BackgroundPediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials.Methods and findingsOur protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as “small sample size, non‑randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested.” We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting.ConclusionsOur meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.

The aim of this paper was to review the up-to-date evidence base on pharmacology and clinical properties of vortioxetine. Vortioxetine is a novel antidepressant, approved by the US Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD). Because vortioxetine exhibits both an antidepressant and anxiolytic effect, it may be effective in treating both depressive and anxiety disorders, such as generalized anxiety disorder (GAD). Based on its pharmacodynamics profile and preclinical studies, it is believe that the drug's clinical action is mediated mainly by selective blockade of serotonin reuptake (by inhibiting the serotonin transporter [SERT]) and direct modulation of 5-HT receptors activity (such as 5-HT, 5-HT, 5-HT and 5-HT). In patients with MDD the recommended doses range is 5-20mg/day. Vortioxetine was shown to be more effective than placebo both in MDD and GAD. In terms of side effects, nausea, vomiting, diarrhea, and dry mouth were most commonly observed in individuals receiving vortioxetine. In direct comparison to duloxetine, vortioxetine is found to have a smaller efficacy but had a lower risk of developing the common antidepressant-induced adverse effects.

Background The shortage and disproportionate distribution of health care workers worldwide is further aggravated by the inadequacy of training programs, difficulties in implementing conventional curricula, deficiencies in learning infrastructure, or a lack of essential equipment. Offline digital education has the potential to improve the quality of health professions education. Objective The primary objective of this systematic review was to evaluate the effectiveness of offline digital education compared with various controls in improving learners’ knowledge, skills, attitudes, satisfaction, and patient-related outcomes. The secondary objectives were (1) to assess the cost-effectiveness of the interventions and (2) to assess adverse effects of the interventions on patients and learners. Methods We searched 7 electronic databases and 2 trial registries for randomized controlled trials published between January 1990 and August 2017. We used Cochrane systematic review methods. Results A total of 27 trials involving 4618 individuals were included in this systematic review. Meta-analyses found that compared with no intervention, offline digital education (CD-ROM) may increase knowledge in nurses (standardized mean difference [SMD]=1.88; 95% CI 1.14 to 2.62; participants=300; studies=3; I2=80%; low certainty evidence). A meta-analysis of 2 studies found that compared with no intervention, the effects of offline digital education (computer-assisted training [CAT]) on nurses and physical therapists’ knowledge were uncertain (SMD 0.55; 95% CI –0.39 to 1.50; participants=64; I2=71%; very low certainty evidence). A meta-analysis of 2 studies found that compared with traditional learning, a PowerPoint presentation may improve the knowledge of patient care personnel and pharmacists (SMD 0.76; 95% CI 0.29 to 1.23; participants=167; I2=54%; low certainty evidence). A meta-analysis of 4 studies found that compared with traditional training, the effects of computer-assisted training on skills in community (mental health) therapists, nurses, and pharmacists were uncertain (SMD 0.45; 95% CI –0.35 to 1.25; participants=229; I2=88%; very low certainty evidence). A meta-analysis of 4 studies found that compared with traditional training, offline digital education may have little effect or no difference on satisfaction scores in nurses and mental health therapists (SMD –0.07; 95% CI –0.42 to 0.28, participants=232; I2=41%; low certainty evidence). A total of 2 studies found that offline digital education may have little or no effect on patient-centered outcomes when compared with blended learning. For skills and attitudes, the results were mixed and inconclusive. None of the studies reported adverse or unintended effects of the interventions. Only 1 study reported costs of interventions. The risk of bias was predominantly unclear and the certainty of the evidence ranged from low to very low. Conclusions There is some evidence to support the effectiveness of offline digital education in improving learners’ knowledge and insufficient quality and quantity evidence for the other outcomes. Future high-quality studies are needed to increase generalizability and inform use of this modality of education.

Background AMSTAR-2 (‘A Measurement Tool to Assess Systematic Reviews, version 2’) and ROBIS (‘Risk of Bias in Systematic Reviews’) are independent instruments used to assess the quality of conduct of systematic reviews/meta-analyses (SR/MAs). The degree of overlap in methodological constructs together with the reliability and any methodological gaps have not been systematically assessed and summarized in the field of nutrition. Methods We performed a systematic survey of MEDLINE, EMBASE, and the Cochrane Library for SR/MAs published between January 2010 and November 2018 that examined the effects of any nutritional intervention/exposure for cancer prevention. We followed a systematic review approach including two independent reviewers at each step of the process. For AMSTAR-2 (16 items) and ROBIS (21 items), we assessed the similarities, the inter-rater reliability (IRR) and any methodological limitations of the instruments. Our protocol for the survey was registered in PROSPERO (CRD42019121116). Results We found 4 similar domain constructs based on 11 comparisons from a total of 12 AMSTAR-2 and 14 ROBIS items. Ten comparisons were considered fully overlapping. Based on Gwet’s agreement coefficients, six comparisons provided almost perfect (> 0.8), three substantial (> 0.6), and one a moderate level of agreement (> 0.4). While there is considerable overlap in constructs, AMSTAR-2 uniquely addresses explaining the selection of study designs for inclusion, reporting on excluded studies with justification, sources of funding of primary studies, and reviewers’ conflict of interest. By contrast, ROBIS uniquely addresses appropriateness and restrictions within eligibility criteria, reducing risk of error in risk of bias (RoB) assessments, completeness of data extracted for analyses, the inclusion of all necessary studies for analyses, and adherence to predefined analysis plan. Conclusions Among the questions on AMSTAR-2 and ROBIS, 70.3% (26/37 items) address the same or similar methodological constructs. While the IRR of these constructs was moderate to perfect, there are unique methodological constructs that each instrument independently addresses. Notably, both instruments do not address the reporting of absolute estimates of effect or the overall certainty of the evidence, items that are crucial for users’ wishing to interpret the importance of SR/MA results.

No abstract

BACKGROUND The shortage and disproportionate distribution of health care workers worldwide is further aggravated by the inadequacy of training programs, difficulties in implementing conventional curricula, deficiencies in learning infrastructure, or a lack of essential equipment. Offline digital education has the potential to improve the quality of health professions education. OBJECTIVE The primary objective of this systematic review was to evaluate the effectiveness of offline digital education compared with various controls in improving learners’ knowledge, skills, attitudes, satisfaction, and patient-related outcomes. The secondary objectives were (1) to assess the cost-effectiveness of the interventions and (2) to assess adverse effects of the interventions on patients and learners. METHODS We searched 7 electronic databases and 2 trial registries for randomized controlled trials published between January 1990 and August 2017. We used Cochrane systematic review methods. RESULTS A total of 27 trials involving 4618 individuals were included in this systematic review. Meta-analyses found that compared with no intervention, offline digital education (CD-ROM) may increase knowledge in nurses (standardized mean difference [SMD]=1.88; 95% CI 1.14 to 2.62; participants=300; studies=3; I2=80%; low certainty evidence). A meta-analysis of 2 studies found that compared with no intervention, the effects of offline digital education (computer-assisted training [CAT]) on nurses and physical therapists’ knowledge were uncertain (SMD 0.55; 95% CI –0.39 to 1.50; participants=64; I2=71%; very low certainty evidence). A meta-analysis of 2 studies found that compared with traditional learning, a PowerPoint presentation may improve the knowledge of patient care personnel and pharmacists (SMD 0.76; 95% CI 0.29 to 1.23; participants=167; I2=54%; low certainty evidence). A meta-analysis of 4 studies found that compared with traditional training, the effects of computer-assisted training on skills in community (mental health) therapists, nurses, and pharmacists were uncertain (SMD 0.45; 95% CI –0.35 to 1.25; participants=229; I2=88%; very low certainty evidence). A meta-analysis of 4 studies found that compared with traditional training, offline digital education may have little effect or no difference on satisfaction scores in nurses and mental health therapists (SMD –0.07; 95% CI –0.42 to 0.28, participants=232; I2=41%; low certainty evidence). A total of 2 studies found that offline digital education may have little or no effect on patient-centered outcomes when compared with blended learning. For skills and attitudes, the results were mixed and inconclusive. None of the studies reported adverse or unintended effects of the interventions. Only 1 study reported costs of interventions. The risk of bias was predominantly unclear and the certainty of the evidence ranged from low to very low. CONCLUSIONS There is some evidence to support the effectiveness of offline digital education in improving learners’ knowledge and insufficient quality and quantity evidence for the other outcomes. Future high-quality studies are needed to increase generalizability and inform use of this modality of education.

Background: Poland has one of the highest cervical cancer mortality rates in Europe. It is related to the problem of late diagnosis and low attendance rate in screening programs. The objective of the study has been to assess the annual production loss due to the cervical cancer morbidity and mortality in Poland in 2012. The outcomes have been to provide comprehensive information on cervical cancer's influence on population's ability to work and its overall economic burden for the society. The study has also provided the methodological framework for disease-related production losses in Polish settings. Material and Methods: The human capital method was used. The production losses were calculated in both monetary and quantitative terms (working days lost) due to 4 following reasons: 1) temporary disability to work, 2) permanent disability, 3) informal care, and 4) mortality. Results: Cervical cancer resulted in approx. 702 964 working days lost in 2012 due to absence at work for both patients and care givers and a total number of 957 678 working days lost due to patients' mortality. The total value of production lost was assessed at 111.4 million euros. More than 66% of this value was attributed to women's mortality. Conclusions: The calculation of production lost due to cervical cancer burden provides strong evidence to support adequate health promotion and disease prevention actions. Actions promoting cervical cancer screening should be intensified including workplace health promotion activities. Med Pr 2016;67(3):289-299Key words: screening, cost of illness, indirect costs, cervical neoplasm, gross domestic product (GDP), economic burden Streszczenie Wstęp: Polska ma jeden z najwyższych w Europie wskaźników umieralności kobiet z powodu nowotworu szyjki macicy. Niewiele kobiet uczestniczy w programach przesiewowych, a u wielu choroba jest późno diagnozowana. Celem badania było oszacowanie produkcji utraconej z powodu występowania nowotworu szyjki macicy w Polsce w 2012 r., a tym samym ocena wpływu choroby na zdolność populacji do pracy. Analizę można traktować również jako przykład metodyki szacowania strat produkcyjnych z powodu występo-wania określonej jednostki chorobowej przy wykorzystaniu dostępnych w Polsce danych. Materiał i metody: Wykorzystano metodę kapitału ludzkiego i oszacowano produkcję utraconą z 4 powodów -1) czasowej niezdolności do pracy, 2) trwałej niezdolności do pracy, 3) opieki członków rodziny nad osobą chorą i 4) umieralności -w kategoriach monetarnych i ilościowych (dni utraconej produkcji). Wyniki: Nowotwór szyjki macicy spowodował w 2012 r. utratę 702 964 dni produkcji z powodu chorobowości i 957 678 dni z powodu umieralności. Całkowitą produkcję utraconą oszacowano na 111,4 mln euro, z czego ponad 66% było spowodowanych zgonami osób chorych na nowotwór. Wnioski: Oszacowanie produkcji utraconej z powodu nowotworu szyjki macicy dostarcza silnych argumentów w procesie alokacji zasobów w sektorze zdrowia na rzecz prewencji nowotworów. Należy zintensyfikować również działania z zak...

Context The last 30 years have yielded a vast number of systematic reviews and/or meta-analyses addressing the link between nutrition and cancer risk. Objective The aim of this survey was to assess overall quality and potential for risk of bias in systematic reviews and meta-analyses (SRMAs) that examined the role of nutrition in cancer prevention. Data Sources MEDLINE, Embase, and the Cochrane Library databases were searched (last search performed November 2018). Study Selection Studies identified as SRMAs that investigated a nutritional or dietary intervention or exposure for cancer prevention in the general population or in people at risk of cancer and in which primary studies had a comparison group were eligible for inclusion. Screening, data extraction, and quality assessment were conducted independently by 2 reviewers. Data Extraction Altogether, 101 studies were randomly selected for analysis. The methodological quality and risk of bias were evaluated using the AMSTAR-2 and ROBIS tools, respectively. Results Most SRMAs included observational studies. Less than 10% of SRMAs reported a study protocol, and only 51% of SRMAs assessed the risk of bias in primary studies. Most studies conducted subgroup analyses, but only a few reported tests of interaction or specified subgroups of interest a priori. Overall, according to AMSTAR-2, only 1% of SRMAs were of high quality, while 97% were of critically low quality. Only 3% had a low risk of bias, according to ROBIS. Conclusions This systematic survey revealed substantial limitations with respect to quality and risk of bias of SRMAs. SRMAs examining nutrition and cancer prevention cannot be considered trustworthy, and results should be interpreted with caution. Peer reviewers as well as users of SRMAs should be advised to use the AMSTAR-2 and/or ROBIS instruments to help to determine the overall quality and risk of bias of SRMAs. Systematic Review Registration PROSPERO registration number CRD42019121116.