History of offending behavior in first episode psychosis patients: A marker of specific clinical needs and a call for early detection strategies among young offenders

OBJECTIVES Previous literature suggests that early psychosis (EP) patients with a history of offending behavior (HOB) have specific clinical needs. The aims of this study were to assess: (1) the prevalence of HOB in a representative sample of EP; (2) the premorbid and baseline characteristics of patients with HOB, and (3) the potential differences in short-term outcome of such patients when compared to patients without HOB. METHODS The Early Psychosis Prevention and Intervention Centre (EPPIC) admitted 786 EP patients between 1998 and 2000. Data were collected from patients' files using a standardized questionnaire. Data of 647 patients could be analyzed. RESULTS HOB patients (29% of the sample) were more likely to be male with lower level of premorbid functioning and education, have used illicit substances and have attempted suicide. They presented with a more complex clinical picture and had poorer 18-month outcome. Most importantly, they had a significantly longer duration of untreated psychosis. CONCLUSIONS On the basis of the high prevalence and specific features of EP patients with HOB, our study confirms a need for additional research in this domain and for the development of specific treatment strategies. Most importantly, it suggests a need for the promotion of early detection strategies among the populations of young offenders, considering that some of them may be going through the early phases of a psychotic disorder and that reduction of treatment delay and provision of well adapted interventions may have a significant impact at numerous levels in such patients

Magnetic resonance imaging features of an extranodal T-cell rich B-cell lymphoma in the pharyngeal mucosa in a horse

An 11-year-old Warmblood gelding was presented for inspiratory stridor and dysphagia. Based on history and clinical examination, a solitary mass localised in the oropharynx was suspected. Due to its inaccessibility and defensive behaviour of the horse, it was difficult to visualise this mass either by upper airway endoscopy or by oral examination and the conventional imaging methods (radiology and ultrasound) provided only limited information. Fine needle aspiration cytology was suggestive of lymphoma, but the exact localisation and the extent of tissue infiltration of the tumour could only be defined by magnetic resonance imaging (MRI). MRI has proved to be a very useful diagnostic tool in equine lameness investigation and, as this case illustrates, it has considerable diagnostic potential for soft tissue examination of the equine head.

Eosinophilic oesophagitis and proton pump inhibitor-responsive oesophageal eosinophilia have similar clinical, endoscopic and histological findings.

BACKGROUND Some patients with a phenotypic appearance of eosinophilic oesophagitis (EoE) respond histologically to PPI, and are described as having PPI-responsive oesophageal eosinophilia (PPI-REE). It is unclear if PPI-REE is a GERD-related phenomenon, a subtype of EoE, or a completely unique entity. AIM To compare demographic, clinical and histological features of EoE and PPI-REE. METHODS Two databases were reviewed from the Walter Reed and Swiss EoE databases. Patients were stratified into two groups, EoE and PPI-REE, based on recent EoE consensus guidelines. Response to PPI was defined as achieving less than 15 eos/hpf and a 50% decrease from baseline following at least a 6-week course of treatment. RESULTS One hundred and three patients were identified (63 EoE and 40 PPI-REE; mean age 40.2 years, 75% male and 89% Caucasian). The two cohorts had similar dysphagia (97% vs. 100%, P = 0.520), food impaction (43% vs. 35%, P = 0.536), and heartburn (33% vs. 32%, P = 1.000) and a similar duration of symptoms (6.0 years vs. 5.8 years, P = 0.850). Endoscopic features were also similar between EoE and PPI-REE; rings (68% vs. 68%, P = 1.000), furrows (70% vs. 70%, P = 1.000), plaques (19% vs. 10%, P = 0.272), strictures (49% vs. 30%, P = 0.066). EoE and PPI-REE were similar in the number of proximal (39 eos/hpf vs. 38 eos/hpf, P = 0.919) and distal eosinophils (50 vs. 43 eos/hpf, P = 0.285). CONCLUSIONS EoE and PPI-responsive oesophageal eosinophilia are similar in clinical, histological and endoscopic features and therefore are indistinguishable without a PPI trial. Further studies are needed to determine why a subset of patients with oesophageal eosinophilia respond to PPI.

VE1 immunohistochemistry predicts BRAF V600E mutation status and clinical outcome in colorectal cancer

AIM VE1 is a monoclonal antibody detecting mutant BRAFV600E protein by immunohistochemistry. Here we aim to determine the inter-observer agreement and concordance of VE1 with mutational status, investigate heterogeneity in colorectal cancers and metastases and determine the prognostic effect of VE1 in colorectal cancer patients. METHODS Concordance of VE1 with mutational status and inter-observer agreement were tested on a pilot cohort of colorectal cancers (n = 34), melanomas (n = 23) and thyroid cancers (n = 8). Two prognostic cohorts were evaluated (n = 259, Cohort 1 and n = 226, Cohort 2) by multiple-punch tissue microarrays. VE1 staining on preoperative biopsies (n = 118 patients) was compared to expression in resections. Primary tumors and metastases from 13 patients were tested for VE1 heterogeneity using a tissue microarray generated from all available blocks (n = 100 blocks). RESULTS Inter-observer agreement was 100% (kappa = 1.0). Concordance between VE1 and V600E mutation was 98.5%. Cohort 1: VE1 positivity (seen in 13.5%) was associated with older age (p = 0.0175) and MLH1 deficiency (p < 0.0001). Cohort 2: VE1 positivity (seen in 12.8%) was associated with female gender (p = 0.0016), right-sided tumor location (p < 0.0001), higher tumor grade (p < 0.0001) and mismatch repair (MMR)-deficiency (p < 0.0001). In survival analysis, MMR status and postoperative therapy were identified as possible confounding factors. Adjusting for these features, VE1 was an unfavorable prognostic factor. Preoperative biopsy staining matched resections in all cases except one. No heterogeneity was found across any primary/metastatic tumor blocks. CONCLUSION VE1 is highly concordant for V600E and homogeneously expressed suggesting staining can be analysed on resection specimens, preoperative biopsies, metastatic lesions and tissue microarrays.

Clinical Significance of NOTCH1 and NOTCH2 Expression in Gastric Carcinomas: An Immunohistochemical Study.

BACKGROUND NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. In this study, we aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC). METHODS NOTCH1 and NOTCH2 expression was determined immunohistochemically in 142 primarily resected GCs using tissue microarrays and in 84 pretherapeutic biopsies from patients treated by neoadjuvant chemotherapy. The results were correlated with survival, response to therapy, and clinico-pathological features. RESULTS Primarily resected patients with NOTCH1-negative tumors demonstrated worse survival. High NOTCH1 expression was associated with early-stage tumors and with significantly increased survival in this subgroup. Higher NOTCH2 expression was associated with early-stage and intestinal-type tumors and with better survival in the subgroup of intestinal-type tumors. In pretherapeutic biopsies, higher NOTCH1 and NOTCH2 expression was more frequent in non-responding patients, but these differences were statistically not significant. CONCLUSION Our findings suggested that, in particular, NOTCH1 expression indicated good prognosis in GC. The close relationship of high NOTCH1 and NOTCH2 expression with early tumor stages may indicate a tumor-suppressive role of NOTCH signaling in GC. The role of NOTCH1 and NOTCH2 in neoadjuvantly treated GC is limited.

Nail melanoma in situ: clinical, dermoscopic, pathologic clues, and steps for minimally invasive treatment

BACKGROUND Nail unit melanoma (NUM) is a variant of acral lentiginous melanoma. The differential diagnosis is wide but an acquired brown streak in the nail of a fair-skinned adult person must be considered a potential melanoma. Dermoscopy helps clinicians to more accurately decide if a nail apparatus biopsy is necessary. OBJECTIVE Detailed evaluation of clinical and dermoscopy features and description of conservative surgery of in situ NUM. METHODS Retrospective study of in situ NUM diagnosed and treated with conservative surgical management in the authors' center from 2008 to 2013. RESULTS Six cases of NUM were identified: 2 male and 4 female patients, age range at diagnosis of 44 to 76 years. All patients underwent complete nail unit removal with at least 6-mm security margins around the anatomic boundaries of the nail. The follow-up varies from 4 to 62 months. CONCLUSION Nail unit melanomas pose a difficult diagnostic and therapeutic challenge. Wide excision is sufficient, whereas phalanx amputation is unnecessary and associated with significant morbidity for patients with in situ or early invasive melanoma. Full-thickness skin grafting or second-intention healing after total nail unit excision is a simple procedure providing a good functional and cosmetic outcome.

An analysis of protocols and publications suggested that most discontinuations of clinical trials were not based on preplanned interim analyses or stopping rules.

OBJECTIVES To investigate the frequency of interim analyses, stopping rules, and data safety and monitoring boards (DSMBs) in protocols of randomized controlled trials (RCTs); to examine these features across different reasons for trial discontinuation; and to identify discrepancies in reporting between protocols and publications. STUDY DESIGN AND SETTING We used data from a cohort of RCT protocols approved between 2000 and 2003 by six research ethics committees in Switzerland, Germany, and Canada. RESULTS Of 894 RCT protocols, 289 prespecified interim analyses (32.3%), 153 stopping rules (17.1%), and 257 DSMBs (28.7%). Overall, 249 of 894 RCTs (27.9%) were prematurely discontinued; mostly due to reasons such as poor recruitment, administrative reasons, or unexpected harm. Forty-six of 249 RCTs (18.4%) were discontinued due to early benefit or futility; of those, 37 (80.4%) were stopped outside a formal interim analysis or stopping rule. Of 515 published RCTs, there were discrepancies between protocols and publications for interim analyses (21.1%), stopping rules (14.4%), and DSMBs (19.6%). CONCLUSION Two-thirds of RCT protocols did not consider interim analyses, stopping rules, or DSMBs. Most RCTs discontinued for early benefit or futility were stopped without a prespecified mechanism. When assessing trial manuscripts, journals should require access to the protocol.

Local Heat Application for the Treatment of Buruli Ulcer: Results of a Phase II Open Label Single Center Non Comparative Clinical Trial.

BACKGROUND Buruli ulcer (BU) is a necrotizing skin disease most prevalent among West African children. The causative organism, Mycobacterium ulcerans, is sensitive to temperatures above 37°C. We investigated the safety and efficacy of a local heat application device based on phase change material. METHODS In a phase II open label single center noncomparative clinical trial (ISRCTN 72102977) under GCP standards in Cameroon, laboratory confirmed BU patients received up to 8 weeks of heat treatment. We assessed efficacy based on the endpoints 'absence of clinical BU specific features' or 'wound closure' within 6 months ("primary cure"), and 'absence of clinical recurrence within 24 month' ("definite cure"). RESULTS Of 53 patients 51 (96%) had ulcerative disease. 62% were classified as World Health Organization category II, 19% each as category I and III. The average lesion size was 45 cm(2). Within 6 months after completion of heat treatment 92.4% (49 of 53, 95% confidence interval [CI], 81.8% to 98.0%) achieved cure of their primary lesion. At 24 months follow-up 83.7% (41 of 49, 95% CI, 70.3% to 92.7%) of patients with primary cure remained free of recurrence. Heat treatment was well tolerated; adverse effects were occasional mild local skin reactions. CONCLUSIONS Local thermotherapy is a highly effective, simple, cheap and safe treatment for M. ulcerans disease. It has in particular potential as home-based remedy for BU suspicious lesions at community level where laboratory confirmation is not available. CLINICAL TRIALS REGISTRATION ISRCT 72102977.

Comparison between magnetic resonance imaging and computed tomography of the lung in patients with cystic fibrosis with regard to clinical, laboratory, and pulmonary functional parameters

OBJECTIVE To evaluate whether magnetic resonance imaging (MRI) is effective as computed tomography (CT) in determining morphologic and functional pulmonary changes in patients with cystic fibrosis (CF) in association with multiple clinical parameters. MATERIALS AND METHODS Institutional review board approval and patient written informed consent were obtained. In this prospective study, 30 patients with CF (17 men and 13 women; mean (SD) age, 30.2 (9.2) years; range, 19-52 years) were included. Chest CT was acquired by unenhanced low-dose technique for clinical purposes. Lung MRI (1.5 T) comprised T2- and T1-weighted sequences before and after the application of 0.1-mmol·kg gadobutrol, also considering lung perfusion imaging. All CT and MR images were visually evaluated by using 2 different scoring systems: the modified Helbich and the Eichinger scores. Signal intensity of the peribronchial walls and detected mucus on T2-weighted images as well as signal enhancement of the peribronchial walls on contrast-enhanced T1-weighted sequences were additionally assessed on MRI. For the clinical evaluation, the pulmonary exacerbation rate, laboratory, and pulmonary functional parameters were determined. RESULTS The overall modified Helbich CT score had a mean (SD) of 15.3 (4.8) (range, 3-21) and median of 16.0 (interquartile range [IQR], 6.3). The overall modified Helbich MR score showed slightly, not significantly, lower values (Wilcoxon rank sum test and Student t test; P > 0.05): mean (SD) of 14.3 (4.7) (range, 3-20) and median of 15.0 (IQR, 7.3). Without assessment of perfusion, the overall Eichinger score resulted in the following values for CT vs MR examinations: mean (SD), 20.3 (7.2) (range, 4-31); and median, 21.0 (IQR, 9.5) vs mean (SD), 19.5 (7.1) (range, 4-33); and median, 20.0 (IQR, 9.0). All differences between CT and MR examinations were not significant (Wilcoxon rank sum tests and Student t tests; P > 0.05). In general, the correlations of the CT scores (overall and different imaging parameters) to the clinical parameters were slightly higher compared to the MRI scores. However, if all additional MRI parameters were integrated into the scoring systems, the correlations reached the values of the CT scores. The overall image quality was significantly higher for the CT examinations compared to the MRI sequences. CONCLUSIONS One major diagnostic benefit of lung MRI in CF is the possible acquisition of several different morphologic and functional imaging features without the use of any radiation exposure. Lung MRI shows reliable associations with CT and clinical parameters, which suggests its implementation in CF for routine diagnosis, which would be particularly important in follow-up imaging over the long term.

Urinary tract endometriosis in patients with deep infiltrating endometriosis: prevalence, symptoms, management, and proposal for a new clinical classification

OBJECTIVE To analyze the prevalence of urinary tract endometriosis (UTE) in patients with deep infiltrating endometriosis (DIE) and to define potential criteria for preoperative workup. DESIGN Retrospective study. SETTING University hospital. PATIENT(S) Six hundred ninety-seven patients with endometriosis. INTERVENTION(S) Excision of all endometriotic lesions. MAIN OUTCOME MEASURE(S) Correlation of preoperative features and intraoperative findings in patients with UTE. RESULT(S) Out of 213 patients presenting DIE, 52.6% suffered from UTE. In patients with ureteral endometriosis, symptoms were not specific. Among the patients with bladder endometriosis, 68.8% complained of urinary symptoms compared to 7.9% in the group of patients without UTE. In patients with rectovaginal endometriosis, the probability of ureterolysis showed a linear correlation with the size of the nodule. We found that 3 cm in diameter provided a specific cutoff value for the likelihood of ureteric involvement. CONCLUSION(S) The prevalence of UTE has often been underestimated. Preoperative questioning is important in the search for bladder endometriosis. The size of the nodule is one of the few reliable criteria in preoperative assessment that can suggest ureteric involvement. We propose a classification of ureteral endometriosis that will allow the standardization of terminology and help to compare the outcome of different surgical treatment in randomized studies.

Expanded Clinical Spectrum of Multiple Evanescent White Dot Syndrome with Multimodal Imaging

PURPOSE: To evaluate and characterize multiple evanescent white dot syndrome abnormalities with modern multimodal imaging modalities. METHODS: This retrospective cohort study evaluated fundus photography, fluorescein angiography, indocyanine green angiography, optical coherence tomography, enhanced depth imaging optical coherence tomography, short-wavelength autofluorescence, and near-infrared autofluorescence. RESULTS: Thirty-four multiple evanescent white dot syndrome patients with mean age of 28.7 years were studied (range, 14-49 years). Twenty-six patients were women, and eight were men. Initial mean visual acuity was 0.41 logMAR. Final mean visual acuity was 0.03 logMAR. Fluorescein angiography shows a variable number of mid retinal early fluorescent dots distributed in a wreathlike pattern, which correlate to fundus photography, fundus autofluorescence, and indocyanine green angiography. Indocyanine green angiography imaging shows the dots and also hypofluorescent, deeper, and larger spots, which are occasionally confluent, demonstrating a large plaque of deep retinal hypofluorescence. Optical coherence tomography imaging shows multifocal debris centered at and around the ellipsoid layer, corresponding to the location of spots seen with photography, indocyanine green angiography, and fluorescein angiography. Protrusions of the hyperreflectant material from the ellipsoid layer toward the outer nuclear layer correspond to the location of dots seen with photography, indocyanine green angiography, and fluorescein angiography. CONCLUSION: Multimodal imaging analysis of the retina in patients with multiple evanescent white dot syndrome shows additional features that may help in the diagnosis of the disease and in further understanding its etiology. Multiple evanescent white dot syndrome is predominantly a disease of the outer retina, centered at the ellipsoid zone, but also involving the interdigitation zone and the outer nuclear layer.

Computer-based summative assessment of clinical reasoning in clerkships: A mixed-method comparison of key feature problems with case-based multiple choice questions

Background: It is yet unclear if there are differences between using electronic key feature problems (KFPs) or electronic case-based multiple choice questions (cbMCQ) for the assessment of clinical decision making. Summary of Work: Fifth year medical students were exposed to clerkships which ended with a summative exam. Assessment of knowledge per exam was done by 6-9 KFPs, 9-20 cbMCQ and 9-28 MC questions. Each KFP consisted of a case vignette and three key features (KF) using “long menu” as question format. We sought students’ perceptions of the KFPs and cbMCQs in focus groups (n of students=39). Furthermore statistical data of 11 exams (n of students=377) concerning the KFPs and (cb)MCQs were compared. Summary of Results: The analysis of the focus groups resulted in four themes reflecting students’ perceptions of KFPs and their comparison with (cb)MCQ: KFPs were perceived as (i) more realistic, (ii) more difficult, (iii) more motivating for the intense study of clinical reasoning than (cb)MCQ and (iv) showed an overall good acceptance when some preconditions are taken into account. The statistical analysis revealed that there was no difference in difficulty; however KFP showed a higher discrimination and reliability (G-coefficient) even when corrected for testing times. Correlation of the different exam parts was intermediate. Conclusions: Students perceived the KFPs as more motivating for the study of clinical reasoning. Statistically KFPs showed a higher discrimination and higher reliability than cbMCQs. Take-home messages: Including KFPs with long menu questions into summative clerkship exams seems to offer positive educational effects.

Automatic quality control in clinical (1) H MRSI of brain cancer.

MRSI grids frequently show spectra with poor quality, mainly because of the high sensitivity of MRS to field inhomogeneities. These poor quality spectra are prone to quantification and/or interpretation errors that can have a significant impact on the clinical use of spectroscopic data. Therefore, quality control of the spectra should always precede their clinical use. When performed manually, quality assessment of MRSI spectra is not only a tedious and time-consuming task, but is also affected by human subjectivity. Consequently, automatic, fast and reliable methods for spectral quality assessment are of utmost interest. In this article, we present a new random forest-based method for automatic quality assessment of (1) H MRSI brain spectra, which uses a new set of MRS signal features. The random forest classifier was trained on spectra from 40 MRSI grids that were classified as acceptable or non-acceptable by two expert spectroscopists. To account for the effects of intra-rater reliability, each spectrum was rated for quality three times by each rater. The automatic method classified these spectra with an area under the curve (AUC) of 0.976. Furthermore, in the subset of spectra containing only the cases that were classified every time in the same way by the spectroscopists, an AUC of 0.998 was obtained. Feature importance for the classification was also evaluated. Frequency domain skewness and kurtosis, as well as time domain signal-to-noise ratios (SNRs) in the ranges 50-75 ms and 75-100 ms, were the most important features. Given that the method is able to assess a whole MRSI grid faster than a spectroscopist (approximately 3 s versus approximately 3 min), and without loss of accuracy (agreement between classifier trained with just one session and any of the other labelling sessions, 89.88%; agreement between any two labelling sessions, 89.03%), the authors suggest its implementation in the clinical routine. The method presented in this article was implemented in jMRUI's SpectrIm plugin. Copyright © 2016 John Wiley & Sons, Ltd.

Childhood cancer survivor satisfaction with characteristics of clinical care

This study investigated the characteristics of a clinic that affect how satisfied survivors of childhood cancer are with their medical care. Questionnaire and interview data from the Passport for Care: Texas Implementation project collected between January 2011 to April 2012 were analyzed. Eleven clinics in Texas participated. Questionnaire respondents were childhood cancer survivor patients who had been off therapy for at least 2 years, or their parents. Interview respondents were clinical providers or research staff at the participating clinics. The outcomes evaluated were answers to a single question on satisfaction with care and a composite Percent Satisfaction Score created from seven other questionnaire items that were correlated (Spearman Rho >0.3) with the question on satisfaction. The following characteristics were also evaluated: sex, age, race, education, and type of cancer. The following clinic indicators were evaluated: type of clinic (general vs. dedicated cancer survivor clinics), number of providers, number of survivors, ratio of survivors/providers, distribution of handouts, distribution of treatment summaries, and use of Children's Oncology Group (COG) guidelines. ^ The only demographic characteristic that affected satisfaction was race. A Kruskal-Wallis test showed a statistically significant difference (Chi-square 6.129, 2 d.f., p = 0.0467). To analyze this further, Wilcoxon Rank Sum test of pairings of the three groups were performed. A Bonferroni correction for multiple testing was applied, with p = 0.017 indicating significance at alpha = 0.05. There was no significant difference between the White and Hispanic groups or between the Hispanic and "Other" groups. For the White and "Other" groups there was a significant difference for the satisfaction item (p = 0.0123) but not for the Percent Satisfaction Score (p = 0.0289). These results suggest that race may influence satisfaction and should be evaluated further in future studies. ^ None of the clinic indicators affected the Percent Satisfaction Score. Going to a clinic that distributed patient information handouts (Wilcoxon Rank Sum p = 0.048) and going to a clinic with >=100 survivors (Wilcoxon Rank Sum p = 0.021) were associated with increased satisfaction. The population of childhood cancer survivors is a growing group of individuals with special health needs. In the future survivors will likely seek medical care in a variety of clinical settings, so it is important to investigate features to improve patient satisfaction with clinical care.^

The Effect of Proximity, Explicitness, and Representation of Basic Science Information on Student Clinical Problem-Solving

Problem: Medical and veterinary students memorize facts but then have difficulty applying those facts in clinical problem solving. Cognitive engineering research suggests that the inability of medical and veterinary students to infer concepts from facts may be due in part to specific features of how information is represented and organized in educational materials. First, physical separation of pieces of information may increase the cognitive load on the student. Second, information that is necessary but not explicitly stated may also contribute to the student’s cognitive load. Finally, the types of representations – textual or graphical – may also support or hinder the student’s learning process. This may explain why students have difficulty applying biomedical facts in clinical problem solving. Purpose: To test the hypothesis that three specific aspects of expository text – the patial distance between the facts needed to infer a rule, the explicitness of information, and the format of representation – affected the ability of students to solve clinical problems. Setting: The study was conducted in the parasitology laboratory of a college of veterinary medicine in Texas. Sample: The study subjects were a convenience sample consisting of 132 second-year veterinary students who matriculated in 2007. The age of this class upon admission ranged from 20-52, and the gender makeup of this class consisted of approximately 75% females and 25% males. Results: No statistically significant difference in student ability to solve clinical problems was found when relevant facts were placed in proximity, nor when an explicit rule was stated. Further, no statistically significant difference in student ability to solve clinical problems was found when students were given different representations of material, including tables and concept maps. Findings: The findings from this study indicate that the three properties investigated – proximity, explicitness, and representation – had no statistically significant effect on student learning as it relates to clinical problem-solving ability. However, ad hoc observations as well as findings from other researchers suggest that the subjects were probably using rote learning techniques such as memorization, and therefore were not attempting to infer relationships from the factual material in the interventions, unless they were specifically prompted to look for patterns. A serendipitous finding unrelated to the study hypothesis was that those subjects who correctly answered questions regarding functional (non-morphologic) properties, such as mode of transmission and intermediate host, at the family taxonomic level were significantly more likely to correctly answer clinical case scenarios than were subjects who did not correctly answer questions regarding functional properties. These findings suggest a strong relationship (p < .001) between well-organized knowledge of taxonomic functional properties and clinical problem solving ability. Recommendations: Further study should be undertaken investigating the relationship between knowledge of functional taxonomic properties and clinical problem solving ability. In addition, the effect of prompting students to look for patterns in instructional material, followed by the effect of factors that affect cognitive load such as proximity, explicitness, and representation, should be explored.