Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease.

Importance: The involvement of chronic inflammation in the pathogenesis of age-related macular degeneration (AMD) opens therapeutic possibilities to AMD management. Objective: To determine whether Janus kinase inhibitors (JAKis) are associated with a reduced risk of AMD development in patients with autoimmune diseases. Design, Setting, and Participants: This retrospective observational cohort study used administrative claims data from Merative MarketScan research databases (Commercial and Medicare Supplemental) and Optum Clinformatics Data Mart databases between January 1, 2010, and January 31, 2022. Patients with autoimmune diseases satisfying study eligibility criteria and who received JAKi treatment (9126 in MarketScan and 5667 in Optum) were propensity score matched (1:1) to identical numbers of study-eligible patients who received non-JAKi-based immunotherapy. Exposure: Treatment duration of 6 months or longer. Main Outcomes and Measures: Incidence rates of AMD (exudative and nonexudative) over the first 6 to 18 months of treatment were determined, and bayesian Poisson regression models were used to estimate incidence rate ratios, 95% CIs, and posterior probabilities of AMD. Results: After matching, female sex represented the majority of the patient population in both MarketScan and Optum (14 019/18 252 [76.6%] and 8563/3364 [75.2%], respectively in the JAKi patient population). More than 60% of the patient population was older than 55 years of age in both cohorts. Over the specified treatment period, a 49% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (10/9126 events; adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19-0.90) vs those who received non-JAKi therapy (43/9126 events; AIRR, 1 [reference]) in MarketScan, and a 73% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (3/5667 events; AIRR, 0.27; 95% CI, 0.03-0.74) vs those who received non-JAKi therapy (21/5667 events; AIRR, 1 [reference]) in Optum. The absolute percentage reductions were 0.36% (MarketScan) and 0.32% (Optum), favoring patients who received JAKi therapy. Posterior probabilities of the adjusted risk being less than unity were 97.6% (MarketScan) and 98.9% (Optum) for those who received JAKi therapy vs those who received non-JAKi therapy in MarketScan and Optum, respectively. Conclusions and Relevance: JAKi use may be associated with a reduced risk of incident AMD in US adults with major autoimmune diseases. The absolute percentage reduction is consistent with a potential role for JAKi in this population. Future studies with long-term follow-up are recommended to investigate the association between JAKi use and incident AMD in other disease indications. Investigation into the role of systemic inflammation and JAK-signal transducers and activators of transcription signaling in AMD may improve understanding of the pathophysiology of AMD and lead to new treatment options.

Microstructural and physicochemical quality maintenance in green bell pepper infected with Botrytis cinerea and treated with thyme essential oil combined with carnauba wax.

Bell pepper presents rapid weight loss and is highly susceptible to gray mold caused by the fungus Botrytis cinerea. The most employed method to control this disease is the application of synthetic fungicides such as thiabendazole (TBZ); however, its continued use causes resistance in fungi as well as environmental problems. For these reasons, natural alternatives arise as a more striking option. Currently, bell pepper fruits are coated with carnauba wax (CW) to prevent weight loss and improve appearance. Moreover, CW can be used as a carrier to incorporate essential oils, and previous studies have shown that thyme essential oil (TEO) is highly effective against B. cinerea. Therefore, this study aimed to evaluate the effect of CW combined with TEO on the development of gray mold and maintenance of microestructural and postharvest quality in bell pepper stored at 13°C. The minimal inhibitory concentration of TEO was 0.5%. TEO and TBZ provoked the leakage of intracellular components. TEO and CW + TEO treatments were equally effective to inhibit the development of gray mold. On the quality parameters, firmness and weight loss were ameliorated with CW and CW + TEO treatments; whereas lightness increased in these treatments. The structural analysis showed that CW + TEO treatment maintained the cell structure reducing the apparition of deformities. The results suggest that CW + TEO treatment could be used as a natural and effective antifungal retarding the appearance of gray mold and maintaining the postharvest quality of bell pepper. PRACTICAL APPLICATION: CW and TEO are classified as generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA). This combination can be employed on the bell pepper packaging system to extend shelf life and oppose gray mold developments. Bell pepper fruits are normally coated with lipid-base coatings such as CW before commercialization; therefore, TEO addition would represent a small investment without any changes on the packaging system infrastructure.

Integrated modeling of labile and glycated hemoglobin with glucose for enhanced diabetes detection and short-term monitoring.

Metabolic biomarkers, particularly glycated hemoglobin and fasting plasma glucose, are pivotal in the diagnosis and control of diabetes mellitus. Despite their importance, they exhibit limitations in assessing short-term glucose variations. In this study, we propose labile hemoglobin as an additional biomarker, providing insightful perspectives into these fluctuations. By utilizing datasets from 40,652 retrospective general participants and conducting glucose tolerance tests on 60 prospective pediatric subjects, we explored the relationship between plasma glucose and labile hemoglobin. A mathematical model was developed to encapsulate short-term glucose kinetics in the pediatric group. Applying dimensionality reduction techniques, we successfully identified participant subclusters, facilitating the differentiation between diabetic and non-diabetic individuals. Intriguingly, by integrating labile hemoglobin measurements with plasma glucose values, we were able to predict the likelihood of diabetes in pediatric subjects, underscoring the potential of labile hemoglobin as a significant glycemic biomarker for diabetes research.

Persons With Chronic Obstructive Pulmonary Disease and High Levels of Activation Improved Their Physical Activity Skills After an Educational Session.

Background: Daily physical activity is part of the self-management of patients with chronic obstructive pulmonary disease (COPD), and didactic information sessions may be insufficient for the provision of these skills. Prior activation can determine sensitivity to these sessions. We evaluated whether the activation in patients with COPD, as measured by the Patient Activation Measure (PAM)-13 questionnaire, determined their responses to an educational group session on physical activity (PA), which were measured with actigraphy by the number of steps/day. Methods: We conducted an uncontrolled clinical trial in an outpatient clinic with 75 patients with nonexacerbating COPD (forced expiratory volume in 1 second 30%-80%) who were selected consecutively. Patients were provided with an actigraph that they used for 15 days and completed the PAM-13 questionnaire. On the eighth day, they attended a group educational session where they were given PA information. We compared the changes in activity after the session by pooled PAM levels and the correlation between the change in the number of steps/day and the PAM-13 questionnaire. Results: A total of 26 patients had activation levels of 1-2, while 49 patients had levels of 3-4. After the session, patients in Levels 1-2 decreased their number of steps (-596±42), while those in Levels 3-4 increased them (680±253, p<0.01). The level of activation was positively correlated with change in the number of steps/day (p<0.05). Conclusion: COPD patients with greater activation showed greater improvements in daily PA after a group educational session.

Comprehensive study on the potential environmental risk of temporal antibiotic usage through wastewater discharges.

Antibiotic residues can reach aquatic ecosystems through urban wastewater discharges, posing an ecotoxicological risk for aquatic organisms and favoring the development of bacterial resistance. To assess the emission rate and hazardousness of these compounds, it is important to carry out periodic chemical monitoring campaigns that provide information regarding the actual performance of wastewater treatment plants (WWTPs) and the potential impact of the treated wastewater in the aquatic environment. In this study, 18 of the most widely consumed antibiotics in Spain were determined by liquid chromatography-tandem mass spectrometry in both influent (IWW) and effluent wastewater (EWW) samples collected over four seasons along 2021-2022. Eleven antibiotics were detected in EWW with azithromycin, ciprofloxacin and levofloxacin showing the highest concentration levels (around 2 µg L-1 of azithromycin and 0.4 µg L-1 of quinolone compounds). Data showed that only 4 out of the 11 compounds were removed by more than 50 % in the WWTP, with sulfamethoxazole standing out with an average removal efficiency >80 %. The risk that treated water could pose to the aquatic environment was also assessed, with 6 compounds indicating a potential environmental risk by exceeding established ecotoxicological and resistance thresholds. Based on the risk assessment, the WWTP removal efficiency required to reduce such risk for antibiotics was estimated. In addition, pooled wastewater samples were screened by LC coupled to high resolution mass spectrometry with ion mobility separation, searching for metabolites and transformation products of the antibiotics investigated to widen future research. Studies like this are crucial to map the impact of antibiotic pollution and to provide the basis for designing water quality and risk prevention monitoring programs.

Evaluating the effects of counterconditioning, novelty-facilitated, and standard extinction on the spontaneous recovery of threat expectancy and conditioned stimulus valence.

Extinction training has proved effective to diminish the expectancy of the aversive unconditioned stimulus (US). However, the negative valence of the conditioned stimulus (CS) may still stay intact. In fact, several studies have suggested that the CS negative valence may be a factor that promotes the return of fear. Our study focuses on the role of changes in the CS valence as a potential mechanism to reduce the spontaneous recovery of threat expectancies. To do that, we evaluated counterconditioning (CC), a technique aimed to reduce the CS negative valence by paring it with a positive stimulus and compared its efficacy to that of a novelty-facilitated extinction (NFE) and a standard extinction interventions. Using a 2-day protocol, participants first learned the relationship between a figure and an aversive sound, using a differential conditioning paradigm, and were then randomly assigned to one of three different groups. For the CC group, CS+ or cue A was paired with a positive US. The standard extinction group was exposed to cue A alone. For a third NFE group, cue A was followed by a neutral US. Finally, on the second day, spontaneous recovery was tested. Our findings did not provide evidence to suggest that CC could be more effective to prevent or reduce the return of threat expectancies or influence valence ratings when compared with NFE and standard extinction.

Standards for the Use of Enteral Nutrition in Patients with Diabetes or Stress Hyperglycaemia: Expert Consensus.

(1) Background: Hyperglycaemia that occurs during enteral nutrition (EN) should be prevented and treated appropriately since it can have important consequences for morbidity and mortality. However, there are few quality studies in the literature regarding the management of EN in this situation. The objective of this project was to attempt to respond, through a panel of experts, to those clinical problems regarding EN in patients with diabetes or stress hyperglycaemia (hereinafter referred to only as hyperglycaemia) for which we do not have conclusive scientific evidence; (2) Methods: The RAND/UCLA Appropriateness Method, a modified Delphi panel method, was applied. A panel of experts made up of 10 clinical nutrition specialists was formed, and they scored on the appropriateness of EN in hyperglycaemia, doing so in two rounds. A total of 2992 clinical scenarios were examined, which were stratified into five chapters: type of formula used, method of administration, infusion site, treatment of diabetes, and gastrointestinal complications. (3) Results: consensus was detected in 36.4% of the clinical scenarios presented, of which 23.7% were deemed appropriate scenarios, while 12.7% were deemed inappropriate. The remaining 63.6% of the scenarios were classified as uncertain; (4) Conclusions: The recommendations extracted will be useful for improving the clinical management of these patients. However, there are still many uncertain scenarios reflecting that the criteria for the management of EN in hyperglycaemia are not completely standardised. More studies are required to provide quality recommendations in this area.

Recent Progress in Micro- and Nanotechnology-Enabled Sensors for Biomedical and Environmental Challenges.

Micro- and nanotechnology-enabled sensors have made remarkable advancements in the fields of biomedicine and the environment, enabling the sensitive and selective detection and quantification of diverse analytes. In biomedicine, these sensors have facilitated disease diagnosis, drug discovery, and point-of-care devices. In environmental monitoring, they have played a crucial role in assessing air, water, and soil quality, as well as ensured food safety. Despite notable progress, numerous challenges persist. This review article addresses recent developments in micro- and nanotechnology-enabled sensors for biomedical and environmental challenges, focusing on enhancing basic sensing techniques through micro/nanotechnology. Additionally, it explores the applications of these sensors in addressing current challenges in both biomedical and environmental domains. The article concludes by emphasizing the need for further research to expand the detection capabilities of sensors/devices, enhance sensitivity and selectivity, integrate wireless communication and energy-harvesting technologies, and optimize sample preparation, material selection, and automated components for sensor design, fabrication, and characterization.

Increased ultra-processed food consumption is associated with worsening of cardiometabolic risk factors in adults with metabolic syndrome: Longitudinal analysis from a randomized trial.

BACKGROUND AND AIMS: The association between changes in ultra-processed food (UPF) consumption and cardiometabolic risk (CMR) factors remains understudied. We evaluated the association between changes in UPF consumption over 12 months of follow-up and changes in CMR factors in adults diagnosed with metabolic syndrome. METHODS: We analysed data from 5373 adults (aged 55-75 years) participating in the PREDIMED-Plus trial. Diet was evaluated at baseline, 6- and 12-month visits using a validated food frequency questionnaire, and UPF consumption (in grams/day and percentage of total daily dietary intake in grams) was categorized based on NOVA classification. We used mixed-effects linear models with repeated measurements at baseline, 6 and 12 months of follow-up to assess the associations between changes in UPF consumption and changes in CMR factors adjusting for sociodemographic and lifestyles variables. RESULTS: In multivariable-adjusted models, when comparing the highest versus the lowest quartile of UPF consumption, positive associations were found for several CMR factors: weight (kg, ß = 1.09; 95% confidence interval 0.91 to 1.26); BMI (kg/m2, ß = 0.39; 0.33 to 0.46); waist circumference (cm, ß = 1.03; 0.81 to 1.26); diastolic blood pressure (mm Hg, ß = 0.67; 0.29 to 1.06); fasting blood glucose (mg/dl, ß = 1.66; 0.61 to 2.70); HbA1c (%, ß = 0.04; 0.01 to 0.07); triglycerides (mg/dl, ß = 6.79; 3.66 to 9.91) and triglycerides and glucose index (ß = 0.06; 0.04 to 0.08). CONCLUSIONS: Higher UPF consumption was associated with adverse evolution in objectively measured CMR factors after 12 months of follow-up in adults with metabolic syndrome. Further research is needed to explore whether these changes persist for longer periods.

Digital Transformation and Local Government Response to the COVID-19 Pandemic: An Assessment of Its Impact on the Sustainable Development Goals.

This paper analyzes how Digital Transformation (DT) processes have influenced the Attitude of local governments (LGs) toward the COVID-19 pandemic and their effect on achieving the United Nations' Sustainable Development Goals (SDGs). The data were collected from LGs in Spain (n = 124) through a questionnaire in which the IT skills of their workers, the DT processes, budgets, degree of regulatory compliance, and implementation of trust seals were measured, together with the IT security measures adopted. The contrast between the proposed model and the results showed that the direct influence of IT security influences the government's attitude toward COVID-19 and DT implementing actions to achieve SDGs. The findings of this work are of great value both for the actors involved in the design and implementation of public policies and for those responsible for local governance in their objective to improve citizens' experience of the services provided and in exceptional situations such as the one experienced as a result, of-COVID-19.

Validación de la escala Five Facet Mindfulness Questionnaire en estudiantes de medicina y médicos en Chile

Background: The increasing use of Mindfulness-based interventions requires standardized construct-based measurement instruments for clinical and research purposes. The Five Facet Mindfulness Questionnaire scale with five factors was developed in the United States and validated in Spain. There are versions of 39, 24 and 15 items (FFMQ-39, FFMQ-24 and FFMQ-15). Objective: To validate the FFMQ-24 and FFMQ-15 scale in Chile. Methodology: Six experts performed a linguistic adaptation of the Spanish version of the FFMQ-24. The adapted instrument was applied to a sample of 795 physicians. Internal validity was analyzed by calculating Cronbach's alpha (α) and confirmatory factor analysis (CFA). Finally, 15 items were retained, and the 5-factor solution was maintained. The FFMQ-15 scale was applied to a sample of 365 medical students and analyzed by calculating (α) and CFA. The external validity of FFMQ-15 was evaluated with the Mental Health Continiuum-14 (MHC-14) scale. Results: Linguistic changes were made. The CFA of FFMQ-24 obtained a lower-than-expected fit for a 5-factor solution. The (α) value varied between .68 and .86 in all dimensions. The FFMQ-15 had an adequate fit for five factors for physicians (c2 = 216.17, df = 80, p < .01; CFI = .96; TLI = .94; RMSEA = .05 [.04, .06]; SRMR = .04) and students (c2 = 163.61, df = 80, p < .01; CF = .96; TLI = .94; RMSEA = .05 [.04, .07]; SRMR = .05). External validity with MHC-14 was adequate. Conclusion: The FFMQ-15 scale has acceptable internal consistency and adequate internal and external validity in Chile.

Randomized Phase IIb Study of Brimonidine Drug Delivery System Generation 2 for Geographic Atrophy in Age-Related Macular Degeneration.

PURPOSE: To evaluate the safety and efficacy of repeat injections of Brimonidine Drug Delivery System (Brimo DDS) Generation 2 (Gen 2) containing 400-µg brimonidine in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: A phase IIb, randomized, multicenter, double-masked, sham-controlled, 30-month study (BEACON). PARTICIPANTS: Patients diagnosed with GA secondary to AMD and multifocal lesions with total area of > 1.25 mm2 and ≤ 18 mm2 in the study eye. METHODS: Enrolled patients were randomized to treatment with intravitreal injections of 400-µg Brimo DDS (n = 154) or sham procedure (n = 156) in the study eye every 3 months from day 1 to month 21. MAIN OUTCOME MEASURES: The primary efficacy endpoint was GA lesion area change from baseline in the study eye, assessed with fundus autofluorescence imaging, at month 24. RESULTS: The study was terminated early, at the time of the planned interim analysis, because of a slow GA progression rate (∼ 1.6 mm2/year) in the enrolled population. Least squares mean (standard error) GA area change from baseline at month 24 (primary endpoint) was 3.24 (0.13) mm2 with Brimo DDS (n = 84) versus 3.48 (0.13) mm2 with sham (n = 91), a reduction of 0.25 mm2 (7%) with Brimo DDS compared with sham (P = 0.150). At month 30, GA area change from baseline was 4.09 (0.15) mm2 with Brimo DDS (n = 49) versus 4.52 (0.15) mm2 with sham (n = 46), a reduction of 0.43 mm2 (10%) with Brimo DDS compared with sham (P = 0.033). Exploratory analysis showed numerically smaller loss over time in retinal sensitivity assessed with scotopic microperimetry with Brimo DDS than with sham (P = 0.053 at month 24). Treatment-related adverse events were usually related to the injection procedure. No implant accumulation was observed. CONCLUSIONS: Multiple intravitreal administrations of Brimo DDS (Gen 2) were well tolerated. The primary efficacy endpoint at 24 months was not met, but there was a numeric trend for reduction in GA progression at 24 months compared with sham treatment. The study was terminated early because of the lower-than-expected GA progression rate in the sham/control group. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.

Validación del instrumento Self-Compassion Scale para valoración de la autocompasión en estudiantes y médicos en Chile / Validation of the 12 items self-compassion scale in Chile

BACKGROUND: Self-compassion is understood as a mental framework when facing difficulties in life or personal insufficiency. It arises in response to the negative aspects of self-esteem. It is assessed using the 26 item and six factor Self-Compassion Scale (SCS) in the United States and Spain but not in Chile. AIM: To validate the 12-item version (SCS-12) of the self-compassion scale. MATERIAL AND METHODS: A back translation process of the original SCS-12 scale was carried out and then it was reviewed by 6 experts. The scale was applied to a sample of 359 medical students and 795 physicians. For internal validity, confirmatory factor analyses (CFA) were performed for one, two, three, and six factors. For external validity, bivariate correlations were made with variables about mental health, burnout, symptoms of depression and anxiety. Finally, a path analysis was carried out to study the relationship between the six factors and mental health. RESULTS: The CFA for the six-factor model presents the best fit for both groups of respondents (χ2 = 216.17, df = 80, p < .01; comparative fit index (CF)I = .96; Tucker-Lewis index (TL)I = .94; Root Mean Square Error of Approximation (RMSEA) = .05 [.04, .06]; Standarized Root Mean-Square(SRMR) = .04 and χ2 = 85.97, df = 39, p < .01; CFI = .97; TLI = .95; RMSEA = .06 [.04, .07]; SRMR = .04). The external validity was adequate. CONCLUSIONS: The 12-item version of the linguistically adapted Self-Compassion Scale instrument applied to medical students and physicians in Chile, had adequate internal validity and psychometric properties.

[Validation of the 12 items self-compassion scale in Chile]. / Validación del instrumento Self-Compassion Scale para valoración de la autocompasión en estudiantes y médicos en Chile.

BACKGROUND: Self-compassion is understood as a mental framework when facing difficulties in life or personal insufficiency. It arises in response to the negative aspects of self-esteem. It is assessed using the 26 item and six factor Self-Compassion Scale (SCS) in the United States and Spain but not in Chile. AIM: To validate the 12-item version (SCS-12) of the self-compassion scale. MATERIAL AND METHODS: A back translation process of the original SCS-12 scale was carried out and then it was reviewed by 6 experts. The scale was applied to a sample of 359 medical students and 795 physicians. For internal validity, confirmatory factor analyses (CFA) were performed for one, two, three, and six factors. For external validity, bivariate correlations were made with variables about mental health, burnout, symptoms of depression and anxiety. Finally, a path analysis was carried out to study the relationship between the six factors and mental health. RESULTS: The CFA for the six-factor model presents the best fit for both groups of respondents (χ2 = 216.17, df = 80, p < .01; comparative fit index (CF)I = .96; Tucker-Lewis index (TL)I = .94; Root Mean Square Error of Approximation (RMSEA) = .05 [.04, .06]; Standarized Root Mean-Square(SRMR) = .04 and χ2 = 85.97, df = 39, p < .01; CFI = .97; TLI = .95; RMSEA = .06 [.04, .07]; SRMR = .04). The external validity was adequate. CONCLUSIONS: The 12-item version of the linguistically adapted Self-Compassion Scale instrument applied to medical students and physicians in Chile, had adequate internal validity and psychometric properties.

[Validation of the Five Facet Mindfulness Questionnaire scale in medical students and doctors in Chile]. / Validación de la escala Five Facet Mindfulness Questionnaire en estudiantes de medicina y médicos en Chile.

BACKGROUND: The increasing use of Mindfulness-based interventions requires standardized construct-based measurement instruments for clinical and research purposes. The Five Facet Mindfulness Questionnaire scale with five factors was developed in the United States and validated in Spain. There are versions of 39, 24 and 15 items (FFMQ-39, FFMQ-24 and FFMQ-15). OBJECTIVE: To validate the FFMQ-24 and FFMQ-15 scale in Chile. METHODOLOGY: Six experts performed a linguistic adaptation of the Spanish version of the FFMQ-24. The adapted instrument was applied to a sample of 795 physicians. Internal validity was analyzed by calculating Cronbach's alpha (α) and confirmatory factor analysis (CFA). Finally, 15 items were retained, and the 5-factor solution was maintained. The FFMQ-15 scale was applied to a sample of 365 medical students and analyzed by calculating (α) and CFA. The external validity of FFMQ-15 was evaluated with the Mental Health Continiuum-14 (MHC-14) scale. RESULTS: Linguistic changes were made. The CFA of FFMQ-24 obtained a lower-than-expected fit for a 5-factor solution. The (α) value varied between .68 and .86 in all dimensions. The FFMQ-15 had an adequate fit for five factors for physicians (c2 = 216.17, df = 80, p < .01; CFI = .96; TLI = .94; RMSEA = .05 [.04, .06]; SRMR = .04) and students (c2 = 163.61, df = 80, p < .01; CF = .96; TLI = .94; RMSEA = .05 [.04, .07]; SRMR = .05). External validity with MHC-14 was adequate. CONCLUSION: The FFMQ-15 scale has acceptable internal consistency and adequate internal and external validity in Chile.

Presencia de síntomas de ansiedad y depresión en estudiantes de medicina durante la pandemia de COVID-19 / Anxiety and depression among medical students during COVID-19 pandemic

BACKGROUND: Medical students are especially prone to anxiety and depression. AIM: To characterize the presence of anxiety and depression and their association with gender and academic year among medical students. MATERIAL AND METHODS: Standardized electronic surveys about anxiety and depression symptoms were sent to 498 medical students with a response rate of 78%. Results: We analyzed 359 surveys. A mean of 11.4 points out of 27 was observed in the depression symptoms scale. Also, 23 and 10% of respondents had moderately severe or symptoms of depression, respectively. A mean of 8.9 out of 21 points in the anxiety symptoms scale was observed. Moderate or severe anxiety symptoms were present in 26 and 15% of respondents, respectively. Women and preclinical students had higher depression and anxiety scores. CONCLUSIONS: A high presence of anxiety and depression symptoms was characterized among medical students during the pandemic. Preclinical students and women had higher scores in both scales.

The role of relief, perceived control, and prospective intolerance of uncertainty in excessive avoidance in uncertain-threat environments.

Excessive avoidance is a key feature of pathological anxiety. However, the precise mechanisms underlying the development of excessive avoidance are still unknown. In the present study, we tested the hypothesis that excessive avoidance, especially in individuals with high Intolerance of Uncertainty (IU) is aimed at distress reduction via the enhancement of subjective perceived control in uncertain-threat environments. In our experiment, participants learned to avoid an uncertain aversive sound through a discriminated free operant procedure. In a later test phase in extinction, we manipulated the amount of avoidance responses available per trial by creating a limited and an unrestricted response condition. Nonetheless, the aversive sound could be effectively avoided in both conditions. We measured response frequency, avoidance confidence ratings and anxiety-predisposing traits such as intolerance of uncertainty, trait anxiety and distress tolerance. The degree of distress suffered during trials was inferred from post-trial relief ratings that were requested after trials in which the aversive sound had been omitted. In the avoidance acquisition phase, we found a positive association between prospective intolerance of uncertainty (P-IU) and the decline rate of distress. This relationship was not significant, however, when inhibitory intolerance of uncertainty (I-IU) was controlled for. At test, we found that the increase in avoidance responses led to distress reduction through the enhancement of avoidance confidence. Finally, we found a significant modulating role of P-IU in the effect of response limit on distress reduction that lends further support to our hypothesis. Specifically, P-IU was positively associated with the effect of response limit on distress. However, such modulating role was not significant when controlling for trait anxiety or I-IU.

Effect of oestriol gel on dyspareunia in postmenopausal women in 2 weeks of treatment: a pilot study.

This brief report evaluates the early effect of ultra-low dose 0.005% oestriol vaginal gel on dyspareunia in postmenopausal women within the first 2 weeks of treatment. This was a prospective and multicentre single-arm pilot study and the effect of the treatment on dyspareunia was evaluated by using a diary. In total 23 women and 150 coitus were studied. 8 coitus were painless in the first week and 42 during the second week (p < .0001). A reduction in pain from the baseline was seen in 116 (77.3%) out of the 150 coitus. 0.005% oestriol vaginal gel produced a rapid and progressive improvement in dyspareunia from the very first days of treatment in postmenopausal women.IMPACT STATEMENTWhat is already known on this subject? Local oestrogen therapy has shown efficacy in the treatment of genitourinary syndrome of menopause (GSM) and dyspareunia when used for a duration of greater than 3 weeks.What do the results of this study add? This study shows that the use of oestriol gel produces clinical effects from the beginning of its use, decreasing dyspareunia in postmenopausal women within just 14 days of daily use.What are the implications of these findings for clinical practice and/or further research? In cases of dyspareunia in relation to menopause, therapy with local oestrogens, in our case oestriol gel, produces an improvement from the beginning of its use. This information is clinically relevant when evaluating therapeutic options.

An extensional strain sensing mechanosome drives adhesion-independent platelet activation at supraphysiological hemodynamic gradients.

BACKGROUND: Supraphysiological hemodynamics are a recognized driver of platelet activation and thrombosis at high-grade stenosis and in blood contacting circulatory support devices. However, whether platelets mechano-sense hemodynamic parameters directly in free flow (in the absence of adhesion receptor engagement), the specific hemodynamic parameters at play, the precise timing of activation, and the signaling mechanism(s) involved remain poorly elucidated. RESULTS: Using a generalized Newtonian computational model in combination with microfluidic models of flow acceleration and quasi-homogenous extensional strain, we demonstrate that platelets directly mechano-sense acute changes in free-flow extensional strain independent of shear strain, platelet amplification loops, von Willebrand factor, and canonical adhesion receptor engagement. We define an extensional strain sensing "mechanosome" in platelets involving cooperative Ca2+ signaling driven by the mechanosensitive channel Piezo1 (as the primary strain sensor) and the fast ATP gated channel P2X1 (as the secondary signal amplifier). We demonstrate that type II PI3 kinase C2α activity (acting as a "clutch") couples extensional strain to the mechanosome. CONCLUSIONS: Our findings suggest that platelets are adapted to rapidly respond to supraphysiological extensional strain dynamics, rather than the peak magnitude of imposed wall shear stress. In the context of overall platelet activation and thrombosis, we posit that "extensional strain sensing" acts as a priming mechanism in response to threshold levels of extensional strain allowing platelets to form downstream adhesive interactions more rapidly under the limiting effects of supraphysiological hemodynamics.

Limitations of occasional reinforced extinction to alleviate spontaneous recovery and reinstatement effects: Evidence for a trial-signalling mechanism.

Fear extinction is not permanent but is instead more vulnerable than the original fear memory, as traditionally shown by the return of fear phenomena. Because of this, techniques to mitigate the return of fear are needed in the clinical treatment of related psychological conditions. One promising strategy is the occasional reinforced extinction treatment, introducing a gradual and sparse number of conditioned stimulus-unconditioned stimulus (CS-US) pairings within the extinction treatment. We present the results of three experiments in which we used a threat conditioning procedure in humans. Our main aim was to evaluate whether occasional reinforced extinction could reduce two different forms of relapse: spontaneous recovery (Experiments 1 and 2) and reinstatement (Experiment 3). Contrary to our predictions and previous literature, the results indicate that an occasional reinforcement treatment did not mitigate relapse compared with standard extinction. From a theoretical standpoint, these results are more consistent with the idea that extinction entails the acquisition of new knowledge than with the idea that there are conditions in which extinction leads to a weakening of the original fear memory. These findings also question the generality of the potential benefits of using occasional reinforced extinction in clinical settings.