bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase III trial of docetaxel versus docetaxel and radium-223 (Ra-223) in patients with metastatic castration-resistant prostate cancer (mCRPC): DORA.
Authors: Morris Michael J. , De Wit Ronald , Vogelzang Nicholas J. , Tagawa Scott T. , Higano Celestia S. , Hamberg Paul
Published: June 2021

TPS5091

Background: Ra-223, a bone-targeted alpha therapy, prolongs survival in patients (pts) with symptomatic mCRPC to bone. Docetaxel targets microtubule trafficking improving survival in the mCRPC and metastatic hormone-sensitive settings. We hypothesized that simultaneously targeting the tumor and bone compartment yields superior outcomes than targeting either alone. We previously determined the dose and schedule of co-administering Ra-223 + docetaxel in a randomized phase I/IIa trial. The combination appeared to have improved declines in prostate specific antigen (PSA) and bone markers, delayed PSA progression, and was better tolerated (with adjusted dose/schedule) relative to standard docetaxel alone. We are now conducting a phase III study to determine the clinical benefit of the regimen. Methods: Randomization (1:1) of 738 men with mCRPC to docetaxel or docetaxel + Ra-223 is planned with a projected hazard ratio for treatment effect (15 vs 20 months median survival) of 0.75. Pts with ≥2 bone lesions and progression by Prostate Cancer Working Group 3 criteria are eligible. Other key inclusion criteria are an Eastern Cooperative Oncology Group performance status of 0–1 and normal organ function. Key exclusion criteria are: use of anticancer therapy ≤4 weeks (wks) before randomization and use of bone-seeking radiopharmaceuticals or chemotherapy in the castration-resistant setting, and bulky visceral metastases (≥3 lung and/or liver or a lesion ≥2 cm in the previous 8 wks). Subjects receive docetaxel 75 mg/m2 IV q3w for 10 doses or docetaxel 60 mg/m2 IV q3w for 10 doses + Ra-223 55 kBq/kg IV q6w for 6 doses. The primary endpoint is overall survival. Secondary and exploratory endpoints include: radiographic progression-free survival, symptomatic skeletal event-free survival, safety, markers of bone metabolism, alterations in circulating tumor cells and DNA, detection of androgen-receptor splice variant 7, changes in automated bone scan index (aBSI), and assessment of patient-reported outcome instruments (FACT-P, Brief Pain Inventory, Brief Fatigue Inventory). The study is open at 32 sites in the US and Netherlands and has 170 subjects enrolled. The study is sponsored by Memorial Sloan Kettering Cancer Center, and managed by the Prostate Cancer Clinical Trials Consortium. Clinical trial information: NCT03574571.
Phase 1b study of AMG 757, a half-life extended bispecific T-cell engager (HLE BiTEimmune-oncology therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC).
Authors: Aggarwal Rahul Raj , Aparicio Ana , Heidenreich Axel , Sandhu Shahneen Kaur , Zhang Yiran , Salvati Mark , Shetty Aditya , Hashemi Sadraei Nooshin
Published: June 2021

TPS5100

Background: NEPC is an aggressive cancer with poor prognosis. No standard treatment approach for NEPC exists and it remains an unmet need. NEPC is usually treatment-emergent, characterized by histological transformation from adenocarcinoma to a high-grade neuroendocrine tumor (NET), and may develop in 15%–20% of patients (pts) treated with standard prostate adenocarcinoma therapies, including novel hormonal therapies. The inhibitory Notch ligand, Delta-like ligand 3 (DLL3), is highly expressed on the surface of cancer cells, including NEPC cells, making it an attractive and a promising therapeutic target. AMG 757 is an HLE BiTE immuno-oncology therapy designed to redirect cytotoxic T cells to tumor cells by binding DLL3 on cancer cells and CD3 on T cells, resulting in T cell activation and expansion and T cell-dependent killing of tumor cells. AMG 757 showed in vitro activity in DLL3-expressing NETs, including NEPC. Preliminary results of an on-going first-in-human study suggest AMG 757 is safe and effective in pts with small cell lung cancer (NCT03319940), which prompted its study in NEPC. Methods: NCT04702737 is an open-label, phase 1b study evaluating AMG 757 infusion in pts with metastatic de novo or treatment-emergent NEPC, consisting of dose exploration and then dose expansion. Key eligibility criteria include adults (≥18 y) with NEPC whose disease progressed/recurred after ≥1 treatment course including a platinum-based regimen for de novo NEPC or an androgen signaling inhibitor, measurable disease per modified RECIST 1.1 per Prostate Cancer Working Group 3 modifications, ECOG performance status ≤2, life expectancy > 3 mo, adequate organ function, and no untreated/symptomatic brain metastases. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose or recommended phase 2 dose of AMG 757. Secondary objectives are to evaluate antitumor activity (ie, objective response, duration of response, progression-free survival, overall response) and characterize pharmacokinetics. The starting dose for dose exploration will be based on the dose deemed safe and tolerable in the ongoing trial of AMG 757 in SCLC. The study is open to enrollment. Clinical trial information: NCT04702737.
eMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.
Authors: Tolaney Sara M. , Fallowfield Lesley , Kaufman Peter A. , Ciruelos Eva M. , Gainford Mary Corona , Lu Yi , Hurt Karla , Wasserstrom Heather Ann , Chen Yanyun , Goel Shom
Published: June 2021

TPS596

Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.
TrilynX: A phase 3 trial of xevinapant and concurrent chemoradiation for locally advanced head and neck cancer.
Authors: Bourhis Jean , Burtness Barbara , Licitra Lisa F. , Nutting Christopher , Schoenfeld Jonathan D. , Ait Sarkouh Rafik , Bouisset Florilene , Nauwelaerts Heidi , Urfer Yulia , Zanna Claudio , Cohen Ezra E.W.
Published: June 2021

TPS6091

Background: Concurrent chemoradiotherapy (CRT) is the standard of care for previously untreated patients with locoregionally advanced squamous cell carcinomas of the head and neck (LA-SCCHN). Xevinapant (Debio 1143) is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumor activity of platinum-based chemotherapy and radiotherapy. The radiosensitizing effect of xevinapant is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. Three-year follow-up results from a randomized Phase 2 study showed significant improvements of xevinapant versus placebo in addition to standard chemoradiation (CRT) for locoregional control (LRC) rate at 18 months, PFS and OS. The addition of xevinapant was well tolerated, manageable and did not jeopardize backbone therapy [1, 2]. Methods: TrilynX is a multinational, Phase 3, double-blind, placebo-controlled, randomized clinical study assessing the efficacy of xevinapant in combination with concurrent CRT compared with placebo in combination with CRT for LA-HNSCC. Adult patients with newly diagnosed, pathologically proven, treatment-naive LA-SCCHN will be enrolled. Study population will include hypopharynx, larynx and p16-negative oropharyngeal. Other eligibility criteria: ECOG PS 0 or 1, AST and ALT ≤ 3.0 x ULN, total bilirubin ≤ 1.5 × ULN, and eligible for definitive CRT. Approximately 700 eligible patients will be randomly assigned to receive oral xevinapant at 200 mg per day on days 1 to 14 of 3-week cycles or placebo for three cycles in combination with cisplatin (100 mg/m², q3w) for three cycles, and concomitant standard fractionation intensity-modulated radiotherapy (70 Gy/7 weeks). The concurrent CRT period will be followed by a monotherapy period consisting of further three cycles of xevinapant or placebo. The primary endpoint is Event Free Survival (EFS) assessed by a Blinded Independent Radiological Committee (BIRC). An interim analysis will occur when 279 EFS events as assessed by the BIRC are observed. The primary analysis will occur once 429 EFS events are observed. TrilynX has ̃90% power to detect the expected hazard ratio benefit of 0.73. Secondary end-points include OS, PFS, LRC, ORR, HRQL, and safety. Data driven design, patients will be followed up for a minimum of 60-months. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. TrilynX started in August 2020 and it is ongoing. References: [1] X. Sun et. al, Lancet Oncol; 21(9): 1173-1187, 2020. [2] J. Bourhis et al., Ann Oncol; 31 (suppl 4): LBA39, 2020. Clinical trial information: NCT04459715.
Coastal: A phase 3 study of the PI3Kδ inhibitor zandelisib with rituximab (R) versus immunochemotherapy in patients with relapsed indolent non-Hodgkin’s lymphoma (iNHL).
Authors: Jurczak Wojciech , Zinzani Pier Luigi , Cunningham David , Yavrom Sharon , Huang Wenying , Gorbatchevsky Igor , Ribrag Vincent
Published: June 2021

TPS7573

Background: Patients (pts) with iNHL treated with front-line immunochemotherapy may benefit from an alternative, chemotherapy-free regimen at relapse. Zandelisib, a potent, selective, and structurally differentiated oral PI3Kδ inhibitor, achieved an 87% response rate, with median duration of response not reached in iNHL when given as a monotherapy or in combination with R. A low rate ( < 10%) of Grade ≥ 3 immune-mediated adverse events of special interest associated with PI3kδ inhibitors is observed in patients administered zandelisib on an intermittent schedule (IS) (JCO 2020 38:15_suppl, 8016). An open-label, phase 2 study (TIDAL, NCT03768505) of zandelisib as monotherapy is ongoing in pts with relapsed/refractory follicular lymphoma (FL) and marginal zone lymphoma (MZL). Methods: The COASTAL study is a randomized, open-label, controlled multicenter phase 3 trial to investigate the safety and efficacy of zandelisib in combination with R versus standard immunochemotherapy in pts with iNHL. Key eligibility criteria: adults with relapsed or refractory FL or MZL who received ≥1 prior lines of therapy which must have included an anti-CD20 antibody in combination with chemotherapy or lenalidomide (L); at least one bi-dimensionally measured lesion > 1.5 cm; adequate bone marrow, renal and hepatic function; ECOG performance status score of 0 to 1. Key exclusion criteria: histologically confirmed diagnosis of FL grade 3b or transformed disease; administration of 2 prior immunochemotherapy regimens; prior PI3K inhibitor therapy; known lymphomatous involvement of the central nervous system. Subjects will be randomized 1:1 to receive R-zandelisib or immunochemotherapy (R-CHOP or R-B) and stratified by type and number of prior treatment regimens, histology, and duration of treatment-free interval after last therapy. Zandelisib will be given in a 28-day cycle comprising of daily dosing for 2 cycles followed by IS dosing on days 1-7 of each 28-day subsequent cycle for a duration of 2 years. Rituximab or immunochemotherapy will be given for a total of 6 cycles. Disease response will be assessed by an Independent Response Review Committee according to the modified Lugano Classification. Radiographic tumor assessment will be performed approximately every 12 weeks for the first 9 months, every 16 weeks for the next 12 months, and every 24 weeks thereafter. The primary efficacy endpoint is progression-free survival. The major secondary endpoints include ORR, complete response rate, overall survival, and safety. The trial will enroll approximately 534 pts in ̃200 sites globally and will begin enrollment in mid-2021. Clinical trial information: NCT04745832.
Randomized, double-blind, placebo-controlled phase 3 study of ibrutinib plus rituximab in patients with previously untreated marginal zone lymphoma (MZL).
Authors: Noy Ariela , Hughes Stephanie , Biggar Erin , Bogdan Matthew
Published: June 2021

TPS7576

Background: First-line treatment options for patients with MZL include single-agent immunotherapy, chemotherapy, or chemoimmunotherapy. While chemoimmunotherapy has a higher toxicity profile than immunotherapy alone, it may lead to longer progression-free survival (PFS). Rituximab, an anti-CD20 antibody, is FDA approved for the first-line treatment of follicular lymphoma but not specifically for advanced MZL. Ibrutinib is a Bruton’s tyrosine kinase inhibitor approved in the United States for patients with MZL who require systemic therapy and have received ≥1 prior anti-CD20-based therapy. The combination of ibrutinib and rituximab has proven effective and is well tolerated in other B-cell lymphomas; it may serve as an effective chemotherapy-free option for the treatment of previously untreated MZL. Methods: NCT04212013 is a multicenter, double-blind, placebo-controlled, randomized, phase 3 study designed to compare the efficacy of ibrutinib + rituximab vs placebo + rituximab in patients with previously untreated MZL. Adults (≥18 y) with histologically documented MZL (splenic, nodal, and extranodal subtypes), no prior systemic treatment for MZL (prior splenectomy or other local surgical or radiation treatment allowed), measurable disease on CT scan, documented evidence of need for treatment, and Eastern Cooperative Oncology Group performance status ≤2 are eligible. Patients will be randomly assigned 1:1 to receive ibrutinib 560 mg once daily or placebo; all patients will also receive rituximab 375 mg/m2 on days 1, 8, 15, and 22 of cycle 1. Subcutaneous dosing after dose 1 is allowed. Treatment with ibrutinib or placebo will continue for 30 mo or until disease progression, unacceptable toxicity, patient or investigator decision to withdraw, noncompliance, death, or study termination. Clinical assessments will occur every 4 weeks until week 13, at week 25, and then every 6 mo thereafter. Imaging assessments will be conducted at week 13, at week 25, and then every 6 mo thereafter. Response will be investigator assessed per the revised International Working Group for Non-Hodgkin Lymphoma (RECIL) criteria. At month 30, patients who have a complete response (CR) will discontinue treatment; patients who have a partial response (PR) or stable disease may continue treatment at investigator discretion. Safety will be assessed throughout the study and for 30 days after the last dose of study treatment. The primary endpoint is CR rate at month 30. Secondary endpoints include overall response rate (CR + PR), duration of response, PFS, overall survival, and safety. Enrollment has started and will continue until approximately 138 patients are enrolled. Clinical trial information: NCT04212013.
CAcTUS: A parallel arm, biomarker driven, phase II feasibility trial to determine the role of circulating tumor DNA in guiding a switch between targeted therapy and immune therapy in patients with advanced cutaneous melanoma.
Authors: Lee Rebecca , Rothwell Dominic G. , Chow Shien , Shaw Heather May , Turajlic Samra , Smith Nigel , Clipson Alexandra , Clarke Harry , Kelso Noel , Mitchell Jackie , Sutton Chris , Sylvestre Gema , Nathan Paul D. , Larkin James , Corrie Philippa Gail , Plummer Elizabeth Ruth , Marais Richard , Dive Caroline , Lorigan Paul
Published: June 2021

TPS9587

Background: Circulating tumor DNA (ctDNA; the tumour derived fraction of circulating free DNA in the blood) has been shown to be a biomarker of tumor burden/progression in many cancers. We recently accurately monitored treatment response and resistance in stage IV melanoma by ctDNA analysis in serial peripheral blood samples. Pre-clinical data has previously revealed that BRAF inhibition provokes a micro-environment with increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines that could enhance immune responses. We aimed to test the hypothesis that ctDNA could be implemented as a personalised, real-time liquid biopsy to identify when tumours are responding to targeted therapy in order optimise a switch to immunotherapy. Methods: We validated the ctDNA assays for BRAF mutation calling as a primary trial endpoint. We designed a phase II multicenter, parallel arm study across 6 UK sites, to assess primary objectives of i). Whether a ctDNA result can be turned around within 7 days and actioned in a clinically relevant timeframe ii). to assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% from baseline on targeted therapy is an appropriate ‘cut off’ to instruct switching to immunotherapy. Secondary endpoints include Overall Response Rate (ORR) to immunotherapy, radiological/clinical and ctDNA determined progression free survival (PFS) on each treatment. Forty patients are planned based on inclusion criteria of stage IV or stage III unresectable cutaneous BRAF mutant melanoma, baseline ctDNA BRAF variant allele frequency (VAF) ≥1.5%, ECOG 0/1/2, no symptomatic brain metastases, no prior adjuvant nivolumab plus ipilimumab (N+I). Prior adjuvant dabrafinib + trametinib (D+T) is allowed as long as recurrence is >6 months from completion. Patients are randomised 1:1 to either standard Arm A; investigator choice of either D+T (150mg BD +2mg OD respectively) or N+I (1 mg/kg N +3 mg/kg I q3 wkly, then N 480mg q4 wkly) first line, then switch on progression to the other treatment. In the experimental Arm B; all patients start on D+T and have BRAF ctDNA monitored q2 wkly for 4 wks then q4 wkly. When ≥80% decrease vs. baseline in ctDNA BRAF VAF occurs, patients switch to N+I. If patients subsequently progress on N+I, they will resume D+T. The study is open with 9 patients enrolled at time of submission. Clinical trial information: NCT03808441.
Overcoming Barriers to Clinical Trial Participation: Outcomes of a National Clinical Trial Matching and Navigation Service for Patients With a Blood Cancer
Authors: Sae-Hau Maria , Disare Kate , Michaels Margo , Gentile Alissa , Szumita Leah , Treiman Katherine , Weiss Elisa S.
Published: June 2021

PURPOSE:

There are numerous barriers to cancer clinical trial participation in the United States. This paper describes the approach and outcomes of The Leukemia & Lymphoma Society's Clinical Trial Support Center (CTSC), whose nurse navigators assist patients with a blood cancer and their oncologists by identifying all appropriate trials based on clinical data and patient preference, facilitating informed and shared decision making, and minimizing enrollment barriers.

METHODS:

Data on patients served from October 2017 to October 2019 were analyzed using bivariate and multivariate analyses to determine demographic and clinical characteristics associated with enrollment. Reasons for nonenrollment were examined.

RESULTS:

The CTSC opened 906 patient cases during this time frame. Among all US patients with a closed case (n = 750), the clinical trial enrollment rate was 16.1%. Among those with a known enrollment outcome after a trial search (n = 537), the enrollment rate was 22.5%. Multivariate analysis controlling for variables significant in bivariate analyses (insurance, treatment status, Eastern Cooperative Oncology Group performance status, and urban or rural residence) revealed that patients with Medicaid were less likely to enroll than those with private or commercial insurance (adjusted odds ratio, 0.054; CI, 0.003 to 0.899), and patients in treatment or maintenance were less likely to enroll than those relapsed or refractory to most recent therapy (adjusted odds ratio, 0.312; CI, 0.139 to 0.702). Primary reasons for nonenrollment were preference for standard of care (66.3%) and patient passed away (16.1%).

CONCLUSION:

The CTSC is an effective, replicable model for addressing multilevel barriers to clinical trial participation. The findings highlight the need to increase opportunities for trial participation sooner after diagnosis and among patients with Medicaid.
GCM2 Silencing in Parathyroid Adenoma Is Associated With Promoter Hypermethylation and Gain of Methylation on Histone 3
Authors: Singh Priyanka , Bhadada Sanjay Kumar , Dahiya Divya , Saikia Uma Nahar , Arya Ashutosh Kumar , Sachdeva Naresh , Kaur Jyotdeep , Behera Arunanshu , Brandi Maria Luisa , Rao Sudhaker Dhanwada
Published: June 2021

Context

Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of the parathyroid glands.

Objective

We sought to identify whether the epigenetic alterations in GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices.

Methods

Messenger RNA (mRNA) and protein expression of GCM2 were analyzed by reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of the GCM2 promoter were measured by bisulfite sequencing and chromatin immunoprecipitation–qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in parathyroid (PTH)-C1 cells by treating with 5-aza-2′-deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels.

Results

mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P < .001) and higher H3K9me3 levels in the GCM2 promoter (P < .04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a nonsignificant change in GCM2 transcription.

Conclusion

These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be a promising avenue of research for parathyroid adenoma therapeutics.
Endocrine Toxicity and Outcomes in Patients With Metastatic Malignancies Treated With Immune Checkpoint Inhibitors
Authors: Al Ashi Suleiman I , Thapa Bicky , Flores Monica , Ahmed Ramsha , Rahim Shab E Gul , Amir Maryam , Alomari Mohammad , Chadalavada Pravallika , Morrison Shannon L , Bena James F , Hercbergs Aleck , Lashin Ossama , Daw Hamed
Published: June 2021

Context

Immune checkpoint inhibitors (ICIs) have gained a revolutionary role in management of many advanced malignancies. However, immune-related endocrine events (irEEs), have been associated with their use. irEEs have nonspecific clinical presentations and variable timelines, making their early diagnosis challenging.

Objective

To identify risk factors, timelines, and prognosis associated with irEEs development.

Design and Setting

Retrospective observational study within the Cleveland Clinic center.

Patients

Metastatic cancer adult patients who received ICIs were included.

Methods

570 charts were reviewed to obtain information on demographics, ICIs used, endocrine toxicities, cancer response to treatment with ICI, and overall survival.

Main Outcome Measures

Incidence of irEEs, time to irEEs development and overall survival of patients who develop irEEs.

Results

The final cohort included 551 patients. The median time for the diagnosis of irEEs was 9 weeks. Melanoma was associated with the highest risk for irEEs (31.3%). Ipilimumab appeared to have the highest percentage of irEEs (29.4%), including the highest risk of pituitary insufficiency (11.7%), the most severe (Grade 4 in 60%) and irreversible (100%) forms of irEEs. Forty-five percent of patients with irEEs had adequate cancer response to ICI compared to 28.3% of patients without irEEs (P = 0.002). Patients with irEEs had significantly better survival compared to patients without irEEs (P < 0.001).

Conclusions

In the adult population with metastatic cancer receiving treatment with ICI, irEEs development may predict tumor response to immunotherapy and a favorable prognosis. Ipilimumab use, combination ICI therapy, and melanoma are associated with a higher incidence of irEEs.
Who Stays at Home? The Politics of Social Distancing in Brazil, Mexico, and the United States during the COVID-19 Pandemic
Authors: Testa Paul F. , Snyder Richard , Rios Eva , Moncada Eduardo , Giraudy Agustina , Bennouna Cyril
Published: June 2021

Context: Reductions in population mobility can mitigate COVID-19 virus transmission and disease-related mortality. But do social distancing policies actually change population behavior and, if so, what factors condition policy effects?

Methods: We leverage subnational variation in the stringency and timing of state-issued social distancing policies to test their effects on mobility across 109 states in Brazil, Mexico, and the United States. We also explore how conventional predictors of compliance, including political trust, socioeconomic resources, health risks, and partisanship, modify these policy effects.

Findings: In Brazil and the United States, stay-at-home orders and workplace closures reduced mobility, especially early in the pandemic. In Mexico, where federal intervention created greater policy uniformity, workplace closures produced the most consistent mobility reductions. Conventional explanations of compliance perform well in the United States but not in Brazil or Mexico, apart from those emphasizing socioeconomic resources.

Conclusions: In addition to new directions for research on the politics of compliance, the article offers insights for policy makers on which measures are likely to elicit compliance. Our finding that workplace closure effectiveness increases with socioeconomic development suggests that cash transfers, stimulus packages, and other policies that mitigate the financial burdens of the pandemic may help reduce population mobility.
The Impact COVID-19 School Closures on Educational Inequalities
Authors: Özer Mahmut , Suna Hayri Eren , Aşkar Petek , Çelik Zafer
Published: June 2021

During the new coronavirus pandemic, schools were closed suddenly in almost every country in the world, and education services continued with the distance education solutions. However, the consequences of the school closures, maintaining education services via distance education and the deprivation of other services provided by schools have not been adequately evaluated. In this study, the effects of school closures and distance education on families and students during the Covid-19 pandemic were reviewed. Parental involvement, physical and technological possessions at home, digital literacy levels of students and parents have become the main factors that determines the efficiency of distance learning during the pandemic. As a result, there is a possibility that inequalities in education will increase more in pandemic. Inequalities in education had an important impact on the unemployment and loss of income, learning loss of students and psychological conditions, reaching healthy nutrition, need for special education, and fragile students. Although distance education was considered as an opportunity to reduce learning loss of students due to school closures during the pandemic, unfortunately it also made possible to increase the inequalities in education during the pandemic period.
Validity and reliability of the Neurodevelopmental Screening Tool (NDST) in screening for neurodevelopmental disorders in children living in rural Kenyan coast
Authors: Bitta Mary A. , Kipkemoi Patricia , Kariuki Symon M. , Abubakar Amina , Gona Joseph , Philips-Owen Jacqueline , Newton Charles R.
Published: June 2021

Background:There are no data on the precise burden of neurodevelopmental disorders (NDD) in Africa, despite high incidence of risk factors. Ten Questions Questionnaire (TQQ) has been used extensively in Africa to screen neurological impairments but not autism spectrum disorders (ASD) and attention-deficit hyperactivity disorders (ADHD). The Neurodevelopmental Screening Tool (NDST) has reliably assessed NDD in Asia; its validity in Africa is unknown.

Methods:Using NDST and TQQ, we screened 11,223 children aged 6-9 years in Kilifi, Kenya. We invited all screen-positives and a proportion of screen-negative children for confirmatory diagnosis of NDD using clinical history, neuropsychological assessments and interviews.

Results:In total, 2,245 (20%) children screened positive for NDD. Confirmatory testing was completed for 1,564 (69.7%) screen-positive and 598 (6.7%) screen-negative children. NDST’s sensitivity was 87.8% (95%CI: 88.3-88.5%) for any NDD, 96.5% (95%CI:96.1-96.8%) ASD and 89.2% (95%CI: 88.7-89.8%) for ADHD. Moderate/severe neurological impairments’ sensitivities ranged from 85.7% (95%CI: 85.1-86.3%) for hearing impairments to 100.00% (100.0-100.0%) for motor impairments. NDST had higher sensitivities than TQQ for epilepsy (88.8vs86.7), motor impairments (100.0vs93.7) and cognitive impairment (88.2vs84.3). Sensitivities for visual and hearing impairments were comparable in both tools. NDST specificity was 82.8% (95%CI: 82.1-83.5%) for any NDD, 94.5% (95%CI: 94.0-94.9%) for ASD and 81.7% (95%CI: 81.0-82.4%) for ADHD. The specificities range for neurological impairments was 80.0% (95%CI: 79.3-80.7%) for visual impairments to 93.8% (95%CI: 93.4-94.3%) for epilepsy. Negative predictive values were generally very high (≤100%), but most positive predictive values (PPV) were low (≤17.8%). Domain specific internal consistency ranged from 0.72 (95%CI: 0.70-0.74) for ADHD to 0.89 (95%CI: 0.87-0.90) for epilepsy.

Conclusions:NDST possesses high sensitivity and specificity for detecting different domains of NDD in Kilifi. Low PPV suggest that positive diagnoses should be confirmed when samples are drawn from a population with low disease prevalence.
electronic methodological guide "Methodological guidelines for the implementation of practical classes in the discipline "Medical and biological foundations of life safety" for students of the specialty 20.02.02 "Emergency protection" of secondary vocational education institutions"
Authors: GONCHAROVA OKSANA
Published: June 2021

Methodological guidelines for the implementation of practical classes in the discipline "Medical and biological foundations of life safety" ARE INTENDED FOR STUDENTS OF THE SPECIALTY 20.02.02 "PROTECTION IN EMERGENCY SITUATIONS" OF SECONDARY VOCATIONAL EDUCATION INSTITUTIONS. THE PURPOSE OF THE GUIDELINES IS TO PROVIDE A CLEAR ORGANIZATION OF PRACTICAL CLASSES IN THE DISCIPLINE, TO CREATE AN OPPORTUNITY FOR STUDENTS WHO WERE ABSENT FROM THE PRACTICAL LESSON TO INDEPENDENTLY PERFORM THE WORK, TO ISSUE A REPORT AND TO PROTECT THE WORK IN A TIMELY MANNER.
Morning Discharges and Patient Length of Stay in Inpatient General Internal Medicine
Authors: Kirubarajan Abirami , Shin Saeha , Fralick Michael , Kwan Janice , Lapointe‐Shaw Lauren , Liu Jessica , Tang Terence , Weinerman Adina , Razak Fahad , Verma Amol
Published: June 2021

BACKGROUND

Many initiatives seek to increase the number of morning hospital discharges to improve patient flow, but little evidence supports this practice.

OBJECTIVE

To determine the association between the number of morning discharges and emergency department (ED) length of stay (LOS) and hospital LOS in general internal medicine (GIM).

DESIGN, SETTING, AND PARTICIPANTS

Multicenter retrospective cohort study involving all GIM patients discharged between April 1, 2010, and October 31, 2017, at seven hospitals in Ontario, Canada.

MAIN MEASURES

The primary outcomes were ED LOS and hospital LOS, and secondary outcomes were 30‐day readmission and in‐hospital mortality. The number of morning GIM discharges (defined as the number of patients discharged alive between 8:00 am and 12:00 pm) on the day of each hospital admission was the primary exposure. Multivariable regression models were fit to control for patient characteristics and situational factors, including GIM census.

RESULTS

The sample included 189,781 patient admissions. In total, 36,043 (19.0%) discharges occurred between 8:00 am and 12:00 pm. The average daily number of morning discharges and total discharges per hospital was 1.7 (SD, 1.4) and 8.4 (SD, 4.6), respectively. The median ED LOS was 14.5 hours (interquartile range [IQR], 10.0‐ 23.1), and the median hospital LOS was 4.6 days (IQR, 2.4‐9.0). After multivariable adjustment, there was not a significant association between morning discharge and hospital LOS (adjusted rate ratio [aRR], 1.000; 95% CI, 0.996‐1.000; P = .997), ED LOS (aRR, 0.999; 95% CI, 0.997‐1.000; P = .307), 30‐day readmission (aRR, 1.010; 95% CI, 0.991‐1.020; P = .471), or in‐hospital mortality (aRR, 0.967; 95% CI, 0.920‐1.020; P = .183). The lack of association between morning discharge and LOS was generally consistent across all seven hospitals. At one hospital, morning discharge was associated with a 1.9% shorter ED LOS after multivariable adjustment (aRR, 0.981; 95% CI, 0.966‐0.996; P = .013).

CONCLUSIONS

The number of morning discharges was not significantly associated with shorter ED LOS or hospital LOS in GIM. Our findings suggest that increasing the number of morning discharges alone is unlikely to substantially improve patient throughput in GIM, but further research is needed to determine the effectiveness of specific interventions.
Just DM Me (Politely): Direct Messaging, Politeness, and Hiring Outcomes in Online Labor Markets
Authors: Hong Yili , Peng Jing , Burtch Gordon , Huang Ni
Published: June 2021

This study examines the role of text-based direct messaging systems in online labor markets, which provide a communication channel between workers and employers, adding a personal touch to the exchange of online labor. We propose the effect of workers’ use of the direct messaging system on employers’ hiring decisions and conceptualize the information role of direct messaging. To empirically evaluate the information role of the direct messaging system, we leverage data on the direct messaging activities between workers and employers across more than 470,000 job applications on a leading online labor market. We report evidence that direct messaging with a prospective employer increases a worker’s probability of being hired by 8.9%. However, the degree to which workers benefit from direct messaging is heterogeneous, and the effect amplifies for workers approaching employers from a position of disadvantage (lacking tenure or fit with the job) and attenuates as more workers attempt to message the same prospective employer. The effects also depend on message content. In particular, we find that the benefits of direct messaging for workers depend a great deal on the politeness of the workers, and this “politeness effect” depends on several contextual factors. The beneficial effects are amplified for lower-status workers (i.e., workers lacking tenure and job fit) and workers who share a common language with the employer. At the same time, the beneficial effects weaken in the presence of typographical errors. These findings provide important insights into when and what to message to achieve favorable hiring outcomes in online employment settings.
Risk-Averse Stochastic Programming: Time Consistency and Optimal Stopping
Authors: Pichler Alois , Liu Rui Peng , Shapiro Alexander
Published: June 2021

Decision making under uncertainty includes reassessing and reevaluating risk after initial decisions. To this end, it is essential to consider a governing value process and to track its evolution over time. The paper, “Risk-Averse Stochastic Programming: Time Consistency and Optimal Stopping,” by Pichler, Liu, and Shapiro, develops a consistent framework by consolidating risk and optimal stopping. The paper develops the notion of time consistency for the stochastic multistage optimization problem. Supermartingales and envelopes characterizing optimal decisions are given explicitly. With that, dynamic equations are derived, which gradually reveal the optimal policy. Taking risk into account requires updating optimal policies, as an explicit example on American options demonstrates.
An exploration of the development of resilience in student midwives
Authors: Williams Jacqui , Lathlean Judith , Norman Kay
Published: June 2021

Student midwives have to complete a demanding programme to become a midwife, and therefore it is questioned whether they need resilience to be successful. The study's aims were to explore whether resilience developed in one cohort of 25 undergraduate student midwives and what the concept of resilience meant to them. This study adopted a longitudinal case study approach in one Higher Education Institution in England during the first 18 months of their programme. The study used Wagnild and Young's (1993) (updated 2015) True Resilience Scale©, administered on three occasions. Additionally, four focus groups were conducted twice and six participants were involved in one-to-one interviews to explore issues raised in the focus group. SPSS Pairwise comparisons revealed that there were significant differences in True Resilience Scale© scores between the first and the second completion (p=0.034), and time one and time three (p=0.002); there were no significant differences between time two and time three (p=1.0). In this cohort of student midwives, the scale showed that the majority had developed their resilience during the study and this was supported in what the students reported. A conceptual model, which defines resilience for student midwives, is presented to strengthen how resilience can be supported and developed.
Preterm birth and associated factors among mothers who gave birth in Dire Dawa, Ethiopia
Authors: Sema Alekaw , Kassie Nigus , Amsalu Bezabih , Belay Yalelet , Guta Alemu , Sintayehu Yitagesu , Desalew Assefa , Abera Legesse
Published: June 2021

Background

The highest rate of preterm birth in the world is in Sub-Saharan Africa and Asia. However, there is limited data in this study area. Therefore, this study aims to assess the prevalence and associated factors of preterm birth in Dire Dawa City, Eastern Ethiopia.

Method

An institutional-based, cross-sectional study was conducted with 420 respondents.

Conclusion

Preterm birth is still a major public health problem in Dire Dawa City.
Are macrolides a risk in pregnancy?
Authors: Mendes Aysha
Published: June 2021

Aysha Mendes has a closer look at the research published on the safety of macrolides in pregnancy and what this means for practising midwives
Anaphylaxis: how to recognise and manage in primary care
Authors: Kramer Hannah , Batt Rebecca
Published: June 2021

Anaphylaxis is a life-threatening emergency. Hannah Kramer and Rebecca Batt explain how correct diagnosis, avoidance and patient education are fundamental in reducing risk

Anaphylaxis is a serious systemic hypersensitivity reaction that is usually rapid in onset and can cause death. It is an immune-mediated reaction, which typically occurs when a person is exposed to a trigger, for example a food, drug, or insect sting. This article aims to assist with the recognition of symptoms and to guide management of anaphylaxis in primary care. Beyond the acute, the practice nurse can play a key role in helping patients to manage their allergies in the long-term, particularly for those who are most vulnerable. Patients should be supported in understanding how best to avoid their triggers, in managing their emergency medication, and in the importance of good asthma control.
The Relationship between the Transformational Leadership, the Cultural Intelligence of Teachers and the Skills of Principals’ Diversity Management
Authors: Cobanoglu Necati
Published: June 2021

It is regarded as considerable values those principles’ skills of managing diversities and teachers’ cultural intelligences which mean they understand and appreciate other cultures. These core values are remarkably vital to be culturally literate in the global world. The organizations and their administrators respecting the diversities of the employees can allocate more time competing their counterparts in the world instead of losing energy with unnecessary conflicts. The aim of the study is to examine the correlation between teachers’ cultural intelligence and Principal’s managing the diversities and their transformational leaderships according to the teachers’ point of views. The research has adopted a correlational model. The data of the research was gathered from 428 primary school teachers in Turkey/Malatya during 2020-2021 academic year. The Data was gathered through the “Cultural Intelligence”, “Diversity Management” and “Transformational Leadership” scales. The data was analyzed by arithmetic mean, correlation analysis and regression analysis. The results of the research suggest that the primary school teacher’s cultural intelligence, the principal’s management of diversity and their transformational leadership levels were “mostly high”. It was revealed that there was a moderate level positive significant correlation between teachers’ cultural intelligence levels and Principal’s skills of managing the diversities and their transformational leaderships. Moreover, teacher’s cultural intelligence levels and Principal’s skills of managing the diversities predict the transformational leaderships of Principles. Consequently, to increase the transformational leadership of Principals, it is recommended to enhance teachers’ socio-cultural awareness and to work on improving the skills of diversity management of principals.
Interaction of Energy-Grid-Load Based on Demand Side Response of Full-cost Electricity Price
Authors: Xu Xin-ying , Jiang Qi-jie , Yin Chuan-bin , Jie Xiao-wen
Published: June 2021

In the research of intelligent grids, people usually pay attention to the interaction between power source and load to absorb more new energy. In contrast, the utilization of power source and load on grid resources is less considered, and energy-grid-load is not fully explored. The profound benefits and value of the three interactions. To this end, the paper proposes the interactive mode and method of power supply, power grid, and load based on full-cost electricity price. The power source side needs to consider the impact of transmission costs when optimizing economic dispatch; the load side needs to calculate the full-cost electricity price based on the power flow tracking method, clarify the load’s use of power and grid resources, and reflect the “who benefits, who bears the cost” Principles and introduce demand-side response to reflect the meaning and value of full-cost electricity prices. The research found that the calculation example analysis based on the IEEE30-node system verifies that the method in this paper can reasonably allocate the cost of the power grid according to the user’s utilization of power grid resources, thereby improving the efficiency, fairness, orderliness and safety of power grid investment and operation.
An Accelerator-based Logistic Map Image Cryptosystems for Grayscale Images
Authors: Holla M. Raviraja , Pais Alwyn R. , Suma D.
Published: June 2021

The logistic map is a class of chaotic maps. It is still in use in image cryptography. The logistic map cryptosystem has two stages, namely permutation, and diffusion. These two stages being computationally intensive, the permutation relocates the pixels, whereas the diffusion rescales them. The research on refining the logistic map is progressing to make the encryption more secure. Now there is a need to improve its efficiency to enable such models to fit for high-speed applications. The new invention of accelerators offers efficiency. But the inherent data dependencies hinder the use of accelerators. This paper discusses the novelty of identifying independent data-parallel tasks in a logistic map, handing them over to the accelerators, and improving their efficiency. Among the two accelerator models proposed, the first one achieves peak efficiency using coalesced memory access. The other cryptosystem further improves performance at the cost of more execution resources. In this investigation, it is noteworthy that the parallelly accelerated logistic map achieved a significant speedup to the larger grayscale image used. The objective security estimates proved that the two stages of the proposed systems progressively ensure security.