Molecular Mechanisms of Prdm16 as a Tumor Suppressor in Pancreatic Ductal Adenocarcinoma

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-b) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis

A diagnosis-based clinical decision rule for spinal pain part 2: review of the literature

<p>Abstract</p> <p>Background</p> <p>Spinal pain is a common and often disabling problem. The research on various treatments for spinal pain has, for the most part, suggested that while several interventions have demonstrated mild to moderate short-term benefit, no single treatment has a major impact on either pain or disability. There is great need for more accurate diagnosis in patients with spinal pain. In a previous paper, the theoretical model of a diagnosis-based clinical decision rule was presented. The approach is designed to provide the clinician with a strategy for arriving at a specific working diagnosis from which treatment decisions can be made. It is based on three questions of diagnosis. In the current paper, the literature on the reliability and validity of the assessment procedures that are included in the diagnosis-based clinical decision rule is presented.</p> <p>Methods</p> <p>The databases of Medline, Cinahl, Embase and MANTIS were searched for studies that evaluated the reliability and validity of clinic-based diagnostic procedures for patients with spinal pain that have relevance for questions 2 (which investigates characteristics of the pain source) and 3 (which investigates perpetuating factors of the pain experience). In addition, the reference list of identified papers and authors' libraries were searched.</p> <p>Results</p> <p>A total of 1769 articles were retrieved, of which 138 were deemed relevant. Fifty-one studies related to reliability and 76 related to validity. One study evaluated both reliability and validity.</p> <p>Conclusion</p> <p>Regarding some aspects of the DBCDR, there are a number of studies that allow the clinician to have a reasonable degree of confidence in his or her findings. This is particularly true for centralization signs, neurodynamic signs and psychological perpetuating factors. There are other aspects of the DBCDR in which a lesser degree of confidence is warranted, and in which further research is needed.</p

A non-surgical approach to the management of lumbar spinal stenosis: A prospective observational cohort study

BACKGROUND: While it is widely held that non-surgical management should be the first line of approach in patients with lumbar spinal stenosis (LSS), little is known about the efficacy of non-surgical treatments for this condition. Data are needed to determine the most efficacious and safe non-surgical treatment options for patients with LSS. The purpose of this paper is to describe the clinical outcomes of a novel approach to patients with LSS that focuses on distraction manipulation (DM) and neural mobilization (NM). METHODS: This is a prospective consecutive case series with long term follow up (FU) of fifty-seven consecutive patients who were diagnosed with LSS. Two were excluded because of absence of baseline data or failure to remain in treatment to FU. Disability was measured using the Roland Morris Disability Questionnaire (RM) and pain intensity was measured using the Three Level Numerical Rating Scale (NRS). Patients were also asked to rate their perceived percentage improvement. RESULTS: The mean patient-rated percentage improvement from baseline to the end to treatment was 65.1%. The mean improvement in disability from baseline to the end of treatment was 5.1 points. This was considered to be clinically meaningful. Clinically meaningful improvement in disability from baseline to the end of treatment was seen in 66.7% of patients. The mean improvement in "on average" pain intensity was 1.6 points. This did not reach the threshold for clinical meaningfulness. The mean improvement in "at worst" pain was 3.1 points. This was considered to be clinically meaningful. The mean duration of FU was 16.5 months. The mean patient-rated percentage improvement from baseline to long term FU was 75.6%. The mean improvement in disability was 5.2 points. This was considered to be clinically meaningful. Clinically meaningful improvement in disability was seen in 73.2% of patients. The mean improvement in "on average" pain intensity from baseline to long term FU was 3.0 points. This was considered to be clinically meaningful. The mean improvement in "at worst" pain was 4.2 points. This was considered to be clinically meaningful. Only two patients went on to require surgery. No major complications to treatment were noted. CONCLUSION: A treatment approach focusing on DM and NM may be useful in bringing about clinically meaningful improvement in disability in patients with LSS

Prevalence and Risk Factors Associated With Long-term Opioid Use After Injury Among Previously Opioid-Free Workers

Importance Using opioids for acute pain can lead to long-term use and associated morbidity and mortality. Injury has been documented as a gateway to long-term opioid use in some populations, but data are limited for injured workers. Objective To evaluate the prevalence and risk factors of long-term opioid use after injury among workers in Tennessee who were opioid free at the time of injury. Design, Setting, and Participants This cohort study identified injured workers aged 15 to 99 years who reported only 1 injury to the Tennessee Bureau of Workers’ Compensation from March 2013 to December 2015 and had no opioid prescription in the 60 days before injury. Participants were matched to their prescription history in Tennessee’s prescription drug monitoring program. Analysis was conducted from November 2017 to March 2018. Logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% CIs for associations of demographic, injury, and opioid use variables with long-term use. Main Outcomes and Measures The primary outcome was long-term opioid use, defined as having an opioid supplied for 45 or more days in the 90 days after injury. Results Among 58 278 injured workers who received opioids after injury (18 977 [32.5%] aged 15-34 years, 27 514 [47.2%] aged 35-54 years, and 11 787 [20.2%] aged 55-99 years; 32 607 [56.0%] men), 46 399 (79.6%) were opioid free at the time of injury. Among opioid-free injured workers, 1843 (4.0%) began long-term opioid use. After controlling for covariates, long-term use was associated with receiving 20 or more days’ supply in the initial opioid prescription compared with receiving less than 5 days’ supply (OR, 28.94; 95% CI, 23.44-35.72) and visiting 3 or more prescribers in the 90 days after injury compared with visiting 1 prescriber (OR, 14.91; 95% CI, 12.15-18.29). However, even just 5 days’ to 9 days’ supply was associated with an increase in the odds of long-term use compared with less than 5 days’ supply (OR, 1.83; 95% CI, 1.56-2.14). Conclusions and Relevance In this study of injured workers, injury was associated with long-term opioid use. The number of days’ supply of the initial opioid prescription was the strongest risk factor of developing long-term use, highlighting the importance of careful prescribing for initial opioid prescriptions

Early Action on HFCs Mitigates Future Atmospheric Change

As countries take action to mitigate global warming, both by ratifying the UNFCCC Paris Agreement and enacting the Kigali Amendment to the Montreal Protocol to manage hydrofluorocarbons (HFCs), it is important to consider the relative importance of the pertinent greenhouse gases (GHGs), the distinct structure of their atmospheric impacts, and how the timing of potential GHG regulations would affect future changes in atmospheric temperature and ozone. Chemistry-climate model simulations demonstrate that HFCs could contribute substantially to anthropogenic climate change by the mid-21st century, particularly in the upper troposphere and lower stratosphere i.e., global average warming up to 0.19K at 80hPa. Three HFC mitigation scenarios demonstrate the benefits of taking early action in avoiding future atmospheric change: more than 90 of the climate change impacts of HFCs can be avoided if emissions stop by 2030

A comparative analysis of chiropractic and general practitioner patients in North America: Findings from the joint Canada/United States survey of health, 2002–03

BACKGROUND: Scientifically rigorous general population-based studies comparing chiropractic with primary-care medical patients within and between countries have not been published. The objective of this study is to compare care seekers of doctors of chiropractic (DCs) and general practitioners (GPs) in the United States and Canada on a comprehensive set of sociodemographic, quality of life, and health-related variables. METHODS: Data are from the Joint Canada/U.S. Survey of Health (JCUSH), 2002–03, a random sample of adults in Canada (N = 3505) and the U.S. (N = 5183). Respondents were categorized according to their pattern of health-care use in the past year. Distributions, percentages, and estimates (adjusted odds ratios) weighted to reflect the complex survey design were produced. RESULTS: Nearly 80% of respondents sought care from GPs; 12% sought DC care. Compared with GP only patients, DC patients in both countries tend to be under 65 and white, with arthritis and disabling back or neck pain. U.S. DC patients are more likely than GP only patients to be obese and to lack a regular doctor; Canadian DC patients are more likely than GP only patients to be college educated, to have higher incomes, and dissatisfied with MD care. Compared with seekers of both GP and DC care, DC only patients in both countries have fewer chronic conditions, take fewer drugs, and have no regular doctor. U.S. DC only patients are more likely than GP+DC patients to be uninsured and dissatisfied with health care; Canadian DC only patients are more likely than GP+DC patients to be under 45, male, less educated, smokers, and not obese, without disabling back or neck pain, on fewer drugs, and lacking a regular doctor. CONCLUSION: Chiropractic and GP patients are dissimilar in both Canada and the U.S., with key differences between countries and between DC patients who do and do not seek care from GPs. Such variation has broad and potentially far-reaching health policy and research implications

Geologic Map of the Ganiki Planitia Quadrangle (V–14), Venus

Our current research focuses on addressing four specific questions. Has the dominant style of volcanic expression within the quadrangle varied in a systematic fashion over time? Does the tectonic deformation within the quadrangle record significant regional patterns that vary spatially or temporally, and if so what are the scales, orientations and sources of the stress fields driving this deformation? If mantle upwelling and downwelling have played a significant role in the formation of Atla Regio and Atalanta Planitia as has been proposed, does the geology of Ganiki Planitia record evidence of northwest-directed lateral mantle flow connecting the two sites? Finally, can integration of the tectonic and volcanic histories preserved within the quadrangle help constrain competing resurfacing models for Venus

A randomised controlled trial comparing graded exercise treatment and usual physiotherapy for patients with non-specific neck pain (the GET UP neck pain trial).

Evidence supports exercise-based interventions for the management of neck pain, however there is little evidence of its superiority over usual physiotherapy. This study investigated the effectiveness of a group neck and upper limb exercise programme (GET) compared with usual physiotherapy (UP) for patients with non-specific neck pain. A total of 151 adult patients were randomised to either GET or UP. The primary measure was the Northwick Park Neck pain Questionnaire (NPQ) score at six weeks, six months and 12 months. Mixed modelling identified no difference in neck pain and function between patients receiving GET and those receiving UP at any follow-up time point. Both interventions resulted in modest significant and clinically important improvements on the NPQ score with a change score of around 9% between baseline and 12 months. Both GET and UP are appropriate clinical interventions for patients with non-specific neck pain, however preferences for treatment and targeted strategies to address barriers to adherence may need to be considered in order to maximise the effectiveness of these approaches

Response of the Antarctic Stratosphere to Warm Pool EI Nino Events in the GEOS CCM

A new type of EI Nino event has been identified in the last decade. During "warm pool" EI Nino (WPEN) events, sea surface temperatures (SSTs) in the central equatorial Pacific are warmer than average. The EI Nino signal propagates poleward and upward as large-scale atmospheric waves, causing unusual weather patterns and warming the polar stratosphere. In austral summer, observations show that the Antarctic lower stratosphere is several degrees (K) warmer during WPEN events than during the neutral phase of EI Nino/Southern Oscillation (ENSO). Furthermore, the stratospheric response to WPEN events depends of the direction of tropical stratospheric winds: the Antarctic warming is largest when WPEN events are coincident with westward winds in the tropical lower and middle stratosphere i.e., the westward phase of the quasi-biennial oscillation (QBO). Westward winds are associated with enhanced convection in the subtropics, and with increased poleward wave activity. In this paper, a new formulation of the Goddard Earth Observing System Chemistry-Climate Model, Version 2 (GEOS V2 CCM) is used to substantiate the observed stratospheric response to WPEN events. One simulation is driven by SSTs typical of a WPEN event, while another simulation is driven by ENSO neutral SSTs; both represent a present-day climate. Differences between the two simulations can be directly attributed to the anomalous WPEN SSTs. During WPEN events, relative to ENSO neutral, the model simulates the observed increase in poleward planetary wave activity in the South Pacific during austral spring, as well as the relative warming of the Antarctic lower stratosphere in austral summer. However, the modeled response to WPEN does not depend on the phase of the QBO. The modeled tropical wind oscillation does not extend far enough into the lower stratosphere and upper troposphere, likely explaining the model's insensitivity to the phase of the QBO during WPEN events

A scoping review of biopsychosocial risk factors and co-morbidities for common spinal disorders

OBJECTIVE: The purpose of this review was to identify risk factors, prognostic factors, and comorbidities associated with common spinal disorders. METHODS: A scoping review of the literature of common spinal disorders was performed through September 2016. To identify search terms, we developed 3 terminology groups for case definitions: 1) spinal pain of unknown origin, 2) spinal syndromes, and 3) spinal pathology. We used a comprehensive strategy to search PubMed for meta-analyses and systematic reviews of case-control studies, cohort studies, and randomized controlled trials for risk and prognostic factors and cross-sectional studies describing associations and comorbidities. RESULTS: Of 3,453 candidate papers, 145 met study criteria and were included in this review. Risk factors were reported for group 1: non-specific low back pain (smoking, overweight/obesity, negative recovery expectations), non-specific neck pain (high job demands, monotonous work); group 2: degenerative spinal disease (workers\u27 compensation claim, degenerative scoliosis), and group 3: spinal tuberculosis (age, imprisonment, previous history of tuberculosis), spinal cord injury (age, accidental injury), vertebral fracture from osteoporosis (type 1 diabetes, certain medications, smoking), and neural tube defects (folic acid deficit, anti-convulsant medications, chlorine, influenza, maternal obesity). A range of comorbidities was identified for spinal disorders. CONCLUSION: Many associated factors for common spinal disorders identified in this study are modifiable. The most common spinal disorders are co-morbid with general health conditions, but there is a lack of clarity in the literature differentiating which conditions are merely comorbid versus ones that are risk factors. Modifiable risk factors present opportunities for policy, research, and public health prevention efforts on both the individual patient and community levels. Further research into prevention interventions for spinal disorders is needed to address this gap in the literature