on input positions.

A better one stage multiple comparison procedure of several treatment mean lifetimes with the control for exponential distributions under heteroscedasticity

In this article, we present a new one-stage multiple comparison procedure for exponential mean lifetimes with the control under heteroscedasticity including one-sided and two-sided confidence intervals by improving the coverage probability and average confidence length compared with the old one. Users can use these simultaneous confidence intervals to identify better-than-the-control, worse-than-the-control and not-much-different-from-the-control products in agriculture, stock market, pharmaceutical industries in terms of the mean lifetimes. In the end, one example is used to demonstrate the proposed procedure.

Melded Confidence Intervals Do Not Provide Guaranteed Coverage

Melded confidence intervals were proposed as a way to combine two independent one-sample confidence intervals to obtain a two-sample confidence interval for a quantity like a difference or a ratio. Simulation-based work has suggested that melded confidence intervals always provide at least the nominal coverage. However, we show here that for the case of melded confidence intervals for a difference in population quantiles, the confidence intervals do not guarantee the nominal coverage. We derive a lower bound on the coverage for a one-sided confidence interval, and we show that there are pairs of distributions that make the coverage arbitrarily close to this lower bound. One specific example of our results is that the 95% melded upper bound on the difference between two population medians offers a guaranteed coverage of only 88.3% when both samples are of size 20.

Efficacy and Safety of a Biosimilar Liraglutide (Melitide®) Versus the Reference Liraglutide (Victoza®) in People with Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Noninferiority Clinical Trial.

Liraglutide effectively controls blood glucose level and reduces body weight. The aim of this study was to compare the efficacy and safety of a biosimilar liraglutide (Melitide®; CinnaGen, Tehran, Iran) to the reference liraglutide (Victoza®; Novo Nordisk, Bagsvaerd, Denmark) in people with type 2 diabetes mellitus (T2DM). In this phase 3 clinical noninferiority trial, adult patients with inadequately controlled T2DM and with hemoglobin A1C (HbA1C) levels of 7-10.5% on at least two oral glucose-lowering drugs with stable doses for at least 3 months were randomized to receive Melitide® (n = 150) or Victoza® (n = 150) 1.8mg/day for 26weeks. The primary outcome was assessment of the noninferiority of Melitide® to Victoza® in terms of change in HbA1C level with a prespecified margin of 0.4%. The secondary outcomes were the assessment of additional efficacy parameters (including the proportion of patients achieving HbA1C levels of < 7%), the incidence of adverse events, and immunogenicity. Of the 300 participants enrolled in this study, 235 were included in the per-protocol analysis (112 in the Melitide® group and 123 in the Victoza® group). The mean (standard deviation) changes in HbA1C were - 1.76% (1.22) in the Melitide® group and - 1.59% (1.31) in the Victoza® group. The upper limit of the 95% one-sided confidence interval (CI) of the mean difference between Melitide® and Victoza® in lowering HbA1C was lower than the predefined margin (mean difference - 0.18, 95% CI - 0.5 to 0.15). Similar findings were obtained with the intention-to-treat analysis. No statistically significant differences were observed between the two study arms regarding the proportion of patients achieving HbA1C < 7% (p = 0.210), other efficacy parameters (p > 0.05), and reported adverse events (p = 0.916). Furthermore, none of the patients developed anti-liraglutide antibodies. The biosimilar liraglutide (Melitide®) was noninferior in efficacy and comparable in safety when compared with the reference liraglutide. NCT03421119.

Bootstrap Probability Errors of the Whittle MLE for Linear Regression Processes with Strongly Dependent Disturbances

This paper determines bounds on the asymptotic orders of the coverage probability errors of parametric bootstrap confidence intervals (CIs) and tests for the covariance parameters of a time series generated by a regression model with Gaussian, stationary, and strongly dependent errors. The CIs and tests are based on the plug-in Whittle maximum&#x0D; likelihood (PWML) estimators. It is shown that, under some sets of conditions on the regression coefficients, the spectral density function, and the parameter values, the bounds on the coverage probability errors of symmetric two-sided and one-sided parametric bootstrap confidence intervals on the plug-in Whittle log-likelihood function are shown to be O(n^{-3/2}\ln{n}) and O(n^{-1}\ln{n}), respectively. Apart from the \ln{n} term, the magnitudes of the coverage probability errors of the one-sided bootstrap confidence intervals for our model is shown to be essentially the same as that of the independent and identically distributed (iid) data. The error for the two-sided confidence intervals is not as small as the error O(n^{-2}) that has been established for many confidence intervals in the literature, see Hall (1992), pp 102-108.

Randomized control study of the use of faropenem for treating patients with pulmonary tuberculosis

Faropenem has antituberculosis activity in vitro but its utility in treating patients with tuberculosis (TB) is unclear. We conducted an open-label, randomized trial in China, involving newly diagnosed, drug-susceptible pulmonary TB. The control group was treated with the standard 6-month regimen. The experimental group replaced ethambutol with faropenem for 2 months. The primary outcome was the treatment success rate after 6 months of treatment. Noninferiority was confirmed if the lower limit of a 95% one-sided confidence interval (CI) of the difference was greater than -10%. A total of 227 patients eligible for the study were enrolled in the trial group and the control group in a ratio of 1:1. Baseline characteristics of participants were similar in both groups. In the modified intention-to-treat population, 88.18% of patients in the faropenem group achieved treatment success, and 85.98% of those in the control group were successfully treated, with a difference of 2.2% (95% CI, -6.73-11.13). In the per-protocol population, treatment success was 96.04% in the faropenem group and 95.83% in the control group, with a difference of 2.1% (95% CI, -5.31-5.72). The faropenem group showed noninferiority to the control group in the 6-month treatment success rates. The faropenem group had significantly fewer adverse events (P <0.01). Our study proved that oral faropenem regimen can be used for the treatment of TB, with fewer adverse events. (Chinese Clinical Trial Registry, ChiCTR1800015959).

Enhanced early skin treatment for atopic dermatitis in infants reduces food allergy

Early-onset atopic dermatitis is a strong risk factor for food allergy, suggesting that early effective treatment may prevent transcutaneous sensitization. This study tested whether enhanced treatment of atopic dermatitis to clinically affected and unaffected skin is more effective in preventing hen's egg allergy than reactive treatment to clinically affected skin only. This was a multicenter, parallel-group, open-label, assessor-blind, randomized controlled trial (PACI [Prevention of Allergy via Cutaneous Intervention] study). This study enrolled infants 7-13 weeks old with atopic dermatitis and randomly assigned infants in a 1:1 ratio to enhanced early skin treatment or conventional reactive treatment using topical corticosteroids (TCSs). The primary outcome was the proportion of immediate hen's egg allergy confirmed by oral food challenge at 28 weeks of age. This study enrolled 650 infants and analyzed 640 infants (enhanced [n= 318] or conventional [n= 322] treatment). Enhanced treatment significantly reduced hen's egg allergy compared with the conventional treatment (31.4% vs 41.9%, P= .0028; risk difference: -10.5%, upper bound of a 1-sided CI: -3.0%), while it lowered body weight (mean difference: -422 g, 95% CI: -553 to -292 g) and height (mean difference: -0.8 cm, 95% CI: -1.22 to -0.33 cm) at 28 weeks of age. This study highlighted the potential of well-controlled atopic dermatitis management as a component of a hen's egg allergy prevention strategy. The enhanced treatment protocol of this trial should be modified before it can be considered as an approach to prevent hen's egg allergy in daily practice to avoid the adverse effects of TCSs. After remission induction by TCSs, maintenance therapy with lower potency TCSs or other topical therapies might be considered as alternative proactive treatments to overcome the safety concerns of TCSs.

One-Stage Multiple Comparisons of the Mean Lifetimes of k Treatments with the Average for Exponential Distributions under Heteroscedasticity

Making use of uniformly minimum-variance unbiased estimators for the parameters of two-parameter exponential distributions and the distribution of pivotal quantities, we propose one-stage multiple comparison procedures for k mean lifetimes with the average under heteroscedasticity. The multiple comparison procedures include one-sided and two-sided confidence intervals. These intervals can be applied to identify which treatment’s mean lifetime is better than the average or worse than the average in terms of the mean lifetimes of all treatments. Critical values are obtained in order to assure users that the given confidence coefficient has been reached; they are organized in table format for practical and convenient use. An example is provided to demonstrate the proposed techniques, wherein the mean survival times of four different lung cancer categories are compared with the average.

Analysis of acute pancreatitis associated with SGLT-2 inhibitors and predictive factors of the death risk: Based on food and drug administration adverse event report system database.

Background and objectives: The US FDA and Health Canada have successively published potential red flags for acute pancreatitis caused by sodium-dependent glucose transporter 2 inhibitors (SGLT-2i). However, existing studies have focused on case reports. We aimed to assess the possible association of SGLT-2i with acute pancreatitis by analyzing postmarketing adverse events reported in the FDA adverse event reporting system (FAERS), to explore risk factors for SGLT-2i-related acute pancreatitis death, and to build a nomogram. Methods and Results: We used a disproportionality analysis of suspected acute pancreatitis-related reports in the FAERS database of patients from the use of SGLT-2i from the first quarter of 2013 to the fourth quarter of 2021. Single-factor and multi-factor logistic regression analyses were performed using the relevant clinical information of patients, and risk factors were combined with the age of patients to construct a SGLT-2i risk prediction model for acute pancreatitis-related death. A total of 757 reports were retrieved. The largest number of acute pancreatitis-related cases were caused by canagliflozin (317 reports), which was also the strongest agent associated with acute pancreatitis, with the information component (IC 2.41, lower 95% one-sided confidence interval 2.16), the reporting odds ratio (ROR 5.37, 95% two-sided confidence interval 4.8-5.99), and the empirical Bayesian geometric mean (EBGM 5.32, lower 90% one-sided confidence interval 4.85). The median time to acute pancreatitis was 54 (interquartile range [IQR] 14-131) days, and approximately 83% of adverse events occurred within 6 months. Odds ratio(OR) adjusted by acute pancreatitis and the coadministration of SGLT-2i with dipeptidyl peptidase 4 inhibitor (DPP-4i), glucagon-like peptide 1 analog (GLP-1RA), and angiotensin converting enzyme inhibitor (ACEIs) was 1.39, 1.97, and 1.34, respectively, all of which were statistically significant. Logistic regression analysis showed that different SGLT-2i type and their combinations with statins were independent risk factors for acute pancreatitis mortality in the patients (p < 0.05). The mortality risk prediction model showed good discrimination and clinical applicability in both the training set (AUC 0.708) and the validation set (AUC 0.732). Conclusion: SGLT-2i may increase the risk of acute pancreatitis especially within the first 6 months of drug administration. Combination with DPP-4i, GLP-1RA or ACEIs significantly increases the risk of acute pancreatitis. In addition, different SGLT-2i type and their combination with statins are risk factors that can predict the risk of death following acute pancreatitis.

Reliability evaluation of electro spindle based on no-failure data

Electric spindle is a key functional component of CNC machining equipment including CNC machine tools, and its reliability level is a key bottleneck factor restricting the reliability of high-end CNC equipment. So far, the research on the reliability evaluation method of electric spindle is still in its infancy, and there is a lack of Systematic and complete theoretical support. The motorized spindle is a typical high-reliability and long-life product, and it is difficult to fail or fail due to obvious performance degradation within a limited test time. Therefore, the traditional reliability evaluation method based on statistical theory is not effective. Therefore, it is of great significance to carry out the early reliability test of the motorized spindle and the reliability evaluation of the motorized spindle without failure data, which is of great significance to reasonably evaluate the reliability level of the motorized spindle. At present, when there is no failure data or very little failure data for the motorized spindle of the machine tool, only the point estimate of the parameter or the one-sided confidence interval of the parameter can be calculated, and it is extremely difficult to obtain the point estimate and the interval estimate at the same time, which will affect the reliability analysis results. Consistency. In order to solve this problem, this paper takes a certain type of CNC machine tool motorized spindle as the research object, and determines the monitoring points and monitoring information according to the failure analysis of similar motorized spindles; combines the test information to evaluate the reliability of the motorized spindle without failure data. The reliability evaluation method of the motorized spindle proposed in this paper can effectively avoid the problem that the traditional method cannot be analyzed when there is no failure data, and provides a new idea for the reliability evaluation of the motorized spindle.

Stereotactic Body Radiation Therapy Plus Anti-PD1/IL8 Therapy for Advanced Solid Tumors

<h3>Purpose/Objective(s)</h3> Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site stereotactic body radiation therapy (SBRT) with anti-PD1 have demonstrated feasibility and showed increased interferon signaling after SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, chiefly melanoma (MEL) and renal cell carcinoma (RCC). <h3>Materials/Methods</h3> This is a phase 1 open label single arm study which will include safety and efficacy cohorts. Patients will receive SBRT to 1-4 metastatic sites in 3 or 5 fractions with a total dose of 30-50 Gy depending on anatomic subsite and dose/fractionation. SBRT treatment planning parameters and organ at risk constraints are based on NRG BR-001 study results. SBRT will be followed by nivolumab (480mg q4 weeks) and IV BMS-986253 (2400mg q2 weeks) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/immunotherapy as opposed to individual components. After completion of the safety phase, an efficacy phase will be launched. To detect a lower bound of 20% for response rate with a one-sided confidence interval, 20 patients are required. Translational correlatives include paired biopsies pre/post SBRT to interrogate gene expression changes using scRNAseq and bulk RNAseq, TCRseq, PBMC profiling for IL8 gene expression, serum IL8 levels before/during/after combination treatment, and T cell radiomics analyses of irradiated metastases to correlate with clinical outcomes. <h3>Results</h3> The phase I trial is active and recruiting patients. <h3>Conclusion</h3> Blocking IL8 in conjunction with anti-PD1 therapy and SBRT is a rational, biomarker-driven approach that may overcome resistance and broaden immunotherapy benefit in patients for whom anti-PD1 therapy is inadequate. This trial is registered at ClinicalTrials.gov, NCT04572451.

Fuzzy confidence interval construction and its application in recovery time for COVID-19 patients

An approach is proposed to construct fuzzy confidence intervals for unknown parameters in statistical models. In this approach, a family of confidence intervals of the unknown crisp parameter has been considered. Such confidence intervals are used to obtain a fuzzy confidence interval for the parameter of interest. ‎The proposed approach benefits a wide range of confidence intervals to obtain a trapezoidal shaped fuzzy set of the parameter space as the fuzzy confidence interval for the parameter of interest. By using the resolution identity, it is shown that the constructed fuzzy confidence intervals are really fuzzy sets of the parameter space.Some numerical examples are provided to explain the approach in one-sided and two-sided fuzzy confidence intervals. ‎‎Moreover, ‎an‎‎‎ application in health sciences ‎‎‎is provided about the ‎‎‎‎recovery time of olfactory and gustatory dysfunctions for COVID-19 patients.

Fragility of Built Urban Objects to Vicious Attacks: Assessment by Means of Limited Data on Abnormal Violent Actions

Abstract An assessment of fragility of objects built (constructed) in urban environment to deliberately imposed abnormal actions (loads) is considered. The actions under analysis are explosions, vehicular impacts and fires that can be imposed by acts of terrorism and sabotage as well as such highly random events as car crashes into structures due to unintentional roadway departures. The fragility is assessed by means of mathematical models known as fragility functions and developed for vulnerable building and transportation structures, protective barriers, and energy supply facilities. The result of fragility assessment is the probability of the damage that can be foreseen and modelled by means of mathematical models used for structural analysis. The case is studied where information on an abnormal action can be expressed in the form of a small-size statistical sample with components acquired in post-mortem investigations of attacks or unintentional accidents. The basic idea is an application of the statistical (bootstrap) resampling for the estimation the damage probability. The resampling procedure is applied to values of the fragility function that can be developed for the damage caused by the abnormal action in question. The values of the fragility function are estimated for components of the small-size sample of abnormal action values. The resampling of the fragility function values yields a conservative estimate of the damage probability expressed by the limit of a one-sided confidence interval. The estimate of the damage probability can be applied to making decisions concerning the level of resilience of vulnerable urban objects.

Confidence intervals for point-of-stabilization of content uniformity.

Within the framework of continuous pharmaceutical manufacturing, we are interested in statistical modeling of the initial behavior of the production line. Assuming a gradually changing sequence of a suitable product quality characteristic (e.g., the content uniformity), we estimate the so-called point-of-stabilization (PoSt) and construct corresponding confidence regions based on appropriate asymptotic distributions and bootstrap. We investigate linear, quadratic, and nonlinear gradual change models both in homoscedastic and heteroscedastic setup. We propose a new nonlinear Emax gradual change model and show that it is applicable even if the true model is linear. Asymptotic distribution of the PoSt estimator is known only in a homoscedastic linear and quadratic model and, therefore, bootstrap approximations are used to construct one-sided PoSt confidence intervals.

Statistical Analysis of the Dynamic Performance of Reinforcement Steel at Elevated Temperatures: The Case of Johnson-Cook Model

Description of mechanical properties of reinforcement steel by means of mathematical models known as constitutive laws is considered. The attention is focussed on the Johnson-Cook (JC) model developed to express the stress-strain relation by considering the coupled effect of strain and strain rate hardening as well as thermal softening of steel. The JC model is analysed due to its prevailing role in the practice of constitutive relation of properties of reinforcement steels. The key element of this study is a new look at the JC model from the statistical viewpoint. The JC model is subjected to examination by confronting its deterministic nature with statistical variability of experimental data that can be acquired from stress-strain records. It is stated that to now this variability has been largely ignored. The current practice of fitting the JC model to individual and non-repetitive stress-strain records is analysed. It is suggested how to address the problem of the model fitting in the case where stress-strain data is obtained by repetitive measurements. A procedure for processing small-size statistical samples extracted from this data is proposed. The essential idea of this procedure is to fit components of the JC model to limits of one-sided confidence intervals calculated by means of the statistical technique known as bootstrap resampling.