The use of healthcare services and disabling chronic pain: results from the cross-sectional population-based Andalusian Health Survey.

BACKGROUND: Several factors seem to be related to the use of healthcare services, and chronic pain (CP) is among these characteristics. The objective is to describe the number of visits to a doctor's surgery or emergency rooms, and the periods of hospitalization; to identify characteristics associated with frequent healthcare use, including disabling chronic pain (DCP) and non-disabling chronic pain (n-DCP). METHODS: Representative population-based cross-sectional study of 6569 people older than 16 years from southern Spain was collected. The frequency of visits to a doctor's surgery or emergency rooms and periods of hospitalization were defined as at or above the 90th percentile. Binary logistic regression analyses were conducted separately on women and men to identify characteristics associated with being frequent visitors. RESULTS: People with DCP are more frequent visitors to a doctor's surgery and emergency rooms and endure longer periods of hospitalization compared to people with n-DCP and without pain. In logistic regression models, people with DCP are twice as likely to over-visit a doctor's surgery; to endure longer periods of hospitalization and more visits to an emergency room service. No relationship was found in n-DCP. CONCLUSIONS: Disability seems to modulate a greater use of health services among the population with CP, doubling it when compared to n-DCP and n-CP, both in women and men. Understanding the role of disability in the use of healthcare services for individuals with CP allows for the identification of needs and strategies to optimize resources.

A rare case of Salmonella-associated acute pancreatitis in a patient with ulcerative colitis.

Inflammatory bowel disease is a known risk factor for enteric infections such as Salmonella. This infection can affect almost all major organs. Acute Salmonella pancreatitis is a rare complication. This is the case of a 61-year-old man with ulcerative colitis who developed acute pancreatitis complicating Salmonella infection.

Endoscopic Vacuum Therapy for Upper Gastrointestinal Leaks and Perforations: Analysis From a Multicenter Spanish Registry.

INTRODUCTION: Endoscopic vacuum therapy (EVT) is a novel technique for closing upper gastrointestinal (UGI) defects. Available literature includes single-center retrospective cohort studies with small sample sizes. Furthermore, evidence about factors associated with EVT failure is scarce. We aimed to assess the efficacy and safety of EVT for the resolution of UGI defects in a multicenter study and to investigate the factors associated with EVT failure and in-hospital mortality. METHODS: This is a prospective cohort study in which consecutive EVT procedures for the treatment of UGI defects from 19 Spanish hospitals were recorded in the national registry between November 2018 and March 2022. RESULTS: We included 102 patients: 89 with anastomotic leaks and 13 with perforations. Closure of the defect was achieved in 84 cases (82%). A total of 6 patients (5.9%) had adverse events related to the EVT. The in-hospital mortality rate was 12.7%. A total of 6 patients (5.9%) died because of EVT failure and 1 case (0.9%) due to a fatal adverse event. Time from diagnosis of the defect to initiation of EVT was the only independent predictor for EVT failure (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05, P = 0.005). EVT failure (OR 24.5, 95% CI 4.5-133, P = 0.001) and development of pneumonia after EVT (OR 246.97, 95% CI 11.15-5,472.58, P = 0.0001) were independent predictors of in-hospital mortality. DISCUSSION: EVT is safe and effective in cases of anastomotic leak and perforations of the upper digestive tract. The early use of EVT improves the efficacy of this technique.

Evaluation of adherence monitoring in buprenorphine treatment: A pilot study using timed drug assays to determine accuracy of testing.

AIMS: Buprenorphine is effective at reducing relapse to opioid misuse, morbidity and mortality in opioid-dependent patients. Urine drug screening (UDS) to assess adherence is used routinely in opioid agonist treatment (OAT). The primary aim of this study was to determine factors which may be associated with a negative qualitative urine drug screen for buprenorphine in OAT patients. METHODS: This prospective pilot study was conducted at a tertiary addiction medicine centre. Twenty participants on stable treatment underwent supervised administration of sublingual buprenorphine. Matched urine and blood samples were collected prior to and 2, 4 and 6 hours after buprenorphine administration. Qualitative urine drug screen results were obtained using gas chromatography-mass spectrometry (GC-MS), while quantitative blood and urine results were obtained using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Qualitative urine assay yielded a negative result for buprenorphine in 57% of tested samples. The median concentration of urinary buprenorphine was 167 mcg/L (range: 2-1730 mcg/L). Thirty percent of all blood samples did not detect buprenorphine (range 0-18 mcg/L). Positive qualitative urine drug screen results were associated with higher urine (343 mcg/L compared with 75 mcg/L; P < .05) and blood (4 mcg/L compared with 2 mcg/L; P < .05) buprenorphine concentrations. Median urine concentrations of buprenorphine were highest at 2 hours and were higher in participants receiving CYP3A4 inhibitors. CONCLUSION: Interpretation of qualitative urine drug screens to assess adherence in OAT is complex. Poor adherence with treatment cannot be assumed in patients returning a negative qualitative GC-MS urine drug screen.

NMDA receptor antagonists reduce amyloid-ß deposition by modulating calpain-1 signaling and autophagy, rescuing cognitive impairment in 5XFAD mice.

Overstimulation of N-methyl-D-aspartate receptors (NMDARs) is the leading cause of brain excitotoxicity and often contributes to neurodegenerative diseases such as Alzheimer's Disease (AD), the most common form of dementia. This study aimed to evaluate a new NMDA receptor antagonist (UB-ALT-EV) and memantine in 6-month-old female 5XFAD mice that were exposed orally to a chronic low-dose treatment. Behavioral and cognitive tests confirmed better cognitive performance in both treated groups. Calcium-dependent protein calpain-1 reduction was found after UB-ALT-EV treatment but not after memantine. Changes in spectrin breakdown products (SBDP) and the p25/p35 ratio confirmed diminished calpain-1 activity. Amyloid ß (Aß) production and deposition was evaluated in 5XFAD mice and demonstrated a robust effect of NMDAR antagonists on reducing Aß deposition and the number and size of Thioflavin-S positive plaques. Furthermore, glycogen synthase kinase 3ß (GSK3ß) active form and phosphorylated tau (AT8) levels were diminished after UB-ALT-EV treatment, revealing tau pathology improvement. Because calpain-1 is involved in autophagy activation, autophagic proteins were studied. Strikingly, results showed changes in the protein levels of unc-51-like kinase (ULK-1), beclin-1, microtubule-associated protein 1A/1B-light chain 3(LC3B-II)/LC3B-I ratio, and lysosomal-associated membrane protein 1 (LAMP-1) after NMDAR antagonist treatments, suggesting an accumulation of autophagolysosomes in 5XFAD mice, reversed by UB-ALT-EV. Likewise, treatment with UB-ALT-EV recovered a WT mice profile in apoptosis markers Bcl-2, Bax, and caspase-3. In conclusion, our results revealed the potential neuroprotective effect of UB-ALT-EV by attenuating NMDA-mediated apoptosis and reducing Aß deposition and deposition jointly with the autophagy rescue to finally reduce cognitive alterations in a mice model of familial AD.

Design and Synthesis of AMPK Activators and GDF15 Inducers.

Targeting growth differentiation factor 15 (GDF15) is a recent strategy for the treatment of obesity and type 2 diabetes mellitus (T2DM). Here, we designed, synthesized, and pharmacologically evaluated in vitro a novel series of AMPK activators to upregulate GDF15 levels. These compounds were structurally based on the (1-dibenzylamino-3-phenoxy)propan-2-ol structure of the orphan ubiquitin E3 ligase subunit protein Fbxo48 inhibitor, BC1618. This molecule showed a better potency than metformin, increasing GDF15 mRNA levels in human Huh-7 hepatic cells. Based on BC1618, structural modifications have been performed to create a collection of diversely substituted new molecules. Of the thirty-five new compounds evaluated, compound 21 showed a higher increase in GDF15 mRNA levels compared with BC1618. Metformin, BC1618, and compound 21 increased phosphorylated AMPK, but only 21 increased GDF15 protein levels. Overall, these findings indicate that 21 has a unique capacity to increase GDF15 protein levels in human hepatic cells compared with metformin and BC1618.

A slightly different polyp: melanoma metastasis diagnosed by colonoscopy.

Melanoma metastases are rare in the colon. Its diagnosis is difficult because they do not usually produce symptoms. They can present through the endoscopic image of a non-pigmented polyp. This is the case of a 56-year-old woman diagnosed with melanoma metastasis through polypectomy of an unusual-looking polyp.

Alcohol, Tobacco and Psychotropic Drugs Use Among a Population with Chronic Pain in Southern Spain. A Cross-Sectional Study.

BACKGROUND: Substance use seems to be higher among populations with chronic pain. AIM: The aim of this study is to examine the relationship between the quantity of alcohol, tobacco, and psychotropic drugs consumed and chronic pain among women and men. METHOD: Linear and logistic regression analyses were carried out using data from the 2015-2016 adults' version of the Andalusian Health Survey which is a representative cross-sectional population-based study (n = 6,569 adults aged >16 years; 50.8% women; 49.2% men). RESULTS: Disabling chronic pain was statistically associated with higher tobacco consumption among men (ß = -30.0, 95% confidenct interval [CI] -59.5 to -0.60; t = -2.0; p < .05). Regarding alcohol, non-disabling chronic pain and a higher quantity of alcohol consumed are statistically associated for both sexes (women: ß = 30.4, 95% CI 2.3-58.6; t = 2.12; p < .05 vs. men: ß = 164.2, 95% CI 24.3-340.1); t = 2.30; p < .05). For women and men, both disabling chronic pain (women: odds ratio [OR] = 8.7, 95% CI 6.0-12.7); p < .05 vs. men: OR = 3.5, 95% CI 1.5-8.2); p < .05) and non-disabling chronic pain (women: OR = 3.7, 95% CI 2.0-7.0); p <.05 vs. men: OR = 4.7, 95% CI 95% CI 1.5-14.9); p < .05) were statistically significantly associated with a higher consumption of psychotropic drugs. CONCLUSIONS: Chronic pain may be related to the quantity of alcohol, tobacco, and psychotropic drugs consumed, and disability appears to be one of the factors that modulates this relationship.

Incidence of inflammatory bowel disease and phenotype at diagnosis in 2011: results of the Epi-IBD 2011 study in the Vigo area.

OBJECTIVE: to validate the incidence of inflammatory bowel disease (IBD) reported in Vigo in 2010 within the Epi-IBD study, which was the highest incidence reported so far in Spain. METHODS: an epidemiological, prospective, population-based inception cohort study. All incident cases of IBD living in the Vigo area at diagnosis from January 1 to December 31, 2011 were included. RESULTS: one hundred patients were diagnosed (62 % men; median age, 43.27 years): 49 with ulcerative colitis (UC), 34 with Crohn's disease (CD), and 17 with IBD unclassified (IBDU). The incidence (per 100,000 inhabitants/year) was 17.56 (CD: 5.97; UC: 8.60; IBDU: 2.98), similar to that reported in 2010. The incidence in the non-pediatric population was 19.66 (CD: 6.89, UC: 9.52; IBDU: 3.04). CD and UC phenotype was similar in 2010 and 2011. CONCLUSION: this study supports the increased incidence of EII in the Vigo area reported in 2010.

In Vitro, In Vivo, and Absorption, Distribution, Metabolism, and Excretion Evaluation of SF5-Containing N,N'-Diarylureas as Antischistosomal Agents.

In recent years, N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a parasite-caused disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N'-diarylureas featuring the scarcely explored pentafluorosulfanyl group (SF5). Low 50% inhibitory concentration (IC50) values for Schistosoma mansoni newly transformed schistosomula (0.6 to 7.7 µM) and adult worms (0.1 to 1.6 µM) were observed. Four selected compounds that were highly active in the presence of albumin (>70% at 10 µM), endowed with decent cytotoxicity profiles (selectivity index [SI] against L6 cells >8.5), and good microsomal hepatic stability (>62.5% of drug remaining after 60 min) were tested in S. mansoni-infected mice. Despite the promising in vitro worm-killing potency, none of them showed significant activity in vivo. Pharmacokinetic data showed a slow absorption, with maximal drug concentrations reached after 24 h of exposure. Finally, no direct correlation between drug exposure and in vivo activity was found. Thus, further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.

Inhibition of Soluble Epoxide Hydrolase Ameliorates Phenotype and Cognitive Abilities in a Murine Model of Niemann Pick Type C Disease.

Niemann-Pick type C (NPC) disease is a rare autosomal recessive inherited childhood neurodegenerative disease characterized by the accumulation of cholesterol and glycosphingolipids, involving the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 12-diols, exerts beneficial effects in modulating inflammation and autophagy, critical features of the NPC disease. This study aims to evaluate the effects of UB-EV-52, an sEH inhibitor (sEHi), in an NPC mouse model (Npc) by administering it for 4 weeks (5 mg/kg/day). Behavioral and cognitive tests (open-field test (OF)), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that the treatment produced an improvement in short- and long-term memory as well as in spatial memory. Furthermore, UB-EV-52 treatment increased body weight and lifespan by 25% and reduced gene expression of the inflammatory markers (i.e., Il-1ß and Mcp1) and enhanced oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. As for autophagic markers, surprisingly, we found significantly reduced levels of LC3B-II/LC3B-I ratio and significantly reduced brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in treated Npc mice group compared to untreated ones in hippocampal tissue. Lipid profile analysis showed a significant reduction of lipid storage in the liver and some slight changes in homogenated brain tissue in the treated NPC mice compared to the untreated groups. Therefore, our results suggest that pharmacological inhibition of sEH ameliorates most of the characteristic features of NPC mice, demonstrating that sEH can be considered a potential therapeutic target for this disease.

Synthesis, Characterization and HPLC Analysis of the (1S,2S,5R)-Diastereomer and the Enantiomer of the Clinical Candidate AR-15512.

AR-15512 (formerly known as AVX-012 and WS-12) is a TRPM8 receptor agonist currently in phase 2b clinical trials for the treatment of dry eye. This bioactive compound with menthol-like cooling activity has three stereogenic centers, and its final structure and absolute configuration, (1R,2S,5R), have been previously solved by cryo-electron microscopy. The route of synthesis of AR-15512 has also been reported, revealing that epimerization processes at the C-1 can occur at specific stages of the synthesis. In order to confirm that the desired configuration of AR-15512 does not change throughout the process and to discard the presence of the enantiomer in the final product due to possible contamination of the initial starting material, both the enantiomer of AR-15512 and the diastereomer at the C-1 were synthesized and fully characterized. In addition, the absolute configuration of the (1S,2S,5R)-diastereomer was determined by X-ray crystallographic analysis, and new HPLC methods were designed and developed for the identification of the two stereoisomers and their comparison with the clinical candidate AR-15512.

Exploratory study on the presence of bisphenol A and bis(2-ethylhexyl) phthalate in the Santa Catarina River in Monterrey, N.L., Mexico.

The current problem related to the supply of drinking water for the metropolitan area of Monterrey, which comprises of five million inhabitants, and the important role played by the El Cuchillo Dam, found downstream of the Santa Catarina River basin as a surface source of drinking water for the city, renders this river an interesting site for assessment. This work evaluates the degree to which the surface water and the subsoil of the river are affected by emerging organic pollutants due to their existence, even at low concentrations, representing a toxic risk enhanced by the absence of stricter standards for regulating these substances. Based on fieldwork, three discharge points that could affect the quality of the surface water were selected: two points on the river stream, and three groundwater wells. Gas chromatography results showed the presence of BisPhenol A (BPA) and bis(2-EthylHexyl) Phthalate (DEHP) in both the surface water and subsoil at different seasons of the year. The highest concentration levels in the samples taken from both types of water were 0.9 and 60 µg L-1 for BPA and DEHP, respectively. Results of this research did not reveal the level at which the aquifer is affected by these substances.

Chronic non-cancer pain management by nurses in specialist pain clinics.

BACKGROUND: Chronic non-cancer pain (CNCP) is one of the major causes of disability globally, and patients who suffer from it are a complex population, which makes it difficult to provide effective care. Specialist pain clinics and nursing professionals in them are the main care providers, but there is little research conducted in this field. AIM: To explore the attitudes and knowledge of nurses working in specialist pain clinics regarding care of CNCP patients. METHODS: Qualitative phenomenological approach. Sixteen semi-structured interviews were conducted in 2017 with nurses who worked in specialist pain clinics in six hospitals in southern Spain. RESULTS: Data analysis led to the formation of two categories, 'being trained and improving knowledge in CNCP' and 'the challenge of caring for patients with CNCP', and five subcategories. CONCLUSION: The need for care in CNCP is not covered by nurses in all the areas it requires. Lack of time, staffing issues, and specific training in this area makes it difficult to provide care. However, some areas for improvement are proposed, such as psychological interventions, group workshops, continuous training, and multidisciplinary teams.

Exploring the size of the lipophilic unit of the soluble epoxide hydrolase inhibitors.

Soluble epoxide hydrolase (sEH) inhibitors are potential drugs for several diseases. Adamantyl ureas are excellent sEH inhibitors but have limited metabolic stability. Herein, we report the effect of replacing the adamantane group by alternative polycyclic hydrocarbons on sEH inhibition, solubility, permeability and metabolic stability. Compounds bearing smaller or larger polycyclic hydrocarbons than adamantane yielded all good inhibition potency of the human sEH (0.4 ≤ IC50 ≤ 21.7 nM), indicating that sEH is able to accommodate inhibitors of very different size. Human liver microsomal stability of diamantane containing inhibitors is lower than that of their corresponding adamantane counterparts.

Comparative Study of Coupling Techniques in Lamb Wave Testing of Metallic and Cementitious Plates.

Lamb waves have emerged as a valuable tool to examine long plate-like structures in a faster way compared to conventional bulk wave techniques, which make them attractive in non-destructive testing. However, they present a multimodal and dispersive nature, which hinders signal identification. Oblique incidence is one of the most known methods to generate and receive Lamb waves and it is applied in different experimental arrangements with different types of sensors. In this work, several setups were conducted and compared to determine the optimal ones to launch and detect ultrasonic Lamb waves, especially in non-homogeneous specimens. The chosen arrangements were contact with angle beam transducers, immersion in a water tank, localised water coupling using conical containers and air coupling. Plates of two different materials were used, stainless steel and Portland cement mortar. Theoretical and experimental dispersion curves were compared to verify the existence of Lamb modes and good correspondence was achieved.

Metastatic tumors in the pancreas: the role of endoscopic ultrasound-guided fine-needle aspiration.

BACKGROUND AND OBJECTIVES: there are few published data on the use of EUS guided fine-needle aspiration in secondary pancreatic lesions. We describe the largest series published so far in a European country. PATIENTS AND METHODS: a retrospective review of the cases identified in our institution from 2004 to 2016 has been recorded. The clinical data are described, comparing the latency period from the primary tumor diagnosis to the detection of the pancreatic metastasis and the survival of patients according to the cytological diagnosis. RESULTS: forty-four patients were diagnosed with pancreatic metastasis using EUS guided fine needle aspiration. Ancillary cytological studies were performed in 28 (63.6%). The most common primary tumor sites were kidney and lung. Thirty-four patients (77.3%) had a previous history of malignancy, with a latency period ranging from 6 months to 18.8 years. Patients diagnosed with primary renal carcinoma had a significantly longer latency period and longer survival compared to those with primary lung cancer. In 13 patients, EUS was either the only technique that detected the PM or showed a greater number of intrapancreatic lesions. These metastases were significantly smaller than those diagnosed by other imaging studies (11.9 ± 4.1 mm vs 30.7 ± 19.8 mm, p < 0.001). CONCLUSIONS: EUS guided fine-needle aspiration plays a crucial role in the diagnosis of pancreatic metastases and may have a major clinical impact. Patients with renal cell carcinoma could benefit from long-term follow-up with EUS.

lme4qtl: linear mixed models with flexible covariance structure for genetic studies of related individuals.

BACKGROUND: Quantitative trait locus (QTL) mapping in genetic data often involves analysis of correlated observations, which need to be accounted for to avoid false association signals. This is commonly performed by modeling such correlations as random effects in linear mixed models (LMMs). The R package lme4 is a well-established tool that implements major LMM features using sparse matrix methods; however, it is not fully adapted for QTL mapping association and linkage studies. In particular, two LMM features are lacking in the base version of lme4: the definition of random effects by custom covariance matrices; and parameter constraints, which are essential in advanced QTL models. Apart from applications in linkage studies of related individuals, such functionalities are of high interest for association studies in situations where multiple covariance matrices need to be modeled, a scenario not covered by many genome-wide association study (GWAS) software. RESULTS: To address the aforementioned limitations, we developed a new R package lme4qtl as an extension of lme4. First, lme4qtl contributes new models for genetic studies within a single tool integrated with lme4 and its companion packages. Second, lme4qtl offers a flexible framework for scenarios with multiple levels of relatedness and becomes efficient when covariance matrices are sparse. We showed the value of our package using real family-based data in the Genetic Analysis of Idiopathic Thrombophilia 2 (GAIT2) project. CONCLUSIONS: Our software lme4qtl enables QTL mapping models with a versatile structure of random effects and efficient computation for sparse covariances. lme4qtl is available at https://github.com/variani/lme4qtl .

Role of capsule endoscopy in alarm features and non-responsive celiac disease: A European multicenter study.

BACKGROUND AND AIM: The role of capsule endoscopy (CE) in established celiac disease (CD) remains unclear. Our objective was to analyze the usefulness of CE in the suspicion of complicated CD. METHODS: This was a retrospective multicenter study. One hundred and eighty-nine celiac patients (mean age: 46.6 ± 16.6, 30.2% males) who underwent CE for alarm symptoms (n = 86, 45.5%) or non-responsive CD (n = 103, 54.5%) were included. Diagnostic yield (DY), therapeutic impact and safety were analyzed. RESULTS: Capsule endoscopy was completed in 95.2% of patients (small bowel transit time: 270.5 ± 100.2 min). Global DY was 67.2%, detecting atrophic mucosa (n = 92, 48.7%), ulcerative jejunoileitis (n = 21, 11.1%), intestinal lymphoma (n = 7, 3.7%) and other enteropathies (n = 7, 3.7%, six Crohn's disease cases and one neuroendocrine tumor). The DY of CE was significantly higher in patients presenting with non-responsive disease compared to patients with alarm symptoms (73.8% vs 59.3%, P = 0.035). The new findings of the CE modified management in 59.3% of the cases. There were no major complications. CONCLUSION: Capsule endoscopy may be a moderately helpful and safe diagnostic tool in the suspicion of complicated CD, modifying the clinical course of these patients.

Exploring N-acyl-4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-enes as 11ß-HSD1 Inhibitors.

We recently found that a cyclohexanecarboxamide derived from 4-azatetracyclo[5.3.2.02,6.08,10]dodec-11-ene displayed low nanomolar inhibition of 11ß-HSD1. In continuation of our efforts to discover potent and selective 11ß-HSD1 inhibitors, herein we explored several replacements for the cyclohexane ring. Some derivatives exhibited potent inhibitory activity against human 11ß-HSD1, although with low selectivity over the isoenzyme 11ß-HSD2, and poor microsomal stability.