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Noda-Like Rna Viruses Infecting Caenorhabditis Nematodes: Sympatry, Diversity, And Reassortment, Lise Frézal, Hyeim Jung, Stephen Tahan, David Wang, Marie-Anne Félix

Open Access Publications

Three RNA viruses related to nodaviruses were previously described to naturally infect the nematode

Maternal Fluoxetine Exposure Alters Cortical Hemodynamic And Calcium Response Of Offspring To Somatosensory Stimuli, Rachel M Rahn, Susan E Maloney, Lindsey M Brier, Joseph D Dougherty, Joseph P Culver

Open Access Publications

Epidemiological studies have found an increased incidence of neurodevelopmental disorders in populations prenatally exposed to selective serotonin reuptake inhibitors (SSRIs). Optical imaging provides a minimally invasive way to determine if perinatal SSRI exposure has long-term effects on cortical function. Herein we probed the functional neuroimaging effects of perinatal SSRI exposure in a fluoxetine (FLX)-exposed mouse model. While resting-state homotopic contralateral functional connectivity was unperturbed, the evoked cortical response to forepaw stimulation was altered in FLX mice. The stimulated cortex showed decreased activity for FLX versus controls, by both hemodynamic responses [oxyhemoglobin (HbO

Diffusion Basis Spectrum Imaging For Identifying Pathologies In Ms Subtypes, Afsaneh Shirani, Peng Sun, Kathryn Trinkaus, Dana C Perantie, Ajit George, Robert T Naismith, Robert E Schmidt, Sheng-Kwei Song, Anne H Cross

Open Access Publications

Diffusion basis spectrum imaging (DBSI) combines discrete anisotropic diffusion tensors and the spectrum of isotropic diffusion tensors to model the underlying multiple sclerosis (MS) pathologies. We used clinical MS subtypes as a surrogate of underlying pathologies to assess DBSI as a biomarker of pathology in 55 individuals with MS. Restricted isotropic fraction (reflecting cellularity) and fiber fraction (representing apparent axonal density) were the most important DBSI metrics to classify MS using brain white matter lesions. These DBSI metrics outperformed lesion volume. When analyzing the normal-appearing corpus callosum, the most significant DBSI metrics were fiber fraction, radial diffusivity (reflecting myelination), and …

Human Monoclonal Antibodies Against Chikungunya Virus Target Multiple Distinct Epitopes In The E1 And E2 Glycoproteins, Jose A. Quiroz, Ryan J. Malonis, Larissa B. Thackray, Courtney A. Cohen, Jesper Pallesen, Rohit K. Jangra, Rebecca S. Brown, Daniel Hofmann, Frederick W. Holtsberg, Sergey Shulenin, Elisabeth K. Nyakatura, Lorellin A. Durnell, Vinayak Rayannavar, Johanna P. Daily, Andrew B. Ward, M. Javad Aman, John M. Dye, Kartik Chandran, Michael S. Diamond, Margaret Kielian, Jonathan R. Lai

Open Access Publications

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two …

Neoadjuvant Cryotherapy Improves Dysphagia And May Impact Remission Rates In Advanced Esophageal Cancer, Tilak Shah, Vladimir Kushnir, Pritesh Mutha, Mankanchan Majhail, Bhaumik Patel, Matthew Schutzer, Drew Mogahanaki, George Smallfield, Milan Patel, Alvin Zfass

Open Access Publications

No abstract provided.

30-Day Emergency Department Revisit Rates Among Older Adults With Documented Dementia, Tyler Kent, Adriane Lesser, Juhi Israni, Ula Hwang, Christopher Carpenter, Kelly J Ko

Open Access Publications

OBJECTIVES: Published literature on national emergency department (ED) revisit rates among older adults with dementia is sparse, despite anecdotal evidence of higher ED utilization. Thus we evaluated the odds ratio (OR) of 30-day ED revisits among older adults with dementia using a nationally representative sample.

DESIGN: We assessed the frequency of claims associated with a 30-day ED revisit among Medicare beneficiaries with and without a dementia diagnosis before or at index ED visit. We used a logistic regression model controlling for dementia, age, sex, race, region, Medicaid status, transfer to a skilled nursing facility after ED, primary care physician use …

Bimodal Release Ondansetron For Acute Gastroenteritis Among Adolescents And Adults: A Randomized Clinical Trial, Robert A. Silverman, Stacey L. House, Andrew C. Meltzer, Barry Hahn, Luis M. Lovato, Jahn Avarello, Joseph B. Miller, Ira N. Kalfus, Reza Fathi, Gilead Raday, Terry F. Plasse, Eric C. Yan

Open Access Publications

Importance: Vomiting resulting from acute gastroenteritis is commonly treated with intravenous antiemetics in acute care settings. If oral treatment were beneficial, patients might not need intravenous administered hydration or medication. Furthermore, a long-acting treatment could provide sustained relief from nausea and vomiting.

Objective: To determine whether an experimental long-acting bimodal release ondansetron tablet decreases gastroenteritis-related vomiting and eliminates the need for intravenous therapy for 24 hours after administration.

Design, Setting, and Participants: This placebo-controlled, double-blind, randomized clinical trial included patients from 19 emergency departments and 2 urgent care centers in the United States from December 8, 2014, to February 17, …

Burden Of Cause-Specific Mortality Associated With Pm2.5 Air Pollution In The United States, Benjamin Bowe, Yan Xie, Yan Yan, Ziyad Al-Aly

Open Access Publications

Importance: Ambient fine particulate matter (PM2.5) air pollution is associated with increased risk of several causes of death. However, epidemiologic evidence suggests that current knowledge does not comprehensively capture all causes of death associated with PM2.5 exposure.

Objective: To systematically identify causes of death associated with PM2.5 pollution and estimate the burden of death for each cause in the United States.

Design, Setting, and Participants: In a cohort study of US veterans followed up between 2006 and 2016, ensemble modeling was used to identify and characterize morphology of the association between PM2.5 and causes of death. Burden of death associated …

Cabozantinib Versus Sunitinib For Untreated Patients With Advanced Renal Cell Carcinoma Of Intermediate Or Poor Risk: Subgroup Analysis Of The Alliance A031203 Cabosun Trial, Daniel J George, Colin Hessel, Susan Halabi, M Dror Michaelson, Olwen Hahn, Meghara Walsh, Joel Picus, Eric J Small, Shaker Dakhil, Darren R Feldman, Milan Mangeshkar, Christian Scheffold, Michael J Morris, Toni K Choueiri

Open Access Publications

Cabozantinib treatment prolonged progression-free survival (PFS) and improved objective response rate (ORR) compared with sunitinib in patients with advanced renal cell carcinoma (RCC) of intermediate or poor risk by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria in the phase II CABOSUN trial (NCT01835158). In the trial, 157 patients were randomized 1:1 to receive cabozantinib or sunitinib, stratified by IMDC risk group and presence of bone metastases. Here, PFS and ORR, both determined by independent radiology committee (IRC), were analyzed by subgroups of baseline characteristics. Cabozantinib treatment was generally associated with improved PFS and ORR versus sunitinib across subgroups, …

Changes In Serum Albumin And Other Nutritional Markers When Using Sucroferric Oxyhydroxide As Phosphate Binder Among Hemodialysis Patients: A Historical Cohort Study, Kamyar Kalantar-Zadeh, Linda H Ficociello, Vidhya Parameswaran, Nicolaos V Athienites, Claudy Mullon, Robert J Kossmann, Daniel W Coyne

Open Access Publications

BACKGROUND: Elevated serum phosphorus concentrations are common among maintenance hemodialysis patients. Protein is a major source of dietary phosphate, but restriction of protein intake can result in hypoalbuminemia and protein-energy wasting. We hypothesized that sucroferric oxyhydroxide (SO), a potent phosphate binder with a low pill burden, may reduce serum phosphorus levels in hemodialysis patients with hypoalbuminemia without adversely impacting albumin levels or dietary intake of protein.

METHODS: We retrospectively examined de-identified data from 79 adult, in-center hemodialysis patients with baseline hypoalbuminemia (≤ 3.5 g/dL) switched to SO as part of routine clinical care for at least 1 year. Temporal changes …

Redefining Noradrenergic Neuromodulation Of Behavior: Impacts Of A Modular Locus Coeruleus Architecture, Dan J. Chandler, Patricia Jensen, Jordan G. Mccall, Anthony E. Pickering, Lindsay A. Schwarz, Nelson K. Totah

Open Access Publications

The locus coeruleus (LC) is a seemingly singular and compact neuromodulatory nucleus that is a prominent component of disparate theories of brain function due to its broad noradrenergic projections throughout the CNS. As a diffuse neuromodulatory system, noradrenaline affects learning and decision making, control of sleep and wakefulness, sensory salience including pain, and the physiology of correlated forebrain activity (ensembles and networks) and brain hemodynamic responses. However, our understanding of the LC is undergoing a dramatic shift due to the application of state-of-the-art methods that reveal a nucleus of many modules that provide targeted neuromodulation. Here, we review the evidence …

Adjuvant Chemotherapy And Survival Among Patients 70 Years Of Age And Younger With Node-Negative Breast Cancer And The 21-Gene Recurrence Score Of 26-30, Seho Park, Yunan Han, Ying Liu, Adetunji T Toriola, Lindsay L Peterson, Graham A Colditz, Seung Il Kim, Young Up Cho, Byeong-Woo Park, Yikyung Park

Open Access Publications

BACKGROUND: The benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18-30, particularly those with RS 26-30, are not known.

METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18-30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox's proportional hazards model.

RESULTS: Among the breast cancer patients with the RS 18-30, 21% of them had RS 26-30. …

Pragmatic Randomised Clinical Trial Of Proton Versus Photon Therapy For Patients With Non-Metastatic Breast Cancer: The Radiotherapy Comparative Effectiveness (Radcomp) Consortium Trial Protocol, Justin E Bekelman, Walter Bosch, Et Al

Open Access Publications

INTRODUCTION: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer.

METHODS: We are conducting a large …

Staphylococcus Aureus Infects Osteoclasts And Replicates Intracellularly, Jennifer L Krauss, Philip M Roper, Anna Ballard, Chien-Cheng Shih, James A J Fitzpatrick, James E Cassat, Pei Ying Ng, Nathan J Pavlos, Deborah J Veis

Open Access Publications

Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by

Chitosan Biosynthesis And Virulence In The Human Fungal Pathogen Cryptococcus Gattii, Woei C Lam, Rajendra Upadhya, Charles A Specht, Abigail E Ragsdale, Camaron R Hole, Stuart M Levitz, Jennifer K Lodge

Open Access Publications

No abstract provided.

Mutation Of The Co-Chaperone Tsc1 In Bladder Cancer Diminishes Hsp90 Acetylation And Reduces Drug Sensitivity And Selectivity, Mark R. Woodford, Michael Hughes, Rebecca A. Sager, Sarah J. Backe, Alexander J. Baker-Williams, Michael S. Bratslavsky, Joseph M. Jacob, Oleg Shapiro, Michael Wong, Gennady Bratslavsky, Dimitra Bourboulia, Mehdi Mollapour

Open Access Publications

The molecular chaperone Heat shock protein 90 (Hsp90) is essential for the folding, stability, and activity of several drivers of oncogenesis. Hsp90 inhibitors are currently under clinical evaluation for cancer treatment, however their efficacy is limited by lack of biomarkers to optimize patient selection. We have recently identified the tumor suppressor tuberous sclerosis complex 1 (Tsc1) as a new co-chaperone of Hsp90 that affects Hsp90 binding to its inhibitors. Highly variable mutations of TSC1 have been previously identified in bladder cancer and correlate with sensitivity to the Hsp90 inhibitors. Here we showed loss of TSC1 leads to hypoacetylation of Hsp90-K407/K419 …

Structured Inhibitory Activity Dynamics In New Virtual Environments, Moises Arriaga, Edward B. Han

Open Access Publications

Inhibition plays a powerful role in regulating network excitation and plasticity; however, the activity of defined interneuron types during spatial exploration remain poorly understood. Using two-photon calcium imaging, we recorded hippocampal CA1 somatostatin- and parvalbumin-expressing interneurons as mice performed a goal-directed spatial navigation task in new visual virtual reality (VR) contexts. Activity in both interneuron classes was strongly suppressed but recovered as animals learned to adapt the previously learned task to the new spatial context. Surprisingly, although there was a range of activity suppression across the population, individual somatostatin-expressing interneurons showed consistent levels of activity modulation across exposure to multiple …

Protocol For A Prospective, Observational Cohort Study Of Awareness In Mechanically Ventilated Patients Admitted From The Emergency Department: The Ed-Awareness Study, Ryan D Pappal, Brian W Roberts, Nicholas M Mohr, Enyo Ablordeppey, Brian T Wessman, Anne M Drewry, Yan Yan, Marin H Kollef, Michael Simon Avidan, Brian M Fuller

Open Access Publications

INTRODUCTION: Awareness with paralysis is a complication with potentially devastating psychological consequences for mechanically ventilated patients. While rigorous investigation into awareness has occurred for operating room patients, little attention has been paid outside of this domain. Mechanically ventilated patients in the emergency department (ED) have been historically managed in a way that predisposes them to awareness events: high incidence of neuromuscular blockade use, underdosing of analgesia and sedation, delayed administration of analgesia and sedation after intubation, and a lack of monitoring of sedation targets and depth. These practice patterns are discordant to recommendations for reducing the incidence of awareness, suggesting …

Ilc3s Integrate Glycolysis And Mitochondrial Production Of Reactive Oxygen Species To Fulfill Activation Demands, Blanda Di Luccia, Susan Gilfillan, Marina Cella, Marco Colonna, Stanley Ching-Cheng Huang

Open Access Publications

Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter …

Association Of Histologic Disease Activity With Progression Of Nonalcoholic Fatty Liver Disease, David E. Kleiner, Elizabeth M. Brundt, Et Al

Open Access Publications

No abstract provided.

Irak4 Mediates Colitis-Induced Tumorigenesis And Chemoresistance In Colorectal Cancer, Qiong Li, Yali Chen, Daoxiang Zhang, Julie Grossman, Lin Li, Namrata Khurana, Hongmei Jiang, Patrick M Grierson, John Herndon, David G Denardo, Grant A Challen, Jingxia Liu, Marianna B Ruzinova, Ryan C Fields, Kian-Huat Lim

Open Access Publications

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have …

Associations Between Social Risk Factors And Surgical Site Infections After Colectomy And Abdominal Hysterectomy, Andrew C. Qi, Kate Peacock, Alina A. Luke, Abigail Barker, Margaret A. Olsen, Karen E. Joynt Maddox

Open Access Publications

Importance: Surgical site infection (SSI) is an important patient safety outcome. Although social risk factors have been linked to many adverse health outcomes, it is unknown whether such factors are associated with higher rates of SSI.

Objectives: To determine whether social risk factors, including race/ethnicity, insurance status, and neighborhood income, are associated with higher rates of SSI after colectomy or abdominal hysterectomy, 2 surgical procedures for which SSI rates are publicly reported and included in pay-for-performance programs by Medicare and other groups.

Design, Setting, and Participants: This cross-sectional study analyzed adults undergoing colectomy or abdominal hysterectomy, as captured in State …

Effect Of A Novel Transition Program On Disability After Stroke: A Trial Protocol, Emily Somerville, Marian Keglovits, Yan Yan, Susan Stark

Open Access Publications

Importance: A gap in care for stroke survivors exists at the point of transition from inpatient rehabilitation to home, when survivors encounter new environmental barriers because of the cognitive and sensorimotor sequelae of stroke. Resolving these barriers and improving independence in the community have the potential to significantly improve stroke survivors' long-term morbidity.

Objective: To investigate the efficacy and safety of a novel enhanced rehabilitation transition program to reduce environmental barriers and improve daily activity performance and community participation among stroke survivors.

Design, Setting, and Participants: This is a phase 2b, single-blind, parallel-group, randomized clinical trial. Participants will be randomized …

Association Of Acquired And Heritable Factors With Intergenerational Differences In Age At Symptomatic Onset Of Alzheimer Disease Between Offspring And Parents With Dementia, Gregory S. Day, Carlos Cruchaga, Thomas Wingo, Suzanne E. Schindler, Dean Coble, John C. Morris

Open Access Publications

Importance: Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD.

Objective: To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD.

Design, Setting, and Participants: This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of …

Stub1 Suppresseses Tumorigenesis And Chemoresistance Through Antagonizing Yap1 Signaling, Dong-E Tang, Yong Dai, Lie-Wen Lin, Yong Xu, Dong-Zhou Liu, Xiao-Ping Hong, Hao-Wu Jiang, Song-Hui Xu

Open Access Publications

Yes-associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. …

Intensity Of Lipid Lowering With Statin Therapy In Patients With Cerebrovascular Disease Versus Coronary Artery Disease: Insights From The Palm Registry, Ying Xian, Ann Marie Navar, Shuang Li, Zhuokai Li, Jennifer Robinson, Salim S Virani, Michael J Louie, Andrew Koren, Anne Goldberg, Veronique L Roger, Peter W F Wilson, Eric D Peterson, Tracy Y Wang

Open Access Publications

Background Current treatment guidelines strongly recommend statin therapy for secondary prevention. However, it remains unclear whether patients' perceptions of cardiovascular risk, beliefs on cholesterol, or the intensity of prescribed statin therapy differs for patients with coronary artery disease (CAD) versus cerebrovascular disease (CeVD) versus both CAD and CeVD (CAD&CeVD). Methods and Results The PALM (Patient and Provider Assessment of Lipid Management) registry collected data on statin use, intensity, and core laboratory low-density lipoprotein cholesterol levels for 3232 secondary prevention patients treated at 133 US clinics. Among individuals with CeVD only (n=403), CAD only (n=2202), and CeVD&CAD (n=627), no significant differences …

Association Of Circulating Ceramides With Cardiac Structure And Function In The Community: The Framingham Heart Study, Chike C Nwabuo, Meredith Duncan, Vanessa Xanthakis, Linda R Peterson, Gary F Mitchell, David Mcmanus, Susan Cheng, Ramachandran S. Vasan

Open Access Publications

Background A higher circulating plasma ceramide ratio (C16:0/C24:0) is associated with an increased risk of heart failure, even after accounting for standard risk factors including lipid markers. However, the pathobiological mechanisms that underlie this association are incompletely understood. We tested the hypothesis that plasma ceramide ratio (C16:0/C24:0) is associated with adverse cardiac remodeling in the community. Methods and Results We evaluated 2652 Framingham Offspring Study participants (mean age, 66±9 years; 55% women) who attended their eighth examination cycle and underwent routine echocardiography and liquid chromatography-tandem mass spectrometry-based assays for circulating ceramide concentrations. We used multivariable linear regression models to relate …

Incidence And Diagnostic Yield Of Repeat Urine Culture In Hospitalized Patients: An Opportunity For Diagnostic Stewardship, Kap Sum Foong, Satish Munigala, Ronald Jackups, Melanie L Yarbrough, Carey-Ann D. Burnham, David K Warren

Open Access Publications

There is limited knowledge on the incidence, diagnostic yield, and cost associated with inappropriate repeat urine cultures. The factors that affect repeat urine culturing practices are not well understood. We conducted a retrospective study of adult inpatients who had ≥1 urine culture performed during their hospitalization between January 2015 and February 2018. We analyzed the proportion of inappropriate repeat urine cultures performed <48 h after the index culture. We defined an inappropriate repeat urine culture to be a repeat urine culture performed following a negative index culture or a repeat urine specimen obtained from the same urinary catheter. Overall, 28,141 urine cultures were performed on 21,306 patients. There were 2,060 (7.3%) urine cultures repeated in <48 h. Of these, 1,120 (54.4%) urine cultures were inappropriate. Predictors for inappropriate repeat urine cultures included collection of the initial urine sample for culture in the emergency department (adjusted odds ratio [aOR], 5.65; 95% confidence interval [CI], 4.70 to 6.78), male gender (aOR, 1.61; 95% CI, 1.42 to 1.84), congestive heart failure (aOR, 1.20; 95% CI, 1.03 to 1.38), and a longer hospital stay (aOR, 1.01 per day; 95% CI, 1.00 to 1.01). A patient with an index urine culture obtained from an indwelling catheter (aOR, 0.65; 95% CI, 0.53 to 0.80) was less likely to have an inappropriate repeat culture. Among 1,120 negative index urine cultures, only 4.7% of repeat cultures were positive for bacteriuria. The estimated laboratory charges for inappropriate repeat urine cultures were $16,800 over the study period. Among inpatients, over half of all urine cultures repeated in <48 h were inappropriate. This offers an opportunity for diagnostic stewardship and optimization of antimicrobial use.

Patient-Reported Outcomes Measurement Information System Physical Function Correlates With Toronto Extremity Salvage Score In An Orthopaedic Oncology Population, Kristen L Ploetze, Jay F Dalton, Ryan P Calfee, Douglas J Mcdonald, Regis J O'Keefe, Cara A Cipriano

Open Access Publications

Background: The National Institute of Health's Patient-Reported Outcomes Measurement Information System (PROMIS) uses computerised-adaptive testing to reduce survey burden and improve sensitivity. PROMIS is being used across medical and surgical disciplines but has not been studied in orthopaedic oncology.

Questions/purposes: The aim of the study was to compare PROMIS measures with upper extremity (UE) and lower extremity (LE) Toronto Extremity Salvage Score (TESS) by assessing the following: (1) responder burden, (2) correlation between scores and (3) floor/ceiling effects.

Patients and methods: This cross-sectional trial analysed all 97 adult patients treated surgically for a bone or soft tissue tumour at a …

Sequence Specificity Despite Intrinsic Disorder: How A Disease-Associated Val/Met Polymorphism Rearranges Tertiary Interactions In A Long Disordered Protein, Ruchi Lohia, Reza Salari, Grace Brannigan

Open Access Publications

The role of electrostatic interactions and mutations that change charge states in intrinsically disordered proteins (IDPs) is well-established, but many disease-associated mutations in IDPs are charge-neutral. The Val66Met single nucleotide polymorphism (SNP) in precursor brain-derived neurotrophic factor (BDNF) is one of the earliest SNPs to be associated with neuropsychiatric disorders, and the underlying molecular mechanism is unknown. Here we report on over 250 μs of fully-atomistic, explicit solvent, temperature replica-exchange molecular dynamics (MD) simulations of the 91 residue BDNF prodomain, for both the V66 and M66 sequence. The simulations were able to correctly reproduce the location of both local and …