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AnteayerPLOS ONE Medicine&Health

Detection of <i>MYD88 L265P</i> mutation by next-generation deep sequencing in peripheral blood mononuclear cells of Waldenström’s macroglobulinemia and IgM monoclonal gammopathy of undetermined significance

by Ayako Nakamura, Chikako Ohwada, Masahiro Takeuchi, Yusuke Takeda, Shokichi Tsukamoto, Naoya Mimura, Oshima-Hasegawa Nagisa, Yasumasa Sugita, Hiroaki Tanaka, Hisashi Wakita, Nobuyuki Aotsuka, Kosei Matsue, Koutaro Yokote, Osamu Ohara, Chiaki Nakaseko, Emiko Sakaida

We investigated the feasibility of using next-generation sequencing (NGS) technique using molecular barcoding technology to detect MYD88 L265P mutation in unselected peripheral blood mononuclear cells (PBMCs) in 52 patients with Waldenström’s macroglobulinemia [1] and 21 patients with IgM-monoclonal gammopathy of undetermined significance (MGUS). The NGS technique successfully detected the MYD88 L265P in unselected PBMCs at a sensitivity of 0.02%, which was ×5 higher than that of AS-PCR. All the results between paired BM and PB samples from 2 IgM MGUS and 4 untreated WM patients matched completely. MYD88 L265P mutation was detected in 14/21 (66.7%), 14/19 (73.7%), and 10/33 (30.3%) with the median mutant allele burden of 0.36% (range, 0.06–2.85%), 0.48% (range, 0.02–32.3%), and 0.16% (range, 0.02–33.8%), in IgM-MGUS, untreated WM, and previously treated WM, respectively. Multiple linear regression analysis identified an absolute peripheral lymphocyte count as the positive predictor of PB mutant allele burden (R2 = 0,72, PMYD88 L265P mutations in PBMCs of IgM MGUS and WM patients, which may especially utilized for monitoring minimal residual tumor burden after treatment.

B7-1 drives TGF-β stimulated pancreatic carcinoma cell migration and expression of EMT target genes

by Jeong-Han Kang, Mi-Yeon Jung, Edward B. Leof

B7-1 proteins are routinely expressed on the surface of antigen presenting cells (APC) and within the innate immune system. They function to establish a biologically optimal and dynamic balance between immune activation and inhibition or self-tolerance. Interactions between B7-1 and its receptors, which include CD28, CTLA4 and PD-L1, contribute to both stimulatory as well as inhibitory or homeostatic regulation. In the current study, we investigated whether the tumor-promoting actions of transforming growth factor beta (TGF-β) disrupted this equilibrium in pancreatic cancer to promote malignant progression and an enhanced means to evade immune detection. The data show that B7-1 is (i) upregulated following treatment of pancreatic carcinoma cells with TGF-β; (ii) induced by TGF-β via both Smad2/3-dependent and independent pathways; (iii) required for pancreatic tumor cell in vitro migration/invasion; and (iv) necessary for TGF-β regulated epithelial-mesenchymal transition (EMT) through induction of Snail family members. Results from the proposed studies provide valuable insights into mechanisms whereby TGF-β regulates both the innate immune response and intrinsic properties of pancreatic tumor growth.

Assessing the effectiveness of an electrical stunning and chilling protocol for the slaughter of Atlantic mackerel (<i>Scomber scombrus</i>)

by Neil Anders, Bjørn Roth, Endre Grimsbø, Michael Breen

Inducing unconsciousness in fish using electrical stunning prior to slaughter may improve fish welfare and fillet quality if such practises can be disseminated into wild capture fisheries. The objectives of this study were to: 1) evaluate if an established slaughter protocol consisting of dry electrical stunning (using a coupled AC/DC current at ≈ 110 Vrms) followed by chilling could be used to stun the wild captured species Atlantic mackerel (Scomber scombrus) unconscious within 0.5 s; 2) determine if death could be induced without consciousness recovery by longer duration stunning (5 s) combined with chilling in an ice/water slurry for 6 min; and 3) examine the extent of quality defects arising from the applied slaughter protocol. We determined consciousness by examination of behavioural responses in a standardised vitality assessment. Out of a sample of 10 mackerel, 9 were assumed to be rendered unconscious by the 0.5 s stun, as determined by the presence of tonic and/or clonic muscle cramping consistent with a general epileptic insult. Assumed unconsciousness was maintained throughout chilling treatment in all fish (n = 25) following a full stun of 5 s. All fish were assumed to have died as a result of the protocol. There was no evidence of spinal damage or haematoma quality defects post filleting. These results suggest that the examined protocol is effective at slaughtering mackerel in a manner consistent with good welfare and without inducing quality defects, but further research is required to verify the unconscious condition via electroencephalogram (EEG) and before the procedure can be applied in wild capture fisheries.

Effects of foliar application of amino acid liquid fertilizers, with or without <i>Bacillus amyloliquefaciens</i> SQR9, on cowpea yield and leaf microbiota

by Dongsheng Wang, Xuhui Deng, Bei Wang, Na Zhang, Chengzhi Zhu, Zixuan Jiao, Rong Li, Qirong Shen

Leaf surface fertilization with liquid fertilizer produced from amino acids constitutes a potentially important source of nitrogen and is important for plant production. However, few reports have focused on the plant growth promotion by novel liquid fertilizers created by new amino acid resources, let alone the influence on leaf microbiota. In this study, the effects of liquid fertilizer, created by amino acids hydrolyzed from animal hairs with or without the PGPR strain Bacillus amyloliquefaciens SQR9, on crop yield and leaf microbiota were investigated. The results showed that leaves sprayed with amino acid liquid fertilizer (AA) and liquid biological fertilizer (AA9) persistently increased cowpea yields compared to the control amended with chemical fertilizer (CF). Fertilization with amino acid fertilizer showed no significant difference in microbial composition compared with the CF treatment; however, the introduction of functional microbes altered the microbial composition. Pearson correlation analysis, VPA analysis and SEM models all revealed that the amino acids liquid fertilizer application, but not the functional strain or the altered microbiota, performed as the direct driver attributing to yield enhancement. We conclude that leaf fertilization with a novel amino acid liquid fertilizer can greatly enhance the crop yield and that the addition of beneficial microbes may perform the role in further altering the composition of leaf microbiota.

Sex and racial differences in cardiovascular disease risk in patients with atrial fibrillation

by Wesley T. O’Neal, Aniqa B. Alam, Pratik B. Sandesara, J’Neka S. Claxton, Richard F. MacLehose, Lin Y. Chen, Lindsay G. S. Bengtson, Alanna M. Chamberlain, Faye L. Norby, Pamela L. Lutsey, Alvaro Alonso


Outcomes among atrial fibrillation (AF) patients may differ according to race/ethnicity and sex due to differences in biology, the prevalence of cardiovascular risk factors, and the use and effectiveness of AF treatments. We aimed to characterize patterns of cardiovascular risk across subgroups of AF patients by sex and race/ethnicity, since doing so may provide opportunities to identify interventions. We also evaluated whether these patterns changed over time.


We utilized administrative claims data from the Optum Clinformatics® Datamart database from 2009 to 2015. Patients with AF with ≥6 months of enrollment prior to the first non-valvular AF diagnosis were included in the analysis. Final analysis utilized Cox proportional hazard models to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for cardiovascular outcomes stratified by sex and race/ethnicity. An additional analysis stratified outcomes by calendar year of AF diagnosis to evaluate changes in outcomes over time.


In a cohort of 380,636 AF patients, women had a higher risk of ischemic stroke [HR (95% CI): 1.25 (1.19, 1.31)] and lower risk of heart failure and myocardial infarction [HR (95% CI): 0.91 (0.88, 0.94) and 0.81 (0.77, 0.86), respectively)] compared to men. Black patients had elevated risk across all endpoints compared to whites, while Hispanics and Asian Americans showed no significant differences in any outcome compared to white patients. These sex and race/ethnic differences did not change over time.


We found sex and race/ethnic differences in risk of cardiovascular outcomes among AF patients, without evidence of improvement over time.

Effect of time interval from diagnosis to treatment for cervical cancer on survival: A nationwide cohort study

by Chao-Ping Chen, Pei-Tseng Kung, Yueh-Hsin Wang, Wen-Chen Tsai


Despite the ease of health care access and the waiver of copayments for cancer patients, treatment is delayed in a small proportion of Taiwanese patients diagnosed with cervical cancer. In this study, we explored the relationship between the time interval from diagnosis to treatment and survival in cervical cancer patients.

Material and methods

The study was a retrospective population-based observational study conducted between 2004 and 2010. In Taiwan, 12,020 patients were newly diagnosed with cervical cancer from 2004 to 2010, and 9,693 patients (80.6%) were enrolled in our final analysis.


Most of the patients received treatment within 90 days of diagnosis (n = 9,341, 96.37%). After adjustment for other variables, patients who received treatment between 90 and 180 days and >180 days after diagnosis had a 1.33 (95% CI: 1.02–1.72, P P 180 days after diagnosis.


A longer interval between diagnosis and treatment is associated with poorer prognosis among cervical cancer patients.

Serum microRNA-based prediction of responsiveness to eribulin in metastatic breast cancer

by Natsuko Satomi-Tsushita, Akihiko Shimomura, Juntaro Matsuzaki, Yusuke Yamamoto, Junpei Kawauchi, Satoko Takizawa, Yoshiaki Aoki, Hiromi Sakamoto, Ken Kato, Chikako Shimizu, Takahiro Ochiya, Kenji Tamura

The identification of biomarkers for predicting the responsiveness to eribulin in patients with metastatic breast cancer pretreated with an anthracycline and a taxane remains an unmet need. Here, we established a serum microRNA (miRNA)-based prediction model for the emergence of new distant metastases after eribulin treatment. Serum samples were collected from metastatic breast cancer patients prior to eribulin treatment and comprehensively evaluated by miRNA microarray. The prediction model for estimating eribulin efficacy was established using the logistic LASSO regression model. Serum samples were collected from 147 patients, of which 52 developed at least one new distant metastasis after eribulin monotherapy and 95 did not develop new distant metastases. A combination of eight serum miRNAs (miR-4483, miR-8089, miR-4755-3p, miR-296-3p, miR-575, miR-4710, miR-5698 and miR-3160-5p) predicted the appearance of new distant metastases with an area under the curve of 0.79, sensitivity of 0.69 and specificity of 0.82. The serum levels of miR-8089 and miR-5698 were significantly associated with overall survival after the initiation of eribulin treatment. The present study provides evidence that serum miRNA profiling may serve as a biomarker for the responsiveness to eribulin and for predicting the development of new distant metastases in metastatic breast cancer.

Detection of two Arctic birds in Greenland and an endangered bird in Korea using RGB and thermal cameras with an unmanned aerial vehicle (UAV)

by Won Young Lee, Mijin Park, Chang-Uk Hyun

Unmanned aerial vehicles (UAVs), so-called ‘drones’, have been widely used to monitor wild animals. Here, we tested a UAV with red, green, and blue (RGB) and thermal cameras to detect free-living birds in a high Arctic region in North Greenland and in a restricted area in the Republic of Korea. Small flocks of molting pink-footed geese (Anser brachyrhynchus) near sea ice and incubating common ringed plovers (Charadrius hiaticula) in the Arctic environment were chosen for the RGB and thermal image studies. From the acquired images, we built mosaicked RGB images and coregistered thermal images, and estimated the animal shapes. Our results showed that geese were discriminated in both RGB and thermal images with water and sea ice backgrounds. Incubating plover bodies were not distinguished in RGB images due to their cryptic coloration, but they were detected in thermal images with cold background areas in the Arctic environment. We further conducted a blind survey in a restricted area under military control in Korea near the breeding sites of black-faced spoonbill (Platalea minor), which is an endangered species. From UAV flights with RGB and thermal cameras operated out of the restricted area, we acquired images of white objects in the mudflats and verified that the objects were resting spoonbills by watching the birds. We suggest that thermal cameras and UAVs can be applied to monitor animals in extreme environments and in restricted areas and help researchers find cryptic wader nests.

Increased functional connectivity of thalamic subdivisions in patients with Parkinson’s disease

by Conor Owens-Walton, David Jakabek, Brian D. Power, Mark Walterfang, Dennis Velakoulis, Danielle van Westen, Jeffrey C. L. Looi, Marnie Shaw, Oskar Hansson

Parkinson’s disease (PD) affects 2–3% of the population over the age of 65 with loss of dopaminergic neurons in the substantia nigra impacting the functioning of basal ganglia-thalamocortical circuits. The precise role played by the thalamus is unknown, despite its critical role in the functioning of the cerebral cortex, and the abnormal neuronal activity of the structure in PD. Our objective was to more clearly elucidate how functional connectivity and morphology of the thalamus are impacted in PD (n = 32) compared to Controls (n = 20). To investigate functional connectivity of the thalamus we subdivided the structure into two important regions-of-interest, the first with putative connections to the motor cortices and the second with putative connections to prefrontal cortices. We then investigated potential differences in the size and shape of the thalamus in PD, and how morphology and functional connectivity relate to clinical variables. Our data demonstrate that PD is associated with increases in functional connectivity between motor subdivisions of the thalamus and the supplementary motor area, and between prefrontal thalamic subdivisions and nuclei of the basal ganglia, anterior and dorsolateral prefrontal cortices, as well as the anterior and paracingulate gyri. These results suggest that PD is associated with increased functional connectivity of subdivisions of the thalamus which may be indicative alterations to basal ganglia-thalamocortical circuitry.

Does numerical similarity alter age-related distractibility in working memory?

by Chiara Francesca Tagliabue, Debora Brignani, Veronica Mazza

Similarity between targets and distracters is a key factor in generating distractibility, and exerts a large detrimental effect on aging. The present EEG study tested the role of a new stimulus dimension in generating distractibility in visual Working Memory (vWM), namely numerical similarity. In a change detection paradigm a varying number of relevant and irrelevant stimuli were presented simultaneously in opposite hemifields. Behavioral results indicated that young participants outperformed older individuals; however, in both groups numerical similarity per se did not modulate performance. At the electrophysiological level, in young participants the Contralateral Delay Activity (CDA, a proxy for item maintenance in vWM) was modulated by the numerosity of the relevant items regardless of numerical similarity. In older participants, the CDA was modulated by target numerosity only in the same numerical condition, where the total number of (relevant and irrelevant) items increased with increasing target numerosities. No effect was present in the dissimilar numerical condition, where the total number of items did not vary substantially across target numerosity. This pattern was suggestive of an age-related effect of the total number of (relevant and irrelevant) items on vWM. The additional analyses on alpha-band lateralization measures support this interpretation by revealing that older adults lacked selective deployment of attentional and vWM resources towards the relevant hemifield. Overall, the results indicate that, while numerical similarity does not modulate distractibility, there is an age-related redistribution of vWM resources across the two visual fields, ultimately leading to a general decrease in task performance of older adults.

Effect of heat stress on blood-brain barrier integrity in iPS cell-derived microvascular endothelial cell models

by Tomoko Yamaguchi, Kentaro Shimizu, Yasuhiro Kokubu, Misae Nishijima, Shuko Takeda, Hiroshi Ogura, Kenji Kawabata

The incidence of heatstroke has been increasing. Heatstroke has been shown to affect physiological barrier functions. However, there are few studies of the effect of heat stress on the blood-brain barrier (BBB) function. In this study, we investigated the influence of heat stress on brain microvascular endothelial cells in vivo and in vitro. Heatstroke model mice administered Texas Red-dextran showed leakage outside the brain vessel walls. In addition, trans-endothelial electrical resistance (TEER) value was significantly reduced in induced pluripotent stem (iPS) cell-derived brain microvascular endothelial cells under heat stress by reducing claudin-5 expression. In addition, our results showed that the expression level of P-glycoprotein (P-gp) was increased in iPS cell-derived brain microvascular endothelial cells under heat stress. Furthermore, serum from heatstroke model mice could impair the BBB integrity of iPS cell-derived brain microvascular endothelial cells. These results suggest that BBB integrity was affected by heat stress in vivo and in vitro and provide important insights into the development of new therapeutic strategies for heatstroke patients.

Expression of sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 in malaria-associated acute lung injury/acute respiratory distress syndrome in a mouse model

by Chuchard Punsawad, Parnpen Viriyavejakul

This study aimed to investigate the expression of sphingosine kinase 1 (SphK-1) and sphingosine 1-phosphate receptor 3 (S1PR-3) in a mouse model of malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS). DBA/2 mice were infected with Plasmodium berghei ANKA to generate an experimental model of malaria-associated ALI/ARDS. The infected mice were divided into 2 groups based on the histopathological study of lung tissues: those with and those without ALI/ARDS. The expression of the SphK-1 and S1PR-3 proteins in the lung tissues was investigated using immunohistochemical staining and Western blot analysis. In addition, the S1P level was quantified in plasma and lung tissues using an enzyme-linked immunosorbent assay (ELISA). The results demonstrated that the cellular expression of the SphK-1 and S1PR-3 proteins was significantly upregulated in endothelial cells, alveolar epithelial cells and alveolar macrophages in the lung tissues of malaria-infected mice with ALI/ARDS compared with those in the control groups. The increased expression of the SphK-1 and S1PR-3 proteins was confirmed using Western blot analysis. The concentration of S1P in plasma and lung tissues was significantly decreased in malaria-infected mice with ALI/ARDS compared with non-ALI/ARDS and control mice. Furthermore, increased expression of the SphK-1 and S1PR-3 proteins significantly correlated with lung injury scores and S1P concentrations in malaria-infected mice with ALI/ARDS. These findings highlight increased expression of SphK-1 and S1PR-3 in the lung tissues of malaria-infected mice with ALI/ARDS.

Double burden of malnutrition at household level: A comparative study among Bangladesh, Nepal, Pakistan, and Myanmar

by Asibul Islam Anik, Md. Mosfequr Rahman, Md. Mostafizur Rahman, Md. Ismail Tareque, Md. Nuruzzaman Khan, M. Mahmudul Alam


The coexistence of overweight mother and stunted child at the same household is a type of Double Burden of Malnutrition at Household Level (DBMHL). This particular public health concern is now emerging at an alarming rate among most of the South Asian and its neighboring lower-and-middle income countries which are going through nutritional transition. This study has examined the prevalence rate and the risk factors of DBMHL along with the socio-economic inequality in DBMHL among Bangladesh, Nepal, Pakistan, and Myanmar.


Latest Demographic and Health Survey datasets were used in this study. To identify the significant association of DBMHL with socio-demographic characteristics, a multivariate technique named as logistic regression model, and for measuring socio-economic inequalities in DBMHL prevalence, relative index of inequality (RII) and slope index of inequality (SII) were used.


The prevalence rates of DBMHL were 4.10% (urban: 5.57%, rural: 3.51%), 1.54% (urban: 1.63%, rural: 1.42%), 3.93% (urban: 5.62%, rural: 3.20%), and 5.54% (urban: 6.16%, rural: 5.33%) respectively in Bangladesh, Nepal, Pakistan, and Myanmar. The risk ratios (RR) obtained from RII for Bangladesh, Nepal, Pakistan and Myanmar were 1.25, 1.25, 1.14, and 1.09, respectively, and β coefficient from SII were 0.01, 0.004, 0.005, and 0.006 unit respectively. In addition to not breastfeeding [Bangladesh (AOR: 1.55; 95% CI: 1.11–2.15), Myanmar (AOR: 1.74; 95% CI: 1.02–2.95)], respondent’s older age (in Bangladesh, Nepal, and Myanmar), child’s older age (in Pakistan and Myanmar), and middle and rich groups of wealth-index (in Bangladesh and Pakistan) were strong risk factors for DBMHL. On the other hand, female child [Nepal (AOR: 0.50; 95% CI: 0.26–0.95), Pakistan (AOR: 0.58; 95% CI: 0.41–0.84)], higher education [in Pakistan], respondent not participated in decision making [in Bangladesh and Nepal] and media access [Nepal (AOR: 0.44; 95% CI: 0.20–0.98)] had negative association with DBMHL.


The DBMHL persists in all selected countries, with a higher prevalence in urban areas than in rural areas. In order to control the higher prevalence of DBMHL in urban areas, respective countries need urgent implementation of multisectoral actions through effective policies and empowering local communities.

Reference gene selection for quantitative gene expression analysis in black soldier fly (<i>Hermetia illucens</i>)

by Zhenghui Gao, Wenhui Deng, Fen Zhu

Hermetia illucens is an important resource insect for the conversion of organic waste. Quantitative PCR (qPCR) is the primary tool of gene expression analysis and a core technology of molecular biology research. Reference genes are essential for qPCR analysis; however, a stability analysis of H. illucens reference genes has not yet been carried out. To find suitable reference genes for normalizing gene expression data, the stability of eight housekeeping genes (including ATP6V1A, RPL8, EF1, Tubulin, TBP, GAPDH, Actin and RP49) was investigated under both biotic (developmental stages, tissues and sex) and abiotic (heavy metals, food, antibiotics) conditions. Gene expression data were analysed by geNorm, NormFinder, BestKeeper, and ΔCt programs. A set of specific reference genes was recommended for each experimental condition using the results of RefFinder synthesis analysis. This study offers a solid foundation for further studies of the molecular biology of H. illucens.

Micro-costing and a cost-consequence analysis of the ‘Girls Active’ programme: A cluster randomised controlled trial

by Joanna M. Charles, Deirdre M. Harrington, Melanie J. Davies, Charlotte L. Edwardson, Trish Gorely, Danielle H. Bodicoat, Kamlesh Khunti, Lauren B. Sherar, Thomas Yates, Rhiannon Tudor Edwards

Physical inactivity has been identified as a leading risk factor for premature mortality globally, and adolescents, in particular, have low physical activity levels. Schools have been identified as a setting to tackle physical inactivity. Economic evidence of school-based physical activity programmes is limited, and the costs of these programmes are not always collected in full. This paper describes a micro-costing and cost-consequence analysis of the ‘Girls Active’ secondary school-based programme as part of a cluster randomised controlled trial (RCT). Micro-costing and cost-consequence analyses were conducted using bespoke cost diaries and questionnaires to collect programme delivery information. Outcomes for the cost-consequence analysis included health-related quality of life measured by the Child Health Utility-9D (CHU-9D), primary care General Practitioner (GP) and school-based (school nurse and school counsellor) service use as part of a cluster RCT of the ‘Girls Active’ programme. Overall, 1,752 secondary pupils were recruited and a complete case sample of 997 participants (Intervention n = 570, Control n = 427) was used for the cost-consequence analysis. The micro-costing analysis demonstrated that, depending upon how the programme was delivered, ‘Girls Active’ costs ranged from £1,054 (£2 per pupil, per school year) to £3,489 (£7 per pupil, per school year). The least costly option was to absorb ‘Girls Active’ strictly within curriculum hours. The analysis demonstrated no effect for the programme for the three main outcomes of interest (health-related quality of life, physical activity and service use).Micro-costing analyses demonstrated the costs of delivering the ‘Girls Active’ programme, addressing a gap in the United Kingdom (UK) literature regarding economic evidence from school-based physical activity programmes. This paper provides recommendations for those gathering cost and service use data in school settings to supplement validated and objective measures, furthering economic research in this field. Trial registration: -ISRCTN, ISRCTN10688342.

Spatial scan statistics for matched case-control data

by Inkyung Jung

Spatial scan statistics are widely used for cluster detection analysis in geographical disease surveillance. While this method has been developed for various types of data such as binary, count, and continuous data, spatial scan statistics for matched case-control data, which often arise in spatial epidemiology, have not been considered. We propose spatial scan statistics for matched case-control data. The proposed test statistics consider the correlations between matched pairs. We evaluate the statistical power and cluster detection accuracy of the proposed methods through simulations compared to the Bernoulli-based method. We illustrate the proposed methods using a real data example. The simulation study clearly revealed that the proposed methods had higher power and higher accuracy for detecting spatial clusters for matched case-control data than the Bernoulli-based spatial scan statistic. The cluster detection result of the real data example also appeared to reflect a higher power of the proposed methods. The proposed methods are very useful for spatial cluster detection for matched case-control data.

How are medical students using the Electronic Health Record (EHR)?: An analysis of EHR use on an inpatient medicine rotation

by Jeffrey Chi, Jason Bentley, John Kugler, Jonathan H. Chen

Physicians currently spend as much as half of their day in front of the computer. The Electronic Health Record (EHR) has been associated with declining bedside skills and physician burnout. Medical student EHR use has not been well studied or characterized. However, student responsibilities for EHR documentation will likely increase as the Centers for Medicare and Medicaid Services (CMS) most recent provisions now allow student notes for billing which will likely increase the role of medical student use of the EHR over time. To gain a better understanding of how medical students use the EHR at our institution, we retrospectively analyzed 6,692,994 EHR interactions from 49 third-year clerkship medical students and their supervising physicians assigned to the inpatient medicine ward rotation between June 25 2015 and June 24 2016 at a tertiary academic medical center. Medical students spent 4.42 hours (37%) of each day at the on the EHR and 35 minutes logging in from home. Improved understanding of student EHR-use and the effects on well-being warrants further attention, especially as EHR use increases with early trainees.