Risk Factors For Adverse Effects Research Articles

Buprenorphine for pain management vs. chronic hydrocodone-acetaminophen therapy when comorbidities increase the risk of opioid-related side effects

A clinical decision report using: Gordon A, Callaghan D, Spink D, et al. Buprenorphine transdermal system in adults with chronic low back pain: a randomized, double-blind, placebo-controlled crossover study, followed by an open-label extension phase. Clin Ther. 2010;32(5):844-860. https://doi.org/10.1016/j.clinthera.2010.04.018 for a patient on long-term opioid therapy with high risk factors for adverse effects

Comparison of the effect between traditional conservation and nasointestinal tube placement in adhesive small bowel obstruction: A matched case-control study

Adhesive small bowel obstruction (ASBO) causes a major burden in emergency medicine. Owing to in situ decompression, nasointestinal tube (NIT) placement has been increasingly used in clinical practice compared with traditional conservation (TC); however, the indications remain controversial. This study was designed to explore the indications for each treatment in ASBOs and then suggest the optimal strategy.After propensity score matching, 128 pairs were included (the NIT and TC groups). The occurrence of severe adverse events (SAEs), peri-treatment clinical parameters, and radiological features were compared between the successful and failed treatment groups.According to different stages of the entire treatment, the independent risk factors for adverse effects for ASBO were analysed in phase I and phase II. In phase I, normal red blood cells (RBC) levels (p = 0.011) and a balanced sodium ion level (p = 0.016) positively affected the outcomes of TC treatment. In phase II, for the TC group, the successful treatment rate reached 79.5% for patients with ASBOs whose normal RBC levels (p = 0.006) or decreasing white blood cells (WBC) levels (p = 0.014) after treatment. For the NIT group, the treatment success rate was 68.1% for patients whose electrolyte imbalance could be reversed or whose neutrophil count/lymphocyte ratio (NLR) levels was lower than 4.3 (p = 0.018).TC treatment is highly recommended for patients with normal RBC counts and sodium levels pretreatment. After dynamic monitoring of the treatment process, for both the TC and NIT groups, once ASBOs had elevated inflammatory biomarkers or irreversible electrolyte disturbances, surgical interference was preferred.

Prevalence and risk factors of adverse effects after the first COVID-19 booster dose: evidence from Greece

BackgroundIn general, COVID-19 vaccines are safe and effective, but minor adverse effects are common. However, adverse effects have not been measured in several countries including Greece. ObjectiveTo estimate the prevalence of adverse effects after the first COVID-19 booster dose, and to identify possible risk factors. Material and methodsWe conducted a cross-sectional study with a convenience sample in Greece during November 2022. We measured several adverse effects after the booster dose, such as fatigue, headaches, fever, chills, nausea, etc. We considered gender, age, chronic disease, self-assessment of health status, COVID-19 diagnóstico, and self-assessment of COVID-19 course as possible predictors of adverse effects. ResultsIn our sample, 96% developed at least one adverse effect. Half of the participants (50.2%) developed one to five adverse effects, 35.9% developed six to ten adverse effects, and 9.5% developed 11 to 16 adverse effects. Mean number of adverse effects was 5.5. The most frequent adverse effects were pain at the injection site (84.3%), fatigue (70.8%), muscle pain (61%), swelling at the injection site (55.2%), headache (49.8%), fever (42.9%), and chills (41%). Females developed more adverse effects than males (p < 0.001). The prevalence of adverse effects of COVID-19 vaccines was statistically significant and positively associated with the severity of COVID-19 among COVID-recovered individuals (p < 0.05). Moreover, younger age was associated with increased adverse effects (p < 0.001). ConclusionsAlmost all participants in our study developed minor adverse effects after the booster dose. Female gender, COVID-19 patients with worse clinical course, and younger individuals experienced more often adverse effects.

Letter to editor in response to 'Risk factors for adverse effects following surgical repair of esophageal atresia. A retrospective cohort study'.

Letter to editor in response to 'Risk factors for adverse effects following surgical repair of esophageal atresia. A retrospective cohort study'.

Prevalence and risk factors of adverse effects after the first COVID-19 booster dose: evidence from Greece

BackgroundIn general, COVID-19 vaccines are safe and effective, but minor adverse effects are common. However, adverse effects have not been measured in several countries including Greece. ObjectiveTo estimate the prevalence of adverse effects after the first COVID-19 booster dose, and to identify possible risk factors. Material and methodsWe conducted a cross-sectional study with a convenience sample in Greece during November 2022. We measured several adverse effects after the booster dose, such as fatigue, headaches, fever, chills, nausea, etc. We considered gender, age, chronic disease, self-assessment of health status, COVID-19 diagnóstico, and self-assessment of COVID-19 course as possible predictors of adverse effects. ResultsIn our sample, 96% developed at least one adverse effect. Half of the participants (50.2%) developed one to five adverse effects, 35.9% developed six to ten adverse effects, and 9.5% developed 11 to 16 adverse effects. Mean number of adverse effects was 5.5. The most frequent adverse effects were pain at the injection site (84.3%), fatigue (70.8%), muscle pain (61%), swelling at the injection site (55.2%), headache (49.8%), fever (42.9%), and chills (41%). Females developed more adverse effects than males (p < 0.001). The prevalence of adverse effects of COVID-19 vaccines was statistically significant and positively associated with the severity of COVID-19 among COVID-recovered individuals (p < 0.05). Moreover, younger age was associated with increased adverse effects (p < 0.001). ConclusionsAlmost all participants in our study developed minor adverse effects after the booster dose. Female gender, COVID-19 patients with worse clinical course, and younger individuals experienced more often adverse effects.

Subglottic hemangioma—prevalence, clinical presentation and treatment

This retrospective study aimed to investigate the clinical features and treatment of pediatric subglottic hemangioma (SH), identify risk factors for treatment-induced adverse effects, and identify a strategy for timely therapy discontinuation in children diagnosed with SH at the national pediatric center. Medical records of patients presented with stridor from 2010 to 2020 were retrieved and assessed, the diagnosis of SH was established via flexible bronchoscopy, and the patients were treated using propranolol with a subsequent gradual dose increase to 3 mg/kg body weight daily. A two-week oral steroids trial was added for those with circumferential lesions. Early indicators of a good therapeutic response included decreased stridor and primary lesion size on follow-up bronchoscopy performed one week after propranolol commencement. Duration of therapy, tailored individually based on bronchoscopy findings, and at least twelve months of treatment were the two main criteria for deciding therapy termination. Outpatient visits were arranged at least every three months. Our results showed that SH was the third most frequent cause of stridor (15/137 patients), and biphasic stridor was uniformly present as a typical symptom. Both clinical improvement and bronchoscopy findings confirmed the efficacy of the treatment. The mean therapy duration was 17 months. The only significant adverse event observed was hypoglycemic seizures in one infant. Contributory factors were all prematurity, high propranolol dose (3 mg/kg) and poor oral intake. Collectively, defining a safe and timely protocol for therapy cessation and avoidance of risk factors for adverse effects is the mainstay of SH treatment.

Prevalence and Risk Factors of Adverse Effects and Allergic Reactions after COVID-19 Vaccines in a Mexican Population: An Analytical Cross-Sectional Study.

Vaccinations have helped to control the COVID-19 pandemic; however, few studies focus on the adverse effects and allergic reactions of these vaccines and fewer have a scope in the Latin American population. The objective of this study was to assess the associations between vaccinations, sex, age, allergic reactions, and adverse effects. This was an analytical cross-sectional study conducted between 1 July and 1 October 2022. The sample consisted of 443 surveyed participants, with a total of 1272 COVID-19 vaccine doses. Seven vaccines (Pfizer BioNTech, Oxford-AstraZeneca, CanSino, Moderna, Johnson and Johnson, Sinovac, and Sputnik V) were evaluated. A total of 12.6% of those surveyed had at least one allergic reaction posterior to vaccination, and females had a greater chance of developing one (p &lt; 0.001, OR 3.1). The most common allergic reaction was chest pain, and Pfizer-BioNTech and Oxford-AstraZeneca were associated with the onset of allergic reactions (p &lt; 0.005). A total of 54.6% of those surveyed developed adverse effects, the most common of which were myalgia, fever, cephalea, asthenia or adynamia, and arthralgia; moreover, older age was associated with the onset of adverse effects (p &lt; 0.5). This study concludes that the BNT162b2 (Pfizer BioNTech) and ChAdOX1 nCOV-19 (Oxford-AstraZeneca) vaccines are strongly associated with the onset of allergic reactions, with ORs of 1.6 (CI 95%, 1.18 to 2.3) and 1.87 (CI 95%, 1.35 to 2.6), respectively. In addition, females have a greater chance of developing allergic reactions associated with COVID-19 vaccinations, and there was a relation found between older age and a greater prevalence of comorbidities, adverse effects after vaccination, and COVID-19 infection after vaccination.

Electrolyte considerations in targeted temperature management.

Targeted temperature management (TTM), including normothermia and therapeutic hypothermia, is used primarily for comatose patients with return of spontaneous circulation after cardiac arrest or following neurological injury. Despite the potential benefits of TTM, risks associated with physiological alterations, including electrolyte shifts, may require intervention. This review describes the normal physiological balance of electrolytes and temperature-related alterations as well as the impact of derangements on patient outcomes, providing general recommendations for repletion and monitoring of key electrolytes, including potassium, phosphate, and magnesium. Frequent monitoring and consideration of patient variables such as renal function and other risk factors for adverse effects are important areas of awareness for clinicians caring for patients undergoing TTM.

Milk and Egg Are Risk Factors for Adverse Effects of Capecitabine-Based Chemotherapy in Chinese Colorectal Cancer Patients.

Background:Chemotherapy-induced adverse effects (CIAEs) remain a challenging problem due to their high incidences and negative impacts on treatment in Chinese colorectal cancer (CRC) patients. We aimed to identify risk factors and predictive markers for CIAEs using food/nutrition data in CRC patients receiving post-operative capecitabine-based chemotherapy.Methods:Food/nutrition data from 130 Chinese CRC patients were analyzed. Univariate and multivariate analyses were used to identify CIAE-related food/nutrition factors. Prediction models were constructed based on the combination of these factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the discrimination ability of models.Results:A total of 20 food/nutrition factors associated with CIAEs were identified in the univariate analysis after adjustments for total energy and potential confounding factors. Based on multivariate analysis, we found that, among these factors, dessert, eggs, poultry, and milk were associated with several CIAEs. Most importantly, poultry was an overall protective factor; milk and egg were risk factors for hand-foot syndrome (HFS) and bone marrow suppression (BMS), respectively. Developed multivariate models in predicting grade 1 to 3 CIAEs and grade 2/3 CIAEs both had good discrimination (AUROC values from 0.671 to 0.778, 0.750 to 0.946 respectively), which had potential clinical application value in the early prediction of CIAEs, especially for more severe CIAEs.Conclusions:Our findings suggest that patients with high milk and egg intakes should be clinically instructed to control their corresponding dietary intake to reduce the likelihood of developing HFS and BMS during capecitabine-based chemotherapy, respectively.Trial registration:ClinicalTrials.gov Identifier: NCT03030508.

Прогностичні критерії судово-медичної оцінки ступеня тяжкості тілесних ушкоджень при закритих переломах кісток нижніх кінцівок

Currently, to determine the severity of injuries in case of adverse effects of subcutaneous fractures of the lower extremities, several forensic examinations are conducted at the stage of treatment, which may lead to loss of confidence in the results of forensic expert opinion of the victims, accompanied by economic losses. Therefore, predicting the consequences of such injuries is an urgent scientific and practical problem of forensic medicine. The purpose of the study is to develop prognostic criteria for forensic assessment of the severity of injuries in fractures of the femur and tibia. Materials and methods. The object of the research was 180 "Expert conclusions (examination of the case file)" with the establishment of the severity of injuries in victims of road accidents: subcutaneous isolated and fractures of the femur (24; 13.3%), tibia – (64; 35.6%); fractures of these bones as the leading injury in polytrauma – (92; 51.1%). In 120 (66.7%) expert opinions the average degree of severity of bodily injuries was established as favorable consequences of road accidents (main sample). In 60 (33.3%) cases, adverse effects of injury were observed with the establishment of severe injuries (a control sample). Research methods which were used are expert examination of the victim with anthropometric studies; radiation diagnostics; alternative computational forecasting. Results and discussion. According to the results of retrospective analysis of the results of treatment, 25 risk factors for adverse effects of subcutaneous fractures of the femur and tibia were identified. The main ones are: passive participation in a road traffic injury as a pedestrian (87.5% in the main sample and 91.7% in the control); combined trauma (70.8% and 75.0%, respectively), multifracture (66.7% and 95.0%, respectively); age &gt;41 years old (48.3% and 81.7%, respectively) and a frontal collision with a car (51.7% and 70.0%, respectively). Risk factors such as intraoperative misalignment of the fragments of the femur and violation of the terms of postoperative X-ray control (23.8% in the main group and absence in the control group) were relatively uncommon. Conclusion. Numerical values of prognostic coefficients of the most probable factors potentiating adverse effects of subcutaneous fractures of long bones of the lower extremities are established. The most informative are: intra-articular multifracture fracture (prognostic coefficient equals -9; I=1.44); multifragmental diaphyseal fracture (prognostic coefficient equals -7; I=1.20); non-elimination of intraoperative displacement of long bone fragments (prognostic coefficient equals -6; I=1.04); discrepancy of the sizes of a clamp to anatomic sizes of the damaged bone (prognostic coefficient equals -6; I=1,04); violation of the terms of postoperative X-ray control (prognostic coefficient equals -4; I=0.50)

A reasoned approach towards administering COVID-19 vaccines to pregnant women.

There are over 50 SARS‐CoV‐2 candidate vaccines undergoing Phase II and III clinical trials. Several vaccines have been approved by regulatory authorities and rolled out for use in different countries. Due to concerns of potential teratogenicity or adverse effect on maternal physiology, pregnancy has been a specific exclusion criterion for most vaccine trials with only two trials not excluding pregnant women. Thus, other than limited animal studies, gradually emerging development and reproductive toxicity data, and observational data from vaccine registries, there is a paucity of reliable information to guide recommendations for the safe vaccination of pregnant women. Pregnancy is a risk factor for severe COVID‐19, especially in women with comorbidities, resulting in increased rates of preterm birth and maternal morbidity. We discuss the major SARS‐CoV‐2 vaccines, their mechanisms of action, efficacy, safety profile and possible benefits to the maternal‐fetal dyad to create a rational approach towards maternal vaccination while anticipating and mitigating vaccine‐related complications. Pregnant women with high exposure risks or co‐morbidities predisposing to severe COVID‐19 infection should be prioritised for vaccination. Those with risk factors for adverse effects should be counselled accordingly. It is essential to support patient autonomy by shared decision‐making involving a risk‐benefit discussion with the pregnant woman.

Linking periodontitis and adverse pregnancy outcomes through CD14+ CD16+ monocytes

One of the prevalent medical issues that deserve global attention is adverse pregnancy outcomes and preterm low birth weight deliveries which have a significant impact on neonatal health. Periodontitis has been implicated as a significant risk factor for adverse effects in pregnancy. Elevated levels of periodontal pathogenic bacteria and proinflammatory cytokines which are pathognomonic features of periodontitis are believed to cause placental infection and premature rupture of the amniotic membrane consequently leading to preterm delivery. The role of CD14+CD16+ monocytes as a causal link between periodontitis and adverse pregnancy outcomes has not been researched so far, although an elevation of these cells has been independently demonstrated in both conditions. With the available background information, this hypothesis attempts to derive a mechanistic link between periodontitis and adverse pregnancy outcomes through the participation of CD14+CD16+ monocytes.

Twenty Years of GH Treatment in Adults with Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder. In adults, the syndrome is characterised by muscular hypotonia, a different body composition with more body fat than muscle mass, hyperphagia, behavioural problems, and cognitive dysfunction. Endocrine deficiencies are common, including growth hormone (GH) deficiency. Here, we present data from a cross-sectional study in adults with PWS with a focus on the long-term safety of GH treatment. A total of 22 patients (14 men) were treated with GH for a median of 20 years. Data on body composition, hormones, and metabolic parameters were retrieved from the patients’ medical records. The median age was 27 years. The median GH dose was 0.5 mg/day. Insulin-like growth factor 1 (IGF-I) and blood lipids were normal, while fasting glucose and HbA1c were slightly elevated in three men with diabetes. Fat mass was less than fat free mass in all, though this was less pronounced in women. GH treatment did not negatively affect the metabolic profile, and none developed cardiovascular diseases or cancer. All adults on long-term GH treatment had a normal body composition and our results indicate that treatment was safe. However, PWS is a complex, multisystemic disease and continuous, individual considerations are required during GH treatment, especially in patients with risk factors for adverse effects.

The triumvirate: why hypertension, obesity, and diabetes are risk factors for adverse effects in patients with COVID-19.

The outbreak of coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a pandemic. The cellular receptor for SARS-CoV-2 entry is the angiotensin-converting enzyme 2, a membrane-bound homolog of angiotensin-converting enzyme. Henceforth, this has brought the attention of the scientific community to study the interaction between COVID-19 and the renin–angiotensin system (RAS), as well as RAS inhibitors. However, these inhibitors are commonly used to treat hypertension, chronic kidney disorder, and diabetes. Obesity is a known risk factor for heart disease, diabetes, and hypertension, whereas diabetes and hypertension may be indirectly related to each other through the effects of obesity. Furthermore, people with hypertension, obesity, diabetes, and other related complications like cardiovascular and kidney diseases have a higher risk of severe COVID-19 infection than the general population and usually exhibit poor prognosis. This severity could be due to systemic inflammation and compromised immune response and RAS associated with these comorbid conditions. Therefore, there is an urgent need to develop evidence-based treatment methods that do not affect the severity of COVID-19 infection and effectively manage these chronic diseases in people with COVID-19. Electronic supplementary materialThe online version of this article (10.1007/s00592-020-01636-z) contains supplementary material, which is available to authorized users.

Research of models of sports success based on the identified variants of relationship of constructions of self-assessment and level of aspirations

The article is devoted to the problem of achieving success in sports of the highest achievements. The author, based on theoretical analysis and empirical studies, shows the psychological causes and conditions of success, as well as identifies risk factors for adverse effects on the athlete’s activities. Based on the study of self-assessment constructs of highly qualified athletes, their claims and personal characteristics, the author established that only the optimal level of consistency of self-assessment parameters and claims leads to success, and their inconsistency – low self-esteem and high inadequate claims – leads to mental malaptension, one of its forms of which is the dissociative complex “Risk Triad,” which prevents athletes from achieving success. As an important research task, the author attempted to distinguish sports success models based on the identified variants of the relationship of self-esteem constructs and claims, covering different relationships of mismatch (divergence) of these selfesteem measurements with the personal characteristics of athletes. The data obtained in the empirical study emphasize the significance of the ratio of self-assessment and claims as important variables for the successful performance of highly qualified athletes in competitions. This area of research is supplemented by a detailed analysis and description of the manifestation of personal features such as motivation, level of anxiety, orientation of the control locus from the points of view of success-failure of highly qualified athletes.

Factors Influencing the Treatment Effect of Superelastic Wire Orthonyxia for Nail Plate Deformity.

Orthonyxia is an effective, noninvasive treatment for transverse nail curvature deformity. To discover the factors influencing treatment results of superelastic wire orthonyxia (SEWO). A retrospective study was conducted using clinical records of patients treated with SEWO. A multiple linear regression model was used to explain the correlation between correction pace (% per week) and the other collected variables (patient age, sex, position of treated toe, wire diameter [WD, mm], wire residence time [WRT, weeks], nail plate thickness [PT, mm], baseline nail curvature index [NCI], number of previous treatments, and the correction pace of previous treatments [CPT, % per week]). A logistic regression model was used to identify risk factors for adverse effects. A total of 475 cases were collected from 197 patients. The correction pace was positively related to baseline NCI, WD, and correction pace in previous treatment. Also, it was negatively related to WRT and nail PT. No clinical factor was correlated with the occurrence of side effects. The correction pace of SEWO is affected by the baseline NCI, the diameter of the wire, nail PT, the CPT, and the WRT.

195. Descriptive Study of the Use of External Cooling Blankets in Hyperthermia

BackgroundFever is a beneficial physiologic response to infection and is protective in gram-negative bacteremia and invasive candidiasis. Cooling blankets (CBs) are used in fevers due to a perception of providing symptomatic relief. However, external cooling of septic patients has been shown to be an independent risk factor for adverse effects. Here, we present a retrospective analysis of CB use in our institution and the associations of infections with CB duration.MethodsWe reviewed electronic medical records of patients aged ≥18 years admitted to a tertiary care hospital between 2015–2017 and in whom a CB was used. Study variables included demographics and clinical characteristics such as infection and fever duration (time of CB start to first defervescence). Correlations between continuous variables were assessed using the Spearman's rank correlation test and differences in the distribution of continuous variables by groups were assessed using Mann–Whitney U and Kruskal–Wallis tests.ResultsThis analysis included 548 patients who used a total of 575 CBs during their stay (27 patients used ≥1 CB). The median age was 61.9 years and 56.9% were male. The most frequent comorbidities were immunocompromised state (40.3%), diabetes mellitus (33.6%) and coronary artery disease (32.3%). Pneumonia was the most common infection within 5 days of CB start (31.9%). Only 174 CBs had a documented discontinuation during hospitalization; for the remaining CBs, such documentation was absent. The median CB duration for these patients was 33.8 hrs (IQR: 18.0–80.9) while median fever duration was only 21.8 hours (IQR: 6.6–52.2). CB duration was highly correlated with fever duration (rho=.773, pConclusionClinician documentation of CB use was poor, only 30.2% recorded a stop time. Documented CB duration exceeded fever duration by more than 1.5 times and led to shivering responses in over 2/3 of patients. These findings suggest that CB use is arbitrary, not in keeping with established protocol or rationale, and its adverse effects may outweigh potential benefits. Their role should be re-evaluated and appropriate institutional protocols formulated.Disclosures All authors: No reported disclosures.

Genomic Instability of iPSCs and Challenges in Their Clinical Applications.

Generation of human-induced pluripotent stem cells (iPSCs) from somatic cells has opened the possibility to design novel therapeutic approaches. In 2014, the first-in-human clinical trial of iPSC-based therapy was conducted. However, the transplantation for the second patient was discontinued at least in part due to genetic aberrations detected in iPSCs. Moreover, many studies have reported genetic aberrations in iPSCs with the rapid progress in genomic technologies. The presence of genomic instability raises serious safety concerns and can hamper the advancement of iPSC-based therapies. Here, we summarize our current knowledge on genomic instability of iPSCs and challenges in their clinical applications. In view of the recent expansion of stem cell therapies, it is crucial to gain deeper mechanistic insights into the genetic aberrations, ranging from chromosomal aberrations, copy number variations to point mutations. On the basis of their origin, these genetic aberrations in iPSCs can be classified as (i) preexisting mutations in parental somatic cells, (ii) reprogramming-induced mutations, and (iii) mutations that arise during in vitro culture. However, it is still unknown whether these genetic aberrations in iPSCs can be an actual risk factor for adverse effects. Intersection of the genomic data on iPSCs with the patients' clinical follow-up data will help to produce evidence-based criteria for clinical application. Furthermore, we discuss novel approaches to generate iPSCs with fewer genetic aberrations. Better understanding of iPSCs from both basic and clinical aspects will pave the way for iPSC-based therapies.

Recent advances in cancer surgery in older patients.

Age is the most important risk factor for the occurrence of cancer, and a declining mortality from heart disease and other non-cancer causes leaves an older population that is at high risk of developing cancer. Choosing the optimal treatment for older cancer patients may be a challenge. Firstly, older age and associated factors such as comorbidities, functional limitations, and cognitive impairment are risk factors for adverse effects of cancer treatment. Secondly, older patients are often excluded from clinical trials, and current clinical guidelines rarely address how to manage cancer in patients who have comorbidities or functional limitations. The importance of incorporating frailty assessment into the preoperative evaluation of older surgical patients has received increasing attention over the last 10 years. Furthermore, studies that include endpoints such as functional status, cognitive status, and quality of life beyond the standard endpoints, i.e. postoperative morbidity and mortality, are starting to emerge. This review looks at recent evidence regarding geriatric assessment and frailty in older surgical cancer patients and provides a summary of newer studies in colorectal, liver, pancreatic, and gynecological cancer and renal and central nervous system tumors.

Sex and age differences in the expression of liver microRNAs during the life span of F344 rats

BackgroundPhysiological factors such as age and sex have been shown to be risk factors for adverse effects in the liver, including liver diseases and drug-induced liver injury. Previously, we have reported age- and sex-related significant differences in hepatic basal gene expression in rats during the life span that may be related to susceptibility to such adverse effects. However, the underlying mechanisms of the gene expression changes were not fully understood. In recent years, increasing evidence for epigenetic mechanisms of gene regulation has fueled interest in the role of microRNAs (miRNAs) in toxicogenomics and biomarker discovery. We therefore proposed that significant age and sex differences exist in baseline liver miRNA expression, and that comprehensive profiling of miRNAs will provide insights into the epigenetic regulation of gene expression in rat liver.MethodsTo address this, liver tissues from male and female F344 rats were examined at 2, 5, 6, 8, 15, 21, 52, 78, and 104 weeks of age for the expression of 677 unique miRNAs. Following data processing, predictive pathway analysis was performed on selected miRNAs that exhibited prominent age and/or sex differences in expression.ResultsOf the 314 miRNAs found to be expressed, 214 were differentially expressed; 65 and 212 miRNAs showed significant (false discovery rate (FDR) <5% and ≥1.5-fold change) sex- and age-related differences in expression, respectively. Thirty-eight miRNAs showed 2-week-specific expression, of which 31 miRNAs were found to be encoded within the Dlk1-Dio3 cluster located on chromosome 6. This cluster has been associated with tissue proliferation and differentiation, and liver energy homeostasis in postnatal development. Predictive pathway analysis linked sex-biased miRNA expression with sexually dimorphic molecular functions and toxicological functions that may reflect sex differences in hepatic physiology and disease. The expression of miRNAs (miR-18a, miR-99a, and miR-203, miR-451) was also found to associate with specific sexually dimorphic hepatic histopathology. The expression of miRNAs involved in regulating cell death, cell proliferation, and cell cycle was found to change as the rats matured from adult to old age.ConclusionsOverall, significant age- and sex-related differences in liver miRNA expression were identified and linked to histopathological findings and predicted functional pathways that may underlie susceptibilities to liver toxicity and disease.