Expanding the molecular landscape of undifferentiated sarcomas of bone with a novel EWSR1-SSX3 gene fusion.

Undifferentiated sarcomas characterized by a primitive monomorphic round to spindle cell phenotype and often non-specific immunoprofile remain difficult to subclassify outside molecular analysis. The increased application of RNA sequencing in clinical practice led to significant advances and discoveries of novel gene fusions that furthered our understanding and refined classification of otherwise undifferentiated neoplasms. In this study, we report an undifferentiated round to spindle cell sarcoma arising in the femur of a 34-year-old female. The round to spindle tumor cells were arranged in short fascicles, with focal rosette formation, within a hyalinized stroma. The tumor immunoprofile included diffuse reactivity for CD99, SATB2, and TLE1 and patchy positivity for Cyclin D1, Keratin AE1/AE3, synaptophysin, and chromogranin. Other markers, such as EMA, SMA, desmin, S100, ERG, and WT1, were negative. Fluorescence in situ hybridization analysis for EWSR1 gene alterations showed a break-apart signal and targeted RNA sequencing revealed an EWSR1::SSX3 gene fusion. The patient received neoadjuvant chemotherapy followed by surgery and subsequently relapsed in less than a year with lung metastasis. Larger series are needed to determine if this fusion defines a novel subset of undifferentiated tumors or represents a genomic variant of already existing primitive round cell sarcoma categories, such as Ewing sarcoma or synovial sarcoma.

Epigenetic and sex differences in opioid use disorder in chronic pain: A real-world study linked with OPRM1 DNA methylation.

Opioid use disorder (OUD) is a multifaceted condition influenced by sex, genetic and environmental factors that could be linked with epigenetic changes. Understanding how these factors interact is crucial to understand and address the development and progression of this disorder. Our aim was to elucidate different potential epigenetic and genetic mechanisms between women and men that correlate with OUD under real-world pain unit conditions. Associations between analgesic response and the DNA methylation level of the opioid mu receptor (OPRM1) gene (CpG sites 1-5 selected in the promoter region) were evaluated in 345 long opioid-treated chronic non cancer pain: cases with OUD (n = 67) and controls (without OUD, n = 278). Cases showed younger ages, low employment status and quality of life, but higher morphine equivalent daily dose and psychotropic use, compared to the controls. The patients with OUD showed a significant decrease in OPRM1 DNA methylation, which correlated with clinical outcomes like pain relief, depression and different adverse events. Significant differences were found at the five CpG sites studied for men, and exclusively in women for CpG site 3, in relation to OUD diagnosis. These findings support the importance of epigenetics and sex as biological variables to be considered toward efficient OUD understanding and therapy development.

Chondroblastomas in Children and Young Adults: Revision of 55 Cases.

BACKGROUND: Chondroblastomas are uncommon primary bone tumors localized in long bone epiphyses in children and young adults. The risk of metastasis is rare, but they have a high capacity for local recurrence. Surgical curettage with bone grafting or bone substitute is the preferred treatment. METHODS: We performed an observational retrospective study of chondroblastomas treated in 2 hospitals in Barcelona from 1988 to 2018. We reviewed the location of the tumor, clinical presentation, imaging, histopathology, initial treatment, and cases of recurrence with a review of their treatment. We assessed the correlation between recurrence and index surgery, anatomic location, and certain histopathologic findings (presence of mitotic figures, necrosis, and positivity for protein S-100). RESULTS: The series included 55 patients treated from 1988 to 2018, with ages ranging from 6 to 26, and a mean follow-up of 6.1 years (±3.7). The most common location was the distal femur metaphyseal/epiphyseal region. The most frequent clinical presentation was pain in the affected. Forty-five cases (81.8%) were treated with curettage of the tumor, and 4 cases (7.3%) with a wide resection. Forty-two cases (85.7%) received bone substitutes after curettage or resection. We found 5 cases of recurrence (9.1% recurrence rate); however, we could not find a statistically significant correlation between index surgery and recurrence ( P =0.24), anatomic location and recurrence ( P =0.49), or recurrence and histopathologic findings (mitotic figures, P =0.49; necrosis, P =0.60; positivity for protein S-100, P =0.52). In all the cases the treatment for the local recurrence was surgical, with a final healing rate of 100%. CONCLUSIONS: Chondroblastomas should be considered in children and adolescents when presenting with pain and an image suggestive of a tumoral lesion on plain x-ray, most frequently in epiphyses of long bones.Surgical treatment is preferred, obtaining good results after curettage and bone substitute. Chondroblastomas are tumors with a high capacity for recurrence, therefore an adequate surgical technique and surgeon experience are paramount to achieve good outcomes. LEVEL OF EVIDENCE: Level IV (case series). Therapeutic studies-investigating results or treatment.

Metal Ion Release in Cancer Patients Following Megaprosthesis Salvage Surgery.

BACKGROUND: Megaprostheses contain many more modular components than conventional total hip and knee arthroplasty, which may lead to higher serum levels of metal ions. The aim of this study was to determine serum concentrations of titanium, chromium, and cobalt ions in cancer patients after limb salvage surgery with a megaprosthesis. METHODS: A retrospective, descriptive cohort analysis consisting of patients who underwent cancer-related limb salvage surgery with a megaprosthesis at our hospital between 2010 and 2020 was conducted. Baseline and follow-up data were extracted from clinical and surgical records. Blood samples were prospectively obtained. Descriptive statistics were used for the analysis. RESULTS: A total of 71 patients underwent limb salvage surgery during the study period. Of these, 22 (10 women, 12 men) were included in the study. The mean age was 52 years (range, 21 to 80). Most cases (n = 16; 72.7%) involved the femur. Most patients (n = 14, 63.6%) underwent total knee megaprosthesis surgery. Implant revision surgery was required in 45% of cases (n = 10), with a mean interval of 4.32 years between the initial and revision surgeries. The mean follow-up time after revision surgery was 4.05 years. High levels of chromium were observed in 22.7% of patients (n = 5). High cobalt levels were found in 68.2% (n = 15) of patients, with toxic levels in 9.1% (n = 2). Titanium levels were high in 77.3% (n = 17) of cases and toxic in 22.7% (n = 5). Postoperative chemotherapy was significantly associated with titanium levels (P = .017). No correlation was observed between metal ion levels and time from primary or revision surgery or time from the first to revision surgery. CONCLUSIONS: This study shows that cancer-related limb salvage surgery with megaprosthesis is associated with metal ion levels that exceed established safe thresholds. Compared to conventional hip arthroplasty, a higher proportion of the patients in this cohort presented elevated levels of metal ions. LEVEL OF EVIDENCE: III.

Opioid Monitoring in Clinical Settings: Strategies and Implications of Tailored Approaches for Therapy.

This review emphasises the importance of opioid monitoring in clinical practice and advocates for a personalised approach based on pharmacogenetics. Beyond effectively managing pain, meticulous oversight is required to address concerns about side effects, specially due to opioid-crisis-related abuse and dependence. Various monitoring techniques, along with pharmacogenetic considerations, are critical for personalising treatment and optimising pain relief while reducing misuse and addiction risks. Future perspectives reveal both opportunities and challenges, with advances in analytical technologies holding promise for increasing monitoring efficiency. The integration of pharmacogenetics has the potential to transform pain management by allowing for a precise prediction of drug responses. Nevertheless, challenges such as prominent pharmacogenetic testing and guideline standardisation persist. Collaborative efforts are critical for transforming scientific advances into tangible improvements in patient care. Standardised protocols and interdisciplinary collaboration are required to ensure consistent and evidence-based opioid monitoring. Future research should look into the long-term effects of opioid therapy, as well as the impact of genetic factors on individual responses, to help guide personalised treatment plans and reduce adverse events. Lastly, embracing innovation and collaboration can improve the standard of care in chronic pain management by striking a balance between pain relief and patient safety.

Follicular Fluid and Blood Monitorization of Infertility Biomarkers in Women with Endometriosis.

Infertility is recognized globally as a social disease and a growing medical condition, posing a significant challenge to modern reproductive health. Endometriosis, the third-most frequent gynecologic disorder, is one of the most common and intricate conditions that can lead to female infertility. Despite extensive research, the etiology, malignant transformation, and biological therapy of endometriosis remain unknown. Blood and follicular fluid are two matrices that have been carefully studied and can provide insights into women's health. These matrices are clinically significant because they contain metabolites closely associated with women's illness stage and reproductive outcomes. Nowadays, the application of metabolomic analysis in biological matrices may be able to predict the outcome of assisted reproductive technologies with greater precision. From a molecular viewpoint on reproductive health, we evaluate and compare the utilization of human follicular fluid and blood as matrices in analysis for diagnostic and assisted reproductive technology (ART) predictors of success for endometriosis patients. In the follicular fluid (FF), plasma, and serum of endometriosis-affected women, researchers identified dysregulations of oxidative stress, upregulation of several immune factors, and aberrations in energy metabolic pathways. The altered signatures negatively correlate with the overall oocyte and embryo quality and fertilization rate.

Pharmacogenetic Guided Opioid Therapy Improves Chronic Pain Outcomes and Comorbid Mental Health: A Randomized, Double-Blind, Controlled Study.

Interindividual variability in analgesic response is at least partly due to well-characterized polymorphisms that are associated with opioid dosing and adverse outcomes. The Clinical Pharmacogenetics Implementation Consortium (CPIC) has put forward recommendations for the CYP2D6 phenotype, but the list of studied drug-gene pairs continues to grow. This clinical trial randomized chronic pain patients (n = 60), referred from primary care to pain unit care into two opioid prescribing arms, one guided by CYP2D6, µ-opioid receptor (OPRM1), and catechol-O-methyl transferase (COMT) genotypes vs. one with clinical routine. The genotype-guided treatment reduced pain intensity (76 vs. 59 mm, p < 0.01) by improving pain relief (28 vs. 48 mm, p < 0.05), increased quality of life (43 vs. 56 mm p < 0.001), and lowered the incidence of clinically relevant adverse events (3 [1-5] vs. 1 [0-2], p < 0.01) and 42% opioid dose (35 [22-61] vs. 60 [40-80] mg/day, p < 0.05) as opposed to usual prescribing arm. The final health utility score was significantly higher (0.71 [0.58-0.82] vs. 0.51 [0.13-0.67] controls, p < 0.05) by improving sleepiness and depression comorbidity, with a significant reduction of 30-34% for headache, dry mouth, nervousness, and constipation. A large-scale implementation analysis could help clinical translation, together with a pharmaco-economic evaluation.

Gender based differences, pharmacogenetics and adverse events in chronic pain management.

Safety data in chronic non-cancer pain (CNCP) with long-term opioid therapy has been poorly studied and can be differently influenced by gender. Furthermore, pharmacogenetics (PGx) could possibly be used to tailor pain medication based on the individual's genetic background. The aim was to assess whether PGx applied to a pharmacovigilance system could help to improve a patient's security profile. A pharmacovigilance data recording system was conducted over 24 months, including genotyping of OPRM1 variants (opioid receptor, A118G) and COMT (enzyme that degrades catecholamines such as norepinephrine, G1947A). Pain intensity (visual analogue scale, VAS), morphine equivalent daily dose (MEDD), adverse events (AEs) and suspected adverse drug reactions (ADRs) were recorded and analysed by gender. The Ethics Committee approved the study and data were analysed with R 3.6.0 software. A total of 748 patients were recruited in the study (67% female, VAS 62 ± 29 mm, MEDD 119 ± 114 mg/day) reporting a median of 6 (3.5-9) AEs/patient. Women presented more nausea, headaches, insomnia, loss of appetite, weight change, depression and dizziness than men. Analysis by genotype demonstrated that PGx influenced the prevalence of vomiting and depression in men, dizziness in women and sexual dysfunction in both. Physicians notified 150 ADRs mostly in females (79%) related to nervous system disorders. PGx applied to a pharmacovigilance recording system provides important information to achieve a better knowledge about AEs in CNCP pharmacological therapy. OPRM1 and COMT polymorphisms were associated with AEs in CNCP patients that differed according to gender.

Spanish list of potentially inappropriate drugs in the elderly (ES-PIA project).

PURPOSE: In the last decades, different criteria have been developed for detecting inappropriate prescription in older patients. In Spain, translations and adaptations of international lists are available but it would be necessary a national list which could cope with the peculiarities of our health system, existing pharmaceutical market, and prescription habits. We propose in this project the creation of a Spanish potentially inappropriate drugs list which could be applicable in our clinical scenario. METHODS: We use a Delphi method involving 25 experts from different backgrounds (Clinical Pharmacology, Geriatrics, Rational Use of Drugs and Pharmacy, Primary Care and Pharmacoepidemiology, and Pharmacovigilance) that were asked to participate in two-round questionnaires. For analysis, current recommendations of Worth and Pigni were applied, and every statement was classified into one of three groups: strong, moderate, or low agreement. Statements with strong agreement were accepted to be part of the inadequate prescription list. Moderate agreement statements were selected to enter the second questionnaire, and statements with low agreement were further analyzed to determine if it was due to heterogeneity or due to dispersion in the answers. RESULTS: The first questionnaire consisted of 160 proposed sentences, of which 106 reached a high agreement, 32 a moderate agreement, and 22 a low agreement. All sentences proposed in the second questionnaire reached a strong agreement. The total accepted sentences were 138. CONCLUSIONS: We offer a list of inadequate prescription in older patients adapted to the Spanish pharmacopeia and according to the prescription habits in our environment.

Health benefits of an adverse events reporting system for chronic pain patients using long-term opioids.

BACKGROUND: Safety data from long-term opioid therapy in the real world has been poorly studied in chronic non-cancer pain (CNCP). The aim was to design a pharmacovigilance data recording system and assess whether participation in this recording system improves pain management, enhancing patient's health status. METHODS: A pharmacovigilance data recording system was conducted during 24 months. Data were self-reported by patients (pain, adverse events [AEs] and healthcare resources use) and physicians (morphine equivalent daily dose [MEDD] prescribed and suspected adverse drug reaction [ADRs]). Outcomes from patients with (case) or without (controls) suspected ADRs and cases follow-up were also compared with Spanish Pharmacovigilance System data. RESULTS: A total of 753 patients were recruited in 897 visits. Fentanyl and tramadol were the most prescribed opioids, 89% with concomitant drugs, pregabalin being the one with the most potential drug interactions. Cases presented significantly higher pain intensity (VAS 67 ± 26 vs 59 ± 30 mm, P < 0.05), number of AEs (8 ± 6 vs 5 ± 3 AEs/patient, P < 0.01), polypharmacy related to pain (65% vs 34%, P < 0.01) and MEDD (139 ± 130 vs 106 ± 99 mg/d, P < 0.01) than controls. Furthermore, cases presented significant higher changes in pharmacological pain therapy due to pain, unplanned emergency visits and hospital admission than controls. Physicians notified 168 suspected ADRs mostly related to neurological or psychiatric events and 8% of them were previously unknown. CONCLUSIONS: This data recording system provided important information to achieve a better control of CNCP pharmacological pain therapy, improving patient's health status and reducing costs to the Health System.

Genetic Contribution in Low Back Pain: A Prospective Genetic Association Study.

OBJECTIVES: Chronic pain is one of the most common reasons individuals seek medical attention. It is a major issue because of the wide interindividual variability in the analgesic response. This might be partly explained by the presence of variants in genes encoding molecules involved in pharmacodynamics and pharmacokinetics. The aim was to analyze opioid effectiveness in chronic low back pain (CLBP) relief after opioid titration, unveiling the impact of pharmacogenetics. METHODS: The study included 231 opioid-naïve patients from the Spine Unit; age 63 ± 14 years, 64% female, body mass index 29 ± 6 kg/m2 , visual analog scale pain intensity score 73 ± 16 mm. Clinical data were collected at baseline, 3 months after opioid titration, and after 2 to 4 years of follow-up concerning pain (intensity and relief), quality of life, disability, comorbidities, and drug prescription (opioid dose, rotations, and adverse events). The genotype influence of OPRM1, COMT, UGT2B7, ABCB1, KCNJ6, and CYP3A5*3A in analgesic response was analyzed by reverse-transcription polymerase chain reaction genotyping. RESULTS: Patients with the COMT G472A-AA genotype (rs4680) and KCNJ6 A1032G-A allele (rs2070995) CLBP responded differently to opioid titration, with higher pain intensity requiring higher dosing. Furthermore, GG- genotypes of A118G (OPRM1, rs1799971) and A854G (UGT2B7, rs776746) influenced the neuropathic component. After opioid titration, CLBP intensity, neuropathic component, low back pain disability, anxiety, and depression significantly decreased, while quality of life improved. CONCLUSION: Single-nucleotide polymorphisms in genes involved in pain transmission and opioid metabolism might predispose to exaggerated sensitivity and differences in the opioid analgesic effect in patients with CLBP. We encourage clinical trials for their clinical application in chronic pain management.

Randomized, Controlled, Crossover Study of Self-administered Jacobson Relaxation in Chronic, Nonspecific, Low-back Pain.

CONTEXT: Opioids decrease pain and improve functional capacity and quality of life; however, they are not always effective and are associated with harmful side effects. Few studies have shown that relaxation-based therapies, in comparison with usual care, can decrease pain. OBJECTIVE: The objective of the study was to investigate whether a controlled relaxation treatment, Jacobson progressive muscular relaxation (PMR), was effective in relieving chronic low-back pain (CLBP) and reducing pain comorbidities. The research team hypothesized that PMR-controlled relaxation could be more effective in reducing CLBP than music. DESIGN: The research team designed a randomized, controlled, crossover study. SETTING: The study took place in the pain unit, a clinic, in the Department of Health at Alicante-General Hospital (Alicante, Spain). PARTICIPANTS: Participants in this study were 58 adults with nononcological CLBP, secondary to lumbar canal stenosis, who had been treated with opioids without any changes in the 3 mo prior to the study. INTERVENTION: Participants were randomly assigned to 1 of 2 groups, each of which received 2 treatments, but in a different order (ie, either AB or BA where A was the standardized PMR, the intervention, and B was relaxing music, the control. For both groups, the 2 treatment periods were 8 wk in length, with a 1-mo washout period between them. OUTCOME MEASURES: The primary outcome measures included (1) a visual analogue scale-pain and relief intensity; (2) the 12-item short form health survey-quality of life; (3) the hospital anxiety and depression scale-anxiety and depression; and (4) the medical outcomes study sleep scale-sleep disturbances. Secondary outcome measures included a self-efficacy scale and a measure of satisfaction with treatment and compliance. RESULTS: Pain was mostly mild to moderate. Greater decreases in pain between baseline and postintervention were observed for the PMR vs the control treatment in the mild pain category, with a VAS difference of 1.8 cm and P = .018. Significant differences were also found in anxiety, depression, quality of life, and sleep between participants in the 3 pain categories. Self-rated adherence was high. CONCLUSIONS: Findings support the efficacy and acceptability of a self-guided PMR intervention for reducing CLBP with minimal time with a therapist.

The relationship of salivary testosterone and male sexual dysfunction in opioid-associated androgen deficiency (OPIAD).

BACKGROUND: Opioids are an effective treatment for chronic non-malignant pain (CNP). Long-term use risks and side effects such as opioid-induced androgen deficiency (OPIAD) exist. This could be measured by saliva testosterone (Sal-T). OBJECTIVES: To evaluate OPIAD in long-term opioid use in CNP patients. METHODS: A cross-sectional study included CNP male outpatients under opioid treatment. Total-Testosterone (Total-T), Free-Testosterone (Free-T), Bio-Testosterone (Bio-T) and Sal-T were measured. Correlations were calculated by Spearman's rho (SPSS 20). RESULTS: From 2012 to 2014, 134 from 249 (54%) consecutive male outpatients reported erectile dysfunction (ED), 37% of them related to opioids and 19% evidenced OPIAD. A total of 120 subjects (94 cases and 26 matched-controls) were included. A significantly lower luteinizing hormone, Total-T and Free-T were found, as well as, a significant correlation between Sal-T and Total-T (r = 0.234, p = 0.039), Bio-T (r = 0.241, p = 0.039), IIEF (r = 0.363, p = 0.003) and HAD-anxiety (r = -0.414, p = 0.012) in OPIAD patients. Sal-T levels were significantly lower in patients with severe-moderate ED versus mild ED (p = 0.045) and in patients with severe ED versus moderate-mild ED (p = 0.036). CONCLUSIONS: These data demonstrate the high prevalence of ED in long-term use of opioids, part of this is associated to OPIAD, which can be tested by Sal-T as a non-invasive approach.

Opioids Increase Sexual Dysfunction in Patients With Non-Cancer Pain.

INTRODUCTION: Long-term opioid therapy has been found to have a strong impact on the hypothalamic-pituitary-gonadal axis that can be manifested clinically by sexual dysfunction (SD). This event is rarely reported and thus unnoticed and undertreated. AIM: To analyze the presence of SD in a large group of patients receiving long-term opioids. METHODS: A descriptive, cross-sectional pilot study of sexual health was conducted for 2 years in 750 consecutive ambulatory patients with chronic non-cancer pain (CNP) receiving opioids for at least 12 months. Cases that reported SD and matched controls were included. Standardized questionnaires and medical record reviews were used to assess rates of pain at diagnosis, daily morphine equivalent doses, and opioid adverse effects. MAIN OUTCOME MEASURES: Sexual function was determined by the Female Sexual Function Index (FSFI; scores = 2-36) and the International Index of Erectile Function erectile function domain (IIEF-EF; scores = 1-30). RESULTS: Thirty-three percent of 33% of 750 patients with CNP recorded SD based on their spontaneous notification at the pain unit. Men reported SD significantly more frequently than women (33% vs 25%, respectively, P < .05), although they reported having a regular partner (84% vs 70%, P = .03) and a sexually active life (69% vs 34%, respectively, P = .00) significantly more often. FSFI scores were significantly influenced by sexual activity in lubrication and arousal. IIEF scores were significantly determined by age in satisfaction with sexual intercourse and overall satisfaction. The morphine equivalent dose was significant higher in men than in women (38%; median = 70 mg/d, interquartile range = 43.1-170, 115.5 ± 110.3 mg/d vs median = 60 mg/d, interquartile range = 30-100.6, 76.67 ± 63.79 mg/d, P = .016) at the same mean intensity of pain (P = .54), which correlated to FSFI scores (r = -0.313, P = .01). CONCLUSION: SD is prevalent in patients with CNP and higher in men who received a significantly higher mean opioid dose at the same intensity pain level than women. The morphine equivalent dose was correlated to SD intensity. Evidence-based interventions to support sexual activity and function in CNP are needed.

The Tobacco mosaic virus movement protein associates with but does not integrate into biological membranes.

UNLABELLED: Plant positive-strand RNA viruses require association with plant cell endomembranes for viral translation and replication, as well as for intra- and intercellular movement of the viral progeny. The membrane association and RNA binding of the Tobacco mosaic virus (TMV) movement protein (MP) are vital for orchestrating the macromolecular network required for virus movement. A previously proposed topological model suggests that TMV MP is an integral membrane protein with two putative α-helical transmembrane (TM) segments. Here we tested this model using an experimental system that measured the efficiency with which natural polypeptide segments were inserted into the ER membrane under conditions approximating the in vivo situation, as well as in planta. Our results demonstrated that the two hydrophobic regions (HRs) of TMV MP do not span biological membranes. We further found that mutations to alter the hydrophobicity of the first HR modified membrane association and precluded virus movement. We propose a topological model in which the TMV MP HRs intimately associate with the cellular membranes, allowing maximum exposure of the hydrophilic domains of the MP to the cytoplasmic cellular components. IMPORTANCE: To facilitate plant viral infection and spread, viruses encode one or more movement proteins (MPs) that interact with ER membranes. The present work investigated the membrane association of the 30K MP of Tobacco mosaic virus (TMV), and the results challenge the previous topological model, which predicted that the TMV MP behaves as an integral membrane protein. The current data provide greatly needed clarification of the topological model and provide substantial evidence that TMV MP is membrane associated only at the cytoplasmic face of the membrane and that neither of its domains is integrated into the membrane or translocated into the lumen. Understanding the topology of MPs in the ER is vital for understanding the role of the ER in plant virus transport and for predicting interactions with host factors that mediate resistance to plant viruses.

Clinical prediction of opioid use disorder in chronic pain patients: a cohort-retrospective study with a pharmacogenetic approach.

BACKGROUND: Opioids are widely used in chronic non-cancer pain (CNCP) management. However, they remain controversial due to serious risk of causing opioid use disorder (OUD). Our main aim was to develop a predictive model for future clinical translation that include pharmacogenetic markers. METHODS: An observational study was conducted in 806 pre-screened Spanish CNCP patients, under long-term use of opioids, to compare cases (with OUD, N.=137) with controls (without OUD, N.=669). Mu-opioid receptor 1 (OPRM1, A118G, rs1799971) and catechol-O-methyltransferase (COMT, G472A, rs4680) genetic variants plus cytochrome P450 2D6 (CYP2D6) liver enzyme phenotypes were analyzed. Socio-demographic, clinical and pharmacological outcomes were also registered. A logistic regression model was performed. The model performance and diagnostic accuracy were calculated. RESULTS: OPRM1-AA genotype and CYP2D6 poor and ultrarapid metabolizers together with three other potential predictors: 1) age; 2) work disability; 3) oral morphine equivalent daily dose (MEDD), were selected with a satisfactory diagnostic accuracy (sensitivity: 0.82 and specificity: 0.85), goodness of fit (P=0.87) and discrimination (0.89). Cases were ten-year younger with lower incomes, more sleep disturbances, benzodiazepines use, and history of substance use disorder in front of controls. CONCLUSIONS: Functional polymorphisms related to OPRM1 variant and CYP2D6 phenotypes may predict a higher OUD risk. Established risk factors such as young age, elevated MEDD and lower incomes were identified. A predictive model is expected to be implemented in clinical setting among CNCP patients under long-term opioids use.

Erectile dysfunction in cardiovascular patients: A prospective study of the eNOS gene T-786C, G894T, and INTRON variable number of the tandem repeat functional interaction.

BACKGROUND: Cardiovascular disease induces erectile dysfunction modulated by endothelial nitric oxide synthase enzyme and an impaired ejection fraction that restricts penis vascular congestion. However, the mechanisms regulating endothelial dysfunction are not understood. OBJECTIVES: Exploring the functional impact of endothelial nitric oxide synthase genetic polymorphisms on erectile dysfunction and drug therapy optimization in high-risk cardiovascular disease patients. MATERIALS AND METHODS: Patients with erectile dysfunction symptoms and candidates for andrology therapy were included (n = 112). Clinical data and endothelial nitric oxide synthase rs1799983 (G894T) and rs2070744 (T-786C), genotyped by fluorescence polarization assays, were registered. The 27-bp variable number of the tandem repeat polymorphism in intron 4 (intron4b/a) was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Association analyses were run with the R-3.2.0 software. RESULTS: A significant association between endothelial nitric oxide synthase 786-TT (p = 0.005) and the aa/ac of intron 4 variable number of the tandem repeat (p = 0.02) with higher erectile dysfunction susceptibility was observed in cardiovascular disease patients (60 ± 9 years, 66% severe erectile dysfunction, 56% ejection fraction). After 3-months of phosphodiesterase type 5 inhibitors, erectile dysfunction (International Index of Erectile Function, 50 ± 16 scores, the International Index of Erectile Function-Erectile Function 21 ± 10 scores, p < 0.001) and sexual quality of life (modified Sexual Life Quality Questionnaire 55 ± 23 scores, p < 0.001) had significantly improved. The cardiovascular ejection fraction was influenced positively with better sexual quality of life (0.1941), and also in the endothelial nitric oxide synthase G894-T allele (p = 0.076) carriers, which could merit future analyses. Erectile dysfunction was present as the primary clinical manifestation in 62% of cases, with cardiovascular disease occurring concurrently. Only former smokers and obese subjects debuted prior to cardiovascular disease than to erectile dysfunction. CONCLUSIONS: Our study provides comprehensive insights into the functional interaction linking endothelial nitric oxide synthase gene polymorphisms, erectile function, and ejection fraction in high-risk cardiovascular disease patients. Future therapeutic strategies could target endothelial nitric oxide synthase activity by including lifestyle changes and epigenetic modulations.

Health-Related Quality of Life in Chronic Pain Treated With Tapentadol Versus Oxycodone/Naloxone and Its Determinants: A Real-World, Single-Center Retrospective Cohort Study in Spain.

OBJECTIVES: A substantial proportion of patients with chronic noncancer pain (CNCP) are treated with tapentadol (TAP) or oxycodone/naloxone (OXN) to improve their perceived physical and mental health over time. METHODS: A cross-sectional study was conducted in 135 CNCP outpatients with usual prescribing (TAP: n = 58, OXN: n = 77) at a tertiary-care Spanish Hospital to compare health-related quality-of-life (HRQoL) records. Health utility was derived from the EQ-5D-3L. Regression models were performed to search for other HRQoL determinants. Pain intensity, relief, analgesic prescription, adverse events, inpatient stays, emergency department visits, and change to painkiller prescriptions were registered from electronic records. RESULTS: Health utility (0.43 ± 0.24 scores, from -0.654 to 1) was similar for both opioids, although TAP showed a significantly low daily opioid dose requirement, neuromodulators use, and constipation side effect compared with OXN. After multivariable adjustment, the significant predictors of impaired HRQoL were pain intensity (ß = -0.227, 95% CI -0-035 to -0.005), number of adverse events (ß = -0.201, 95% CI -0.024 to -0.004), and opioid daily dose (ß = -0.175, 95% CI -0.097 to -0.012). Male sex (ß = -0.044) and pain relief (ß = 0.158) should be taken into account for future studies. CONCLUSIONS: HRQoL was similar for TAP and OXN in real-world patients with CNCP, albeit with a TAP opioid-sparing effect. More work is needed to explore HRQoL determinants in relation to long-term opioid use in CNCP.

Circulating miRNA-21 is an innovative biomarker for cardiovascular events in erectile dysfunction patients.

Introduction: It is well-known that circulating microRNAs (miRNAs) play a relevant role in many kinds of diseases by regulating the expression of genes involved in various pathophysiologic processes, including erectile dysfunction (ED) and cardiovascular diseases (CVD). Purpose: This study aimed to identify the miRNA-21 profile in the blood samples of patients with ED, CVD, and the combination of both pathologies to elucidate the potential function of miRNA-21. Methods: A total of 45 patients with CVD and/or who underwent the erectile function test were included and divided into the following categories: CVD with ED (cases, n = 29) and controls (n = 16) with either ED or CVD. Real-time polymerase chain reaction analysis verified the results. miRNA-21 expression was quantified, and informatics analysis was applied to predict the functions of this differentially expressed miRNA-21. Results: A total of 64% of cases (63 ± 9 years, 66% with severe ED, 56% with CV ejection fraction) first presented ED as the sentinel clinical manifestation. Serum miRNA-21 levels in the control ED were significant, up to 10-fold higher than in the CVD controls and cases. A significant inverse (p = 0.0368, ß = -2.046) correlation was found between erectile function and miRNA-21 levels. Conclusions: Our study provides comprehensive insights into the functional interaction between miRNA-21 and ED in CVD patients. Its relevance lies in the potential of miRNA as a biomarker to be applied in the cardiovascular predictive medicine field.

Systemic transport of Alfalfa mosaic virus can be mediated by the movement proteins of several viruses assigned to five genera of the 30K family.

We previously showed that the movement protein (MP) gene of Alfalfa mosaic virus (AMV) is functionally exchangeable for the cell-to-cell transport of the corresponding genes of Tobacco mosaic virus (TMV), Brome mosaic virus, Prunus necrotic ringspot virus, Cucumber mosaic virus and Cowpea mosaic virus. We have analysed the capacity of the heterologous MPs to systemically transport the corresponding chimeric AMV genome. All MPs were competent in systemic transport but required the fusion at their C terminus of the coat protein-interacting C-terminal 44 aa (A44) of the AMV MP. Except for the TMV MP, the presence of the hybrid virus in upper leaves correlated with the capacity to move locally. These results suggest that all the MPs assigned to the 30K superfamily should be exchangeable not only for local virus movement but also for systemic transport when the A44 fragment is present.