Association of tooth loss and gallstones: National Health and Nutrition Examination Survey 2017-2018.

Introduction: Gallstones are one of the most common digestive diseases globally, with an estimated affected population of 15% in the United States. Our aim is to assess the current association between oral health and gallstones, exploring potential mediation factors. Methods: Self-reported gallstones were determined based on medical condition questionnaires. Dental status was assessed by dental professionals and oral health questionnaire. Mediation analysis was conducted for body mass index, blood glucose, triglycerides, and cholesterol, and the percentage of mediation effects was calculated. Results: We included 444 patients with gallstones and 3565 non-gallstone participants from National Health and Nutrition Examination Survey. After fully adjusting for all covariates, the prevalence of gallstones is higher when the number of missing teeth is at T3 compared to T1 (odds ratio [OR]: 1.93, confidence interval [CI]: 1.14 - 3.26, p = 0.02, p-trend = 0.01), and there was an inverted L-shaped association between missing teeth and gallstones, with an inflection point of 17. Bone loss around mouth was also associated with gallstones (OR: 1.78, 95% CI: 1.27 - 2.48, p = 0.002), but not root caries and gum disease. Mediation analysis identified blood glucose as a crucial mediator, with a mediation effect ratio of 4.91%. Conclusions: Appropriate lifestyle interventions for patients with missing teeth may help delay the onset of gallstones, such as healthy dietary habits, trace elements supplementing, and managing weight and blood sugar levels. Further exploration of the relationship between oral health and overall health contributes to disease prevention and comprehensive medical management.

Rapid and Amplification-free Nucleic Acid Detection with DNA Substrate-Mediated Autocatalysis of CRISPR/Cas12a.

To enable rapid and accurate point-of-care DNA detection, we have developed a single-step, amplification-free nucleic acid detection platform, a DNA substrate-mediated autocatalysis of CRISPR/Cas12a (DSAC). DSAC makes use of the trans-cleavage activity of Cas12a and target template-activated DNA substrate for dual signal amplifications. DSAC employs two distinct DNA substrate types: one that enhances signal amplification and the other that negatively modulates fluorescent signals. The positive inducer utilizes nicked- or loop-based DNA substrates to activate CRISPR/Cas12a, initiating trans-cleavage activity in a positive feedback loop, ultimately amplifying the fluorescent signals. The negative modulator, which involves competitor-based DNA substrates, competes with the probes for trans-cleaving, resulting in a signal decline in the presence of target DNA. These DNA substrate-based DSAC systems were adapted to fluorescence-based and paper-based lateral flow strip detection platforms. Our DSAC system accurately detected African swine fever virus (ASFV) in swine's blood samples at femtomolar sensitivity within 20 min. In contrast to the existing amplification-free CRISPR/Dx platforms, DSAC offers a cost-effective and straightforward detection method, requiring only the addition of a rationally designed DNA oligonucleotide. Notably, a common ASFV sequence-encoded DNA substrate can be directly applied to detect human nucleic acids through a dual crRNA targeting system. Consequently, our single-step DSAC system presents an alternative point-of-care diagnostic tool for the sensitive, accurate, and timely diagnosis of viral infections with potential applicability to human disease detection.

3D-printed Mg-incorporated PCL-based scaffolds improves rotator cuff tendon-bone healing through regulating macrophage polarization.

Introduction: Rotator cuff tear (RCT) is a common shoulder injury impacting mobility and quality of life, while traditional surgeries often result in poor healing. Tissue engineering offers a promising solution, with poly (ε-caprolactone) (PCL) being favored due to its slow degradation, biocompatibility, and non-toxicity. However, PCL lacks sufficient compression resistance. Incorporating Mg, which promotes bone growth and has antibacterial effects, could enhance RCT repair. Methods: The Mg-incorporated PCL-based scaffolds were fabricated using a 3D printing technique. The scaffolds were incorporated with different percentages of Mg (0%, 5%, 10%, 15%, and 20%). The osteogenic activities and anti-inflammatory properties of the scaffolds were evaluated in vitro using human osteoblasts and macrophages. The tissue ingrowth and biocompatibility of the scaffolds were assessed in vivo using a rat model of RCT repair. The ability of the scaffolds to enhance macrophage polarization towards the M2 subtype and inhibit inflammation signaling activation was also investigated. Results: It was found that when incorporated with 10% Mg, PCL-based scaffolds exhibited the optimal bone repairing ability in vitro and in vivo. The in vitro experiments indicated that the successfully constructed 10 Mg/PCL scaffolds enhance osteogenic activities and anti-inflammatory properties. Besides, the in vivo studies demonstrated that 10 Mg/PCL scaffolds promoted tissue ingrowth and enhanced biocompatibility compared to the control PCL scaffolds. Furthermore, the 10 Mg/PCL scaffolds enhanced the macrophages' ability to polarize towards the M2 subtype and inhibited inflammation signaling activation. Discussion: These findings suggest that 3D-printed Mg-incorporated PCL scaffolds have the potential to improve RCT by enhancing osteogenesis, reducing inflammation, and promoting macrophage polarization. The incorporation of 10% Mg into PCL-based scaffolds provided the optimal combination of properties for RCT repair augmentation. This study highlights the potential of tissue engineering approaches in improving the outcomes of RCT repair and provides a foundation for future clinical applications.

Association Between Cardiovascular Health and Cirrhosis and Mortality: Insights From a Comprehensive Cross-sectional Study.

GOAL: We aim to explore the relationship between the newly introduced CVH indicator "Life's Essential 8 (LE8)" and cirrhosis. BACKGROUND: The global burden of cirrhosis is increasing, with a rising number of deaths, leading to significant societal and economic challenges. Cardiovascular health (CVH) has been found to have potential associations with liver diseases. MATERIALS AND METHODS: All participants aged 20 and older from National Health and Nutrition Examination Survey 2005 to 2018 were included. CVH was accessed by LE8, consisting of 4 health behaviors (diet, physical activity, nicotine exposure, and sleep health) and 4 health factors (body mass index, lipid levels, blood sugar, and blood pressure). Cirrhosis was determined based on abnormal liver function test results, with an aspartate aminotransferase to platelet ratio index >2. Participants' mortality status was obtained by matching with the National Death Index and all-cause mortality served as the follow-up endpoint. RESULTS: This extensive cross-sectional study reveals that LE8 was not associated with cirrhosis. A higher health behaviors score was associated with lower cirrhosis. Moreover, there is an inverse U-shaped relationship between the LE8 score and all-cause mortality in participants with cirrhosis, signifying a decrease in all-cause mortality when LE8 surpasses 60. A greater health behaviors score is linked to a decreased proportion of all-cause mortality in cirrhosis patients. CONCLUSION: Maintaining better health behaviors may be beneficial for cirrhosis, especially through a balanced diet, regular exercise, smoking cessation, and quality sleep.

Exploring the association between cardiovascular health and bowel health.

Chronic constipation, diarrhea, and fecal incontinence have high incidence, potential disability, and socioeconomic impact, imposing a heavy burden on the quality of life. We aim to explore the association between cardiovascular health (CVH) and bowel health from National Health and Nutrition Survey 2005-2010. CVH is assessed using Life's Essential 8 (LE8). Chronic constipation, chronic diarrhea, and fecal incontinence are assessed based on Bristol Stool Form Scale classification, bowel movements, and bowel leakage. Better health behaviors (odds ratio [OR]: 0.71, 95% confidence interval [CI] 0.53-0.94, p = 0.02) and worse health factors (OR: 1.45, CI 1.03-2.04, p = 0.04) were associated with less chronic constipation. Less chronic diarrhea is correlated with better CVH (OR: 0.53, 95% CI 0.35-0.79, p = 0.003) and health factors (OR: 0.61, CI 0.46-0.81, p = 0.001). Meanwhile, the proportion of chronic diarrhea significantly decreases when the health behaviors score exceeds 59.42. Lower fecal incontinence was associated with better health behaviors (OR: 0.63, CI 0.44-0.90, p = 0.01) CVH. Better CVH and health behaviors are both linked to lower all-cause mortality in participants with chronic constipation and chronic diarrhea. A higher health behaviors score is also associated with less all-cause mortality in patients with fecal incontinence. Maintaining CVH at the population level contributes to intestinal health, achieving the dual management of both while saving on healthcare costs. However, further prospective research is needed to confirm these associations.

Opioid Prescribing Rate for Nonoperative Distal Radius Fractures and Clinician Response to a Clinical Decision Support Alert.

BACKGROUND: Opioids are commonly prescribed for the management of acute orthopedic trauma pain, including nonoperative distal radius fractures. OBJECTIVES: This prospective study aimed to determine if a clinical decision support intervention influenced prescribing decisions for patients with known risk factors. We sought to quantify frequency of opioid prescriptions for acute nonoperative distal radius fractures treated. METHODS: We performed a prospective study at one large health care system. Utilizing umbrella code S52.5, we identified all distal radius fractures treated nonoperatively, and the encounters were merged with the Prescription Reporting with Immediate Medication Mapping (PRIMUM) database to identify encounters with opioid prescriptions and patients with risk factors for opioid use disorder. We used multivariable logistic regression to determine patient characteristics associated with the prescription of an opioid. Among encounters that triggered the PRIMUM alert, we calculated the percentage of encounters where the PRIMUM alert influenced the prescribing decision. RESULTS: Of 2984 encounters, 1244 (41.7%) included an opioid prescription. Age increment is a significant factor to more likely receive opioid prescriptions (p < 0.0001) after adjusting for other factors. Among encounters where the physician received an alert, those that triggered the alert for early refill were more likely to influence physicians' opioid prescribing when compared with other risk factors (p = 0.0088). CONCLUSION: Over 90% of patients (106/118) continued to receive an opioid medication despite having a known risk factor for abuse. Additionally, we found older patients were more likely to be prescribed opioids for nonoperatively managed distal radius fractures.

Radiographic Cone Zone Classification of Metaphyseal Cone Fixation in Revision Total Knee Arthroplasty.

Background: No objective radiographic scoring system exists to classify metaphyseal cone stability. Our purpose was to create a novel, systematic method to radiographically evaluate metaphyseal cone fixation based on radiographic findings suggestive of cone stability. Methods: A retrospective analysis was conducted of revision total knee arthroplasty patients (6/2015-12/2017) using porous titanium femoral or tibial metaphyseal cones in conjunction with short cemented stems (50 mm-75 mm). Minimum follow-up was 2 years. Survivorship free of aseptic loosening and reoperation, as well as radiographic evaluation using a novel cone zone scoring system were analyzed. Results: Forty-nine revision total knee arthroplasties were included in the study (12 femoral, 48 tibial cones), the majority, performed for aseptic loosening (25/49, 51%). Median follow-up was 39 months (range 25-58). Using the radiographic cone zone scoring method, >90% of all femoral cones were classified as likely stable or stable with strong, statistically significant intraclass correlations between all 3 reviewers. Similarly, >97% of all tibial cones were classified as likely stable or stable, with moderate, statistically significant intraclass correlations between all 3 reviewers. Only 1 femoral and 1 tibial cone were considered at risk of loosening. The study sample demonstrated 100% survivorship free of revision for aseptic loosening without evidence of radiographic loosening in any case. Conclusions: Using a novel systematic cone zone scoring and classification method, the overwhelming majority of femoral and tibial cones were classified as likely stable or stable, with no identified cases of aseptic loosening or related revision. Further studies are needed to validate this objective classification method.

Differences in the incidence and mortality of digestive cancer between Global Cancer Observatory 2020 and Global Burden of Disease 2019.

The burden of digestive cancers is increasing worldwide. The Global Cancer Observatory (GLOBOCAN) 2020 and the Global Burden of Disease (GBD) 2019 are two primary cancer databases, which have a significant impact on policy formulation and resource allocation. We aim to compare the incidence and mortality of digestive cancers between them. Digestive cancer (esophageal, stomach, colorectal, liver, gallbladder and pancreatic cancer) incidence was obtained from the Cancer Today and GBD 2019 result tool. The top five countries with the most or minor difference between GLOBOCAN 2020 and GBD 2019 in age-standardized incidence rates (ASIRs) of digestive cancers were identified. A systematic search on the incidence of specific digestive cancer in selected countries from PubMed and Embase was conducted, and 20 of 281 publications were included. The most significant differences in digestive cancers incidence were commonly found in Asian countries (70%), particularly Indonesia, Vietnam and Myanmar, located in Southeast Asia. The ASIRs for most digestive cancers, except liver cancer, in GLOBOCAN 2020 were higher than those in GBD 2019. Gallbladder cancer had the highest average ratio, followed by liver cancer. The most commonly used standard population was Segi's standard population, followed by the World Health Organization standard population. The data sources nor the processing methods of GLOBOCAN 2020 and GBD 2019 were not similar. Low- and middle-income countries without population-based cancer registries were more likely to have selection bias in data collection and amplify regional variations of etiological factors. Better judgments on the quality of cancer data can be made.

Outcomes of Humerus Nonunion Surgery in Patients With Initial Operative Fracture Fixation.

OBJECTIVES: To describe outcomes following humerus aseptic nonunion surgery in patients whose initial fracture was treated operatively and to identify risk factors for nonunion surgery failure in the same population. DESIGN: Retrospective case series. SETTING: Eight, academic, level 1 trauma centers. PATIENTS SELECTION CRITERIA: Patients with aseptic humerus nonunion (OTA/AO 11 and 12) after the initial operative management between 1998 and 2019. OUTCOME MEASURES AND COMPARISONS: Success rate of nonunion surgery. RESULTS: Ninety patients were included (56% female; median age 50 years; mean follow-up 21.2 months). Of 90 aseptic humerus nonunions, 71 (78.9%) united following nonunion surgery. Thirty patients (33.3%) experienced 1 or more postoperative complications, including infection, failure of fixation, and readmission. Multivariate analysis found that not performing revision internal fixation during nonunion surgery (n = 8; P = 0.002) and postoperative de novo infection (n = 9; P = 0.005) were associated with an increased risk of recalcitrant nonunion. Patient smoking status and the use of bone graft were not associated with differences in the nonunion repair success rate. CONCLUSIONS: This series of previously operated aseptic humerus nonunions found that more than 1 in 5 patients failed nonunion repair. De novo postoperative infection and failure to perform revision internal fixation during nonunion surgery were associated with recalcitrant nonunion. Smoking and use of bone graft did not influence the success rate of nonunion surgery. These findings can be used to give patients a realistic expectation of results and complications following humerus nonunion surgery. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Does Anterior Plating of Pelvic Ring Fractures Increase Infection Risk in Patients With Bladder or Urethral Injuries?

OBJECTIVES: Evaluate the effect of anterior fixation on infection in patients with operative pelvic fractures and bladder or urethral injuries. DESIGN: Retrospective. SETTING: Eight centers. PATIENT SELECTION CRITERIA: Adult patients with closed pelvic fractures with associated bladder or urethral injuries treated with anterior plating (AP), intramedullary screw (IS), or no anterior internal fixation (NAIF, including external fixation or no fixation). OUTCOME MEASURES AND COMPARISONS: Deep infection. RESULTS: There were 81 extraperitoneal injuries and 57 urethral injuries. There was no difference in infection between fixation groups across all urologic injuries (AP: 10.8%, IS: 0%, NAIF: 4.9%, P = 0.41). There was a higher rate of infection in the urethral injury group compared with extraperitoneal injuries (14.0% vs. 2.5%, P = 0.016). Among extraperitoneal injuries, specifically, there was no difference in deep infection related to fixation (AP: 2.6%, IS 0%, NAIF: 2.9%, P = 0.99). Among urethral injuries, there was no statistical difference in deep infection related to fixation (AP: 23.1%, IS: 0%, NAIF: 7.4%, P = 0.21). There was a higher rate of suprapubic catheter (SPC) use in urethral injuries compared with extraperitoneal injuries (57.9% vs. 4.9%, P < 0.0001). In the urethral injury group, SPC use did not have a statistically significant difference in infection rate (SPC: 18.2% vs. No SPC: 8.3%, P = 0.45). Early removal of the SPC before or during the definitive orthopaedic intervention did not significantly affect infection rate (early: 0% vs. delayed: 25.0%, P = 0.16). CONCLUSIONS: Surgeons should approach operative pelvic fractures with associated urologic injuries with caution given the high risk of infection. Further work must be done to elucidate the effect of anterior implants and SPC use and duration. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Size and morphology of the coracoid and glenoid in pediatric and adolescent patients: implications for Latarjet procedure.

Background: Glenohumeral instability is a challenging problem in children and adolescents. For patients with anterior glenoid bone loss, the Latarjet procedure is an effective treatment option. However, concerns about coracoid size and morphology may limit its utilization within this patient population. The purpose of this study was to establish normative data on coracoid and glenoid size and morphology among a large cohort of adolescent patients and describe the anatomic relationships with demographic factors. Methods: This is a retrospective cross-sectional study of a consecutive series of 584 patients aged 12-21 years after a chest computed tomography scan for non-shoulder related trauma at a single level I trauma center. Demographic characteristics were collected from the electronic medical record, and the following coracoid anatomic measurements were obtained from computed tomography scans: coracoid length, coracoid thickness, coracoid width, glenoid height, and glenoid width. The ratio of coracoid thickness to glenoid width was calculated to estimate the percent bone loss that could be addressed with a traditional Latarjet coracoid transfer. To ensure reliability among 3 reviewers, all measured the same 25 scans and inter-rater reliability was excellent with all Kappa coefficients >0.81. The remaining scans were divided equally and assessed separately by these reviewers. Correlation coefficients were used to quantify the relationships between all anatomic measures and the age, weight, and height of individuals. Growth curves for each measurement were modeled using quantile regression with height and height∗height as predictors. Additionally, we stratified the growth curves by sex, when significant. Of the 584 subjects, 55% were male, and average age was 19 years (range 12, 21). Results: All growth curves illustrated increase anatomic size across the height range of 145-190 cm. The growth curve including all patients (Fig. 1) illustrated that the 50% percentile of median coracoid length increased from approximately 28 to 32 mm. In addition to height, sex was a significant predictor for coracoid width and glenoid width. The median coracoid width increased from approximately 9.5 to 10.2 mm for females compared to an increased width from approximately 10 to 11 mm for males. The median glenoid width for females increased from approximately 21 to 25 mm and for males the median glenoid width increased from just under 22 to 25.5 mm. Conclusions: Among children and adolescents, coracoid and glenoid size are correlated with patient height. These data can help guide patient selection for the Latarjet procedure.

Adherence to legislation limiting opioid prescription duration following musculoskeletal injury.

OBJECTIVES: North Carolina had implemented legislation (Strengthen Opioid Misuse Prevention (STOP) Act) limiting opioid prescriptions to 5 days for acute pain and 7 days for post-operative pain. This study aimed to identify patient, prescriber, and facility characteristics associated with STOP Act adherence for patients with acute or post-surgical musculoskeletal (MSK) conditions. DESIGN: A three-level hierarchical logistic regression model was used to predict odds of adherence with STOP Act duration limits, accounting for fixed and random effects at the patient, prescriber, and facility levels. SETTING: A large healthcare system in North Carolina. PATIENTS AND PARTICIPANTS: Patients (N = 6,849) presenting from 2018 to 2020 with a diagnosis of an acute MSK injury. INTERVENTIONS: The STOP Act limited the duration of opioid prescriptions in North Carolina. MAIN OUTCOME MEASURE: Prescriptions adhering to the STOP Act duration limits of 5 days (nonoperative) or 7 days (operative) were the primary outcome. RESULTS: Opioids were compliant with STOP Act duration limits in 69.3 percent of encounters, with 33 percent of variation accounted for by clinician and 29 percent by facility. Patients prescribed >1 opioid (odds ratio (OR) 0.46, 95 percent confidence interval (CI): 0.36, 0.58) had reduced odds of a compliant prescription; surgical patients had increased odds of a compliant prescription (outpatient surgery: OR 5.89, 95 percent CI: 2.43-14.29; inpatient surgery: OR 7.71, 95 percent CI: 3.04-19.56). Primary care sports medicine clinicians adhered to legislation less frequently than orthopedic surgeons (OR 0.38, 95 percent CI: 0.15, 0.97). CONCLUSIONS: Most prescriptions adhered to STOP Act legislation. Tailored interventions to improve adherence among targeted groups of prescribers, eg, those treating nonoperative injuries and sport medicine clinicians, could be useful.

Disrupted circadian rhythms in the plateau pika.

The plateau pika (Ochotona curzoniae) is the most populous mammal on the 'third pole', the Qinghai-Tibet Plateau, and is presumed to have inhabited the region before the plateau rose up from sea level. Herein we discuss the disrupted circadian rhythm in the plateau pika and the gene polymorphism behind this phenotype, placing these findings in the broader context of circadian rhythms under extreme conditions.

Myeloid-specific deletion of Capns1 attenuates myocardial infarction injury via restoring mitochondrial function and inhibiting inflammasome activation.

BACKGROUND: Mitochondrial dysfunction of macrophage-mediated inflammatory response plays a key pathophysiological process in myocardial infarction (MI). Calpains are a well-known family of calcium-dependent cysteine proteases that regulate a variety of processes, including cell adhesion, proliferation, and migration, as well as mitochondrial function and inflammation. CAPNS1, the common regulatory subunit of calpain-1 and 2, is essential for the stabilization and activity of the catalytic subunit. Emerging studies suggest that calpains may serve as key mediators in mitochondria and NLRP3 inflammasome. This study investigated the role of myeloid cell calpains in MI. METHODS: MI models were constructed using myeloid-specific Capns1 knockout mice. Cardiac function, cardiac fibrosis, and inflammatory infiltration were investigated. In vitro, bone marrow-derived macrophages (BMDMs) were isolated from mice. Mitochondrial function and NLRP3 activation were assessed in BMDMs under LPS stimulation. ATP5A1 knockdown and Capns1 knock-out mice were subjected to MI to investigate their roles in MI injury. RESULTS: Ablation of calpain activities by Capns1 deletion improved the cardiac function, reduced infarct size, and alleviated cardiac fibrosis in mice subjected to MI. Mechanistically, Capns1 knockout reduced the cleavage of ATP5A1 and restored the mitochondria function thus inhibiting the inflammasome activation. ATP5A1 knockdown antagonized the protective effect of Capns1 mKO and aggravated MI injury. CONCLUSION: This study demonstrated that Capns1 depletion in macrophages mitigates MI injury via maintaining mitochondrial homeostasis and inactivating the NLRP3 inflammasome signaling pathway. This study may offer novel insights into MI injury treatment.

METTL14-Mediated m6A Modification of TNFAIP3 Involved in Inflammation in Patients With Active Rheumatoid Arthritis.

OBJECTIVE: The aim of the study was to investigate the role of N6 -methyladenosine (m6A) modification in the progression of rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMCs) from patients with RA and healthy controls were collected. The expression of m6A modification-related proteins and m6A levels were detected using polymerase chain reaction (PCR), western blot, and m6A enzyme-linked immunosorbent assay (ELISA). The roles of methyltransferase-like 14 (METTL14) in the regulation of inflammation in RA was explored using methylated RNA immunoprecipitation (MeRIP) sequencing and RNA immunoprecipitation assays. Collagen antibody-induced arthritis (CAIA) mice were used as an in vivo model to study the role of METTL14 in the inflammation progression of RA. RESULTS: We found that m6A writer METTL14 and m6A levels were decreased in PBMCs of patients with active RA and correlated negatively with the disease activity score using 28 joint counts (DAS28). Knockdown of METTL14 downregulated m6A and promoted the secretion of inflammatory cytokines interleukin 6 (IL-6) and IL-17 in PBMCs of patients with RA. Consistently, METTL14 knockdown promoted joint inflammation accompanied by upregulation of IL-6 and IL-17 in CAIA mice. MeRIP sequencing and functional studies confirmed that tumor necrosis factor α induced protein 3 (TNFAIP3), a key suppressor of the nuclear factor-κB inflammatory pathway, was involved in m6A-regulated PBMCs. Mechanistic investigations revealed that m6A affected TNFAIP3 expression by regulation of messenger RNA stability and translocation in TNFAIP3 protein coding sequence. CONCLUSIONS: Our study highlights the critical roles of m6A on regulation of inflammation in RA progression. Treatment strategies targeting m6A modification may represent a new option for management of RA.

Trimetazidine Affects Mitochondrial Calcium Uniporter Expression to Restore Ischemic Heart Function via Reactive Oxygen Species/NFκB Pathway Inhibition.

ABSTRACT: Studies have demonstrated the roles of trimetazidine beyond being an antianginal agent in ischemic heart disease (IHD) treatment associated with mechanisms of calcium regulation. Our recent studies revealed that mitochondrial calcium uniporter (MCU, the pore-forming unit responsible for mitochondrial calcium entrance) inhibition provided cardioprotective effects for failing hearts. Because trimetazidine and MCU are associated with calcium homeostasis, we hypothesized that trimetazidine may affect MCU to restore the failing heart function. In the present study, we tested this hypothesis in the context of cardiac ischemia in vivo and in vitro. The IHD model was established in male C57BL/6 mice followed by trimetazidine administration intraperitoneally at 20 mg/kg q.o.d for 8 weeks. In vitro studies were performed in a hypoxia model using primary rat neonate cardiomyocytes. The mice survival outcomes and heart function, pathohistologic, and biological changes were analyzed. The results demonstrated that trimetazidine treatment resulted in longer life spans and heart function improvement accompanied by restoration of mitochondrial calcium levels and increase in ATP production via MCU down-regulation. Studies in vitro further showed that trimetazidine treatment and MCU inhibition decreased reactive oxygen species (ROS) production, inhibited the NFκB pathway, and protected the cardiomyocytes from hypoxic injury, and vice versa. Thus, the present study unveils a unique mechanism in which trimetazidine is involved in ameliorating the ischemic failing heart via MCU down-regulation and the following mitochondrial calcium homeostasis restoration, ROS reduction, and cardiomyocyte protection through NFκB pathway inhibition. This mechanism provides a novel explanation for the treatment effects of trimetazidine on IHD.

Implementation of required sedation assessment in nursing workflow to address naloxone utilization.

OBJECTIVE: Opioid-related adverse drug events continue to occur. This study aimed to characterize the patient population receiving naloxone to inform future intervention efforts. DESIGN: We describe a case series of patients who received naloxone in the hospital during a 16-week time frame in 2016. Data were collected on other administered medications, reason for admission to the hospital, pre-existing diagnoses, comorbidities, and demographics. SETTING: Twelve hospitals within a large healthcare system. PATIENTS: 46,952 patients were admitted during the study period. 31.01 percent (n = 14,558) of patients received opioids, of which 158 received naloxone. INTERVENTION: Administration of naloxone. Main outcome of interest: Sedation assessment via Pasero Opioid-Induced Sedation Scale (POSS), administration of sedating medications. RESULTS: POSS score was documented prior to opioid administration in 93 (58.9 percent) patients. Less than half of patients had a POSS documented prior to naloxone administration with 36.8 percent documented 4 hours prior. 58.2 percent of patients received multimodal pain therapy with other nonopioid medications. Most patients received more than one sedating medication concurrently (n = 142, 89.9 percent). CONCLUSIONS: Our findings highlight areas for intervention to prevent opioid oversedation. Investing in electronic clinical decision support mechanisms, such as sedation assessment, could detect patients at risk for oversedation and ultimately prevent the need for naloxone. Coordinated order sets for pain management can reduce the percentage of patients receiving multiple sedating medications and promote the use of multimodal pain management in efforts to reduce opioid reliance while optimizing pain control.

GAS-STING signaling plays an essential pathogenetic role in Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: The severe unfavorable effects of doxorubicin on the heart restrict its clinical usage. Numerous investigations document that cyclic GMP-AMP synthase (cGAS) activator of interferon genes (STING) cascade influences inflammation along with the immune response in a variety of diseases. The pathophysiological function of the cGAS-STING cascade in Doxorubicin-induced cardiomyopathy (DIC) is, nevertheless, unknown. METHODS: In vivo, cardiotoxicity was triggered by a single dose of intra-peritoneal inoculation of doxorubicin (15 mg/kg) in wild-type C57BL/6J mice and STING knockdown animals. Adeno-associated virus 9 (AAV9) was utilized to silence STING. qPCR along with Western blotting were adopted to assess alterations in the cGAS/STING cascade. To assess cardiac function, we employed echocardiography coupled with histology, as well as molecular phenotyping. In vitro, HL-1 cardiomyocytes were introduced as test models. RESULTS: In wild type mice, doxorubicin stimulation significantly activated the cGAS/STING pathway. STING silencing increased rate of survival along with heart function in mice, as well as diminished myocardial inflammatory cytokines along with apoptosis. These observations were also confirmed by utilizing siRNA of STING in vitro studies. CONCLUSION: This research premise established that STING inhibition could alleviate Dox-triggered cardiotoxicity in mice. As a result, preventing DIC by repressing STING in cardiomyocytes might be a possible treatment approach.

Opioid and benzodiazepine use in gynecologic oncology patients.

OBJECTIVE: The goals of this study were to describe opioid and benzodiazepine prescribing practices in the gynecologic oncology patient population and determine risks for opioid misuse in these patients. METHODS: Retrospective study of opioid and benzodiazepine prescriptions for patients treated for cervical, ovarian (including fallopian tube/primary peritoneal), and uterine cancers within a single healthcare system from January 2016 to August 2018. RESULTS: A total of 7643 prescriptions for opioids and/or benzodiazepines were dispensed to 3252 patients over 5754 prescribing encounters for cervical (n=2602, 34.1%), ovarian (n=2468, 32.3%), and uterine (n=2572, 33.7%) cancer. Prescriptions were most often written in an outpatient setting (51.0%) compared with inpatient discharge (25.8%). Cervical cancer patients were more likely to have received a prescription in an emergency department or from a pain/palliative care specialist (p=0.0001). Cervical cancer patients were least likely to have prescriptions associated with surgery (6.1%) compared with ovarian cancer (15.1%) or uterine cancer (22.9%) patients. The morphine milligram equivalents prescribed were higher for patients with cervical cancer (62.6) compared with patients with ovarian and uterine cancer (46.0 and 45.7, respectively) (p=0.0001). Risk factors for opioid misuse were present in 25% of patients studied; cervical cancer patients were more likely to have at least one risk factor present during a prescribing encounter (p=0.0001). Cervical cancer was associated with a higher number of risk factors (p<0.001). CONCLUSIONS: Opioid and benzodiazepine prescribing patterns differ for cervical, ovarian, and uterine cancer patients. Gynecologic oncology patients are overall at low risk for opioid misuse; however, patients with cervical cancer are more likely to have risk factors present for opioid misuse.

Isolated Osteochondral Autograft Versus Allograft Transplantation for the Treatment of Symptomatic Cartilage Lesions of the Knee: A Systematic Review and Meta-analysis.

BACKGROUND: Focal cartilage lesions of the knee remain a difficult entity to treat. Current treatment options include arthroscopic debridement, microfracture, autograft or allograft osteochondral transplantation, and cell-based therapies such as autologous chondrocyte transplantation. Osteochondral transplantation techniques restore the normal topography of the condyles and provide mature hyaline cartilage in a single-stage procedure. However, clinical outcomes comparing autograft versus allograft techniques are scarce. PURPOSE: To perform a comprehensive systematic review and meta-analysis of high-quality studies to evaluate the results of osteochondral autograft and allograft transplantation for the treatment of symptomatic cartilage defects of the knee. STUDY DESIGN: Systematic review and meta-analysis; Level of evidence, 2. METHODS: A comprehensive search of the literature was conducted using various databases. Inclusion criteria were level 1 or 2 original studies, studies with patients reporting knee cartilage injuries and chondral defects, mean follow-up ≥2 years, and studies focusing on osteochondral transplant techniques. Exclusion criteria were studies with nonknee chondral defects, studies reporting clinical outcomes of osteochondral autograft or allograft combined with other procedures, animal studies, cadaveric studies, non-English language studies, case reports, and reviews or editorials. Primary outcomes included patient-reported outcomes and failure rates associated with both techniques, and factors such as lesion size, age, sex, and the number of plugs transplanted were assessed. Metaregression using a mixed-effects model was utilized for meta-analyses. RESULTS: The search resulted in 20 included studies with 364 cases of osteochondral autograft and 272 cases of osteochondral allograft. Mean postoperative survival was 88.2% in the osteochondral autograft cohort as compared with 87.2% in the osteochondral allograft cohort at 5.4 and 5.2 years, respectively (P = .6605). Patient-reported outcomes improved by an average of 65.1% and 81.1% after osteochondral autograft and allograft, respectively (P = .0001). However, meta-analysis revealed no significant difference in patient-reported outcome percentage change between osteochondral autograft and allograft (P = .97) and a coefficient of 0.033 (95% CI, -1.91 to 1.98). Meta-analysis of the relative risk of graft failure after osteochondral autograft versus allograft showed no significant differences (P = .66) and a coefficient of 0.114 (95% CI, -0.46 to 0.69). Furthermore, the regression did not find other predictors (mean age, percentage of female patients, lesion size, number of plugs/grafts used, and treatment location) that may have significantly affected patient-reported outcome percentage change or postoperative failure between osteochondral autograft versus allograft. CONCLUSION: Osteochondral autograft and allograft result in favorable patient-reported outcomes and graft survival rates at medium-term follow-up. While predictors for outcomes such as mean age, percentage of female patients, lesion size, number of plugs/grafts used, and treatment location did not affect the comparison of the 2 cohorts, proper patient selection for either procedure remains paramount to the success and potentially long-term viability of the graft.