bluuebunny/crossref_metadata_2025_split huggingface dataset:
Harms and benefits of opioids for management of non-surgical acute and chronic low back pain: a systematic review
Authors: Tucker Hannah-Rose , Scaff Katie , McCloud Tess , Carlomagno Kimberly , Daly Kathleen , Garcia Alessandra , Cook Chad E 
Published: March 2019

Background
Consequences of prescription opioid use involve harms, addiction, tolerance and death. Despite routine prescription, opioids are not recommended for initial intervention by any major multidisciplinary low back pain (LBP) guideline.

Objective
Our primary purpose was to improve overall understanding of the harms and benefits associated with oral opioid interventions prescribed for treatment of acute or chronic back pain. Our second goal was to evaluate pain intensity and to compare and contrast these data with the harms. Our last objective was to evaluate conflicts of interest among the study authors and the findings.

Design/data/eligibility criteria
Studies incorporating oral prescription opioid management of non-surgical LBP were evaluated. After systematic assessment, no studies that met inclusion included participants with specifically acute LBP. Therefore, extracted data reflects only populations with subacute and chronic LBP. Data on reported harms, severe harms, pain outcomes and withdrawal rates were extracted and meta-analyses were completed for opioid versus placebo trials and opioids versus non-opioid trials.

Results
Fourteen studies met inclusion/exclusion requirements. All trials involved short-term management with limited follow-up. A high percentage of harms were identified across most studies. Opioids were not shown to be superior to other medications, and only showed superiority to placebo comparators (at cost of additional harms).

Conclusion
This review identified trends of higher harms rates and higher percentages of severe harms in opioid arms for the management of subacute and chronic LBP. The majority of trials that demonstrated benefits with opioids also had potential conflicts of interest. Lastly, non-opioid medications demonstrated statistically significant pain improvement compared with opioids. We feel that the results of the trial are supportive of current LBP guidelines and do not condone the initial use of opioids in management of subacute or chronic LBP.

Trial registration number
CRD42017070914
Ultrasound therapy reduces persistent post-thoracotomy tactile allodynia and spinal substance P expression in rats
Authors: Lin Heng-Teng , Chiu Chong-Chi , Liu Chen-Chih , Chen Yu-Wen , Wang Jhi-Joung , Hung Ching-Hsia 
Published: March 2019

Background
Therapeutic ultrasound (TU) alleviates nerve injury-associated pain, while the molecular mechanisms are less clear. This is an investigator-initiated experimental study to evaluate the mechanisms and effects of ultrasound on prolonged post-thoracotomy pain in a rodent model.

Methods
The rats were randomly separated into four groups (n=8 per group): sham-operation (sham; group 1), thoracotomy and rib retraction (TRR; group 2), and TRR procedure followed by TU (TRR+TU-3; group 3) or TU with the ultrasound power turned off (TRR+TU-0; group 4). TU was delivered daily, beginning on postoperative day 11 (POD 11) for the next 2 weeks. Mechanical sensitivity, subcutaneous tissue temperature, and spinal substance P and interleukin-1 beta (IL-1β) were evaluated on PODs 11 and 23.

Results

Group 3, which received ultrasound treatment (3 MHz; 1.0 W/cm
2
) for 5 min each day, demonstrated higher mechanical withdrawal thresholds when compared with the group without ultrasound intervention (group 2) or sham ultrasound (group 4). Ultrasound treatment also inhibited the upregulation of spinal substance P and IL-1β measured from spinal cord dorsal horns extract and increased subcutaneous temperature.

Conclusions
The results of this study suggest an increase in mechanical withdrawal thresholds and subcutaneous temperature, as well as a downregulation of spinal substance P and IL-1β, in the group which received ultrasound treatment. The regulation of spinal substance P and IL-1β may mediate potential effects of this non-invasive treatment.
A maternal high-fat, high-sucrose diet induces transgenerational cardiac mitochondrial dysfunction independently of maternal mitochondrial inheritance
Authors: Ferey Jeremie L. A. , Boudoures Anna L. , Reid Michaela , Drury Andrea , Scheaffer Suzanne , Modi Zeel , Kovacs Attila , Pietka Terri , DeBosch Brian J. , Thompson Michael D. , Diwan Abhinav , Moley Kelle H. 
Published: March 2019

Maternal obesity is correlated with cardiovascular disease in offspring, with a 1.3-fold increase in events observed in offspring of obese women. We have observed that obesity-exposed oocytes demonstrate impaired mitophagy and transmit damaged mitochondria to the offspring. Accordingly, we hypothesized that maternal obesity induces cardiac mitochondrial dysfunction in the offspring via transgenerational inheritance of abnormal oocyte mitochondria. We mated female mice fed a high-fat/high-sucrose (HFS) diet (or chow) with chow-fed males and assessed cardiac structure and function in their descendants that were chow fed in each generation. All F1 to F3 descendants bred via the female in each generation were nonobese and demonstrated cardiac mitochondrial abnormalities with crystal rarefaction and reduced oxygen consumption pointing to a transgenerational effect, while obese F0 dams’ hearts were unaffected. Furthermore, male offspring from F1 to F3 generations and female F1 and F2 offspring developed increased left ventricular (LV) mass (vs. chow-fed controls). Increased LV mass was also observed in offspring generated by in vitro fertilization of obesity-exposed oocytes and gestation in nonobese surrogates, ruling out a gestational environment effect. Contrary to our hypothesis, male F1 also transmitted these effects to their offspring, ruling out maternal mitochondria as the primary mode of transmission. We conclude that transmission of obesity-induced effects in the oocyte nucleus rather than abnormal mitochondria underlie transgenerational inheritance of cardiac mitochondrial defects in descendants of obese females. These findings will spur exploration of epigenetic alterations in the oocyte genome as potential mechanisms whereby a family history of maternal obesity predisposes to cardiovascular disease in humans. Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/maternal-obesity-induces-transgenerational-cardiac-mitochondrial-dysfunction/ .
Novel approach for quantification of endoplasmic reticulum Ca2+transport
Authors: Bovo Elisa , Nikolaienko Roman , Bhayani Siddharth , Kahn Daniel , Cao Quan , Martin Jody L. , Kuo Ivana Y. , Robia Seth L. , Zima Aleksey V. 
Published: March 2019

The type 2a sarco-/endoplasmic reticulum Ca2+-ATPase (SERCA2a) plays a key role in Ca2+regulation in the heart. However, available techniques to study SERCA function are either cell destructive or lack sensitivity. The goal of this study was to develop an approach to selectively measure SERCA2a function in the cellular environment. The genetically encoded Ca2+sensor R-CEPIA1er was used to measure the concentration of Ca2+in the lumen of the endoplasmic reticulum (ER) ([Ca2+]ER) in HEK293 cells expressing human SERCA2a. Coexpression of the ER Ca2+release channel ryanodine receptor (RyR2) created a Ca2+release/reuptake system that mimicked aspects of cardiac myocyte Ca2+handling. SERCA2a function was quantified from the rate of [Ca2+]ERrefilling after ER Ca2+depletion; then, ER Ca2+leak was measured after SERCA inhibition. ER Ca2+uptake and leak were analyzed as a function of [Ca2+]ERto determine maximum ER Ca2+uptake rate and maximum ER Ca2+load. The sensitivity of this assay was validated by analyzing effects of SERCA inhibitors, [ATP]/[ADP], oxidative stress, phospholamban, and a loss-of-function SERCA2a mutation. In addition, the feasibility of using R-CEPIA1er to study SERCA2a in a native system was evaluated by using in vivo gene delivery to express R-CEPIA1er in mouse hearts. After ventricular myocyte isolation, the same methodology used in HEK293 cells was applied to study endogenous SERCA2a. In conclusion, this new approach can be used as a sensitive screening tool to study the effect of different drugs, posttranslational modifications, and mutations on SERCA function.NEW & NOTEWORTHY The aim of this study was to develop a sensitive approach to selectively measure sarco-/endoplasmic reticulum Ca2+-ATPase (SERCA) function in the cellular environment. The newly developed Ca2+sensor R-CEPIA1er was used to successfully analyze Ca2+uptake mediated by recombinant and native cardiac SERCA. These results demonstrate that this new approach can be used as a powerful tool to study new mechanisms of Ca2+pump regulation.
Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model
Authors: Okawa Yoshifumi , Hoshino Atsushi , Ariyoshi Makoto , Kaimoto Satoshi , Tateishi Shuhei , Ono Kazunori , Uchihashi Motoki , Iwai-Kanai Eri , Matoba Satoaki 
Published: March 2019

Despite the advances in medical therapy, the morbidity and mortality of heart failure (HF) remain unacceptably high. HF results from reduced metabolism–contraction coupling efficiency, so the modulation of cardiac metabolism may be an effective strategy for therapeutic interventions. Tumor suppressor p53 (TP53) and its downstream target TP53-induced glycolysis and apoptosis regulator (TIGAR) are known to modulate cardiac metabolism and cell fate. To investigate TIGAR’s function in HF, we compared myocardial, metabolic, and functional outcomes between TIGAR knockout (TIGAR−/−) mice and wild-type (TIGAR+/+) mice subjected to chronic thoracic transverse aortic constriction (TAC), a pressure-overload HF model. In wild-type mice hearts, p53 and TIGAR increased markedly during HF development. Eight weeks after TAC surgery, the left ventricular (LV) dysfunction, fibrosis, oxidative damage, and myocyte apoptosis were significantly advanced in wild-type than in TIGAR−/−mouse heart. Further, myocardial high-energy phosphates in wild-type hearts were significantly decreased compared with those of TIGAR−/−mouse heart. Glucose oxidation and glycolysis rates were also reduced in isolated perfused wild-type hearts following TAC than those in TIGAR−/−hearts, which suggest that the upregulation of TIGAR in HF causes impaired myocardial energetics and function. The effects of TIGAR knockout on LV function were also replicated in tamoxifen (TAM)-inducible cardiac-specific TIGAR knockout mice ( TIGARflox/flox/Tg(Myh6-cre/Esr1) mice). The ablation of TIGAR during pressure-overload HF preserves myocardial function and energetics. Thus, cardiac TIGAR-targeted therapy to increase glucose metabolism will be a novel strategy for HF.NEW & NOTEWORTHY The present study is the first to demonstrate that TP53-induced glycolysis and apoptosis regulator (TIGAR) is upregulated in the myocardium during experimental heart failure (HF) in mice and that TIGAR knockout can preserve the heart function and myocardial energetics during HF. Reducing TIGAR to enhance myocardial glycolytic energy production is a promising therapeutic strategy for HF.
The PKR-Like Endoplasmic Reticulum Kinase Promotes the Dissemination of Myc-Induced Leukemic Cells
Authors: Gui Jun , Katlinski Kanstantsin V. , Koumenis Constantinos , Diehl J. Alan , Fuchs Serge Y. 
Published: March 2019

Abstract

Hyperactive oncogenic Myc stimulates protein synthesis that induces the unfolded protein response, which requires the function of the eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Activated PERK acts to limit mRNA translation, enable proper protein folding, and restore the homeostasis in the endoplasmic reticulum. Given that Myc activation contributes to many types of lymphoid and myeloid human leukemias, we used a mouse model to examine the importance of PERK in development and progression of Myc-induced leukemias. We found that genetic ablation of Perk does not suppress the generation of the leukemic cells in the bone marrow. However, the cell-autonomous Perk deficiency restricts the dissemination of leukemic cells into peripheral blood, lymph nodes, and vital peripheral organs. Whereas the loss of the IFNAR1 chain of type I IFN receptor stimulated leukemia, Perk ablation did not stabilize IFNAR1, suggesting that PERK stimulates the leukemic cells' dissemination in an IFNAR1-independent manner. We discuss the rationale for using PERK inhibitors against Myc-driven leukemias.

Implications:
The role of PERK in dissemination of Myc-induced leukemic cells demonstrated in this study argues for the use of PERK inhibitors against leukemia progression.
Performance Evaluation of MHC Class-I Binding Prediction Tools Based on an Experimentally Validated MHC–Peptide Binding Data Set
Authors: Bonsack Maria , Hoppe Stephanie , Winter Jan , Tichy Diana , Zeller Christine , Küpper Marius D. , Schitter Eva C. , Blatnik Renata , Riemer Angelika B. 
Published: March 2019

AbstractKnowing whether a protein can be processed and the resulting peptides presented by major histocompatibility complex (MHC) is highly important for immunotherapy design. MHC ligands can be predicted by in silico peptide–MHC class-I binding prediction algorithms. However, prediction performance differs considerably, depending on the selected algorithm, MHC class-I type, and peptide length. We evaluated the prediction performance of 13 algorithms based on binding affinity data of 8- to 11-mer peptides derived from the HPV16 E6 and E7 proteins to the most prevalent human leukocyte antigen (HLA) types. Peptides from high to low predicted binding likelihood were synthesized, and their HLA binding was experimentally verified by in vitro competitive binding assays. Based on the actual binding capacity of the peptides, the performance of prediction algorithms was analyzed by calculating receiver operating characteristics (ROC) and the area under the curve (AROC). No algorithm outperformed others, but different algorithms predicted best for particular HLA types and peptide lengths. The sensitivity, specificity, and accuracy of decision thresholds were calculated. Commonly used decision thresholds yielded only 40% sensitivity. To increase sensitivity, optimal thresholds were calculated, validated, and compared. In order to make maximal use of prediction algorithms available online, we developed MHCcombine, a web application that allows simultaneous querying and output combination of up to 13 prediction algorithms. Taken together, we provide here an evaluation of peptide–MHC class-I binding prediction tools and recommendations to increase prediction sensitivity to extend the number of potential epitopes applicable as targets for immunotherapy.
Revised Reference Values for the Intake of Protein
Authors: Richter Margrit , Baerlocher Kurt , Bauer Jürgen M. , Elmadfa Ibrahim , Heseker Helmut , Leschik-Bonnet Eva , Stangl Gabriele , Volkert Dorothee , Stehle Peter ,   on behalf of the German Nutrition Society (DGE)
Published: March 2019

<b><i>Background:</i></b> Following a timely update process, the nutrition societies of Germany, Austria, and Switzerland (D-A-CH) revised the reference values for the intake of protein in 2017. The Working Group conducted a structured literature search in PubMed considering newly published papers (2000– 2017). <b><i>Summary:</i></b> For infants &#x3c; 4 months, the estimated values were set based on the protein intake via breast milk. Reference values for infants &#x3e; 4 months, children, adolescents, pregnant, and lactating women were calculated using the factorial method considering both requirement for growth and maintenance. For adults, reference values were derived from nitrogen balance studies; for seniors (&#x3e; 65 years), reports on metabolic and functional parameters under various protein intakes were additionally considered. Reference ­values (g protein/kg body weight per day) were set as follows: infants &#x3c; 4 months: 2.5–1.4, children: 1.3–0.8, adults &#x3c; 65 years: 0.8, adults &#x3e; 65 years: 1.0. <b><i>Key Messages:</i></b> The reference values for infants, children, adolescents, and adults &#x3c; 65 years are essentially unchanged compared to recently published values. Scientifically reliable data published between 2000 and 2017 guided the D-A-CH Working Group to set a higher estimated value for adults &#x3e; 65 years. Since the energy consumption continuously decreases with age, this new estimated protein intake value might be a challenge for the introduction of food-based nutrition concepts for older people.
Association of Variability in Body Mass Index and Metabolic Health With Cardiometabolic Disease Risk
Authors: Sponholtz Todd R. , van den Heuvel Edwin R. , Xanthakis Vanessa , Vasan Ramachandran S. 
Published: March 2019

Background
Metabolic syndrome is associated with high risk of cardiovascular disease, although risk may differ according to the specific conditions present and variability in those conditions.

Methods and Results

We defined obesity (body mass index [BMI] ≥30 kg/m
2
) and metabolic health (<2 nonobesity National Cholesterol Education Program Adult Treatment Panel III conditions) among 3632 Framingham Heart Study offspring cohort participants (mean age, 50.8 years; 53.8% women) who were followed up from 1987 to 2014. We defined participants whose variance independent of the mean for a metabolic syndrome–associated measure was in the top quintile as being “variable” for that measure. Variable metabolic health was defined as ≥2 variable nonobesity metabolic syndrome components. We investigated the interaction between obesity and metabolic health in their associations with cardiometabolic disease and cardiovascular disease using Cox proportional hazards regression. In addition, we estimated the associations of BMI variability and variable metabolic health with study outcomes within categories of obesity and metabolic health status, respectively. We observed 567 incident obesity (41 439 person‐years), 771 incident metabolically unhealthy state (25 765 person‐years), 272 incident diabetes mellitus (56 233 person‐years), 503 incident hypertension (12 957 person‐years), 589 cardiovascular disease (60 300 person‐years), and 195 chronic kidney disease (47 370 person‐years) events on follow‐up. Obesity and being metabolically unhealthy were independently and positively associated with all outcomes. BMI variability, compared with stable BMI, was associated with 163%, 67%, 58%, and 74% higher risks of having obesity, becoming metabolically unhealthy, having diabetes mellitus, and having hypertension, respectively, among nonobese participants. Variable metabolic health, compared with stable metabolic health, was associated with a 28% higher risk of cardiovascular disease, among metabolically healthy participants.

Conclusions
We did not observe evidence for a positive interaction between obesity and metabolic health status with regard to study outcomes. BMI and metabolic health variability are associated with adverse health outcomes.
Effectiveness and Safety of Platelet ADP–P2Y12 Receptor Inhibitors Influenced by Smoking Status: A Systematic Review and Meta‐Analysis
Authors: Liu Zhiyan , Xiang Qian , Mu Guangyan , Xie Qiufen , Zhou Shuang , Wang Zining , Chen Shuqing , Hu Kun , Gong Yanjun , Jiang Jie , Cui Yimin 
Published: March 2019

Background

As reports on the influence of cigarette smoking, an important cardiovascular risk factor, on platelet
ADP
–P2Y12 receptor inhibitors lack consistency, we aimed to assess the effectiveness and safety of platelet
ADP
–P2Y12 receptor inhibitors influenced by smoking status.

Methods and Results

PubMed, Web of Science,
EMBASE
, Clinical Trials, and the Cochrane Library were searched from inception until June 2018. Among the 5076 citations retrieved, 22 studies, including 163 011 patients with or without percutaneous coronary intervention, were included for meta‐analysis. Compared with nonsmokers within the first year of follow‐up, the reductions of stroke and major adverse cardiovascular event rate were 18% (
P
=0.008) and 26% (
P
=0.02), respectively. A 20% reduction in stroke (
P
=0.02) and a 34% reduction in major adverse cardiovascular event (
P
=0.0001) rates were observed in smoking patients without percutaneous coronary intervention. No significant difference was observed in clinical outcome rates among prasugrel, ticagrelor, and clopidogrel in different smoking status. No significant difference was found in myocardial infarction and bleeding event incidence between current smokers and nonsmokers.

Conclusions
We concluded that current smokers had a lower incidence of major adverse cardiovascular events and stroke events than did nonsmokers, particularly in the early period (1 year) and among patients without percutaneous coronary intervention. However, because of the lack of original adjusted data, smoker's paradox still needs to consider the impact of age and other covariates. Thus, a differential risk‐benefit evaluation should be considered, according to different smoking status, patient conditions, and therapy time points.
Risk‐Adjusted Comparison of In‐Hospital Outcomes of Transcatheter and Surgical Aortic Valve Replacement
Authors: Stachon Peter , Kaier Klaus , Zirlik Andreas , Bothe Wolfgang , Heidt Timo , Zehender Manfred , Bode Christoph , von zur Mühlen Constantin 
Published: March 2019

Background
Transfemoral transcatheter aortic valve replacement (TF‐TAVR) is recommended for patients suffering from aortic valve stenosis at increased operative risk. Beyond that, patients with different comorbidities could benefit from TF‐TAVR. The present study compares real‐world in‐hospital outcomes of surgical aortic valve replacement and TF‐TAVR.

Methods and Results

For all 33 789 isolated TF‐TAVR and surgical aortic valve replacement procedures performed in Germany in 2014 and 2015, comorbidities and in‐hospital outcomes were identified by
International Classification of Diseases (ICD)
‐ and OPS (Operation and procedure key)‐codes. Patients undergoing TF‐TAVR were older and at increased estimated risk. Outcomes were risk‐adjusted to allow comparison. TF‐TAVR was associated with a lower risk for acute kidney injuries (odds ratio [OR] 0.62,
P
<0.001), for bleeding (OR 0.17,
P
<0.001), and for prolonged mechanical ventilation (>48 hours, OR 0.21,
P
<0.001). Risk for stroke was similar (OR 1.07,
P
=0.558). As expected, the risk for pacemaker implantations was higher after TF‐TAVR (OR 4.61,
P
<0.001). In all patients, none of the treatment strategies had a clear advantage on the risk for in‐hospital mortality (OR 0.83,
P
=0.068). However, in patients aged >80 years and at high operative risk undergoing TF‐TAVR in‐hospital mortality was lower (TF‐TAVR versus surgical aortic valve replacement 80–84, OR 0.55;
P
=0.002; ≥85 years, OR 0.42,
P
=0.006; EuroSCORE (European System for Cardiac Operative Risk Evaluation) >9: OR 0.62,
P
=0.001). TF‐TAVR was superior in patients with renal failure and in NYHA (New York Heart Association)‐Class III/IV. Other risk groups were not found to be factors favoring a treatment strategy.

Conclusions
The present study indicates a superiority of TF‐TAVR in clinical practice for patients at increased operative risk, aged >80 years, in NYHA‐Class III/IV, and with renal failure.