Problematic ArF-Alkynyl Coupling with Fluorinated Aryls. From Partial Success with Alkynyl Stannanes to Efficient Solutions via Mechanistic Understanding of the Hidden Complexity.

The synthesis of aryl-alkynyl compounds is usually achieved via Sonogashira catalysis, but this is inefficient for fluorinated aryls. An alternative method reported by Shirakawa and Hiyama, using alkynylstannanes and hemilabile PN ligands, works apparently fine for conventional aryls, but it is also poor for fluorinated aryls. The revision of the unusual literature cycle reveals the existence and nature of unreported byproducts and uncovers coexisting cycles and other aspects that explain the reasons for the conflict. This knowledge provides a full understanding of the real complexity of these aryl/alkynylstannane systems and the deviations of their evolution from that of a classic Stille process, providing the clues to design several very efficient alternatives for the catalytic synthesis of the desired ArF-alkynyl compounds in almost quantitative yield. The same protocols are also very efficient for the catalytic synthesis of alkynyl-alkynyl' hetero- and homocoupling.

Decay kinetics of HIV-1-RNA in seminal plasma with dolutegravir/lamivudine versus dolutegravir plus emtricitabine/tenofovir alafenamide in treatment-naive people living with HIV.

BACKGROUND: This was a substudy of a Phase IV, randomized clinical trial (ClinicalTrials.gov identifier: NCT04295460) aiming to compare the activity of dolutegravir/lamivudine versus dolutegravir plus tenofovir alafenamide/emtricitabine (DTG + TAF/FTC) in the male genital tract. METHODS: Participants were asymptomatic adults without sexually transmitted diseases, treatment-naive people living with HIV (PLWH), with CD4+ T cell counts >200 cells/mm3 and plasma HIV-1-RNA levels >5000 and <500 000 copies/mL, randomized (1:1) to DTG + TAF/FTC or dolutegravir/lamivudine. Blood plasma (BP) and seminal plasma (SP) were collected at baseline and Weeks 4, 8, 12 and 24. HIV-1-RNA was measured in BP and SP using the Cobas 6800 system (Roche Diagnostics) with a lower detection limit of 20 copies/mL. The primary efficacy endpoint was the proportion of subjects with undetectable SP HIV-1-RNA at Week 12 by intention-to-treat analysis. RESULTS: Fifteen participants in the DTG + TAF/FTC and 16 in the dolutegravir/lamivudine arms were analysed, with basal SP viral load of 4.81 (4.30-5.43) and 4.76 (4.09-5.23), P = 0.469, respectively. At Week 12, only one participant in each treatment arm had a detectable SP HIV-1-RNA (DTG + TAF/FTC, 141 copies/mL; dolutegravir/lamivudine, 61 copies/mL). Based on the estimated means, there was no significant difference in the decay of HIV-1-RNA in both BP and SP over time between the two arms of treatment (F = 0.452, P = 0.662, and F = 1.147, P = 0.185, respectively). CONCLUSIONS: After 12 weeks of treatment, there were no differences in the percentage of undetectable SP HIV-1-RNA in naive PLWH who started dolutegravir/lamivudine compared with DTG + TAF/FTC.

How to recognise a Behçet's ulcer from other types of oral ulceration? Defining Behçet's ulceration by an International Delphi Consultation.

OBJECTIVES: To define the clinical characteristics of oral ulceration (OU) in Behçet's disease (BD), to allow differentiation from other causes of OU, including aphthous ulcers, by an International Delphi consultation. To develop a clinical guideline on how to recognise BD ulcers. METHODS: Round 1. 40 clinical images of OU in BD, recurrent aphthous stomatitis (RAS), inflammatory bowel disease (IBD) and mucous membrane pemphigoid (MMP) were shown. Participants answered, independently, which images would be consistent with a BD ulcer. Round 2. The results from marking independently were shown. The panel remarked the questions through iteration process. The images not agreed to be a possible BD ulcer were discarded. Round 3. 10 clinical descriptors that may define BD ulcers were suggested. Participants ranked the level of importance for each descriptor on each image presented. Round 4. Participants re-ranked their level of agreement for each descriptor through iteration process. Whether the clinical pictures would be different from RAS was also explored. A final agreement was reached. RESULTS: This study has shown clear differentiation between BD, IBD and MMP ulcers when defining them by phenotype through clinical images only. On the other hand, no differentiation between RAS and BD ulcers was found. The most important clinical descriptors that define BD ulcers have been agreed. CONCLUSIONS: New clinical guidance for Health Care Professionals (HCP) on how to recognise a BD ulcer has been proposed. This should elucidate an earlier diagnosis, quicker access to treatment and control of the disease enhancing patient's quality of life.

Long-term effectiveness of a novel intra-oral electro-stimulator for the treatment of dry mouth in patients with Sjogren's syndrome: A randomised sham-controlled feasibility study (LEONIDAS-1).

BACKGROUND: Effective treatments for dry mouth of Sjogren's syndrome are limited and hampered by adverse effects. The aim of LEONIDAS-1 was to explore the feasibility of salivary electrostimulation in individuals with primary Sjogren's syndrome, as well as parameters required to inform the design of a future phase III trial. METHODS: Multicentre, parallel-group, double-blind, randomised sham-controlled trial in two UK centres. Participants were randomised (1:1, computer-generated) to active or sham electrostimulation. The feasibility outcomes included screening/eligibility ratio, consent, and recruitment and drop-out rates. Preliminary efficacy outcome included dry mouth visual analogue scale, Xerostomia Inventory, the EULAR Sjögren's syndrome patient reported index-Q1, and unstimulated sialometry. RESULTS: Forty-two individuals were screened, of whom 30 (71.4%) met the eligibility criteria. All eligible individuals consented to recruitment. Out of the 30 randomised participants (active n = 15, sham n = 15), 4 dropped out and 26 (13 vs. 13) completed all study visits as per protocol. Recruitment rate was 2.73 participants/month. At 6-month post-randomisation the difference in mean reduction in visual analogue scale, xerostomia inventory and EULAR Sjögren's syndrome patient reported index-Q1 scores between groups were 0.36 (95% CI: -0.84, 1.56), 3.31 (0.43, 6.18), and 0.23 (-1.17, 1.63), respectively; unstimulated salivary flow increased by a mean of 0.98 mL/15 min, all in favour of the active group. No adverse events were reported. CONCLUSION: LEONIDAS-1 results support progression to a phase III definitive randomised controlled trial of salivary electrostimulation in individuals with Sjogren's syndrome. Xerostomia inventory could be considered the primary patient-centred outcome measure and the corresponding observed treatment effect could inform the sample size of a future trial.

Real-Time Intracellular Temperature Imaging Using Lanthanide-Bearing Polymeric Micelles.

Measurement of thermogenesis in individual cells is a remarkable challenge due to the complexity of the biochemical environment (such as pH and ionic strength) and to the rapid and yet not well-understood heat transfer mechanisms throughout the cell. Here, we present a unique system for intracellular temperature mapping in a fluorescence microscope (uncertainty of 0.2 K) using rationally designed luminescent Ln3+-bearing polymeric micellar probes (Ln = Sm, Eu) incubated in breast cancer MDA-MB468 cells. Two-dimensional (2D) thermal images recorded increasing the temperature of the cells culture medium between 296 and 304 K shows inhomogeneous intracellular temperature progressions up to ∼20 degrees and subcellular gradients of ∼5 degrees between the nucleolus and the rest of the cell, illustrating the thermogenic activity of the different organelles and highlighting the potential of this tool to study intracellular processes.

Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus.

The activation phenotypes and functional changes in monocyte subsets during hepatitis C virus (HCV) elimination in HIV/HCV-coinfected patients were evaluated. Twenty-two HIV/HCV-coinfected patients on suppressive combination antiretroviral treatment (cART) achieving HCV elimination after direct-acting antiviral (DAA) therapy and 10 HIV-monoinfected patients were included. The activation phenotype (10 markers) and polyfunctionality (intracellular interleukin-1α [IL-1α], IL-1ß, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], and IL-10 production) in three monocyte subsets (classical, intermediate, and nonclassical) were evaluated by flow cytometry before and at the end of treatment. Cell-associated HIV DNA levels were assayed by droplet digital PCR. After HCV clearance, there was a significant increase in classical monocyte and decreases in intermediate and nonclassical monocyte levels. The levels of the activation markers CD49d, CD40, and CX3CR1 were decreased after treatment in the monocyte subsets, reaching the levels in HIV-monoinfected patients. After lipopolysaccharide (LPS) stimulation, although polyfunctionality significantly decreased in intermediate and nonclassical monocytes, some combinations, such as the IL-1α- (IL-1α-negative) IL-1ß- IL-6+ (IL-6-producing) IL-8- TNF-α- IL-10- combination, were remarkably increased at the end of treatment compared to the control group. Cell-associated HIV DNA levels correlated with activation markers before but not after treatment. HCV clearance after DAA treatment in patients on cART exerts an anti-inflammatory profile on monocyte subsets, activation phenotypes, and polyfunctionality. However, there is not a complete normalization compared with HIV-monoinfected patients.

Mediterranean diet and risk of Sjögren's syndrome.

OBJECTIVES: Non-genetic risk factors for Sjögren's syndrome (SS) are poorly understood. Adherence to a Mediterranean diet has been associated with reduction in other autoimmune diseases. We examined the association of Mediterranean diet with SS. METHODS: New patients attending a single centre warranting investigation for primary SS (pSS) were recruited into the Optimising Assessment in Sjögren's Syndrome cohort established in Birmingham, UK (2014-2018). Participants were classified into pSS and non-SS sicca, considered as cases and non-cases, respectively, and asked to complete an optional food frequency questionnaire on their diet before onset of symptoms. A semi-quantitative Mediterranean diet score (MDS) was calculated (possible range=0 to 18). Using multivariate logistic regression, corrected for energy intake, body-mass index, sex, age, symptom duration, and smoking status, we examined the association of MDS with SS. RESULTS: Dietary data were available for 133/243 (55%) eligible patients (n=82 pSS and n=51 sicca). In the adjusted model, a higher total MDS (mean ± SD, 9.41±2.31 points) was associated with lower odds of pSS (OR 0.81, 95% CI 0.66-0.99; p=0.038) per one unit of MDS. Among MDS components, the strongest association was seen with fish with OR 0.44 (95% CI 0.24-0.83; p=0.01) in the comparison between <1 portion/week and 1 to 2.5 portions/week. Higher galactose, vitamin A-retinol-equivalents and vitamin C showed associations with lower odds of pSS in multivariate analysis, where the association of vitamin C was attenuated when adjusted for MDS. CONCLUSIONS: When adjusted for potential confounders, adherence to the Mediterranean diet was associated with lower likelihood of having pSS.

Surveillance to Monitor the Impact of the Trump Administration on the Health of New York City Residents.

CONTEXT: The Trump administration has enacted or proposed many policies that could impact public health. These include attempts to dismantle or repeal the Patient Protection and Affordable Care Act (ACA), restricting funding for women's health care, and loosening of environmental regulations. OBJECTIVE: To develop a surveillance system to monitor the public health impacts of the Trump administration in New York City. DESIGN: Epidemiologic assessment. Public health surveillance system. SETTING: New York City. PARTICIPANTS: New York City residents. MAIN OUTCOMES MEASURES: We identified approximately 25 indicators across 5 domains: access to care, food insecurity, reproductive health, environmental health, and general physical and mental health. Sources of data include the New York City Department of Health and Mental Hygiene's (DOHMH's) health and risk behavior telephone survey, vital statistics, emergency department visits, DOHMH sexual health clinics, Federally Qualified Health Centers, lead and diabetes registries, Medicaid claims, Supplementary Nutrition Assistance Program enrollment, Women, Infant, and Children program enrollment, and 311 call records. Data are collected monthly or quarterly where possible. We identified measures to stratify indicators by individual and area-based measures of immigration and poverty. RESULTS: Since April 2017, we have compiled quarterly reports, including establishing a historical baseline of 10 years to account for secular trends and encompass the establishment and enactment of the ACA. Indicators are interpreted within the context of changes in programming or local policy that might explain trends. CONCLUSIONS: We have successfully established an adaptive surveillance system that is poised to rapidly detect changes in the health of New York City residents resulting from changes by the Trump administration to public health policy. The development of such systems is a critical function for health departments across the country to play a role in the current political and policy environment.

Multiple Multicomponent Reactions: Unexplored Substrates, Selective Processes, and Versatile Chemotypes in Biomedicine.

Multiple multicomponent reactions rapidly assemble complex structures. Despite being very productive, the lack of selectivity and the reduced number of viable transformations restrict their general application in synthesis. Hereby, we describe a rationale for a selective version of these processes based in the preferential generation of intermediates which are less reactive than the initial substrates. In this way, applying the Groebke-Blackburn-Bienaymé reaction on a range of α-polyamino-polyazines, we prepared a family compact heterocyclic scaffolds with relevant applications in medicinal and biological chemistry (live cell imaging probes, selective binders for DNA quadruplexes, and antiviral agents against human adenoviruses). The approach has general character and yields complex molecular targets in a selective, tunable and direct manner.

Birmingham Behçet's service: classification of disease and application of the 2014 International Criteria for Behçet's Disease (ICBD) to a UK cohort.

BACKGROUND: This study reports on the analysis of the application and diagnostic predictability of the revised 2014 ICBD criteria in an unselected cohort of UK patients, and the ensuing organ associations and patterns of disease. METHODS: A retrospective cohort study was conducted using a database of electronic medical records. Three categories were recognised: clinically defined BD, incomplete BD and rejected diagnoses of BD. We applied the ISG 1990 and ICBD 2014 classification criteria to these subgroups to validate diagnostic accuracy against the multidisciplinary assessment. RESULTS: Between 2012 and 2015, 281 patients underwent initial assessment at an urban tertiary care centre: 190 patients with a confirmed diagnosis of BD, 7 with an incomplete diagnosis, and 84 with a rejected diagnosis. ICBD 2014 demonstrated an estimated sensitivity of 97.89% (95% CI: 94.70 to 99.42) and positive likelihood ratio of 1.21 (1.10 to 1.28). The strongest independent predictors were: Central nervous lesions (OR = 10.57, 95% CI: 1.34 to 83.30); Genital ulceration (OR = 9.05, 95% CI: 3.35 to 24.47); Erythema nodosum (OR = 6.59, 95% CI: 2.35 to 18.51); Retinal vasculitis (OR = 6.25, 95% CI: 1.47 to 26.60); Anterior uveitis (OR = 6.16, 95% CI: 2.37 to 16.02); Posterior uveitis (OR = 4.82, 95% CI: 1.25 to 18.59). CONCLUSIONS: The ICBD 2014 criteria were more sensitive at picking up cases than ISG 1990 using the multidisciplinary assessment as the gold standard. ICBD may over-diagnose BD in a UK population. Patients who have an incomplete form of BD represent a distinct group that should not be given an early diagnostic label. Behçet's disease is a complex disease that is best diagnosed by multidisciplinary clinical assessment. Patients in the UK differ in their clinical presentation and genetic susceptibility from the original descriptions. This study also highlights an incomplete group of Behçet's patients that are less well defined by their clinical presentation.

Periodontitis prevalence and serum antibody reactivity to periodontal bacteria in primary Sjögren's syndrome: a pilot study.

AIMS: The aims of this study were as follows: (i) To assess the prevalence of periodontitis among patients with primary Sjögren's syndrome (pSS) and comparator groups of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). (ii) To perform a pilot study to compare serum antibody responses to 10 oral/periodontal bacteria in these patient groups and a historical comparator group of patients with periodontitis. MATERIALS AND METHODS: Standard clinical periodontal assessments were performed on 39 pSS, 36 RA and 23 OA patients and "In-house" antibody ELISAs for serum antibodies against 10 oral/periodontal bacteria were performed in these groups. RESULTS: Forty-six percent of the pSS group, 64% of the RA group and 48% of the OA group had moderate/severe periodontitis. These frequencies did not reach statistical significance between groups. Raised antibody levels to Prevotella denticola were found in the pSS, RA and periodontitis groups compared to the OA group. Significant between group differences were seen for Aggregatibacter actinomycetemcomitans, Prevotella intermedia and Campylobacter showae. None of these differences were specifically associated with pSS. CONCLUSION: This study showed no increase in periodontitis in pSS patients. Although the P. denticola data are of interest, identifying bacterial triggering factors for pSS will likely require alternative strategies including modern techniques such as microbiome analysis.

[Duodenal adenocarcinoma: a rare diagnosis]. / Adenocarcinoma duodenal: un diagnóstico poco frecuente.

Duodenal adenocarcinoma is a rare disease whose symptoms are usually vomit, weight loss and lack of appetite; appearing more frequently in men in their sixties. Upper gastrointestinal endoscopy is the technique chosen for its diagnosis, also relying on other techniques such as endoscopic ultrasonography or computed tomography for the extension study. In this regard we report the case of a patient diagnosed of bulbar duodenal adenocarcinoma in our hospital.

The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti-B-cell therapy in patients with primary Sjögren's Syndrome.

BACKGROUND: Primary Sjögren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes. METHODS/DESIGN: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition. DISCUSSION: The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity. TRIAL REGISTRATION: UKCRN Portfolio ID: 9809 ISRCTN65360827.

Psychometric examination of the Multidimensional Psychological Flexibility Inventory Short Form (MPFI-24) and the Psy-Flex Spanish versions in individuals with chronic pain.

BACKGROUND: Acceptance and Commitment Therapy (ACT) has been found to be beneficial for individuals dealing with chronic pain. The theoretical mechanisms of change proposed by ACT are based on the Hexaflex model. To comprehensively reflect this model, the Multidimensional Psychological Flexibility Inventory (MPFI) and Psy-Flex have been developed. The study aimed to adapt the MPFI-24 and the Psy-Flex for Spanish-speaking populations with chronic pain and to examine their dimensionality, internal consistency, convergent validity and incremental validity. METHODS: This cross-sectional study involved 309 Spanish-speaking adults with chronic pain who completed an online survey. The majority of the participants were women (88.3%). The ages ranged from 18 to 79 years. RESULTS: Factor analysis showed that the Spanish version of the MPFI-24 has 12 factors, consisting of six flexibility and six inflexibility factors, similar to the original version, but lacking second-order general factors. The Psy-Flex demonstrated a single-factor structure, maintaining the general factor of psychological flexibility seen in the original version. The MPFI-24 showed good internal consistency and adequate convergent validity, with the exception of the Acceptance and Experiential Avoidance subscales. The Psy-Flex showed good internal consistency and convergent validity. Notably, both the MPFI-24 and Psy-Flex scores significantly explained additional variance in psychological distress beyond other ACT-related measures of Hexaflex processes; however, only the Psy-Flex explained pain interference. CONCLUSIONS: The Spanish adaptations of the MPFI-24 and Psy-Flex are valid and reliable instruments for assessing the Hexaflex model processes in Spanish-speaking adults with chronic pain. SIGNIFICANCE STATEMENT: Practitioners and researchers in chronic pain will find the Spanish versions of the MPFI-24 and the Psy-Flex here, along with recommendations for their use and scoring based on a robust psychometric rationale. It should be noted that these measures surpass the Chronic Pain Acceptance Questionnaire (CPAQ) and the Psychological Inflexibility in Pain Scale (PIPS), which are considered gold standards in chronic pain assessment.

Bariatric-Metabolic Surgery is the Most Effective Intervention in Reducing Food Addiction Symptoms: A Systematic Review and Meta-Analysis.

There are different treatments for food addiction (FA) symptomatology, but a comprehensive review with a meta-analysis to determine the most effective intervention is lacking. The aim of this review is to investigate the efficacy of pharmacological, behavioral, and bariatric-metabolic surgical interventions in reducing FA symptomatology. Meta-analyses including 15 studies in adults showed a significantly positive effect (std mean difference in FA symptoms before vs after intervention 0.72 (0.58-0.95)), with bariatric-metabolic surgical interventions showing the highest efficacy in improving FA symptoms (1.17 (0.58-1.76) before vs after intervention). The existing evidence suggests a beneficial effect of bariatric-metabolic surgical, pharmacological, and behavioral interventions, in that order, on FA symptomatology in people with overweight/obesity. Weight loss and behavioral and lifestyle changes after surgery may be determinants in improving FA symptomatology.