Recurrence of low back pain: A difficult outcome to predict. Development and validation of a multivariable prediction model for recurrence in patients recently recovered from an episode of non-specific low back pain.

BACKGROUND: Recurrence of low back pain (LBP) is common. If clinicians could identify an individual's risk of recurrence, this would enhance clinical decision-making and tailored patient care. OBJECTIVE/DESIGN: To develop and validate a simple tool to predict the probability of a recurrence of LBP by 3- or 12-months following recovery. METHODS: Data utilised for the prediction model development came from a prospective inception cohort study of participants (n = 250) recently recovered from LBP, who had sought care from chiropractic or physiotherapy services. The outcome measure was a recurrence of activity-limiting LBP. Candidate predictor variables (e.g., basic demographics, LBP history, levels of physical activity, etc) collected at baseline were considered for inclusion in a multivariable Cox model. The model's performance was tested in a separate validation dataset of participants (n = 261) involved in a randomised controlled trial investigating exercise for the prevention of LBP recurrences. RESULTS: The final model included the number of previous episodes, total sitting time, and level of education. In the development sample, discrimination was acceptable (Harrell's C-statistic = 0.61, 95% CI, 0.59-0.62), but in the validation sample, discrimination was poor (0.56, 95% CI, 0.54-0.58). Calibration of the model in the validation dataset was acceptable at 3 months but was less precise at 12 months. CONCLUSION: The developed prediction model, which included number of previous episodes, total sitting time, and level of education, did not perform adequately in the validation sample to recommend its use in clinical practice. Predicting recurrence of LBP in clinical practice remains challenging.

Steroid hormones, energetic state, and immunocompetence vary across reproductive contexts in a parthenogenetic lizard.

Reproduction is energetically expensive and investing in this life history trait is likely accompanied by significant changes in physiological activity. Investment strategy necessary for achieving reproductive success in reptiles can vary with reproductive form and pattern, potentiating different consequences for competing fitness-related traits such as those key to survival. The goal of this study was to assess if and how energetic state (i.e., energy metabolites) and self-maintenance (i.e., immunocompetence) are hormonally modulated across reproductive contexts in an oviparous, parthenogenetic lizard, the Colorado Checkered Whiptail Aspidoscelis neotesselata. Here blood plasma samples were collected from lizards within the US Army Fort Carson Military Installation near Colorado Springs, CO, USA, during seasons of reproductive activity (i.e., June) and inactivity (i.e., August). Measures of reproductive (i.e., estradiol) and energy-mobilizing (i.e., corticosterone) hormones, energy metabolites (i.e., glucose, triglycerides, and free glycerol), and innate immunity (i.e., bactericidal ability) were compared by season and reproductive stage. Levels of energy metabolites and bactericidal ability were compared to levels of E2 and CORT. Bactericidal ability was also compared to levels of energy metabolites. Corticosterone and glucose levels were lower during the reproductive season while triglyceride levels and bactericidal ability were higher, but both estradiol and free glycerol levels did not differ between seasons. Throughout vitellogenesis, corticosterone and glucose levels as well as bactericidal ability did not differ, but estradiol levels were higher during early and mid-stage and both triglyceride and free glycerol levels were lower during gravidity. Corticosterone levels were negatively associated with circulating triglycerides and bactericidal ability, but were not related to glucose nor free glycerol levels. Estradiol levels were positively associated with free glycerol levels and bactericidal ability, but were not related to glucose nor triglyceride levels. Finally, bactericidal ability was negatively associated with glucose, but positively associated with triglycerides. Differences in energetic state and immunocompetence are thus reflected by shifts in hormone secretion across reproductive investment. These findings provide partial support for the hypothesis that energetic state is differentially regulated by steroid hormones to afford reproduction, potentially at the cost of future survival.

CHECK: A randomized trial evaluating the efficacy and cost-effectiveness of home visitation in pediatric weight loss treatment.

BACKGROUND: Socioeconomically-disadvantaged households have a high prevalence of pediatric overweight/obesity, and also face barriers to accessing weight loss treatment in healthcare settings. Delivering family-based pediatric weight loss treatment in the home setting may enhance its efficacy by facilitating treatment attendance, enabling more tailored treatment recommendations informed by observations of the home environment, and increasing accountability. This paper describes the design of the Creating Health Environments for Chicago Kids (CHECK) Trial, which evaluates the efficacy, cost-effectiveness, and mechanisms of home visitation in family-based pediatric weight loss treatment for children in low-income households. DESIGN: CHECK is a two-arm, parallel group, randomized controlled trial that is enrolling N = 266 children, ages 6-12 y, who have overweight/obesity (BMI percentile ≥85) and live in a low-income household. Participants are randomized in a 1:1 ratio to either standard of care family-based weight loss treatment delivered in the home, or the identical intervention delivered in an academic medical center. The primary outcome is change in child BMI z-score from baseline to 12 months. Program delivery costs are rigorously documented to enable cost-effectiveness analyses from the societal and payer perspectives. Objectively-documented changes to the home environment and aspects of intervention delivery (e.g., hours of in-person contact received, quantity of behavioral goals set per session) will be tested as hypothesized treatment mechanisms. IMPLICATIONS: Findings will inform the design of future interventions, and treatment dissemination decisions by public health agencies and third-party payers. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03195790.

Quality Measures and Quality Improvement Initiatives in Osteoporosis-an Update.

PURPOSE OF REVIEW: The aims of this review are to summarize current performance for osteoporosis quality measures used by Centers for Medicare and Medicaid (CMS) for pay-for-performance programs and to describe recent quality improvement strategies around these measures. RECENT FINDINGS: Healthcare Effectiveness Data and Information (HEDIS) quality measures for the managed care population indicate gradual improvement in osteoporosis screening, osteoporosis identification and treatment following fragility fracture, and documentation of fall risk assessment and plan of care between 2006 and 2016. However, population-based studies suggest achievement for these process measures is lower where reporting is not mandated. Performance gaps remain, particularly for post-fracture care. Elderly patients with increased comorbidity are especially vulnerable to fractures, yet underperformance is documented in this population. Gender and racial disparities also exist. As has been shown for other areas of health care, education alone has a limited role as a quality improvement intervention. Multifactorial and systems-based interventions seem to be most successful in leading to measurable change for osteoporosis care and fall prevention. Despite increasing recognition of evidence-based quality measures for osteoporosis and incentives to improve upon performance for these measures, persistent gaps in care exist that will require further investigation into sustainable and value-adding quality improvement interventions.

Correction to: Effectiveness of a new model of primary care management on knee pain and function in patients with knee osteoarthritis: Protocol for THE PARTNER STUDY.

After the publication of this protocol [1], our collaborator Prima Health solutions advised us of their intent to withdraw from the study.

The role of Tec kinase signaling pathways in the development of Mallory Denk Bodies in balloon cells in alcoholic hepatitis.

Several research strategies have been used to study the pathogenesis of alcoholic hepatitis (AH). These strategies have shown that various signaling pathways are the target of alcohol in liver cells. However, few have provided specific mechanisms associated with Mallory-Denk Bodies (MDBs) formed in Balloon cells in AH. The formation of MDBs in these hepatocytes is an indication that the mechanisms of protein quality control have failed. The MDB is the result of aggregation and accumulation of proteins in the cytoplasm of balloon degenerated liver cells. To understand the mechanisms that failed to degrade and remove proteins in the hepatocyte from patients suffering from alcoholic hepatitis, we investigated the pathways that showed significant up regulation in the AH liver biopsies compared to normal control livers (Liu et al., 2015). Analysis of genomic profiles of AH liver biopsies and control livers by RNA-seq revealed different pathways that were up regulated significantly. In this study, the focus was on Tec kinase signaling pathways and the genes that significantly interrupt this pathway. Quantitative PCR and immunofluorescence staining results, indicated that several genes and proteins are significantly over expressed in the livers of AH patients that affect the Tec kinase signaling to PI3K which leads to activation of Akt and its downstream effectors.

Bladder-sparing Radiotherapy for Muscle-invasive Bladder Cancer: A Qualitative Study to Identify Barriers and Enablers.

AIMS: Bladder-sparing radiotherapy for muscle-invasive bladder cancer (MIBC) may be underutilised in North America. To understand factors driving practice we used the Theoretical Domains Framework (TDF) to identify barriers and enablers of bladder-sparing radiotherapy utilisation. MATERIALS AND METHODS: A convenience sample of Canadian urologists, medical oncologists and radiation oncologists participated in individual semi-structured 1 h interviews. An interview guide was developed using the TDF to assess barriers and enablers of bladder-sparing radiotherapy use. Interviews were recorded and transcribed. Two investigators independently identified barriers and enablers and assigned them to specific themes. Participant recruitment continued until saturation. RESULTS: In total, 71 physicians were invited to participate and 34 (48%) agreed to be interviewed; 13 urologists, 11 radiation oncologists and 10 medical oncologists. We identified the following barriers to the use of bladder-sparing radiotherapy (relevant TDF domains in parentheses): (1) beliefs that radiotherapy has inferior survival compared with cystectomy (beliefs about consequences); (2) lack of referral from urology to radiation oncology (behavioural regulation; memory, attention and decision-making); (3) lack of 'champions' who advocate for radiotherapy (social and professional role); and (4) inadequate multidisciplinary collaboration (environmental context and resources). Predominant enablers to the use of bladder-sparing radiotherapy included: (1) 'champions' who believe in the value of radiotherapy (social and professional role); (2) beliefs by urologists that radiation oncologists should present radiotherapy options to all patients (social and professional role); (3) institutional policy that all MIBC patients should be seen by multiple specialists (environmental context and resources); (4) system facilitators of radiation oncology referral (i.e. nurse navigator) (environmental context and resources); and (5) patient-driven consultations seeking alternatives to cystectomy (social influences). CONCLUSIONS: These findings identify important barriers and enablers to the use of bladder-sparing radiotherapy in MIBC. Physician beliefs, access to multidisciplinary care and institutional context should be considered in efforts to increase the use of bladder-sparing radiotherapy.

The role of the IL-8 signaling pathway in the infiltration of granulocytes into the livers of patients with alcoholic hepatitis.

BACKGROUND AND AIM: IL-8 (C-X-L motif chemokine ligase 8) and CXCR2 (C-X-C-motif chemokine receptor 2) are up regulated in alcoholic hepatitis (AH) liver biopsies. One of the consequences is the attraction and chemotactic neutrophilic infiltrate seen at the AH stage of alcoholic liver disease. MATERIALS AND METHODS: Human formalin-fixed, paraffin-embedded (FFPE) liver biopsies from patients who have AH were studied by (2.1) RNA sequencing, (2.2) PCR and (2.3) semi quantitation of specific proteins in biopsy sections using immunohistochemical measurements of antibody fluorescent intensity with morphometric technology. RESULTS: Immunohistochemistry of IL-8 showed that the expression was increased in the cytoplasm of the hepatocytes in AH liver biopsies compared to the controls. IL-8 and ubiquitin were co-localized in the MDBs. Numerous neutrophils were found throughout and satellitosis of neutrophils around MDBs was present. This suggested that IL-8 may be involved in MDB pathogenesis. RNA seq analysis revealed activation by IL-8 which included neutrophil chemotaxis by LIM domain kinase 2 (LIMK2) (17.5 fold increase) and G protein subunit alpha 15 (GNA15) (27.8 fold increase). CONCLUSIONS: The formation of MDBs by liver cells showed colocalization of ubiquitin and IL-8 in the MDBs. This suggested that IL-8 in these hepatocytes attracted the neutrophils to form satellitosis. This correlated with up regulation of the proteins downstream from the IL-8 pathways including LIMK2, GNG2 (guanine nucleotide binding proteins) and PIK3CB (phosphatidyl isitol-4, 5-biophosphate-3-kinase, catalytic subunit beta).

A Simulated Heat Wave Has Diverse Effects on Immune Function and Oxidative Physiology in the Corn Snake (Pantherophis guttatus).

Animals will continue to encounter increasingly warm environments, including more frequent and intense heat waves. Yet the physiological consequences of heat waves remain equivocal, potentially because of variation in adaptive plasticity (reversible acclimation) and/or aspects of experimental design. Thus, we measured a suite of physiological variables in the corn snake (Pantherophis guttatus) after exposure to field-parameterized, fluctuating temperature regimes (moderate temperature and heat wave treatments) to address two hypotheses: (1) a heat wave causes physiological stress, and (2) thermal performance of immune function exhibits adaptive plasticity in response to a heat wave. We found little support for our first hypothesis because a simulated heat wave had a negative effect on body mass, but it also reduced oxidative damage and did not affect peak performance of three immune metrics. Likewise, we found only partial support for our second hypothesis. After exposure to a simulated heat wave, P. guttatus exhibited greater performance breadth and reduced temperature specialization (the standardized difference between peak performance and performance breadth) for only one of three immune metrics and did so in a sex-dependent manner. Further, a simulated heat wave did not elicit greater performance of any immune metric at higher temperatures. Yet a heat wave likely reduced innate immune function in P. guttatus because each metric of innate immune performance in this species (as in most vertebrates) was lower at elevated temperatures. Together with previous research, our study indicates that a heat wave may have complex, modest, and even positive physiological effects in some taxa.

Over expression of proteins that alter the intracellular signaling pathways in the cytoplasm of the liver cells forming Mallory-Denk bodies.

In this study, liver biopsy sections fixed in formalin and embedded in paraffin (FFPE) from patients with alcoholic hepatitis (AH) were used. The results showed that the expression of the SYK protein was up regulated by RNA-seq and real time PCR analyses in the alcoholic hepatitis patients compared to controls. The results were supported by using the IHC fluorescent antibody staining intensity morphometric quantitation. Morphometric quantification of fluorescent intensity measurement showed a two fold increase in SYK protein in the cytoplasm of the cells forming MDBs compared to surrounding normal hepatocytes. The expression of AKT1 was also analyzed. AKT1 is a serine/threonine-specific protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription and cell migration. The AKT protein was also increased in hepatocyte balloon cells forming MDBs. This observation demonstrates the role of SYK and its subsequent effect on the internal signaling pathways such as PI3K/AKT as well as p70S6K, as a potential multifunctional target in protein quality control mechanisms of hepatocytes when ER stress is activated.

Upregulation of autophagy components in alcoholic hepatitis and nonalcoholic steatohepatitis.

There are many homeostatic mechanisms for coping with stress conditions in cells, including autophagy. In many studies autophagy, as an intracellular pathway which degrades misfolded and damaged protein, and Mallory-Denk Body (MDB) formation have been shown to be protective mechanisms against stress such as alcoholic hepatitis. Alcohol has a significant role in alteration of lipid homeostasis, sterol regulatory element-binding proteins (SREBPs) and peroxidase proliferator-activated receptors through AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK is one of the kinases that regulate autophagy through the dephosphorylation of ATG1. Activation of ATG1 (ULK kinases family) activates ATG6. These two activated proteins relocate to the site of initial autophagosome and activate the other downstream components of autophagocytosis. Many other proteins regulate autophagocytosis at the gene level. CHOP (C/EBP homologous protein) is one of the most important parts of stress-inducible transcription that encodes a ubiquitous transcription factor. In this report we measure the upregulation of the gene that are involved in autophagocytosis in liver biopsies of alcoholic hepatitis and NASH. Electron microscopy was used to document the presence of autophagosomes in the liver cells. Expression of AMPK1, ATG1, ATG6 and CHOP in ASH were significantly (p value<0.05) upregulated in comparison to control. Electron microscopy findings of ASH confirmed the presence of autophagosomes, one of which contained a MDB, heretofore undescribed. Significant upregulations of AMPK-1, ATG-1, ATG-6, and CHOP, and uptrending of ATG-4, ATG-5, ATG-9, ATR, and ATM in ASH compared to normal control livers indicate active autophagocytosis in alcoholic hepatitis.

The mechanisms of Mallory-Denk body formation are similar to the formation of aggresomes in Alzheimer's disease and other neurodegenerative disorders.

There is a possibility that the aggresomes that form in the brain in neurodegenerative diseases like Alzheimer's disease (AD) and in the liver where aggresomes like Mallory-Denk Bodies (MDB) form, share mechanisms. MDBs can be prevented by feeding mice sadenosylmethionine (SAMe) or betaine. Possibly these proteins could prevent AD. We compared the literature on MDBs and AD pathogenesis, which include roles played by p62, ubiquitin UBB +1, HSPs70, 90, 104, FAT10, NEDD8, VCP/97, and the protein quality control mechanisms including the 26s proteasome, the IPOD and JUNQ and autophagosome pathways.

Pulmonary Veno-Occlusive Disease: A Newly Recognized Cause of Severe Pulmonary Hypertension in Dogs.

Pulmonary hypertension is a well-known though poorly characterized disease in veterinary medicine. In humans, pulmonary veno-occlusive disease (PVOD) is a rare cause of severe pulmonary hypertension with a mean survival time of 2 years without lung transplantation. Eleven adult dogs (5 males, 6 females; median age 10.5 years, representing various breeds) were examined following the development of severe respiratory signs. Lungs of affected animals were evaluated morphologically and with immunohistochemistry for alpha smooth muscle actin, desmin, CD31, CD3, CD20, and CD204. All dogs had pulmonary lesions consistent with PVOD, consisting of occlusive remodeling of small- to medium-sized pulmonary veins, foci of pulmonary capillary hemangiomatosis (PCH), and accumulation of hemosiderophages; 6 of 11 dogs had substantial pulmonary arterial medial and intimal thickening. Ultrastructural examination and immunohistochemistry showed that smooth muscle cells contributed to the venous occlusion. Increased expression of CD31 was evident in regions of PCH indicating increased numbers of endothelial cells in these foci. Spindle cells strongly expressing alpha smooth muscle actin and desmin co-localized with foci of PCH; similar cells were present but less intensely labeled elsewhere in non-PCH alveoli. B cells and macrophages, detected by immunohistochemistry, were not co-localized with the venous lesions of canine PVOD; small numbers of CD3-positive T cells were occasionally in and around the wall of remodeled veins. These findings indicate a condition in dogs with clinically severe respiratory disease and pathologic features resembling human PVOD, including foci of pulmonary venous remodeling and PCH.

Inhibition of protease-activated receptor 4 impairs platelet procoagulant activity during thrombus formation in human blood.

UNLABELLED: Essentials The platelet thrombin receptor, PAR4, is an emerging anti-thrombotic drug target. We examined the anti-platelet & anti-thrombotic effects of PAR4 inhibition in human blood. PAR4 inhibition impaired platelet procoagulant activity in isolated cells and during thrombosis. Our study shows PAR4 is required for platelet procoagulant function & thrombosis in human blood. SUMMARY: Background Thrombin-induced platelet activation is important for arterial thrombosis. Thrombin activates human platelets predominantly via protease-activated receptor (PAR)1 and PAR4. PAR1 has higher affinity for thrombin, and the first PAR1 antagonist, vorapaxar, was recently approved for use as an antiplatelet agent. However, vorapaxar is contraindicated in a significant number of patients, owing to adverse bleeding events. Consequently, there is renewed interest in the role of platelet PAR4 in the setting of thrombus formation. Objectives To determine the specific antiplatelet effects of inhibiting PAR4 function during thrombus formation in human whole blood. Methods and Results We developed a rabbit polyclonal antibody against the thrombin cleavage site of PAR4, and showed it to be a highly specific inhibitor of PAR4-mediated platelet function. This function-blocking anti-PAR4 antibody was used to probe for PAR4-dependent platelet functions in human isolated platelets in the absence and presence of concomitant PAR1 inhibition. The anti-PAR4 antibody alone was sufficient to abolish the sustained elevation of cytosolic calcium level and consequent phosphatidylserine exposure induced by thrombin, but did not significantly inhibit integrin αII b ß3 activation, α-granule secretion, or aggregation. In accord with these in vitro experiments on isolated platelets, selective inhibition of PAR4, but not of PAR1, impaired thrombin activity (fluorescence resonance energy transfer-based thrombin sensor) and fibrin formation (anti-fibrin antibody) in an ex vivo whole blood flow thrombosis assay. Conclusions These findings demonstrate that PAR4 is required for platelet procoagulant function during thrombus formation in human blood, and suggest PAR4 inhibition as a potential target for the prevention of arterial thrombosis.

Physical changes in the home environment to reduce television viewing and sugar-sweetened beverage consumption among 5- to 12-year-old children: a randomized pilot study.

This study evaluated the feasibility of a home-based intervention to reduce sugar-sweetened beverage intake and television viewing among children. Lower income parents of overweight children aged 5-12 years (n = 40) were randomized to a home environment intervention to reduce television viewing with locking devices and displace availability of sugar-sweetened beverages with home delivery of non-caloric beverages (n = 25), or to a no-intervention control group (n = 15) for 6 months. Data were collected at baseline and 6 months. After 6 months, television viewing hours per day was significantly lower in the intervention group compared with the control group (1.7 [SE = .02] vs. 2.6 [SE = .25] hours/day, respectively, P < .01). Sugar-sweetened beverage intake was marginally significantly lower among intervention group compared to control group children (0.21 [SE = .09] vs. 0.45 [SE = .10], respectively, P < .09). Body mass index (BMI) z-score was not significantly lower among intervention compared to control children. Among a lower income sample of children, a home-based intervention reduced television viewing, but not sugar-sweetened beverage intake or BMI z-score.

Understanding patient beliefs regarding the use of imaging in the management of low back pain.

BACKGROUND: Imaging for low back pain (LBP) remains common despite guidelines recommending against routine imaging. Patient beliefs about imaging may contribute to the problem. This study aimed to quantitatively investigate patient beliefs regarding the need for imaging in managing LBP and to investigate whether personal characteristics, pain characteristics or back pain beliefs are associated with imaging beliefs. METHODS: A survey was performed of consecutive patients presenting to general medical practitioners in Sydney, Australia. Nine medical clinics were selected across varied socioeconomic regions. Survey questions assessed beliefs about the importance of imaging for LBP, collected demographic information, LBP history and general beliefs about back pain. Descriptive statistics and multivariate logistic regression were used to analyse findings. RESULTS: Three hundred completed surveys were collected with a 79.6% response rate. The mean age was 44 years and 60.7% of respondents were women. Exactly, 54.3% (95% CI: 48.7-58.9%) believed that imaging was necessary for the best medical care for LBP. Exactly, 48.0% (95% CI: 42.4-53.6%) believed that everyone with LBP should obtain imaging. Increased age, lower education level, non-European or non-Anglo-saxon cultural background, history of previous imaging and Back Beliefs Questionnaire scores were associated with beliefs that imaging was necessary. CONCLUSION: Approximately, half of all patients presenting to a medical doctor consider low back imaging to be necessary. This may have important implications for overutilization of low back imaging investigations. Knowledge of the factors associated with the patient's belief that imaging is necessary may be helpful in designing appropriate interventions to reduce unnecessary imaging for LBP.