bluuebunny/crossref_metadata_2025 huggingface dataset:
Anxiety related disorders in adolescents in the United Arab Emirates: a population based cross-sectional study
Authors: Al-Yateem Nabeel , Bani issa Wegdan , Rossiter Rachel C. , Al-Shujairi Arwa , Radwan Hadia , Awad Manal , Fakhry Randa , Mahmoud Ibrahim
Published: May 2020

Background

Anxiety disorders are common among children and adolescents. However, there is a paucity of up-to-date data on the prevalence and correlates of anxiety-related disorders among children and adolescents in the United Arab Emirates (UAE).

Methods

We conducted a cross sectional study to determine the prevalence of specific anxiety-related disorders (e.g., generalized anxiety disorder, panic disorder, separation anxiety, social anxiety) in the UAE, and identify correlations between these disorders and adolescents’ demographic variables. Participants were 968 adolescents aged 13–18 years attending secondary schools across the UAE. Convenience sampling was used to recruit participants. We collected demographic information and data about participants’ anxiety levels. Anxiety was assessed using the Arabic and English versions of the Screen for Child Anxiety Related Disorders scale. Univariate analyses (independent sample t-tests and analysis of variance) were performed to evaluate factors affecting participants’ anxiety scores. Chi-square tests were used to compare factors associated with anxiety disorders.

Results

Participants’ mean age was 16 ± 1.8 years, and 65.8% were female. The overall prevalence of anxiety disorders was 28%, with this being significantly higher in girls (33.6%) than boys (17.2%) (p < 0.0001). Participants aged < 16 years had higher generalized anxiety, separation anxiety, and social anxiety scores compared with those aged ≥16 years (p ≤ 0.05). Those from households with a maid had significantly higher generalized anxiety, panic disorder, separation anxiety, and significant school avoidance scores than those without a maid (p ≤ 0.05). In addition, participants from middle and low economic backgrounds had higher separation anxiety scores compared with children from high economic backgrounds (p ≤ 0.05). The multivariate analysis showed the main associated factors with anxiety were gender (being female, p < 0.001) and caregiver (other than mother and father together, p < 0.001).

Conclusions

We found a high incidence of anxiety-related disorders among school-aged adolescents in the UAE, with girls being more affected than boys. This suggests that age-appropriate initiatives are urgently needed to reduce the high rate of anxiety-related disorders. It may also be necessary to further investigate the two main associated factors with anxiety identified in this study (being female and non-parental caregivers).
Emerging pesticides responsible for suicide in rural Sri Lanka following the 2008–2014 pesticide bans
Authors: Weerasinghe Manjula , Pearson Melissa , Konradsen Flemming , Agampodi Suneth , Sumith J. A. , Jayamanne Shaluka , Senanayake S. M. H. M. K. , Rajapaksha Sandamali , Eddleston Michael
Published: May 2020

Background

Sri Lanka has reduced its overall suicide rate by 70% over the last two decades through means restriction, through a series of government regulations and bans removing highly hazardous pesticides from agriculture. We aimed to identify the key pesticide(s) now responsible for suicides in rural Sri Lanka to provide data for further pesticide regulation.

Methods

We performed a secondary analysis of data collected prospectively during a cluster randomized controlled trial in the Anuradhapura district of Sri Lanka from 2011 to 16. The identity of pesticides responsible for suicides were sought from medical or judicial medical notes, coroners’ records, and the person’s family. Trend analysis was done using a regression analysis with curve estimation to identify relative importance of key pesticides.

Results

We identified 337 suicidal deaths. Among them, the majority 193 (57.3%) were due to ingestion of pesticides while 82 (24.3%) were due to hanging. A specific pesticide was identified in 105 (54.4%) of the pesticide suicides. Ingestion of carbosulfan or profenofos was responsible for 59 (56.2%) of the suicides with a known pesticide and 17.5% of all suicides. The increasing trend of suicides due to carbosulfan and profenofos over time was statistically significant (R square 0.846, F 16.541, p 0.027).

Conclusion

Ingestion of pesticides remains the most important means of suicides in rural Sri Lanka. The pesticides that were once responsible for most pesticide suicides have now been replaced by carbosulfan and profenofos. Their regulation and replacement in agriculture with less hazardous pesticides will further reduce the incidence of both pesticide and overall suicides in rural Sri Lanka.
Correction to: Informal payments for inpatient health care in post-health transformation plan period: evidence from Iran
Authors: Doshmangir Leila , Sajadi Haniye Sadat , Ghiasipour Maryam , Aboutorabi Ali , Gordeev Vladimir Sergeevich
Published: May 2020

An amendment to this paper has been published and can be accessed via the original article.
Comparison of sputum induction and bronchoscopy in diagnosis of sputum smear-negative pulmonary tuberculosis: a systemic review and meta-analysis
Authors: Luo Wen , Lin Yihua , Li Zhibin , Wang Wanyu , Shi Yonghong
Published: May 2020

Background

Pulmonary tuberculosis is one of the most common infectious diseases worldwide. Patients with suspected pulmonary tuberculosis with negative smear are recommended to undergo further tests including sputum induction and bronchoscopy. Our study is aimed to compare sputum induction and bronchoscopic specimens in the diagnosis of sputum smear-negative pulmonary tuberculosis.

Method

PubMed, Web of Science, Cochrane Library and Embase were searched for eligible studies. The pooled sensitivities (SEN), specificities (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR) and 95% confidence intervals (CI) were constructed, and the areas under the curves (AUCs) were calculated.

Results

Five studies with a total number of 586 cases were included. For mycobacterial culture, the SEN and SPE of sputum induction were 0.72(95% CI, 0.66–0.77) and 1.00(95%CI, 0.99–1.000) respectively, whereas the SEN and SPE of bronchoscopy were 0.70(95%CI, 0.64–0.75) and 1.00(95%CI, 0.99–1.00) respectively. Sputum induction had a similar AUC (0.9564, SE = 0.0749) with bronchoscopy (0.8618, SE = 0.1652) (P = 0.602). For specimen of acid-fast bacilli smear, the SEN and SPE of sputum induction were 0.35(95% CI, 0.29–0.42) and 0.99(95% CI, 0.96–1.00) respectively, whereas the SEN and SPE of bronchoscopy were 0.38(95% CI, 0.32–0.45) and 0.99(95% CI, 0.96–1.00) respectively. There is no statistically significant difference in the AUC for sputum induction (0.6016) compared with bronchoscopy (0.8163) (P = 0.792).

Conclusions

For the diagnosis of sputum smear-negative pulmonary tuberculosis, the diagnosis yield of sputum induction and bronchoscopy is similar.
Adaptation and psychometric evaluation of the simplified Chinese version of the identification of functional ankle instability questionnaire in Chinese-speaking patients with chronic ankle instability disorders
Authors: Wang Wei , Sheng Jun , Tang Yinchao , Xie Qingyun , Wei Meng , Li Zhiqiang , Zheng Wei
Published: May 2020

Background

The aims of this study were to adapt the Identification of Functional Ankle Instability (IdFAI) questionnaire into a simplified Chinese version and to assess its reliability, validity, and responsiveness in Chinese-speaking patients with chronic ankle instability (CAI) disorders.

Methods

The simplified Chinese version of the IdFAI (SC-IdFAI) questionnaire was developed with a five-step procedure involving cross-cultural translation and adaptation. Three questionnaires, including the SC-IdFAI, Medical Outcomes Study Short-Form 36 (SF-36), and Foot and Ankle Ability Measure (FAAM), were administered to the recruited patients. Then, the Cronbach’s alpha value, intraclass correlation coefficient (ICC), standard error of measurement (SEM), minimal detectable change (MDC), Spearman’s correlation coefficient (rs), effect size (ES), and standardized response mean (SRM) were calculated to evaluate the reliability, validity, and responsiveness of the SC-IdFAI questionnaire.

Results

A total of 131, 119, and 86 patients with CAI successfully completed the first, second, and third rounds of the questionnaires, respectively. Good or excellent internal consistency and test–retest reliability were found for the overall scale and subscales of the SC-IdFAI questionnaire. The values for the SEM (1.346) and MDC (3.73) were low, indicating that small clinical changes can be detected by the SC-IdFAI questionnaire. The correlations of the SC-IdFAI with FAAM and SF-36 were generally in agreement with the a priori hypotheses (85%, 34/40), suggesting the SC-IdFAI questionnaire has good construct validity. Moreover, the results suggest that the SC-IdFAI (ES = 1.123 and SRM = 1.554) has an acceptable level of responsiveness.

Conclusion

The SC-IdFAI scale may be an effective tool, and it is responsive, reliable and valid for the assessment of Chinese patients suffering from CAI.
Understanding family caregivers’ needs to support relatives with advanced progressive disease at home: an ethnographic study in rural Portugal
Authors: Teixeira Maria João Cardoso , Abreu Wilson , Costa Nilza , Maddocks Matthew
Published: May 2020

Background

Family caregivers play an important role supporting their relatives with advanced progressive disease to live at home. There is limited research to understand family caregiver needs over time, particularly outside of high-income settings. The aim of this study was to explore family caregivers’ experiences of caring for a relative living with advanced progressive disease at home, and their perceptions of met and unmet care needs over time.

Methods

An ethnographic study comprising observations and interviews. A purposive sample of 10 family caregivers and 10 relatives was recruited within a rural area in the north of Portugal. Data were collected between 2014 and 16 using serial participant observations (n = 33) and in-depth interviews (n = 11). Thematic content analysis was used to analyse the data.

Results

Five overarching themes were yielded: (1) provision of care towards independence and prevention of complications; (2) perceived and (3) unknown caregiver needs; (4) caregivers’ physical and emotional impairments; and (5) balancing limited time. An imbalance towards any one of these aspects may lead to reduced capability and performance of the family caregiver, with increased risk of complications for their relative. However, with balance, family caregivers embraced their role over time.

Conclusions

These findings enhance understanding around the needs of family caregivers, which are optimally met when professionals and family caregivers work together with a collaborative approach over time. Patients and their families should be seen as equal partners. Family-focused care would enhance nursing practice in this context and this research can inform nursing training and educational programs.
Community-based outreach associated with increased health utilization among Navajo individuals living with diabetes: a matched cohort study
Authors: Franz Calvin , Atwood Sidney , Orav E. John , Curley Cameron , Brown Christian , Trevisi Letizia , Nelson Adrianne Katrina , Begay Mae-Gilene , Shin Sonya
Published: May 2020

Background

Navajo community members face high rates of diabetes mellitus and other chronic diseases. The Navajo Community Health Representative Outreach Program collaborated with healthcare providers and academic partners to implement structured and coordinated outreach to patients living with diabetes. The intervention, called Community Outreach and Patient Empowerment or COPE, provides home-based health coaching and community-clinic linkages to promote self-management and engagement in healthcare services among patients living with diabetes. The purpose of this study was to evaluate how outreach by Navajo Community Health Representatives (“COPE Program”) affected utilization of health care services among patients living with diabetes.

Methods

De-identified data from 2010 to 2014 were abstracted from electronic health records at participating health facilities. In this observational cohort study, 173 cases were matched to 2880 controls. Healthcare utilization was measured as the number of times per quarter services were accessed by the patient. Changes in utilization over 4 years were modeled using a difference-in-differences approach, comparing the trajectory of COPE patients’ utilization before versus after enrollment with that of the control group. The model was estimated using generalized linear mixed models for count outcomes, controlling for clustering at the patient level and the service unit level.

Results

COPE enrollees showed a 2.5% per patient per quarter (pppq) greater increase in total utilization (p = 0.001) of healthcare services than non-COPE enrollees; a 3.2% greater increase in primary care visits (p = 0.024); a 6.3% greater increase in utilization of counseling and behavioral health services (p = 0.013); and a 9.0% greater increase in pharmacy visits (p <  0.001). We found no statistically significant differences in utilization trends of inpatient, emergency room, specialty outpatient, dental, laboratory, radiology, or community encounter services among COPE participants versus control.

Conclusions

A structured intervention consisting of Community Health Representative outreach and coordination with clinic-based providers was associated with a modest increase in health care utilization, including primary care and counseling services, among Navajo patients living with diabetes. Community health workers may provide an important linkage to enable patients to access and engage in clinic-based health care.

Trial registration

NCT03326206, registered 10/31/2017, retrospectively registered.
Identification of immune-related biomarkers associated with tumorigenesis and prognosis in cutaneous melanoma patients
Authors: Huang Biao , Han Wei , Sheng Zu-Feng , Shen Guo-Liang
Published: May 2020

Background

Skin cutaneous melanoma (SKCM) is one of the most malignant and aggressive cancers, causing about 72% of deaths in skin carcinoma. Although extensive study has explored the mechanism of recurrence and metastasis, the tumorigenesis of cutaneous melanoma remains unclear. Exploring the tumorigenesis mechanism may help identify prognostic biomarkers that could serve to guide cancer therapy.

Method

Integrative bioinformatics analyses, including GEO database, TCGA database, DAVID, STRING, Metascape, GEPIA, cBioPortal, TRRUST, TIMER, TISIDB and DGIdb, were performed to unveil the hub genes participating in tumor progression and cancer-associated immunology of SKCM. Furthermore, immunohistochemistry (IHC) staining was performed to validate differential expression levels of hub genes between SKCM tissue and normal tissues from the First Affiliated Hospital of Soochow University cohort.

Results

A total of 308 differentially expressed genes (DEGs) and 12 hub genes were found significantly differentially expressed between SKCM and normal skin tissues. Functional annotation indicated that inflammatory response, immune response was closely associated with SKCM tumorigenesis. KEGG pathways in hub genes include IL-10 signaling and chemokine receptors bind chemokine signaling. Five chemokines members (CXCL9, CXCL10, CXCL13, CCL4, CCL5) were associated with better overall survival and pathological stages. IHC results suggested that significantly elevated CXCL9, CXCL10, CXCL13, CCL4 and CCL5 proteins expressed in the SKCM than in the normal tissues. Moreover, our findings suggested that IRF7, RELA, NFKB1, IRF3 and IRF1 are key transcription factors for CCL4, CCL5, CXCL10. In addition, the expressions of CXCL9, CXCL10, CXCL13, CCL4 and CCL5 were positively correlated with infiltration of six immune cells (B cell, CD8+T cells, CD4+T cells, macrophages, neutrophils, dendritic cells) and 28 types of TILs. Among them, high levels of B cells, CD8+T cells, neutrophils and dendritic cells were significantly related to longer SKCM survival time.

Conclusion

In summary, this study mainly identified five chemokine members (CXCL9, CXCL10, CXCL13, CCL4, CCL5) associated with SKCM tumorigenesis, progression, prognosis and immune infiltrations, which might help us evaluate several immune-related targets for cutaneous melanoma therapy.
Health-related quality of life among Jewish older persons in Mexico and its determinants
Authors: López-Ortega Mariana , Konigsberg Mina
Published: May 2020

Purpose

Aging research in Mexico has significantly increased in the past decades, however, little is known on health related quality of life (HRQoL) of older adults. The aim of this study was to expand this field by examining HRQL in a representative sample of Jewish older adults in Mexico, and to investigate its association with different factors.

Methods

This was a cross-sectional survey of a random sample of community dwelling Jewish men and women aged 60 years and older. HRQoL was measured using the Short Form Health Survey (SF-36). Bivariate analysis was performed to estimate the association of scores of HRQoL and different characteristics of the study sample and multiple linear regression models were estimated using ordinary least squares (OLS), to explore determinant factors associated to HRQoL in this sample, for the eight domains of the SF-36 sub-scales separately.

Results

Two hundred ninety-five older persons were interviewed. Mean age was 72.7 years (SD 7.9), men made up 57% of the sample, 67% were married and 52% reported living with another person, mostly the spouse. Higher HRQoL was associated with higher educational attainment, being married, and having higher social support, while lower HRQoL was associated with being widowed, in worse financial situation, having chronic diseases and being in the oldest age groups.

Conclusions

Findings show that gender, socioeconomic level, educational attainment, marital status as well as social support & community participation are relevant factors influencing HRQoL in our study sample. With respect to the SF-36 subscales, HRQoL of Jewish older adults in Mexico present higher scores than that of adults and older adults previously found in other studies in Mexico. Further studies comparing other characteristics among them could help bring further understanding of these differentiated ageing processes.
Prospective randomized study evaluating the usefulness of a surgical smoke evacuation system in operating rooms for breast surgery
Authors: Tokuda Yutaka , Okamura Takuho , Maruta Miki , Orita Mutsuko , Noguchi Miyuki , Suzuki Toshiyasu , Matsuki Hideaki
Published: May 2020

Background

No prospective evaluation of surgical smoke evacuation systems has yet been conducted anywhere in the world. A prospective randomized study was conducted to clarify the usefulness of a surgical smoke evacuation system in terms of reducing the quantity of environmental pollutants found in operating room air and reducing the occupational exposure of doctors and nurses involved in surgical procedures to surgical smoke, volatile organic compounds, formaldehyde, etc.

Methods

Operating room environment conditions with and without the use of a surgical smoke evacuation system were measured, and the personal exposure levels of doctors and nurses involved in surgical procedures were also surveyed. Use of the evacuation system was determined randomly, and the procedures involved were breast-conserving surgery and mastectomy, which were treated as stratification factors.

Results

The average total volatile organic compound concentration in the operating room was significantly lower when the evacuation system was used compared with when it was not used. The findings were similar for formaldehyde concentration. Multiple regression analysis for healthcare professionals’ personal exposure levels showed that the evacuation system was a factor that significantly impacted their formaldehyde and acetaldehyde personal exposure levels, which were greatly reduced by the use of the system.

Conclusion

This study’s findings demonstrate the effectiveness of the evacuation systems, which should increase awareness that their benefits take priority over the drawbacks.

Trial registration

The study was conducted after explaining to participants that it was a study of operating room environments in which their participation was voluntary and obtaining their consent. The study was also approved by the Tokai University Hospital clinical research review committee (no. 5R-022) and registered with the UMIN registry (UMIN000029092) on 13, September, 2017- retrospectively registered.
Lifestyle and the presence of helminths is associated with gut microbiome composition in Cameroonians
Authors: Rubel Meagan A. , Abbas Arwa , Taylor Louis J. , Connell Andrew , Tanes Ceylan , Bittinger Kyle , Ndze Valantine N. , Fonsah Julius Y. , Ngwang Eric , Essiane André , Fokunang Charles , Njamnshi Alfred K. , Bushman Frederic D. , Tishkoff Sarah A.
Published: May 2020

Background

African populations provide a unique opportunity to interrogate host-microbe co-evolution and its impact on adaptive phenotypes due to their genomic, phenotypic, and cultural diversity. We integrate gut microbiome 16S rRNA amplicon and shotgun metagenomic sequence data with quantification of pathogen burden and measures of immune parameters for 575 ethnically diverse Africans from Cameroon. Subjects followed pastoralist, agropastoralist, and hunter-gatherer lifestyles and were compared to an urban US population from Philadelphia.

Results

We observe significant differences in gut microbiome composition across populations that correlate with subsistence strategy and country. After these, the variable most strongly associated with gut microbiome structure in Cameroonians is the presence of gut parasites. Hunter-gatherers have high frequencies of parasites relative to agropastoralists and pastoralists.Ascaris lumbricoides,Necator americanus,Trichuris trichiura, andStrongyloides stercoralissoil-transmitted helminths (“ANTS” parasites) significantly co-occur, and increased frequency of gut parasites correlates with increased gut microbial diversity. Gut microbiome composition predicts ANTS positivity with 80% accuracy. Colonization with ANTS, in turn, is associated with elevated levels of TH1, TH2, and proinflammatory cytokines, indicating an association with multiple immune mechanisms. The unprecedented size of this dataset allowed interrogation of additional questions—for example, we find that Fulani pastoralists, who consume high levels of milk, possess an enrichment of gut bacteria that catabolize galactose, an end product of lactose metabolism, and of bacteria that metabolize lipids.

Conclusions

These data document associations of bacterial microbiota and eukaryotic parasites with each other and with host immune responses; each of these is further correlated with subsistence practices.
Eliminating senescent chondrogenic progenitor cells enhances chondrogenesis under intermittent hydrostatic pressure for the treatment of OA
Authors: Dai Hanhao , Chen Ran , Gui Chang , Tao Tianqi , Ge Yingbin , Zhao Xilian , Qin Ran , Yao Wangxiang , Gu Song , Jiang Yiqiu , Gui Jianchao
Published: May 2020

Background

Osteoarthritis (OA) is a major cause of limb dysfunction, and distraction arthroplasty which generates intermittent hydrostatic pressure (IHP) is an effective approach for OA treatment. However, the result was not always satisfactory and the reasons remained unresolved. Because aging is recognized as an important risk factor for OA and chondrogenic progenitor cells (CPCs) could acquire senescent phenotype, we made a hypothesis that CPCs senescence could have harmful effect on chondrogenesis and the outcome of distraction arthroplasty could be improved by eliminating senescent CPCs pharmacologically.

Methods

The role of senescent CPCs on distraction arthroplasty was first determined by comparing the cartilage samples from the failure and non-failure patients. Next, the biological behaviors of senescent CPCs were observed in the in vitro cell culture and IHP model. Finally, the beneficial effect of senescent CPCs clearance by senolytic dasatinib and quercetin (DQ) on cartilage regeneration was observed in the in vitro and in vivo IHP model.

Results

Larger quantities of senescent CPCs along with increased IL-1 β secretion were demonstrated in the failure patients of distraction arthroplasty. Senescent CPCs revealed impaired proliferation and chondrogenic capability and also had increased IL-1 β synthesis, typical of senescence-associated secretory phenotype (SASP). CPCs senescence and SASP formation were mutually dependent in vitro. Greater amounts of senescent CPCs were negatively correlated with IHP-induced chondrogenesis. In contrast, chondrogenesis could be significantly improved by DQ pretreatment which selectively induced senescent CPCs into apoptosis in the in vitro and in vivo IHP model. Mechanistically, senescent CPCs elimination could decrease SASP formation and therefore promote the proliferation and chondrogenic regeneration capacity of the surrounding survived CPCs under IHP stimulation.

Conclusions

Eliminating senescent CPCs by senolytics could decrease SASP formation and improve the result of joint distraction arthroplasty effectively. Our study provided a novel CPCs senescence-based therapeutic target for improving the outcome of OA treatment.
Correction to: Commentary to: TDOA versus ATDOA for wide area multilateration system
Authors: Frisch Daniel , Hanebeck Uwe D.
Published: May 2020

An amendment to this paper has been published and can be accessed via the original article.

Following publication of the original article [1], two concerns were brought to the attention of EURASIP Journal on Wireless Communications and Networking.
Correction to: Nationwide system to centralize decisions around ECMO use for severe COVID-19 pneumonia in Japan (Special Correspondence)
Authors:   Japan ECMOnet for COVID-19
Published: May 2020

An amendment to this paper has been published and can be accessed via the original article.
A clinical study of inferior alveolar nerve damage caused by Carnoy’s solution used as a complementary therapeutic agent in a cystic lesion
Authors: Jo Hyun-Jun , Kim Hee-Youl , Kang Dong-Cheol , Leem Dae-Ho , Baek Jin-A , Ko Seung-O
Published: May 2020

Background

Cyst enucleation, which extracts only the tumor with the application of Carnoy’s solution (CS), has been suggested as a conservative treatment with a low recurrence rate and morbidity. However, there has been a concern that CS’s contact with inferior alveolar nerve (IAN) can cause neurons to degenerate and cause sensory dysfunction. The purpose of this retrospective cohort study aimed to investigate the neurosensory function after surgical treatment with or without the application of CS.

Methods

While controlling the effects of sex, age, follow-up period, and invasion size of the tumor, we performed the binary logistic regression analysis to examine whether or not the sensory function of the patients who were treated with CS (n = 19) for the cyst enucleation procedure was significantly different from those who were not treated with CS (n = 58) at the end of the follow-up period.

Results

The logistic regression result showed that the use of CS was not significantly related to the normalness of sensory function at the end of the follow-up period. Rather, the invasion size of the cyst was significantly associated with sensory dysfunction.

Conclusions

CS may be used for patients who are diagnosed with OKC and UAM without much fear of its impact on sensory dysfunction. However, a small number of patients who were treated with CS experienced severe sensory damage and did not recover at the end of the follow-up period, suggesting the need for further analysis of these patients.
Learning principles of accounting in ICT-supported learning environments of Malaysian secondary schools: future-oriented approach
Authors: Tan Boon See , Wong Su Luan
Published: May 2020

This research was undertaken to identify the learning approaches used by Malaysian secondary school students of Principles of Accounting in the context of ICT-supported learning environments. The revised Two-Factor version of the Learning Process Questionnaire (R-LPQ-2F) was adapted to appraise the learning approaches used, while the Technology-Rich Outcomes-Focused Learning Environment Inventory (TROFLEI) was adapted to obtain the perceptions of students in ICT-supported learning environments which practising the ICT-pedagogy. The sample for the study comprised 371 Form Four Malaysian students. There were indications from this study that students employed the deep approach to learning Principles of Accounting; whereas the surface approach was not discernible. Only two scales measured the sub constructs of surface motive and surface strategy, namely aim for qualification and minimising scope of study merged and evolved into what is referred to as the future-oriented approach in this study. Aiming for qualification as a motive is complemented by a non-surface learning strategy of non-minimisation of scope of study, i.e. learning beyond the minimum scope. The future-oriented approach was influenced by socio-cultural and educational contextual factors in Malaysia. The findings also reflected the influence of ICT-supported learning environment perceptions on learning approaches.
Does a 6-point scale approach to post-treatment 18F-FDG PET-CT allow to improve response assessment in head and neck squamous cell carcinoma? A multicenter study
Authors: Bonomo P. , Merlotti A. , Morbelli S. , Berti V. , Saieva C. , Bergesio F. , Bacigalupo A. , Belgioia L. , Franzese C. , Lopci E. , Casolo A. , D’Angelo E. , Alterio D. , Travaini L. , Berretta L. , Pirro V. , Ursino S. , Volterrani D. , Roncali M. , Vigo F. , Cicchetti S. , Scalone F. , Belli G. , Cauda S. , Desideri I. , Russi E. , Livi L. , Bianchi A.
Published: May 2020

Purpose

Response assessment to definitive non-surgical treatment for head and neck squamous cell carcinoma (HNSCC) is centered on the role of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET-CT) 12 weeks after treatment. The 5-point Hopkins score is the only qualitative system available for standardized reporting, albeit limited by suboptimal positive predictive value (PPV). The aim of our study was to explore the feasibility and assess the diagnostic accuracy of an experimental 6-point scale (“Cuneo score”).

Methods

We performed a retrospective, multicenter study on HNSCC patients who received a curatively-intended, radiation-based treatment. A centralized, independent qualitative evaluation of post-treatment FDG-PET/CT scans was undertaken by 3 experienced nuclear medicine physicians who were blinded to patients’ information, clinical data, and all other imaging examinations. Response to treatment was evaluated according to Hopkins, Cuneo, and Deauville criteria. The primary endpoint of the study was to evaluate the PPV of Cuneo score in assessing locoregional control (LRC). We also correlated semi-quantitative metabolic factors as included in PERCIST and EORTC criteria with disease outcome.

Results

Out of a total sample of 350 patients from 11 centers, 119 subjects (oropharynx, 57.1%; HPV negative, 73.1%) had baseline and post-treatment FDG-PET/CT scans fully compliant with EANM 1.0 guidelines and were therefore included in our analysis. At a median follow-up of 42 months (range 5-98), the median locoregional control was 35 months (95% CI, 32-43), with a 74.5% 3-year rate. Cuneo score had the highest diagnostic accuracy (76.5%), with a positive predictive value for primary tumor (Tref), nodal disease (Nref), and composite TNref of 42.9%, 100%, and 50%, respectively. A Cuneo score of 5-6 (indicative of residual disease) was associated with poor overall survival at multivariate analysis (HR 6.0; 95% CI, 1.88-19.18; p = 0.002). In addition, nodal progressive disease according to PERCIST criteria was associated with worse LRC (OR for LR failure, 5.65; 95% CI, 1.26-25.46; p = 0.024) and overall survival (OR for death, 4.81; 1.07-21.53; p = 0.04).

Conclusions

In the frame of a strictly blinded methodology for response assessment, the feasibility of Cuneo score was preliminarily validated. Prospective investigations are warranted to further evaluate its reproducibility and diagnostic accuracy.
Pembrolizumab versus placebo after complete resection of high-risk stage III melanoma: New recurrence-free survival results from the EORTC 1325-MG/Keynote 054 double-blinded phase III trial at three-year median follow-up.
Authors: Eggermont Alexander M. , Blank Christian U. , Mandalà Mario , Long Georgina V. , Atkinson Victoria , Dalle Stéphane , Haydon Andrew Mark , Meshcheryakov Andrey , Khattak Muhammad , Carlino Matteo S. , Sandhu Shahneen Kaur , Puig Susana , Ascierto Paolo Antonio , Van Akkooi Alexander Christopher Jonathan , Krepler Clemens , Ibrahim Nageatte , Marreaud Sandrine , Kicinski Michal , Suciu Stefan , Robert Caroline
Published: May 2020

10000

Background: We conducted the phase 3 double-blind EORTC 1325/KEYNOTE-054 trial to evaluate pembrolizumab vs placebo in patients (pts) with resected high-risk stage III melanoma. Based on 351 recurrence-free survival (RFS) events and at a median follow-up of 1.25 years (yrs), pembrolizumab improved RFS (hazard ratio (HR) 0.57, P<0.0001) as compared to placebo (Eggermont, NEJM 2018). This led to the approval of pembrolizumab adjuvant treatment by EMA and FDA. Methods: Eligible pts included those ≥18 yrs of age with complete resection of cutaneous melanoma metastatic to lymph node(s), classified as AJCC-7 stage IIIA (at least one lymph node metastasis >1 mm), IIIB or IIIC (without in-transit metastasis). A total of 1019 pts were randomized (stratification by stage and region) to pembrolizumab at a flat dose of 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year) or until disease recurrence or unacceptable toxicity. The 2 co-primary endpoints were RFS in the intention-to-treat overall population and in pts with PD-L1-positive tumors. Here, we report an updated RFS analysis based on a longer follow-up. Results: Overall, 15%/46%/39% of pts had stage IIIA/IIIB/IIIC. At 3.05-yr median follow-up, pembrolizumab (190 RFS events) compared with placebo (283 RFS events) prolonged RFS, in the overall population and in the PD-L1 positive tumor subgroup (see Table). RFS was consistently prolonged across subgroups, in particular according to AJCC-7 staging, BRAF-V600 E/K mutation status. Conclusions: Pembrolizumab, administered at 200 mg every 3 weeks for up to 1 year as adjuvant therapy, provided, at a 3-yr median follow-up, a sustained improvement in RFS, which was clinically meaningful, in resected high-risk stage III melanoma. This improvement was consistent across subgroups. In the overall population, the 3-yr cumulative incidence of distant metastasis being the first recurrence was 22.3% (pembrolizumab group) vs 37.3% (placebo group) (HR 0.55, 95% CI 0.44-0.69). Clinical trial information: NCT02362594. [Table: see text]
Using machine learning to predict immunotherapy response in advanced melanoma.
Authors: Johannet Paul , Coudray Nicolas , Donnelly Douglas M. , Jour George , Illa-Bochaca Irineu , Xia Yuhe , Johnson Douglas Buckner , Wheless Lee E , Patrinely James Randall , Pavlick Anna C. , Weber Jeffrey S. , Zhong Hua , Tsirigos Aristotelis , Osman Iman
Published: May 2020

10010

Background: Several predictors of response to checkpoint inhibitors show potential, but use pathological assays and/or molecular characterization, which limits their clinical utility outside of the academic setting. We aimed to develop a streamlined approach by leveraging information immediately available through standard care. Here, we present a computational method that integrates deep learning on histology specimens with clinicodemographic variables to predict treatment outcomes in advanced melanoma. Methods: We used hematoxylin and eosin (H&E) sections from 72 patients ( n= 153 slides) from New York University (NYU) to build a Segmentation Classifier that distinguishes tumor, lymphocyte, and connective tissue. Using pre-treatment H&E slides from 121 NYU patients ( n =302 slides), we trained a Response Classifier to predict response by selectively analyzing tumor regions. We then developed a logistic regression classifier that combines neural network output with clinicodemographic variables. The classifiers were tested on an independent cohort of 32 patients from Vanderbilt University ( n =42 slides). Area under the curve (AUC) was calculated as a measure of prediction accuracy. Results: The Segmentation Classifier distinguished tumor, lymphocyte, and connective tissue with AUCs 0.886-0.984. For the Response Classifier, optimal learning conditions were identified through training on NYU patients and testing on Vanderbilt patients (AUCs 0.685 and 0.728, respectively). The fully trained Response Classifier performed with AUC 0.711 on Vanderbilt patients. The logistic regression model performed with enhanced prediction accuracy with AUC 0.803 on NYU patients and AUC 0.793 on Vanderbilt patients. Conclusions: Histology slides and patients’ clinicodemographic characteristics are readily available through routine standard of care and have the potential to predict immunotherapy response. Our approach is time-efficient, reproducible, and requires minimal resource allocation, thus overcoming multiple common barriers to generalizability for contemporary biomarkers.
Final analysis of relapse-free survival in a multicenter, double-blind, placebo-controlled trial of seviprotimut-L polyvalent melanoma vaccine after resection of high-risk melanoma.
Authors: Slingluff Craig L. , Blumenstein Brent A. , Lewis Karl D. , Andtbacka Robert Hans Ingemar , Hyngstrom John Robert , Milhem Mohammed M. , Markovic Svetomir , Hamid Omid , Hernandez-Aya Leonel Fernando , Bowles Tawnya Lynn , Philips Prejesh , Jang Sekwon , Lutzky Jose , Bar Anna , Beitsch Peter D.
Published: May 2020

10017

Background: Seviprotimut-L is a vaccine prepared from antigens of 3 human melanoma cell lines, administered with alum. Prior formulations induced T cell and antibody responses and improved survival in a small phase II clinical trial. Part B1 of MAVIS (Melanoma Antigen Vaccine Immunotherapy Study, a three part, Phase III clinical program), was a multicenter, double-blind, placebo-controlled trial to assess efficacy of seviprotimut-L, with the primary endpoint of relapse-free survival (RFS). The goal of Part B1 was to guide design of the pivotal Part B2. Methods: Patients with AJCC v7 stage IIB-III cutaneous melanoma, after surgical resection, age 18-75, ECOG PS 0-1, were randomized 2:1 to seviprotimut-L 40 mcg or placebo, injected subcutaneously every 2 weeks x 5, then monthly x 4, then every 3 months x 9. Patients were stratified by stage (IIB/C, IIIA, IIIB/C). Target enrollment was 325. The study was powered for assessment of RFS, with target hazard ratio (HR) of 0.625, one-sided alpha of 0.10, and power 80%. Final data are presented. Results: 347 patients were randomized. Arms were well-balanced. Treatment-related adverse events (AEs) led to discontinuation in 0.4% and 0%, respectively, for vaccine and placebo arms. There were no treatment-related SAEs. By intent-to-treat (ITT) analysis, RFS was not significantly longer for seviprotimut-L in the full study population but trended toward benefit (HR 0.88). Subgroup analysis based on planned stratification revealed the hazard ratio (HR) for the Stage IIB/IIC subset (randomization stratum, n=111) to be 0.65 (95% CI [0.37, 1.17]), favoring seviprotimut-L. Age can decrease immune competence: RFS was longer with vaccine for patients age <60 overall (N = 191, HR = 0.64 [0.38, 1.08]) and among Stage IIB/C patients (N = 52, HR = 0.32 [0.12, 0.86]). The effect modification interaction p value for age for stage IIB/IIC patients was 0.056. In a multivariable RFS model, for IIB/IIC patients <60 with ulceration (n=38), HR = 0.209 [0.07,0.61]. For overall survival, for patients < 60, HR = 0.41 [0.33,1.14] (n=191, 19 deaths) and for those ≥60, HR = 0.92 [0.39,2.12] (n = 156, 24 deaths). Conclusions: Seviprotimut-L is very well-tolerated. Subgroup efficacy analyses identified populations who may benefit from Seviprotimut-L: those with Stage IIB/IIC melanoma and those under age 60. These data support design of the definitive part B2 of the MAVIS phase III trial to test seviprotimut-L for stage IIB/C patients, with stratification by age and ulceration. Clinical trial information: NCT01546571.
The impact of BRAF mutation status on clinical outcomes with single-agent PD-1 inhibitor versus combination ipilimumab/nivolumab.
Authors: Ma Vincent The-Luc , Daignault Stephanie , Waninger Jessica , Fecher Leslie Anne , Green Michael , Alva Ajjai Shivaram , Lao Christopher D.
Published: May 2020

10024

Background: Nearly half of all metastatic melanoma patients possess the BRAF V600 mutation. Several therapies are approved for BRAF mutant metastatic melanoma, but it is unclear if there is a differential outcome to various immunotherapy regimens. Our aim was to better assess if BRAF mutation status has any impact on survival to combination ipilimumab/nivolumab (I/N) versus single-agent PD-1 inhibitor (PD-1i). Methods: We performed a single center, retrospective analysis on a cohort of patients diagnosed with metastatic or unresectable melanoma from 2012 to 2019 at the University of Michigan who were treated with standard I/N or PD-1i (nivolumab or pembrolizumab). A univariate analysis of progression free survival (PFS) and overall survival (OS) was stratified by treatment type and BRAF mutation status. A multivariate Cox regression of survival was used to compare the effects of the treatment groups adjusted by BRAF status, age, gender, pre-treatment LDH level, prior treatment status, and brain metastases status. Results: 323 patients were identified. 132 had BRAF V600 mutation and 191 had BRAF wildtype (WT) status. 138 patients received I/N and 185 patients received PD-1i. In our univariate analysis, there was no difference in PFS [HR: 0.72, 95% CI, 0.46 – 1.13] or OS [HR: 0.78, 0.44 – 1.38] with I/N versus PD-1i in the BRAF mutant cohort, but there was improved PFS [HR: 0.55, 0.35 – 0.88) and OS [HR: 0.52, 0.28 – 0.95] with I/N compared to PD-1i in the BRAF WT group. In the multivariate analysis, the BRAF WT group continued to show PFS benefit with I/N compared to PD-1i [HR: 0.57, 95% CI, 0.35 – 0.95], but the OS benefit no longer achieved statistical significance [HR: 0.54, 0.28 – 1.03]. Conclusions: Our study results were discordant with the observation in the landmark CheckMate 067 trial, which noted improved PFS and OS with I/N compared to nivolumab alone in the BRAF mutant group and no difference in the BRAF WT group. In our real-world retrospective analysis, I/N over PD-1i should be considered as initial immunotherapy for metastatic melanoma patients regardless of BRAF mutation status, but even more favorably in BRAF WT.
Initial report of treatment of uveal melanoma with hepatic metastases with yttrium90 internal radiation followed by ipilimumab and nivolumab.
Authors: Minor David R. , Sato Takami , Orloff Marlana M. , Luke Jason J. , Eschelman David J. , Gonsalves Carin F. , Adamo Robert D. , Tong Ricky T , Char Devron H. , Anne Rani , Kim Kevin B.
Published: May 2020

10025

Background: Hepatic metastases from uveal melanoma have no established therapy, with a median survival of only 6-12 months. To date therapy with checkpoint inhibitors has yielded minimal results. To take advantage of possible synergy between radiation and immunotherapy we treated patients with yttrium90 internal radiation followed by immunotherapy. Methods: Patients received yttrium90 (Sir-Spheres) via hepatic artery infusion in two treatments, one to each lobe 3-4 weeks apart, followed in 3-6 weeks by ipilimumab and nivolumab for 4 doses, then nivolumab maintenance. Results: We are presenting interim results because of the excessive toxicity seen when these FDA-approved modalities were used in sequence with the FDA-approved dosages. Initially dosing of yttrium90 (Y90) followed the package insert “BSA method” but after 8 patients we had 5 cases of grade 3-4 hepatic toxicity; in 4 cases the toxicity was observed after just the Y90. One case of cirrhosis occurred in a patient whose liver received 40-45Gy; her cirrhosis was felt most likely due to the Y90. Y90 dosing was then reduced to limit dosage to normal liver to 35Gy, and none of the next 5 patients have had more than grade 2 hepatic toxicity. Dosage to the normal liver is approximated by the MIRD formula: Actual delivered liver dose [Gy] = 50 * Administered activity [GBq] * (1 – Lung shunt fraction) / kg of treated liver. If calculated dose was > 35GY, dosage in GBq is reduced proportionally. Toxicity in the first 5 patients to receive immunotherapy included one grade 4, two grade 3 and two grade 2 hepatic toxicities, and only 3 of the 5 patients received more than one dose of ipilimumab. We then reduced dosing of ipilimumab from 3mg/kg x 4 to 1mg/kg x 4 because of this excessive autoimmune toxicity. Of 13 patients, 10 received both Y90 and immunotherapy, and 3 had responses (1 CR, 2 PR) with 3 patients stable > 5months. Median progression-free survival for all patients is 27 weeks and median overall survival is greater than 48 weeks. Treatment with Y90 produced an over 50% fall in peripheral blood lymphocytes which was reversed in most patients by the immunotherapy. Conclusions: With dose modifications this therapy appears feasible and objective tumor responses were seen. Sequential therapy with Y90 and immunotherapy appears tolerable if radiation to normal liver is limited to 35Gy and ipilimumab dose is 1mg/kg. Clinical trial information: NCT02913417.