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Background Cancer cachexia is a life‐threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre‐clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre‐clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient‐derived xenograft (PDX) mice. Methods To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome‐wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up‐regulated in the DIA were enriched for extracellular matrix protein‐encoding genes and genes related to the inflammatory response, while down‐regulated genes were enriched for mitochondria related protein‐encoding genes. Conversely, the TA showed up‐regulation of canonical atrophy‐associated pathways such as ubiquitin‐mediated protein degradation and apoptosis, and down‐regulation of genes encoding extracellular matrix proteins. Conclusions These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.

Background Historically, a positive margin after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) was associated with decreased survival. In an era when neoadjuvant chemotherapy (NAC) is being used frequently, the prognostic significance of margin status is unclear. Study Design Patients with localized PDAC who received NAC and underwent pancreatectomy from 2011 to 2018 were identified from a single-institution database. Patients with fewer than 2 months of NAC, R2 resection, or fewer than 90 days of follow-up were excluded. A positive margin included tumors within 1 mm of the surgical margin. Results Four hundred and sixty-eight patients met inclusion criteria. Median age was 65 years and 53% were female. Preoperative clinical staging demonstrated that most had locally advanced (n = 222 [47%]) or borderline resectable (n = 172 [37%]) disease. Median follow-up was 18.5 months (interquartile range 10.6 to 30.0 months). Median duration of NAC was 119 days (interquartile range 87 to 168 days). FOLFIRINOX was first-line therapy for 67%, and 73% received neoadjuvant radiotherapy. Most underwent pancreaticoduodenectomy (69%). Forty percent were node-positive and 80% had an R0 resection. Fifty-six percent received at least 1 cycle of adjuvant therapy. Median overall survival and recurrence-free survival were 22.0 months (95% CI, 19.4 to 25.1 months) and 11.0 months (95% CI, 10.0 to 12.1 months). On multivariate analysis, margin status was not a significant predictor of overall survival or recurrence-free survival. Factors associated with overall survival included clinical stage, duration of NAC, nodal status, histopathologic treatment response score, and receipt of adjuvant chemotherapy. Conclusions Microscopic margin positivity is not associated with recurrence and survival in localized PDAC patients resected after treatment with NAC. Aggressive surgical extirpation in high-volume centers should be considered in selected patients after extensive NAC.

Purpose To identify baseline characteristics of adults with chronic low back pain (cLBP) that predict response (i.e., a clinically important improvement) and/or modify treatment effect across three nonpharmacologic interventions. Design Secondary analysis of a randomized controlled trial. Setting Academic safety net hospital and seven federally qualified community health centers. Subjects Adults with cLBP (N = 299). Methods We report patient characteristics that were predictors of response and/or modified treatment effect across three 12-week treatments: yoga, physical therapy [PT], and a self-care book. Using preselected characteristics, we used logistic regression to identify predictors of “response,” defined as a ≥30% improvement in the Roland Morris Disability Questionnaire. Then, using “response” as our outcome, we identified baseline characteristics that were treatment effect modifiers by testing for statistical interaction (P Results Overall, 39% (116/299) of participants were responders, with more responders in the yoga-or-PT group (42%) than the self-care (23%) group. There was no difference in proportion responding to yoga (48%) vs PT (37%, odds ratio [OR] = 1.5, 95% confidence interval = 0.88 − 2.6). Predictors of response included having more than a high school education, a higher income, employment, few depressive symptoms, lower perceived stress, few work-related fear avoidance beliefs, high pain self-efficacy, and being a nonsmoker. Effect modifiers included use of pain medication and fear avoidance beliefs related to physical activity (both P = 0.02 for interaction). When comparing yoga or PT with self-care, a greater proportion were responders among those using pain meds (OR = 5.3), which differed from those not taking pain meds (OR = 0.94) at baseline. We also found greater treatment response among those with lower (OR = 7.0), but not high (OR = 1.3), fear avoidance beliefs around physical activity. Conclusions Our findings revealed important subgroups for whom referral to yoga or PT may improve cLBP outcomes.

The complexity of transplant medicine pushes the boundaries of innate, human reasoning. From networks of immune modulators to dynamic pharmacokinetics to variable postoperative graft survival to equitable allocation of scarce organs, machine learning promises to inform clinical decision making by deciphering prodigious amounts of available data. This paper reviews current research describing how algorithms have the potential to augment clinical practice in solid organ transplantation. We provide a general introduction to different machine learning techniques, describing their strengths, limitations, and barriers to clinical implementation. We summarize emerging evidence that recent advances that allow machine learning algorithms to predict acute post-surgical and long-term outcomes, classify biopsy and radiographic data, augment pharmacologic decision making, and accurately represent the complexity of host immune response. Yet, many of these applications exist in pre-clinical form only, supported primarily by evidence of single-center, retrospective studies. Prospective investigation of these technologies has the potential to unlock the potential of machine learning to augment solid organ transplantation clinical care and health care delivery systems.

Background One proposed mechanism of chronic low back pain might be paraspinal muscle impairment. Commonly, this impairment is treated with stabilization exercises. However, the effect size of stabilization exercises has been previously reported to be small. Design Randomized controlled trial. Objective To investigate the clinical benefit of using neuromuscular electrical stimulation as a supplement to stabilization exercises in patients with chronic low back pain. Methods Thirty participants with chronic low back pain were randomized into a stabilization exercise only group (n = 15) or a stabilization exercise plus neuromuscular electrical stimulation group (n = 15). The stabilization exercises included abdominal, side support, and quadruped exercises. The neuromuscular electrical stimulation was applied to the lumbar paraspinal muscles for 20 min each session. Both groups received their respective interventions twice a week for 6 weeks. Participant eligibility for inclusion was age between 18 and 60 years, body mass index ≤34, chronic low back pain ≥3 months, Numeric Pain Rating Scale ≥3, Modified Oswestry Disability Questionnaire score ≥20 and ability to understand English. Outcome measurements were self-reported neuromuscular electrical stimulation tolerability scale, Modified Oswestry Disability Questionnaire, Numeric Pain Rating Scale, Fear-Avoidance Beliefs Questionnaire and paraspinal muscle strength. Results The neuromuscular electrical stimulation was reported to be tolerable. There were no significant between-group differences on any of the outcome measures (p > 0.05). Conclusions The application of neuromuscular electrical stimulation on the paraspinal muscles was reported to be tolerable. Supplementing stabilization exercises with neuromuscular electrical stimulation did not offer any additional clinical benefit for the chronic low back pain patients.

Objective The purpose of this study was to determine the association between fear-avoidance beliefs and disability in 3 months in people with vestibular disorders while accounting for demographic and clinical characteristics. Methods This prospective cohort study included people aged 18 to 100 years who reported dizziness. Participants were recruited from a balance disorders clinic and outpatient physical therapy clinics. All participants completed the Vestibular Activities Avoidance Instrument (VAAI) and the Hospital Anxiety and Depression Scale at baseline and the Vestibular Activities and Participation measure (VAP), dizziness Visual Analogue Scale (VAS), and 12-item Short Form Health Questionnaire at baseline and 3-month follow-up. A modified version of the VAAI included 9 items abstracted from the 81-item VAAI. The relationships between 9-item VAAI scores and follow-up measures of disability were assessed using Spearman correlation coefficients. Linear regression models were analyzed to determine the effect of fear-avoidance beliefs on follow-up VAP score while accounting for baseline outcome measures. Results All participants (n = 404) completed the baseline assessment (mean age = 54 years), and 286 (71%) completed the 3-month assessment. The mean 9-item VAAI score was 25 (SD = 14) at baseline and was significantly associated with VAP (ρ = 0.54), 12-item Short Form Health Questionnaire component scores (ρ = −0.53; −0.44), and dizziness VAS at follow-up (ρ = 0.37). Approximately 38% of the variation in VAP score at follow-up was predicted by age, number of medications, 9-item VAAI score, dizziness VAS, and Hospital Anxiety and Depression Scale-depression score when considered together (R2 = 0.38). Conclusion Fear-avoidance beliefs are associated with measures of disability at 3 months and are predictive of activity limitations and participation restrictions at 3 months when controlling for age, medications, baseline dizziness, and depression symptom severity in people with vestibular disorders. Impact Measurement of fear-avoidance beliefs may provide important prognostic information, suggesting that an assessment of fear-avoidance beliefs could be used by clinicians to identify individuals at greater risk of disability after a vestibular disorder. Lay Summary Fear-avoidance beliefs in people who have vestibular disorders are associated with disability at 3 months and predict limitations in daily activities at 3 months.

Key Points Question Is the transition from acute to chronic low back pain (LBP) associated with risk strata, defined by a standardized prognostic tool, and/or with early exposure to guideline nonconcordant care? Findings In this cohort study of 5233 patients with acute LBP from 77 primary care practices, nearly half the patients were exposed to at least 1 guideline nonconcordant recommendation within the first 21 days after the index visit. Patients were significantly more likely to transition to chronic LBP as their risk on the prognostic tool increased and as they were exposed to more nonconcordant recommendations. Meaning In this study, the transition rate to chronic LBP was substantial and increased correspondingly with risk strata and early exposure to guideline nonconcordant care., This cohort study assesses the associations between the transition from acute to chronic lower back pain with risk strata from a standardized prognostic tool; demographic, clinical, and physician characteristics; and guideline nonconcordant processes of care., Importance Acute low back pain (LBP) is highly prevalent, with a presumed favorable prognosis; however, once chronic, LBP becomes a disabling and expensive condition. Acute to chronic LBP transition rates vary widely owing to absence of standardized operational definitions, and it is unknown whether a standardized prognostic tool (ie, Subgroups for Targeted Treatment Back tool [SBT]) can estimate this transition or whether early non–guideline concordant treatment is associated with the transition to chronic LBP. Objective To assess the associations between the transition from acute to chronic LBP with SBT risk strata; demographic, clinical, and practice characteristics; and guideline nonconcordant processes of care. Design, Setting, and Participants This inception cohort study was conducted alongside a multisite, pragmatic cluster randomized trial. Adult patients with acute LBP stratified by SBT risk were enrolled in 77 primary care practices in 4 regions across the United States between May 2016 and June 2018 and followed up for 6 months, with final follow-up completed by March 2019. Data analysis was conducted from January to March 2020. Exposures SBT risk strata and early LBP guideline nonconcordant processes of care (eg, receipt of opioids, imaging, and subspecialty referral). Main Outcomes and Measures Transition from acute to chronic LBP at 6 months using the National Institutes of Health Task Force on Research Standards consensus definition of chronic LBP. Patient demographic characteristics, clinical factors, and LBP process of care were obtained via electronic medical records. Results Overall, 5233 patients with acute LBP (3029 [58%] women; 4353 [83%] White individuals; mean [SD] age 50.6 [16.9] years; 1788 [34%] low risk; 2152 [41%] medium risk; and 1293 [25%] high risk) were included. Overall transition rate to chronic LBP at six months was 32% (1666 patients). In a multivariable model, SBT risk stratum was positively associated with transition to chronic LBP (eg, high-risk vs low-risk groups: adjusted odds ratio [aOR], 2.45; 95% CI, 2.00-2.98; P

Background Physical therapy (PT) is frequently used for the management of low back pain (LBP) within the US Departments of Defense (DOD) and Veterans Affairs (VA). However, variations in PT practice patterns and use of ineffective interventions lower the quality and increase the cost of care. Although adherence to the clinical practice guidelines (CPGs) can improve the outcomes and cost-effectiveness of LBP care, PT CPG adherence remains below 50%. The Resolving the Burden of Low Back Pain in Military Service Members and Veterans (RESOLVE) trial will evaluate the effectiveness of an active PT CPG implementation strategy using an education, audit, and feedback model for reducing pain, disability, medication use, and cost of LBP care within the DOD and VA health care systems. Design The RESOLVE trial will include 3,300 to 7,260 patients with LBP across three DOD and two VA medical facilities using a stepped-wedge study design. An education, audit, and feedback model will be used to encourage physical therapists to better adhere to the PT CPG recommendations. The Oswestry Disability Index and the Defense and Veterans Pain Rating Scale will be used as primary outcomes. Secondary outcomes will include the LBP-related medication use, medical resource utilization, and biopsychosocial predictors of outcomes. Statistical analyses will be based on the intention-to-treat principle and will use linear mixed models to compare treatment conditions and examine the interactions between treatment and subgrouping status (e.g., limb loss). Summary The RESOLVE trial will provide a pragmatic approach to evaluate whether better adherence to PT CPGs can reduce pain, disability, medication use, and LBP care cost within the DOD and VA health care systems.

Importance Fear avoidance is a behavioral response to dizziness that can lead to chronic symptoms and maladaptation of the vestibular system, but there is no valid and reliable clinical measure of fear avoidance for persons with dizziness. Although the Vestibular Activities Avoidance Instrument (VAAI) was developed to identify fear avoidance beliefs in persons with dizziness, it was considered too long for clinical use. Objective To continue development of the VAAI for clinical use by reducing its length and by assessing the internal consistency and construct validity through associations with measures of disability, quality of life, and psychological well-being. Design, Setting, and Participants This prospective cohort study conducted from February 2018 to December 2019 at a tertiary care balance disorders clinic and in outpatient physical therapy clinics in the United States included 404 adults with dizziness. Main Outcomes and Measures Participants completed the 81-item VAAI, the Vestibular Activities and Participation (VAP) measure, the 12-Item Short Form Health Survey (SF-12), and the Hospital Anxiety and Depression Scale (HADS) at baseline. Exploratory factor analysis of the VAAI was conducted to reduce the number of items. Internal consistency of the reduced VAAI was determined by calculating the Cronbach α. Convergent validity was assessed by examining the associations between the reduced VAAI and the VAP, the SF-12, and the HADS using Spearman correlation coefficients. Results Data from 404 adults (mean [SD] age, 54.0 [17.0] years; 64.6% women) were included in the analyses. The exploratory factor analysis indicated that 2 factors explained the underlying constructs of the 81-Item VAAI. The first factor was retained and measured the construct of fear avoidance. The VAAI was reduced to 9 items (VAAI-9). The VAAI-9 showed excellent internal consistency (Cronbach α = 0.92) and was positively associated with the VAP (ρ = 0.81) and the HADS anxiety (ρ = 0.47) and depression (ρ = 0.64) subscales, and negatively associated with physical (ρ = −0.76) and mental (ρ = −0.47) health–related quality of life. Conclusions and Relevance These findings indicate that the VAAI-9 is a short, internally consistent, valid measure of fear avoidance and is associated with quality of life, activity limitations and participation restrictions, and psychological well-being. The next steps in the development of the VAAI-9 will include validation in an external sample, assessment of test-retest validity, and prospective investigations of its association with future disability.

Background Tumor-specific antibodies have been reported in patients with cancers responding to immune checkpoint inhibitors (ICI), and there is an increasing appreciation for the potential role of B cells in mediating ICI responses. However, the humoral immune response to melanoma remains incompletely defined. We hypothesized that screening sera for antibodies by immunoprecipitation with lysates of cultured melanoma cells would increase the likelihood of detecting circulating antibodies in melanoma patients receiving ICI, and potentially identify novel antibody targets associated with treatment response and/or immune-related adverse events (IRAEs). Methods Pre-and on/post-treatment sera or plasma from 12 clinically-annotated patients with advanced metastatic melanoma receiving ICI were assayed for tumor-specific antibodies with an established immunoprecipitation platform. 35S-methionine-labeled lysates from cultured 624Mel cells were used for immunoprecipitation. 624Mel expresses several shared non-mutated melanoma antigens (e.g., MAGEA3, tyrosinase, MART-1/Melan-A, gp75, and gp100). Antigen identity was determined using on-bead digests followed by mass spectrometry, and was confirmed by immunoprecipitation with in vitro transcription/translation (IVTT) products. Results Antibodies reactive against 624Mel proteins were detected in 4 of 12 (33%) patients (table 1). Mass spectrometric sequencing performed on proteins captured with sera from 3 of 4 patients identified several putative antigens. Immunoprecipitation with IVTT candidate proteins confirmed antibodies against melanoma-associated and cancer testis antigens NY-ESO-1, SSX2 and MAGEA10. Antibodies were observed in 1 of 1 (100%) patient with a complete response, 2 of 4 (50%) with a partial response, 1 of 1 (100%) with stable disease, and 0 of 6 (0%) with progressive disease. Antibody levels varied over the course of therapy, with previously undetectable specificities arising during treatment response in patients #1–3. Patient #1 with a complete tumor regression developed antibodies to SSX2 and MAGEA10 that were absent before treatment. Further, detection of these antibodies coincided with diagnosis of IRAEs (anti-SSX2 with pancreatitis and anti-MAGEA10 with dermatitis). In contrast, patient #3, initially with a partial tumor regression, demonstrated a loss of detectable anti-NY-ESO-1 antibodies upon disease progression, and subsequent metastasectomy demonstrated loss of NY-ESO-1 protein expression in the progressing tumor. Testing sera from all 12 patients with IVTT products for NY-ESO-1, SSX2 and MAGEA10 did not reveal additional humoral responses. Conclusions Our comprehensive screening platform detected circulating antibodies specific to multiple melanoma-associated and cancer testis antigens in patients deriving clinical benefit from ICI. Expanded investigations of the evolution of antibody production over the course of ICI therapy, associated with tumor response to treatment and development of IRAEs, are warranted. Acknowledgements This study was supported by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, and NIH P30-AR070254. Ethics Approval This study was approved by the Johns Hopkins Institutional Review Board, approval #NA_00090257.

Background Context Psychological comorbidities are important prognostic factors for low back pain (LBP). To develop improved treatment paradigms, it is first necessary to characterize and determine current patterns of treatment in this population. Purpose Identify how comorbid depression or anxiety in patients with LBP is related to use of healthcare resources. Study Design/Setting Retrospective cohort study using electronic health records from outpatient offices at a large multisite academic medical center. Patient Sample Data from 513,088 unique patients seen between January 2010 and July 2020 (58.0% female, 52.6±19.5 years) with a diagnosis of LBP, indicated by predetermined ICD-9 and ICD-10 codes. Outcome Measures Average self-reported pain scores, absolute differences and unadjusted risk ratios to compare opioid use, emergency department visits, hospitalizations, advanced imaging orders, spinal injections, and back surgeries between cohorts. Methods Clinical characteristics and data regarding use of healthcare resources were extracted from the electronic health record. Clinical features and patterns in healthcare utilization were determined for patients with depression or anxiety compared to those without. Results Depression or anxiety was coded for 21.4% of patients at first LBP visit. Those with depression or anxiety were more likely to be on opioids (unadjusted risk ratio: 1.22, CI: [1.22,1.23]), go to the emergency department (1.31 [1.30–1.33]), be hospitalized (1.15 [1.13, 1.17]), receive advanced imaging (1.09 [1.08, 1.11]), receive an epidural steroid injection (1.16 [1.15, 1.18]), and less likely to have back surgery (0.74 [0.72, 0.77]). Differences in pain scores for those with depression/anxiety compared to those without were not clinically significant. Conclusions Depression/anxiety is associated with increased use of healthcare resources, and is not associated with clinically meaningful elevated pain scores. Limitations come from use of an aggregate data set and reliance on administrative coding.

Background Although risk-stratifying patients with acute lower back pain is a promising approach for improving long-term outcomes, efforts to implement stratified care in the US healthcare system have had limited success. The objectives of this process evaluation were to 1) examine variation in two essential processes, risk stratification of patients with low back pain and referral of high-risk patients to psychologically informed physical therapy and 2) identify barriers and facilitators related to the risk stratification and referral processes. Methods We used a sequential mixed methods study design to evaluate implementation of stratified care at 33 primary care clinics (17 intervention, 16 control) participating in a larger pragmatic trial. We used electronic health record data to calculate: 1) clinic-level risk stratification rates (proportion of patients with back pain seen in the clinic over the study period who completed risk stratification questionnaires), 2) rates of risk stratification across different points in the clinical workflow (front desk, rooming, and time with clinician), and 3) rates of referral of high-risk patients to psychologically informed physical therapy among intervention clinics. We purposively sampled 13 clinics for onsite observations, which occurred in month 24 of the 26-month study. Results The overall risk stratification rate across the 33 clinics was 37.8% (range: 14.7–64.7%). Rates were highest when patients were identified as having back pain by front desk staff (overall: 91.9%, range: 80.6–100%). Rates decreased as the patient moved further into the visit (rooming, 29.3% [range: 0–83.3%]; and time with clinician, 11.3% [range: 0–49.3%]. The overall rate of referrals of high-risk patients to psychologically informed physical therapy across the 17 intervention clinics was 42.1% (range: 8.3–70.8%). Barriers included staffs’ knowledge and beliefs about the intervention, patients’ needs, technology issues, lack of physician engagement, and lack of time. Adaptability of the processes was a facilitator. Conclusions Adherence to key stratified care processes varied across primary care clinics and across points in the workflow. The observed variation suggests room for improvement. Future research is needed to build on this work and more rigorously test strategies for implementing stratified care for patients with low back pain in the US healthcare system. Trial registration Trial registration: ClinicalTrials.gov (NCT02647658). Registered January 6, 2016

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets.

Background: Many patients with acute low back pain (LBP) first seek care from primary care physicians. Evidence is lacking for interventions to prevent transition to chronic LBP in this setting. We aimed to test if implementation of a risk-stratified approach to care would result in lower rates of chronic LBP and improved self-reported disability. Methods: We conducted a pragmatic, cluster randomized trial using 77 primary care clinics in four health care systems across the United States. Practices were randomly assigned to a stratified approach to care (intervention) or usual care (control). Using the STarTBack screening tool, adults with acute low back pain were screened low, medium, and high-risk. Patients screened as high-risk were eligible. The intervention included electronic best practice alerts triggering referrals for psychologically informed physical therapy (PIPT). PIPT education was targeted to community clinics geographically close to intervention primary care clinics. Primary outcomes were transition to chronic LBP and self-reported disability at six months. Findings: Between May 2016 and June 2018, 1207 patients from 38 intervention and 1093 from 37 control practices were followed. In the intervention arm, around 50% of patients were referred for physical therapy (36% for PIPT) compared to 30% in the control. At 6 months, 47% of patients reported transition to chronic LBP in the intervention arm (38 practices, n=658) versus 51% of patients in the control arm (35 practices, n=635; OR=0.83 95% CI 0·64, 1·09; p=0·18). No differences in function were detected (difference -2·1, 95% CI -4·9-0·6; p=0·12). Opioids and imaging were prescribed 25% (21%, 28%) and 27% (23%, 31%) of initial visits, respectively. Twelve-month LBP utilization was similar in the two groups. Interpretation: There were no differences in transition to chronic LBP among patients presenting with acute LBP using a stratified approach to care. Opioid and imaging prescribing rates were non-concordant with clinical guidelines. Trial Registration: ClinicalTrials.gov NCT02647658. Funding Statement: Patient-Centered Outcomes Research Institute (PCORI) contract # PCS-1402-10867. Declaration of Interests: We declare that we have no conflicts of interest. Ethics Approval Statement: Approval of the study protocol by all site institutional research ethics boards specified: (1) for processes conducted at the primary care clinics, the study was viewed as a quality improvement initiative, (2) for the follow-up assessments at six months, the study was viewed as research requiring patient informed consent for collection of patient-reported primary outcomes, and (3) for the 12-month EMR review patient consent or waiver of HIPAA authorization and patient consent was required.

Treating pancreatic ductal adenocarcinoma (PDAC) remains a major hurdle in the field of oncology. Less than half of patients respond to frontline chemotherapy and the pancreatic tumor microenvironment limits the efficacy of immunotherapeutic approaches. Targeted therapies could serve as effective treatments to enhance the clinical response rate. One potential therapeutic target is survivin, a protein that is normally expressed during embryonic and fetal development and has a critical impact on cell cycle control and apoptosis. In adulthood, survivin is not present in most normal adult cells, but is significantly re-expressed in tumor tissues. In PDAC, elevated survivin expression is correlated with treatment resistance and lower patient survival, although the underlying mechanisms of survivin's action in this type of cancer is poorly understood. Using patient derived xenografts of PDAC and their corresponding primary pancreatic cancer lines (PPCL-46 and PPCL-LM1) possessing increased expression of survivin, we aimed to evaluate the therapeutic response of a novel survivin inhibitor, UFSHR, with respect to survivin expression and the tumorigenic characteristics of PDAC. Cell viability and apoptosis analyses revealed that repressing survivin expression by UFSHR or YM155, a well-known inhibitor of survivin, in PPCLs effectively reduces cell proliferation by inducing apoptosis. Tumor cell migration was also hindered following treatment with YM155 and UFSHR. In addition, both survivin inhibitors, particularly UFSHR, effectively reduced progression of PPCL-46 and PPCL-LM1 tumors, when compared to the untreated cohort. Overall, this study provides solid evidence to support the critical role of survivin in PDAC progression and proposes a novel survivin inhibitor UFSHR that can become an alternative strategy for this type of cancer.

BACKGROUND Cancer cachexia is a metabolic wasting syndrome that is strongly associated with a poor prognosis. The initiating factors causing fat and muscle loss are largely unknown. Previously, we found that leukaemia inhibitory factor (LIF) secreted by C26 colon carcinoma cells was responsible for atrophy in treated myotubes. In the present study, we tested whether C26 tumour-derived LIF is required for cancer cachexia in mice by knockout of Lif in C26 cells. METHODS A C26 Lif null tumour cell line was made using CRISPR-Cas9. Measurements of cachexia were compared in mice inoculated with C26 vs. C26Lif-/- tumour cells, and atrophy was compared in myotubes treated with medium from C26 vs. C26Lif-/- tumour cells. Levels of 25 cytokines/chemokines were compared in serum of mice bearing C26 vs. C26Lif-/- tumours and in the medium from these tumour cell lines. RESULTS At study endpoint, C26 mice showed outward signs of sickness while mice with C26Lif-/- tumours appeared healthy. Mice with C26Lif-/- tumours showed a 55-75% amelioration of body weight loss, muscle loss, fat loss, and splenomegaly compared with mice with C26 tumours (P

Periodontal diseases are a class of non-resolving inflammatory diseases, initiated by a pathogenic subgingival biofilm, in a susceptible host, which if left untreated can result in soft and hard tissue destruction. Oral epithelial cells are the first line of defense against microbial infection within the oral cavity, whereby they can sense the environment through innate immune receptors including toll-like receptors (TLRs). Therefore, oral epithelial cells directly and indirectly contribute to mucosal homeostasis and inflammation, and disruption of this homeostasis or over-activation of innate immunity can result in initiation and/or exacerbation of localized inflammation as observed in periodontal diseases. Dynamics of TLR signaling outcomes are attributable to several factors including the cell type on which it engaged. Indeed, our previously published data indicates that oral epithelial cells respond in a unique manner when compared to canonical immune cells stimulated in a similar fashion. Thus, the objective of this study was to evaluate the role of oral epithelial cell innate sensing on periodontal disease, using a murine poly-microbial model in an epithelial cell specific knockout of the key TLR-signaling molecule MyD88 (B6(K5Cre.MyD88plox)). Following knockdown of MyD88 in the oral epithelium, mice were infected with Porphorymonas gingivalis and Aggregatibacter actinomycetemcomitans by oral lavage 4 times per week, every other week for 6 weeks. Loss of oral epithelial cell MyD88 expression resulted in exacerbated bone loss, soft tissue morphological changes, soft tissue infiltration, and soft tissue inflammation following polymicrobial oral infection. Most interestingly while less robust, loss of oral epithelial cell MyD88 also resulted in mild but statistically significant soft tissue inflammation and bone loss even in the absence of a polymicrobial infection. Together these data demonstrate that oral epithelial cell MyD88-dependent TLR signaling regulates the immunological balance within the oral cavity under conditions of health and disease.

Objective: To characterize skeletal muscle fat (SMF), intermuscular adipose tissue (IMAT) and subcutaneous adipose tissue (SAT) in individuals with rheumatoid arthritis (RA), and assess the associations between these fat depots and physical function and physical activity. Methods: Cross-sectional analysis from an RA cohort. SMF, IMAT and SAT were measured using computed tomography imaging of the mid-thigh cross-sectional region. Physical function was measured with the Health Assessment Questionnaire (HAQ) and a battery of performance-based tests that included quadriceps muscle strength, gait speed, repeated chair-stands, stair ascend, and single leg-stance. Physical activity was assessed using an activity monitor. Associations between SMF, IMAT and SAT, and physical function and activity were assessed by multiple linear regression models adjusted for potential confounders such as age, gender, body mass index, muscle area, and strength. Results: Sixty subjects with RA (82% female, age 59 ± 10 years, BMI: 31.79 ± 7.16) were included. In the adjusted models, lower SMF was associated with greater gait speed, single leg stance, quadriceps strength, and physical activity, and less disability (R2Δ range .06-.25, p

Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal, in large part due to a protective fibrotic barrier generated by tumor-associated stromal (TAS) cells. This barrier is thought to promote cancer cell survival and confounds attempts to develop effective therapies. We present a 3D in vitro system that replicates the mechanical properties of the PDAC microenvironment, representing an invaluable tool for understanding the biology of the disease. Mesoscale indentation quantified viscoelastic metrics of resected malignant tumors, inflamed chronic pancreatitis regions, and histologically normal tissue. Both pancreatitis (2.15 ± 0.41 kPa, Mean ± SD) and tumors (5.46 ± 3.18 kPa) exhibit higher Steady-State Modulus (SSM) than normal tissue (1.06 ± 0.25 kPa; p .005). The average viscosity of pancreatitis samples (63.2 ± 26.7 kPa·s) is significantly lower than that of both normal tissue (252 ± 134 kPa·s) and tumors (349 ± 222 kPa·s; p .005). To mimic this remodeling behavior, PDAC and TAS cells were isolated from human PDAC tumors. Conditioned medium from PDAC cells was used to culture TAS-embedded collagen hydrogels. After 7 days, TAS-embedded gels in control medium reached SSM (1.45 ± 0.12 kPa) near normal pancreas, while gels maintained with conditioned medium achieved higher SSM (3.38 ± 0.146 kPa) consistent with tumors. Taken together, we have demonstrated an in vitro system that recapitulates in vivo stiffening of PDAC tumors. In addition, our quantification of viscoelastic properties suggests that elastography algorithms incorporating viscosity may be able to more accurately distinguish between pancreatic cancer and pancreatitis.Understanding tumor-stroma crosstalk in pancreatic ductal adenocarcinoma (PDAC) is challenged by a lack of stroma-mimicking model systems. To design appropriate models, pancreatic tissue must be characterized with a method capable of evaluating in vitro models as well. Our indentation-based characterization tool quantified the distinct viscoelastic signatures of inflamed resections from pancreatitis, tumors from PDAC, and otherwise normal tissue to inform development of mechanically appropriate engineered tissues and scaffolds. We also made progress toward a 3D in vitro system that recapitulates mechanical properties of tumors. Our in vitro model of stromal cells in collagen and complementary characterization system can be used to investigate mechanisms of cancer-stroma crosstalk in PDAC and to propose and test innovative therapies.

ObjectiveThe Stand Back study evaluated the feasibility and effects of a multicomponent intervention targeting reduced prolonged sitting and pain self-management in desk workers with chronic low back pain (LBP).MethodsThis randomised controlled trial recruited 27 individuals with chronic LBP, Oswestry Disability Index (ODI) >10% and desk jobs (sitting ≥20 hours/week). Participants were randomised within strata of ODI (>10%–ResultsBaseline mean (SD) age was 52 (11) years, 78% were women, and ODI was 24.1 (10.5)%. Across the 6-month follow-up in models adjusted for baseline value, work sitting time was 1.5 hour/day (PConclusionAn intervention coupling behavioural counselling targeting reduced sedentary behaviour and pain self-management is a translatable treatment strategy that shows promise for treating chronic LBP in desk-bound employees.Trial registration numberNCT0224687; Pre-results.

The purpose of this secondary analysis was to identify treatment effect moderators from a large, pragmatic, cluster randomized trial for prevention of chronic low back pain (LBP). The TARGET trial was conducted at 76 primary care clinics in 4 health systems across the United States between May 2016 and June 2018. Practices were randomly assigned (1:1) to stratified care (intervention) or usual care (control). The intervention included identifying high risk patients with acute LBP and triggering an electronic best practice alert for referral for psychologically informed physical therapy (PIPT). We estimated and compared average Oswestry Disability Questionnaire (ODQ) scores at 6 months using linear mixed models controlling for baseline ODQ scores with site (fixed effects) and clinic (random effects) to account for cluster randomization. Baseline factors were considered treatment effect moderators if the type III test for the treatment x factor interaction resulted in a p-value ≤0.15. These analyses included 1,250 patients with completed baseline data and 6-month ODQ scores. Baseline characteristics were (Intervention, Control respectively): under 45 years of age (44%, 43%), female (61%, 62%), White (81%, 74%), non-Hispanic (91%, 92%), obese (50%, 48%), and non-smoking (65%, 68%). Potential effect modifiers were pain medication and smoking (p's ≤ 0.15). The intervention group had larger 6 month ODQ improvement for patients taking ≥3 pain medications, (7.0 points, P = 0.05) and current smokers (5.7 points, P = 0.02). In the TARGET trial smoking and taking ≥3 pain medications were patient level factors related to larger ODQ improvements from PIPT. The magnitude of improvements did not exceed clinically meaningful thresholds, however these factors still could be used to tailor receipt of PIPT treatment. These findings add to the existing treatment moderation literature for LBP but need to confirmed in additional trials. Patient-Centered Outcomes Research Institute (PCORI) contract # PCS-1402-10867.

Cancer cachexia represents a debilitating syndrome that diminishes quality of life and augments the toxicities of conventional treatments. Cancer cachexia is particularly debilitating in patients with pancreatic cancer (PC). Mechanisms responsible for cancer cachexia are under investigation and are largely derived from observations in syngeneic murine models of cancer which are limited in PC. We evaluate the effect of human PC cells on both muscle wasting and the systemic inflammatory milieu potentially contributing to PC-associated cachexia. Specifically, human PC xenografts were generated by implantation of pancreatic cancer cells, L3.6pl and PANC-1, either in the flank or orthotopically within the pancreas. Mice bearing orthotopic xenografts demonstrated significant muscle wasting and atrophy-associated gene expression changes compared to controls. Further, despite the absence of adaptive immunity, splenic tissue from orthotopically engrafted mice demonstrated elevations in several pro-inflammatory cytokines associated with cancer cachexia, including TNFα, IL1β, IL6 and KC (murine IL8 homologue), when compared to controls. Therefore, data presented here support further investigation into the complexity of cancer cachexia in PC to identify potential targets for this debilitating syndrome.

Background Neoadjuvant chemoradiation is currently standard of care in stage II-III rectal cancer, resulting in tumor downstaging for patients with treatment-responsive disease. However, the prognosis of the downstaged patient remains controversial. This work critically analyzes the relative contribution of pre- and post-therapy staging to the anticipated survival of downstaged patients. Methods The National Cancer Database (NCDB) was queried for patients with rectal cancer treated with transabdominal resection between 2004 and 2014. Stage II-III patients downstaged with neoadjuvant radiation were compared with stage I patients treated with definitive resection alone. Patients with positive surgical margins were excluded. Overall survival was evaluated using both Kaplan-Meier analyses and Cox proportional hazards models. All statistical tests were two-sided. Results A total of 44 320 patients were eligible for analysis. Survival was equivalent for patients presenting with cT1N0 disease undergoing resection (mean survival = 113.0 months, 95% confidence interval [CI] = 110.8 to 115.3 months) compared with those downstaged to pT1N0 from both cT3N0 (mean survival = 114.9 months, 95% CI = 110.4 to 119.3 months, P = .12) and cT3N1 disease (mean survival = 115.4 months, 95% CI = 110.1 to 120.7 months, P = .22). Survival statistically significantly improved in patients downstaged to pT2N0 from cT3N0 disease (mean survival = 109.0 months, 95% CI = 106.7 to 111.2 months, P < .001) and cT3N1 (mean survival = 112.8 months, 95% CI = 110.0 to 115.7 months, P < .001), compared with cT2N0 patients undergoing resection alone (mean survival = 100.0 months, 95% CI = 97.5 to 102.5 months). Multiple survival analysis confirmed that final pathologic stage dictated long-term outcomes in patients undergoing neoadjuvant radiation (hazard ratio [HR] of pT2 = 1.24, 95% CI = 1.10 to 1.41; HR of pT3 = 1.81, 95% CI = 1.61 to 2.05; HR of pT4 = 2.72, 95% CI = 2.28 to 3.25, all P ≤ .001 vs pT1; HR of pN1 = 1.50, 95% CI = 1.41 to 1.59; HR of pN2 = 2.17, 95% CI = 2.00 to 2.35, both P < .001 vs pN0); while clinical stage at presentation had little to no predictive value (HR of cT2 = 0.81, 95% CI = 0.69 to 0.95, P = .008; HR of cT3 = 0.83, 95% CI = 0.72 to 0.96, P = .009; HR of cT4 = 1.02, 95% CI = 0.85 to 1.21, P = .87 vs cT1; HR of cN1 = 0.96, 95% CI = 0.91 to 1.02, P = .19; HR of cN2 = 0.96, 95% CI = 0.86 to 1.08, P = .48 vs cN0). Conclusions Survival in patients with rectal cancer undergoing neoadjuvant radiation is driven by post-therapy pathologic stage, regardless of pretherapy clinical stage. These data will further inform prognostic discussions with patients.

Background Low back pain (LBP) is a public health concern because it is highly prevalent and the leading cause of disability worldwide. Psychologically informed physical therapy (PIPT) is a secondary prevention approach that first aims to identify individuals at high risk for transitioning to chronicity and then provides tailored treatment to reduce that risk. Training models that are feasible to implement with acceptable training quality are needed to improve scalability for widespread implementation of PIPT. This manuscript describes the PIPT training program that was developed for training physical therapists providing PIPT in the TARGET trial. Methods The PIPT training program was developed, tested, and modified using an iterative process. Content development consisted of stakeholder engagement, beta testing, modification of training, and confirmation of final course objectives. Methods of delivery consisted of a website that included brief online educational modules followed by a live 8-h workshop that included video-based mock case scenarios and case-based role playing. Attitudes, beliefs, and confidence in implementing PIPT principles were assessed before and immediately after training to measure training quality and impact. Results Early stakeholder engagement and beta testing indicated the need for increased emphasis on experiential learning opportunities and patient-centered communication training. Booster training varied extensively across TARGET sites with involvement of ‘clinician champions’ providing brief follow-up sessions identified as best practice. Favorable post-training changes in physical therapist attitudes and beliefs toward biopsychosocial treatment orientation and increased confidence in implementing PIPT principles were observed. Conclusions PIPT training for provider participation in the TARGET trial was feasible to deliver. Course content was acceptable to physical therapists and resulted in improved beliefs and confidence in applying PIPT skills during clinical practice. Ongoing consultation and site-based continuing education were methods by which specific TARGET sites maintained or augmented PIPT skill training; however, implementing ongoing training was challenging in general. Due to the pragmatic nature of the TARGET trial, it was not possible to directly measure the effect of PIPT training on treatment fidelity, which was a limitation of our approach. Trial registration ClinicalTrials.gov, NCT02647658. Registered on 6 January 2016.

OBJECTIVE The aim of this study was to compare the feasibility and effectiveness of neuromuscular electrical stimulation (NMES) with that of high-intensity volitional resistance training for improving muscle structure and function and physical function in patients with rheumatoid arthritis (RA). We also compared pre-intervention and post-intervention values of myocyte characteristics. METHODS In this 2-group, single-blind, randomized pilot study, adult patients with RA were assigned to 36 sessions of NMES (n = 31 patients) or volitional training (n = 28 patients) over 16 weeks. Outcome measures included muscle structure and function (quadriceps muscle area, density, and strength), physical function (performance-based and patient-reported), feasibility (increased pain, increased disease activity, attrition, and adherence), and myocyte characteristics (area, proportion of type I or II muscle fibers, and intramyocellular lipid content). Analysis of covariance was used to compare groups. RESULTS The intervention intensity in the NMES group was less than half that in the volitional exercise group (31% versus 77% of maximum effort). Both groups experienced significant improvements in muscle structure and function (P < 0.001 to 0.019). Improvements in muscle characteristics and physical function were not different between groups. Exercise did not result in serious adverse events or increases in pain and disease activity. Attrition was 29% in the NMES group and 7% in the volitional exercise group. CONCLUSION Both NMES and high-intensity volitional resistance training can be used as effective approaches to improving muscle structure and function in patients with RA. NMES may be a viable alternative for improving muscle function in patients in whom high-intensity resistance exercise may not be tolerated or is contraindicated, but attrition must be considered when using this approach.

Background Low back pain (LBP) is one of the most prevalent and potentially disabling conditions for which people seek health care. Patients, providers, and payers agree that greater effort is needed to prevent acute LBP from transitioning to chronic LBP. Methods and study design The TARGET (Targeted Interventions to Prevent Chronic Low Back Pain in High-Risk Patients) Trial is a primary care-based, multisite, cluster randomized, pragmatic trial comparing guideline-based care (GBC) to GBC + referral to Psychologically Informed Physical Therapy (PIPT) for patients presenting with acute LBP and identified as high risk for persistent disabling symptoms. Study sites include primary care clinics within each of five geographical regions in the United States, with clinics randomized to either GBC or GBC + PIPT. Acute LBP patients at all clinics are risk stratified (high, medium, low) using the STarT Back Tool. The primary outcomes are the presence of chronic LBP and LBP-related functional disability determined by the Oswestry Disability Index at 6 months. Secondary outcomes are LBP-related processes of health care and utilization of services over 12 months, determined through electronic medical records. Study enrollment began in May 2016 and concluded in June 2018. The trial was powered to include at least 1860 high-risk patients in the randomized controlled trial cohort. A prospective observational cohort of approximately 6900 low and medium-risk acute LBP patients was enrolled concurrently. Discussion The TARGET pragmatic trial aims to establish the effectiveness of the stratified approach to acute LBP intervention targeting high-risk patients with GBC and PIPT. Trial Registration: ClinicalTrials.gov NCT02647658 Registered Jan. 6, 2016.

The treatment-based classification (TBC) system for the treatment of patients with low back pain (LBP) has been in use by clinicians since 1995. This perspective article describes how the TBC was updated by maintaining its strengths, addressing its limitations, and incorporating recent research developments. The current update of the TBC has 2 levels of triage: (1) the level of the first-contact health care provider and (2) the level of the rehabilitation provider. At the level of first-contact health care provider, the purpose of the triage is to determine whether the patient is an appropriate candidate for rehabilitation, either by ruling out serious pathologies and serious comorbidities or by determining whether the patient is appropriate for self-care management. At the level of the rehabilitation provider, the purpose of the triage is to determine the most appropriate rehabilitation approach given the patient's clinical presentation. Three rehabilitation approaches are described. A symptom modulation approach is described for patients with a recent—new or recurrent—LBP episode that has caused significant symptomatic features. A movement control approach is described for patients with moderate pain and disability status. A function optimization approach is described for patients with low pain and disability status. This perspective article emphasizes that psychological and comorbid status should be assessed and addressed in each patient. This updated TBC is linked to the American Physical Therapy Association's clinical practice guidelines for low back pain.

BACKGROUND AND PURPOSE: Unwarranted variation in practice is among the principal contributors of suboptimal outcomes in health care. This variation can be minimized via quality improvement initiatives. However, quality improvement projects focus mostly on assessing processes, and less attention is given to the effect of the variation on clinical outcomes. An effective implementation of a clinical treatment algorithm (CTA) could improve care for individuals with balance and vestibular disorders. The first aim of this quality improvement project was to examine adherence to a CTA developed by physical therapists who treat persons with balance and vestibular disorders. The second aim was to examine the effect of adherence on patient outcomes. METHODS: Twenty-three physical therapists who provided rehabilitation for individuals with balance and vestibular disorders participated in the quality improvement project. All physical therapists worked for the same health care provider, and developed the minimum data set and CTA. The physical therapists were cluster randomized into 2 groups; both groups received educational training and reminders regarding adherence to the CTA. The first group received the training and reminders after an 8-week baseline period (initial group), and the second group (delayed group) after a 12-week baseline period. The prescribed interventions were classified as being adherent or nonadherent to the CTA. Clinical outcomes, including the Activities-Specific Balance Confidence (ABC) scale, Dizziness Handicap Inventory (DHI), and the Global Rating of Change (GRC), were recorded at the initial evaluation and discharge for 454 individual with balance or vestibular disorders. RESULTS: Across the 16-week project, adherence rates improved significantly by 9% and 12% for the initial and delayed groups, respectively (P = 0.008), but there was no difference between groups related to the timing of the educational training and adherence reminders. Clinical outcomes improved for individuals, with balance or vestibular disorders but there was no differences in the change in ABC, DHI, and GRC scores based on whether the interventions were or were not adherent to the CTA. DISCUSSION AND CONCLUSIONS: This quality improvement project was effective in increasing the adherence to the CTA in both groups. Although on average individuals with balance and vestibular disorders showed improvement on the clinical outcomes, there was no additional benefit in the clinical outcome for adherent interventions.Video abstract is available for more insights from the authors (see Supplemental Digital Content 1, http://links.lww.com/JNPT/A125). Language: en

Background Endoscopic ultrasound-guided fine-needle aspiration fails to diagnose up to 25% of patients with pancreatic ductal adenocarcinoma (PDAC). Proteomics can help to overcome this clinical dilemma. We hypothesized that soluble protein signatures can differentiate PDAC from benign tissues. Study Design Tissues were obtained from resected surgical specimens, lysed, and homogenates collected for analysis with a 41-protein multiplex assay. Analyte concentrations were normalized to total protein. Statistical analysis was performed to evaluate for differences in PDAC vs benign tissue. Results Tissues were obtained from 159 patients, 82 patients with PDAC naive to therapy and 77 with benign pancreatic pathology. Fourteen analytes had a receiver operating characteristic curve area of >0.75 for predicting PDAC vs benign tissue. A recursive partitioning model using only 2 analytes, interleukin 1 receptor antagonist and transforming growth factor-α, provided an accuracy, sensitivity, and specificity of 91.2%, 90.2%, and 92.2%, respectively. A penalized logistic regression model found 12 analytes that provide diagnostic value to a protein signature. The mean area under the receiver operating characteristic after 50 tenfold cross-validations was 0.951. Accuracy, sensitivity, and specificity of this model were 91.2%, 87.8%, and 94.8%, respectively. Applying the scenario of 80% disease prevalence in patients undergoing endoscopic ultrasound with fine-needle aspiration for a pancreatic head mass, positive predictive value is 98.5% (95% CI 93.0% to 99.7%) and negative predictive value is 66.0% (95% CI 54.9% to 75.6%). Conclusions Protein signatures from pancreatic specimens can differentiate PDAC from benign tissue. Additional work to validate these findings in a unique sample set is warranted.

Objective To compare skeletal muscle fat (SMF), intermuscular adipose tissue (IMAT) and subcutaneous adipose tissue (SAT) between individuals with rheumatoid arthritis (RA), and healthy individuals of the same age, and healthy individuals at least 10 years older than those with RA. Methods Two cross-sectional studies. In the first study, RA subjects were matched by age, sex, and BMI with healthy adults. In the second, RA subjects were matched by sex and BMI to adults 10–20 years older. SMF, IMAT and SAT were measured with Computed Tomography images of the mid-thigh region. We used parametric or non-parametric related-sample tests to compare fat accumulation between RA subjects and healthy adults. Results In the first study SMF was significantly higher in the RA cohort compared to their age-matched healthy counterparts (mean difference = −3.5 HU (95% −6.2, −0.9), p = 0.011), but IMAT and SAT were similar between cohorts. In the second study, SMF, IMAT and SAT were not significantly different between the RA and matched older healthy cohorts. In both studies, there were no significant differences in mid-thigh muscle area between RA subjects and healthy adults. Conclusion SMF accumulation in RA was higher than in healthy individuals of similar age, sex, BMI. Accumulation of fat within and around the muscles in RA was not different compared to the matched healthy older individuals, indicating that muscle fat accumulation in RA might mimic a pattern not different from healthy aging.

Background: Low back pain (LBP) is a public health concern because it is highly prevalent and the leading cause of disability worldwide. Psychologically Informed Physical Therapy (PIPT) is secondary prevention approach that first aims to identify individuals at high risk for transitioning to chronicity and then provides tailored treatment to reduce that risk. Training models that are feasible to implement with acceptable training quality are needed to improve scalability for widespread implementation of PIPT. This manuscript describes the PIPT training program that was developed for training physical therapists providing PIPT in the TARGET Trial. Methods: The PIPT training program was developed, tested, and modified using an iterative process. Content development consisted of stakeholder engagement, beta testing, modification of training and confirmation of final course objectives. Methods of delivery consisted of a website that included brief educational modules followed by a live 8 hour workshop that included video based mock case scenarios and case-based role playing. Attitudes, beliefs and confidence in implementing PIPT principles were assessed before and immediately after training to measure training quality and impact. Results: Early stakeholder engagement and beta testing indicated the need for increased emphasis on experiential learning opportunities and patient-centered communication training. Booster training varied extensively across TARGET sites with involvement of ‘clinician champions’ brief follow-up sessions identified as best practice. Favorable post training changes in physical therapist attitudes and beliefs toward biopsychosocial treatment orientation and increased confidence in implementing PIPT principles were observed. Conclusions: PIPT training for provider participation in the TARGET Trial was feasible to deliver. Course content was acceptable to physical therapists and resulted in improved beliefs and confidence in applying PIPT skills during clinical practice. Ongoing consultation and site-based continuing education were methods by which specific TARGET sites maintained or augmented PIPT skill training, however implementing ongoing training was challenging in general. Consistent with a pragmatic trial whether this training directly impacted treatment fidelity was not measured, which was a limitation to our training approach.

Background Cancer cachexia is a catabolic condition characterized by skeletal muscle wasting, consequent to tumor burden, which negatively impacts tolerance to cancer therapies and contributes to increased mortality. Partly because of the limited knowledge of the underlying mechanisms of cancer cachexia derived from human studies, however, the ability to therapeutically intervene remains elusive. The purpose of the current study was therefore to better define the phenotype of skeletal muscle obtained from patients with pancreatic ductal adenocarcinoma (PDAC), which has one of the highest rates of cachexia. Methods Morphological analyses were performed on rectus abdominis muscle biopsies obtained from resectable PDAC patients undergoing tumor resection surgery (N = 20) and from weight-stable non-cancer control subjects undergoing benign abdominal surgery (N = 16). PDAC patients with a body weight loss of greater than 5% during the previous 6 months were considered cachectic (N = 15). Statistical tests were two sided. Results Skeletal muscle from cachectic PDAC patients had increased collagen content compared with non-cancer control subjects (1.43% vs 9.66%, P = .0004, Dunn test). Across all PDAC patients, collagen content positively correlated with body weight loss (P = .0016, r = 0.672), was increased in patients with lymph node metastasis (P = .007, Mann-Whitney U test), and was associated with survival on univariate (HR = 1.08, 95% confidence interval [CI] = 1.02 to 1.04, P = .008) and multivariable analyses (HR = 1.08, 95% CI = 1.00 to 1.17, P = .038). Cachectic PDAC patients also displayed increased lipid deposition (2.63% vs 5.72%, P = .042), infiltration of CD68+ macrophages (63.6 cells/mm2 vs 233.8 cells/mm2, P = .0238), calcium deposition (0.21% vs 2.51%, P = .030), and evidence of deficient cellular quality control mechanisms (Mann-Whitney U test). Transcriptional profiling of all patients supported these findings by identifying gene clusters related to wounding, inflammation, and cellular response to TGF-β upregulated in cachectic PDAC patients compared with non-cancer control subjects. Conclusions To our knowledge, this work is the first to demonstrate increased collagen content in cachectic PDAC patients that is associated with poor survival.

Rationale: The pathophysiology of persistent injury-associated anemia is incompletely understood, and human data are sparse. Objectives: To characterize persistent injury-associated anemia among critically ill trauma patients with the hypothesis that severe trauma would be associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, and decreased erythropoiesis. Methods: A translational prospective observational cohort study comparing severely injured, blunt trauma patients who had operative fixation of a hip or femur fracture (n = 17) with elective hip repair patients (n = 22). Bone marrow and plasma obtained at the index operation were assessed for circulating catecholamines, systemic inflammation, erythropoietin, iron trafficking pathways, and erythroid progenitor growth. Bone marrow was also obtained from healthy donors from a commercial source (n = 8). Measurements and Main Results: During admission, trauma patients had a median of 625 ml operative blood loss and 5 units of red blood cell transfusions, and Hb decreased from 10.5 to 9.3 g/dl. Compared with hip repair, trauma patients had higher median plasma norepinephrine (21.9 vs. 8.9 ng/ml) and hepcidin (56.3 vs. 12.2 ng/ml) concentrations (both P < 0.05). Bone marrow erythropoietin and erythropoietin receptor expression were significantly increased among patients undergoing hip repair (23% and 14% increases, respectively; both P < 0.05), but not in trauma patients (3% and 5% increases, respectively), compared with healthy control subjects. Trauma patients had lower bone marrow transferrin receptor expression than did hip repair patients (57% decrease; P < 0.05). Erythroid progenitor growth was decreased in trauma patients (39.0 colonies per plate; P < 0.05) compared with those with hip repair (57.0 colonies per plate; P < 0.05 compared with healthy control subjects) and healthy control subjects (66.5 colonies per plate). Conclusions: Severe blunt trauma was associated with neuroendocrine activation, erythropoietin dysfunction, iron dysregulation, erythroid progenitor growth suppression, and persistent injury-associated anemia. Clinical trial registered with www.clinicaltrials.gov (NCT 02577731).

Note fr'5ym PTJ's Editor in Chief: Both investigators and readers get frustrated reading research on low back pain because of different definitions of “chronic” and different outcome measures. Lack of consensus on study methods makes it difficult to determine if contradictory findings are based on different methods or different interventions; lack of consensus also prevents synthesis across studies. Dr. Partap Khalsa, Deputy Director, National Center for Complementary and Integrative Health, announced the release of Research Standards for Chronic Low Pain, and the hope is that future investigations will adopt them and reduce variability in research reporting. The task force on research standards was an international, multidisciplinary team including Anthony Delitto, PT, PhD, FAPTA. Its findings have been published in leading pain journals. PTJ is among the first professional journals to share the report with its readers. Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting “responder analyses” in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. Perspective: A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

Background and Purpose Our nation's suboptimal health care quality and unsustainable costs can be linked to the failure to implement evidence-based interventions. Implementation is the bridge between the decision to adopt a strategy and its sustained use in practice. The purpose of this case report is threefold: (1) to outline the historical implementation of an evidence-based quality improvement project, (2) to describe the program's future direction using a systems perspective to identify implementation barriers, and (3) to provide implications for the profession as it works toward closing the evidence-to-practice gap. Case Description The University of Pittsburgh Medical Center (UPMC) Centers for Rehab Services is a large, multicenter physical therapy organization. In 2005, they implemented a Low Back Initiative utilizing evidence-based protocols to guide clinical decision making. Outcomes The initial implementation strategy used a multifaceted approach. Formative evaluations were used repeatedly to identify barriers to implementation. Barriers may exist outside the organization, they can be created internally, they may result from personnel, or they may be a direct function of the research evidence. Since the program launch, 3 distinct improvement cycles have been utilized to address identified implementation barriers. Discussion Implementation is an iterative process requiring evaluation, measurement, and refinement. During this period, behavior change is actualized as clinicians become increasingly proficient and committed to their use of new evidence. Successfully incorporating evidence into routine practice requires a systems perspective to account for the complexity of the clinical setting. The value the profession provides can be enhanced by improving the implementation of evidence-based strategies. Achieving this outcome will require a concerted effort in all areas of the profession. New skills will be needed by leaders, researchers, managers, and clinicians.

Improving health care in our country requires simultaneous pursuit of 3 aims: improving the effectiveness of care, improving the health of our population, and reducing the per capita costs of health care.1 As our nation focuses on ways to achieve this triple aim, the unwarranted overuse of health care resources is a significant concern. The continuing rise in health care costs, estimated at $2.8 trillion or 17.2% of gross domestic product in 2012, puts financial pressure on our national economy. Consequently, individuals are burdened by rising insurance premiums, deductibles, and copayments, often in addition to lost wage increases due to rising costs of premiums incurred by employers.2 Proponents of the triple aim have suggested there is ample capacity in our current health care system to achieve these goals by reducing unnecessary tests, treatments, and procedures.1 In fact, the Institute of Medicine estimates that in 2009 alone more than $750 billion (or 1 in 3 dollars spent on health care) was spent on unnecessary medical tests, procedures, and missed prevention opportunities.3 Implementing strategies that reduce unnecessary tests and procedures becomes a challenge, particularly when considering that most of these tests and procedures are covered by insurance. The federal government and private payers have attempted to control health care expenditures and utilization by increasing the number and complexity of regulations and requirements that govern the provision of care. Although the intent may be to improve patient care, these frequently changing and increasingly intricate regulations have led to a burdensome practice environment, challenging the ability of clinicians and administrators to remain compliant. Additionally, attempts to control utilization and costs have led to a significant increase in audits and investigations.4 Because of the complexity of the regulatory environment, even the most diligent health care professionals may find themselves the subject of costly investigations or audits.5

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P &lt, 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1, P &lt, 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P &lt, 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P &lt, 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

Parkinson disease is a progressive neurologic disorder. Limited evidence suggests endurance exercise modifies disease severity, particularly high-intensity exercise.To examine the feasibility and safety of high-intensity treadmill exercise in patients with de novo Parkinson disease who are not taking medication and whether the effect on motor symptoms warrants a phase 3 trial.The Study in Parkinson Disease of Exercise (SPARX) was a phase 2, multicenter randomized clinical trial with 3 groups and masked assessors. Individuals from outpatient and community-based clinics were enrolled from May 1, 2012, through November 30, 2015, with the primary end point at 6 months. Individuals with idiopathic Parkinson disease (Hoehn and Yahr stages 1 or 2) aged 40 to 80 years within 5 years of diagnosis who were not exercising at moderate intensity greater than 3 times per week and not expected to need dopaminergic medication within 6 months participated in this study. A total of 384 volunteers were screened by telephone; 128 were randomly assigned to 1 of 3 groups (high-intensity exercise, moderate-intensity exercise, or control).High-intensity treadmill exercise (4 days per week, 80%-85% maximum heart rate [n = 43]), moderate-intensity treadmill exercise (4 days per week, 60%-65% maximum heart rate [n = 45]), or wait-list control (n = 40) for 6 months.Feasibility measures were adherence to prescribed heart rate and exercise frequency of 3 days per week and safety. The clinical outcome was 6-month change in Unified Parkinson's Disease Rating Scale motor score.A total of 128 patients were included in the study (mean [SD] age, 64 [9] years; age range, 40-80 years; 73 [57.0%] male; and 108 [84.4%] non-Hispanic white). Exercise rates were 2.8 (95% CI, 2.4-3.2) days per week at 80.2% (95% CI, 78.8%-81.7%) maximum heart rate in the high-intensity group and 3.2 (95% CI, 2.8-3.6; P = .13) days per week at 65.9% (95% CI, 64.2%-67.7%) maximum heart rate in the moderate-intensity group (P .001). The mean change in Unified Parkinson's Disease Rating Scale motor score in the high-intensity group was 0.3 (95% CI, -1.7 to 2.3) compared with 3.2 (95% CI, 1.4 to 5.1) in the usual care group (P = .03). The high-intensity group, but not the moderate-intensity group, reached the predefined nonfutility threshold compared with the control group. Anticipated adverse musculoskeletal events were not severe.High-intensity treadmill exercise may be feasible and prescribed safely for patients with Parkinson disease. An efficacy trial is warranted to determine whether high-intensity treadmill exercise produces meaningful clinical benefits in de novo Parkinson disease.clinicaltrials.gov Identifier: NCT01506479.

A hallmark of aggressive hepatocellular carcinomas (HCCs) is the ability to metastasize. Metastatic lesions are difficult to manage in clinical practice as the extent of disease typically precludes curative resection and resistance to systemic treatments is common [1, 2]. Metastasis is a multistage process in which cancer cells (1) delaminate from the primary site and locally invade the host stroma (initiation), (2) enter into blood and/or lymphatic vasculature (intravasation), (3) survive and exit the circulation into distant sites (extravasation), and (4) colonize the new microenvironment and proliferate to form a macroscopic secondary tumor (colonization) [3, 4]. This simplified model provides a framework for a sequence of biological properties that must be acquired during cancer dissemination. Different malignancies, however, demonstrate unique regulatory events in this process largely governed by the complex microenvironment in which the metastatic cells originate and that of the distant location(s) where the metastasis is established [5]. Given the anatomic and physiologic complexity of the liver, the HCC microenvironment is one of the most difficult to reproduce experimentally and, consequently, understand in its totality. In the context of this chapter, HCC metastasis is discussed, with an emphasis on the role of the hepatic microenvironment and the role of circulating cancer cells in the metastatic process.

OBJECTIVE: Limitations associated with current animal models serve as a major obstacle to reliable preclinical evaluation of therapies in pancreatic cancer (PC). In an effort to develop more reliable preclinical models, we have recently established a subcutaneous patient-derived xenograft (PDX) model. However, critical aspects of PC responsible for its highly lethal nature, such as the development of distant metastasis and cancer cachexia, remain underrepresented in the flank PDX model. The purpose of this study was to evaluate the degree to which an orthotopic patient-derived xenograft (PDX) model of pancreatic cancer (PC) recapitulates these aspects of the human disease. METHODS: Human PDX-derived PC tumors were implanted directly into the pancreas of NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mice. Tumor growth, metastasis and muscle wasting were then evaluated. RESULTS: Orthotopically implanted PDX-derived tumors consistently incorporated into the murine pancreatic parenchyma, metastasized to both the liver and lungs and induced muscle wasting directly proportional to the size of the tumor, consistent of the cancer cachexia syndrome. CONCLUSIONS: Through the orthotopic implantation technique described, we demonstrate a highly reproducible model that recapitulates both local and systemic aspects of human PC.

We sought to determine if laparoscopic pancreatoduodenectomy (LPD) is a cost-effective alternative to open pancreatoduodenectomy (OPD).Hospital cost data, discharge disposition, readmission rates, and readmission costs from periampullary cancer patient cohorts of LPD and OPD were compared. The surgical cohorts over a 40-month period were clinically similar, consisting of 52 and 50 patients in the LPD and OPD groups, respectively.The total operating room costs were higher in the LPD group as compared to the OPD group (median US$12,290 vs US$11,299; P = 0.05) due to increased costs for laparoscopic equipment and regional nerve blocks (P ≤ 0.0001). Although hospital length of stay was shorter in the LPD group (median 7 vs 8 days; P = 0.025), the average hospital cost was not significantly decreased compared to the OPD group (median $28,496 vs $28,623). Surgery-related readmission rates and associated costs did not differ between groups. Compared to OPD patients, significantly more LPD patients were discharged directly home rather than to other healthcare facilities (88% vs 72%; P = 0.047).For the index hospitalization, the cost of LPD is equivalent to OPD. Total episode-of-care costs may favor LPD via reduced post-hospital needs for skilled nursing and rehabilitation.

Despite rapidly increasing intervention, functional disability due to chronic low back pain (cLBP) has increased in recent decades. We often cannot identify mechanisms to explain the major negative impact cLBP has on patients' lives. Such cLBP is often termed non-specific and may be due to multiple biologic and behavioral etiologies. Researchers use varied inclusion criteria, definitions, baseline assessments, and outcome measures, which impede comparisons and consensus. Therefore, NIH Pain Consortium charged a Research Task Force (RTF) to draft standards for research on cLBP. The resulting multidisciplinary panel recommended using 2 questions to define cLBP; classifying cLBP by its impact (defined by pain intensity, pain interference, and physical function); use of a minimum dataset to describe research participants (drawing heavily on the PROMIS methodology); reporting "responder analyses" in addition to mean outcome scores; and suggestions for future research and dissemination. The Pain Consortium has approved the recommendations, which investigators should incorporate into NIH grant proposals. The RTF believes that these recommendations will advance the field, help to resolve controversies, and facilitate future research addressing the genomic, neurologic, and other mechanistic substrates of chronic low back pain. We expect that the RTF recommendations will become a dynamic document and undergo continual improvement. Perspective A task force was convened by the NIH Pain Consortium with the goal of developing research standards for chronic low back pain. The results included recommendations for definitions, a minimum dataset, reporting outcomes, and future research. Greater consistency in reporting should facilitate comparisons among studies and the development of phenotypes.

The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these clinical practice guidelines is to describe the peer-reviewed literature and make recommendations related to nonarthritic hip joint pain. J Orthop Sports Phys Ther. 2014;44(6):A1–A32. doi:10.2519/jospt.2014.0302

The significant involvement of mutant KRas in human cancer development underscores the need to develop approaches that disable mutant KRas-driven tumors. Targeting KRas directly is challenging, and such identifying vulnerabilities specific for mutant KRas tumors is an important alternative approach. In this study, we discovered that glycogen synthase kinase 3 (GSK3) is required for the in vitro and in vivo growth and survival of human mutant KRas-dependent tumors but not for mutant KRas-independent tumors. Pharmacological inhibition with the GSK3 inhibitor SB as well as siRNA depletion of GSK3 lead to tumor suppression that is mediated at least in part by inhibition of the phosphorylation of the GSK3 substrates c-Myc on T58 and β-catenin on S33/S37/T41. CRISPR/Cas9 targeted knock out studies demonstrated that c-Myc and β-catenin upregulation mediate the antitumor activity of SB. Importantly, GSK3 blockade inhibits the in vivo growth of G12D, G12V, and G12C mutant KRas primary and metastatic patient-derived xenografts from pancreatic cancer patients who progressed on chemo- and radiation therapies. This discovery warrants advanced pre-clinical and clinical investigations of GSK3 inhibitors in mutant KRas-dependent cancers. Note: This abstract was not presented at the meeting. Citation Format: Aslamuzzaman Kazi, Shengyan Xiang, Hua Yang, Daniel Delitto, Jose Trevino, Rays H. Jiang, Muhammad Ayaz, Harshani Lawrence, Perry Kennedy, Said M. Sebti. Abrogation of KRas-addicted tumors by GSK3 suppression-mediated upregulation of β-catenin and c-myc [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1310.