A novel long non-coding RNA connects obesity to impaired adipocyte function.

BACKGROUND: Long non-coding RNAs (lncRNAs) can perform tasks of key relevance in fat cells, contributing, when defective, to the burden of obesity and its sequelae. Here, scrutiny of adipose tissue transcriptomes before and after bariatric surgery (GSE53378) granted identification of 496 lncRNAs linked to the obese phenotype. Only expression of linc-GALNTL6-4 displayed an average recovery over 2-fold and FDR-adjusted p-value <0.0001 after weight loss. The aim of the present study was to investigate the impact on adipocyte function and potential clinical value of impaired adipose linc-GALNTL6-4 in obese subjects. METHODS: We employed transcriptomic analysis of public dataset GSE199063, and cross validations in two large transversal cohorts to report evidence of a previously unknown association of adipose linc-GALNTL6-4 with obesity. We then performed functional analyses in human adipocyte cultures, genome-wide transcriptomics, and untargeted lipidomics in cell models of loss and gain of function to explore the molecular implications of its associations with obesity and weight loss. RESULTS: The expression of linc-GALNTL6-4 in human adipose tissue is adipocyte-specific and co-segregates with obesity, being normalized upon weight loss. This co-segregation is demonstrated in two longitudinal weight loss studies and two cross-sectional samples. While compromised expression of linc-GALNTL6-4 in obese subjects is primarily due to the inflammatory component in the context of obesity, adipogenesis requires the transcriptional upregulation of linc-GALNTL6-4, the expression of which reaches an apex in terminally differentiated adipocytes. Functionally, we demonstrated that the knockdown of linc-GALNTL6-4 impairs adipogenesis, induces alterations in the lipidome, and leads to the downregulation of genes related to cell cycle, while propelling in adipocytes inflammation, impaired fatty acid metabolism, and altered gene expression patterns, including that of apolipoprotein C1 (APOC1). Conversely, the genetic gain of linc-GALNTL6-4 ameliorated differentiation and adipocyte phenotype, putatively by constraining APOC1, also contributing to the metabolism of triglycerides in adipose. CONCLUSIONS: Current data unveil the unforeseen connection of adipocyte-specific linc-GALNTL6-4 as a modulator of lipid homeostasis challenged by excessive body weight and meta-inflammation.

Reward processing in young people with self-harm behaviour.

Twenty percent of young people report a lifetime presence of self-harm (SH) behaviour, associated with negative health and functional outcomes. Understanding the underlying cognitive mechanisms is needed to develop targeted early interventions. Reward processing biases may underlie SH, aligning with accounts of the behaviour acquiring "addictive" characteristics. However, the specific nature of such biases remains unclear, particularly its relationship with negative affect (NA) that frequently triggers SH. In Study 1, we compared young people (aged 16-25) with SH to a group with NA but no SH history and a healthy control group on performance of a novel Incentive Delay Task (IDT), with SH-related (SH trials), positive social (social trials) or monetary images (money trials) as stimuli. In Study 2, a different sample of SH and HC participants completed the same IDT following NA induction via an online Trier Social Stress Test. For both studies, we hypothesised faster and more correct responses in the SH group than control groups on SH trials. Contradicting our hypothesis, there were no significant between-group differences in IDT performance on SH, social and money trials in either study. Certain SH characteristics (positive reinforcement, SH mental imagery, urge) were significantly correlated with better performance on SH trials in SH participants. Thus, broadly SH behaviour may not be underpinned by motivational biases towards SH-related cues or naturalistic rewards. Future studies should clarify whether incentivisation of SH-related cues instead explains individual differences in SH behaviour and its relation with treatment and prognosis.

Efficacy and safety of an ultra-low-dose 0.005 % estriol vaginal gel in the prevention of urinary tract infections in postmenopausal women with genitourinary syndrome of menopause: A randomized double-blind placebo-controlled trial.

OBJECTIVES: This study evaluated the efficacy of an ultra-low-dose 0.005 % estriol vaginal gel in the prevention of urinary tract infections in postmenopausal women with genitourinary syndrome of menopause. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter clinical trial conducted across 28 Spanish sites involving specialists in gynecology, urology, and primary care. A total of 108 postmenopausal women were randomly assigned in a 1:1 ratio to receive 1 g of vaginal gel with 50 micrograms of estriol or an identical moisturizing vaginal gel without estriol. MAIN OUTCOME MEASURES: The primary outcome was the number of episodes of urinary tract infection by the end of the 24-week treatment. Secondary measures encompassed percentage of patients without recurrence, time to first recurrence, use of antibiotic treatment, vaginal pH, safety, and tolerability, among others. RESULTS: The incidence rate of urinary tract infections (new cases per 100 women-year) was 26 % lower in the group that received estriol vs. the group that received placebo (32.34 vs. 43.76 (RR = 0.74) p < 0.001). The frequency of urinary tract infections fell during treatment in all patients in the estriol group. Favorable pH changes from baseline were observed in the estriol arm at all follow-up visits. CONCLUSIONS: Ultra-low-dose 0.005 % estriol vaginal gel is safe and effective in preventing recurrent urinary tract infections in postmenopausal women with genitourinary syndrome of menopause, reducing the incidence and potentially decreasing the susceptibility to urogenital infections by improving vaginal pH. Study registration N°: 2018-001481-42. Date of registration: 09-04-2018.

Allogenic bone marrow-derived mesenchymal stromal cell-based therapy for patients with chronic low back pain: a prospective, multicentre, randomised placebo controlled trial (RESPINE study).

OBJECTIVES: To assess the efficacy of a single intradiscal injection of allogeneic bone marrow mesenchymal stromal cells (BM-MSCs) versus a sham placebo in patients with chronic low back pain (LBP). METHODS: Participants were randomised in a prospective, double-blind, controlled study to receive either sham injection or intradiscal injection of 20 million allogeneic BM-MSC, between April 2018 and December 2022. The first co-primary endpoint was the rate of responders defined by improvement of the Visual Analogue Scale (VAS) for pain of at least 20% and 20 mm, or improvement of the Oswestry Disability Index (ODI) of 20% between baseline and month 12. The secondary structural co-primary endpoint was assessed by the disc fluid content measured by quantitative MRI T2, between baseline and month 12. Secondary endpoints included pain VAS, ODI, the Short Form (SF)-36 and the minimal clinically important difference in all timepoints (1, 3, 6, 12 and 24 months). We determined the immune response associated with allogeneic cell injection between baseline and 6 months. Serious adverse events (SAEs) were recorded. RESULTS: 114 patients were randomised (n=58, BM-MSC group; n=56, sham placebo group). At 12 months, the primary outcome was not reached (74% in the BM-MSC group vs 69% in the placebo group; p=0.77). The groups did not differ in all secondary outcomes. No SAE related to the intervention occurred. CONCLUSIONS: While our study did not conclusively demonstrate the efficacy of allogeneic BM-MSCs for LBP, the procedure was safe. Long-term outcomes of MSC therapy for LBP are still being studied. TRIAL REGISTRATION NUMBER: EudraCT 2017-002092-25/ClinicalTrials.gov: NCT03737461.

Invasive neurophysiological recordings in human basal ganglia. What have we learned about non-motor behaviour?

Research into the function of deep brain structures has benefited greatly from microelectrode recordings in animals. This has helped to unravel physiological processes in the healthy and malfunctioning brain. Translation to the human is necessary for improving basic understanding of subcortical structures and their implications in diseases. The use of microelectrode recordings as a standard component of deep brain stimulation surgery offers the most viable route for studying the electrophysiology of single cells and local neuronal populations in important deep structures of the human brain. Most of the studies in the basal ganglia have targeted the motor loop and movement disorder pathophysiology. In recent years, however, research has diversified to include limbic and cognitive processes. This review aims to provide an overview of advances in neuroscience made using intraoperative and post-operative recordings with a focus on non-motor activity in the basal ganglia.

CAR expression in invasive breast carcinoma and its effect on adenovirus transduction efficiency.

BACKGROUND: Breast cancer is the second leading cause of death in women, with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) as the two most common forms of invasive breast cancer. While estrogen receptor positive (ER+) IDC and ILC are treated similarly, the multifocality of ILC presents challenges in detection and treatment, worsening long-term clinical outcomes in patients. With increasing documentation of chemoresistance in ILC, additional treatment options are needed. Oncolytic adenoviral therapy may be a promising option, but cancer cells must express the coxsackievirus & adenovirus receptor (CAR) for adenoviral therapy to be effective. The present study aims to evaluate the extent to which CAR expression is observed in ILC in comparison to IDC, and how the levels of CAR expression correlate with adenovirus transduction efficiency. The effect of liposome encapsulation on transduction efficiency is also assessed. METHODS: To characterize CAR expression in invasive breast carcinoma, 36 formalin-fixed paraffin-embedded (FFPE) human breast tumor samples were assayed by CAR immunohistochemistry (IHC). Localization of CAR in comparison to other junctional proteins was performed using a multiplex immunofluorescence panel consisting of CAR, p120-catenin, and E-cadherin. ILC and IDC primary tumors and cell lines were transduced with E1- and E3-deleted adenovirus type 5 inserted with a GFP transgene (Ad-GFP) and DOTAP liposome encapsulated Ad-GFP (DfAd-GFP) at various multiplicities of infection (MOIs). Transduction efficiency was measured using a fluorescence plate reader. CAR expression in the human primary breast carcinomas and cell lines was also evaluated by IHC. RESULTS: We observed membranous CAR, p120-catenin and E-cadherin expression in IDC. In ILC, we observed cytoplasmic expression of CAR and p120-catenin, with absent E-cadherin. Adenovirus effectively transduced high-CAR IDC cell lines, at MOIs as low as 12.5. Ad-GFP showed similar transduction as DfAd-GFP in high-CAR IDC cell lines. Conversely, Ad-GFP transduction of ILC cell lines was observed only at MOIs of 50 and 100. Furthermore, Ad-GFP did not transduce CAR-negative IDC cell lines even at MOIs greater than 100. Liposome encapsulation (DfAd-GFP) improved transduction efficiency 4-fold in ILC and 17-fold in CAR-negative IDC cell lines. CONCLUSION: The present study demonstrates that oncolytic adenoviral therapy is less effective in ILC than IDC due to differences in spatial CAR expression. Liposome-enhanced delivery may be beneficial for patients with ILC and tumors with low or negative CAR expression to improve adenoviral therapeutic effectiveness.

Impact of a social media-delivered distance learning program on mhGAP training among primary care providers in Jalisco, Mexico.

BACKGROUND: The World Health Organization's (WHO) Mental Health Gap Action Programme (mhGAP) aims to provide evidence-based guidelines for the management of mental, neurological, and substance use disorders in non-specialized healthcare settings. However, implementing these guidelines remains a challenge due to various factors, including limited training opportunities for primary care providers. This study con the effectiveness of a social media-delivered distance education program on the mhGAP intervention guide, to overcome barriers of technology access and digital literacy, providing a familiar and accessible platform for primary care providers in Jalisco. METHODS: A quasi-experimental study with a pre-test/post-test design was conducted. Primary care providers from Jalisco were invited to participate in a distance education program on the mhGAP intervention guide. The program consisted of online modules, webinars, and discussion forums facilitated by mental health experts. Knowledge assessments were conducted before and after the intervention using a standardized questionnaire. Participant satisfaction and perceived utility were also evaluated through surveys and focus group discussions. RESULTS: A total of 1,096 primary care providers completed the program. The mean knowledge score significantly improved from 58.2% (SD = 12.8%) in the pre-test to 81.4% (SD = 9.6%) in the post-test (p < 0.001), with a large effect size (Cohen's d = 2.04). Subgroup analyses revealed consistent knowledge gains across different demographic and professional characteristics. Participant satisfaction was high, with 92% rating the program's overall quality as "good" or "excellent." Qualitative findings highlighted the benefits of accessibility, flexibility, interactivity, and practical applicability of the distance education approach. CONCLUSIONS: The social media-delivered distance education program on the mhGAP intervention guide effectively improved the knowledge of primary care providers in Jalisco, Mexico. Participants reported high levels of satisfaction and perceived utility. This study demonstrates the potential of distance education strategies to disseminate evidence-based guidelines and enhance mental health service delivery in primary care settings, particularly in resource-limited areas.

Screening for advanced liver disease incorporating the use of transitional elastography in primary care. / Detección de enfermedad hepática avanzada incorporando el uso de la elastografía de transición en atención primaria.

OBJECTIVES: To describe the proportion of patients with liver fibrosis in at-risk populations in primary care (PC). To know the agreement between FIB-4 and transitional elastography (TE), interobserver agreement between PC and hospital care (HC) in TE, and associated risk Factors (RF). METHODS: Observational, descriptive, cross-sectional study in ≥16 years of age with RF for chronic liver disease. Sex and age, RF (alteration of liver tests [LT], metabolic syndrome, diabetes, obesity, alcohol consumption, hepatic steatosis), and FIB-4, controlled attenuation parameter and TE in PC and in HC, were collected. According to a consensus algorithm, vibration-controlled TE was performed in PC in patients with FIB-4≥1,3, and those with measurement ≥8kPa were referred to HC. RESULTS: 326 patients were studied. 71% were not referred to HC, due to liver stiffness <8kPa. 83 of the 95 derivations did TE in HC. 45 (54%) had TE ≥8, and 25 (30%) ≥12. The proportion of patients with stiffness ≥8kPa was 13,8% (45/326) and ≥12kPa, 7,6% (25/326). The predictive values of the FIB-4 were low. The interobserver correlation coefficient between TE in PC and HC was 0,433. Variables associated with TE ≥8 in PC: LT alteration, diabetes and steatosis. With TE ≥12: LT alteration, diabetes and obesity. PREDICTOR VARIABLES: LT alteration and obesity. CONCLUSIONS: The study supports the sequential performance of serum indices and TE as a screening for fibrosis in the at-risk population in PC, which allows a reduction in the percentage of patients referred to AH, and a better stratification of risk patients.

First consensus document of waiting list prioritization for liver transplantation by the Spanish Society of Liver Transplantation (SETH).

Spain is worldwide leader in deceased donation rates per million habitants and count on a strong network of twenty-five liver transplant institutions. Although the access to liver transplantation is higher than in other countries, approximately 10% of patients qualifying for liver transplantation in Spain will die in the waiting list or would be excluded due to clinical deterioration. A robust waiting list prioritization system is paramount to grant the sickest patients with the first positions in the waiting list for an earlier access to transplant. In addition, the allocation policy may not create or perpetuate inequities, particularly in a public and universal healthcare system. Hitherto, Spain lacks a unique national allocation system for elective liver transplantation. Most institutions establish their own rules for liver allocation and only two autonomous regions, namely Andalucía and Cataluña, share part of their waiting list within their territory to provide regional priority to patients requiring more urgent transplantation. This heterogeneity is further aggravated by the recently described sex-based disparities for accessing liver transplantation in Spain, and by the expansion of liver transplant indications, mainly for oncological indications, in absence of clear guidance on the optimal prioritization policy. The present document contains the recommendations from the first consensus of waiting list prioritization for liver transplantation issued by the Spanish Society of Liver Transplantation (SETH). The document was supported by all liver transplant institutions in Spain and by the Organización Nacional de Trasplantes (ONT). Its implementation will allow to homogenize practices and to improve equity and outcomes among patients with end-stage liver disease.

Transitions and Long-Term Clinical Outcomes in Patients Admitted in Intensive Care Units Receiving Continuous Renal Replacement Therapy.

Introduction: Acute kidney injury (AKI) significantly disrupts vital renal functions and is a common and serious condition in intensive care units (ICUs). AKI leads to extended hospital stays, increases mortality rates, and often necessitates nephrology consultations. Continuous renal replacement therapy (CRRT) plays a central role in managing AKI, requiring a multidisciplinary approach involving nephrologists, intensivists, and anesthesiologists. This study examines the clinical profile and progression of AKI in ICU patients requiring CRRT, with a focus on CRRT indications and modalities. Materials and Methods: We conducted a single-center retrospective observational study on ICU patients with AKI requiring CRRT from January to December 2019. AKI diagnosis followed the RIFLE criteria, and patients who received CRRT for less than 36 h were excluded. Data collected included demographics, hemodynamic parameters, and renal function parameters, with follow-ups at 1 week, 1 month, 6 months, and 12 months. Statistical analyses evaluated outcomes and transitions between CRRT and other renal replacement therapies. Results: Among 123 evaluated patients, 95 met inclusion criteria. Fifteen patients received CRRT for less than 36 h, with an early mortality rate of 80%. The final cohort comprised 80 patients who underwent CRRT for over 36 h, with a mean age of 65.3 years (SD = 13.6) and a Charlson index of 6.4. Patients were categorized based on primary diagnosis into heart failure, cardiac surgery, sepsis, other surgeries, and miscellanea groups. Mortality rates were highest in the heart failure and miscellanea groups. Significant variability was observed in therapy transitions and long-term outcomes. Continuous venovenous hemodiafiltration (CVVHDF) was the most frequently used CRRT modality. Conclusions: This study highlights the variability in CRRT practices and the poor prognosis for critically ill patients with AKI requiring CRRT. Timely nephrology consultation and tailored treatment plans may improve patient outcomes and optimize CRRT utilization. Future research should focus on refining CRRT protocols and exploring preventive strategies for AKI.

The impact of the embryonic DNA methylation program on CTCF-mediated genome regulation.

During mammalian embryogenesis, both the 5-cytosine DNA methylation (5meC) landscape and three dimensional (3D) chromatin architecture are profoundly remodeled during a process known as 'epigenetic reprogramming.' An understudied aspect of epigenetic reprogramming is how the 5meC flux, per se, affects the 3D genome. This is pertinent given the 5meC-sensitivity of DNA binding for a key regulator of chromosome folding: CTCF. We profiled the CTCF binding landscape using a mouse embryonic stem cell (ESC) differentiation protocol that models embryonic 5meC dynamics. Mouse ESCs lacking DNA methylation machinery are able to exit naive pluripotency, thus allowing for dissection of subtle effects of CTCF on gene expression. We performed CTCF HiChIP in both wild-type and mutant conditions to assess gained CTCF-CTCF contacts in the absence of 5meC. We performed H3K27ac HiChIP to determine the impact that ectopic CTCF binding has on cis-regulatory contacts. Using 5meC epigenome editing, we demonstrated that the methyl-mark is able to impair CTCF binding at select loci. Finally, a detailed dissection of the imprinted Zdbf2 locus showed how 5meC-antagonism of CTCF allows for proper gene regulation during differentiation. This work provides a comprehensive overview of how 5meC impacts the 3D genome in a relevant model for early embryonic events.

Safety, pharmacokinetics, and pharmacodynamics of LBP-EC01, a CRISPR-Cas3-enhanced bacteriophage cocktail, in uncomplicated urinary tract infections due to Escherichia coli (ELIMINATE): the randomised, open-label, first part of a two-part phase 2 trial.

BACKGROUND: The rate of antibiotic resistance continues to grow, outpacing small-molecule-drug development efforts. Novel therapies are needed to combat this growing threat, particularly for the treatment of urinary tract infections (UTIs), which are one of the largest contributors to antibiotic use and associated antibiotic resistance. LBP-EC01 is a novel, genetically enhanced, six-bacteriophage cocktail developed by Locus Biosciences (Morrisville, NC, USA) to address UTIs caused by Escherichia coli, regardless of antibiotic resistance status. In this first part of the two-part phase 2 ELIMINATE trial, we aimed to define a dosing regimen of LBP-EC01 for the treatment of uncomplicated UTIs that could advance to the second, randomised, controlled, double-blinded portion of the study. METHODS: This first part of ELIMINATE is a randomised, uncontrolled, open-label, phase 2 trial that took place in six private clinical sites in the USA. Eligible participants were female by self-identification, aged between 18 years and 70 years, and had an uncomplicated UTI at the time of enrolment, as well as a history of at least one drug-resistant UTI caused by E coli within the 12 months before enrolment. Participants were initially randomised in a 1:1:1 ratio into three treatment groups, but this part of the trial was terminated on the recommendation of the safety review committee after a non-serious tolerability signal was observed based on systemic drug exposure. A protocol update was then implemented, comprised of three new treatment groups. Groups A to C were dosed with intraurethral 2 × 1012 plaque-forming units (PFU) of LBP-EC01 on days 1 and 2 by catheter, plus one of three intravenous doses daily on days 1-3 of LBP-EC01 (1 mL of 1 × 1010 PFU intravenous bolus in group A, 1 mL of 1 × 109 PFU intravenous bolus in group B, and a 2 h 1 × 1011 PFU intravenous infusion in 100 mL of sodium lactate solution in group C). In all groups, oral trimethoprim-sulfamethoxazole (TMP-SMX; 160 mg and 800 mg) was given twice daily on days 1-3. The primary outcome was the level of LBP-EC01 in urine and blood across the treatment period and over 48 h after the last dose and was assessed in patients in the intention-to-treat (ITT) population who received at least one dose of LBP-EC01 and had concentration-time data available throughout the days 1-3 dosing period (pharmacokinetic population). Safety, a secondary endpoint, was assessed in enrolled patients who received at least one dose of study drug (safety population). As exploratory pharmacodynamic endpoints, we assessed E coli levels in urine and clinical symptoms of UTI in patients with at least 1·0 × 105 colony-forming units per mL E coli in urine at baseline who took at least one dose of study drug and completed their day 10 test-of-cure assessment (pharmacodynamic-evaluable population). This trial is registered with ClinicalTrials.gov, NCT05488340, and is ongoing. FINDINGS: Between Aug 22, 2022, and Aug 28, 2023, 44 patients were screened for eligibility, and 39 were randomly assigned (ITT population). Initially, eight participants were assigned to the first three groups. After the protocol was updated, 31 participants were allocated into groups A (11 patients), B (ten patients), and C (ten patients). One patient in group C withdrew consent on day 2 for personal reasons, but as she had received the first dose of the study drug was included in the modified ITT population. Maximum urine drug concentrations were consistent across intraurethral dosing, with a maximum mean concentration of 6·3 × 108 PFU per mL (geometric mean 8·8 log10 PFU per mL and geometric SD [gSD] 0·3). Blood plasma level of bacteriophages was intravenous dose-dependent, with maximum mean concentrations of 4·0 × 103 (geometric mean 3·6 log10 PFU per mL [gSD 1·5]) in group A, 2·5 × 103 (3·4 log10 PFU per mL [1·7]) in group B, and 8·0 × 105 (5·9 log10 PFU per mL [1·4]) in group C. No serious adverse events were observed. 44 adverse events were reported across 18 (46%) of the 39 participants in the safety population, with more adverse events seen with higher intravenous doses. Three patients in groups 1 to 3 and one patient in group C, all of whom received 1 × 1011 LBP-EC01 intravenously, had non-serious tachycardia and afebrile chills after the second intravenous dose. A rapid reduction of E coli in urine was observed by 4 h after the first treatment and maintained at day 10 in all 16 evaluable patients; these individuals had complete resolution of UTI symptoms by day 10. INTERPRETATION: A regimen consisting of 2 days of intraurethral LBP-EC01 and 3 days of concurrent intravenous LBP-EC01 (1 × 1010 PFU) and oral TMP-SMX twice a day was well tolerated, with consistent pharmacokinetic profiles in urine and blood. LBP-EC01 and TMP-SMX dosing resulted in a rapid and durable reduction of E coli, with corresponding elimination of clinical symptoms in evaluable patients. LBP-EC01 holds promise in providing an alternative therapy for uncomplicated UTIs, with further testing of the group A dosing regimen planned in the controlled, double-blind, second part of ELIMINATE. FUNDING: Federal funds from the US Department of Health and Human Services, Administration for Strategic Preparedness and Response, and Biomedical Advanced Research and Development Authority (BARDA).

Causal attributions of impulsive and compulsive behaviors.

Introduction: Aggression, and therefore gender-based violence, can be an impulsive or compulsive behavior, depending on the consumption of alcohol and/or drugs. In Europe, the prevalence of gender-based violence is 16 to 23%. This prevalence shows that there is a need to make further progress in the treatment of aggression against women. Qualitative techniques allow us to understand perceptions and attributions holistically by analyzing what people who commit the crime say, why they say it and how they say it. Aim: To explore the experience of physical and verbal aggression by a partner, dependent on the presence or absence of alcohol and drug use, in the prison population. Method: A mixed methodology was used (combining qualitative and quantitative techniques). The sample was made up of 140 men divided into two focus groups [with alcohol and/or drug consumption (SAD) and without alcohol and/or drug consumption (NSAD)] who completed the Demographic, Criminal and Behavioral Interview in Penitentiary Institutions; the Gender Violence Questionnaire (both developed for this study) and the MultiCAGE CAD-4 Questionnaire. Qualitative data were analyzed using thematic analysis and quantitative data were obtained using contingency tables. Results: It was found that the SAD group attributed the crime committed to alcohol and/or drug consumption, while the NSAD group attributed it to jealousy and to their partner. The SAD group revealed that the consequence of the physical aggressions was to get what they were looking for from their partner and the consequences of the verbal aggressions was regret, unlike the NSAD group that did not get anything from the aggressions. The SAD group recognized that to avoid future aggressions they would have to avoid alcohol and/or drug use, while the NSAD group mentioned that they would have to avoid contact with their partner. Discussion: The need to include perceptions and attributions as well as the use of alcohol and/or drugs is emphasized when assessing individuals who commit the crime of gender-based violence.

Exploración del conducto en C con tomografía computada de haz cónico / Exploration of C-shaped canals with cone-beam computed tomography

El «conducto en C¼ es un tipo de anatomía dentaria compleja que debe ser evaluado previo a la realiza- ción de un tratamiento endodóntico. Esta variación anatómica es vista principalmente en segundos mola- res inferiores aunque también puede encontrarse en premolares y molares, tanto superior como inferior. Para su diagnóstico se solicitan distintos tipos de estudios imagenológicos. Debemos tener en cuenta que este tipo de anatomía no es observado fácilmen- te en imágenes bidimensionales por lo cual es muy importante considerar para estos casos complejos, la solicitud de un estudio de alta complejidad como lo es la tomografía computada de haz cónico, la cual nos permitirá explorar este tipo de anatomía para tenerlo en cuenta al momento de realizar un correcto aborda- je del conducto en C (AU)

The "C-canal" is a type of complex dental anatomy that must be evaluated prior to performing endodontic treatment. This anatomical variation is seen mainly in lower second molars although it can also be found in premolars and molars, both upper and lower. For its diagnosis we can use different types of imaging studies. We must keep in mind that this type of anatomy is not easily observed in two-dimensional images, which is why it is very important to consider, for these complex cases, the request for a highly complex study such as cone beam computed tomography, which will allow us to explore this type of anatomy to take it into account when performing a correct approach to the C-duct (AU)

In situ forming PLA and PLGA implants for the parenteral administration of Cannabidiol.

Cannabidiol (CBD) is the main non-psychotropic cannabinoid. It has attracted a great deal of interest in the treatment of several diseases such as inflammatory disorders and cancer. Despite its promising clinical interest, its administration is very challenging. In situ forming implants (ISFIs) could be a simple and cheap strategy to administer CBD while obtaining a prolonged effect with a single administration. This work aims to design, develop, and characterize for the first time ISFIs for the parenteral administration of CBD with potential application in cancer disease. Formulations made of PLGA-502, PLGA-502H, and PLA-202 in NMP or DMSO and PLA-203 in DMSO at a polymer concentration of 0.25 mg/µL and loaded with CBD at a drug: polymer ratio of 2.5:100 and 5:100 (w/w) were developed. The formulations prepared with NMP exhibited a faster drug release. CBD implants elaborated with PLGA-502 and DMSO with the highest CBD: polymer ratio showed the most suitable drug release for one month. This formulation was successfully formed in ovo onto the chorioallantoic chick membrane without exhibiting signs of toxicity and exhibited a superior antiangiogenic activity than CBD in solution administered at the same doses. Consequently, implants made of PLGA-502 and DMSO represent a promising strategy to effectively administer CBD subcutaneously as combination therapy in cancer disease.

Growth fitness, virulence, and heat tolerance of Salmonella Typhimurium variants resistant to food preservation methods.

To study potential ramifications of antimicrobial resistance, we carried out adaptive laboratory evolution assays (ALE) to isolate three resistant variants (RVs) of Salmonella enterica Typhimurium, employing three different types of food preservation methods: 1) an emergent technology, plasma-activated water (PAW), leading to variant RV-PAW; a traditional method, heat, leading to variant RV-HT, and a natural antimicrobial compound, carvacrol, leading to variant RV-CAR. The variant resistant to plasma-activated water, RV-PAW, had mutations in rpoA and rpoD; it showed increased tolerance to heat in orange juice but ultimately did not pose a significant threat, as it exhibited a fitness cost at refrigeration temperature (8 °C), whereas its virulence against Caenorhabditis elegans decreased. The variant resistant to heat, RV-HT, had mutations in flhC, dnaJ: it exhibited a fitness cost at high growth temperatures (43 °C) and induced morphofunctional alterations in C. elegans. The variant resistant to carvacrol, RV-CAR, had mutations in sseG, flhA, wbaV, lon; this variant not only exhibited significantly higher thermotolerance in both laboratory media and food models but also effectively increased its growth fitness at refrigeration temperatures while retaining its virulence, evidenced by the highest percentage of Smurf phenotype in C. elegans. To address these challenges, we applied a process combining thermal treatment with citral, with the aim of leveraging the sublethal damage caused in RVs by heat treatments in orange juice. This approach achieves enhanced microbial inactivation without having to escalate the intensity of the thermal treatment. The result was particularly encouraging in the case of RV-CAR, the most challenging strain, for which we improved lethality by up to 3 log10 inactivation cycles.

Hepatitis C virus NS5A and core protein induce fibrosis-related genes regulation on Huh7 cells through activation of LX2 cells.

INTRODUCTION AND OBJECTIVES: Liver fibrosis remains a complication derived from a chronic Hepatitis C Virus (HCV) infection even when it is resolved, and no liver antifibrotic drug has been approved. Molecular mechanisms on hepatocytes and activation of hepatic stellate cells (HSCs) play a central role in liver fibrogenesis. To elucidate molecular mechanisms, it is important to analyze pathway regulation during HSC activation and HCV infection. MATERIALS AND METHODS: We evaluate the fibrosis-associated molecular mechanisms during a co-culture of human HSCs (LX2), with human hepatocytes (Huh7) that express HCV NS5A or Core protein. We evaluated LX2 activation induced by HCV NS5A or Core expression in Huh7 cells during co-culture. We determined a fibrosis-associated gene expression profile in Huh7 that expresses NS5A or Core proteins during the co-culture with LX2. RESULTS: We observed that NS5A induced 8.3-, 6.7- and 4-fold changes and that Core induced 6.5-, 1.8-, and 6.2-fold changes in the collagen1, TGFß1, and timp1 gene expression, respectively, in LX2 co-cultured with transfected Huh7. In addition, NS5A induced the expression of 30 genes while Core induced 41 genes and reduced the expression of 30 genes related to fibrosis in Huh7 cells during the co-culture with LX2, compared to control. The molecular pathways enriched from the gene expression profile were involved in TGFB signaling and the organization of extracellular matrix. CONCLUSIONS: We demonstrated that HCV NS5A and Core protein expression regulate LX2 activation. NS5A and Core-induced LX2 activation, in turn, regulates diverse fibrosis-related gene expression at different levels in Huh7, which can be further analyzed as potential antifibrotic targets during HCV infection.

Activities and genetic interactions of fission yeast Aps1, a Nudix-type inositol pyrophosphatase and inorganic polyphosphatase.

Inositol pyrophosphate 1,5-IP8 regulates expression of a fission yeast phosphate homeostasis regulon, comprising phosphate acquisition genes pho1, pho84, and tgp1, via its action as an agonist of precocious termination of transcription of the upstream lncRNAs that repress PHO mRNA synthesis. 1,5-IP8 levels are dictated by a balance between the Asp1 N-terminal kinase domain that converts 5-IP7 to 1,5-IP8 and three inositol pyrophosphatases-the Asp1 C-terminal domain (a histidine acid phosphatase), Siw14 (a cysteinyl-phosphatase), and Aps1 (a Nudix enzyme). In this study, we report the biochemical and genetic characterization of Aps1 and an analysis of the effects of Asp1, Siw14, and Aps1 mutations on cellular inositol pyrophosphate levels. We find that Aps1's substrate repertoire embraces inorganic polyphosphates, 5-IP7, 1-IP7, and 1,5-IP8. Aps1 displays a ~twofold preference for hydrolysis of 1-IP7 versus 5-IP7 and aps1∆ cells have twofold higher levels of 1-IP7 vis-à-vis wild-type cells. While neither Aps1 nor Siw14 is essential for growth, an aps1∆ siw14∆ double mutation is lethal on YES medium. This lethality is a manifestation of IP8 toxicosis, whereby excessive 1,5-IP8 drives derepression of tgp1, leading to Tgp1-mediated uptake of glycerophosphocholine. We were able to recover an aps1∆ siw14∆ mutant on ePMGT medium lacking glycerophosphocholine and to suppress the severe growth defect of aps1∆ siw14∆ on YES by deleting tgp1. However, the severe growth defect of an aps1∆ asp1-H397A strain could not be alleviated by deleting tgp1, suggesting that 1,5-IP8 levels in this double-pyrophosphatase mutant exceed a threshold beyond which overzealous termination affects other genes, which results in cytotoxicity. IMPORTANCE: Repression of the fission yeast PHO genes tgp1, pho1, and pho84 by lncRNA-mediated interference is sensitive to changes in the metabolism of 1,5-IP8, a signaling molecule that acts as an agonist of precocious lncRNA termination. 1,5-IP8 is formed by phosphorylation of 5-IP7 and catabolized by inositol pyrophosphatases from three distinct enzyme families: Asp1 (a histidine acid phosphatase), Siw14 (a cysteinyl phosphatase), and Aps1 (a Nudix hydrolase). This study entails a biochemical characterization of Aps1 and an analysis of how Asp1, Siw14, and Aps1 mutations impact growth and inositol pyrophosphate pools in vivo. Aps1 catalyzes hydrolysis of inorganic polyphosphates, 5-IP7, 1-IP7, and 1,5-IP8 in vitro, with a ~twofold preference for 1-IP7 over 5-IP7. aps1∆ cells have twofold higher levels of 1-IP7 than wild-type cells. An aps1∆ siw14∆ double mutation is lethal because excessive 1,5-IP8 triggers derepression of tgp1, leading to toxic uptake of glycerophosphocholine.

Unveiling relevant emotions, cognitions, and behaviours from the viewpoint of people with chronic low back pain: A qualitative study with patient involvement.

OBJECTIVE: To gain insight into the emotions, cognitions, and behaviours experienced by people with chronic low back pain (CLBP) undergoing invasive treatment in a pain unit. DESIGN: A cross-sectional qualitative study based on individual interviews. This study included patient involvement in its design and development. METHODS: An interpretative phenomenological approach was adopted to understand the multidimensional experience of patients. The interview script was a translated, adapted, and expanded version of the one proposed by Cognitive and Functional Therapy. A mixed coding method was applied to structure the interviews. Three themes were created, with the three most frequently reported emotions, cognitions, and behaviours as subthemes. A patient with CLBP approved the initial protocol and the aim of the study. Subsequently, the patient contributed questions to the interview script, checked the coding process, and approved the final version of the manuscript. RESULTS: Twenty-two patients undergoing epidural infiltrations in a pain unit were interviewed. (i)"Fears", (ii)"Frustration", and (iii)"Worry" were the three most commonly expressed emotions. Cognitions related to (i)"Pain predictability", (ii)"Pain description and perception", and (iii)"Pain interference/disability" were also widely reported. The theme "Behaviours" was composed of the following subthemes: (i)"Strategies for managing symptoms", (ii)"Social behaviours", and (iii)"Strategies for coping with daily tasks". Noteworthily, cognitions related to the (i)"Diagnosis", (ii)"Health system attention", and (iii)"Medical prescriptions" arose from questions provided by patient involvement. CONCLUSION: Patients with CLBP expressed a wide variety of emotions, cognitions, and behaviours that must be considered by health professionals with the goal of providing the best patient-centred care.

Aging suppresses subthalamic neuronal activity in patients with Parkinson's disease.

Age is a primary risk factor for Parkinson's disease (PD); however, the effects of aging on the Parkinsonian brain remain poorly understood, particularly for deep brain structures. We investigated intraoperative micro-electrode recordings from the subthalamic nucleus (STN) of PD patients aged between 42 and 76 years. Age was associated with decreased oscillatory beta power and non-oscillatory high-frequency power, independent of PD-related variables. Single unit firing and burst rates were also reduced, whereas the coefficient of variation and the structure of burst activity were unchanged. Phase synchronization (debiased weighed phase lag index [dWPLI]) between sites was pronounced in the beta band between electrodes in the superficial STN but was unaffected by age. Our results show that aging is associated with reduced neuronal activity without changes to its temporal structure. We speculate that the loss of activity in the STN may mediate the relationship between PD and age.